US20090104243A1

Movatterモバイル変換

Info

Publication number: US20090104243A1
Application number: US12/231,986
Authority: US
Inventors: Deepank Utkhede; Robert W. Shimizu; Rachna Jain; Stephen Boyd; Hanson S. Gifford; Eugene de Juan, Jr.; Cary J. Reich
Original assignee: QLT Plug Delivery Inc
Current assignee: Mati Therapeutics Inc
Priority date: 2007-09-07
Filing date: 2008-09-05
Publication date: 2009-04-23
Also published as: BRPI0817075A2; KR20170005905A; TW201002367A; JP5555162B2; JP2017205545A; NZ598483A; JP2010538696A; MX2010002616A; WO2009035562A2; SG184738A1; DK2207529T3; AU2008300013A1; US8628792B2; ES2533359T3; JP2020062381A; CN101984745A; ES2538838T3; CN103349799B; NZ583678A; JP2016165503A

Abstract

A solid drug core insert can be manufactured by injecting a liquid mixture comprising a therapeutic agent and a matrix precursor into a sheath body. The injection can be conducted at subambient temperatures. The mixture is cured to form a solid drug-matrix core. The therapeutic agent can be a liquid at about room temperature that forms a dispersion of droplets in the matrix material. A surface of the solid drug core is exposed, for example by cutting the tube, and the exposed surface of the solid drug core releases therapeutic quantities of the therapeutic agent when implanted into the patient. In some embodiments, the insert body inhibits release of the therapeutic agent, for example with a material substantially impermeable to the therapeutic agent, such that the therapeutic quantities are released through the exposed surface, thereby avoiding release of the therapeutic agent to non-target tissues.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS

This non-provisional application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Ser. Nos. 60/970,699, filed Sep. 7, 2007; 60/970,709, filed Sep. 7, 2007; 60/970,820, filed Sep. 7, 2007; and 61/049,317, filed Apr. 30, 2008, which are incorporated herein by reference in their entireties.

The subject matter of this application is related to that of U.S. patent application Ser. No. 11/695,537, filed on Apr. 2, 2007, (attorney docket no. SLW 2755.001US1) which claims the benefit of U.S. Provisional Application No. 60/871,864, filed on Dec. 26, 2006, the disclosures of which are incorporated herein by reference in their entireties.

The subject matter of this application is related to that of U.S. Pat. App. No. 61/057,246, filed on May 30, 2008 (attorney docket no. SLW 2755.036PRV) and U.S. Pat. App. No. 61/132,927, filed on Jun. 24, 2008 (attorney docket no. SLW 2755.036PV2), and U.S. patent application Ser. No. ______, filed herewith (attorney docket no. SLW 2755.044US1), entitled “LACRIMAL IMPLANTS AND RELATED METHODS.”

BACKGROUND

A variety of challenges face patients and physicians in the area of drug delivery, for example, ocular drug delivery. In particular, the repetitive nature of the therapies (multiple injections, instilling multiple eye drop regimens per day), the associated costs, and the lack of patient compliance may significantly impact the efficacy of the therapies available, leading to reduction in vision and many times blindness.

Patient compliance in taking the medications, for example, instilling the eye drops, can be erratic, and in some cases, patients may not follow the directed treatment regime. Lack of compliance can include, failure to instill the drops, ineffective technique (instilling less than required), excessive use of the drops (leading to systemic side effects), and use of non-prescribed drops or failure to follow the treatment regime requiring multiple types of drops. Many of the medications may require the patient to instill them up to 4 times a day.

In addition to compliance, the cost of at least some eye drop medications is increasing, leading some patients on limited incomes to be faced with the choice of buying basic necessities or instead getting their prescriptions filled. Many times insurance does not cover the total cost of the prescribed eye drop medication, or in some cases eye drops containing multiple different medications.

Further, in many cases, topically applied medications have a peak ocular effect within about two hours, after which additional applications of the medications should be performed to maintain the therapeutic benefit. In addition, inconsistency in self-administered or ingested medication regimes can result in a suboptimal therapy. PCT Publication WO 06/014434 (Lazar), which is incorporated herein by reference in its entirety, may be relevant to these and/or other issues associated with eye drops.

One promising approach to ocular drug delivery is to place an implant that releases a drug in tissue near the eye. Although this approach can offer some improvement over eye drops, some potential problems of this approach may include implantation of the implant at the desired tissue location, retention of the implant at the desired tissue location, and sustaining release of the drug at the desired therapeutic level for an extended period of time. For example in the case of glaucoma treatment, visits to the treating physician can be months apart, and premature depletion and/or premature release of a drug from an implant can result in insufficient drug being delivered for a portion of the treatment period. This can result in the patient potentially suffering a reduction in vision or blindness. In light of the above, it would be desirable to provide for the manufacture of improved drug delivery implants that overcome at least some of the above mentioned shortcomings.

SUMMARY

The present invention is directed to various embodiments of drug inserts and drug cores containing therapeutic agents for use in implant bodies adapted for disposition in a body tissue, fluid, cavity, or duct. The implant bodies can be adapted to be disposed in or adjacent to an eye of a patient. The implants release the agent to the body, for example, into an eye or surrounding tissues, or both, over a period of time, for treatment of a malcondition in the patient for which use of the therapeutic agent is medically indicated. The invention is also directed to various embodiments of methods of manufacture of the drug inserts and drug cores, and to methods of treatment of patients using implants containing the drug inserts or drug inserts.

In various embodiments, the invention provides a plurality of the drug inserts as described above wherein each of the plurality of the inserts comprises a similar amount of the agent dispersed respectively therewithin. For example, the similar amount of agent dispersed respectively therein can vary no greater than about 30% therebetween. For example, the similar amount of agent dispersed respectively therein can vary no greater than about 20% therebetween. For example, the similar amount of agent dispersed respectively therein can vary no greater than about 10% therebetween. For example, the similar amount of agent dispersed respectively therein can vary no greater than about 5% therebetween.

In various embodiments, the invention provides an implant for sustained delivery of a therapeutic agent to a patient, wherein the entire implant comprises a drug core comprising a therapeutic agent and a matrix, wherein the matrix comprises a polymer. A porous or absorbent material can alternatively be used to make up the entire implant or plug which can be saturated with the active agent.

In various embodiments, the invention provides a method of manufacturing a drug insert for an implant body adapted for disposition within or adjacent to an eye of a patient, the insert comprising a drug core comprising a therapeutic agent and a matrix wherein the matrix comprises a polymer, wherein the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent when the implant is inserted into the patient; the method comprising injecting, at a subambient temperature of less than about 20° C., a mixture comprising a matrix precursor and the agent into the sheath body such that the sheath body is substantially filled therewith; then, curing the mixture comprising the matrix precursor within the sheath body to form the drug insert such that a drug core having an exposed surface is formed therein. In various embodiments, the drug insert can be adapted to release the agent to the eye, surrounding tissues, systemically, or any combination thereof, and/or for providing sustained release of a therapeutic agent to the eye or surrounding tissues, or systemically, or any combination thereof.

In various embodiments, the invention provides a method of manufacturing a drug insert for an implant body adapted for disposition within or adjacent to an eye of a patient, the method comprising injecting, at a subambient temperature of less than about 20° C., a mixture comprising a therapeutic agent and a matrix precursor into a precursor sheath body, wherein the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core, the precursor sheath body being substantially impermeable to the agent, such that the precursor sheath is substantially filled therewith to provide a filled precursor sheath; then, curing the mixture such that a precursor drug core is formed within the precursor sheath body, and then, dividing the filled precursor sheath to form a plurality of drug inserts therefrom, wherein each drug insert comprises a drug core and a sheath body, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core, when the insert is disposed with an implant and the implant is inserted into the patient; each insert being adapted fit within a respective implant body and to release, through the exposed surface of the insert, therapeutic quantities of the agent to tear liquid; wherein each of the plurality of drug inserts is of substantially the same length, wherein an amount of the agent in each of the plurality of inserts divided from the filled precursor sheath is similar.

In further embodiments, the method of manufacturing a drug insert further comprises, after the curing step as described herein, extruding the drug core from the sheath body prior to or after dividing the filled sheath body into a plurality of drug insert, thereby forming the drug cores free of the sheath body material.

In various embodiments, the above methods are employed to manufacture an implant for sustained delivery of a therapeutic agent to a patient, wherein the entire implant comprises a drug core comprising a therapeutic agent and a matrix, wherein the matrix comprises a polymer. A porous or absorbent material can alternatively be used to make up the entire implant or plug which can be saturated with the active agent. In other embodiments, a therapeutic agent and a matrix as described herein are added to a mold to form the drug core; the drug core is then cured, then used as an implant for sustained delivery of the therapeutic agent to a patient.

In various embodiments, the invention provides a drug insert made by a method of the invention.

In various embodiments, the invention provides a method of treating a malcondition in a patient in need thereof, comprising disposing an implant comprising a drug insert of the invention, or a drug core of the invention, or a drug core obtained by division of a filled precursor sheath of the invention, or a drug implant of the invention, or a drug insert prepared by the method of the invention, wherein the therapeutic agent is adapted to treat the malcondition, in or adjacent to an eye of the patient such that the drug is released into a body tissue or fluid.

In various embodiments, the invention provides the use of a drug insert of the invention, or a drug core of the invention, or a drug core obtained by division of a filled precursor sheath of the invention, or a drug implant of the invention, or a drug insert prepared by the method of the invention, in the manufacture of an implant adapted for treatment of a malcondition in a patient in need thereof.

In various embodiments, the invention provides a drug insert adapted for disposition within an punctal plug for providing sustained release of a latanoprost to the eye for treatment of glaucoma, the insert comprising a core and a sheath body partially covering the core, the core comprising the latanoprost and a matrix wherein the matrix comprises a silicone polymer, the latanoprost being contained within the silicone as droplets thereof, wherein an amount of the latanoprost in a volumetric portion of the drug core is similar to an amount of the latanoprost in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the core to inhibit release of the latanoprost from said portion, an exposed surface of the core not covered by the sheath body being adapted to release the latanoprost to the eye.

In various embodiments, the invention provides a drug insert adapted for disposition within an punctal plug for providing sustained release of a cyclosporine to the eye for treatment of dry eye or inflammation, the insert comprising a core and a sheath body partially covering the core, the core comprising the cyclosporine and a matrix wherein the matrix comprises a polyurethane polymer, the cyclosporine being contained within the polyurethane, wherein an amount of the cyclosporine in a volumetric portion of the drug core is similar to an amount of the cyclosporine in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the core to inhibit release of the cyclosporine from said portion, an exposed surface of the core not covered by the sheath body being adapted to release the cyclosporine to the eye.

In various embodiments, the invention provides a drug insert adapted for disposition within an implant, the implant being adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid, for providing sustained release of a therapeutic agent to the cavity, duct, tissue, or surrounding tissues or any combination thereof, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent and a matrix wherein the matrix comprises a polymer, wherein the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the cavity, duct, tissue, or surrounding tissues or any combination thereof, when the implant is inserted into the patient.

In various embodiments, the invention provides a drug insert adapted for disposition within an implant, the implant being adapted for disposition within or adjacent to an eye of a patient, for providing sustained release of a therapeutic agent systemically, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent and a matrix wherein the matrix comprises a polymer, wherein the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent systemically when the implant is inserted into the patient.

In various embodiments, the invention provides a drug core comprising a therapeutic agent and a matrix wherein the matrix comprises a polymer, for disposition as or into a drug insert or an implant, the drug insert or the implant being adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid, for providing sustained release of a therapeutic agent to the cavity, duct, tissue, or surrounding tissues or any combination thereof, wherein the therapeutic agent is uniformly homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix; wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

In various embodiments, the invention provides a drug core comprising a therapeutic agent and a matrix wherein the matrix comprises a polymer, for disposition as or into a drug insert or an implant, the drug insert or the implant being adapted for disposition within or adjacent to an eye of a patient for providing sustained release of the therapeutic agent systemically, wherein the therapeutic agent is uniformly homogeneously dispersed throughout the matrix, or the therapeutic agent at least in part forms solid or liquid inclusions within the matrix; wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core. The drug core may be formed into an implant or drug insert by molding the matrix with the therapeutic agent into an appropriate shape. The implant of this form has no sheath or outer implant body or housing.

Although it is not intended to be a limitation of the invention, it is believed the therapeutic agent transports through the matrix to its surface whereupon the agent becomes dispersed, dissolved or otherwise entrained with body fluid for delivery to target tissue. The transport may be the result of and/or influenced by diffusion, molecular interaction, domain formation and transport, infusion of body fluid into the matrix or other mechanisms. For delivery to the eye, therapeutic quantities of agent transport to the exposed surface of the matrix whereupon tear liquid will sweep away the agent for delivery to target tissue or tissues.

To better illustrate the invention described herein, a non-limiting list of exemplary aspects and embodiments of the invention is provided as follows.

Aspect A1 concerns a drug insert adapted for disposition within an implant, the implant being adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent and a matrix, the matrix comprising a polymer, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the cavity, tissue, duct, or fluid, or any combination thereof when the implant is inserted into the patient, and wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

Embodiment A2 concerns the drug insert of aspect A1 wherein the amount of the therapeutic agent within the volumetric portion of the drug core varies from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment A3 concerns the drug insert of aspect A1 wherein the amount of the therapeutic agent within the volumetric portion of the drug core varies from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment A4 concerns the drug insert of aspect A1 wherein the amount of the therapeutic agent within the volumetric portion of the drug core varies from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment A5 concerns the drug insert of aspect A1 wherein the amount of the therapeutic agent within the volumetric portion of the drug core varies from the amount of the therapeutic agent within any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment A6 concerns the drug insert of aspect A1 wherein the implant is a punctal plug.

Embodiment A7 concerns a plurality of the drug inserts of aspect A1 wherein each of the plurality of the inserts comprises a similar concentration of the agent relative to the other inserts of the plurality.

Embodiment A8 concerns the plurality of drug inserts of embodiment A7 wherein the similar concentration of agent varies no greater than about 30% therebetween.

Embodiment A9 concerns the plurality of drug inserts of embodiment A7 wherein the similar concentration of agent varies no greater than about 20% therebetween.

Embodiment A10 concerns the plurality of drug inserts of embodiment A7 wherein the similar concentration of agent varies no greater than about 10% therebetween.

Embodiment A11 concerns the plurality of drug inserts of embodiment A7 wherein the similar concentration of agent varies no greater than about 5% therebetween.

Embodiment A12 concerns the drug insert of aspect A1 wherein the exposed surface is adapted to release therapeutic quantities of the agent for a time period of at least several days into tear liquid when the implant is inserted into the patient.

Embodiment A13 concerns the plurality of drug inserts of embodiment A7 wherein the exposed surface of each of the plurality of drug inserts is adapted to release therapeutic quantities of the agent for a time period of at least several days into tear liquid when the implant is inserted into the patient, wherein the therapeutic quantity of the agent released by each of the plurality of drug insert is similar.

Embodiment A14 concerns the plurality of embodiment A13, wherein the therapeutic quantity of the agent released by each of the plurality of the inserts varies by no greater than about 30% therebetween.

Embodiment A15 concerns the plurality of embodiment A13, wherein the therapeutic quantity of the agent released by each of the plurality of the inserts varies by no greater than about 20% therebetween.

Embodiment A16 concerns the plurality of embodiment A13, wherein the therapeutic quantity of the agent released by each of the plurality of the inserts varies by no greater than about 10% therebetween.

Embodiment A17 concerns the plurality of embodiment A13, wherein the therapeutic quantity of the agent released by each of the plurality of the inserts varies by no greater than about 5% therebetween.

Embodiment A18 concerns the drug insert of aspect A1 wherein the drug core comprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment A19 concerns the drug insert of aspect A1 wherein the matrix comprises a non-biodegradable silicone or a polyurethane, or combination thereof.

Embodiment A20 concerns the drug insert of aspect A1 wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or cast; or a metal comprising stainless steel or titanium.

Embodiment A21 concerns the drug insert of aspect A1 wherein the agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog; an anti-inflammatory agent; an anti-infective agent; a dry eye medication; or any combination thereof.

Embodiment A22 concerns the drug insert of embodiment A21 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and other compounds with analgesic properties.

Embodiment A23 concerns the drug insert of embodiment A21 wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antimycotic.

Embodiment A24 concerns the drug insert of embodiment A21 wherein the dry eye medication comprises cyclosporine, antihistamine, mast cell stabilizer such as olapatadine, a demulcent, or sodium hyaluronate.

Embodiment A25 concerns the drug insert of aspect A1 wherein the agent comprises latanoprost, and the amount of the agent in the drug insert is about 10-50 μg.

Embodiment A26 concerns the drug insert of aspect A1 wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment A27 concerns the drug insert of aspect A1 wherein the drug core is substantially cylindrical in form, having an axis, wherein the exposed surface of the drug core is disposed on one end of the cylindrical form and a surface of the drug core covered by the sheath body constitutes a remainder of the surface of the cylindrical form.

Embodiment A28 concerns the drug insert of aspect A1 wherein the agent is dissolved in the matrix within the drug core.

Embodiment A29 concerns the drug insert of embodiment A28 wherein the agent comprises cyclosporine and the matrix comprises polyurethane.

Embodiment A30 concerns the drug insert of aspect A1 wherein the agent is present at least in part as a plurality of solid or liquid inclusions throughout the matrix, the inclusions comprising, at a temperature of less than about 25° C., droplets of the agent of no greater than about 100 μm diameter when the agent is a liquid at less than about 25° C., or particles of the agent of no greater than about 100 μm diameter when the agent is a solid at less than about 25° C.

Embodiment A31 concerns the drug insert of embodiment A30 wherein an average inclusion diameter and a size distribution of a plurality of inclusion diameters within a population of inclusions have an effect on a rate of release of the agent from the drug core to the patient.

Embodiment A32 concerns the drug insert of embodiment A30 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment A33 concerns the drug insert of embodiment A32 wherein a standard deviation of diameters of the inclusions is less than about 8 μm.

Embodiment A34 concerns the drug insert of embodiment A30 wherein the inclusions have an average diameter of less than about 15 μm.

Embodiment A35 concerns the drug insert of embodiment A34 wherein a standard deviation of diameters of the inclusions is less than about 6 μm.

Embodiment A36 concerns the drug insert of embodiment A30 wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment A37 concerns the drug insert of embodiment A36 wherein a standard deviation of diameters of the inclusions is less than about 4 μm.

Embodiment A38 concerns the drug insert of embodiment A30 wherein a distribution of diameters of the inclusions is a monodisperse distribution.

Embodiment A39 concerns the drug insert of embodiment A30 wherein the inclusions predominantly comprise a cross-sectional size within a range from about 0.1 μm to about 50 μm.

Embodiment A40 concerns the drug insert of embodiment A30 wherein the agent forms inclusions in the matrix that are in a liquid physical state at less than about 25° C.

Embodiment A41 concerns the drug insert of embodiment A40 wherein substantially all the inclusions are droplets of the agent of less than about 30 μm in diameter within the matrix.

Embodiment A42 concerns the drug insert of embodiment A40 wherein the droplets have an average diameter of less than about 10 μm,

Embodiment A43 concerns the drug insert of embodiment A42 wherein a standard deviation of diameters of the inclusions is less than about 4 μm

Embodiment A44 concerns the drug insert of embodiment A40 wherein the agent is latanoprost.

Embodiment A45 concerns the drug insert of embodiment A30 wherein the agent forms inclusions in the matrix that are in a solid physical state at less than about 25° C.

Embodiment A46 concerns the drug insert of embodiment A45 wherein substantially all the inclusions are particles of the agent of less than about 30 μm in diameter within the matrix.

Embodiment A47 concerns the drug insert of embodiment A45 wherein an average particle diameter within the matrix is about 5-50 μm.

Embodiment A48 concerns the drug insert of embodiment A45 wherein the agent is bimatoprost, olopatadine, or cyclosporine.

Embodiment A49 concerns the drug insert of aspect A1 wherein the core comprises two or more therapeutic agents.

Embodiment A50 concerns the drug insert of aspect A1 wherein the drug core comprises first and second drug cores.

Embodiment A51 concerns the drug insert of embodiment A50 wherein the drug insert comprises two drug cores disposed within the sheath body, a first drug core comprising a first agent and a first matrix, and a second drug core comprising a second agent and a second matrix, wherein the first agent and the second agent are different, and wherein the first matrix and the second matrix are either the same or differ from each other; the implant body comprising an aperture adapted to receive the first and the second cores disposed within the sheath body, the drug cores being adapted to be disposed, within the sheath, within the aperture of the implant body.

Embodiment A52 concerns the drug insert of embodiment A50 wherein the first matrix and the second matrix differ from each other with respect to at least one of a composition, an exposed surface area, a surfactant, a crosslinker, an additive, a matrix material, a formulation, a release rate modifying reagent, or a stability.

Embodiment A53 concerns the drug insert of embodiment A50 wherein the first drug core and the second drug core are disposed within the sheath body such that the first drug core has a surface exposed directly to tear liquid and the second drug core does not have a surface exposed directly to tear liquid when the drug insert is disposed within the implant body and the implant body is disposed in or adjacent to the eye of the patient.

Embodiment A54 concerns the drug insert of embodiment A50 wherein the first drug core and the second drug core are disposed side by side within the sheath body.

Embodiment A55 concerns the drug insert of embodiment A50, wherein the first drug core and the second drug core are each cylindrical in shape and disposed with the sheath body, the first drug core being positioned near a proximal end of an aperture in the implant body and the second drug core being positioned near a distal end of the aperture, when the drug insert is disposed within the implant body.

Embodiment A56 concerns the drug insert of embodiment A50, wherein the first drug core and the second drug core are each cylindrical in shape provided that the first drug core has a first central opening, the drug cores being positioned concentrically within the sheath body within an aperture of the implant body adapted to receive the drug insert, and the second drug core being configured to fit within the first central opening of the first drug core.

Embodiment A57 concerns the drug insert of embodiment A56 wherein the first and second drug cores are concentrically positioned within the aperture of the implant body, the first drug core having a first central opening exposing a first inner surface and the second drug core having a second central opening exposing a second inner surface, the second drug core being configured to fit within the first central opening of the first drug core, and wherein the aperture extends from a proximal end to a distal end of the implant body thereby being adapted to allow tear liquid to pass through the aperture and contact the first and second inner surfaces of the first and second central openings and release the first and second therapeutic agents into a canaliculus of the patient when the implant body is inserted into a patient.

Embodiment A58 concerns the drug insert of embodiment A50 wherein the first therapeutic agent has a release profile wherein the first agent is released at therapeutic levels throughout a first time period and the second therapeutic agent has a second release profile wherein the second agent is released at therapeutic levels throughout a second time period.

Embodiment A59 concerns the drug insert of embodiment A58 wherein the first time period and the second time period are between one week and five years.

Embodiment A60 concerns the drug insert of embodiment A58 wherein the first release profile and the second release profile are substantially the same.

Embodiment A61 concerns the drug insert of embodiment A58 wherein the first release profile and the second release profile are different.

Embodiment A62 concerns the drug insert of embodiment A50 wherein any inclusions in the first drug core and in the second drug core respectively have an average diameter of less than about 20 μm.

Embodiment A63 concerns the drug insert of embodiment A50 wherein any inclusions in the first drug core and in the second drug core respectively have a standard deviation of diameters of less than about 8 μm.

Embodiment A64 concerns the drug insert of embodiment A50 wherein the implant body comprises a central bore that extends from a proximal end to a distal end of the implant body so as to be adapted to allow a tear liquid to pass through the implant body and the first and second therapeutic agents are released into the tear liquid into a canaliculus of the patient when the implant body is disposed in or adjacent to the eye.

Embodiment A65 concerns the drug insert of embodiment A50 wherein the first agent provides a first effect and a side effect to the patient, and the second agent provides a second effect that mitigates or counters the side effect of the first agent.

Embodiment A66 concerns the drug insert of embodiment A50, further comprising disposing a medication-impregnated porous material within the first matrix, the second matrix, or both, wherein the medication-impregnated porous material is adapted so as to permit tear liquid to release the first agent, the second agent, or both, from the medication-impregnated porous material at therapeutic levels over a sustained period when a drug core-containing implant is disposed within a punctum, and wherein the medication-impregnated porous material is a gel material that can swell from a first diameter to a second diameter when in contact with tear liquid.

Embodiment A67 concerns the drug insert of embodiment A66 wherein in which the second diameter is about 50% greater than the first diameter.

Embodiment A68 concerns the drug insert of embodiment A66 wherein the medication-impregnated porous material is a HEMA hydrophilic polymer.

Embodiment A69 concerns the drug insert of aspect A1 wherein the matrix comprises a polyurethane polymer or copolymer.

Embodiment A70 concerns the drug insert of embodiment A69 wherein the polyurethane polymer or copolymer comprises an aliphatic polyurethane, an aromatic polyurethane, a polyurethane hydrogel-forming material, a hydrophilic polyurethane, or a combination thereof.

Embodiment A71 concerns the drug insert of embodiment A69 wherein the polyurethane polymer or copolymer comprises a hydrogel adapted to swell when contacted with an aqueous medium and the sheath body is adapted to be of sufficient elasticity to expand in response thereto.

Embodiment A72 concerns the drug insert of embodiment A71 wherein the swelling is adapted to retain the implant body within a punctal canal of the patient.

Embodiment A73 concerns the drug insert of embodiment A69 wherein the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or a derivative of cyclosporine or olopatadine, or any combination thereof.

Embodiment A74 concerns the drug insert of embodiment A73 wherein a weight ratio of the cyclosporine or the olopatadine, or the cyclosporine prodrug or derivative, or the olopatadine prodrug or derivative, or the combination thereof, to the polyurethane polymer or copolymer is about 1 wt % to about 70 wt %.

Embodiment A75 concerns the drug insert of aspect A1 wherein a concentration of the agent in the core is similar in a portion of the drug core proximate to the exposed surface, a portion distal to the exposed surface, and a portion disposed between the proximate portion and the distal portion.

Embodiment A76 concerns the drug insert of embodiment A75 wherein the proximal portion is in length at least about one tenth a length of the drug core.

Embodiment A77 concerns the drug insert of aspect A1 wherein the drug insert or the implant is adapted for disposition within or adjacent to an eye of a patient.

Embodiment A78 concerns the drug insert of aspect A1 wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

The drug insert aspects and embodiments of aspect A1 and embodiments A2 through A76 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment A6 may be combined with any of embodiments A2 through A5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for this aspect and embodiment set.

Aspect B1 concerns a drug core comprising a therapeutic agent and a matrix for disposition into or as a drug insert or an implant, the drug insert or the implant being adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid of a patient, the matrix comprising a polymer, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

Embodiment B2 concerns a drug core of aspect B1 wherein the drug insert or the implant is adapted for disposition within or adjacent to an eye of a patient.

Embodiment B3 concerns a core of aspect B1 wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

Embodiment B4 concerns the drug core of aspect B1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment B5 concerns the drug core of aspect B1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment B6 concerns the drug core of aspect B1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment B7 concerns the drug core of aspect B1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment B8 concerns the drug core of aspect B1, wherein the therapeutic agent is uniformly homogeneously distributed throughout the matrix.

Embodiment B9 concerns the drug core of aspect B1, wherein the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

Embodiment B10 concerns the drug core of aspect B1, wherein the therapeutic agent at least in part forms solid or liquid inclusions within the matrix, wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment B11 concerns the drug core of embodiment B10 wherein a standard deviation of diameters of the inclusions is less than about 8 μm.

Embodiment B12 concerns the drug core of aspect B1, wherein the therapeutic agent at least in part forms solid or liquid inclusions within the matrix, wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment B13 concerns the drug core of embodiment B12 wherein a standard deviation of diameters of the inclusions is less than about 4 μm.

Embodiment B14 concerns the drug core of aspect B1, wherein the amounts of the therapeutic agent in equal volumetric portions at about the proximal portion, at about the middle portion and at about the distal portion of the drug core are similar.

Embodiment B15 concerns the drug core of embodiment B14, wherein the amounts of the therapeutic agent vary by no greater than about 30%.

Embodiment B16 concerns the drug core of embodiment B14, wherein the amounts of the therapeutic agent vary by no greater than about 20%.

Embodiment B17 concerns the drug core of embodiment B14, wherein the amounts of the therapeutic agent vary by no greater than about 10%.

Embodiment B18 concerns the drug core of embodiment B16, wherein the amounts vary by no greater than about 5%.

Embodiment B19 concerns the drug core of aspect B1, wherein the polymer comprises a non-biodegradable silicone or polyurethane, or combination thereof.

Embodiment B20 concerns the drug core of aspect B1, wherein the therapeutic agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog; an anti-inflammatory agent; an anti-infective agent; a dry eye medication; or any combination thereof.

Embodiment B21 concerns the drug core of embodiment B20 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or other compounds with analgesic properties.

Embodiment B22 concerns the drug core of embodiment B20 wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antimycotic.

Embodiment B23 concerns the drug core of embodiment B20 wherein the dry eye medication comprises cyclosporine, antihistamines and mast cell stabilizers, olapatadine, a demulcent, or sodium hyaluronate.

Embodiment B24 concerns the drug core of aspect B1, wherein the polymer comprises silicone.

Embodiment B25 concerns the drug core of aspect B1, wherein the therapeutic agent comprises cyclosporine and the polymer comprises a polyurethane.

Embodiment B26 concerns the drug core of aspect B1 comprising a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment B27 concerns the drug core of aspect B1 disposed within a sheath body.

Embodiment B28 concerns the drug core of aspect B1 which has been formed into a shape of an implant body for disposition in or adjacent to a body cavity, tissue, duct, or fluid of a patient.

The drug core aspects and embodiments of aspect B1 and embodiments B2 through B28 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment B6 may be combined with any of embodiments B2 through B5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for this aspect and embodiment set.

Aspect C1 concerns a filled precursor sheath comprising a precursor sheath body containing a precursor drug core, the drug core comprising a therapeutic agent and a matrix, the matrix comprising a polymer, the precursor sheath body being substantially impermeable to the agent, wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core.

Embodiment C2 concerns the filled precursor sheath of aspect C1 adapted for manufacture of a plurality of drug inserts by division of the filled precursor sheath, each drug insert being adapted for disposition within a respective implant, the implant being adapted for disposition within or adjacent a body cavity, tissue, duct or fluid.

Embodiment C3 concerns the filled precursor sheath of aspect C1 wherein the implant is adapted for disposition within or adjacent to an eye of a patient.

Embodiment C4 concerns the precursor sheath of aspect C1 wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core varies from an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core by no greater than about 30%.

Embodiment C5 concerns the precursor sheath of aspect C1 wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core varies from an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core by no greater than about 20%.

Embodiment C6 concerns the precursor sheath of aspect C1 wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core varies from an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core by no greater than about 10%.

Embodiment C7 concerns the precursor sheath of aspect C1 wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core varies from an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core by no greater than about 5%.

Embodiment C8 concerns the precursor sheath of aspect C1 wherein the amount of the agent in a first insert of the plurality of inserts is similar to the amount of agent in any other insert of the plurality of inserts.

Embodiment C9 concerns the precursor sheath of embodiment C8 wherein the amount of the agent in the first insert varies by no greater than about 30% compared with the amount of agent in any other insert.

Embodiment C10 concerns the precursor sheath of embodiment C8 wherein the amount of the agent in the first insert varies by no greater than about 20% compared with the amount of agent in any other insert.

Embodiment C11 concerns the precursor sheath of embodiment C8 wherein the amount of the agent in the first insert varies by no greater than about 10% compared with the amount of agent in any other insert.

Embodiment C12 concerns the precursor sheath of embodiment C8 wherein the amount of the agent in the first insert varies by no greater than about 5% compared with the amount of agent in any other insert.

Embodiment C13 concerns the precursor sheath of aspect C1 wherein the implant comprises a punctal plug and each of the plurality of inserts is adapted for disposition within a respective plurality thereof.

Embodiment C14 concerns the precursor sheath of embodiment C13 wherein each exposed surface of each drug insert divided therefrom is adapted to release therapeutic quantities of the agent for a time period of at least several days into tear fluid, when the insert is disposed within a punctal plug and the punctal plug is disposed within a punctum of a patient.

Embodiment C15 concerns the precursor sheath of aspect C1 wherein the drug core comprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment C16 concerns the precursor sheath of aspect C1 wherein the matrix comprises a non-biodegradable silicone or a polyurethane, or combination thereof.

Embodiment C17 concerns the precursor sheath of aspect C1 wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, PET, wherein the polymer is extruded or cast, or stainless steel, or titanium.

Embodiment C18 concerns the precursor sheath of aspect C1 wherein the agent comprises wherein the agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog; an anti-inflammatory agent; an anti-infective agent; a dry eye medication; or any combination thereof.

Embodiment C19 concerns the precursor sheath of embodiment C18 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or other compounds with analgesic properties.

Embodiment C20 concerns the precursor sheath of embodiment C18 wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antimycotic.

Embodiment C21 concerns the precursor sheath of embodiment C18 wherein the dry eye medication comprises cyclosporine, antihistamines and mast cell stabilizers, olapatadine, a demulcent, or sodium hyaluronate.

Embodiment C22 concerns the precursor sheath of aspect C1 wherein the agent comprises latanoprost, and the amount of the agent in each of the plurality of drug inserts is about 10-50 μg.

Embodiment C23 concerns the precursor sheath of aspect C1 wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment C24 concerns the precursor sheath of aspect C1 adapted for division by cutting with a blade or with a laser.

Embodiment C25 concerns the precursor sheath of aspect C1 wherein the agent is dissolved in the matrix.

Embodiment C26 concerns the precursor sheath of aspect C1 wherein the agent is dispersed as a plurality of solid or liquid inclusions throughout the matrix, the inclusions comprising, at a temperature of less than about 25° C., droplets of the agent of no greater than about 100 μm diameter when the agent is a liquid at less than about 25° C., or particles of the agent of no greater than about 100 μm diameter when the agent is a solid at less than about 25° C.

Embodiment C27 concerns the precursor sheath of embodiment C26 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment C28 concerns the precursor sheath of embodiment C27 wherein a standard deviation of diameters of the inclusions is less than about 8 μm.

Embodiment C29 concerns the precursor sheath of embodiment C26 wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment C30 concerns the precursor sheath of embodiment C29 wherein a standard deviation of diameters of the inclusions is less than about 4 μm.

Embodiment C31 concerns the precursor sheath of embodiment C26 wherein a size distribution of diameters of the plurality of inclusions is monodisperse.

Embodiment C32 concerns the precursor sheath of aspect C1 wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

The filled precursor sheath aspects and embodiments of aspect C1 and embodiments C2 through C32 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment C6 may be combined with any of embodiments C2 through C5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for this aspect and embodiment set.

Aspect D1 concerns an implant body for disposition in or adjacent to a body cavity, tissue, duct, or fluid of a patient, the implant body comprising a channel therein adapted to receive a drug insert such that an exposed surface of the insert will be exposed to the body cavity, tissue, duct or fluid when the insert is disposed within the implant and when the implant is disposed in or adjacent to the body cavity, tissue, duct or fluid, the drug insert comprising a sheath body that is substantially impermeable to the agent, the sheath body containing a drug core comprising a therapeutic agent and a matrix comprising a polymer, wherein an amount of the therapeutic agent in a volumetric portion of the precursor drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the precursor drug core.

Embodiment D2 concerns an implant body of aspect D1 wherein the implant is adapted for disposition within or adjacent to an eye of a patient.

Embodiment D3 concerns the implant body of aspect D1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment D4 concerns the implant body of aspect D1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment D5 concerns the implant body of aspect D1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment D6 concerns the implant body of aspect D1, wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment D7 concerns the implant of aspect D1, wherein the exposed surface is capable of releasing the therapeutic quantities into at least one of a sclera, a cornea or a vitreous when disposed in or adjacent to the eye of the patient.

Embodiment D8 concerns the implant of aspect D1 comprising a punctal plug adapted for disposition within a punctum of a patient for release of the agent into tear liquid.

Embodiment D9 concerns the implant of aspect D1, wherein the therapeutic agent is soluble in the matrix.

Embodiment D10 concerns the implant of aspect D1 wherein the therapeutic agent forms inclusions within the matrix but is sufficiently soluble in or transportable through the matrix such that when the implant is disposed adjacent to an eye, the exposed surface is capable of releasing therapeutic quantities of the agent to the tear liquid for a period of time when the implant is disposed in or adjacent to the eye.

Embodiment D11 concerns the implant of aspect D1 wherein a rate of release of the agent is determined in part by a concentration of the agent that dissolves in the matrix.

Embodiment D12 concerns the implant of aspect D1 wherein the matrix comprises a crosslinked water insoluble solid material that contains the inclusions.

Embodiment D13 concerns the implant of embodiment D12 wherein the crosslinked water insoluble solid material comprises a silicone or a polyurethane.

Embodiment D14 concerns the implant of aspect D1 wherein the matrix further comprises an effective amount of a release rate varying material, the release rate varying material comprising at least one of a crosslinker, an inert filler material, a surfactant, a dispersant, a second polymer, or an oligomer, or any combination thereof.

Embodiment D15 concerns the implant of aspect D1 wherein the drug core comprises from about 5% to about 50% of the therapeutic agent.

Embodiment D16 concerns the implant of embodiment D10 wherein the inclusions of agent are in physical form liquid or solid.

Embodiment D17 concerns the implant of aspect D1 wherein the sheath body comprises a polymer comprising at least one of polyimide, PMMA, PET, wherein the polymer is extruded or case, or stainless steel, or titanium.

Embodiment D18 concerns the implant of aspect D1 wherein the implant body comprises at least one of a silicone or a hydrogel.

Embodiment D19 concerns the implant of aspect D1 wherein the agent is dispersed as a plurality of solid or liquid inclusions throughout the matrix, the inclusions comprising, at a temperature of less than about 25° C., droplets of the agent of no greater than about 200 μm diameter when the agent is a liquid at less than about 25° C., or particles of the agent of no greater than about 200 μm diameter when the agent is a solid at less than about 25° C.

Embodiment D20 concerns the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment D21 concerns the implant of embodiment D20 wherein a standard deviation of diameters of the inclusions is less than about 8 μm.

Embodiment D22 concerns the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 15 μm.

Embodiment D23 concerns the implant of embodiment D22 wherein a standard deviation of diameters of the inclusions is less than about 6 μm.

Embodiment D24 concerns the implant of embodiment D19 wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment D25 concerns the implant of embodiment D24 wherein a standard deviation of diameters of the inclusions is less than about 4 μm.

Embodiment D26 concerns the implant of embodiment D19 wherein a size distribution of diameters of the plurality of inclusions is monodisperse.

Embodiment D27 concerns the implant of embodiment D19 wherein the inclusions comprise a cross-sectional size within a range from about 0.1 μm to about 50 μm.

Embodiment D28 concerns the implant of embodiment D19 wherein the agent forms inclusions in the matrix that are in a liquid physical state at less than about 25° C.

Embodiment D29 concerns the implant of embodiment D19 wherein the agent forms inclusions in the matrix that are in a solid physical state at less than about 25° C.

Embodiment D30 concerns the implant of aspect D1 wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

The implant body aspects and embodiments of aspect D1 and embodiments D2 through D30 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment D6 may be combined with any of embodiments D2 through D5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for this aspect and embodiment set.

Aspect E1 concerns a method of manufacturing a drug insert for an implant body adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid of a patient, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent and a matrix the matrix comprising a polymer, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent when the implant is inserted into the patient, the method comprising injecting into the sheath body, at a temperature of less than about 25° C., a mixture comprising a matrix precursor and the therapeutic agent such that the sheath body is substantially filled therewith; then, curing the mixture within the sheath body to form within the sheath body the drug core wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

Aspect E2 concerns a method of manufacturing a drug insert for an implant body adapted for disposition within or adjacent to a body cavity, tissue, duct, or fluid of a patient, the method comprising injecting into a precursor sheath body, at a temperature of less than about 25° C., a mixture comprising a therapeutic agent and a precursor matrix such that the precursor sheath is substantially filled therewith, the precursor sheath body being substantially impermeable to the agent, curing the mixture in the precursor sheath body to provide a cured, filled precursor sheath body containing a precursor drug core; and dividing the cured filled precursor sheath to form a plurality of drug inserts, each drug insert being adapted to fit within a respective implant body, wherein each drug insert comprises a drug core and a sheath body, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent when the insert is disposed with an implant and the implant is inserted into the patient, and wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

Embodiment E3 concerns a method of manufacturing a drug insert of aspect E2 wherein each of the plurality of drug inserts is of substantially the same length, and wherein an amount of the agent in a first insert of the plurality is similar to the amount of agent in any other insert of the plurality.

Embodiment E4 concerns the method of manufacturing a drug insert according to aspect E1, aspect E2, or embodiment E3 wherein the implant is adapted for disposition in or adjacent to an eye of a patient.

Embodiment E5 concerns the method of aspect E1 or E2 wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment E6 concerns the method of aspect E1 or E2 wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment E7 concerns the method of aspect E1 or E2 wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment E8 concerns the method of aspect E1 or E2 wherein the amount of the therapeutic agent in a volumetric portion of the drug core varies from the amount of the therapeutic agent in any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment E9 concerns the method of aspect E2 wherein the amount of the agent in each of the plurality of inserts varies by no greater than about 30% therebetween.

Embodiment E10 concerns the method of aspect E2 wherein the amount of the agent in each of the plurality of inserts varies by no greater than about 20% therebetween.

Embodiment E11 concerns the method of aspect E2 wherein the amount of the agent in each of the plurality of inserts varies by no greater than about 10% therebetween.

Embodiment E12 concerns the method of aspect E2 wherein the amount of the agent in each of the plurality of inserts varies by no greater than about 5% therebetween.

Embodiment E13 concerns the method of aspect E2 wherein dividing the precursor insert comprises cutting the precursor insert with a blade or with a laser.

Embodiment E14 concerns the method of aspect E1 or E2 wherein the implant comprises a punctal plug adapted to be disposed within the punctum of the patient.

Embodiment E15 concerns the method of embodiment E14 wherein the exposed surface is adapted to release therapeutic quantities of the agent for a time period of at least several days into tear fluid when the insert is disposed in the punctal plug and the punctal plug is disposed within a punctum of a patient.

Embodiment E16 concerns the method of aspect E1 or E2 wherein the mixture further comprises a solvent in which the matrix precursor and the agent are soluble, and wherein curing comprises at least partial removal of the solvent following injection into the sheath body or precursor sheath body respectively.

Embodiment E17 concerns the method of embodiment E16 wherein curing comprises heating, vacuum treatment, or both.

Embodiment E18 concerns the method of embodiment E16 wherein the solvent comprises a hydrocarbon, an ester, a halocarbon, an alcohol, an amide, or a combination thereof.

Embodiment E19 concerns the method of embodiment E16 wherein the solvent comprises a halocarbon and the agent comprises cyclosporine.

Embodiment E20 concerns the method of aspect E1 or E2 wherein curing the mixture comprises heating the mixture to a temperature, at a relative humidity, for a period of time.

Embodiment E21 concerns the method of embodiment E20 wherein the temperature comprises a range from about 20° C. to about 100° C., the relative humidity comprises a range from about 40% to about 100%, and the period of time comprises a range from about 1 minute to about 48 hours.

Embodiment E22 concerns the method of embodiment E21 wherein the temperature is at least about 40° C., the relative humidity is at least about 80%, or both.

Embodiment E23 concerns the method of aspect E1 or E2 wherein curing comprises a step of polymerization or cross-linking, or both, of the matrix precursor.

Embodiment E24 concerns the method of embodiment E23 comprising polymerization or cross-linking, or both, in the presence of a catalyst.

Embodiment E25 concerns the method of embodiment E24 wherein the catalyst comprises a tin compound or a platinum compound.

Embodiment E26 concerns the method of embodiment E24 wherein the catalyst comprises at least one of a platinum with vinyl hydride system or a tin with alkoxy system.

Embodiment E27 concerns the method of aspect E1 or E2 wherein the mixture is prepared by a method comprising sonication.

Embodiment E28 concerns the method of aspect E1 or E2 wherein injecting comprises injecting under a pressure of at least about 40 psi.

Embodiment E29 concerns the method of aspect E1 or E2 wherein the temperature comprises a temperature of about −50° C. to about 25° C.

Embodiment E30 concerns the method of aspect E1 or E2 wherein the temperature comprises a temperature of about −20° C. to about 0° C.

Embodiment E31 concerns the method of aspect E1 or E2 wherein the mixture is injected such that the sheath body or precursor sheath body, respectively, is filled at a rate of no greater than about 0.5 cm/sec.

Embodiment E32 concerns the method of aspect E1 or E2 wherein each drug insert is sealed at one end thereof, a second end providing the exposed surface.

Embodiment E33 concerns the method of embodiment E32 wherein each drug insert is sealed at one end thereof with a UV-curable adhesive, a cyanoacrylate, an epoxy, by pinching, with a heat weld, or with a cap.

Embodiment E34 concerns the method of embodiment E33 further comprises irradiating the drug insert with a UV-curable adhesive with UV light.

Embodiment E35 concerns the method of embodiment E33 further comprising, after sealing one end thereof, inserting each drug insert into a channel of an implant body adapted to receive the insert therein.

Embodiment E36 concerns the method of aspect E1 or E2 wherein the insert comprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment E37 concerns the method of aspect E1 or E2 wherein the matrix comprises a non-biodegradable silicone or a polyurethane.

Embodiment E38 concerns the method of aspect E1 or E2 wherein the sheath or precursor sheath comprises at least one of polyimide, PMMA, PET, stainless steel, or titanium.

Embodiment E39 concerns the method of aspect E1 or E2 wherein the agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, or a prostaglandin or prostaglandin analog; an antiinflammatory agent; an anti-infective agent; a dry eye medication; or any combination thereof.

Embodiment E40 concerns the method of embodiment E39 wherein the anti-inflammatory agent comprises a steroid, a soft steroid, or an NSAID and/or any other compound with analgesic properties.

Embodiment E41 concerns the method of embodiment E39 wherein the anti-infective agent comprises an antibiotic, an antiviral, or an antimicotic.

Embodiment E42 concerns the method of embodiment E39 wherein the dry eye medication comprises cyclosporine, olapatadine, delmulcents, or sodium hyaluronate.

Embodiment E43 concerns the method of aspect E1 or E2 wherein the agent comprises latanoprost, the matrix comprises silicone or polyurethane, and the amount of the agent in each of the plurality of drug inserts is about 10-50 μg.

Embodiment E44 concerns the method of aspect E1 or E2 wherein the agent comprises cyclosporine, the matrix comprises silicone or polyurethane, and a relative amount of the agent in each of the plurality of drug inserts is ranges from about 1% to about 50% of the core.

Embodiment E45 concerns the method of aspect E1 or E2 wherein the drug insert comprises a release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof.

Embodiment E46 concerns the method of aspect E1 or E2 wherein the drug core is substantially cylindrical in form, having an axis, wherein a surface of the drug core is not covered by the sheath is disposed on one end on the cylindrical form and is the drug core covered by the sheath is disposed on a remainder of the surface of the cylindrical form.

Embodiment E47 concerns the method of aspect E1 or E2 wherein the agent is dissolved in the matrix.

Embodiment E48 concerns the method of embodiment E47 wherein the agent comprises cyclosporine and the matrix comprises polyurethane.

Embodiment E49 concerns the method of aspect E1 or E2 wherein the agent is dispersed as a plurality of solid or liquid inclusions within the matrix, the inclusions comprising, at a temperature of less than about 25° C., droplets of the agent of no greater than about 200 μm diameter when the agent is a liquid at less than about 25° C., or particles of the agent of no greater than about 200 μm diameter when the agent is a solid at less than about 25° C.

Embodiment E50 concerns the method of embodiment E49 wherein the inclusions have an average diameter of less than about 20 μm.

Embodiment E51 concerns the method of embodiment E50 wherein a standard deviation of diameters of the inclusions is less than about 8 μm.

Embodiment E52 concerns the method of embodiment E49 wherein the inclusions have an average diameter of less than about 15 μm.

Embodiment E53 concerns the method of embodiment E52 wherein a standard deviation of diameters of the inclusions is less than about 6 μm.

Embodiment E54 concerns the method of embodiment E49 wherein the inclusions wherein the inclusions have an average diameter of less than about 10 μm.

Embodiment E55 concerns the method of embodiment E54 wherein a standard deviation of diameters of the inclusions is less than about 4 μm.

Embodiment E56 concerns the method of embodiment E49 wherein a distribution of diameters of the inclusions is a monodisperse distribution.

Embodiment E57 concerns the method of embodiment E49 wherein the mixture is prepared by a process comprising sonication.

Embodiment E58 concerns the method of embodiment E49 wherein the inclusions comprise a cross-sectional size within a range from about 0.1 μm to about 50 μm.

Embodiment E59 concerns the method of embodiment E49 wherein the agent forms inclusions within the matrix that are in physical state a liquid at less than about 25° C.

Embodiment E60 concerns the method of embodiment E59 wherein substantially all the inclusions are droplets of the agent of less than about 50 μm in diameter within the matrix.

Embodiment E61 concerns the method of embodiment E59 wherein an average droplet diameter within the matrix is about 5-50 μm.

Embodiment E62 concerns the method of embodiment E59 wherein the agent is latanoprost.

Embodiment E63 concerns the method of embodiment E49 wherein the physical state of the agent is a solid at less than about 25° C.

Embodiment E64 concerns the method of embodiment E63 wherein the agent forms inclusions in the matrix and the physical state of the inclusions is a solid at less than about 25° C.

Embodiment E65 concerns the method of embodiment E63 wherein substantially all the inclusions are particles of the agent of less than about 50 μm in diameter within the matrix.

Embodiment E66 concerns the method of embodiment E63 wherein an average particle diameter within the matrix is about 5-50 μm.

Embodiment E67 concerns the method of embodiment E63 wherein the agent is bimatoprost, olopatadine, or cyclosporine.

Embodiment E68 concerns the method of aspect E1 or E2 wherein each drug insert comprises two or more therapeutic agents.

Embodiment E69 concerns the method of aspect E1 or E2 wherein each drug core comprises first and second drug cores.

Embodiment E70 concerns the method of embodiment E69 wherein the first and second drug cores are positioned side by side and together form a cylinder which is the drug core within the sheath body.

Embodiment E71 concerns the method of embodiment E69 wherein the drug core comprises two drug cores, a first drug core comprising a first agent and a first matrix, and a second drug core comprising a second agent and a second matrix, wherein the first agent and the second agent are different, and wherein the first matrix and the second matrix are either the same or differ from each other, the implant body comprising an aperture adapted to receive the drug insert comprising the first and the second drug cores, the method further comprising disposing the drug cores within the insert prior to disposing the insert within the aperture of the implant body.

Embodiment E72 concerns the method of embodiment E71 wherein the first matrix and the second matrix differ from each other with respect to at least one of a composition, an exposed surface area, a surfactant, a crosslinker, an additive, a matrix material, a formulation, or a stability.

Embodiment E73 concerns the method of embodiment E71 wherein the first drug core and the second drug core are disposed within the sheath such that the first drug core has a surface exposed directly to tear liquid and the second drug core has a surface exposed the first drug core.

Embodiment E74 concerns the method of embodiment E71 wherein the first drug core and the second drug core are disposed side by side within the sheath.

Embodiment E75 concerns the method of embodiment E71 wherein the first drug core and the second drug core are each cylindrical in shape and disposed with the drug core, the first drug core being positioned near a proximal end of an aperture in the implant body adapted to receive the drug core and the second drug core being positioned near a distal end of the aperture.

Embodiment E76 concerns the method of embodiment E71 wherein the first drug core and the second drug core are each cylindrical in shape and are positioned concentrically within an aperture of the implant body adapted to receive the drug cores, the first drug core having a first central opening and the second drug core being configured to fit within the first central opening of the first drug core.

Embodiment E77 concerns the method of embodiment E71 wherein the first and second drug cores are concentrically positioned within the aperture, the first drug core having a first central opening exposing a first inner surface and the second drug core having a second central opening exposing a second inner surface, the second drug core being configured to fit within the first central opening of the first drug core, and wherein the aperture extends from a proximal end to a distal end of the implantable body adapted to allow a tear or tear film fluid to pass through the aperture and contact the first and second inner surfaces of the first and second central openings and release the first and second therapeutic agents into a canaliculus.

Embodiment E78 concerns the method of embodiment E71 wherein the insert is adapted such that when it is implanted the first therapeutic agent releases at therapeutic levels throughout a first time period and the second therapeutic agent releases at therapeutic levels throughout a second time period.

Embodiment E79 concerns the method of embodiment E71 wherein the first therapeutic agent releases at therapeutic levels throughout a first time period and the second therapeutic agent releases at therapeutic levels throughout a second time period.

Embodiment E80 concerns the method of embodiment E79 wherein the first time period and the second time period are between one week and five years.

Embodiment E81 concerns the method of embodiment E79 wherein the first time period and the second time period are substantially the same.

Embodiment E82 concerns the method of embodiment E79 wherein the first time period and the second timer period are different.

Embodiment E83 concerns the method of embodiment E71 further comprising disposing a head coupled to the implant body covering the aperture, the head being permeable to the first and second therapeutic agents.

Embodiment E84 concerns the method of embodiment E71, wherein the therapeutic levels are drop administered quantities or less.

Embodiment E85 concerns the method of embodiment E71, wherein the therapeutic levels are less than 10% of drop administered quantities.

Embodiment E86 concerns the method of embodiment E71, further comprising disposing a medication-impregnated porous material within the first matrix, the second matrix, or both, the medication-impregnated porous material being adapted such that tear liquid releases the first agent, the second agent, or both, therefrom at therapeutic levels over a sustained period when a drug core-containing implant is disposed within a punctum, wherein the medication-impregnated porous material is a gel material that can swell from a first diameter to a second diameter.

Embodiment E87 concerns the method of embodiment E86 wherein in which the second diameter is about 50% greater than the first diameter.

Embodiment E88 concerns the method of embodiment E86 wherein the medication-impregnated porous material is a HEMA hydrophilic polymer.

Embodiment E89 concerns the method of embodiment E71 wherein the implant body comprises a central bore that extends from a proximal end to a distal end of the implant body adapted to allow a tear liquid to pass through the implant body and release the first and second therapeutic agents into a canaliculus.

Embodiment E90 concerns the method of embodiment E71 wherein the first agent provides a first effect and a side effect to the patient, and the second agent provides a second effect that mitigates or counters the side effect of the first agent.

Embodiment E91 concerns the method of aspect E1 or E2 wherein the matrix comprises a polyurethane polymer or copolymer.

Embodiment E92 concerns the method of embodiment E91 wherein the polyurethane polymer or copolymer comprises an aliphatic polyurethane, an aromatic polyurethane, a polyurethane hydrogel-forming material, a hydrophilic polyurethane, or a combination thereof.

Embodiment E93 concerns the method of embodiment E91 wherein the polyurethane polymer or copolymer comprises a hydrogel adapted to swell when contacted with an aqueous-medium and the sheath is adapted to be of sufficient elasticity to expand in response thereto.

Embodiment E94 concerns the method of embodiment E93 wherein the swelling is adapted to retain the plug within the punctal canal.

Embodiment E95 concerns the method of embodiment E91 wherein the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or a derivative of cyclosporine or olopatadine or any combination thereof.

Embodiment E96 concerns the method of embodiment E95 wherein a weight ratio of the cyclosporine or the olopatadine or the cyclosporine prodrug or derivative, or the olopatadine prodrug or derivative, or the combination thereof, to the polyurethane polymer or copolymer is about 1 wt % to about 70 wt %.

Embodiment E97 concerns the method of embodiment E95 wherein the polyurethane polymer or copolymer, and a quantity or a concentration of the cyclosporine or olopatadine, or the prodrug or derivative of cyclosporine or olopatadine, or combination thereof, therein, is selected to provide a release profile of the agent into tear liquid of the patient.

Embodiment E98 concerns the method of embodiment E91 wherein the drug core further comprises a second therapeutic agent.

Embodiment E99 concerns the method of embodiment E91, comprising forming the mixture by melting and mixing the polyurethane polymer or copolymer and the therapeutic agent.

Embodiment E100 concerns the method of embodiment E99 wherein the therapeutic agent is in molten form in the mixture.

Embodiment E101 concerns the method of embodiment E99 wherein the therapeutic agent is in solid form in the mixture.

Embodiment E102 concerns the drug insert made by a method of aspect E1 or E2.

Embodiment E103 concerns the method of aspect E1 or E2, wherein the temperature comprises a temperature of less than about 25° C.

Embodiment E104 concerns the method of aspect E1 or E2, wherein the temperature comprises a temperature of less than about 15° C.

Embodiment E105 concerns the method of aspect E1 or E2, wherein the temperature comprises a temperature of less than about 10° C.

Embodiment E106 concerns the method of aspect E1 or E2, wherein the temperature comprises a temperature of less than about 5° C.

Embodiment E107 concerns the method of aspect E1 or E2 wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the matrix; or b) the therapeutic agent at least in part forms solid or liquid inclusions within the matrix.

The method of manufacturing aspects and embodiments of aspects E1 and E2 and embodiments E3 through E107 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment E6 may be combined with any of embodiments E3 through E5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for this aspect and embodiment set.

Aspect F1 concerns a method of treating a malcondition in a patient in need thereof, comprising disposing in the patient an implant comprising a drug insert of any one of aspect A1 and embodiments A2-A78 or a drug core of any one of aspect B1 and embodiments B2-B28, or a drug core obtained by division of a filled precursor sheath of any one of aspect C1 and embodiments C2-C32, or a drug implant of any one of aspect D1 and embodiments D2-D30, or a drug insert of embodiment E102, wherein the therapeutic agent is adapted to treat the malcondition, in or adjacent to an eye of the patient such that the drug is released into a body tissue or fluid.

Embodiment F2 concerns the method of aspect F1 wherein the malcondition comprises glaucoma, and the agent is a prostaglandin analog.

Embodiment F3 concerns the method of embodiment F2 wherein the matrix comprises a non-biodegradable silicone or polyurethane polymer.

Embodiment F4 concerns the method of embodiment F2 wherein the prostaglandin analog is latanoprost.

Embodiment F5 concerns the method of aspect F1 wherein the malcondition comprises dry eye or eye inflammation and the agent is cyclosporine or olopatadine or a prodrug or derivative of cyclosporine or olopatadine.

Embodiment F6 concerns the method of embodiment F5 wherein the matrix comprises polyurethane.

Aspect G1 concerns a drug insert adapted for disposition within a lacrimal implant for providing sustained release of latanoprost to an eye of a patient in need of treatment of glaucoma, the drug insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising latanoprost and a matrix, the matrix comprising a silicone polymer, the sheath body being disposed over a portion of the drug core to inhibit release of the latanoprost from that portion and so as to define at least one exposed surface of the drug core not covered by the sheath body thereby being adapted to release the latanoprost to the eye, wherein an amount of the latanoprost in a volumetric portion of the drug core is similar to an amount of the latanoprost in any other equal volumetric portion of the drug core.

Embodiment G2 concerns the drug insert of aspect G1 wherein the amount of the latanoprost in a volumetric portion of the drug core varies from the amount of the latanoprost in any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment G3 concerns the drug insert of aspect G1 wherein the amount of the latanoprost in a volumetric portion of the drug core varies from the amount of the latanoprost in any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment G4 concerns the drug insert of aspect G1 wherein the amount of the latanoprost in a volumetric portion of the drug core varies from the amount of the latanoprost in any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment G5 concerns the drug insert of aspect G1 wherein the amount of the latanoprost in a volumetric portion of the drug core varies from the amount of the latanoprost in any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment G6 concerns the drug insert of aspect G1, wherein the latanoprost is dispersed within the silicone as droplets thereof.

The drug insert aspects and embodiments of aspect G1 and embodiments G2 through G6 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment G6 may be combined with any of embodiments G2 through G5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for an aspect and embodiment set.

Aspect H1 concerns a drug insert adapted for disposition within an punctal plug for providing sustained release of a cyclosporine to the eye for treatment of dry eye or inflammation, the insert comprising a drug core and a sheath body partially covering the core, the drug core comprising the cyclosporine and a matrix, the matrix comprising a polyurethane polymer, the sheath body being disposed over a portion of the core to inhibit release of the cyclosporine from said portion and so as to define at least one exposed surface of the drug core not covered by the sheath body being adapted to release the cyclosporine to the eye, wherein an amount of the cyclosporine in a volumetric portion of the drug core is similar to an amount of the cyclosporine in any other equal volumetric portion of the drug core.

Embodiment H2 concerns the drug insert of aspect H1 wherein the amount of the cyclosporine in a volumetric portion of the drug core varies from the amount of the cyclosporine in any other equal volumetric portion of the drug core by no greater than about 30%.

Embodiment H3 concerns the drug insert of aspect H1 wherein the amount of the cyclosporine in a volumetric portion of the drug core varies from the amount of the cyclosporine in any other equal volumetric portion of the drug core by no greater than about 20%.

Embodiment H4 concerns the drug insert of aspect H1 wherein the amount of the cyclosporine in a volumetric portion of the drug core varies from the amount of the cyclosporine in any other equal volumetric portion of the drug core by no greater than about 10%.

Embodiment H5 concerns the drug insert of aspect H1 wherein the amount of the cyclosporine in a volumetric portion of the drug core varies from the amount of the cyclosporine in any other equal volumetric portion of the drug core by no greater than about 5%.

Embodiment H6 concerns the drug insert of aspect H1, wherein the cyclosporine is dissolved within the polyurethane.

The drug insert aspects and embodiments of aspect H1 and embodiments H2 through H6 can be combined in any manner, as long as the combination is not internally inconsistent. For example, embodiment H6 may be combined with any of embodiments H2 through H5. These combinations are intended to provide the same concepts and meanings as multiply-dependent claims have and also the concepts and meanings that multiply-dependent claims upon other multiply-dependent claims have, so that any and all combinations of preceding and succeeding subject matter are included for an aspect and embodiment set. Further aspects and embodiments include the following.

The drug insert of any one of aspect A1 and embodiments A1-A78, or the drug core of any one of aspect B1 and embodiments B2-B28, or the drug core obtained by division of a filled precursor sheath of any one of aspects C1 and embodiments C2-C32, or the drug implant of any one of aspect D1 and embodiments D2-D30, or the drug insert of embodiment E102, adapted for providing sustained release of a therapeutic agent to the eye or surrounding tissues, or systemically, or any combination thereof.

A drug core of any of aspect A1 and embodiments A2-A78 which has been formed into a shape of an implant body for disposition in or adjacent to a body cavity, tissue, duct, or fluid of a patient.

Another aspect of the invention concerns the use of a drug insert of any one of aspect A1 and embodiments A2-A78, or a drug core of any one of aspect B1 or embodiments B2-B28, or a drug core obtained by division of a filled precursor sheath of any one of aspect C1 or embodiments C2-C32, or a drug implant of any one of aspect D1 or embodiments D2-D30, or a drug insert of E102, in the manufacture of an implant adapted for treatment of a malcondition in a patient in need thereof.

Another aspect of the invention concerns an implant comprising a polymer and a therapeutic agent disposed therein, wherein an amount of the therapeutic agent in a volumetric portion of the implant is similar to an amount of the therapeutic agent in any other equal volumetric portion of the implant.

A further aspect of the invention concerns a method of manufacturing an implant comprising a polymer and a therapeutic agent disposed therein, wherein an amount of the therapeutic agent in a volumetric portion of the implant is similar to an amount of the therapeutic agent in any other equal volumetric portion of the implant, in which the method comprises injecting a mixture comprising a polymer and a therapeutic agent into a mold, the method comprising injecting said mixture at a temperature less than about 25° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a top cross sectional view of a sustained release implant to treat an optical defect of an eye, according to an embodiment of the present invention.

FIG. 1B shows a side cross sectional view of the sustained release implant ofFIG. 1A.

FIG. 1C shows a perspective view of a sustained release implant with a coil retention structure, according to an embodiment of the present invention.

FIG. 1D shows a perspective view of a sustained release implant with a retention structure comprising struts, according to an embodiment of the present invention.

FIG. 1E shows a perspective view of a sustained release implant with a cage retention structure, according to an embodiment of the present invention.

FIG. 1F shows a perspective view of a sustained release implant comprising a core and sheath, according to an embodiment of the present invention.

FIG. 1G schematically illustrates a sustained release implant comprising a flow restricting retention element, a core and a sheath, according to an embodiment of the present invention.

FIG. 2A shows a cross sectional view of a sustained release implant with core comprising an enlarged exposed surface area, according to an embodiment of the present invention.

FIG. 2B shows a cross sectional view of a sustained release implant with a core comprising an enlarged exposed surface area, according to an embodiment of the present invention.

FIGS. 2C and 2D show perspective view and cross sectional views, respectively, of a sustained release implant with a core comprising a reduced exposed surface area, according to an embodiment of the present invention.

FIG. 2E shows a cross sectional view of a sustained release implant with a core comprising an enlarged exposed surface area with an indentation and castellation, according to an embodiment of the present invention.

FIG. 2F shows a perspective view of a sustained release implant comprising a core with folds, according to an embodiment of the present invention.

FIG. 2G shows a perspective view of a sustained release implant with a core comprising a channel with an internal surface, according to an embodiment of the present invention.

FIG. 2H shows a perspective view of a sustained release implant with a core comprising porous channels to increase drug migration, according to an embodiment of the invention.

FIG. 2I shows a perspective view of a sustained release implant with a convex exposed drug core surface, according to an embodiment of the present invention.

FIG. 2J shows a side view of a sustained release implant with a core comprising an exposed surface area with several soft brush-like members extending therefrom, according to an embodiment of the present invention.

FIG. 2K shows a side view of a sustained release implant with a drug core comprising a convex exposed surface and a retention structure, according to an embodiment of the present invention.

FIG. 2L shows a side view of a sustained release implant with a drug core comprising a concave indented surface to increase exposed surface area of the core, according to an embodiment of the present invention.

FIG. 2M shows a side view of a sustained release implant with a drug core comprising a concave surface with a channel formed therein to increase an exposed surface area of the core, according to an embodiment of the present invention.

FIGS. 3A and 3B show an implant comprising a silicone body, a drug core and retention structures, according to embodiments of the present invention.

FIG. 3C shows insertion of the implant as inFIG. 3A into an upper canaliculus of an eye.

FIG. 3D shows an implant as inFIG. 3A in an expanded profile configuration following implantation in the canaliculus of the eye.

FIG. 4A shows a drug core insert suitable for use with an implant, according to embodiments of the present invention.

FIG. 4B shows an of implant suitable for use with a drug core insert, according to embodiments of the present invention.

FIG. 4C shows an annular drug core insert suitable for use with an implant for systemic delivery of a therapeutic agent, according to embodiments of the present invention.

FIG. 4D shows an of implant suitable for use with a drug core insert as inFIG. 4C.

FIGS. 4E and 4F show a side cross-sectional view and an end view, respectively, of a drug core insert with two drug cores, according to embodiments of the present invention.

FIGS. 5A to 5C schematically illustrate replacement of a drug core and a sheath body, according to an embodiment of the present invention.

FIGS. 5D and 5E show an implant comprising a filament that extends from a drug core insert for removal the drug core insert from the implant, according to embodiments of the present invention.

FIG. 5F shows an implant comprising a filament that extends along a drug core insert bonded to a distal end of the drug core insert for removal of the drug core insert from a body of the implant, according to embodiments of the present invention.

FIG. 6A shows a method of manufacturing a punctal plug, according to embodiments of the present invention.

FIG. 6B shows a method of manufacturing a hydrogel rod in accordance with the method ofFIG. 6A.

FIG. 6C shows a method of molding a silicone plug in accordance with the method ofFIG. 6A.

FIG. 6D shows a method of assembling the punctal plug component in accordance with the method of inFIG. 6A.

FIG. 6E shows a method of manufacturing a drug core insert, in accordance with the method of inFIG. 6A.

FIG. 6F showsmethod690 of final assembly in accordance withmethod600 ofFIG. 6A.

FIGS. 7A and 7B show elution data of latanoprost atday 1 andday 14, respectively, for the three core diameters of 0.006, 0.012 and 0.025 inches and three Latanoprost concentrations of approximately 5%, 11% and 18%, according to embodiments of the present invention.

FIG. 7C shows elution data for Latanoprost from 0.32 mm diameter, 0.95 mm long drug cores with concentrations of 5, 10 and 20% and drug weights of 3.5, 7 and 14 μg, respectively, according to embodiments of the present invention.

FIGS. 7D and 7E show dependence of the rate of elution on exposed surface area of the drug core for the three core diameters and the three concentrations as inFIGS. 7A and 7B Latanoprost atday 1 andday 14, respectively, according to embodiments of the present invention.

FIG. 8 shows elution profiles of cyclosporine from drug cores into a buffer solution with surfactant and a buffer solution with surfactant, according to embodiments of the present invention.

FIG. 9 shows normalized elution profiles in nano-grams per device per day over 100 days for bulk sample of silicone with 1% Bimatoprost, according to embodiments of the present invention.

FIG. 10 shows profiles of elution of Latanoprost from the cores for four formulations of Latanoprost, according to embodiments of the present invention;

FIG. 11A shows the effect on elution of material and crosslinking on drug cores with 20% latanoprost, according to embodiments of the present invention.

FIG. 11B shows the effect of drug concentration on the elution of latanoprost, according to embodiments of the present invention.

FIG. 11C shows the effect of covering one end of the drug core insert, according to embodiments of the present invention.

FIG. 12 shows the elution of fluorescein and the effect of surfactant on fluorescein elution, according to embodiments of the present invention.

FIG. 13 shows the elution of sterilized and non-sterilized drug cores, according to embodiments of the present invention.

FIG. 14 shows the effect of salt on the elution of therapeutic agent, according to embodiments of the present invention.

FIGS. 15 A-D shows scanning electron micrographs of longitudinal sections of a silicone/latanoprost drug insert prepared by a method of the invention; A, B,=extrusion at ambient and superambient temperatures; C, D=extrusion at subambient temperatures.

FIG. 16 shows a plot of latanoprost content per 1 mm section of a filled precursor sheath prepared by an extrusion method which was carried out at about 0 degrees, about −25, about 40, and room temperatures.

FIG. 17 shows an implant comprising a silicone body, a drug core and retention structures, according to embodiments of the present invention.

FIG. 18A shows a sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent to treat an eye, the first and second drug cores being in a concentric configuration, according to an embodiment of the present invention.

FIG. 18B shows a side cross-sectional view of the sustained release implant ofFIG. 18A.

FIG. 19A shows a sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent to treat an eye, the first and second drug cores being in a side by side configuration, according to an embodiment of the present invention.

FIG. 19B shows a side cross-sectional view of the sustained release implant ofFIG. 19A.

FIG. 20A shows a sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agent to treat an eye, the first and second drug cores being in a concentric configuration with a hollow center to allow fluid flow through the implant, according to an embodiment of the present invention.

FIG. 20B shows a side cross-sectional view of the sustained release implant ofFIG. 20A.

FIG. 21 schematically illustrates a lacrimal insert in the shape of a punctal plug for use in a therapeutic implant.

FIG. 22 shows one embodiment of a therapeutic implant to treat an eye having a punctal plug and a sustained release implant having a drug core with a first therapeutic agent and a second therapeutic agent.

FIGS. 23-25 show different embodiments of therapeutic implants to treat an eye having a punctual plug and a sustained release implant having a first drug core with a first therapeutic agent and a second drug core having a second therapeutic agent.

FIGS. 26A-26C show different embodiments of therapeutic implants to treat an eye that encompass punctual plugs made of a medication-impregnable porous material having with two therapeutic agents.

FIG. 27 shows therapeutic implants containing first and second therapeutic agents as applied to the eye.

FIG. 28 shows various core elements that are combinable into a cylindrical shaped drug core.

FIGS. 29A-29D show different embodiments of a cylindrical shaped drug core using the core elements ofFIG. 28.

FIGS. 30A and 30B show other embodiments of a cylindrical shaped drug core assembled from core elements of different shapes.

FIG. 31 shows a sectional view of a sustained release implant having a first drug core with a first therapeutic agent and a second drug core with a second therapeutic agents to treat an eye, the first and second drug cores being in a stacked configuration, according to an embodiment of the present invention.

FIG. 32 shows one embodiment of a therapeutic implant to treat an eye having a punctal plug and a sustained release implant having a first drug core with a first therapeutic agent and a second drug core having a second therapeutic agent, the first and second drug cores being in a stacked configuration, according to an embodiment of the present invention.

FIG. 33 shows one embodiment of a therapeutic implant to treat a body condition, the implant having a first therapeutic agent and a second therapeutic agent.

FIGS. 34 and 35 show anatomical tissue structures of the eye suitable for use with implants, according to embodiments of the present invention.

FIG. 36 shows one embodiment of the implant having the bent design.

DETAILED DESCRIPTIONDefinitions

Unless otherwise indicated, the words and phrases presented in this document have their ordinary meanings to one of skill in the art. Such ordinary meanings can be obtained by reference to their use in the art and by reference to general and scientific dictionaries, for example,Webster's Third New International Dictionary, Merriam-Webster Inc, Springfield, Mass., 1993,The American Heritage Dictionary of the English Language, Houghton Mifflin, Boston Mass., 1981, andHawley's Condensed Chemical Dictionary,14^thedition, Wiley Europe, 2002.

The following explanations of certain terms are meant to be illustrative rather than exhaustive. These terms have their ordinary meanings given by usage in the art and in addition include the following explanations.

As used herein, the term “about” refers to a variation of 10 percent of the value specified; for example about 50 percent carries a variation from 45 to 55 percent.

As used herein, the term “and/or” refers to any one of the items, any combination of the items, or all of the items with which this term is associated.

As used herein, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

“Subject” or “patient” as used herein, includes mammals such as humans, non-human primates, rats, mice, dogs, cats, horses, cows and pigs.

A “therapeutic agent” is a medicinal compound or mixture thereof that is effective and medically indicated for treatment of a malcondition in a patient.

“Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. Similarly, as used herein, an “effective amount” in the context of a therapeutic agent, or a “therapeutically effective amount” of a therapeutic agent refers to an amount of the agent that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, an “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects. When the term “effective amount” is used in the context of a functional material, such as an effective amount of a dispersant, what is meant is that the amount of the functional material used is effective to achieve the desired result.

An “implant” as the term is used herein refers to a physical device adapted for insertion within or adjacent to a portion of a patient's body, not necessarily by surgical emplacement. For example, insertion of an implant such as a punctal plug through the punctum into the canaliculus of the eye of a patient need not involve surgical intervention, similarly with the emplacement of a device adapted to be held under an eyelid in contact with the orb of the eye. An implant is formed of biocompatible materials to the extent the materials actually come in contact with body tissues or fluids when disposed in their operative location. As defined herein, an implant is adapted to receive a “drug insert”, that is, a structure that contains the therapeutic agent to be administered to the particular patient for treatment of the particular condition, and which is adapted to release the therapeutic agent to the target tissues or organs over a period of time. Release of therapeutic quantities of an agent over a period of time is referred to as “sustained release” or “controlled release”, as is well known in the art.

By the terms “eye and surrounding tissues” is meant not just the orb of the eye, but surrounding conjunctival membranes, tear ducts, canaliculi (ducts draining tear liquid to the sinus), eyelids, and associated body structures.

A “polymer” as the term is used herein, refers to an organic macromolecule containing one or more repeating units, as is well known in the art. A “copolymer” refers to a polymer in which there are at least two types of repeating units included. A copolymer can be a block copolymer, in which there are segments containing multiple repeating units of one type, bonded to segments containing multiple repeating units of a second type. A “polymer” or “polymeric material” can be a silicone, a polyurethane, a polyamide, a polyester, a polysaccharide, a polyimide, or the like, or any copolymer thereof. When a polymeric material is to come in contact with a body tissue or fluid, the polymeric material is biocompatible.

A “matrix” is a material comprising an organic polymer in which the therapeutic agent is dispersed, the combination of which materials, referred to as a “core”, serves as the reservoir of the agent from which the agent is released over a period of time.

The term “precursor” as used in the context of this invention and as applied to any particular item means an intermediate or forerunner or prior article, device, item, or compound that is subsequently manipulated to form a final article, device, item or compound, or the like. For example, a “precursor sheath” is the elongated tube that, when filled with matrix and then cut, forms the sheath of the insert. In another example in the language used herein, a “matrix precursor” is “cured” to form the matrix. The matrix precursor can itself be a polymer, and can be cured, for example, by crosslinking. Or, the matrix precursor can be a polymer dissolved in a solvent, and curing includes removal of the solvent to provide the polymeric matrix material. Or, the matrix precursor can be a monomer, and curing can involve polymerization of the monomer, and can also involve removal of a solvent, and crosslinking of a polymer formed by polymerization. In a further example, a precursor drug core is a cured matrix containing the therapeutic agent that can be cut into appropriate lengths to form a drug core. A typical application of the precursor drug core is the filled precursor sheath. The filled precursor sheath is a precursor sheath body containing the precursor drug core that can be cut into appropriate lengths thereby producing a drug insert of the invention.

The terms “agent”, “therapeutic agent”, or “drug” as used herein refer to a medicinal material, a compound or a mixture thereof, suitable and medically indicated for treatment of a malcondition in a patient. The agent can be in a solid physical form or a liquid physical form at about room temperature or at about body temperature, depending on the melting point of the material. Examples of therapeutic agents are provided herein; for treatment of malconditions of the eye, specific examples of types or classes of agents that can be included in the inventive inserts include a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, or a prostaglandin or prostaglandin analog; an antiinflammatory agent; an anti-infective agent; a dry eye medication; or any combination thereof. More specifically, an example of a glaucoma medication is a prostaglandin or a prostaglandin analog. An example of a muscarinic agent is pilocarpine. An example of a beta blocked is betaxolol. An example of an alpha agonist is brimonidine. Examples of a carbonic anhydrase inhibitor are dorzolamide or brinzolamide. Examples of an antiinflammatory agent include a steroid, a soft steroid, or an non-steroidal antiinflammatory drug (NSAID) such as ibuprofen. An example of an analgesic includes, salicylic acid and acetaminophen. An antibiotic (antibacterial) can be a beta-lactam antibiotic, a macrocyclic antibiotic such as erythromycin, a fluoroquinolone, or the like. An antiviral compound can be a reverse transcriptase inhibitor or a viral protease inhibitor. An antimycotic can be a triazole antifungal compound. A dry eye medication can be cyclosporine, olapatadine, a delmulcent, or sodium hyaluronate.

The agent can be dissolved in the matrix in some embodiments, when the chemical identities of the agent and the matrix, and the concentration of the agent in the matrix, are such that dissolution is achieved. For example, as is known in the art, certain lipophilic steroid derivatives can dissolve at significant concentrations in silicones. In this event, the agent is referred to as being “dissolved” in the polymer, or as being uniformly, homogeneously dispersed throughout the matrix or “dispersed at a molecular level” in the polymer, just as a compound can be dissolved in a solvent, to form a “solid solution” of the agent in the polymeric material of the matrix.

In other embodiments, the agent does not completely dissolve in the matrix, but is present as domains or “inclusions” of the agent within the polymeric matrix. The inclusions can be liquid or solid at about room temperature or at about the temperature of the human body. After the matrix precursor has been cured to form the matrix, the inclusions are non-uniformly distributed in the now-solid or near solid matrix, and are thus prevented at least to some extent from recombining with each other, such as by liquid droplet accretion. This form is referred to as a “heterogeneous” distribution of the agent in the matrix. When inclusions of the agent are present, it is believed that a certain proportion of the agent may also be dissolved in the matrix. However, dissolution is not necessary for operation and function of the invention. Furthermore, the heterogeneous distribution of the agent with the matrix can be managed on a macroscopic level as discussed in connection with the definition of the terms “concentration” and “similar” given below.

A “concentration” of a therapeutic agent, as the term is used herein, refers to a concentration of the agent within a macroscopic portion of the matrix-agent core, that is controlled to have a degree of reproducibility from sample to sample of the core. A concentration of the agent in a macroscopic portion of the core can vary, but only within limits, relative to that in any other equal macroscopic portion of the core. The term does not relate to concentrations at the molecular level, where discontinuous and/or irregular domains or inclusions of the agent in concentrated form may be present, but rather refers to bulk concentrations of the agent in volumes of the core that are greater than at least about 0.1 mm³, for example, a cubic sample of core about 100 μm on a side, or a 0.1 mm thick slice of a core with cross-sectional area of about 1 mm.

The inclusions can be of various sizes, and various distributions of sizes of a plurality of the inclusions are possible, as are defined herein. When it is stated that the inclusions are no greater than about 100 μm in diameter, what is meant is that the largest inclusion observed within a drug insert of the invention has a greatest dimension of no greater than about 100 μm. When a particular size distribution of inclusions is recited, what is meant is that a predominant proportion of all the inclusions are of the stated dimension. When an average size or “average diameter” of inclusions within a population of inclusions is stated, what is meant is a numerical average of the greatest dimensions of all the inclusions. When a “standard deviation” of the distribution of inclusion diameters with in a population of inclusions is stated, what is meant that the distribution of inclusion diameters is normal or near normal, and that the standard deviation is a measure of the spread of the values, as is well known in the art. A small standard deviation relative to the average diameter denotes a tight distribution of inclusion diameters, a feature of various embodiments of the present invention.

In various embodiments, the inclusions can have an average diameter of less than about 20 μm, and a standard deviation of diameters of the inclusions is less than about 8 μm. Or, the inclusions can have an average diameter of less than about 15 μm, and a standard deviation of diameters of the inclusions is less than about 6 μm. Or, the inclusions can have an average diameter of less than about 10 μm, and a standard deviation of diameters of the inclusions is less than about 4 μm. A relative uniformity of inclusion size distribution, and a relative uniformity of the amount of agent dispersed per unit volume of the core within the insert, are features of various embodiments according to the present invention.

The size distribution of inclusion diameters can be monodisperse, and can be tightly so. By “monodisperse” is meant herein that the size distribution of the diameters of the plurality of inclusions is relatively tightly clustered around the average inclusion diameter, even if the distribution is not a normal distribution. For example, the distribution can have a fairly sharp upper size limit of inclusions of greater than average diameter, but can trail off in the distribution of inclusions of less than average diameter. Nevertheless, the size distribution can be tightly clustered, or monodisperse.

A “polyurethane” refers to a variety of polymer or copolymer containing repeating units bonded covalently through urethane, i.e., carbamate, bonds, —N-C(O)-O— wherein the N and O atoms are attached to an organic radical. The organic radical can be aliphatic, aromatic, or mixed; can contain other functional groups. Each radical, other than the radicals at the ends of the molecular chains, is bonded via two (or more) urethane groups to other radicals. A polyurethane polymer contains only urethane-type groups joining the repeating units. A polyurethane copolymer, such as a polyurethane-silicone copolymer or a polyurethane-carbonate copolymer, contains urethane and other types of groups joining the repeating units, i.e., silicone and carbonate type groups respectively.

A polyurethane-silicone copolymer contains segments of polyurethane chains and segments of silicone chains, as is well known in the art. A polyurethane-carbonate copolymer contains urethane segments and carbonate (—O—C(O)O—) segments. An example of a polyurethane-carbonate copolymer is Carbothane TPU® (Lubrizol).

A “hydrogel” as the term is used herein refers to a polymeric material that has absorbed greater than 100 wt %, for example up to 500-2000 wt %, of water within the polymeric structure and has consequently swelled substantially in physical size. A hydrogel possesses physical integrity, has tensile strength, and is not substantially fluid. A “hydrogel-forming polymer” is a polymeric material capable of forming a hydrogel upon contact with water. Examples include TG-500 and TG-2000.

“TG-500” and “TG-2000” are polyurethane hydrogel-forming polymers manufactured by the Thermedics Polymer Products division of Lubrizol Advanced Materials, Inc., of Wilmington, Mass. They are described by the manufacturer as aliphatic, polyether based thermoplastic polyurethanes capable of forming hydrogels. Such hydrogel-forming polymers can absorb greater than 100 wt %, for example up to 500-2000 wt % of water, and consequently swell in physical dimensions.

A “hydrophilic polymer” is a polymer that can be wetted by water, i.e., does not have a water-repellant surface. A hydrophilic polymer can absorb water to a small degree, for example about 0-100 wt % of water, but does not greatly swell in volume as does a hydrogel-forming polymer.

“Cyclosporine” is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It has been studied in transplants of skin, heart, kidney, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Cyclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungusTolypocladium inflatumGams. The structure of cyclosporine is:

“Olopatadine”, the structure of which is shown below, is a NSAID that can be administered in the form of a hydrochloride salt:
A “prodrug” is a substance, for example, that releases a therapeutic agent such as cyclosporine or olopatidine, or a biologically active derivative of either of these substances, when administered to a mammal. A prodrug can be a chemical derivative that contains a bond that is cleavable by an endogenous enzyme of the mammalian circulatory system such as an esterase or a phosphatase. For example, an amide NH of cyclosporine can be substituted with an ester group, providing a carbamate of structure ROC(O)N-cyclosporine. An endogenous esterase can cleave the ester bond, yielding an N-carboxyamide, which can spontaneously decarboxylate to yield cyclosporine. An ester of olopatidine, which can be cleaved by an endogenous esterase to yield olopatidine, is an example of an olopatidine prodrug. By formation of prodrugs, the polarity (hydrophobicity/hydrophilicity) of cyclosporine or olopatidine can be modified.
A “derivative” is a substance chemically allied to the therapeutic agent, and retaining at least some of the therapeutic agent's biological activity, but which need not be metabolized to the agent itself in the mammalian body to provide the desired beneficial result.
A “release profile”, as in a “defined release profile”, refers to a rate of release as a function of time of the therapeutic agent from an inventive plug into the eye, which can be defined or determined by selection of a particular polyurethane polymer or copolymer for a particular therapeutic agent. The release profile will in turn govern both the concentration of the agent in the eye and surrounding tissue over the time period during which the plug releases the agent.

DETAILED DESCRIPTION

The present invention is directed to various embodiments of drug inserts and drug cores containing therapeutic agents for use in implant bodies adapted for disposition in a body tissue, fluid, cavity, or duct. The implant bodies can be adapted to be disposed in or adjacent to an eye of a patient. The implants release the agent to the body, for example, into an eye or surrounding tissues, or both, over a period of time, for treatment of a malcondition in the patient for which use of the therapeutic agent is medically indicated. The invention is also directed to various embodiments of methods of manufacture of the drug inserts, and to methods of treatment of patients using implants containing the drug inserts.

In various embodiments, the invention provides a drug core adapted for disposition within a sheath and hence within an implant. The implant is adapted for disposition within or adjacent to an eye of a patient, for providing sustained release of a therapeutic agent to the eye or surrounding tissues or both.

The drug core comprises a therapeutic agent and a matrix wherein the matrix comprises a polymer, wherein an amount of the therapeutic agent in a volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other equal volumetric portion of the drug core.

The sheath body is disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the eye or surrounding tissues, or both, when the implant is inserted into the patient.

The exposed surface of the core is adapted to release therapeutic quantities of the agent into body tissues or fluids, for example into tear liquid, for a time period of at least several days into tear liquid when the implant is inserted into the patient. The sheath, which is impermeable to the agent, serves to block, at least in part, exposure of non-target tissues to the agent. For example, when the drug insert is disposed within an implant inserted into the canaliculus of the eye, the sheath acts to inhibit the release of the agent to the therapeutic target, e.g., the eye, while blocking release to non-target tissue, such as the interior of the canaliculus, or the nasal sinus.

In an embodiment, the drug core can be substantially cylindrical in form, having an axis, wherein the exposed surface of the drug core is disposed on one end of the cylindrical form and a surface of the drug core covered by the sheath body constitutes a remainder of the surface of the cylindrical form.

In a plurality of drug inserts of the invention, the therapeutic quantity of the agent released by each of the drug inserts is similar from one insert to another. For example, among a plurality of drug inserts of the invention, the therapeutic quantity of the agent released by each of the plurality of the inserts can vary by no greater than about 30% therebetween, or by no greater than about 20% therebetween, or by no greater than about 10% therebetween, or by no greater than about 5% therebetween. In some embodiments, among a plurality of drug inserts of the invention, the therapeutic quantity of the agent released by each of the plurality of the inserts can be the same.

The drug core or drug insert can have various relative contents of the therapeutic agent therein. For example, the drug core can include about 0.1 wt % to about 50 wt % of the agent. The agent is dispersed within the matrix, the matrix comprising a polymer, to form a composite material that can be disposed within the sheath. For example, the matrix can be formed of a non-biodegradable silicone or a polyurethane, or combination thereof. The sheath is formed of a substantially drug-impermeable substance to block release of the agent except through an exposed surface. It can be formed of any suitable biocompatible material, such as a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or cast; or a metal comprising stainless steel or titanium.

A therapeutic agent for use in the inventive insert or core can include anti-glaucoma medications, (e.g. adrenergic agonists, adrenergic antagonists (beta blockers), carbonic anhydrase inhibitors (CAIs, systemic and topical), parasympathomimetics, prostaglandins such as latanoprost, and hypotensive lipids, and combinations thereof), antimicrobial agent (e.g., antibiotic, antiviral, antiparasitic, antimycotic, etc.), a corticosteroid or other anti-inflammatory (e.g., an NSAID or other analgesic and pain management compounds) such as cyclosporine or olopatidine, a decongestant (e.g., vasoconstrictor), an agent that prevents of modifies an allergic response (e.g., an antihistamine, cytokine inhibitor, leucotriene inhibitor, IgE inhibitor, immunomodulator such as cyclosporine), a mast cell stabilizer, cycloplegic, mydriatic or the like.

Examples of agents further include, but are not limited to, thrombin inhibitors; antithrombogenic agents; thrombolytic agents; fibrinolytic agents; vasospasm inhibitors; vasodilators; antihypertensive agents; antimicrobial agents, such as antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate), antifungals (such as amphotericin B and miconazole), and antivirals (such as idoxuridine trifluorothymidine, acyclovir, gancyclovir, interferon); inhibitors of surface glycoprotein receptors; antiplatelet agents; antimitotics; microtubule inhibitors; anti-secretory agents; active inhibitors; remodeling inhibitors; antisense nucleotides; anti-metabolites; antiproliferatives (including antiangiogenesis agents); anticancer chemotherapeutic agents; anti-inflammatories (such as cyclosporine, olopatidine, hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone, triamcinolone acetonide); non steroidal anti-inflammatories (NSAIDs) (such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naxopren, piroxicam and nabumetone). Examples of such anti-inflammatory steroids contemplated for use with the present punctum plugs, include triamcinolone acetonide and corticosteroids that include, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, and derivatives thereof.); antiallergenics (such as sodium chromoglycate, antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin); decongestants (such as phenylephrine, naphazoline, tetrahydrazoline); miotics and anti-cholinesterase (such as pilocarpine, salicylate, carbachol, acetylcholine chloride, physostigmine, eserine, diisopropyl fluorophosphate, phospholine iodine, demecarium bromide); antineoplastics (such as carmustine, cisplatin, fluorouracil); immunological drugs (such as vaccines and immune stimulants); hormonal agents (such as estrogens, estradiol, progestational, progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamus releasing factor); immunosuppressive agents, growth hormone antagonists, growth factors (such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotrapin, fibronectin); inhibitors of angiogenesis (such as angiostatin, anecortave acetate, thrombospondin, anti-VEGF antibody); dopamine agonists; radiotherapeutic agents; peptides; proteins; enzymes; extracellular matrix; components; ACE inhibitors; free radical scavengers; chelators; antioxidants; anti polymerases; photodynamic therapy agents; gene therapy agents; and other therapeutic agents such as prostaglandins, antiprostaglandins, prostaglandin precursors, including antiglaucoma drugs including beta-blockers such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogues such as bimatoprost, travoprost, latanoprost etc; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorphenamide, diamox; and neuroprotectants such as lubezole, nimodipine and related compounds; and parasympathomimetrics such as pilocarpine, carbachol, physostigmine and the like.

Additional agents that can be used with the present implants include, but are not limited to, drugs that have been approved under Section 505 of the United States Federal Food, Drug, and Cosmetic Act or under the Public Health Service Act, some of which can be found at the U.S. Food and Drug Administration (FDA) website http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. The present punctum plugs can also be used with drugs listed in the Orange Book, either in paper or in electronic form, which can be found at the FDA Orange Book website (http://www.fda.gov/cder/ob/)), that has or records the same date as, earlier date than, or later date than, the filing date of this patent document. For example, these drugs can include, among others, dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporin, brimonidine, moxifloxacin, tobramycin, brinzolamide, aciclovir timolol maleate, ketorolac tromethamine, prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen, suprofenac, binoxan, patanol, dexamethasone/tobramycin combination, moxifloxacin, or acyclovir.

In various embodiments, a agent can be cyclosporine, or a prodrug or derivative thereof, or olopatidine, or a prodrug or derivative thereof, and, optionally, a second agent selected from the above-listed therapeutic agents.

In various embodiments, the agent can be a prostaglandin analog, such as latanoprost, bimatoprost, or travoprost, and the amount of the agent in the drug insert can be about 10-50 μg.

In various embodiments, the agent can be dissolved in the matrix within the drug core, i.e., at an effective concentration for use as with an implant, wherein the agent is sufficiently soluble in the polymer such that no inclusions or concentrated domains of the agent are present. This is known in the art as a solid solution, i.e. a uniform, homogeneous dispersion on the molecular level, wherein the solid polymer plays the role of a solvent, and no liquid solvent is present. For example, when the agent comprises cyclosporine and the matrix comprises polyurethane, a solid solution is formed at useful concentrations of the cyclosporine in the insert. This solubility is believed to result, at least in part, from interaction of the abundant amide bonds found in the cyclosporine molecule, which is a cyclic peptide, with the amide-like urethane bonds of the polyurethane polymer.

In various embodiments, the agent is insufficiently soluble in the matrix to form a solid solution. In these embodiments, the agent can be distributed at least in part as a plurality of solid or liquid inclusions throughout the matrix, the inclusions comprising, at a temperature of about 20° C., droplets of the agent of no greater than about 100 μm diameter when the agent is a liquid at about 20° C., or particles of the agent of no greater than about 100 μm diameter when the agent is a solid at about 20° C.; wherein the inclusions of the agent are dispersed throughout each drug core.

As discussed above, the size and size distribution of the inclusions can have an effect on a rate of release of the agent from the drug core to the patient. For example, smaller, more uniform inclusions can serve to infuse the bulk matrix with the agent more effectively, at a higher rate, due to a more favorable surface area to volume ratio. Accordingly, inventive methods provide for control or regulation of the average inclusion diameter or the distribution of inclusion diameters. For example, the inclusions can have an average diameter of less than about 20 μm. Inclusions of this average diameter can have a standard deviation of diameters of the inclusions of less than about 8 μm. For example, the inclusions can have an average diameter of less than about 15 μm. Inclusions of this average diameter can have a standard deviation of diameters of the inclusions of less than about 6 μm. Or, the inclusions can have an average diameter of less than about 10 μm. Inclusions of this average diameter can have a standard deviation of diameters of the inclusions of less than about 4 μm. In various embodiments, the distribution of diameters of the inclusions can be a monodisperse distribution. In various embodiments, the inclusions predominantly comprise a cross-sectional size within a range from about 0.1 μm to about 50 μm. It is believed that tight, or monodisperse, distributions of inclusion diameter are favorable from the point of view of therapeutic aspects of the drug core or a drug insert containing the core.

Various embodiments of the invention also provide a drug core or an insert containing a drug core wherein the agent forms inclusions in the matrix that are in a liquid physical state at about 20° C. For example, substantially all the inclusions can be droplets of the agent of less than about 30 μm in diameter within the matrix. And, the droplets can have an average diameter of less than about 10 μm, or can have a standard deviation of diameters of the inclusions is less than about 4 μm. An example of an agent in a liquid physical state at about 20° C. is latanoprost.

Various embodiments of the invention also provide a drug core or an insert containing a drug core wherein the agent forms inclusions in the matrix that are in a solid physical state at about 20° C. For example, substantially all the inclusions can be particles of the agent of less than about 30 μm in diameter within the matrix. For example, an average particle diameter within the matrix can be about 5-50 μm. Examples of agents in a solid physical state at about 20° C. include bimatoprost, olopatadine, or cyclosporine.

In various embodiments, the first therapeutic agent can have a release profile wherein the first agent is released at therapeutic levels throughout a first time period and the second therapeutic agent can have a second release profile wherein the second agent is released at therapeutic levels throughout a second time period. For example, the first time period and the second time period can be between one week and five years. The first release profile and the second release profile can be substantially the same, or can be different.

In various embodiments, the first agent can provides a first effect and a side effect to the patient, and the second agent can provide a second effect that mitigates or counters the side effect of the first agent.

In various embodiments, any inclusions in the first drug core and in the second drug core respectively have an average diameter of less than about 20 μm, and can have a standard deviation of diameters of less than about 8 μm.

In various embodiments, the implant body can comprise a central bore that extends from a proximal end to a distal end of the implant body so as to be adapted to allow a tear liquid to pass through the implant body such that the first and second therapeutic agents are released into the tear liquid into a canaliculus of the patient when the implant body is disposed in or adjacent to the eye.

In various embodiments, the drug insert or the drug core can further include a medication-impregnated porous material within the first matrix, the second matrix, or both, wherein the medication-impregnated porous material is adapted so as to permit tear liquid to release the first agent, the second agent, or both, from the medication-impregnated porous material at therapeutic levels over a sustained period when a drug core-containing implant is disposed within a punctum or within a lacrimal canaliculus, and wherein the medication-impregnated porous material is a gel material that can swell from a first diameter to a second diameter when in contact with tear liquid. The second diameter can be about 50% greater than the first diameter. An example of a suitable material for the medication-impregnated porous material is a hydroxyethylmethacrylate (HEMA) hydrophilic polymer.

In various embodiments, the drug insert or drug core can comprise a polyurethane polymer or copolymer. For example, the polyurethane polymer or copolymer can be an aliphatic polyurethane, an aromatic polyurethane, a polyurethane hydrogel-forming material, a hydrophilic polyurethane, or a combination thereof. In various embodiments, the polyurethane polymer or copolymer can include a hydrogel adapted to swell when contacted with an aqueous medium and the sheath body is adapted to be of sufficient elasticity to expand in response thereto. For example, the swelling can be adapted to retain the implant body within a duct, such as within a punctal canal, of the patient.

In various embodiments, when the matrix comprises a polyurethane, the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or a derivative of cyclosporine or olopatadine, or any combination thereof. For example, the cyclosporine or the olopatadine, or the cyclosporine prodrug or derivative, or the olopatadine prodrug or derivative, or the combination thereof, can be present in a weight ratio to the polyurethane polymer or copolymer of about 1 wt % to about 70 wt %. A concentration of the cyclosporine in the core can be similar in a portion of the drug core proximate to the exposed surface, a portion distal to the exposed surface, and a portion disposed between the proximate portion and the distal portion. For example, the proximal portion can be in length at least about one tenth a length of the drug core.

In various embodiments of the inventive drug insert for an implant for disposition in or adjacent to a patient's eye, the implant can be a lacrimal implant insertable into a lacrimal canaliculus, which is commonly referred to as a punctal plug, i.e., an implant adapted to insertion through a punctum of the eye to reside within the canaliculus of the eye, wherein the drug insert can come in contact with tear liquid and thereby release the therapeutic agent for contact with the eye or surrounding tissues or both.

In various embodiments, the core of the insert comprising the agent and a matrix, the matrix comprising a polymeric material, is surrounded by a sheath body. The sheath body is substantially impermeable to the agent, such that the agent is released to the tear liquid only through an exposed surface of the core that comes in contact with the tear liquid. The agent contained within the core serves as a reservoir in order to release therapeutic quantities or concentrations of the agent over a period of time, which can range from days to months. For example, in treatment of glaucoma, the drug insert can contain a prostaglandin analog such as latanoprost

The drug core is adapted to be disposed within a larger structure, an implant, which is in turn adapted for disposition within the body tissue, cavity, or duct. In various embodiments, the implant can be a punctal plug adapted for emplacement within the canaliculus of the eye, that is, within the duct(s) that drain tears from the surface of the eye.

For example, various embodiments of the drug cores can be used in implants, such as punctal plugs, adapted for placement near the eye to treat a patient suffering from a malcondition of the eye through the release of one or more drugs from the core within the implant onto the surface of the eye, such as by diffusion into tear fluids. Although specific reference is made to punctal plugs with drug delivery capabilities for use within the canaliculus of the eye, various embodiments of the implants may be useful for sustained release of the drug and treatment of other structures near and/or within the eye, for example the sclera, the conjunctiva, the cul-de-sac of the eyelid, the trabecular meshwork, the ciliary body, the cornea, the choroid, the suprachoroidal space, the sclera, the vitreous humor, aqueous humor and retina. Also, the inventive implants with their cores can be used for release of therapeutic agents into tissues, body cavities, or ducts, other than an eye or adjacent structures. In various embodiments, the drug cores can be used for sustained release of therapeutic agents into the ears and/or Eustachian tubes, nasal and/or sinus cavities, urethra, skin, gastrointestinal tract (including colon, bowel duct, and the like), and in or near joints such as knee, finger, and intervertebral joints.

In various embodiments, a drug core comprising a composite of a therapeutic agent and a matrix is partially contained within or surrounded by a sheath, the sheath being substantially impermeable to the agent. The sheath can cover part, but not all, of the surface of the core comprising the drug and the matrix material, the core having an exposed surface such that the therapeutic agent can be released therethrough. The drug core and its sheath together are adapted for inclusion within an implant structure that is itself adapted for implantation within a body of a patient, such as within a body cavity, tissue, duct, or fluid. For example, the implant can be an ocular implant, adapted for disposition in or around the eye, such as a punctal plug, adapted to disposition within the canaliculus of the eye such that the agent can be released through the punctum of the eye to contact the orb and surrounding tissues.

The sheath can be composed of any suitable biocompatible material which is substantially impermeable to the therapeutic agent. For example, the sheath can be an impermeable polymeric material such as a polyimide, polymethylmethacrylate, or a polyester such as PET, or a biocompatible metal such as stainless steel or titanium, or an inorganic glass, such as formed from silicon oxide. The agent can be any therapeutic substance capable of at least some diffusion through the matrix, which comprises a polymer, such that the agent can be released into a body tissue or fluid. A matrix can comprise a polymeric material, for example, the matrix can include a silicone, a polyurethane, or any non-biodegradable polymer wherein the agent has at least sufficient solubility to diffuse therethrough. The matrix can comprise other materials, including but not limited to other types of polymers such as polyolefins, polyamides, polyesters, polyvinyl alcohol or acetate, ethylene-vinyl acetate copolymers, polysaccharides such as cellulose or chitin, or the like, provided the material is biocompatible. Accordingly, selection of a material for the matrix can be made at least in part based on the agent selected for the particular application intended, such that a sufficient degree of solubility of the agent in the matrix can be achieved for a therapeutic level of the agent in the target tissue can be maintained over a period of time.

Other substances, such as release rate modifying substances such as surfactants, dispersants, fillers, other polymers and oligomers, and the like, can be included with the matrix in the core.

The substantially impermeable sheath prevents the diffusion of the agent therethrough. Accordingly, the agent diffuses into surrounding body fluids, tissues, etc. largely via that portion of the core that is not covered by the sheath. The rate of diffusion of the agent into the surrounding body fluids, tissues, etc. is governed at least in part by the rate of diffusion of the agent through the matrix. Once a molecule of the agent reaches the exposed surface of the composite in contact with the environment, it can diffuse into the surrounding fluid or tissue. In certain embodiments, the therapeutic agent can initially be released into a tissue structure adjacent to the target, for example into a punctum of a patient located near the target ocular tissues, from where it can diffuse to the site of action.

In various embodiments, the agent can be soluble or substantially insoluble in the polymeric matrix material. In embodiments wherein the agent is soluble at the concentration used in the polymeric matrix material, the drug core comprises a homogeneous composite wherein the agent is dispersed at a molecular level within the polymeric matrix material. For example, a highly lipophilic agent such as ethynodiol diacetate can dissolve at significant concentrations in silicone polymer, such that a core can be a homogeneous dispersion of the agent in the matrix at the molecular level. For example, cyclosporine, a cyclic peptide analog, can dissolve in significant concentrations in polyurethane, a polymer that contains linkages resembling amide bonds. When a homogeneous dispersion of the agent in the matrix is present, the rate of release of the agent from the exposed surface of the core into the body fluid or tissue can be controlled by the rate of diffusion or transport of the agent through the matrix. In embodiments wherein the agent is soluble in the polymeric matrix material, the rate of release of the agent into the body tissue or fluid can be determined at least in part by the concentration of the agent dissolved in the matrix of the core. In various embodiments, the concentration of therapeutic agent dissolved in the matrix can be a saturation concentration The kinetics of such release can be zero order, first order, or a fractional order between zero and first orders.

In embodiments wherein the agent is only partially or sparingly soluble or insoluble in the matrix at the concentration used, the core comprises a heterogeneous composition wherein the drug substance is dispersed as solid or liquid inclusions throughout the polymeric matrix material. Where some solubility, however slight, exists, a certain amount of the drug will be dissolved in the matrix. In various embodiments, the inclusions can range in size from about 0.1 μm to about 100 μm. When inclusions of the agent in the matrix are present, the agent may be at least slightly soluble in the matrix to enable at least some diffusion of the agent from an inclusion to an exposed surface of the drug core such that the agent can further diffuse into body fluid or tissue, for example, the agent can diffuse into tear fluid. When the agent is insoluble in the matrix, the agent will form domains or inclusions as a separate phase within the matrix that may cooperate to enable microchannels for transport of drug to the matrix surface. In various embodiments, the agent can be transported via channels or pores in the matrix, which can be permeated by the body fluid. In various embodiments, the agent can be transported through pores or channels present in the matrix.

The agent is present in the core, dispersed in the matrix, in a concentration. The concentration is a concentration of the agent within a macroscopic portion of the matrix-agent core, that is controlled to be similar from sample to sample of the core. A similar concentration of the agent in a macroscopic portion of the core can vary, but only within limits, relative to that in any other equal macroscopic portion of the core. The term does not relate to concentrations at the molecular level, where domains or inclusions of the agent in concentrated form may be present, but rather refers to bulk concentrations of the agent in volumes of the core that are greater than at least about 0.1 mm³, for example, a cubic sample of core about 1.00 μm on a side, or a 0.1 mm thick slice of a core with cross-sectional area of about 1 mm². The concentration can vary within no greater than about 30%, or no greater than about 20%, or no greater than about 10%, or no greater than about 5%.

In various embodiments, the inclusions can have an average diameter of less than about 20 μm, or less than about 15 μm, or less than about 10 μm. The distribution of diameters of the inclusions can be monodisperse, that is, relatively tightly grouped around the average diameter. If the distribution of inclusion diameters is a normal or near-normal distribution, and the monodispersity can be expressed in terms of a standard deviation, a standard deviation of diameters of the inclusions can be less than about 8 μm, or less than about 6 μm, or less than about 4 μm.

Although it is not intended to be a limitation of the invention, the factors controlling the rate of release of the agent from the matrix to the patient, such as the release of an ocular drug into tear liquid, are believed to be complex and dependent on many variables. For example, a drug and a matrix material may together define a saturation concentration of the drug in that matrix. For some drug-matrix combinations, high concentrations of the drug can dissolve in the matrix. For others, a saturation concentration is lower. For still others, no solubility exists, and separate domain phases often manage rate of release. Another possible factor is the rate of mass transfer from inclusions to the surface of the matrix. Yet another possible factor is the rate of diffusion of the agent from the matrix into a body fluid, such as tear liquid.

A rate of release of the therapeutic agent at therapeutic quantities can be determined at least in part by a concentration of therapeutic agent in the matrix of the drug core. The therapeutic agent can be capable of sufficiently dissolving into the matrix from the inclusions, if present, so as to maintain the concentration of therapeutic agent dissolved in the matrix such that the rate of release is within a therapeutic window for the extended period. This can lead to a desirable zero order rate of release of the agent, as substantial reservoirs of the agent are present in the inclusions, while the limited solubility of the agent in the matrix is rate-determining in bringing the agent to the exposed surface of the core, where it can be released in tear fluids or other media. In embodiments wherein the agent is insoluble and forms inclusions in the matrix material, the rate of release of the agent into the body tissue or fluid can be determined at least in part by the concentration of the agent as it diffuses from the inclusions through separate domains in the matrix material to the point of exposure to the body tissue or fluid.

In various embodiment, the matrix includes a release rate varying material in a quantity sufficient to release the therapeutic agent from the drug core at the therapeutic quantities for an extended period when implanted for use. The release rate modifying material can include an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof. For example, the core can include a surfactant or a dispersant material, or a filler, an oligomer, another polymer, or the like, in addition to the one or more drugs and the polymeric matrix material. Examples include polymers such as polyethyleneglycols (PEGs), sodium alginate, low molecular weight silicones or polyurethanes, etc. Non-polymeric additives can include hydrophilic solvents such as ethylene glycol or glycerol.

In various embodiments, the core comprises from about 5% to about 50% of the drug. Depending on the drug, and the rate of release of the drug from the polymer selected for the matrix, the concentration can control the period of time over which therapeutic quantities of the drug are released into body fluid, such as tear liquid.

In various embodiments, as discussed above, the core can include two or more drugs. In certain embodiments, both drugs are substantially soluble in the matrix material. In other embodiments, a first drug is substantially soluble in the matrix material and a second drug forms inclusions within the matrix material. In some embodiments, the implant comprise a single drug core with two therapeutic agents mixed within a matrix. In other embodiments, the implant comprise two drug cores, each with a single therapeutic agent.

In some embodiments, the second drug can be a counteractive agent to avoid a side effect of the first therapeutic agent. In one example, the first drug can be a cycloplegic drug, i.e., one that blocks accommodation (focusing) of the eye, e.g., atropine or scopolamine, and the second therapeutic agent cab be at least one of an anti-glaucoma drug or a miotic drug, selected to reduce the known glaucoma-inducing side effect of cycloplegic drugs or to cause pupil contraction counteracting the known mydriatic effects of atropine or scopolamine. The anti-glaucoma drug may comprise at least one of a sympathomimetic, a parasympathomimetic, a beta blocking agent, a carbonic anhydrase inhibitor, or prostaglandin analogue. In another example, the first therapeutic agent may be a steroid and the second therapeutic agent may be an antibiotic, wherein the steroids compromise the immune response, but the antibiotics provides protection against infection. In another example, the first therapeutic agent may be pilocarpine and the second therapeutic agent may be non-steroidal anti-inflammatory drug (NSAID). An analgesic may be a good compliment for the treatment.

In specific embodiments, the core insert comprises a single drug-matrix composite having two drugs contained therein. In other embodiments, the core insert comprises two separate drug-matrix composites (“subcores” or first and second cores), disposed adjacent to each other within the sheath. The two separate composites can be disposed in a concentric spatial configuration, in a sector configuration, or otherwise, provided that exposed surfaces of both composites are exposed to body tissue or fluid when disposed within the body tissue, cavity, or duct of the patient.

In some embodiments the therapeutic agents can be released with a profile that corresponds to a kinetic order of therapeutic agents release and the order can be within a range from about zero to about one. In specific embodiments, the range is from about zero to about one half, for example from about zero to about one quarter. The therapeutic agents may be released with a profile that corresponds to a kinetic order of therapeutic agents release and the order is within a range from about zero to about one half for at least about a month after the structure is inserted, for example the order can be within the range at least about 3 months after the structure is inserted.

In various embodiments, the filled precursor sheath can be adapted to provide any of the above-discussed drug inserts by division of the filled precursor sheath. In various embodiments, the precursor sheath can be divided by cutting with a blade or with a laser, or the like.

In various embodiments, an exposed surface of the drug core contained within the implant is capable of releasing the therapeutic quantities into at least one of a sclera, a cornea or a vitreous when disposed in or adjacent to the eye of the patient. For example, the implant can be a punctal plug adapted for disposition within a punctum of a patient for release of the agent into tear liquid.

In various embodiments of the inventive methods described above, the mixture can further comprise a solvent in which the matrix precursor and the agent are soluble, and curing can comprise at least partial removal of the solvent following injection into the sheath body or precursor sheath body respectively. Curing can involve heating, vacuum treatment, or both. The solvent can be a hydrocarbon, an ester, a halocarbon, an alcohol, an amide, or a combination thereof. For example, when the agent is cyclosporine, the solvent can be a halocarbon.

In various embodiments, curing the mixture can comprise heating the mixture to a temperature, at a relative humidity, for a period of time. For example, the temperature can include a range from about 20 degrees C. to about 100 degrees C., the relative humidity can include a range from about 40% to about 100%, and the period of time can include a range from about 1 minute to about 48 hours. More specifically, the temperature can be at least about 40° C., the relative humidity can be at least about 80%, or both. In various embodiments, curing can include a step of polymerization or cross-linking, or both, of the matrix, the matrix precursor, or both. For example, polymerization or cross-linking, or both, can be carried out in the presence of a catalyst. For instance, the catalyst can be a tin compound or a platinum compound, such as a platinum with vinyl hydride catalyst system or a tin with alkoxy catalyst system.

In various embodiments, the mixture can be prepared by a method comprising sonication. The matrix precursor and the agent can be mixed to provide a thoroughly dispersed emulsion-like composite, wherein the agent, if insoluble or slightly soluble in the matrix precursor, is dispersed in small particles or droplets.

In various embodiments, the step of injecting the mixture into the sheath can be carried out under a pressure of at least about 40 psi. The mixture can be injected such that the sheath body or precursor sheath body, respectively, is filled at a rate of no greater than about 0.5 cm/sec.

The injection or extrusion of the mixture including the agent and the matrix precursor or matrix can be carried out at room temperature (20° C.), or above room temperature, or can be carried out at subambient temperatures of less than 20° C. For example, the injection can be carried out wherein the subambient temperature comprises a temperature of about −50° C. to about 20° C., or wherein the subambient temperature comprises a temperature of about −20° C. to about 0° C.

As discussed below,FIGS. 15 and 16 provide graphical evidence of the advantages of subambient extrusion, both in terms of uniformity of inclusion diameter, and in terms of uniformity of distribution of the therapeutic agent throughout the length of a filled precursor sheath.FIG. 15 shows electron micrographs of cryogenically section portions of a drug core wherein the extrusion was carried out at various temperatures. As can be seen, the average diameter of the included droplets of latanoprost is smaller when the extrusion is carried out at 0° C. or −25° C. than when the extrusion is carried out at 25° C. or at 40° C.

In a parallel experiment, described in Examples 12 and 13, average inclusion diameters, and diameter size distributions, were determined for extrusions carried out at room temperature and at −5° C. for a latanoprost—silicone mixture:

Cold extrusion (−5° C.): 0.006±0.002 mm (n=40 inclusion),
Room temp (22° C.): 0.019±0.019 mm (n=40 inclusion),
showing that the cold extrusion technique produced inclusions of smaller average diameter and of more uniform size than when the extrusion was carried out at ambient temperature.

FIG. 16 shows graphically the content of latanoprost in a 10 cm precursor sheath filled with the latanoprost-silicone mixture, as discussed in Examples 12 and 13. As can be seen, cold extrusion at −25° C. and 0° C. (squares) unexpectedly produced a more uniform distribution of therapeutic agent latanoprost in the silicone matrix, after curing, along the entire length of the 10 cm precursor sheath, which was subsequently divided into 1 mm sections, and the latanoprost content of each sections (drug insert) determined. Extrusions carried out at room temperature (circles) and at 40° C. (triangles) were significantly more variable. The results are significant in terms of manufacturing medically useful devices, as it is desirable to maintain a uniform content of the therapeutic agent among a plurality of drug inserts manufactured by this method.

In various embodiments, each drug insert can be sealed at one end thereof, the second end thereby providing the exposed surface for release of the agent when the insert is disposed within an implant and inserted into a patient. Each drug insert can be sealed at one end thereof using a UV-curable adhesive, a cyanoacrylate, an epoxy, by pinching, with a heat weld, or with a cap. When a UV-curable adhesive is used, curing is carried out by irradiation with UV light.

In various embodiments, the inventive methods further comprise, after sealing one end thereof, inserting each drug insert into a channel of a respective implant body adapted to receive the insert therein.

In various embodiments, when the drug core comprises two drug cores, a first drug core comprising a first agent and a first matrix, and a second drug core comprising a second agent and a second matrix, wherein the first agent and the second agent are different, and wherein the first matrix and the second matrix are either the same or differ from each other, the implant body comprising an aperture adapted to receive the drug insert comprising the first and the second drug cores, the method can further comprise disposing the drug cores within the insert prior to disposing the insert comprising the drug cores within the aperture of the implant body.

In various embodiments, where the therapeutic agent comprises cyclosporine or olopatadine, a prodrug or a derivative of cyclosporine or olopatadine or any combination thereof, the matrix includes polyurethane, and a weight ratio of the cyclosporine or the olopatadine or the cyclosporine prodrug or derivative, or the olopatadine prodrug or derivative, or the combination thereof, to the polyurethane polymer or copolymer is about 1 wt % to about 70 wt %, the method can include forming the mixture by melting and mixing the polyurethane polymer or copolymer and the therapeutic agent. The therapeutic agent can be in molten form in the mixture, or can be in solid form in the mixture.

In some embodiments, the matrix comprises an inert filler material mixed with the therapeutic agent such that the exposed surface releases the therapeutic agent at therapeutic quantities for a sustained period of time.

In some embodiments, a salt is mixed with the matrix precursor such that the exposed surface of the matrix, after curing, releases the therapeutic agent at therapeutic quantities for a sustained period of time.

In some embodiments, a surfactant is mixed with the matrix precursor such that the exposed surface of the matrix, after curing, releases the therapeutic agent at therapeutic quantities for a sustained period of time.

In some embodiments a second polymer or an oligomer is mixed with the matrix precursor, and after curing to form the matrix, the presence of the second polymer or oligomer can serve to vary the rate of release of the therapeutic agent.

Various embodiments of the invention provide a punctum plug for insertion into a punctal canal of a patient, the plug comprising a drug core having a distal end and a proximal end, at least the distal end of the drug core having a cross section suitable for insertion through a punctum, the drug core comprising a polyurethane polymer or copolymer comprising a therapeutic agent deliverable into the eye or surrounding tissues; and a substantially impermeable sheath disposed over a portion of the drug core to define at least one exposed surface of the drug core, at least one exposed surface of the drug core being located near the proximal end to contact a tear or tear film fluid of a patient and release the therapeutic agent at therapeutic levels over a sustained period when the plug is implanted for use within the punctal canal of the patient. The inventive plug includes a core, in which the therapeutic agent is contained, that is formed from a polyurethane polymer or copolymer. The polyurethane polymer or copolymer of the core can be an aliphatic polyurethane, an aromatic polyurethane, a polyurethane hydrogel-forming material, a hydrophilic polyurethane, or a combination thereof. For example, the core can be formed of the polyurethane hydrogel-forming material TG-500 or TG-2000 aliphatic, polyether based thermoplastic polyurethanes capable of forming hydrogels. Such hydrogel-forming polymers can absorb greater than 100 wt %, for example up to 500-2000 wt % of water, and consequently swell in physical dimensions. Alternatively, the core can be formed of a hydrophilic polyurethane such as Pursil, which swells much less, to the extent of about 20-100%, upon contact with an aqueous medium. Other examples include Lubrizol products including Tecophilic grades such as HP-60D20, HP-60D35, HP-60D60, or HP-93A100.

In various embodiments, the therapeutic agent can comprise cyclosporine, or a prodrug or a derivative of cyclosporine. Cyclosporine, as is well-known in the art, is an immunomodulator, and can be used in the treatment of dry eye and inflammations of the eye, such as those resulting from an allergic response. The weight ratio of the cyclosporine or the cyclosporine prodrug or derivative, respectively, to the polyurethane polymer or copolymer can be about 1 wt % up to as high as about 70 wt %, or even greater. The rate of the release of the cyclosporine, or its prodrug or derivative, can be controlled by selection of the specific kind of polyurethane for the core and by modulating the polarity (hydrophobicity/hydrophilicity) of the therapeutic agent. Cyclosporine is a rather hydrophobic compound, but can be rendered more hydrophilic by incorporation of functional groups, such as groups that can be cleaved in vivo by endogenous enzymes like esterases, wherein the functional groups incorporated have hydrophilic moieties included.

In various embodiments, the therapeutic agent can be olopatidine, or a prodrug or a derivative of olopatidine. For instance, the agent can be olopatidine hydrochloride, also known as patanol. Used to treat allergic conjunctivitis (itching eyes), olopatadine inhibits the release of histamine from mast cells. It is a relatively selective histamine H1 antagonist that inhibits the in vivo and in vitro type I immediate hypersensitivity reaction including inhibition of histamine induced effects on human conjunctival epithelial cells.

The plug further includes a substantially impermeable sheath, to limit the zone or region of release of the therapeutic agent to the at least one exposed surface of the drug core, disposed immediately adjacent to the punctum of the eye such that the therapeutic agent is readily contacted by tear fluid and can thus diffuse over the surface of the eye. For example, cyclosporine can be released into the tear fluid to assist in treatment of the eye for dryness or for inflammation, such as caused by an allergic reaction. The sheath can also be adapted to provide a second exposed surface of the drug core is located near the distal end of the plug to release the therapeutic agent into the punctal canal, if such is desired. For example, a second therapeutic agent can be included, such as an antibiotic for treatment of infections of the punctal canal.

The sheath can be of sufficient elasticity or flexibility that when the core is adapted to swell when in contact with an aqueous medium, such as when the core is constructed of a hydrophilic or hydrogel-forming polyurethane polymer or copolymer, that the sheath can expand in response to the swelling of the hydrophilic or hydrogel-forming polyurethane polymer or copolymer. The swelling is adapted to assist in retaining the plug within the punctal canal.

The core can further contain a second bioactive agent, such as are listed below, such as for treatment of a secondary condition or to assist in treatment of the condition, for example, for which administration of cyclosporine or olopatidine, or both, is medically indicated.

The lacrimal implant can be any suitable shape adapted for insertion into the punctal canal of the eye. For example, the implant can be substantially cylindrical at the time of insertion into the canal, prior to swelling of any hydrogel-forming core of the plug. Or, the implant can be of a conical shape, or can be bent in the form of an “L”, or can have any other shape which can be disposed within the punctal canal of a patient's eye such that the therapeutic agent can be released from the core into the tear fluid bathing the eye. Accordingly, the core of the implant, when the implant is disposed within the punctal canal, has access to the opening of the punctum such that the agent can diffuse into the tear fluid and thereby bathe the eye surface. In various embodiments, the core has access to the interior of the punctal canal for release of the agent thereto.

For example, the implant can be a shape termed the “bent-design” as disclosed in a patent application filed concurrently with this application. Or, the implant can be a design referred to as the “H-design”, as disclosed in a patent application filed concurrently with this application. Or, the implant can be what is termed the “skeleton” design as disclosed in a patent application filed concurrently with this application.

In various embodiments, a method of manufacture of the inventive implant, comprising melting and mixing the polyurethane polymer or copolymer and adding the therapeutic agent to form a mixed melt, then, either casting the mixed melt within the sheath, or, casting the mixed melt to form the core, then disposing the sheath around the core, is provided.

The polyurethane selected to form the core of the implant can be thermoplastic such that the implant can be manufactured by a melt extrusion or casting process. For example, a melt of the core polyurethane can be prepared and the therapeutic agent can be incorporated therein. In various embodiments, the agent can melt at a temperature around the melting point of a suitable polyurethane polymer or copolymer, and the agent can itself be incorporated in a molten state, provided the melting point is at a temperature at or below the decomposition temperature of the polyurethane, and the melting point of the polyurethane is below a temperature at which the agent undergoes significant thermal decomposition. For example, cyclosporine melts at about 135° C., while TG-500 melts at about 170° C. and TG-2000 melts at about 115° C. Thus, a mixed melt can be prepared at about 135° C., or higher with TG-2000 wherein both the cyclosporine and the polyurethane core material are both in a molten state. A higher melting material like TG-500 can be used when the cyclosporine is stable for the time period it is held at the elevated temperate in the process used.

In various embodiments, the agent does not melt in the molten polyurethane, but is dispersed as a solid, which in be in the form of a fine powder, such as a microparticulate form. For example, olopatidine, which melts in excess of 200° C., can be dispersed in solid form in a melt of a polyurethane. The polyurethane melt containing the solid agent is then cast, optionally within a sheath, to provide the inventive plug.

Thus, melt mixing processes can be cast to form an inventive implant. For example, the mixed melt can be cast into a mold already lined with a higher melting sheath material, which can be a polyurethane that is not substantially permeable to diffusion of the cyclosporine. In this way the sheathed implant can be prepared. Alternatively, the core can be case in a mold, then the sheath material coated or cast on the surface of the implant, except for regions where the core material is to be left exposed. Or, the sheath material can be cast to cover the entire implant, then a portion removed to expose the core material in at least one location near the proximal end, where the cyclosporine can readily come into contact with tear fluid and thereby diffuse into the eye.

In various embodiments, a method of manufacture of the inventive implant, comprising dissolving the polyurethane polymer or copolymer and mixing in the therapeutic agent in a solvent to form a mixed solution, then, either casting the mixed solution within the sheath, then removing the solvent, or, casting the mixed solution to form the core, then removing the solvent, then disposing the sheath around the core, is provided.

The polyurethane selected to form the core of the implant can be soluble in an organic solvent, such as dichloromethane or tetrahydrofuran. Many therapeutic agent, for example, cyclosporine, are also soluble in many organic solvents, including dichloromethane or tetrahydrofuran. In this way a mixed solution can be prepared. This solution can then be used to cast the core of the implant, with removal of the solvent. The solvent can be removed by evaporation, which can be carried out under ambient conditions, or can involve the application of heat, reduced atmospheric pressure, or both. After removal of the solvent, the sheath can be coated or cast around the core, either leaving an exposed section of the core, or removing a portion of the sheath to provide an exposed section.

In various embodiments, a method of manufacture of an inventive implant comprises dissolving the polyurethane polymer or copolymer in a solvent, then adding a therapeutic agent in solid form, the agent being substantially insoluble in the solvent, then removing the solvent to cast the core. The solid form of the agent can be a fine powder, such as a microparticulate form, to provide for a favorable surface area/mass ratio. In various embodiments the implant comprises a dispersion of a solid form of the agent in the polyurethane polymer or copolymer.

The polyurethane polymer or copolymer making up the core can be an aliphatic polyurethane, an aromatic polyurethane, a polyurethane hydrogel-forming material, a hydrophilic polyurethane, or a combination thereof. The particular polyurethane used for the therapeutic agent can be selected to control the release profile of the agent over time.

The inventive implant can be used to treat a malcondition of the eye or of surrounding tissue. For example, the implant incorporating cyclosporine or olopatidine, or both, can be used to treat an eye malcondition involving dry eye or eye inflammation. The therapeutic agent can be released into the eye, as well as into surrounding tissue such as the interior of the punctal canal, over a period of time. The period of time can be about 1 week to about 6 months. When a swelling polyurethane is used, the swelling of the implant can be used to secure the plug within the punctal canal for the full time period over which the drug is adapted to be released.

In various embodiments, the invention provides a drug insert adapted for disposition within an punctal plug for providing sustained release of a latanoprost to the eye for treatment of glaucoma, the insert comprising a core and a sheath body partially covering the core, the core comprising the latanoprost and a matrix wherein the matrix comprises a silicone polymer, the latanoprost being dispersed within the silicone as droplets thereof, wherein an amount of the latanoprost in a volumetric portion of the drug core is similar to an amount of the latanoprost in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the core to inhibit release of the latanoprost from said portion, an exposed surface of the core not covered by the sheath body being adapted to release the latanoprost to the eye.

In various embodiments, the invention provides a drug insert adapted for disposition within an punctal plug for providing sustained release of a cyclosporine to the eye for treatment of dry eye or inflammation, the insert comprising a core and a sheath body partially covering the core, the core comprising the cyclosporine and a matrix wherein the matrix comprises a polyurethane polymer, the cyclosporine being dissolved within the polyurethane, wherein an amount of the cyclosporine in a volumetric portion of the drug core is similar to an amount of the cyclosporine in any other equal volumetric portion of the drug core, the sheath body being disposed over a portion of the core to inhibit release of the cyclosporine from said portion, an exposed surface of the core not covered by the sheath body being adapted to release the cyclosporine to the eye.

Discussion of the Figures

Drug core

110 is surrounded by asheath body120.Sheath body120 is can be substantially impermeable to the therapeutic agent, so that the therapeutic agent is often released from an exposed surface on an end ofdrug core110 that is not covered withsheath body120. Aretention structure130 is connected todrug core110 andsheath body120.Retention structure130 is shaped to retain the implant in a hollow tissue structure, for example, a punctum of a canaliculus as described above.

Anocclusive element140 is disposed on and aroundretention structure130.Occlusive element140 is impermeable to tear flow and occludes the hollow tissue structure and may also serve to protect tissues of the tissue structure fromretention structure130 by providing a more benign tissue-engaging surface.Sheath body120 includes asheath body portion150 that connects toretention structure130 to retainsheath body120 anddrug core110.Sheath body portion150 can include a stop to limit movement ofsheath body120 anddrug core110. In many embodiments,sheath body portion150 can be formed with abulbous tip150B.Bulbous tip150B can comprise a convex rounded external portion that provides atraumatic entry upon introduction into the canaliculus. In many embodiments,sheath body portion150B can be integral withocclusive element140.

FIG. 1B shows a side cross sectional view of the sustained release implant ofFIG. 1A.Drug core110 is cylindrical and shown with a circular cross-section.Sheath body120 comprises an annular portion disposed ondrug core110.Retention structure130 comprises several longitudinal struts131. Longitudinal struts131 are connected together near the ends of the retention structure. Although longitudinal struts are shown, circumferential struts can also be used.Occlusive element140 is supported by and disposed over longitudinal struts131 ofretention structure130 and may comprise a radially expandable membrane or the like.

FIG. 1C shows a perspective view of asustained release implant102 with acoil retention structure132, according to an embodiment of the present invention.Retention structure132 comprises a coil and retains adrug core112. A lumen, forexample channel112C, may extend through thedrug core112 to permit tear flow through the lumen for the delivery of therapeutic agent for nasal and systemic applications of the therapeutic agent. In addition or in combination withchannel112C,retention structure132 andcore112 can be sized to permit tear flow around the drug core and sheath body while the retention element holds tissue of the canaliculus away from the drug core.Drug core112 may be partially covered. The sheath body comprises afirst component122A that covers a first end ofdrug cove112 and asecond component122B that covers a second end of the drug core. An occlusive element can be placed over the retention structure and/or the retention structure can be dip coated as described above.

FIG. 1D shows a perspective view of asustained release implant104 with aretention structure134 comprising struts, according to an embodiment of the present invention.Retention structure134 comprises longitudinal struts and retains adrug core114.Drug core114 is covered with asheath body124 over most ofdrug core114. The drug core releases therapeutic agent through an exposed end andsheath body124 is annular over most of the drug core as described above. An occlusive element can be placed over the retention structure or the retention structure can be dip coated as described above. A protrusion that can be engaged with an instrument, for example a hook, a loop, a suture, orring124R, can extend fromsheath body124 to permit removal of the drug core and sheath body together so as to facilitate replacement of the sheath body and drug core while the retention structure remains implanted in the canaliculus. In some embodiments, a protrusion that can be engaged with an instrument comprising hook, a loop, a suture or a ring, can extend fromretention structure134 to permit removal of the sustained release implant by removing the retention structure with the protrusion, drug core and sheath body.

FIG. 1E shows a perspective view of asustained release implant106 with acage retention structure136, according to an embodiment of the present invention.Retention structure136 comprises several connected strands of metal and retains adrug core116.Drug core116 is covered with asheath body126 over most ofdrug core116. The drug core releases therapeutic agent through an exposed end andsheath body126 is annular over most of the drug core as described above. An occlusive element can be placed over the retention structure or the retention structure can be dip coated as described above.

FIG. 1F shows a perspective view of a sustained release implant comprising a core and sheath, according to an embodiment of the present invention.Drug core118 is covered with asheath body128 over most ofdrug core118. The drug core releases therapeutic agent through an exposed end andsheath body128 is annular over most of the drug core as described above. The rate of therapeutic agent release is controlled by the surface area of the exposed drug core and materials included withindrug core118. In many embodiments, the rate of elution of the therapeutic agent is strongly and substantially related to the exposed surface area of the drug core and weakly dependent on the concentration of drug disposed in the inclusions in the drug core. For circular exposed surfaces the rate of elution is strongly dependent on the diameter of the exposed surface, for example the diameter of an exposed drug core surface near an end of a cylindrical drug core. Such an implant can be implanted in ocular tissues, for example belowconjunctival tissue layer9 of the eye and either abovesclera tissue layer8, as shown inFIG. 1F, or only partially within the scleral tissue layer so as not to penetrate the scleral tissue. It should be noted thatdrug core118 can be used with any of the retention structures and occlusive elements as described herein.

In an embodiment, the drug core is implanted betweensclera8 andconjunctiva9 withoutsheath body128. In this embodiment without the sheath body, the physical characteristics of the drug core can be adjusted to compensate for the increased exposed surface of drug core, for example by reducing the concentration of dissolved therapeutic agent in the drug core matrix as described herein.

FIG. 1G schematically illustrates asustained release implant180 comprising a flow restrictingretention structure186, acore182 and asheath184, according to an embodiment of the present invention.Sheath body184 can at least partially coverdrug core182.Drug core182 may contain inclusions of the therapeutic agent therein to provide a sustained release of the therapeutic agent.Drug core182 can include an exposedconvex surface area182A. Exposedconvex surface area182A may provide an increased surface area to release the therapeutic agent. Anocclusive element188 can be disposed overretention structure186 to block the flow of tear through the canaliculus. In many embodiments,retention structure186 can be located withinocclusive structure188 to provide the occlusive element integrated with the retention structure. Flow restrictingretention structure186 andocclusive element188 can be sized to block tear flow through the canaliculus.

The cores and sheath bodies described herein can be implanted in a variety of tissues in several ways. Many of the cores and sheaths described herein, in particular the structures described with reference toFIGS. 2A to 2J can be implanted alone as punctal plugs. Alternatively, many of the cores and sheath bodies described herein can comprise a drug core, sheath body, and/or the like so as to be implanted with the retention structures and occlusive elements described herein.

FIG. 2A shows a cross sectional view of asustained release implant200 with core comprising an enlarged exposed surface area, according to an embodiment of the present invention. Adrug core210 is covered with asheath body220.Sheath body220 includes anopening220A.Opening220 has a diameter that approximates the maximum cross sectional diameter ofdrug core210.Drug core210 includes an exposedsurface210E, also referred to as an active surface. Exposedsurface210E includes 3 surfaces: anannular surface210A, acylindrical surface210B and anend surface210C.Annular surface210A has an outer diameter that approximates the maximum cross sectional diameter ofcore210 and an inner diameter that approximates the outer diameter ofcylindrical surface210B.End surface210C has a diameter that matches the diameter ofcylindrical surface210B. The surface area of exposedsurface210E is the sum of the areas ofannular surface210A,cylindrical surface210B andend surface210C. The surface area may be increased by the size ofcylindrical surface area210B that extends longitudinally along an axis ofcore210.

FIG. 2B shows a cross sectional view of asustained release implant202 with acore212 comprising an enlarged exposedsurface area212A, according to an embodiment of the present invention. Asheath body222 extends overcore212. The treatment agent can be released from the core as described above. Exposedsurface area212A is approximately conical, can be ellipsoidal or spherical, and extends outward from the sheath body to increase the exposed surface area ofdrug core212.

FIGS. 2C and 2D show perspective and cross sectional views, respectively, of asustained release implant204 with adrug core214 comprising a reduced exposedsurface area214A, according to an embodiment of the present invention.Drug core214 is enclosed within asheath body224. Sheath body22 includes anannular end portion224A that defines an opening through whichdrug core214 extends.Drug core214 includes an exposedsurface214A that releases the therapeutic agent. Exposedsurface214A has adiameter214D that is less than a maximum dimension, for example a maximum diameter, acrossdrug core214.

FIG. 2E shows a cross sectional view of asustained release implant206 with adrug core216 comprising an enlarged exposedsurface area216A with castellation extending therefrom, according to an embodiment of the present invention. The castellation includes several spaced apartfingers216F to provide increased surface area of the exposedsurface216A. In addition to increased surface area provided by castellation,drug core216 may also include anindentation216I.Indentation216I may have the shape of an inverted cone.Core216 is covered with asheath body226.Sheath body226 is open on one end to provide an exposedsurface216A ondrug core216.Sheath body226 also includes fingers and has a castellation pattern that matchescore216.

FIG. 2F shows a perspective view of asustained release implant250 comprising a core with folds, according to an embodiment of the present invention.Implant250 includes acore260 and asheath body270.Core260 has an exposedsurface260A on the end of the core that permits drug migration to the surrounding tear or tear film fluid.Core260 also includesfolds260F.Folds260F increase the surface area of core that is exposed to the surrounding fluid tear or tear film fluid. With this increase in exposed surface area, folds260F increase migration of the therapeutic agent fromcore260 into the tear or tear film fluid and target treatment area.Folds260F are formed so that achannel260C is formed incore260.Channel260C connects to the end of the core to an opening in exposedsurface260A and provides for the migration of treatment agent. Thus, the total exposed surface area ofcore260 includes exposedsurface260A that is directly exposed to the tear or tear film fluid and the surfaces offolds260F that are exposed to the tear or tear film fluids via connection ofchannel260C with exposedsurface260A and the tear or tear film fluid.

FIG. 2G shows a perspective view of a sustained release implant with a core comprising a channel with an internal surface, according to an embodiment of the present invention.Implant252 includes acore262 andsheath body272.Core262 has an exposedsurface262A on the end of the core that permits drug migration to the surrounding tear or tear film fluid.Core262 also includes a channel262C. Channel262C increases the surface area of the channel with an internal surface262P formed on the inside of the channel against the core. In some embodiment, the internal exposed surface may also be porous. Channel262C extends to the end of the core near exposedsurface262A of the core. The surface area of core that is exposed to the surrounding tear or tear film fluid can include the inside ofcore262 that is exposed to channel262C. This increase in exposed surface area can increase migration of the therapeutic agent fromcore262 into the tear or tear film fluid and target treatment area. Thus, the total exposed surface area ofcore262 can include exposedsurface260A that is directly exposed to the tear or tear film fluid and internal surface262P that is exposed to the tear or tear film fluids via connection of channel262C with exposedsurface262A and the tear or tear film fluid.

FIG. 2I shows a perspective view of asustained release implant256 with adrug core266 comprising a convex exposedsurface266A, according to an embodiment of the present invention.Drug core266 is partially covered with asheath body276 that extends at least partially overdrug core266 to define convex exposedsurface266A.Sheath body276 comprises ashaft portion276S. Convex exposedsurface266A provides an increased exposed surface area above the sheath body. A cross sectional area of convex exposedsurface266A is larger than a cross sectional area ofshaft portion276S ofsheath body276. In addition to the larger cross sectional area, convex exposedsurface266A has a larger surface area due to the convex shape which extends outward from the core.Sheath body276 comprisesseveral fingers276F that supportdrug core266 in the sheath body and provide support to the drug core to holddrug core266 in place insheath body276.Fingers276F are spaced apart to permit drug migration from the core to the tear or tear film fluid between the fingers.Protrusions276P extend outward onsheath body276.Protrusions276P can be pressed inward to ejectdrug core266 fromsheath body276.Drug core266 can be replaced with another drug core after an appropriate time, for example afterdrug core266 has released most of the therapeutic agent.

FIG. 2J shows a side view of asustained release implant258 with acore268 comprising an exposed surface area with several soft brush-like members268F, according to an embodiment of the present invention.Drug core268 is partially covered with asheath body278 that extends at least partially overdrug core268 to define exposedsurface268A.Sheath body278 comprises ashaft portion278S. Soft brush-like members268F extend outward fromdrug core268 and provide an increased exposed surface area todrug core268. Soft brush-like members268F are also soft and resilient and easily deflected such that these members do not cause irritation to neighboring tissue. Althoughdrug core268 can be made of many materials as explained above, silicone is a suitable material for the manufacture ofdrug core268 also comprises soft brush likemembers268F. Exposedsurface268A ofdrug core268 also includes anindentation2681 such that at least a portion of exposedsurface268A is concave.

FIG. 2K shows a side view of asustained release implant259 with adrug core269 comprising a convex exposedsurface269A, according to an embodiment of the present invention.Drug core269 is partially covered with asheath body279 that extends at least partially overdrug core269 to define convex exposedsurface269A.Sheath body279 comprises ashaft portion279S. Convex exposedsurface269 provides an increased exposed surface area above the sheath body. A cross sectional area of convex exposedsurface269A is larger than a cross sectional area ofshaft portion279S ofsheath body279. In addition to the larger cross sectional area, convex exposedsurface269A has a larger surface area due to the convex shape that extends outward on the core. Aretention structure289 can be attached tosheath body279.Retention structure289 can comprise any of the retention structures as describe herein, for example a coil comprising a super elastic shape memory alloy such as Nitinol™.Retention structure289 can be dip coated to makeretention structure289 biocompatible.

FIG. 2L shows a side view of asustained release implant230 with adrug core232 comprising a concaveindented surface232A to increase exposed surface area of the core, according to an embodiment of the present invention. Asheath body234 extends at least partially overdrug core232. Concaveindented surface232A is formed on an exposed end ofdrug core232 to provide an increased exposed surface area of the drug core.

FIG. 2M shows a side view of asustained release implant240 with adrug core242 comprising aconcave surface242A with achannel242C formed therein to increase an exposed surface area of the core, according to an embodiment of the present invention. Asheath body244 extends at least partially overdrug core242. Concaveindented surface242A is formed on an exposed end ofdrug core232 to provide an increased exposed surface area of the drug core.Channel242C formed indrug core242 to provide an increased exposed surface area of the drug core.Channel242C can extend to concaveindented surface242A such thatchannel242C and provide an increase in surface area of the core exposed to the tear or tear film.

Referring now toFIGS. 3A and 3B an implant, for example apunctal plug300, is shown which comprises asilicone body310, adrug core320 and aretention structures330, according to embodiments of the present invention.Body310 comprises aproximal channel314 sized to receivedrug core insert320.Body310 comprises adistal channel318.Distal channel318 can be sized to receive ahydrogel rod332. Apartition319 may separate the proximal channel from the distal channel. Afilament334 can be embedded inbody310 and wrapped aroundhydrogel rod332 to affixhydrogel rod332 tobody310.

Drug core insert

320 may comprise asheath322, which is substantially impermeable to the drug so as to direct the drug toward an exposedsurface326 of the drug core.Drug core320 may comprises asilicone matrix328 withinclusions324 of the drug encapsulated therein. The drug core insert and manufacture of the drug core insert are described in U.S. application Ser. Nos. 11/695,537 and 11/695,545, the full disclosures of which are incorporated herein by reference. In some embodiments,body310 may comprise an annular rim315 near exposedsurface326, that extends intoproximal channel314 and presses onsheath body322 so as to indent the sheath body and decrease the exposed surface area of the drug core near the proximal end of the body. In some embodiments, optional annular rim315 may press on the sheath body to retain the drug core in the channel without indentation of the sheath body.

Retention structures

330 may comprisehydrogel rod332,hydrogel coating336,protrusions312 andprotrusion316.Hydrogel rod332 can be inserted through the punctum into a canalicular lumen in a narrow profile configuration. After insertion into thelumen hydrogel rod332 andhydrogel coating336 can hydrate and expand to a wide profile configuration.Protrusions312 andprotrusion316 can retain and/or stabilizeimplant300 in the lumen, for example while the hydrogel coating and rod expand.

FIG. 3C shows insertion ofpunctal plug300 as inFIG. 3A into an upper canaliculus of an eye.Punctal plug300 can be oriented withhydrogel rod332 aligned for placement in the upper canaliculus.Punctal plug300 can be advanced intovertical portion10V of the canaliculus such that the exposed surface of the drug core and proximal end of the implant are substantially aligned with the exterior of the punctal opening.

FIG. 3D shows a punctal plug as inFIG. 3A in an expanded profile configuration following implantation in the canaliculus of the eye.Hydrogel rod332 andhydrogel coating336 are shown in an expanded profile configuration.

Sheath body

410 is sized to fit within a channel of an implant. The distal end ofdrug core insert404 can be inserted into the implant such that exposedsurface422 remains exposed when the drug core insert is inserted into the implant.FIG. 4B shows an example ofimplant450 suitable for use with adrug core insert400 as inFIG. 4A, according to embodiments of the present invention.Implant450 comprises a proximal452 and adistal end454.Implant450 comprises aretention structure460 that includes an indentation to retainimplant450 in the punctum of the eye.Implant450 comprises achannel456 that extends from within the implant to an opening formedproximal end452.Channel456 can be sized to receivedrug core insert400.Drug core insert400 can be inserted intochannel456 such thatdistal end404 ofdrug core insert400 is embedded withinimplant450 whileproximal end402 comprisingsurface422 is exposed. Whenimplant450 is placed in the punctum,surface422 is exposed to the tear fluid of the eye such that the therapeutic agent can be delivered to the eye. In many embodiments, the punctual plug has a length of about 2 mm and a width of about 1 mm.

Many implants can be used withdrug core insert400. Some embodiments can employ a commercially available implant, for example the Soft Plug silicone punctum plug commercially Oasis Medical of Glendora Calif., the Tear Pool Punctal Plug commercially available form Medtronic, the “Parasol Punctal Occluder System” available from Odyssey of Memphis, Tenn., and/or the Eagle Vision Plug available from Eagle Vision of Memphis, Tenn. In some embodiments, the punctual plug may comprise a custom punctual plug, for example sized custom plugs that are selected in response to patient measurements. In some embodiments, the implant used with the drug core insert may comprise implants as described in U.S. application Ser. No. 11/695,537, filed on Apr. 2, 2007, entitled “DRUG DELIVERY METHODS, STRUCTURES, AND COMPOSITIONS FOR NASOLACRIMAL SYSTEM” (attorney docket no. SLW 2755.001US1); Ser. No. 11/695,545, filed on Apr. 2, 2007, entitled “NASOLACRIMAL DRAINAGE SYSTEM IMPLANTS FOR DRUG THERAPY” (attorney docket no. SLW 2755.003US1); 60/871,867, filed on Dec. 26, 2006, entitled “DRUG DELIVERY IMPLANTS FOR INHIBITION OF OPTICAL DEFECTS” (attorney docket no. 2755.024PRV), the priority of which was claimed in PCT application no. PCT/US2007/088701; and Ser. No. 10/825,047, filed Apr. 15, 2004, entitled “DRUG DELIVERY VIA PUNCTAL PLUG,” (attorney docket no. SLW 2755.025US1); the full disclosures of which are all incorporated herein by reference.

In some embodiments, such as shown inFIG. 36 and discussed in U.S. patent application Ser. No. ______, filed herewith (attorney docket no. SLW 2755.044US1), entitled “LACRIMAL IMPLANTS AND RELATED METHODS,” the implant can be insertable through a lacrimal punctum and into the associated canaliculus. The insertion of the implant through the lacrimal punctum and into the associated canaliculus can allow for one or more of: inhibition or blockage of tear flow therethrough (e.g., to treat dry eyes) or the sustained delivery of a drug or other therapeutic agent to an eye (e.g., to treat an infection, inflammation, glaucoma or other ocular disease or disorder), a nasal passage (e.g., to treat a sinus or allergy disorder) or an inner ear system (e.g., to treat dizziness or a migraine). The implant can comprise an implant body including first and second portions, and can extend from a proximal end of the first portion to a distal end of the second portion. In various examples, the proximal end can define a longitudinal proximal axis and the distal end can define a longitudinal distal axis. The implant body can be configured such that, when implanted within the lacrimal punctum and associated canaliculus, an at least 45 degree angled intersection exists between the proximal axis and the distal axis for biasing at least a portion of the implant body against at least a portion of a lacrimal canaliculus located at or more distal to a canaliculus curvature. In some examples, the implant body can be configured such that the angled intersection is between about 45 degrees and about 135 degrees. In this example, the implant body is configured such that the angled intersection is about 90 degrees (i.e., the intersection is about perpendicular). In various examples, a distal end of the first portion can be integral with the second portion at or near a proximal end of the second portion.

In certain examples, the implant body can include angularly disposed cylindrical-like structures comprising one or both of a first cavity disposed near the proximal end or a second cavity disposed near the distal end. In this example, the first cavity extends inward from the proximal end of the first portion, and the second cavity extends inward from the distal end of the second portion. A first drug-releasing or other agent-releasing drug core insert can be disposed in the first cavity to provide a sustained drug or other therapeutic agent release to an eye, while a second drug core insert can be disposed in the second cavity to provide a sustained drug or other therapeutic agent release to a nasal passage or inner ear system, for example. An implant body septum can be positioned between the first cavity and the second cavity, and can be used to inhibit or prevent communication of a material (e.g., agent) between the first drug core insert and the second drug core insert. In some examples, the implant body is solid and does not include one or more cavities or other voids.

FIG. 4C shows an annulardrug core insert470 suitable for use with an implant for systemic delivery of a therapeutic agent.Drug core insert470 comprises asheath body472 which is substantially impermeable to the therapeutic agent so as to inhibit flow of the therapeutic agent through the sheath body.Drug core insert470 comprises asolid drug core474.Drug core474 comprises a matrix material with inclusions of the therapeutic agent dispersed therein, as described above.Drug core474 comprises an exposedsurface478.Drug core474 comprises a generally annular shape with achannel476 formed therein, such that exposedsurface478 is inwardly directed and exposed to bodily fluids in the channel, for example the tear liquid when implanted in the channel. Therapeutic quantities, or levels, of the therapeutic agent can be released from inner exposedsurface478 to the bodily fluid within the channel.

FIG. 4D shows an ofimplant480 suitable for use with a drug core insert as inFIG. 4C.Implant480 comprises abody484, for example a molded silicone body, andretention structures482. Achannel486 withinbody484 is sized to receivedrug core insert470.Implant480 may comprise ahydrogel coating488 on the outside.Hydrogel coating488 may be located nearretention structure488. In some embodiments,hydrogel coating488 may be located away from the ends ofimplant480, such that the hydrogel does not inhibit flow throughchannel476 of the drug core insert when implanted in the patient. In some embodiments, the retention structure may comprise an expandable coil or stent like structure with a proximal portion embedded inbody484 and an exposed distal portion that expands to permit flow through the coil between the punctum and lacrimal sac, for example a shape memory capable of expansion to anchor the implant in the canaliculus.

FIGS. 4E and 4F show a side cross-sectional view and an end view, respectively, of adrug core insert490 comprising afirst drug core494 and asecond drug core496.First drug core494 comprisesinclusions494I of a first therapeutic agent, andsecond drug core496 comprises inclusions496I of a second therapeutic agent. Therapeutic quantities of the first therapeutic agent are released through an exposedsurface494S offirst drug core494, and therapeutic quantities of a second therapeutic agent are released through an exposedsurface496S ofsecond drug core496

Insert

490 comprises anouter sheath body492 arounddrug core496 and aninner sheath body498 disposed betweendrug core494 anddrug core496, so as to inhibit release of one drug core to the other drug core. Thesheath body492 andsheath body498 may comprise materials substantially impermeable to the therapeutic agent, so as to inhibit release of the therapeutic agent away from the exposed surfaces. In some embodiments, the sheath bodies may comprise thin walled tubes.

In some embodiments, the drug core insert can be used with an implant for insertion in tissues in or near the eye, for example the sclera, the conjunctiva, the cul-de-sac of the eyelid, the trabecular meshwork, the ciliary body, the cornea, the choroid, the suprachoroidal space, the sclera, the vitreous humor, aqueous humor and retina.

In some embodiments, the drug core insert can be manufactured with a structure to facilitate removal of the drug core insert, for example a filament as described in U.S. App. Nos. 60/970,696, filed on Sep. 7, 2007, and 60/974,367 filed on Sep. 21, 2007 entitled “EXPANDABLE NASOLACRIMAL DRAINAGE SYSTEM IMPLANTS”, (attorney docket no. SLW 2755.004PRV and 2755.005PRV respectively), the priorities of which are claimed in U.S. application Ser. No. ______, filed concurrently herewith; the full disclosures of which are all incorporated herein by reference.

FIGS. 5A to 5C schematically illustrate replacement of adrug core510 and asheath body520, according to an embodiment of the present invention. Animplant500 comprisesdrug core510,sheath body520 and aretention structure530.Implant500 can include an occlusive element support by and movable withretention structure530. Oftenretention structure530 can assume a first small profile configuration prior to implantation and a second large profile configuration while implanted.Retention structure530 is shown in the large profile configuration and implanted in the canalicular lumen.Sheath body520 includesextension525A andextension525B to attach the sheath body and drug core toretention structure530 so that the sheath body and drug core are retained byretention structure530.Drug core510 andsheath body520 can be removed together by drawingdrug core510 proximally as shown byarrow530.Retention structure530 can remain implanted in the canalicular tissue afterdrug core510 andsheath body520 have been removed as shown inFIG. 5B. Areplacement core560 andreplacement sheath body570 can be inserted together as shown inFIG. 5C. Such replacement can be desirable afterdrug core510 has released effective amounts of therapeutic agent such that the supply of therapeutic agent in the drug core has diminished and the rate of therapeutic agent released is near the minimum effective level.Replacement sheath body570 includes extension575A andextension575B.Replacement drug core560 andreplacement sheath body570 can be advanced distally as shown byarrow590 to insertreplacement drug core560 andreplacement sheath body570 intoretention structure530.Retention structure530 remains at substantially the same location whilereplacement drug core560 andreplacement sheath body570 are inserted intoresilient member530.

FIGS. 5D and 5E show an implant comprising800 afilament810 that extends from adrug core insert808 for removal drug core insert808 fromimplant800, according to embodiments of the present invention.Implant800 comprises a body805 andexpandable retention structure820, as described above.Body810 comprises aproximal end802 and adistal end803.Implant800 extends fromproximal end802 to adistal end804 ofretention structure820.Implant800 comprises a channel to receive the drug core insert, as described above.Filament810 extends from a proximal end of the drug core insert to a distal end of the drug core insert.Filament810 can be molded into the drug core insert.Filament840 may comprise many of the filaments described above, for example a suture, a thermoset polymer, a shape memory alloy, and the like.

FIG. 5F shows an implant830 comprising afilament840 that extends along adrug core insert831 bonded to a distal end of the drug core insert for removal of the drug core insert from abody832 of the implant, according to embodiments of the present invention. Implant830 comprises aproximal end833.Filament840 may be bonded to the distal end ofdrug core insert831 with an adhesive842.Filament840 can be bonded to the distal end ofdrug core insert831 in many ways, for example with cyanoacrylate, acrylic, epoxy, urethane and hot melt adhesives and the like.

Sheath Body

The sheath body comprises appropriate shapes and materials to control migration of the therapeutic agent from the drug core. The sheath body houses the core and can fit snugly against the core. The sheath body is made from a material that is substantially impermeable to the therapeutic agent so that the rate of migration of the therapeutic agent may be largely controlled by the exposed surface area of the drug core that is not covered by the sheath body. In many embodiments, migration of the therapeutic agent through the sheath body can be about one tenth of the migration of the therapeutic agent through the exposed surface of the drug core, or less, often being one hundredth or less. In other words, the migration of the therapeutic agent through the sheath body is at least about an order of magnitude less that the migration of the therapeutic agent through the exposed surface of the drug core. Suitable sheath body materials include polyimide, polyethylene terephthalate” (hereinafter “PET”), polymethylmethacrylate (“PMMA”), stainless steel (for example, type316 stainless steel, tubing size 25XX), or titanium. The sheath body has a wall thickness from about 0.00025″ to about 0.0015″. In some embodiments, the wall thickness can be defined as the distance from the sheath surface adjacent the core to the opposing sheath surface away from the core. The total diameter of the sheath that extends across the core ranges from about 0.2 mm to about 1.2 mm. The core may be formed by dip coating the core in the sheath material. Alternatively or in combination, the sheath body can comprise a tube and the core introduced into the sheath, for example as a liquid or solid that can be slid, injected and/or extruded into the sheath body tube. The sheath body can also be dip coated around the core, for example dip coated around a pre-formed core.

The sheath body can be provided with additional features to facilitate clinical use of the implant. For example, the sheath may receive a drug core that is exchangeable while the retention structure and sheath body remain implanted in the patient. The sheath body may be rigidly attached to the retention structure as described above, and the core is exchangeable while the retention structure retains the sheath body. In specific embodiments, the sheath body can be provided with external protrusions that apply force to the sheath body when squeezed and eject the core from the sheath body. Another drug core can then be positioned in the sheath body. In many embodiments, the sheath body and/or retention structure may have a distinguishing feature, for example a distinguishing color, to show placement such that the placement of the sheath body and/or retention structure in the canaliculus or other body tissue structure can be readily detected by the patient. The retention element and/or sheath body may comprise at least one mark to indicate the depth of placement in the canaliculus such that the retention element and/or sheath body can be positioned to a desired depth in the canaliculus based on the at least one mark.

Retention Structure

The retention structure comprises an appropriate material that is sized and shaped so that the implant can be easily positioned in the desired tissue location, for example the canaliculus. The retention structure is mechanically deployable and typically expands to a desired cross sectional shape, for example with the retention structure comprising a super elastic shape memory alloy such as Nitinol™. Other materials in addition to Nitinol™ can be used, for example resilient metals or polymers, plastically deformable metals or polymers, shape memory polymers, and the like, to provide the desired expansion. In some embodiments polymers and coated fibers available from Biogeneral, Inc. of San Diego, Calif. may be used. Many metals such as stainless steels and non-shape memory alloys can be used and provide the desired expansion. This expansion capability permits the implant to fit in hollow tissue structures of varying sizes, for example canaliculae ranging from 0.3 min to 1.2 mm (i.e. one size fits all). Although a single retention structure can be made to fit canaliculae from 0.3 to 1.2 mm across, a plurality of alternatively selectable retention structures can be used to fit this range if desired, for example a first retention structure for canaliculae from 0.3 to about 0.9 mm and a second retention structure for canaliculae from about 0.9 to 1.2 mm. The retention structure has a length appropriate to the anatomical structure to which the retention structure attaches, for example a length of about 3 mm for a retention structure positioned near the punctum of the canaliculus. For different anatomical structures, the length can be appropriate to provide adequate retention force, e.g. 1 mm to 15 mm lengths as appropriate.

Although the sheath body and drug core can be attached to one end of the retention structure as described above, in many embodiments the other end of retention structure is not attached to drug core and sheath body so that the retention structure can slide over the sheath body and drug core while the retention structure expands. This sliding capability on one end is desirable as the retention structure may shrink in length as the retention structure expands in width to assume the desired cross sectional width. However, it should be noted that many embodiments may employ a sheath body that does not slide in relative to the core.

In many embodiments, the retention structure can be retrieved from tissue. A protrusion, for example a hook, a loop, or a ring, can extend from the retention structure to facilitate removal of the retention structure.

Occlusive Element

The occlusive element comprises an appropriate material that is sized and shaped so that the implant can at least partially inhibit, even block, the flow of fluid through the hollow tissue structure, for example lacrimal fluid through the canaliculus. The occlusive material shown is a thin walled membrane of a biocompatible material, for example silicone, that can expand and contract with the retention structure. The occlusive element is formed as a separate thin tube of material that is slid over the end of the retention structure and anchored to one end of the retention structure as described above. Alternatively, the occlusive element can be formed by dip coating the retention structure in a biocompatible polymer, for example silicone polymer. The thickness of the occlusive element can be in a range from about 0.01 mm to about 0.15 mm, and often from about 0.05 mm to 0.1 mm.

Therapeutic Agents

A “therapeutic agent” can comprise a drug and may be any of the following or their equivalents, derivatives or analogs, including, anti-glaucoma medications, (e.g. adrenergic agonists, adrenergic antagonists (beta blockers), carbonic anhydrase inhibitors (CAIs, systemic and topical), parasympathomimetics, prostaglandins, prostaglandin analogs, and hypotensive lipids, and combinations thereof), antimicrobial agent (e.g., antibiotic, antiviral, antiparacytic, antifungal, etc.), a corticosteroid or other anti-inflammatory such as olopatadine (e.g., an NSAID), a decongestant (e.g., vasoconstrictor), an agent that prevents of modifies an allergic response (e.g., cyclosporine, an antihistamine, cytokine inhibitor, leucotriene inhibitor, IgE inhibitor, immunomodulator), a mast cell stabilizer, cycloplegic or the like. Examples of conditions that may be treated with the therapeutic agent(s) include but are not limited to glaucoma, pre and post surgical treatments, dry eye and allergies. In some embodiments, the therapeutic agent may be a lubricant or a surfactant, for example a lubricant to treat dry eye.

Exemplary therapeutic agents include, but are not limited to, thrombin inhibitors; antithrombogenic agents; thrombolytic agents; fibrinolytic agents; vasospasm inhibitors; vasodilators; antihypertensive agents; antimicrobial agents, such as antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate), antifungals (such as amphotericin B and miconazole), and antivirals (such as idoxuridine trifluorothymidine, acyclovir, gancyclovir, interferon); inhibitors of surface glycoprotein receptors; antiplatelet agents; antimitotics; microtubule inhibitors; anti-secretory agents; active inhibitors; remodeling inhibitors; antisense nucleotides; anti-metabolites; antiproliferatives (including antiangiogenesis agents); anticancer chemotherapeutic agents; anti-inflaTnmatories (such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone, triamcinolone acetonide); non steroidal anti-inflammatories (NSAIDs) (such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naxopren, piroxicam and nabumetone). Such anti inflammatory steroids contemplated for use in the methodology of the present invention, include triamcinolone acetonide (generic name) and corticosteroids that include, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, and derivatives thereof.); antiallergenics (such as sodium chromoglycate, antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin); decongestants (such as phenylephrine, naphazoline, tetrahydrazoline); miotics and anti-cholinesterase (such as pilocarpine, salicylate, carbachol, acetylcholine chloride, physostigmine, eserine, diisopropyl fluorophosphate, phospholine iodine, demecarium bromide); antineoplastics (such as carmustine, cisplatin, fluorouracil3; immunological drugs (such as vaccines and immune stimulants); hormonal agents (such as estrogens, -estradiol, progestational, progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamus releasing factor); immunosuppressive agents such as cyclosporine, growth hormone antagonists, growth factors (such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotrapin, fibronectin); inhibitors of angiogenesis (such as angiostatin, anecortave acetate, thrombospondin, anti-VEGF antibody); dopamine agonists; radiotherapeutic agents; peptides; proteins; enzymes; extracellular matrix; components; ACE inhibitors; free radical scavengers; chelators; antioxidants; anti polymerases; photodynainic therapy agents; gene therapy agents; and other therapeutic agents such as prostaglandins, antiprostaglandins, prostaglandin precursors, including antiglaucoma drugs including beta-blockers such as Timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogues such as Bimatoprost, travoprost, Latanoprost etc; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorphenamide, diamox; and neuroprotectants such as lubezole, nimodipine and related compounds; and parasympathomimetrics such as pilocarpine, carbachol, physostigmine and the like.

For use in ophthalmic applications, some specific therapeutic agents that can be used include glaucoma medications (muscarinics, beta blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandins and their analogs), antiinflammatories (steroids, soft steroids, NSAIDs), anti infectives including antibiotics such as beta lactams, fluoro quinolones, etc.), antivirals, and antimicotics, dry eye medications (CsA, delmulcents, sodium hyaluronate), or combinations thereof.

The amount of drug associated with the drug-delivery device may vary depending on the particular agent, the desired therapeutic benefit and the time during which the device is intended to deliver the therapy. Since the devices of the present invention present a variety of shapes, sizes and delivery mechanisms, the amount of drug associated with the device will depend on the particular disease or condition to be treated, and the dosage and duration that is desired to achieve the therapeutic effect. Generally, the amount of drug is at least the amount of drug that upon release from the device, is effective to achieve the desired physiological or pharmacological effects.

Embodiments of the drug delivery devices of the present invention can be adapted to provide delivery of drug at a daily rate that is substantially below the therapeutically effective drop form of treatment so as to provide a large therapeutic range with a wide safety margin. For example, many embodiments treat the eye with therapeutic levels for extended periods that are no more than 5 or 10 percent of the daily drop dosage. Consequently, during an initial period of about seven days, more typically of about one to three days, the implant can elute the therapeutic agent at a rate that is substantially higher than the sustained release levels but still below the daily drop form dosage. For example, with an average sustained release level of 100 ng per day, and an initial release rate of 1000 to 1500 ng per day, the amount of drug initially released is less than the 2500 ng of drug that may be present in a drop of drug delivered to the eye. This use of sustained release levels substantially below the amount of drug in a drop and/or drops administered daily allows the device to release a therapeutically beneficial amount of drug to achieve the desired therapeutic benefit with a wide safety margin, while avoiding an inadequate or excessive amount of drug at the intended site or region.

An extended period of time may mean a relatively short period of time, for example minutes or hours (such as with the use of an anesthetic), through days or weeks (such as the use of pre-surgical or post-surgical antibiotics, steroids, or NSAIDs and the like), or longer (such as in the case of glaucoma treatments), for example months or years (on a recurring basis of use of the device).

For example, drug such as Timolol maleate, a beta1 and beta2 (non-selective) adrenergic receptor blocking agent can be used in the device for a release over an extended period of time such as 3 months. Three months is a relatively typical elapsed time between physician visits for a glaucoma patient undergoing topical drop therapy with a glaucoma drug, although the device could provide treatment for longer or shorter durations. In the three month example, a 0.25% concentration of Timolol translates to from 2.5 to 5 mg/1000 μL, typically being 2.5 mg/l 000 μL. A drop of Timolol for topical application is usually in the range of 40-60 μL, typically being 50 μL. Thus, there may be 0.08-0.15 mg, typically being 0.125 mg of Timolol in a drop. There may be approximately 8% (e.g. 6-10%) of the drop left in the eye after 5 minutes, so about 10 μg of the drug is available at that time. Timolol may have a bioavailability of 30-50%, which means that from 1.5 to 7.5 μg, for example 4 μg of the drug is available to the eye. Timolol is generally applied twice a day, so8 (or 3-15) μg is available to the eye each day. Therefore, a delivery device might contain from 270 to 1350 μg, for example 720 μg, of the drug for a 90 day, or 3 month, extended release. The drug would be contained within the device and eluted based on the design of the device, including the polymers used and the surface area available for drug elution. The drug can be similarly contained on the device and eluted for olopatadine hydrochloride (Patanol®) and other drugs in a manner similar to Timolol.

Commercially available solutions of Timolol maleate are available in 0.25% and 0.5% preparations, and the initial dosage can be 1 drop twice per day of 0.25% solution. A 0.25% concentration of Timolol is equivalent to 2.5 mg per 1000 μl. A sustained release quantity of Timolol released each day from the drug core can be from about 3 to 15 μg each day. Although the sustained release quantity delivered each day from the device may vary, a sustained release delivery of about 8 μg per day corresponds to about 3.2% of the 0.250 mg of Timolol applied with two drops of a 0.25% solution.

For example, in the case of Latanoprost (Xalatan), a prostaglandin F2α analogue, this glaucoma medication has concentrations that are about 1/50th that of Timolol. Therefore, the amount of drug on the implantable device, depending on the bioavailability, would be significantly less—approximately 5-135 μg and typically 10-50 μg—for Latanoprost and other prostaglandin analogues. This also translates to a device that can either be smaller than one required for a beta blocker delivery or can house more drug for a longer release period.

A drop of Xalatan contains about 2.5 μg of Latanoprost, assuming a 50 μL drop volume. Therefore, assuming that about 8% of 2.5 μg is present 5 minutes after instillation, only about 200 ng of drug remains on the eye. Based on the Latanoprost clinical trials, this amount is effective in lowering IOP for at least 24 hours. Pfizer/Pharmacia conducted several dose-response studies in support of the NDA for Xalatan. The doses ranged from 12.5 μg/mL to 115 μg/mL of Latanoprost. The current dose of Latanoprost, 50 pg/mL, given once per day, was shown to be optimal. However, even the lowest doses of 12.5 μg/mL QD or 15 μg/mL BID consistently gave about 60-75% of the IOP reduction of the 50 μg/mL QD dose. Based on the assumptions above, a 12.5 μg/mL concentration provides 0.625 μg of Latanoprost in a 50 μL drop, which results in only about 50 ng (8%) of drug remaining in the eye after 5 minutes.

In many embodiments, the concentrations of Latanoprost are about 1/100th, or 1 percent, that of Timolol, and in specific embodiments the concentrations of Latanoprost may be about 1/50th, or 2 percent, that of Timolol. For example, commercially available solution preparations of Latanoprost are available at concentrations 0.005%, often delivered with one drop per day. In many embodiments, the therapeutically effective concentration of drug released from the device per day can be about 1/100th of Timolol, about 30 to 150 ng per day, for example about 80 ng, assuming tear washout and bioavailability similar to Timolol. For example, the amount of drug on the implantable device, can be significantly less-approximately 1% to 2% of Timolol, for example 2.7 to 13.5 μg, and can also be about 3 to 20 μg, for Latanoprost and other prostaglandin analogues. Although the sustained release amount of Latanoprost released each day can vary, a sustained release of 80 ng per day corresponds to about 3.2% of the 2.5 μg of Latanoprost applied with a single drop of a 0.005% solution

For example, in the case of Bimatoprost (Lumigan), a synthetic prostamide prostaglandin analogue, this glaucoma medication may have concentrations that are 1/20th or less than that of Timolol. Therefore, the amount of drug loaded on the extended release device for a 3 to 6 month extended release, depending on the bioavailability, can be significantly less, approximately 5-30 μg and typically 10-μg—for Bimatoprost and analogues and derivatives thereof. In many embodiments, the implant can house more drug for a longer sustained release period, for example 20-40 μg for a sustained release period of 6 to 12 months with Bimatoprost and its derivatives. This decrease in drug concentration can also translate to a device that can be smaller than one required for a beta blocker delivery.

Commercially available solution concentrations of Bimatoprost are 0.03% by weight, often delivered once per day. Although the sustained release amount of Bimatoprost released each day can vary, a sustained release of 300 ng per day corresponds to about 2% of the 15 μg of Bimatoprost applied with a single drop of a 0.03% solution. Work in relation with the present invention suggests that even lower sustained release doses of Bimatoprost can provide at least some reduction in intraocular pressure, for example 20 to 200 ng of Bimatoprost and daily sustained release dosages of 0.2 to 2% of the daily drop dosage.

For example, in the case of Travoprost (Travatan), a prostaglandin F2α analogue, this glaucoma medication may have concentrations that are 2% or less than that of Timolol. For example, commercially available solution concentrations are 0.004%, often delivered once per day. In many embodiments, the therapeutically effective concentration of drug released from the device per day can be about 65 ng, assuming tear washout and bioavailability similar to Timolol. Therefore, the amount of drug on the implantable device, depending on the bioavailability, would be significantly less. This also translates to a device that can either be smaller than one required for a beta blocker delivery or can house more drug for a longer release period. For example, the amount of drug on the implantable device, can be significantly less-approximately 1/100 of Timolol, for example 2.7 to 13.5 μg, and typically about 3 to 20 μg, for Travoprost, Latanoprost and other prostaglandin F2α analogues. Although the sustained release amount of Latanoprost released each day can vary, a sustained release of 65 ng per day corresponds to about 3.2% of the 2.0 μg of Travoprost applied with a single drop of a 0.004% solution.

In some embodiments, the therapeutic agent may comprise a corticosteriod, for example fluocinolone acetonide, to treat a target ocular tissue. In specific embodiments, fluocinolone acetonide can be released from the canaliculus and delivered to the retina as a treatment for diabetic macular edema (DME).

It is also within the scope of this invention to modify or adapt the devices to deliver a high release rate, a low release rate, a bolus release, a burst release, or combinations thereof. A bolus of the drug may be released by the formation of an erodable polymer cap that is immediately dissolved in the tear or tear film. As the polymer cap comes in contact with the tear or tear film, the solubility properties of the polymer enable the cap to erode and the drug is released all at once. A burst release of a drug can be performed using a polymer that also erodes in the tear or tear film based on the polymer solubility. In this example, the drug and polymer may be stratified along the length of the device so that as the outer polymer layer dissolves, the drug is immediately released. A high or low release rate of the drug could be accomplished by changing the solubility of the erodable polymer layer so that the drug layer released quickly or slowly. Other methods to release the drug could be achieved through porous membranes, soluble gels (such as those in typical ophthalmic solutions), microparticle encapsulations of the drug, or nanoparticle encapsulation, depending on the size of the drug molecule.

Drug Core

In another embodiment, the therapeutic agent can be soluble at relatively high levels in the matrix, such that inclusions are not formed when the agent is present at therapeutically useful concentrations. For example, cyclosporine can be dissolved in a polyurethane matrix at high concentrations, and the cyclosporine is dispersed throughout the polyurethane matrix at molecular levels, i.e., a “solid solution” of the cyclosporine in the polyurethane matrix can be achieved.

When the inclusion is solid, various comminuted forms of the solid material can be used to achieve a particular average particle diameter and size distribution of diameters. Such solid powders can be obtained by any suitable method known in the art. See, for example, machines manufactured for the pharmaceutical industry by Glatt GmbH, at http://www.glatt.com/e/00_home/00.htm. In the milling process a range of sizes can be generated. Fluidized beds and coaters can be used to increase particle size to a desired dimension. Particle size will influence surface area and may affect dissolution. Inclusion size and associated size distribution can be used to control an elution rate of the agent from the drug core, both in the situation where the inclusions are solid, such as bimatoprost, and where the inclusions are liquid, such as latanoprost oil.

The drug core can comprise one or more biocompatible materials capable of providing a sustained release of the therapeutic agent. Although the drug core is described above with respect to an embodiment comprising a matrix with a substantially non-biodegradable silicone matrix with inclusions of the drug located therein that dissolve, the drug core can include structures that provide sustained release of the therapeutic agent, for example a biodegradable matrix, a porous drug core, liquid drug cores and solid drug cores. A matrix that contains the therapeutic agent can be formed from either biodegradable or non-biodegradable polymers. A non-biodegradable drug core can include silicone, acrylates, polyethylenes, polyurethane, polyurethane, hydrogel, polyester (e.g., DACRON® from E.I. Du Pont de Nemours and Company, Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam, silicone rubber, polyethylene terephthalate, ultra high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimides, stainless steel, nickel-titanium alloy (e.g., Nitinol), titanium, stainless steel, cobalt-chrome alloy (e.g., ELGILOY® m Elgin Specialty Metals, Elgin, Ill.; CONICHROME® from Carpenter Metals Corp., Wyomissing, PA.). A biodegradable drug core can comprise one or more biodegradable polymers, such as protein, hydrogel, polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(alpha-hydroxy acid) and combinations thereof. In some embodiments the drug core can comprise at least one of hydrogel polymer.

Release of Therapeutic Agent at Effective Levels

The rate of release of the therapeutic agent can be related to the concentration of therapeutic agent in the drug core. In many embodiments, the drug core comprises non-therapeutic agents that are selected to provide a desired solubility of the therapeutic agent in the drug core. The non-therapeutic agent of the drug core can comprise polymers as described herein and additives. A polymer of the core can be selected to provide the desired solubility and/or dispersability of the therapeutic agent in the matrix. For example, the core can comprise hydrogel that may promote solubility or dispersability of hydrophilic treatment agent. In some embodiments, functional groups can be added to the polymer to provide the desired solubility or dispersity of the therapeutic agent in the matrix. For example, functional groups can be attached to silicone polymer.

In some embodiments, release rate modifying additives may be used to control the release kinetics of therapeutic agent. For example, the additives may be used to control the concentration of therapeutic agent by increasing or decreasing solubility of the therapeutic agent in the drug core so as to control the release kinetics of the therapeutic agent. The solubility may be controlled by providing appropriate molecules and/or substances that increase and/or decrease the solubility of the therapeutic agent to the matrix. The solubility of the therapeutic agent may be related to the hydrophobic and/or hydrophilic properties of the matrix and therapeutic agent. For example, surfactants, tinuvin, salts and water can be added to the matrix and may increase the solubility of hydrophilic therapeutic agent in the matrix. Salts can be water soluble, such as sodium chloride, or water-insoluble, such as titanium dioxide. In addition, oils and hydrophobic molecules and can be added to the matrix and may increase the solubility of hydrophobic treatment agent in the matrix. Alternatively, various oligomers and polymers, for example polysaccharides such as alginates, or proteins such as albumin, can be added. Solvents such as glycerol can also be used to modify the rate of release of the agent from the matrix into the tear liquid.

Instead of or in addition to controlling the rate of migration based on the concentration of therapeutic agent dissolved in the matrix, the surface area of the drug core can also be controlled to attain the desired rate of drug migration from the core to the target site. For example, a larger exposed surface area of the core will increase the rate of migration of the treatment agent from the drug core to the target site, and a smaller exposed surface area of the drug core will decrease the rate of migration of the therapeutic agent from the drug core to the target site. The exposed surface area of the drug core can be increased in any number of ways, for example by any of castellation of the exposed surface, a surface having exposed channels connected with the tear or tear film, indentation of the exposed surface, protrusion of the exposed surface. The exposed surface can be increased by the addition of salts that dissolve and leave cavities once the salt dissolves. Hydrogels may also be used, and can swell in size to provide a larger exposed surface area.

In addition, drug impregnated porous materials, such as meshes, may be used such as those disclosed in US Patent Publication No. 2002/0055701 or layering of biostable polymers as described in US Patent Publication No. 2005/0129731. Certain polymer processes may be used to incorporate drug into the devices of the present invention such as, so-called “self-delivering drugs” or PolymerDrugs (Polymerix Corporation, Piscataway, N.J.) are designed to degrade only into therapeutically useful compounds and physiologically inert linker molecules, further detailed in US Patent Publication No. 2005/0048121 (East), hereby incorporated by reference in its entirety. Such delivery polymers may be employed in the devices of the present invention to provide a release rate that is equal to the rate of polymer erosion and degradation and is constant throughout the course of therapy. Such delivery polymers may be used as device coatings or in the form of microspheres for a drug depot injectable (such as a reservoir of the present invention). A further polymer delivery technology may also be adapted to the devices of the present invention such as that described in US Patent Publication No. 2004/0170685 (Carpenter), and technologies available from Medivas (San Diego, Calif.).

In specific embodiments, the drug core matrix comprises a solid material, for example silicone, that encapsulates inclusions of the drug. The drug comprises molecules which are very insoluble in water and slightly soluble in the encapsulating drug core matrix. The inclusions encapsulated by the drug core can be micro-particles having dimensions from about 1 μm to about 100 μm across. The drug inclusions can comprise crystals, for example bimatoprost crystals, and/or droplets of oil, for example with latanoprost oil. The drug inclusions can dissolve into the solid drug core matrix and substantially saturate the drug core matrix with the drug, for example dissolution of latanoprost oil into the solid drug core matrix. The drug dissolved in the drug core matrix is transported, often by diffusion, from the exposed surface of the drug core into the tear film. As the drug core is substantially saturated with the drug, in many embodiments the rate limiting step of drug delivery is transport of the drug from the surface of the drug core matrix exposed to the tear film. As the drug core matrix is substantially saturated with the drug, gradients in drug concentration within the matrix are minimal and do not contribute significantly to the rate of drug delivery. As surface area of the drug core exposed to the tear film is nearly constant, the rate of drug transport from the drug core into the tear film can be substantially constant. Work in relation with the present invention suggests that the solubility of the therapeutic agent in water and molecular weight of the drug can effect transport of the drug from the solid matrix to the tear. In many embodiments, the therapeutic agent is nearly insoluble in water and has a solubility in water of about 0.03% to 0.002% by weight and a molecular weight from about 400 grams/mol. to about 1200 grams/mol.

In many embodiments the therapeutic agent has a very low solubility in water, for example from about 0.03% by weight to about 0.002% by weight, a molecular weight from about 400 grams per mole (g/mol.) to about 1200 g/mol and is readily soluble in an organic solvent. Cyclosporin A (CsA) is a solid with an aqueous solubility of 27.67 μg/mL at 25° C., or about 0.0027% by weight, and a molecular weight (M.W.) of 1202.6 g/mol. Latanoprost (Xalatan) is a prostaglandin F2α analogue, a liquid oil at room temperature, and has an aqueous solubility of 50 μg/mL in water at 25° C., or about 0.005% by weight and a M.W. of 432.6 g/mol.

Bimatoprost (Lumigan) is a synthetic prostamide analogue, a solid at room temperature solubility in water of 300 μg/mL in water at 25° C., or 0.03% by weight, and has a M.W. of 415.6 g/mol.

Work in relation with the present invention indicates that naturally occurring surfactants in the tear film, for example surfactant D and phospholipids, may effect transport of the drug dissolved in the solid matrix from the core to the tear film. The drug core can be adapted in response to the surfactant in the tear film to provide sustained delivery of the drug into the tear film at therapeutic levels. For example, empirical data can be generated from a patient population, for example 10 patients whose tears are collected and analyzed for surfactant content. Elution profiles in the collected tears for a drug that is sparingly soluble in water, for example cyclosporine, can also be measured and compared with elution profiles in buffer and surfactant such that an in vitro model of tear surfactant is developed. An in vitro solution with surfactant based on this empirical data can be used to adjust the drug core in response to the surfactant of the tear film.

The drug cores may also be modified to utilize carrier vehicles such as nanoparticles or microparticles depending on the size of the molecule to be delivered such as latent-reactive nanofiber compositions for composites and nanotextured surfaces (Innovative Surface Technologies, LLC, St. Paul, Minn.), nanostructured porous silicon, known as BioSilicon®, including micron sized particles, membranes, woven fivers or micromachined implant devices (pSividia, Limited, UK) and protein nanocage systems that target selective cells to deliver a drug (Chimeracore).

In many embodiments, the drug insert comprises of a thin-walled polyimide tube sheath with a drug core comprising latanoprost dispersed in Nusil 6385 (MAF 970), a medical grade solid silicone that serves as the matrix for drug delivery. The distal end of the drug insert is sealed with a cured film of solid Loctite 4305 medical grade adhesive. The drug insert may be placed within the bore of the punctum plug, the Loctite 4305 adhesive does not come into contact with either tissue or the tear film. The inner diameter of the drug insert can be 0.32 mm; and the length can be 0.95 mm. Three Latanoprost concentrations in the finished drug product can be tested clinically: Drug cores can comprise 3.5, 7 or 14 μg latanoprost, with percent by weight concentrations of 5, 10 and 20% respectively. Assuming an overall elution rate of approximately 100 ng/day, the drug core comprising 14 μg of latanoprost is adapted to deliver drug for approximately at least 100 days, for example 120 days. The overall weight of the drug core, including latanoprost, can be ˜70 μg. The weight of the drug insert including the polyimide sleeve can be approximately 100 μg.

In many embodiments, the drug core may elute with an initial elevated level of therapeutic agent followed by substantially constant elution of the therapeutic agent. In many instances, an amount of therapeutic agent released daily from the core may be below the levels found in drops and still provide a benefit to the patient. An elevated level of eluted therapeutic agent can result in a residual amount of therapeutic agent and/or residual effect of the therapeutic agent to provide relief to the patient. In embodiments where therapeutic level is about 80 ng per day, the device may deliver about 100 ng per day for an initial delivery period. The extra20 ng delivered per day can have a beneficial immediate effect. As the amount of drug delivered can be precisely controlled, an initial elevated dose may not result in complications and/or adverse events to the patient.

Further, an implant may be used that includes the ability to release two or more drugs in combination, such as the structure disclosed in U.S. Pat. No. 4,281,654 (Shell). For example, in the case of glaucoma treatment, it may be desirable to treat a patient with multiple prostaglandins or a prostaglandin and a cholinergic agent or an adrenergic antagonist (beta blocker), such as Alphagan®, or prostaglandin and a carbonic anhydrase inhibitor.

In various embodiments, the implant may have at least one surface and release a therapeutic quantity of two therapeutic agents into tear or tear film fluid of the eye throughout a time period of at least one week when the implant is implanted with the at least one surface exposed to the tear or tear film fluid. For example, the implant can be adapted to release the therapeutic agents in therapeutic amounts over a period of time from about one to twelve months. The release rate of each of the therapeutic agents may be the same or each of the therapeutic agents may have different release rates.

In some embodiments, the implant comprise a single drug core with two therapeutic agents mixed within a matrix. In other embodiments, the implant comprise two drug cores, each with a single therapeutic agent.

In specific embodiments, at least a portion of the implant may be bioerodable, and the therapeutic agents can be released while the a portion of the implant erodes.

In some embodiments, the second therapeutic agent may comprise a counteractive agent to avoid a side effect of the first therapeutic agent. In one example, the second therapeutic agent may comprise at least one of an anti-glaucoma drug or a miotic drug. The anti-glaucoma drug may comprise at least one of a sympathomimetic, a parasympathomimetic, a beta blocking agent, a carbonic anhydrase inhibitor, or prostaglandin analogue. In another example, the first therapeutic agent may be steroids and the second therapeutic agent may be antibiotics, where the steroids compromise the immune response, but the antibiotics provides coverage for infection. In another example, the first therapeutic agent may be pilocarpine and the second therapeutic agent may be non-steroidal anti-inflammatory drug (NSAID). An analgesic may be a good compliment for the treatment.

In some embodiments the therapeutic agents can be released with a profile that corresponds to a kinetic order of therapeutic agents release and the order can be within a range from about zero to about one. In specific embodiments, the range is from about zero to about one half, for example from about zero to about one quarter.

The therapeutic agents may be released with a profile that corresponds to a kinetic order of therapeutic agents release and the order is within a range from about zero to about one half for at least about a month after the structure is inserted, for example the order can be within the range at least about 3 months after the structure is inserted.

Referring now toFIG. 17, an implant, for example apunctal plug1700, is shown which comprises asilicone body1710, adrug core1720 and aretention structures1730, according to embodiments of the present invention.Body1710 comprises aproximal channel1714 sized to receivedrug core insert1720. Afilament1734 can be embedded inbody1710 and wrapped aroundhydrogel rod1732 to affixhydrogel rod1732 tobody1710. The drug core insert and manufacture of the drug core insert are described in U.S. application Ser. Nos. 11/695,537 and 11/695,545, the full disclosures of which are incorporated herein by reference.

Although a drug core insert is shown, some embodiments may comprises a drug reservoir, a semi-permeable membrane, a drug coating or the like, as described in U.S. Pat. No. 6,196,993 (Cohan) and U.S. application Ser. No. 10/899,416 (Prescott); Ser. No. 10/899,417 (Prescott); Ser. No. 10/762,421 (Ashton); Ser. No. 10/762,439 (Ashton); Ser. No. 11/571,147 (Lazar) and Ser. No. 10/825,047 (Odrich), the full disclosures of which are herein incorporated by reference for all purposes. In some embodiments, the implant comprises a punctal plug without drug carried on the implant, for example an implant similar topunctal plug1700 withoutchannel1714 anddrug core insert1720.

Retention structures

1730 may comprise hydrogel rod, hydrogel coating, and protrusions.Hydrogel rod1732 can be inserted through the punctum into a canalicular lumen in a narrow profile configuration. After insertion into the lumen the hydrogel rod, hydrogel coating, or both, can hydrate expand to a wide profile configuration.

FIG. 18A shows a cross sectional view of asustained release implant1800 having two therapeutic agents to treat an eye, according to embodiments of the present invention.Implant1800 has aproximal end1812 in which the therapeutic agents are released and adistal end1814.Implant1800 includes two

concentric drug cores

1810,1815.First drug core1810 is a cylindrical shaped structure with a central opening that includes a first therapeutic agent, andsecond drug core1815 is a cylindrical shaped structure that includes a second therapeutic agent.Second drug core1815 is configured to fit within the central opening offirst drug core1810, as shown in the figures.First drug core1810 comprises afirst matrix1870 that containsfirst inclusions1860 of the first therapeutic agent, andsecond drug core1815 comprises asecond matrix1875 that containssecond inclusions1865 of the second therapeutic agent. First and

second inclusions

1860,1865 will often comprise a concentrated form of the first and second therapeutic agents, for example a liquid or solid form of the therapeutic agents, and the therapeutic agents may over time dissolve intofirst matrix1870 offirst drug core1810 andsecond matrix1875 ofsecond drug core1815. First and

second matrixes

1870,1875 can comprise a silicone matrix or the like, and the mixture of therapeutic agents within matrixes can be non-homogeneous. In many embodiments, the non-homogenous mixture comprises a silicone matrix portion that is saturated with the therapeutic agents and an inclusions portion comprising inclusions of the therapeutic agents, such that the non-homogenous mixture comprises a multiphase non-homogenous mixture. The first matrix may differ from the second matrix, including, for example, an exposed surface area, a surfactant, a cross-linking, an additive, and/or matrix materials including formulation and/or solubility. In some embodiments, first and

second inclusions

1860,1865 comprise droplets of an oil of the therapeutic agent, for example Latanoprost oil. In some embodiments, first and

second inclusions

1860,1865 may comprise particles of the therapeutic agents, for example solid bimatoprost particles. In many embodiments,first matrix1870 containsfirst inclusions1860 andsecond matrix1875 containssecond inclusions1865. First and

second inclusions

1860,1865 may comprise microparticles having dimensions from about 0.1 μm to about 100 μm, or 200 μm. The contained inclusions at least partially dissolve into the surrounding solid matrix, for example silicone, that contains the micro particles such that first and

second matrixes

1870,1875 are substantially saturated with the therapeutic agent while the therapeutic agent is released from the core.

First and

second drug cores

1810,1815 are surrounded by asheath body1820, except at an exposed surface where the therapeutic agents are released, in this case at theproximal end1812.Sheath body1820 is substantially impermeable to the therapeutic agents, so that the therapeutic agents are released from the exposed surface on the open end of first and

second drug cores

1810,1815 that are not covered withsheath body1820. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

FIG. 18B shows a side cross sectional view of the sustained release implant ofFIG. 18A.First drug core1810 with a first therapeutic agent is a cylindrical shaped structure and shown with a circular cross-section with an open center.Second drug core1815 with a second therapeutic agent is a cylindrical shaped structure and shown with a circular cross-section and is configured to fit withinfirst drug core1810, as shown in the figures.Sheath body1820 comprises an annular portion disposed onfirst drug core310.

FIG. 19A shows a cross sectional view of asustained release implant1900 having therapeutic agents to treat an eye, according to embodiments of the present invention.Implant1900 has aproximal end1912 in which the therapeutic agents are released and adistal end1914.Implant1900 includes first and

second drug cores

1910,1915 that are positioned in a side by side configuration.First drug core1910 is a cylindrical shaped structure that includes the first therapeutic agent andsecond drug core1915 is a cylindrical shaped structure that includes the second therapeutic agent. First and

second drug cores

1910 and1915 are placed adjacent to each other and may have the same length, or different lengths, such as shown in the figure.First drug core1910 comprises afirst matrix1970 that containsfirst inclusions1960 of the first therapeutic agent and second drug core415 comprises asecond matrix1975 that containssecond inclusions1965 of the second therapeutic agent. First and

second inclusions

1960,1965 will often comprise a concentrated form of the first and second therapeutic agents, for example a liquid or solid form of the therapeutic agents, and the therapeutic agents may over time dissolve intofirst matrix1970 offirst drug core1910 andsecond matrix1975 ofsecond drug core1915. First and

second matrixes

1970,1975 can comprise a silicone matrix or the like, and the mixture of therapeutic agents within matrixes can be non-homogeneous. In many embodiments, the non-homogenous mixture comprises a silicone matrix portion that is saturated with the therapeutic agents and an inclusions portion comprising inclusions of the therapeutic agents, such that the non-homogenous mixture comprises a multiphase non-homogenous mixture. The first matrix may differ from the second matrix, including, for example, an exposed surface area, a surfactant, a cross-linking, an additive, and/or matrix materials including formulation and/or solubility. In some embodiments, first and

second inclusions

1960,1965 comprise droplets of an oil of the therapeutic agent, for example Latanoprost oil. In some embodiments, inclusions may comprise particles of the therapeutic agent, for example solid bimatoprost particles. First and

second inclusions

1960,1965 may comprise microparticles having dimensions from about 0.1 μm to about 100 μm, or 200 μm. The contained inclusions at least partially dissolve into the surrounding solid matrix, for example silicone, that contains the micro particles such that first and

second matrixes

1970,1975 are substantially saturated with the therapeutic agent while the therapeutic agent is released from the core.

First and

second drug cores

1910,1915 are surrounded by asheath body1920, except at an exposed surface where the therapeutic agents are released, in this case at theproximal end1912.Sheath body1920 is substantially impermeable to the first and second therapeutic agents, so that the first and second therapeutic agents are released from the exposed surface on the open end of first and

second drug cores

1910,1915 that are not covered withsheath body1920. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

FIG. 19B shows a side cross sectional view of the sustained release implant ofFIG. 19A.First drug core1910 with the first therapeutic agent is a cylindrical shaped structure and shown with a circular cross-section.Second drug core1915 with the second therapeutic agent is also a cylindrical shaped structure and shown with a circular cross-section. First and

second drug cores

1910,1915 may have different diameters or the same diameter, as shown in the figures.Sheath body1920 comprises an annular portion disposed around first and

second drug cores

1910,1915.

FIG. 20A shows a cross sectional view of asustained release implant2000 having therapeutic agents to treat an eye, according to embodiments of the present invention.Implant2000 has aproximal end2012 and adistal end2014.Implant2000 includes two

concentric drug cores

2010,2015 with hollow centers to allow fluid flow through theimplant2000.First drug core2010 is a hollow cylindrical shaped structure that includes a first therapeutic agent andsecond drug core2015 is a hollow cylindrical shaped structure that includes a second therapeutic agent.Second drug core2015 is configured to fit within a central opening offirst drug core2010, as shown in the figures. First and

second drug cores

2010,2015 may have the same length, or different lengths, as shown in the figures.First drug core2010 comprises afirst matrix2070 that containsfirst inclusions2060 of the first therapeutic agent andsecond drug core2015 comprises asecond matrix2075 that containssecond inclusions2065 of the second therapeutic agent. First and

second inclusions

2060,2065 will often comprise a concentrated form of the first and second therapeutic agents, for example a liquid or solid form of the therapeutic agents, and the therapeutic agents may over time dissolve into afirst matrix2070 offirst drug core2010 and asecond matrix2075 ofsecond drug core2015, respectively. First and

second matrixes

2070,2075 can comprise a silicone matrix or the like, and the mixture of therapeutic agents within matrixes can be non-homogeneous. In many embodiments, the non-homogenous mixture comprises a silicone matrix portion that is saturated with the therapeutic agents and an inclusions portion comprising inclusions of the therapeutic agents, such that the non-homogenous mixture comprises a multiphase non-homogenous mixture. The first matrix may differ from the second matrix, including, for example, an exposed surface area, a surfactant, a cross-linking, an additive, and/or matrix materials including formulation and/or solubility. In some embodiments, first and

second inclusions

2060,2065 comprise droplets of an oil of the therapeutic agent, for example latanoprost oil. In some embodiments, inclusions may comprise particles of the therapeutic agent, for example solid bimatoprost particles. First and

second inclusions

2060,2065 may comprise microparticles having dimensions from about 0.1 μm to about 100 μm, or about 200 μm. The contained inclusions at least partially dissolve into the surrounding solid matrix, for example silicone, that contains the micro particles such that first and

second matrixes

2070,2075 are substantially saturated with the therapeutic agent while the therapeutic agent is released from the core.

First drug core

2010 is surrounded on its outer surface by asheath body2020, havingfirst drug core2010 with an openinner surface2085 and exposed proximal and distal end surfaces.Sheath body2020 is substantially impermeable to the first therapeutic agents infirst drug core2010, so that the first therapeutic agents are released from the exposed surfaces of thedrug core2010.Second drug core2015 is surrounded on its outer surface byfirst drug core2010, with an openinner surface2080 and exposed proximal and distal end surfaces. Thesecond drug core2015 is shorter than thefirst drug core2010 so that portions of theinner surface2085 are exposed. First therapeutic agents are released from the exposed surfaces offirst drug core2010 that are not covered by thesheath body2020 andsecond drug core2015, and second therapeutic agents are released from the exposed surfaces ofsecond drug core2015 that are not covered withfirst drug core2010. In some embodiments, the implant may be incorporated into a different structure, such as a punctal plug.

FIG. 20B shows a side cross sectional view of the sustained release implant ofFIG. 20A with concentric drug cores.First drug core510 with the first therapeutic agent is shown with a circular cross-section with a first open center portion.Second drug core2015 with the second therapeutic agent is shown with a circular cross-section with a second open center and is configured to fit within the first open center portion offirst drug core2010, while allowing flow through the center of thesecond drug core2015, as shown in the figures.Sheath body2020 comprises an annular portion disposed onfirst drug core2010.

The drug cores can be made from any biocompatible material capable of providing a sustained release of the therapeutic agents. Although the drug cores are described above with respect to embodiments comprising a matrix with a substantially non-biodegradable silicone matrix with particles of the drugs located therein that at least partially dissolve, the drug cores can include any structure that provides sustained release of the first and second therapeutic agents, for example biodegradable matrix, a porous drug core, liquid drug cores and solid drug cores. In some embodiments, the drug cores have the same structure, while in other embodiments, the drugs cores have different structures. The structures can be adapted to release the first and second therapeutic agents in therapeutic amounts over a period of time from about one to twelve months after the structure is inserted into the eye. In some embodiments the release rate for the first and second therapeutic agents may be the same or similar. In other embodiments the release rate for the first and second therapeutic agents may be different, with one therapeutic agent being released at a higher rate than the other therapeutic agent. A matrix that contains the first and second therapeutic agents can be formed from either biodegradable or non-biodegradable polymers. Examples of biodegradable polymers may include poly(L,-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxidc copolymers, modified cellulose, collagen, polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(alpha-hydroxy acid), collagen matrices and combinations thereof. The devices of the present invention may be fully or partially biodegradable or non-biodegradable. Examples of non-biodegradable materials are various commercially available biocompatible polymers including but not limited to silicone, polyethylene terephthalate, acrylates, polyethylenes, polyolefins, including ultra high molecular weight polyethylene, expanded polytetrafloroethylene, polypropylene, polycarbonate urethane, polyurethanes, polyamides, sheathed collagen. Additional examples of polymers may include cyclodextrans, chitans, hyaluronic acid, chrondroitin sulfate and any cross limited derivatives of these polymers. In some embodiments the drug cores may comprise a hydrogel polymer, either degradable or non-degradable. In some embodiments, the therapeutic agents can be comprised in a drug eluting material used as a coating, such as those commercially available from Surmodics of Eden Prairie, Minn., and Angiotech Pharmaceuticals of British Columbia, Canada, and the like.

The first and second therapeutic agents can comprise any substance, for example a drug, that effects the eye. In some embodiments, the first and second therapeutic agents work together in treating the eye. In other embodiments, the first therapeutic agent can counteract possible side effects of the second therapeutic agent. The additional counteractive therapeutic agent can be comprised within the core that releases the therapeutic agent that treats the eye, such as shown inFIG. 2A, or separate drug cores can be provided to separately release the additional counteractive therapeutic agent, such as shown inFIGS. 3A,4A and5A.

For example, one possible side effect of a cycloplegic therapeutic agent is pupil dilation that can result in photophobia. Therefore, a miotic therapeutic agent is released into the eye to counteract the pupil dilation caused by the cycloplegic. Cycloplegic therapeutic agents may include atropine, cyclopentolate, succinylcholine, homatropine, scopolamine, and tropicamide. Miotic therapeutic agents may include echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, carbachol, methacholine, bethanechol, epinephrine, dipivefrin, neostigmine, echothiopateiodide and demecium bromide. Other suitable therapeutic agents include mydriatics such as hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium and eucatropine. In addition, anti-cholinergics may be employed such as, pirenzepine. Examples of applicable therapeutic agents may be found in United States Patent Applications 20060188576 and 20030096831, hereby incorporated by reference in their entirety.

Another potential side effect of cycloplegic therapeutic agents is glaucoma, possibly related to the dilation of the pupil. Therefore, the second therapeutic agent is an anti-glaucoma agent released to counteract a possible glaucoma inducing side effect of the first therapeutic agent used to treat the eye. Suitable anti-glaucoma therapeutic agents include: sympathomimetics such as Apraclonidine, Brimonidine, Clonidine, Dipivefrine, and Epinephrine; parasympathomimetics such as Aceclidine, Acetylcholine, Carbachol, Demecarium, Echothiophate, Fluostigmine, Neostigmine, Paraoxon, Physostigmine, and Pilocarpine; carbonic anhydrase inhibitors such as Acetazolamide, Brinzolamide, Diclofenamide, Dorzolamide, and Methazolamide, beta blocking agents such as Befunolol, Betaxolol, Carteolol, Levobunolol, Metipranolol, and Timolol; prostaglandin analogues such as Bimatoprost, Latanoprost, Travoprost, and Unoprostone; and other agents such as Dapiprazole, and Guanethidine. In a preferred embodiment, atropine is released as a first therapeutic agent to treat developmental myopia in children, and bimatoprost and/or latanoprost is released as a second therapeutic agent for anti-glaucoma treatment.

Other non-limiting examples of the active agents or medications which are appropriate for use with the invention include, for example only: topical prostaglandin derivatives such as latanoprost, travaprost and bimataprost used for the topical treatment of glaucoma. Also a treatment for corneal infections is appropriate using ciprofloxacin, moxifloxacin or gatifloxacin. Systemic medications useful for this invention are those used for hypertension such as atenolol, nifedipine or hydrochlorothiazide. Any other chronic disease requiring chronic medication could be used. The active agents or medications may by antiinfective agents. For example for bacteria use fluoroquinolones, lactan, aminoglycosides or cephalasporins. For antiviral agents use antimycotics. For anti-inflammatory agents use gluco corticoid steroid, NSAIDs and other analgesics.

The treatment of allergic conjunctivitis and rhinitis are also applications for the invention, e.g. using antihistamine and anti-allergy medication such as olopatadine and cromalyn sodium in or on the implant.

This list of active agents is not comprehensive in that many other agents can be used with the present invention. For example, a treatment for dry eye by topical cyclosporin is particularly interesting for administration by the present invention, in which a therapeutic amount of cyclosporin may be delivered each day that is less than the daily drop administered quantity, for example, the therapeutic amount may be 5 to 10% of the drop administered quantity of cyclosporin or Restasis®, commercially available from Allergan. There are many other active agents can also be administered using the method and apparatus of the invention. The active agents may be lubricants and emollients like PVA, PVP, modified cellulose molecules like carboxymethyl cellulose and hydroxypropyl methyl cellulose, also Hyaluronic acid and mucin stiulators.

It should be noted that some therapeutic agents will have more than one effect on the eye. For example, anti-glaucoma therapeutic agents can also cause pupil constriction. Thus in some embodiments, the second therapeutic agent can counteract more than one side effect of the first therapeutic agent that is released to treat the eye.

The rate of release of the first and second therapeutic agents can be related to the concentration of first and second therapeutic agents dissolved in the drug cores. In many embodiments, the drug cores comprise additional non-therapeutic agents that are selected to provide a desired solubility of the first and second therapeutic agents in the drug cores. The non-therapeutic agent of the drug cores can comprise polymers as described above and additives. A polymer of the drug core can be selected to provide the desired solubility of the first and second therapeutic agents in the matrix. For example, the drug core can comprise hydrogel that may promote solubility of hydrophilic treatment agents. In some embodiments, functional groups can be added to the polymer to modulate the release kinetics of one or both of the therapeutic agents. For example, functional groups can be attached to silicone polymer. In some embodiments different ions may generate different salts with different solubility.

In some embodiments, additives may be used to control the concentration of the first and second therapeutic agents by increasing or decreasing solubility of the therapeutic agents in the drug cores. The solubility may be controlled by providing appropriate molecules and/or substances that increase and/or decrease the solubility of the dissolved form of the therapeutic agents to the matrixes. The solubility of the dissolved form of the therapeutic agents may be related to the hydrophobic and/or hydrophilic properties of the matrix and therapeutic agents. For example, surfactants, salts, hydrophilic polymers can be added to the matrix to modulate the release kinetics. In addition, oils and hydrophobic molecules can be added to the matrix to modulate the release kinetics of the matrix.

Instead of or in addition to controlling the rate of migration based on the concentration of the first and second therapeutic agents dissolved in the matrix, the surface area of the drug cores can also be controlled to attain the desired rate of drug migration from the core to the target site. For example, a larger exposed surface area of the drug cores will increase the rate of migration of the first and second therapeutic agents from the drug core to the target site, and a smaller exposed surface area of the drug core will decrease the rate of migration of the first and second therapeutic agents from the drug core to the target site. The exposed surface area of the drug cores can be increased in any number of ways, for example by making the exposed surface tortuous or porous, thereby increasing the surface area available to the drug cores.

The sheath body of the implants disclosed above comprise appropriate shapes and materials to control migration of the first and second therapeutic agents from the drug cores. The sheath body houses the drug cores and can fit snugly against the cores. The sheath body is made from a material that is substantially impermeable to the therapeutic agents so that the rate of migration of the therapeutic agents may be largely controlled by the exposed surface area of the drug cores that are not covered by the sheath body. Typically, migration of the therapeutic agents through the sheath body will be about one tenth of the migration of the therapeutic agents through the exposed surface of the drug cores, or less, often being one hundredth or less. In other words, the migration of the therapeutic agents through the sheath body is at least about an order of magnitude less that the migration of the therapeutic agents through the exposed surface areas of the drug cores. Suitable sheath body materials include polyimide, polyethylene terephthalate” (hereinafter “PET”). The sheath body has a wall thickness from about 0.00025″ to about 0.0015″. The total diameter of the sheath that extends across the drug cores range from about 0.2 mm to about 1.2 mm. The drug cores may be formed by dip coating the drugs cores in the sheath material. Alternatively, the sheath body can be a tube and the drug cores introduced into the sheath as a liquid or slid into the sheath body tube,

The sheath body can be provided with additional features to facilitate clinical use of the implant. For example, the sheath may replaceable receive drug cores that are exchangeable while the retention element and sheath body remain implanted in the patient. The sheath body is often rigidly attached to the retention element as described above, and the drugs cores are exchangeable while the retention element retains the sheath body. For example, the sheath body can be provided with external protrusions that apply force to the sheath body when squeezed and eject the drug cores from the sheath body. Another drug core can then be positioned in the sheath body.

In another embodiment, the therapeutic implant includes an implantable body that is sized and shaped for insertion into the patient body. The implantable body has a first receptacle and a second receptacle. The first receptacle includes a first therapeutic agent and a first surface for releasing the first therapeutic agent. The second receptacle includes a second therapeutic agent and a second surface for releasing the second therapeutic agent. The first and second therapeutic agents may be any therapeutic agent described herein. The first and second therapeutic agents may be released at therapeutic levels through the first and second surfaces of the first and second receptacles over a sustained period when the implant is implanted for use. As disclosed herein, the release rate and/or the release period of the first and second therapeutic agents may be the same or different. In other embodiments, the first and second receptacles be shaped and positioned within the sustained release implants and therapeutic implants described in the present application.

FIG. 21 schematically illustrates one embodiment of a lacrimal insert in the shape of apunctal plug2100 for use in a therapeutic implant configured to hold a sustained release implant with at least one drug core containing first and second therapeutic agents. Thepunctal plug2100 includes acollarette2110 at a proximal end which rests on the exterior of thepunctum11,13 (seeFIG. 34), abulb2120 with a taperedportion2125 terminating in atip2135 at a distal end that blockingly projects into thecanaliculus10,12 (seeFIG. 34), and abody portion2130 connecting thecollarette2110 and thebulb2120. Thepunctal plug2100 is approximately 2.0 mm in length. Thebulb2120 is designed to prevent thepunctal plug2100 from being easily dislodged from the

canaliculus

10,12, and may be tapered for ease of insertion into the

punctum

11,13. Thecollarette2110 is designed to have a diameter to prevent thepunctal plug2100 from completely entering the

canaliculus

10,12, and is preferably smooth to minimize irritation of the eye. Thebody portions2130 of thepunctual plug2100 is essentially anon-functional connection between thecollarette2110 and thebulb2120 portions. Thecollarette2110 includes anaperture2140 extending into thebody portion2130 into which animplant2145 is placed. The size of theaperture2140 is selected to hold the implant in place during treatment. In some embodiments, a sheath body of the implant may be omitted and the drug core(s) may be inserted directly into theaperture2140 of thepunctal plug2100. In some embodiments, thetip2135 is closed, in other embodiments, anopening2150 in thetip2135 at the distal end allows access to theaperture2140, allowing fluid flow through the punctal plug. In some embodiments, an optionalnon-porous head2115 is provided over thecollarette2110 to enclose theaperture2140. In accord with one aspect of the invention, thebody2110 andhead2115 are made of different materials, with thebody2110 may be molded or otherwise formed from a flexible material, such as silicone, that is impermeable to the therapeutic agents, and thehead2115 being made from a biocompatible, preferably soft and flexible second material which is permeable to the medication. When thepunctal plug2100 is in place, the therapeutic agents are deployed from the drug core(s) into the tears of the lacrimal lake where the therapeutic agents mix, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. The size of theaperture2140 is selected to hold the implant in place during treatment.

FIGS. 22-25 show different embodiments of therapeutic implants having a structure, such as apunctual plug2100. Other structures suitable for incorporation with the present invention are described in U.S. Pat. App. Pub. Nos. 2006/0020253, entitled “Implantable device having controlled release of medication and method of manufacturing the same”, published in the name of Prescott on Jan. 26, 2006; and U.S. Pat. No. 7,117,870, entitled “Lacrimal insert having reservoir with controlled release of medication and method of manufacturing the same”, issued on Oct. 10, 2006 in the name of Prescott, the full disclosures of which are incorporated herein by reference. The reservoir can include any of the therapeutic agents described herein to treat the eye, for example medications to treat optical defects of the eye.

FIG. 22 schematically illustrates one embodiment of atherapeutic implant2200 having apunctal plug2100 and a sustained release implant containing first and second therapeutic agents. In the embodiment shown, the sustained release implant is sustainedrelease implant2200 discussed above havingdrug core2210 withfirst inclusions2260 of a first therapeutic agent andsecond inclusions2265 of a second therapeutic agent. This embodiment of thetherapeutic implant2200 further includes theoptional head2115 at a proximal end that is permeable to the first and second therapeutic agents. When thetherapeutic implant2200 is in place, the first and second therapeutic agents are deployed from proximal end of the drug core through the permeable head into the tears of the lacrimal lake where the first and second therapeutic agents mix, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. The size of the aperture2240 is selected to hold the sustained release implant in place during treatment. In the embodiment shown, the sheath body is also within theaperture2140. In other embodiments, thesheath body2220 may be omitted and thedrug core2210 may be inserted directly into theaperture2140 of thepunctal plug2100.

FIG. 23 schematically illustrates one embodiment of atherapeutic implant2300 having apunctal plug2100 and a sustained release implant having first and second concentric drug cores with first and second therapeutic agents. In the embodiment shown, the sustained release implant is sustainedrelease implant2300 having an outerfirst drug core2310 withfirst inclusions2360 of a first therapeutic agent and an innersecond drug core2315 withsecond inclusions2365 of a second therapeutic agent. When thetherapeutic implant2300 is in place, the first and second therapeutic agents are deployed from the drug cores at the exposed or proximal end and into the tears of the lacrimal lake where the first and second therapeutic agents mix, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. The size of theaperture2140 is selected to hold the sustained release implant in place during treatment. In some embodiments, thesheath body2320 of theimplant2300 may be omitted and the first and

second drug cores

2310,2315 may be inserted directly into theaperture2140 of thepunctal plug2100. Optionally, ahead2115 may be used that is permeable to the first and second therapeutic agents, wherein first and second therapeutic agents are deployed from first and

second drug cores

2310,2315 throughpermeable head2115.

FIG. 24 schematically illustrates one embodiment of atherapeutic implant2400 having apunctal plug2100 and a sustained release implant having first and second drug cores containing first and second therapeutic agents. In the embodiment shown, the sustained release implant is sustainedrelease implant2400 having afirst drug core2410 withfirst inclusions2460 of a first therapeutic agent next to asecond drug core2415 withsecond inclusions2465 of a second therapeutic agent. When thetherapeutic implant2400 is in place, the first and second therapeutic agents are deployed from the drug cores at the exposed or proximal ends and into the tears of the lacrimal lake where the first and second therapeutic agents mix, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. The size of theaperture2140 is selected to hold theimplant2400 in place during treatment. In some embodiments, thesheath body2420 of theimplant400 may be omitted and the first and

second drug cores

2410,2415 may be inserted directly into theaperture2140 of thepunctal plug2100. Optionally, ahead2115 may be used that is permeable to the first and second therapeutic agents, wherein first and second therapeutic agents are deployed from the first and

second drug cores

2410,2415 through thepermeable head2115.

FIG. 25 schematically illustrates one embodiment of atherapeutic implant2500 having apunctal plug2100 and a sustained release implant having first and second concentric drug cores in a flow-through configuration, with each drug core containing a therapeutic agent. In the embodiment shown, the sustained release implant is sustainedrelease implant2500 having an outerfirst drug core2510 withfirst inclusions2560 of a first therapeutic agent and an innersecond drug core2515 withsecond inclusions2565 of a second therapeutic agent. In the embodiment shown, thepunctal plug2100 includes anopening2150 in thetip2135 at the distal end allowing fluid flow through the body of thepunctal plug2100 from the proximal end to the distal end and through first and

second drug cores

2510,2515. When thetherapeutic implant2500 is in place, the first and second therapeutic agents are deployed from the

drug cores

2510,2515 at the exposed ends and exposed

inner surfaces

2585,2580 as the fluid flows through. The size of theaperture2140 of thepunctal plug2100 is selected to hold the implant in place during treatment and theopening2150 is sized to allow sufficient flow through theimplant2100 and first and

second drug cores

2510,2515. In some embodiments, the sheath body of the implant may be omitted and first and

second drug cores

510,2515 may be inserted directly into theaperture2140 of thepunctal plug2100. Optionally, ahead2115 may be used that is permeable to the first and second therapeutic agents. Other flow-through structures suitable for incorporation with the present invention are described in U.S. patent application Ser. No. 11/695,545, entitled “Nasolacrimal Drainage System Implants for Drug Therapy, filed Apr. 2, 2007, the full disclosure of which is incorporated herein by reference.

FIGS. 26A-26C show

therapeutic implants

2600,2600′,2600″ that encompass punctual plugs and structures that release first and second therapeutic agents, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. No. 3,949,750, entitled “Punctum plug and method for treating keratoconjunctivitis sicca and other ophthalmic aliments using same”, issued in the name of Freeman on Apr. 13, 1976, the full disclosure of which is incorporated herein by reference. The head portion can include any two of the therapeutic agents described herein to treat the eye.

In the treatment of ophthalmic ailments where it is desired to prevent or decrease the drainage of lacrimal fluid and/or medication from the eye, the punctal aperture in one or both of the upper and lower lids are to be blocked by therapeutic implants, two respective embodiments of which are shown inFIGS. 26A and 26B. Referring initially to the embodiment ofFIG. 26A, thetherapeutic implant2600 has a blunted tip orbarb portion2620 at a distal end, a middle neck or waist portion26130 of somewhat smaller diameter than the tip, and a smooth disc-like head portion2610 at a proximal end of relatively larger diameter. Thetherapeutic implant2600′ ofFIG. 26B is of generally similar dimensions to the first described embodiment with a blunted tip orbarb portion2620′, a cylindricalmiddle portion2630′ of substantially the same dimension, and a dome-shapedhead portion2610′ of somewhat smaller diameter than its counterpart in the embodiment ofFIG. 26A.

The

head portion

2610,2610′ of both embodiments may be provided, if desired as an alternative to grasping it with forceps, with a

central bore opening

2640,2640′ adapted to receive the projecting tip of an inserter tool to provide a releasable grip on the therapeutic implant as it is manipulated for insertion, as hereinafter described.

FIG. 26C shows a hollowtherapeutic implant2600″ that is of generally similar dimensions to the first-described embodiment having a blunted tip orbarb portion2620″, a middle neck orwaist portion2630″ of somewhat smaller diameter than the tip, a smooth disc-like head portion2610″ of relatively larger diameter and acentral bore2640″ extending through the plug. Thecentral bore2640″ allows fluid flow from a proximal end to distal end of thetherapeutic implant2600″.

In some embodiments of the invention, the two therapeutic agents as described herein are incorporated in a punctal plug as described in U.S. App. Pub. No. 2005/0197614, the full disclosure of which is incorporated herein by reference. A gel can be used to form the

therapeutic implant

2600,2600′,2600″ and the gel can swell from a first diameter to a second diameter in which the second diameter is about 50% greater than the first diameter. The gel can be used to entrap the first and second therapeutic agents, for example within a microporous structure in which the agents are uniformly dispersed, and the gel can slowly elute the first and second therapeutic agents into the patient. Various therapeutic agents have been describe herein and additional therapeutic agents are described in U.S. Provisional Application No. 60/550,132, entitled “Punctum Plugs, Materials, And Devices”, the full disclosure of which is incorporated herein by reference, and may be combined with the gels and devices described herein.

In other embodiments of the invention, the entire body or only portions of the

therapeutic implants

2600,2600′,2600″ may be made of a medication-impregnable porous material such as HEMA hydrophilic polymer, or may be otherwise adapted as with capillaries or the like, to store and slowly dispense ophthalmic drugs to the eye as they are leached out by the lacrimal fluids. For example, the

head portion

2610,2610′,2610″ of each embodiment may be medication-impregnable porous material impregnated with first and second therapeutic agents.

FIG. 27 shows therapeutic implants containing first and second therapeutic agents as applied to the eye. In the embodiment shown, atherapeutic implant2700 is designed for insertion into thelower punctal aperture13 of theeye2, and along thecanaliculus12 communicating with the aperture. Thetherapeutic implant2700 includes acollarette2710 at a proximal end, a flaredportion2720 at a distal end, aneck portion2730. Thecollarette2710 is designed for seating against theaperture13. Examples of suitabletherapeutic implants2700 containing two therapeutic agents have been described above, and include

therapeutic implants

2200,2300,2400,2500,2600,2600′ and2600″. Thetherapeutic implant2700 may be used to block fluid flow, or may have a hollow portion allowing fluid flow. In the embodiment shown inFIG. 27, thetherapeutic implant2700 is shown as being a hollow like a straw shape for the passage of tears. Examples of these include

therapeutic implants

2500 and2600″. Unlike the tear stopping

therapeutic implants

2200,2300,2400,2600 and2600′, the hollow

therapeutic implants

2500 and2600″ provide a very different drug administering method, scheme and structure. The hollow therapeutic implant is particularly useful in that the active agents are available at the inner surface or interior of the therapeutic implant, and is uniquely structured to pass tears and thus administer the active therapeutic agents to the tear stream in a fashion that is controlled by the flow of tears which thus act as the carrier for the therapeutic agents.

FIG. 27 further shows animplant2700′ containing first and second therapeutic agents that is a substantially cylindrical in shape that has been inserted into theupper punctum aperture11, to block the flow of tears tocanaliculus10, whilelower punctal plug2700 passes the tears tocanaliculus12. Examples ofsuitable implants2700′ containing two therapeutic agents may be any one of the implants disclosed herein, or it may be an occlusive plug of some inert biocompatible material.

Thetherapeutic implant2700 andimplant2700′ can be used in any desired combination, either separately or in combination (shown inFIG. 27). For example,implant2700′ can be positioned in the lower canaliculus andtherapeutic implant2700 can be positioned in the upper canaliculus. Alternatively, two of the same

therapeutic implants

2700 or2700′ can be positioned in both canaliculi.

FIGS. 28,29A-29D,30A, and30B show embodiments of various drug delivery core elements for use in a therapeutic implant that can be tailored to each individual patient based on their needs. The core elements of the therapeutic implant are pie slice shaped and can be assembled into cylindrical shaped drug cores with many different configurations with many different therapeutic agents. Doing this can achieve therapeutic implant configurations to maximize individual patient management. This approach can tailor treatment to use multiple therapeutic agents for disease management. The approach can also tailor the dose of the therapeutic agent based on the genetic and/or physiological condition of the patient.

FIG. 28 shows various core elements, or drug cores, that are combinable into a, for example, cylindrical shaped drug core according to embodiments of the present invention. The drug core need not be cylindrical, but a cylindrical drug core is preferred for ease of manufacture.Drug core2810 is a blank core element that does not contain a therapeutic agent,drug core2820 contains atherapeutic agent2825 with a concentration X,drug core2830 contains atherapeutic agent2835 with a concentration Y, anddrug core2840 contains atherapeutic agent2845 with a concentration Z. The cores and the therapeutic agents may be any of the cores and therapeutic agents disclosed herein. While the drug cores are shown as pie slice shaped (sectors), the drug cores are not limited to any particular shape. Since the

drug cores

2810,2820,2830, and2840, or any combination thereof, together can form a right cylindrical shape, (for example, seeFIGS. 29A-D) each drug core in this instance is a right prismatic shape with the particular cross-section, for example, a sector cross-section. The drug cores may have many different combinable shapes, for example square, rectangular, oval, jig saw puzzle piece, to name a few.

FIGS. 29A-29D show different embodiments of a cylindrical shaped drug core using the core elements ofFIG. 28 surrounded by asheath body2920.Sheath body2920 is can be substantially impermeable to the therapeutic agents, so that the therapeutic agents are often released from an exposed surface on an end of the cylindrical shaped drug core that is not covered withsheath body2920. In some embodiments, the sheath body may be omitted and the cylindrical shaped drug core be place directly into the implant, such as placement in an aperture of a punctal plug. While only four embodiments are shown for the cylindrical shaped drug core, any suitable drug cores and therapeutic agents may be used.

FIG. 29A shows one embodiment of a cylindrical shapeddrug core2900 assembled using two core elements2810 (blank cores), onecore element2820 and onecore element2830. The cylindrical shapeddrug core2900 is then able to delivertherapeutic agent2825 with a concentration X andtherapeutic agent2835 with a concentration Y.

FIG. 29B shows one embodiment of a cylindrical shapeddrug core2905 assembled using one core element2810 (blank core), onecore element2820, onecore element2830 and onecore element2840. The cylindrical shapeddrug core2905 is then able to delivertherapeutic agent2825 with a concentration X, therapeutic agent2935 with a concentration Y andtherapeutic agent2845 with a concentration Z.

FIG. 29C shows one embodiment of a cylindrical shapeddrug core2910 assembled using two core elements2810 (blank core) and twocore elements2840. The cylindrical shapeddrug core2910 is then able to deliver two dosestherapeutic agent2845 with a concentration Z.

FIG. 29D shows one embodiment of a cylindrical shapeddrug core2915 assembled using fourcore elements2840. The cylindrical shapeddrug core2915 is then able to deliver four dosestherapeutic agent2845 with a concentration Z.

FIGS. 30A and 30B show other embodiments of a cylindrical shaped drug core assembled from core elements of different shapes.FIG. 30A shows a cylindrical shapeddrug core3000 made from two

core elements

3010,3015 that are semicircular in shape surrounded by asheath body3020.FIG. 30B shows a cylindrical shapeddrug core3030 made from three

core elements

3040,3045 and3050 surrounded bysheath body3020. While embodiments may include a plurality of core elements of substantially even sizes as shown, other embodiments may include core elements of two or more differing sizes. For example, asemicircular core element3010 may be combined with two ¼

circular core elements

2830 and2840. A wide variety of different sizes and uneven shapes may also be combined with a variety of geometries, with or without sheath body material (or other material that is substantially impermeable to one or more of the therapeutic agents) being disposed between the adjacent drug core elements. For example, sheets of drug core material (including matrix and an associated agent) may formed separately and stacked or layered, and/or may be formed sequentially by polymerizing the matrix over a substrate or underlying drug core element sheet. The multi-layered drug core element sheets could then be cut across the layers to a desired drug core length and/or width. An end and/or side of the sheet could be exposed in the implanted device, with the exposed end or side of each layered drug core element having a surface area dependent on a thickness of the associated drug core layer or sheet.

FIG. 31 shows a sectional view of asustained release implant3100 having afirst drug core3110 with a firsttherapeutic agent3160 and asecond drug core3115 with a secondtherapeutic agent3165 to treat an eye, the first and second drug cores being in a stacked configuration, according to an embodiment of the present invention.

FIG. 31 shows a cross sectional view of asustained release implant3100 having two therapeutic agents to treat aneye2, according to embodiments of the present invention.Implant3100 has aproximal end3112 in which the therapeutic agents are released and adistal end3114.Implant3100 includes two

drug cores

3110,3115.First drug core3110 is a cylindrical shaped structure that includes a first therapeutic agent, andsecond drug core3115 is a cylindrical shaped structure that includes a second therapeutic agent. Thefirst drug core3110 and thesecond drug core3115 are assembled in a stacked configuration, as shown in the figures, with thefirst drug core3110 being positioned near theproximal end3112.First drug core3110 comprises afirst matrix3170 that containsfirst inclusions3160 of the first therapeutic agent, andsecond drug core3115 comprises asecond matrix3175 that containssecond inclusions3165 of the second therapeutic agent. First and

second inclusions

3160,3165 will often comprise a concentrated form of the first and second therapeutic agents, for example a liquid or solid form of the therapeutic agents, and the therapeutic agents may over time dissolve intofirst matrix3170 offirst drug core3110 andsecond matrix3175 ofsecond drug core3115. First and

second matrixes

3170,3175 can comprise a silicone matrix or the like, and the mixture of therapeutic agents within matrixes can be non-homogeneous. In many embodiments, the non-homogenous mixture comprises a silicone matrix portion that is saturated with the therapeutic agents and an inclusions portion comprising inclusions of the therapeutic agents, such that the non-homogenous mixture comprises a multiphase non-homogenous mixture. The first matrix may differ from the second matrix, including, for example, an exposed surface area, a surfactant, a cross-linking, an additive, and/or matrix materials including formulation and/or solubility. In some embodiments, first and

second inclusions

3160,3165 comprise droplets of an oil of the therapeutic agent, for example latanoprost oil. In some embodiments first and

second inclusions

3160,3165 may comprise particles of the therapeutic agents, for example solid bimatoprost particles. In many embodiments,first matrix3170 containsfirst inclusions3160 andsecond matrix3175 containssecond inclusions3165. First and

second inclusions

3160,3165 may comprise microparticles having dimensions from about 0.1 μm to about 100 μm, or about 200 μm. The contained inclusions at least partially dissolve into the surrounding solid matrix, for example silicone, that contain the micro particles such that first and

second matrixes

3170,3175 are substantially saturated with the therapeutic agent while the therapeutic agent is released from the core.

First and

second drug cores

3110,3115 are surrounded by asheath body3120, except at an exposed surface where the therapeutic agents are released, in this case at theproximal end3112.Sheath body3120 is substantially impermeable to the therapeutic agents, so that the therapeutic agents are released from the exposed surface on the open end of first and

second drug cores

3110,3115 that are not covered withsheath body3120. In some embodiments, the sheath body is similar tosheath body3120 disclosed above, and a retention structure and an occlusive element, such as retention element and occlusive element as discussed above, may be connected to the sheath body. In other embodiments, the implant may be incorporated into a different structure, such as a punctal plug (seeFIG. 32).

FIG. 32 schematically illustrates one embodiment of atherapeutic implant3200 having a punctal plug and a sustained release implant having first and second stacked drug cores with first and second therapeutic agents. In the embodiment shown, the sustained release implant is sustainedrelease implant3100 having a proximalfirst drug core3110 withfirst inclusions3160 of a first therapeutic agent and a distalsecond drug core3115 withsecond inclusions3165 of a second therapeutic agent. When thetherapeutic implant3200 is in place, the first therapeutic agent is deployed from the proximal first drug core at the exposed or proximal end and into the tears of the lacrimal lake where the first therapeutic agent mixes, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. Subsequent to that, the second therapeutic agent is deployed from the distal second drug core, through the first drug core to the exposed or proximal end and into the tears of the lacrimal lake where the second therapeutic agent mixes, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. The size of theaperture2140 is selected to hold thesustained release implant3100 in place during treatment. In some embodiments, thesheath body3120 of theimplant3100 may be omitted and the first and

second drug cores

3110,3115 may be inserted directly into theaperture2140 of thepunctal plug2100. Optionally, ahead2115 may be used, such as shown inFIG. 22, that is permeable to the first and second therapeutic agents, wherein first and second therapeutic agents are deployed from first and

second drug cores

3110,3115 throughpermeable head3115.

In other embodiments, referring toFIG. 33, the multiple drug deliverytherapeutic implants3310 may be implanted in other portions of abody3300, not just in the punctum, to treat a body condition, as shown inFIG. 33. Thetherapeutic implants3310 are sustained release implants with at least one drug core containing first and second therapeutic agents that is used to delivery multiple drugs to treat other conditions or diseases other than the eye.Therapeutic implant3310 may include therapeutic implants having two or more therapeutic agents released from an exposed surface of core(s), such as the therapeutic implants described above. The therapeutic implant may be implanted by known means.

The first and second therapeutic agents are released at therapeutic levels to provide a desired treatment response when the implants are implanted in a body. The first and second therapeutic agents are preferably released at therapeutic levels over a sustained period. In some embodiments the drug cores may release first and second therapeutic agents at an effective rate for the period of 1 week to 5 years, more particularly in the range of 3-24 months. In some embodiments it may be desirable for the drugs cores to have similar release rates for the first and second therapeutic agents. In other embodiments, it may be desirable for the drug cores to have different release rates for the first and second therapeutic agents, depending on the therapeutic agents used. In some embodiments, the therapeutic level is less than a dose administered quantity or less or 5-10% of the dose administered quantity, typically being less than 10% and often being 5% or less than the dose administered quantity each day for an extended period of days. The dose administered quantity may be the oral dose or may be an injectable dose.

In use, thetherapeutic implant3310 is implanted in thebody3300, where a body fluid may contact the exposed surface of the drug core(s), releasing the first and second therapeutic agents. Depending on the implant location, any body fluid proximate the therapeutic implant, such as blood, may contact the exposed surface, releasing the first and second therapeutic agents from the implant. The therapeutic implant location may include body locations for local drug delivery to joints, such as proximate the shoulder, knee, elbow, or atrauma location3315, or atrauma location3320, other locations, such as the abdomen, for general drug delivery. Thetherapeutic implant3310 may include one or more retention elements known in the art to retain thetherapeutic implant3310 near a body location, such as the body locations listed above.

In one embodiment, a therapeutic implant may be used in oncology, where chemotherapy involves use of a cocktail that is dependent upon the primary tumor type. Use of a local therapeutic implant drug delivery could allow an extra benefit of treating a tumor site post surgically, and minimizing the collateral damage to the rest of the body. An example would be lumpectomy for breast tumor or surgical treatment of prostate cancer, where the therapeutic implant would be implanted near the cancer site. In fact any solid tumor would be a target, with the therapeutic implant being implanted near the tumor.

In another embodiment, a therapeutic implant may be used for the delivery of multiple drugs, sometimes called cocktails, for the treatment of HIV. In this instance, the therapeutic implant would be treating a systemic disease. One example of the multiple drugs in the therapeutic implant is a protease inhibitor and a nucleic acid target.

Some treatments are contraindicated due to other disease states. An example is diabetics where surgeries including amputation are often required in patients where circulation and wound healing is impaired. The use of steroids could not be used systemically in these patients, but could be used locally. In this embodiment, the therapeutic implant is positioned post surgically in the body at the appropriate location for local delivery of a steroid and another drug, such as an antiinflammatory or anti-infective drug. In some embodiments, the steroid may be released at therapeutic levels for 8 or more weeks and the anti-inflammatory may be released at therapeutic levels for 2-4 weeks.

In joints, non-steroidal anti-inflammatory drugs (NSAIDs) may be used for the treatment of such things as osteoarthritis and rheumatoid arthritis. Delivery of NSAIDs locally would reduce the risk associated with systemic cox II inhibitors, such as gastrointestinal problems (problems in the stomach or intestine) the may include stomach ulcers or bleeding, and possibly life threatening perforations (rips or holes) in the wall of the stomach or intestine. In this embodiment, the therapeutic implant is positioned near the joint to deliver NSAIDs locally and may also include the delivery of a nutritional supplement, like glucosamine, and perhaps get a positive physiological response in local tissue.

In another embodiment, a therapeutic implant may be used for localized delivery of multiple drugs to a trauma site, such as delivering an analgesic and an antiinfectives.

FIGS. 34 and 35 show anatomical tissue structures of aneye2 suitable for treatment with implants, according to an embodiment of the present invention.Eye2 includes acornea4 and aniris6. Asclera8 surroundscornea4 andiris6 and appears white. Aconjunctival layer9 is substantially transparent and disposed oversclera8. Acrystalline lens5 is located within the eye. Aretina7 is located near the back ofeye2 and is generally sensitive to light.Retina7 includes afovea7F that provides high visual acuity and color vision.Cornea4 andlens5 refract light to form an image onfovea7F andretina7. The optical power ofcornea4 andlens5 contribute to the formation of images onfovea7F andretina7. The relative locations ofcornea4,lens5 andfovea7F are also important to image quality. For example, if the axial length ofeye2 fromcornea4 toretina7F is large,eye2 can be myopic. Also, during accommodation,lens5 moves towardcornea4 to provide good near vision of objects proximal to the eye.

The anatomical tissue structures shown inFIG. 34 also include the lacrimal system, which includes anupper canaliculus10 and alower canaliculus12, collectively the canaliculae, and a naso-lacrimal duct orsac14. Theupper canaliculus10 andlower canaliculus12 extend from thelacrimal sac14 and terminate in anupper punctum11 and alower punctum13, respectively, that also referred to as punctal apertures. The punctal apertures are situated on a slight elevation at the medial end of the lid margin at thejunction15 of the ciliary and lacrimal portions near themedial canthus17. The punctal apertures are round or slightly ovoid openings surrounded by a connective ring of tissue. Each canaliculus extends from

punctal openings

11,13, and comprises avertical position10v,12vof the respective canaliculus before turning horizontally to join its other canaliculus at the entrance of alacrimal sac14. The canaliculae are tubular and lined by stratified squamous epithelium surrounded by elastic tissue which permits the canaliculus to be dilated. The upper and lower canaliculi may each comprise an

ampulla

10a,12a, or small dilation, in the respective canaliculus.

Manufacture of Implants

FIG. 6A shows amethod600 of manufacturing an implant, according to embodiments of the present invention. Asub method610 manufactures a punctal plug. Asub method650 manufactures a drug core insert, for example as described above. Asub method690 assembles the components into an integrated drug delivery system.

FIG. 6B shows amethod620 of manufacturing a hydrogel rod for the punctal plug in accordance withmethod600 ofFIG. 6A. In some embodiments,method620 comprises a sub method, or sub-step, ofmethod610. Astep622 combines 40% by weight hydrogel with an organic solvent. In some embodiments, the percentage of hydrogel comprises a range from about 5% to about 50% hydrogel, for example from about 20% to about 40% hydrogel. Astep624 mixes the hydrogel with the solvent. In some embodiments, the hydrogel may dissolve in the organic solvent. Astep626 injects the hydrogel into a silicone tube. In many embodiments, the silicone tube is permeable to the organic solvent. The silicone tube comprises a mold to form the hydrogel. Astep628 cures the hydrogel. At least one of a heat or a pressure, in many embodiments both, can be used to drive off the solvent, for example through the permeable mold, to cure the hydrogel. Astep629 cuts the cured hydrogel to a desired length. The curing can be optimized with empirical process/validation studies with an adequate a sample size, for example 10 sample of cured hydrogels, to determine material variability and/or process variability over time. Process variable that can be optimized include time, pressure and temperature of curing. Tolerance analysis associated with the process can also be performed.

FIG. 6C shows amethod630 of molding asilicone plug body637 in accordance withmethod600 ofFIG. 6A. Astep632 winds a filament comprising a solid material, for example acoil632C, and heat sets the filament. Astep634 places the filament comprising heat setcoil632C in a mold. Astep636 molds plugbody637 withcoil632C embedded therein. The plug body may comprise sleeves, tubes, retention structures and/or at least one chamber as described above. The filament may comprise at least one of a heat activated material, Nitinol, a shape memory material, a polymer, polypropylene, polyester, nylon, natural fibers, stainless steel, polymethylmethacrylate or polyimide. In some embodiments, the filament may comprise an absorbable thermoplastic polymer, for example at least one of polylactic acid (PLA), poly glycolic acid (PGA) or poly-lactic-co-glycolic acid (PLGA). The heat setting of the filament can be optimized by appropriately controlling the time and/or temperature of the heat filament based on empirical data from a sample of heat set filaments, for example 10 filaments. The molding of the plug atstep636 can be optimized in several ways, such as appropriate time and temperature, hard tooling of the mold, a multiple cavity mold, and mold equipment parameters. In some embodiments, a filament for removal of the drug core insert, as described above, can be molded with the plug body such that the filament is embedded in the plug body and positioned near the channel that receives the drug core insert.

FIG. 6D shows amethod640 of assembling the punctal plug components in accordance withmethod600 of inFIG. 6A. Step630 molds thepunctal plug body637 with acoil632C. Step620 molds a hydrogel rod. Astep642 inserts the hydrogel rod component into a channel of the plug body component. Astep644 extends windings ofcoil632C over the hydrogel rod. Astep648 dip coats the hydrogel rod and plug body. Astep646 may prepare ahydrogel coating solution646 comprising for example a 5% solution of hydrogel by weight. Aneedle648N may be placed in a channel of the plug body to hold the body while the hydrogel rod and plug body are dipped in the solution.

FIG. 6E shows amethod650 of manufacturing a drug core insert, in accordance withmethod600 of inFIG. 6A. A step661 prepares a syringe assembly to inject a drug matrix into a polyimide tubing. Astep662 prepares a polyimide tubing for injection. Astep670 prepares a drug core matrix for injection into the tubing. Astep672 injects the drug core matrix into the polyimide tubing. Astep680 cures the matrix inside the polyimide tubing. Astep682 cuts the polyimide tubing and cured matrix to a length and applies an adhesive.

Step661 can use known commercially available syringes in the syringe assembly. The syringe assembly may comprise a syringe tube and cartridge assembly. The syringe tube and cartridge assembly may comprise a tube attached to a modified needle tip that attaches that attaches to a syringe. The syringe can be connected to a syringe pump or other mechanism to pressurize the tube. The syringe assembly can be used for injection of the drug core mixture and/or material into the polyimide tubing. In some embodiments, multiple syringes can be used, for example with the manufacture of drug inserts that comprise two or- more drug cores. In some embodiments, the syringe assembly may comprise a manifold with two or more injection pots that can be used to with separate syringes in which each syringe includes a different drug core mixture.

Step662 can prepare the polyimide tubing for injection by attaching a 15 cm length of polyimide tubing to a luer. The luer can be connected to the syringe for injection of the drug core mixture and/or material. In some embodiments, the tubing connected to the syringe may comprise PMMA and/or PET. In many embodiments the tubing comprises a material that inhibits release of the therapeutic agent from the drug core through the tubing, for example a material that is substantially impermeable to the flow of the therapeutic agent through the tubing, such that the flow of therapeutic agent is directed toward the exposed end of the drug core. In some embodiments, for example drug core inserts comprising two or more concentric drug cores, the tubing may comprise concentric tubes, for example concentric polyimide tubes, with an outer tube arranged to receive and outer drug core mixture, and an inner tube arranged to receive an inner drug core mixture. With an annular drug core as described above, concentric tubes may be used to form the annular drug core, with an inner tube that can be removed after the drug core matrix material has solidified.

In some embodiments, a filament for removal of the drug core insert can be embedded in the drug core. The filament may be run through the sheath, for example tubing, and the mixture injected into the tubing. The matrix material is then cured with the filament embedded in the matrix.

Step670 can prepare a drug core mixture comprising a therapeutic agent with a matrix material, for example silicone. In some embodiments, the therapeutic agent may comprise at least one of latanoprost, bimatoprost or travoprost. Embodiments can use silicones that comprise dimethylsiloxane, for example Med-4011, Med-6385 and Med-6380 each of which is commercially available from NuSil of Lafayette, Calif. In some embodiments, two or more drug core mixtures are prepared, each for injection for a separate drug core, for example two mixtures one for an inner drug core and one for an outer drug core.

In a specific embodiment, step670 can prepare a drug core mixture comprising inclusions of latanoprost oil in silicone. The therapeutic agent and drug core matrix material can be prepared prior to mixing the therapeutic agent with the drug core matrix material.

Preparation of Therapeutic Agent:

Latanoprost oil can be provided as a 1% solution in methyl acetate. An appropriate amount of the 1% solution can be placed in a dish. A stream of dry nitrogen can be used to evaporate the solution until only the latanoprost remains. The dish with latanoprost oil can be placed under vacuum for 30 minutes. In some embodiments, for example those which use bimatoprost available as crystals as the therapeutic agent, the evaporation and vacuum may not be used to prepare the therapeutic agent.

In some embodiments with solid therapeutic agent, for example bimatoprost crystals, the therapeutic agent can be ground and passed through a sieve, prior to mixing with the matrix material. In some embodiments, the sieve may comprise a 120 sieve (125 um) and/or a 170 sieve (90 um). Work in relation to embodiments of the present invention indicates that a sieve may remove a very small fraction of therapeutic agent and that many embodiments will work with inclusions of therapeutic agent having a size greater than the optional sieve. In many embodiments, the release rate is independent of the size and/or distribution of size of the inclusions, and the release rate can be independent of particle size for particles from about 0.1 um to about 100 um. In some embodiments, the size and/or distribution of sizes of the particles and/or inclusions can be characterized with at least one of a sieve, light scatter measurements of the core, light microscopy of the core, scanning electron microscopy of the core or transmission electron microscopy of sections of the core. A sieve can generally be used to create desirable particle sizes and/or exclude undesirable particle sizes before mixing with the matrix. The exemplary sieve comprises a fine mesh that passes only the desired size particles or smaller, thereby limiting the therapeutic agent to finer drug particles. This can be used to produce a more homogenous drug core and/or drug particle size that is easier to mix with the silicone matrix than one with excessively large particles, although significant variations among particle sizes may remain. A variety of sieves may be used. For example, aSieve # 120 can be used so that the largest particle diameter passed is about 0.0049 inches.Sieve # 170 may pass particles of 0.0035 inch diameter or smaller. ASieve # 70 will allow a particle size of 0.0083 inch diameter to pass through. Sieves may optionally be used in series.

Preparation of Silicone:

Silicone, forexample NuSil 6385, can be obtained from the manufacturer in a sealed container. An appropriate amount of silicone can be weighed based on the lot size of the build.

Combine Therapeutic Agent with Silicone:

The therapeutic agent, for example latanoprost, can be combined with silicone, based on the intended and/or measured percentage of therapeutic agent in the drug core matrix. The percent of latanoprost to silicone can be determined by the total weight of the drug matrix. The therapeutic agent, for example latanoprost, is incorporated into the silicone by weighing out the appropriate amount of the components. The following formula can be used to determine the percentage of therapeutic agent in the drug core matrix:

Percent Drug=(weight of drug)/(weight of drug+weight of silicone)×100

For the specific example of latanoprost in silicone the percentage of latanoprost is silicone is given by:

(20 mg of latanoprost)/(20 mg of latanoprost+80 mg of silicone)×100=20%.

The therapeutic agent, for example latanoprost is combined and mixed with the silicone using known methods and apparatus for mixing silicones. In some embodiments, the therapeutic agent comprising latanoprost oil may form a micro emulsion comprising inclusions that may scatter light and appear white.

When a therapeutic agent such as latanoprost, which is in a liquid physical state at about room temperature (22° C.), and thus is also in a liquid physical state at human body temperature (37° C.), is used, the agent and the matrix material can be mixed by techniques that bring about a high degree of dispersion of the liquid latanoprost droplets in the matrix material in which it can be substantially insoluble. Mixing techniques should provide for a dispersion of the droplet within the matrix material, such that when curing takes place, the liquid therapeutic agent is present as relatively small, relatively homogeneously dispersed discrete droplets within the matrix of solid silicone material. For example, mixing can include sonication, i.e., the use of ultrasonic frequencies, such as are generated by an ultrasonic probe. The probe can be put in contact with the mixture of matrix material and liquid therapeutic agent to prepare an intimate mixture of the two substantially immiscible materials. See, for instance, Example 12 below.

Step672 can inject the mixture of therapeutic agent and silicone into the tubing. A syringe, for example a 1 ml syringe, can be connected to the syringe tube and cartridge assembly. A drop of catalyst appropriate for the silicone, for example MED-6385 curing agent, can be placed into the syringe and the syringe is then filled with the uncured mixture of silicone and therapeutic agent, or silicone drug matrix. The mixture, i.e., mixture of the uncured silicone and agent still liquid enough to flow or pump, can be chilled to subambient temperatures. For example, the mixture can be chilled to temperatures of less than 20° C. For example, the mixtures can be chilled to 0° C., or to −25° C. The polyimide tube is injected with the drug/matrix mixture until the tube is filled. The tube and associated apparatus can also be chilled to maintain the subambient temperature of the mixture throughout the process of filling or injecting the sheath with the mixture. In various embodiments, the polyimide tube, or sheath, is filled with the drug matrix mixture under pressure, for example through use of a high pressure pump. For instance, the drug/matrix mixture, such as can be obtained in mixtures of latanoprost with MED-6385 Part A to which amounts of catalyst Part B have been added, can be pumped into the tube under at least about 40 psi pressure. The tube can be filled at any suitable rate, but preferably, at rates of less than about 0.5 linear cm/sec. It is believed by the inventors herein that filling the tube relatively rapidly under a relatively high head of pressure can reduce the degree of phase separation of the substantially immiscible latanoprost oil and silicone monomer material, such that upon polymerization (“curing”) to provide the final silicone polymeric product, the latanoprost droplets are finely dispersed in the solid matrix in which they are only slightly soluble.

Curing takes place in the presence of the catalyst (“Part B”) of the NuSil MED-6385, and can be carried out at temperatures of at least about 40° C., at relative humidity (RH) of at least about 80%, or both. Curing can be initiated directly after filling the tube and clamping the ends of the filled tube to prevent the formation of voids and loss of the precursor material from the tube ends.

After curing, which can be complete in about 16-24 hours at 40° C. and 80% RH, the clamps can be removed from the ends of the tubing, as the silicone is fully set up. The tubing can then be cut into sections of suitable length for use as drug inserts, for example, lengths of about 1 mm.

When the extrusion is carried out at subambient temperatures, small and more uniform inclusions of the agent can result. For example, when the agent is latanoprost, a liquid at room temperature, extrusion at −5° C. provides significantly smaller and more uniform inclusion droplets. In an example, cold extrusion yielded a drug core comprising a silicone matrix with latanoprost droplets of average diameter of 6 μm, with a standard deviation of diameter of 2 μm. In comparison, an extrusion carried out at room temperature yielded a drug core comprising a silicone matrix with latanoprost droplets of average diameter of 19 μm, with a standard deviation of droplet diameter of 19 μm. It is apparent that the cold extrusion technique provides smaller, more uniform inclusions than does extrusion at room temperature. This in turn results in a more uniform concentration of drug throughout the core, or the insert containing the core, which is desirable for medical applications as uniformity of dose is improved.

The open end of the polyimide tube can be closed off until the silicone begins to solidify. In some embodiments with two or more drug cores, two or more separate mixtures can each be separately injected from two or more syringes.

Step680 cures the drug core matrix comprising the mixture silicone and therapeutic agent. The silicone is allowed to cure, for example for 12 hours. The amount of time and temperature of the cure may be controlled, and empirical data can be generated to determine ideal times and temperatures of the curing. Work in relation with embodiments of the present invention indicates that the silicone material and drug loading of the core, for example a percentage of therapeutic agent in the core, may effect the optimal time and temperature of the cure. In some embodiments, empirical data can be generated for each silicone matrix material and percentage of each therapeutic agent to determine an optimal amount of time to cure the injected mixture. In some embodiments with two or drug cores in a drug core insert, two or more mixtures can be cured together to cure the drug cores of the insert.

Table 1 shows drug insert silicones that may be used and associated cure properties, according to embodiments of the present invention. The drug core insert matrix material can include a base polymer comprising dimethyl siloxane, such as MED-4011,MED 6385 and MED 6380, each of which is commercially available from the NuSil company. The base polymer can be cured with a cure system such as a platinum-vinyl hydride cure system and/or a tin-alkoxy cure system, both commercially available from NuSil. In many embodiments, the cure system may comprise a known cure system commercially available for a known material, for example a known platinum vinyl hydride cure system with known MED-4011. In a specific embodiment shown in Table 1, 90 parts of MED-4011 can be combined with 10 parts of the crosslinker, such that the crosslinker comprises 10% of the mixture. A mixture with MED-6385 may comprise 2.5% of the crosslinker, and mixtures of MED-6380 may comprise 2.5% or 5% of the crosslinker.

TABLE 1

Drug Insert Silicone Selections

			Crosslinker	Curing
Material	Base Polymer	Cure System	Percent	Properties

MED-	Dimethyl	Platinum		10%	Curing inhibited
4011	Siloxane	vinyl hydride		at high
	Silica filler	system		concentrations
	material			of latanoprost
MED-	Dimethyl	Tin-Alkoxy	2.5%	Very slight
6385	siloxane			inhibition of
	Diatomaceous			curing at high
	earth filler			concentrations
	material			of latanoprost
MED-	Dimethyl	Tin-Alkoxy	2.5% to 5%	Very slight
6380	siloxane			inhibition of
	without			curing at high
	filler material			concentrations
				of latanoprost

Work in relation with embodiments of the present invention suggests that the cure system and type of silicone material can effect the curing properties of the solid drug core insert, and may potentially effect the yield of therapeutic agent from the drug core matrix material. In specific embodiments, curing of MED-4011 with the platinum vinyl hydride system can be inhibited with high concentrations of latanoprost, for example over 20% latanoprost, such that a solid drug core may not be formed. In specific embodiments, curing of MED-6385 and/orMED 630 with the tin alkoxy system can be slightly inhibited with high concentrations, e.g. 20%, of latanoprost. This slight inhibition of curing can be compensated by increasing the time and/or temperature of the curing process. For example, embodiments of the present invention can make drug cores comprising 40% latanoprost and 60% MED-6385 with the tin alkoxy system using appropriate cure times and temperatures. Similar results can be obtained with the MED-6380 system the tin-alkoxy system and an appropriate curing time and/or temperature. In many embodiments, the solid drug core forms so as to form a solid structure, for example a solid cylinder, within the drug core that corresponds to the dimensions of the tube. Even with the excellent results for the tin alkoxy cure system, work in relation with embodiments of the present invention suggests that there may be an upper limit, for example above 50% latanoprost, at which the tin-alkoxy cure system may not produce a solid drug core. In many embodiments, the therapeutic agent comprises the prostaglandin analogue, for example latanoprost, in the drug solid drug core may be at least about 5%, for example a range from about 5% to 50%, and can be from about 20% to about 40% by weight of the drug core. In specific embodiments with moderate to high loading of the therapeutic agent in the drug core, the drug core may comprise from about 25% to about 50% of the therapeutic agent in the drug core, for example 50% latanoprost oil in the drug core and/or matrix material.

In some embodiments, the therapeutic agent may comprise a functional group that can, at least potentially, react with the cure system. In some embodiments, the therapeutic agent may comprise a prostaglandin analogue such as latanoprost, bimatoprost or travoprost, each of which may comprise an unsaturated carbon-carbon double bond that can potentially react with the platinum vinyl hydride cure system. These unsaturated carbon-carbon double bonds can be similar to the vinyl group in the platinum cure vinyl hydride system, and can potentially react with the vinyl hydride cure system via a hydrosilation reaction. Latanoprost comprise an unsaturated carbon-carbon double bond in one of the side chains. Bimatoprost and travoprost each comprise two unsaturated carbon-carbon double bonds, one in each side chain. Work in relation with embodiments of the present invention indicate that the hydrosilation reaction of the unsaturated double bond in the prostaglandin analogues with in the platinum vinyl hydride cure system does not significantly reduce the quantity of prostaglandin analogue available for release from the drug core.

In some embodiments, the therapeutic agent may comprise a prostaglandin analogue such as latanoprost, bimatoprost or travoprost, each of which may comprise hydroxyl groups that can potentially react with the tin alkoxy cure system. These hydroxyl groups can potentially react with the alkoxy groups via an alkoxy condensation reaction. Bimatoprost, latanoprost and travoprost each comprise a molecule with three hydroxyl groups that can potentially react via the alkoxy condensation reaction. Work in relation with embodiments of the present invention indicate that the alkoxy condensation reaction of the hydroxyl groups in the prostaglandin analogues with in the tin alkoxy cure system does not significantly reduce the quantity of prostaglandin analogue available for release from the drug core. Work in relation to embodiments of the present invention indicates that a negligible amount of therapeutic agent is consumed by solidification or otherwise not available, as extraction data of the therapeutic agent for solid cores shows that at least 95%, for example 97% or more, of therapeutic agent can be extracted from the drug core.

In some embodiments, the silicone material may comprise an inert filler to add rigidity to the cured matrix. Work in relation with embodiments of the present invention suggests that the filler material may increase the rate of release of the therapeutic agent. The MED-4011 and MED-6385 materials are commercially available with the filler material. The MED-4011 material may comprise an inert silica filler material to add rigidity to the cured silicone matrix. The MED-4385 may comprise inert diatomaceous earth filler material to add rigidity to the cured silicone matrix.

The inert filler material can increase the concentration of drug in the silicone of the component matrix as the filler material may not substantially absorb the therapeutic agent and the inert filler material can reduce the fraction of silicone in the material drug core matrix. In some embodiments, MED-4385 comprises approximately 25% diatomaceous earth filler and approximately 75% dimethyl siloxane. In a specific embodiment, the drug core may comprise 40% of the therapeutic agent and 60% of the material. The 60% of material, e.g. MED-4385, corresponds to 45% dimethyl siloxane base polymer and 15% inert diatomaceous earth filler. Assuming that very little therapeutic agent is absorbed into the inert filler material, the 40% of therapeutic agent is contained within the 45% of dimethyl siloxane base polymer, such that the concentration of therapeutic agent in the base polymer is 47% or about 50%. Consequently, the release rate of the therapeutic agent from the exposed surface of the silicone drug core insert can be increased slightly as the concentration of therapeutic agent in the silicone portion of the matrix material can be elevated due to the presence of the filler material. In some embodiments, the drug core may comprise a matrix material without a filler material, such that the therapeutic agent, for example latanoprost oil, comprises approximately 50% of the material in the cured solid drug core and may also comprise a concentration approximately 50% in the matrix base polymer.

In many embodiments, the size and/or distribution of sizes of the inclusions in the core can be characterized with at least one of light scatter measurements of the core, light microscopy of the core, scanning electron microscopy of the core or transmission electron microscopy of sections of the core. Step680 cuts the polyimide tubing with the cured solid matrix mixture to an intended length and may apply an adhesive to one end of the cut length of tubing.

In many embodiments, the matrix material is cured so as to form a solid drug core structure, for example a cylindrical rod that corresponds to the shape of the tubing, such that the exposed surface of the cut solid drug core substantially retains its shape when implanted into the patient. In some embodiments with two or more drug cores in a drug core insert, the two or more drug cores can be cut together, for example the tubes and cores of concentric drug cores can be cut together.

Cut Drug Inserts to Length:

The polyimide tubing may be inserted into a fixture and cut to a section of the specified length. In some embodiments, the cut sections of polyimide tubing may be placed in a vacuum for 30 minutes. The cut section polyimide tubing comprising the drug core insert can be inspected and weighed following the vacuum and the weight may be recorded.

Close Off End of Drug Core Insert:

An adhesive can be applied to one end of the drug core insert. The adhesive may be applied as a liquid and cured under UV light, for example cured under UV light for five seconds. In specific embodiments, the adhesive may comprise Loctite 4305 UV adhesive. In many embodiments the material applied to one end of the drug core insert comprises a material that is substantially impermeable to the therapeutic agent such that release of the therapeutic agent through the covered end is inhibited. This inhibition of release from the drug core through the covered end can result in effective and/or efficient delivery of the drug through the exposed surface of the drug core on the opposite end, such that the drug is selectively released to the target tissue and/or bodily fluid, for example to the tear liquid tear film. In some embodiments, a filament may be bonded to the end as described above, to facilitate removal of the drug core insert from the implant.

In some embodiments, the end can be closed by heat welding, pinching the tube end closed, and covering the end of the tube with a cap comprising a material that is substantially impermeable to the therapeutic agent to inhibit release of the therapeutic agent through the cap. In embodiments with two or more drug cores in the drug core insert, the covered end may cover both cores, for example cover an inner cylindrical core and an outer annular core.

In some embodiments, with flow of the drug through the drug core, the end of the drug core may not be closed off, or the end may be partially closed, for example with a cap having an opening to let fluid flow though the channel in the core while the periphery of the cap covers an annular end of the core.

In some embodiments, the exposed end opposite the closed end can be shaped to increase surface area of the exposed end as described above. In some embodiments, a cone with a sharp tip, similar to a sharp pencil tip, can be inserted into the exposed surface to indent the exposed surface with an inverted cone shape that increases surface area. In some embodiments, the exposed end may be crimped to decrease the surface area.

FIG. 6F showsmethod690 of final assembly in accordance withmethod600 ofFIG. 6A. Astep692 inserts a drug core component into a channel in the punctal plug. Astep694 packages the punctal plug with the drug core insert in the channel. Astep696 sterilizes the packaged plug and drug core insert. Astep698 releases the product.

Step692 inserts the drug core into the implant, for example a punctual plug. The drug core can be inspected prior to insertion and may be part of the step of insertion. The inspection can comprise visual inspection to ensure that the sleeve comprising the cut tubing is completely filled with no voids or foreign particles in the silicone matrix, that the silicone is flush and the same length as the polyimide tube, that the adhesive comprising cyanoacrylate completely covers one end of the tube, and that the tube is the correct length. The drug insert and implant comprising the punctual plug can be loaded into a drug insertion tool and holding fixture. The drug insert can be loaded into the implant bore, or channel, using the plunger on the drug insertion tool. The drug insert insertion tool can be removed. The implant comprising the punctum plug can be inspected to verify that the drug core insert is fully seated in the bore, that the drug core insert is below the surface of the punctual plug flange, and that there is no visible damage to the implant/drug core assembly. Step694 packages the punctual plug with the drug core inserted into the channel.

The punctual plug may be packaged with known packaging and methods, for example with an inner pouch, an outer Mylar pouch, a pouch sealer, argon gas, and an inflation needle. In specific embodiments, two completed drug delivery systems, each comprising the punctual plug implant with drug core insert, are placed in the inner pouch and sealed in the inner pouch. The sealed inner pouch is placed in an outer pouch. The outer pouch may extend about ¼ beyond a pouch sealer element. Thenumber 25 gauge needle can be inserted into the pouch and under the sealing element with the Argon flowing. The sealer element can be clamped and the package allowed to inflate. The argon flow needle can be removed and the sealing operation repeated. The package can be inspected by pressing gently on the argon filled pouch to check for leaks. If a leak is detected, the inner pouch can be removed and repacked in a new Mylar outer pouch.

Step696 can sterilize the packaged plug and drug core insert with known sterilization methods, for example with commercially available e-beam from Nutek Corporation of Hayward, Calif.

Step698 can release the product in accordance with final testing and release procedures.

It should be appreciated that the specific steps illustrated inFIGS. 6A to 6E provide a particular method of manufacturing a plug with a drug core insert, according to some embodiments of the present invention. Other sequences of steps may also be performed according to alternative embodiments. For example, alternative embodiments of the present invention may perform the steps outlined above in a different order. Moreover, the individual steps illustrated inFIGS. 6A to 6E may include multiple sub-steps that may be performed in various sequences as appropriate to the individual step. Furthermore, additional steps may be added or removed depending on the particular applications. One of ordinary skill in the art would recognize many variations, modifications, and alternatives.

EXAMPLESExample 1Latanoprost Drug Core Elution Data

Drug cores as described above have been fabricated with different cross sectional sizes of 0.006 inches, 0.012 inches, and 0.025 inches, and drug concentrations of 5%, 10% and 20% in a silicone matrix. Theses drug cores can be made with a Syringe Tube and Cartridge Assembly, Mixing Latanoprost with Silicone, and Injecting the mixture into a polyimide tube which is cut to desired lengths and sealed. The length of the drug cores were approximately 0.80 to 0.95 mm, which for a diameter of 0.012 inches (0.32 mm) corresponds to total Latanoprost content in the drug cores of approximately 3.5 μg, 7 μg and 14 μg for concentrations of 5%, 10% and 20%, respectively.

Syringe Tube and Cartridge Assembly. 1. Take polyimide tubing of three different diameters 0.006 inches, 0.0125 inches and 0.025 inches. 2. Cut polyimide tubing of different diameters to ˜15 cm length. 3. Insert Polyimide tubes into a Syringe Adapter. 4. Adhesive bond polyimide tube into luer adapter (Loctite, low viscosity UV cure). 5. Trim end of assembly. 6. Clean the cartridge assembly using distilled water and then with methanol and dry it in oven at 60° C.

Mix Latanoprost with Silicone. Prepare Latanoprost. Latanoprost is provided as a 1% solution in methylacetate. Place the appropriate amount of solution into a dish and using a nitrogen stream, evaporate the solution until only the Latanoprost remains. Place the dish with the Latanoprost oil under vacuum for 30 minutes. Combine Latanoprost with silicone. Prepare three different concentrations of Latanoprost (5%, 10% and 20%) insilicone Nusil 6385 and inject it into tubing of different diameters (0.006 in, 0.012 in and 0.025 inches) to generate 3×3 matrixes. The percent of Latanoprost to silicone is determined by the total weight of the drug matrix. Calculation: Weight of Latanoprost/(weight of Latanoprost+weight of silicone)×100=percent drug.

Inject tube. 1. Insert Cartridge and Polyimide tubes assembly into 1 ml syringe. 2. Add one drop of catalyst, (MED-6385 Curing Agent) in the syringe. 3. Force excess catalyst out of the polyimide tube with clean air. 4. Fill syringe with silicone drug matrix. 5. Inject tube with drug matrix until the tube is filled or the syringe plunger becomes too difficult to push. 6. Close off the distal end of the polyimide tube and maintain pressure until the silicone begins to solidify. 7. Allow to cure at room temperature for 12 hours. 8. Place under vacuum for 30 minutes. 9. Place tube in right size trim fixture (prepared in house to hold different size tubing) and cut drug inserts to length (0.80-0.95 mm).

Testing. Elution study (in vitro). 1.Place10 plugs of same size and same concentration per centrifuge tube and add 1.5 ml of 7.4 pH buffer solution to it. 2. Change the solvent with fresh 7.4 pH buffer after appropriate time. 3. Take HPLC of the elutant at 210 nm with PDA detector2996 using Sunfire C18, 3 mm×10 mm column (Waters Corporation, Milford, Mass.). Acetonitrile and water mixture is used for gradient elution. Calibration was done in house before and after each analysis, using in-house standards with precisely weighed concentration of Latanoprost. 4.

Calculate the amount of drug release per day per device for different size tubings having different concentrations of Latanoprost. 5. Plot elution rate vs area and concentration forday 1 andday 14.

FIGS. 7A and 7B show elution data of Latanoprost atday 1 andday 14, respectively, for the three core diameters of 0.006, 0.012 and 0.025 inches and three Latanoprost concentrations of approximately 5%, 11% and 18%. Elution rate of the Latanoprost in nanograms (ng) per day is plotted versus percent concentration. These data show that the rate of elution is mildly dependent on the concentration and strongly dependent on the exposed surface area at both time periods. Atday 1, the 0.006 inch, 0.012 inch and 0.025 inch diameter cores released about 200 ng, 400 ng and 1200 ng of Latanoprost, respectively, showing that the quantity of Latanoprost released increases with an increased size of the exposed surface area of the drug core. For each tube diameter, the quantity of Latanoprost released is compared to the concentration of drug in the drug core with a least square regression line. For the 0.006, 0.012 and 0.025 inch drug cores the slope of the regression lines are 11.8, 7.4 and 23.4, respectively. These values indicate that a doubling of concentration of the Latanoprost drug in the core does not lead to a doubling of the elution rate of the Latanoprost from the core, consistent with droplets of Latanoprost suspended in a drug core matrix and substantial saturation of the drug core matrix with Latanoprost dissolved therein, as described above.

Atday 14, the 0.006 inch, 0.012 inch (0.32 mm) and 0.025 inch diameter cores released about 25 ng, 100 ng and 300 ng of Latanoprost, respectively, showing that the quantity of Latanoprost released increases with an increased size of the exposed surface area of the drug core at extended periods of time, and that the quantity of Latanoprost released is mildly dependent on the concentration of therapeutic agent in the core. For each tube diameter, the quantity of Latanoprost released is compared to the concentration of drug in the drug core with a least square regression line. For the 0.006, 0.012 and 0.025 inch drug cores the slope of the regression lines are 3.0, 4.3 and 2.2, respectively. For the 0.012 and 0.025 inch cores, these values indicate that a doubling of concentration of the Latanoprost drug in the core does not lead to a doubling of the elution rate of the Latanoprost from the core, consistent with droplets of Latanoprost suspended in a drug core matrix and substantial saturation of the drug core matrix with Latanoprost dissolved therein, as described above. However, for the 0.006 inch diameter core, there is an approximately first order relationship between the quantity of initially in the core and the amount of drug released atday 14, which can may be caused by depletion of Latanoprost drug droplets in the core.

FIG. 7C shows elution data for Latanoprost from 0.32 mm diameter, 0.95 mm long drug cores with concentrations of 5, 10 and 20% and drug weights of 3.5, 7 and 14 μg, respectively, according to embodiments of the present invention. The drug cores were manufactured as described above. The elution rate is plotted in ng per day from 0 to 40 days. The 14 μg core shows rates of approximately 100 ng per day from about 10 to 40 days. The 7 μg core shows comparable rates from 10 to 20 days. These data are consistent with droplets of Latanoprost suspended in a drug core matrix and substantial saturation of the drug core matrix with Latanoprost dissolved therein, as described above.

Table 2 shows the expected parameters for each drug concentration. As shown inFIG. 7C, in vitro results in a buffered saline elution system show that the plug initially elutes approximately 500 ng of Latanoprost per day, dropping off rapidly within 7-14 days to approximately 100 ng/day, depending on the initial concentration of drug.

TABLE 2

Drug Elution Properties

Total Latanoprost content	14μg	7 μg	3.5 μg
In vitro elution rate	See FIG. 7C	See FIG. 7C	See FIG. 7C
Duration	~100 days	~45 days	~25 days

In many embodiments, the duration of the drug core can be determined based on the calculated time when ˜10% of the original amount of drug remains in drug insert, for example where the elution rate levels out and remains substantially constant at approximately 100 ng/day.

Example 2Cyclosporin Drug Core Elution Data

Drug cores as described in Example 1 were made with cyclosporin having a concentration of 21.2%.FIG. 8A shows elution profiles of cyclosporin from drug cores into a buffer solution without surfactant and into a buffer solution with surfactant, according to embodiments of the present invention. The buffer solution was made as described above. The solution with surfactant includes 95% buffer and 5% surfactant, UP-1005 Ultra Pure Fluid from Dow Corning, Midland Mich. Work in relation with embodiments of the present invention indicates that in at least some instances, surfactants may be used in in vitro to model in situ elution from the eye as the eye can include natural surfactants, for example Surfactant Protein D, in the tear film. The elution profile of cyclosporin into surfactant is approximately 50 to 100 ng per day from 30 to 60 days. Empirical data from tears of a patient population, for example 10 patients, can be measured and used to refine the in vitro model with appropriate amounts of surfactant. The drug core matrix may be modified in response to the human tear surfactant as determined with the modified in vitro model. The drug core can be modified in many ways in response to the human tear film surfactant, for example with an increased exposed surface area and/or additives to increase an amount of cyclosporine drug dissolved in the core, as described above, to increase elution from the core to therapeutic levels, if appropriate.

Example 3Bimatoprost Bulk Elution Data

Bulk samples of 1% Bimatoprost having a known diameter of 0.076 cm (0.76 mm) were prepared. The height of each sample was determined from the weight and known diameter of the sample.

TABLE 3

Bulk Sample Size

				Exposed
	wt	Diameter	calculated	Surface
Sample	(mg)	(cm)	height (cm)	Area (cm{circumflex over ( )}2)

14-2-10	1.9	0.076	0.42	0.109
14-2-11	1.5	0.076	0.33	0.088
14-2-12	1.9	0.076	0.42	0.109

The calculated heights ranged from 0.33 cm to 0.42 cm. The exposed surface area on each end of each bulk sample was approximately 0.045 cm2, providing volumes of 0.019 cm3 and 0.015 cm3 for the 0.42 and 0.33 cm samples, respectively. The exposed an exposed surface area of samples calculated from the height and diameter without a drug sheath was approximately 0.1 cm2. Three formulations were evaluated: 1)

silicone

4011, 1% Bimatoprost, 0% surfactant; 2)

silicone

4011, 1% Bimatoprost, approximately 11% surfactant; and 3)

silicone

4011, 1% Bimatoprost, approximately 33% surfactant. The elution data measured for the bulk samples with

formulation

1, 2 and 3 were normalized to ng per device per day (ng/device/day) assuming a surface area of the bulk device is 0.1 cm2 and the surface area of the clinical device is 0.00078 cm2 (0.3 mm diameter).FIG. 9A shows normalized elution profiles in ng per device per day over 100 days for bulk sample of silicone with 1% Bimatoprost, assuming an exposed surface diameter of 0.3 mm on the end of the device, according to embodiments of the present invention. The normalized elution profile is about 10 ng per day. The data show approximately zero order release kinetics from about ten days to about 90 days for each of the formulations. These data are consistent with particles of Bimatoprost suspended in a drug core matrix and substantial saturation of the drug core matrix with Bimatoprost dissolved therein, as described above. Similar formulations can be used with drug core sheaths and a shaped exposed surface of the core exposed to the tear to increase the exposed surface area as described above and deliver the drug in therapeutic amounts over an extended period.

In some embodiments, the core can comprise a 0.76 mm diameter core with an exposed surface diameter of 0.76 mm, corresponding to an exposed surface area of 0.0045 cm2. The core can be covered with a sheath to define the exposed surface of the core as described above The normalized elution profile for such a device, based on the bulk sample data above, is approximately 6 times (0.0045 cm2/0.00078 cm2) the elution profile for the device with a 0.3 mm diameter exposed surface area.

Thus, a zero order elution profile with an elution rate of about 60 ng per day can be obtained over a period of about 90 days. If the exposed surface area is increased to about 0.0078 cm2, for example with many of the exposed surface shapes as described above, the zero order elution rat is about 100 ng per day over a period of about 90 days. The concentration can also be increased from 1%. Similar elution profiles can be obtained with Latanoprost.

Example 4Latanoprost Elution Data

Drug cores were manufactured as described above in Example 1 with Latanoprost and

silicone

4011, 6385 and/or NaCl. Four formulations were manufactured as follows: A)silicone 4011, approximately 20% Latanoprost, and approximately 20% NaCL;B) silicone 4011 approximately 20% Latanoprost, and approximately 10% NaCl; C)silicone 4011, approximately 10% Latanoprost, and approximately 10% NaCl; and D)silicone 6385, approximately 20% Latanoprost.

FIG. 10A shows profiles of elution of Latanoprost form the cores for four formulations of Latanoprost, according to embodiments of the present invention. The results show initial rates of approximately 300 ng per device per day that decreases to about 100 ng per device per day by 3 weeks (21 days). The results shown are for non-sterile drug cores. Similar results have been obtained with sterile drug cores of Latanoprost. These data are consistent with droplets of Latanoprost suspended in a drug core matrix and substantial saturation of the drug core matrix with Latanoprost dissolved therein, as described above.

Example 5Drug Release as a Function of Crosslinking

FIG. 11A shows the effect on elution of material and crosslinking on drug cores with 20% latanoprost, according to embodiments of the present invention. Drug cores were manufactured as described above with manufacturing methods as inFIG. 6E and Table 1. The drug cores comprised 4011 silicone, 6385 silicone with 2.5% crosslinker, 6380 with 2.5% crosslinker and 6380 with 5% crosslinker. The therapeutic agent in all samples comprised approximately 20% latanoprost. The 6380 material with 5% crosslinker provided the lowest elution rate at all time points. As the 6380 material with 5% crosslinker elutes at a lower rate than the 6385 material with 2.5% crosslinker, increased crosslinker and concomitant crosslinking appears to decrease the rate of elution. The 6385 material with 2.5% crosslinker provides the highest elution rates at 1, 4, 7 and 14 days. The 6380 material with 2.5% crosslinker has slightly lower elution rate at 1, 4, 7 and 14 days than the 6385 material. Both the 6385 and 6380 materials elute faster than the 4011 material that does not include a filler material. The 4011, 6380 and 6385 materials comprise dimethyl siloxane as the base polymer. As noted above, the 6385 material comprises diatomaceous earth filler material, and the 6380 material comprises silica filler material, indicating, based on the above elution rates, that the inert filler material can increase the rate of elution.

Example 6Effect of Drug Concentration on the Elustion of Latanoprost

FIG. 11B shows the effect of drug concentration on the elution of latanoprost, according to embodiments of the present invention. Drug cores were manufactured as described above with manufacturing methods as inFIG. 6E and Table 1. The drug cores comprised 6385 material with 5, 10, 20, 30 and 40% latanoprost, respectively. The amount of tin-alkoxy cure system was 2.5% in all samples. The release of latanoprost is weakly dependent on the concentration of latanoprost at all time periods with 40% the latanoprost material eluting at the highest rate and 5% latanoprost eluting at the lowest rate. The elution rate for all samples falls below 500 ng per day by 7 days and continues to be released at therapeutic levels thereafter.

Example 7Effect of Covering One End of the Drug Core Insert

FIG. 11C shows the effect of covering one end of the drug core insert, according to embodiments of the present invention. Drug cores were manufactured as described above with manufacturing methods as inFIG. 6E and Table 1. The drug cores comprised 6385 material with 20% latanoprost. The elution rate of cut tubes as described above was measured with both ends of each cut tube open, referred to as both ends open. The elution rate of cut tubes with one end exposed and one end covered with uv cured Loctite, as described above, was measured, referred to as one end open. For comparison, the elution rate for the drug core inserts with both ends open divided by two is shown, referred to as “both ends open/2”. The both ends open/2 values are very close to the one end open data at all time points, indicating that covering one end of the drug core insert with an adhesive material that is substantially impermeable to the therapeutic agent can inhibit the release of therapeutic agent from the drug core, such that the drug is effectively delivered through the exposed surface of the drug core on the open end of the tube.

Example 8Elution of Fluorescein and the Effect of Surfactant on Fluorescein Elution

FIG. 12A shows the elution of fluorescein and the effect of surfactant on fluorescein elution, according to embodiments of the present invention. The elution data for fluorescein show the flexibility of the above drug core and manufacturing processes for the sustained release of many therapeutic agents, including both water soluble and water insoluble therapeutic agents, and relatively low molecular weight and high molecular weight therapeutic agents. Fluorescein has a molecular mass of 332.32 g/mol, is soluble in water, and can serve as a model for the release water soluble therapeutic agents released from the eye. Work in relation with embodiments of the present invention indicates that molecular weight and solubility in water can each effect the release rate of the drug from the solid drug core matrix. For example, lower molecular weight may increase diffusion through the solid matrix material, i.e. through silicone, such that low molecular weight compounds may be released more quickly. Also, solubility in water can also effect the release rate of the drug, and in some instances increased water solubility of the drug may increase the rate of release from the solid drug core matrix, for example via transport from the solid matrix material to the bodily liquid, such as tear liquid. In accordance with these embodiments, therapeutic agents with higher molecular weight than fluorescein and with lower water solubility than fluorescein, for example cyclosporin and prostaglandins as shown above, may be released from the solid core at lower rates. Surfactants may also effect the rate of release of the therapeutic agent from the drug core into the surrounding bodily tissue and/or fluid, for example tear film fluid.

Each drug core tested comprisedMED 4011 silicone. In one embodiments, adrug core formulation1210 comprised 9% surfactant and 0.09% fluorescein. Anexponential fit1212 is shown for the elution rate ofdrug core formulation1210. In another embodiment, adrug core formulation1220 comprised 16.5% surfactant and 0.17% fluorescein. Anexponential fit1222 is shown for the elution rate ofdrug core formulation1220. In another embodiment, adrug core formulation1230 comprised 22.85% surfactant and 0.23% fluorescein. Anexponential fit1232 is shown for the elution rate ofdrug core formulation1230. In an embodiment without surfactant, adrug core formulation1240 comprised 0% surfactant and 0.3% fluorescein. Anexponential fit1242 is shown for the elution rate ofdrug core formulation1240.

The drug cores were manufactured with key formulations comprising: Silicone Surfactant “190 Fluid” (Dow Corning); Surfactant Mix: “190 Fluid”+Fluorescein; Silicone (Nusil):MED 4011 Part A,MED 4011 Part B; Centrifuge Tubes; 3 mL Syringe; 20 ga. Needle; 0.031 inch inner diameter Teflon Tube; and Buffer.

Key parameters included: Prepare a mixture of 2.5 g of silicone surfactant and 0.025 g of fluorescein; Prepare silicone compositions ofNusil MED 4011 containing 3.5 g Part A and 0.37 g Part B (10:1 ratio); Prepare four (4) centrifuge tubes each with 0.5 g of silicone and varying surfactant mixture weights as follows: A. 0.05 g surfactant mix: 9% surfactant, 0.09% fluorescein; B. 0.1 g surfactant mix: 16.5% surfactant, 0.17% fluorescein; C. 0.15 surfactant mix: 22.85% surfactant, 0.23% fluorescein; D. 0.0015 g fluorescein: 0% surfactant, 0.3% fluorescein; Inject each of the four formulations into respective teflon tubes using the syringe and needle; Cure the injected tube at 140° C. for 45 minutes in the oven; Cut each tube into 3 pieces in length to 4 mm; and Immerse each cut piece into a centrifuge tube containing 0.3 mL of buffer

Data collection comprised: Collect samples at

time points

24, 48, 72, 192, and 312 hours; Submit each sample for UV spectrometry analysis; Convert each elution rate from μg/mL/hr to μg/cm2/hr by using the dimensions of the teflon tube (4 mm length, 0.031 inch inner diameter); Plot data for elution rate vs. time to compare the rates of each surfactant mix formulation.

Analysis comprised fitting trendlines for each elution rate to an exponential curve, as shown in Table 4.

TABLE 4

Trendlines for each elution rate fit to exponential curves.

Sample #	% Surfactant	% Fluorescein	R2	Trendline Equation

A	9.0	0.09	0.9497	636.66 × −1.1161
B	16.5	0.17	0.8785	4289.6 × −1.3706
C	22.85	0.23	0.9554	1762.0 × −1.0711
D	0	0.30	0.9478	1142.1 × −1.2305

The trendline equations of table 4 indicate the following: The data fit experimental curves well with R2 values of 0.8785 to 0.9554. The trendline equations shows exponent coefficients of −1.0711 to −1.3706. Elution rates increased with increasing surfactant levels. Despite relatively similar amounts of fluorescein, there is a dramatic increase in elution rates between Samples C and D—this demonstrates that the addition of surfactant to the silicone matrix dramatically affects the elution rate of the water-soluble compound. The elution rate of Sample A is comparable to that of Sample D, even though Sample A contains only one-third the amount of fluorescein. This also demonstrates that the rate of elution can be affected by the addition of surfactant to the silicone matrix.

Although the trendline equation exponent coefficients of −1.0711 to −1.3706 are consistent with first order release, the data include an initial 48 hour period in which bolus release of fluorescein from the core is observed. Such an initial washout period of 2 to 3 days with high levels of the therapeutic agent delivered followed by a period of sustained release at therapeutic levels can be helpful in some embodiments, for example where elevated levels for a short period of time are tolerated and can lead to an accelerated effect on the eye. Work in relation with embodiments of the present invention suggests that after 48 hours the elution data can be closer to zero order, for example within a range from about zero order to about first order. In some embodiments, the level of release therapeutic agent can be decreased with a decreased exposed surface area of the drug core, for example as described above, to release the drug at therapeutic levels for sustained periods

Example 9The Effect of Sterilization on Elution of Therapeutic Agent

Work in relation to embodiments of the present invention suggests that radicals generated in the sterilization process may crosslink the drug core matrix material so as to inhibit the initial release rate of therapeutic agent from the drug core matrix material. In specific embodiments with e-beam sterilization, this cross-linking may be limited to the surface and/or near the surface of the drug core matrix. In some embodiments, a known Mylar bag can be penetrated with the e-beam to sterilize the surface of the drug core. In some embodiments, other sterilization techniques that effect sterilization can be used, for example gamma ray sterilization, and that are not limited to the surface of the drug core and fully and/or uniformly penetrate the drug core material.

Drug cores were synthesized and e-beam sterilized in Mylar packaging, as described above.FIG. 13A shows the elution of sterilized and non-sterilized drug cores. The sterile and non-sterile drug cores each comprised 20% latanoprost in 6385 synthesized as described above. The drug cores were e-beam sterilized and the elution rates measured as described above. The sterile and non-sterile drug cores show elution rates for the first day of about 450 and 1400 ng/day, respectively.

At

days

4 and7, the sterile and non-sterile drug cores show similar elution rates at about 400 ng/day. At 14 day the sterile and non-sterile drug cores show elution rates of 200 and about 150 ng/day, respectively. These data show that sterilization may decrease an initial release, or bolus, of the therapeutic agent, and that sterilization may be used to provide a more uniform rate of release of the therapeutic agent, for example in combination with embodiments described above.

Example 10The Effect of Salt on Elution of Therapeutic Agent

Work in relation to embodiments of the present invention suggests that known salts, for example sodium chloride can effect the rate of elution from the drug core.

FIG. 14A shows the effect of salt on the elution of therapeutic agent. Drug cores comprising 20% bimatoprost (BT) and silicone drug corematrix comprising NuSil 6385 were manufactured as described above. Drug cores were manufactured with salt concentrations of 0%, 10% and 20%. At 1 day the drug cores showed elution rates of about 750 ng/day, 400 ng per day and about 100 ng per day for 20%, 10% and 0%, respectively. At all time periods measured to two weeks, the 20% salt data showed the highest elution rate and the 0% salt data showed the lowest elution rate. This data shows that salt, for example many known salts such as sodium chloride, can be added to the matrix to increase the order of the elution rate of therapeutic agent.

Example 111Extraction of Therapeutic Agent from Drug Cores to Determine Therapeutic Agent Yield

Drug core inserts comprising MED-6385 and 20% and 40% latanoprost were synthesized as described above. Each drug core was weighed and the weight of solid drug core material determined with correction for the weight of the drug tube and adhesive. The amount of therapeutic agent present in each sample was determined based on the weight of drug core material and percentage of therapeutic agent in the drug core material as described above. The therapeutic agent was extracted from the drug cores with 1 ml aliquots of methyl acetate. The concentration of therapeutic agent in the solution for each sample was measured with reverse phase gradient HPLC with optical detection and peak integration at 210 nm. Measurements were taken for 6 drug cores with 20% latanoprost and 4 drug cores with 40% latanoprost. For the 20% samples, the average extraction of latanoprost was 104.8% with a standard deviation of about 10%. For the 40% samples, the average extraction of latanoprost was 96.8% with a standard deviation of about 13%.

Example 12High Pressure Filling

A two part silicone formulation (MED6385, Nusil Technologies) was used in the preparation of a composite resin containing latanoprost, which was used to fill a section of polyimide sheathing. The sheathing containing the polymerized silicone incorporates discrete latanoprost domains, existing in the form of droplets of less than about 25 μm maximum diameter, within the matrix. Several experiments were conducted.

Part A of the MED6385 silicone formulation was mixed with 0.43 μL of Part B, the tin catalyst, using syringes, to bring about partial coagulation of the polymer over 30 minutes. Then, 37 mg of that material was mixed with a premixed solution of 0.14 μL additional catalyst and 13 mg latanoprost, and that mixture could be further mixed by sonication with an ultrasonic probe. The resulting mixture was transferred to a syringe needle connected to a HP7x syringe adapter, which is connected to an EFD pump, which is in turn connected to a compressed air system and the delivery pressure set to 40 psi. The silicone-latanoprost mixture is then extruded down the length (10 cm) of polyimide tubing (IWG High Performance Conductors, Inc.). When the viscous mixture reached the bottom of polyimide tubing, clamps were applied at the bottom of the tubing and at the top connection with the syringe adapter, then pressure is released and the tubing section removed. The clamped section of tubing was placed in a humidity chamber (Thunder Scientific) for curing at 40° C. and 80% relative humidity (RH) for approximately 16-24 hrs.

To process the filled polyimide tubing containing the now-solid matrix containing the latanoprost into individual drug inserts, the filled precursor sheath was then cut into 1 mm segments with a jig and a razor blade. One end of each of the 1 mm segments was then sealed with Loctite 4305 UV Flash cure adhesive, and cured with a Loctite UV wand. Each of the segments at this point was ready for insertion into a punctal plug (Quintess) adapted to receive the insert, sealed end inward.

Results

Scanning electron micrographs of the sheath containing the cured matrix, i.e., the filled precursor sheath, are shown inFIG. 15A-D at the magnifications indicated. The inserts were sectioned cryogenically.FIGS. 15A and 15B, respectively, show the insert cores wherein the extrusion was carried at 40° C. (A) or 25° C. (B).

Example 13

The temperature of the mixture, and of the associated apparatus involved in filling the polyimide sheath was held at various temperatures during the injection process. Among the temperatures used were a slightly elevated temperature (40° C.), approximate room temperature (25° C.), and subambient temperatures, such as 0° C., −5° C., and −25° C. The subambient injection procedures are provided in this Example.

Manufacture of Latanprost/Silicone Mixture

The silicone formulation (MED6385) is a two part system. Part A contains the silicone and crosslinker while Part B contains the tin catalyst to promote crosslinking. The two parts are combined in a final ratio of 200:1 (Part A:Part B). The required amounts of Latanoprost, MED6385 Part A and B are weighed onto a glass slide and mixed for approximately 2 minutes using a plastic mini spatula. The weight or volume of components required to prepare 50 mg of mixture to be extruded is presented in the Table below.

Ratio of Components

Strength
(μg	Part A	Part B	Latanoprost
latanoprost/′plug)	(mg)	(μl)	(mg)

3.5	47.8	0.21	2.2
14	41.1	0.18	8.9
21	36.7	0.16	13.3

Extrusion into Polyimide Tubing

Preparation of Syringe Extrusion System

15 cm sections are threaded through a plastic luer adaptor and glued in place using Loctite 4304 UV flash cure adhesive (FIG. 2). A 1 mL syringe (Henke Sass Wolf NORMJect) is modified by cutting the tip of the plunger flush. The previously assembled tubing/adaptor piece is inserted into the syringe barrel and threaded through the luer outlet and fitted in place.

Extrusion

After the silicone/latanoprost mixing is complete, the mixture is loaded in the barrel of the syringe extrusion system. The plunger is inserted and excess air is removed. The syringe is then ready to be loaded into the chilled extrusion apparatus. The apparatus is an all stainless steel jacketed tube in a tube sanitary welded heat exchanger and includes a gas purge that is internally cooled by coiling inside the coolant side of the heat exchanger. The operating temperature setpoint of the cooling system shall be −10° C. The temperature inside the heat exchanger shall be uniform +/−2.5° C. over the useable length of the polyimide tubing. The steady state temperature of the cooling system is to be verified prior to insertion of syringe and tubing.

After setup, the EFD is activated and a silicone latanoprost mixture is extruded down the length of the polyimide tubing. Once the mixture reaches the bottom of the tubing, it can be visually detected. The syringe including tubing is quickly removed from the cooling system. The syringe is removed by cutting the tubing with a razor blade; then the tubing is clamped on both ends.

Curing

The clamped section of tubing is placed in a humidity chamber (Thunder Scientific) to be cured at 40° C. and 80% RH for approximately 16-24 hours.

Results

Scanning electron micrographs of the sheath containing the cured matrix, i.e., the filled precursor sheath, are shown inFIG. 15A-D at the magnifications indicated. The inserts were sectioned cryogenically.FIGS. 15C and 15D show the results of extrusions carried out at 0° C. and −25° C. respectively. They can be compared withFIGS. 15A and 15B that were carried out at ambient temperature (25° C.) or above (40° C.).

Measurements of average inclusion diameters, and standard deviation thereof, are as shown:

Cold extrusion (−5° C.): 0.006±0.002 mm (n=40 inclusion)
Room temp (22° C.): 0.019±10.019 mm (n=40 inclusion)

Measurements of average latanoprost content (μg) per 1 mm section (core) divided (razor blade) from a filled precursor tube are as shown:

Cold extrusion (−5° C.): 20.9±0.5 (Average±SD) RSD=2.4
Room temperature (22° C.): 20.2±1.9 (Average±SD) RSD=9.4

FURTHER EMBODIMENTS

While described above primarily with reference to treatment of an eye, embodiments of the drug release structures described herein may also find applications for treatment of a wide variety of tissues to treat a range of differing disease states. In some embodiments, these structures may be used for systemic and/or (more commonly) localized elution of a therapeutic agent to treat cancer. In embodiments used for chemotherapy, the matrix may be configured to release of a therapeutic cocktail that is dependent upon the primary tumor type. Use of a local delivery may be particularly beneficial for treating a tumor site post-surgically, and may help minimizing side effects and collateral damage to healthy tissues of the body. In some embodiments, a lumpectomy for breast tumor and/or or surgical treatment of prostate cancer can be treated. In many embodiments, a tumor is targeted with positioning of the matrix within and/or adjacent the targeted tumor. In some embodiments, the implant may comprise a radioactive agent to treat the tumor in combination with the therapeutic agent.

Still further alternative embodiments may facilitate elution of a therapeutic agent into a tissue of an ear, into a mouth, into a urethra, into a skin, into a knee joint (or other joint) of a patient, or the like. Conditions of joints that can be treated include arthritis and other joint diseases, and the therapeutic agents that may be used may comprise (for example) at least one COX II inhibitor, NSAIDs, and/or the like. Such localized use of NSAIDs and COX II inhibitors may reduce the risks associated with systemic use of these compounds. In some embodiments, the matrix may comprise nutritional supplements like glucosamine to effect a positive physiological response in local tissue of and/or near the joint. Implants for elution of therapeutic agents into or adjacent an intervertebral joint may be particularly advantageous. Similar (or other) pain relievers, antibiotics, antimicrobials, and/or the like may also be included in an implant for elution of one or more therapeutic agent into a localized trauma. Implants (optionally implants having structures derived from the punctual implants described above may allow elution of one or more therapeutic agent into a nasal cavity. Modifications or differences between such nasal implants and the punctual implants described above may include providing a passage for controlled release of medicated tear fluid through the canilicular lumen. Alternative nasal tissue structures may be quite different in overall form, optionally including any of a variety of known nasal cavity drug release shapes, but optionally taking advantage of one or more aspects of the drug cores or other drug release structures described above for long term release of one or more appropriate therapeutic agents.

Still further alternative embodiments find application in cosmetic uses. For example, these uses include administration of a prostaglandin to enhance eye lash growth.

While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modification, adaptations, and changes may be employed. For example, multiple delivery mechanisms may be employed, and each device embodiment may be adapted to include features or materials of the other, and further multiple features or multiple materials may be employed in a single device. Hence, the scope of the present invention may be limited solely by the appending claims.