US20030135202A1 - Implantable osmotic pump - Google Patents

Abstract

An implantable osmotic pump for delivering a pharmaceutical agent to a patient includes an osmotic engine, a substantially toroidal compartment disposed at least partially around the osmotic engine and a piston disposed within the compartment. The osmotic engine is configured to cause the piston to travel within the compartment and deliver a dose pharmaceutical agent contained within the compartment when the pump is implanted in an aqueous environment. A dose escalation assembly may be fitted to the pump, the dose escalation assembly being adapted to selectively increase the rate at which the pharmaceutical agent is delivered from the pump.

Description

BACKGROUND OF THE INVENTION
• 1. Field of the Invention[0001]
• The present invention relates generally to the field of drug delivery systems. In particular, the present invention relates to implantable osmotic pump systems.[0002]
• 2. Description of the Related Art[0003]
• Since the beginning of modern medicine, drugs have been administered orally. Patients have taken pills as recommended by their physician. The pills must pass through the digestive system and then the liver before they reach their intended delivery site (e.g., the vascular system). The actions of the digestive tract and the liver typically reduce the efficacy of medication by about 33%. Furthermore, oral medications must be administered by the patient. Patient compliance to the prescribed delivery profile is often poor. Studies suggest that 40% of patients do not comply with their oral medication consumption instructions. This causes two concerns. First, patients who do not take their medication as instructed are not maintaining blood drug levels within the therapeutic window and are therefore not receiving adequate therapy for their disease. A second, worse scenario than receiving too little medication occurs when the patient may be taking too much medication either by accident or purposefully in order to make up for a missed dose. Both of these patient-controlled scenarios can be dangerous to the patient, and at a minimum may prolong or aggravate their disease. Subcutaneous drug delivery and intravenous drug delivery have the advantage of bypassing the acidic and enzymatic action of the digestive system. Unfortunately, IV administration requires the use of a percutaneous catheter or needle to deliver the drug to the vein. The percutaneous site requires extra cleanliness and maintenance to minimize the risk of infection. Infection is such a significant risk that IV administration is often limited to a number of weeks, at most. In addition, the patient must wear an external pump connected to the percutaneous catheter if the therapy is intended to last longer than a few hours and the patient desires to be ambulatory. Subcutaneous drug delivery can be either partially implanted or totally implanted. Partially implanted systems rely on a percutaneous catheter or needle stick to deliver the medication, therefore, partially implanted systems have the same limitations as IV systems. Totally implanted systems have fewer maintenance requirements and are far less prone to infection than IV or partially implanted systems.[0004]
• In the 1970s, a new approach toward sustained drug delivery was commercialized for animal use only. The driving force of such pumps was based upon a new approach utilizing the principle of osmosis. A recent example of such a pump is described listed in U.S. Pat. No. 5,728,396. This patent discloses an implantable osmotic pump that achieves a sustained delivery of leuprolide. The pump includes a right-cylindrical impermeable reservoir that is divided into a water-swellable agent chamber and a drug chamber, the two chambers being divided by a movable piston. Fluid from the body is imbibed through a semipermeable membrane into the water-swellable agent chamber. As the water-swellable agent in the water-swellable agent chamber expands in volume, it pushes on the movable piston, which correspondingly decreases the volume of the drug chamber and causes the drug to be released through a diffusion outlet at a substantially constant rate.[0005]
• A limitation of the osmotic pump disclosed in the above-identified patent, however, is that its infusion rate cannot be adjusted once it is implanted. This is acceptable for medications that do not need rate adjustment, but often physicians desire to adjust the infusion rate based on the clinical status of the patient. One example of when a physician would want to increase the infusion rate is in the field of pain management. Osmotic pumps can be used to deliver medication to treat pain lasting over an extended period of time. Pain, however, often increases with time, and sometimes patients become tolerant to pain medications; therefore, more medication is needed to effectively treat the pain. The system disclosed in the above-identified patent does not allow a rate increase after implantation, so the physician must surgically remove the current implant and implant an additional pump to deliver the correct dosage. However, the prospect of yet another surgical procedure may cause many patients to forego the potential benefits of the larger dose and may also cause their physicians to advise against the initial procedure altogether.[0006]
• The aspect ratio of such cylindrical osmotic pump delivery devices is large, and often not compatible with the human body. Indeed, the human body does not have naturally-formed right-cylindrical cavities in which to implant such devices in the patient, in an unobtrusive and comfortable manner.[0007]
• What are needed, therefore, are improved osmotic pumps. What are also needed are improved implantable osmotic pumps that conform to the patient's anatomy and that more closely match the topology of the implant site. Also needed are novel implantable osmotic pumps for long term delivery of a pharmaceutical agent that do not rely upon a right-cylindrical pharmaceutical agent compartment and/or conventional cylindrical pistons. Also needed are implantable pumps that enable the physician to increase the dose of pharmaceutical agent delivered to the patient without, however, removing the pump from the implant site.[0008]
SUMMARY OF THE INVENTION
• It is an object of the present invention, therefore, to provide improved pumps. Another object of the present invention is to provide improved implantable osmotic pumps that conform to the patient's anatomy and that more closely match the topology of the implant site. A still further object is to provide novel implantable osmotic pumps for long term delivery of a pharmaceutical agent that do not rely upon a right-cylindrical pharmaceutical agent compartment and/or conventional cylindrical pistons. Preferably, such improved pumps should enable the physician to increase the dose of pharmaceutical agent delivered to the patient without removing the pump from the implant site.[0009]
• In accordance with the above-described objects and those that will be mentioned and will become apparent below, an implantable osmotic pump for delivering a pharmaceutical agent to a patient, according to an embodiment of the present invention, includes an osmotic engine; a substantially toroidal compartment adapted to store a pharmaceutical agent, and a piston disposed within the compartment, the osmotic engine being configured to cause the piston to travel within the compartment and deliver the pharmaceutical agent when the pump is implanted in the patient.[0010]
• The pump may include a tube coiled at least partially around the osmotic engine, an inner lumen of the tube defining the pharmaceutical agent compartment. The tube may include or be formed of metals, polymers and/or polyimid, for example. The compartment may be disposed at least partially around the osmotic engine. The tube may be rigid and the osmotic engine may be disposed within the tube.[0011]
• According to other embodiments, the osmotic engine may include a base, a cylindrical wall attached to the base and a free end opposite the base. The pump may include a housing configured to enclose at least the osmotic engine and the tube. The housing may include a first housing half and a second housing half that mates with the first housing half. Each of the first and second housing halves may define a saucer shape, for example. Each of the first and the second housing halves may be substantially circular in shape. The first housing half may define a substantially circular opening. The pump may further include a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and including an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted. The pump may be configured to deliver an initial dose of the pharmaceutical agent to the patient at a selected initial infusion rate, the selected initial infusion rate being related to a thickness, a composition and/or a surface area of the initial dose semipermeable membrane. The initial dose semipermeable membrane may be fitted with an initial dose impermeable membrane that initially seals the initial dose semipermeable membrane.[0012]
• A dose escalation assembly may be fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path. The first and second impermeable membranes may be disposed in the membrane enclosure in a stacked configuration wherein the first impermeable membrane must be breached before the second impermeable membrane can be breached. The first fluid path may include a first semipermeable membrane and the second fluid path may include a second semipermeable membrane that is distinct from the first semipermeable membrane. The pump may be configured to deliver a first dose of the pharmaceutical agent to the patient at a selected first infusion rate and a second dose of the pharmaceutical agent to the patient at a selected second infusion rate that is greater than the first infusion rate, the selected first and second infusion rates being related to a thickness, a composition and/or a surface area of the first and second semipermeable membranes, respectively.[0013]
• The osmotic engine may include a hygroscopic salt and/or an absorbent polymer. The absorbent polymer may include a material selected from a group including poly(acrylic acid), potassium salt; poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide), potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethylene oxide); poly (2-hydroxethyl methacrylate); poly(2-hydroxypropyl methacrylate) and poly(isobutylene-co-maleic acid) or derivatives thereof.[0014]
• The tube-shaped compartment may have a substantially constant inner diameter over a length thereof. Alternatively, the tube-shaped compartment may have a non-constant inner diameter over a length thereof. The tube may be coiled at least twice around the osmotic engine. A layer of epoxy may encase at least the tube. The tube may include polyimid, for example. The tube may define a proximal end adjacent the osmotic engine and a distal end at an end opposite the proximal end, and the pump may further include a catheter coupled to the distal end. The catheter may include a radiopaque tip. The piston may include a sphere, an elastomeric cylinder and/or an elastomeric conical section and may include stainless steel, a refractory metal, plastic, nylon and/or rubber, for example.[0015]
• The tube-shaped compartment may be pre-loaded with a volume of the pharmaceutical agent. For example, the pharmaceutical agent may be therapeutically effective for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy, allergy therapy, hypertension therapy, antibiotic therapy, bronchodilation therapy, asthmatic therapy, arrhythmia therapy, nootropic therapy, cytostatic and metastasis inhibition therapy, migraine therapy, gastrointestinal therapy and/or other pharmaceutical therapies.[0016]
• The dose escalation assembly may include a first saturated saline solution between the first impermeable membrane and the first semipermeable membrane, and a second saturated saline solution between the second impermeable membrane and the second semipermeable membrane.[0017]
• The present invention is also a kit, comprising an implantable osmotic pump for delivering a pharmaceutical agent to a patient, including an osmotic engine, a tube coiled around the osmotic engine, the tube defining an inner tube-shaped compartment adapted to store a pharmaceutical agent, and a piston disposed within the tube-shaped compartment, the osmotic engine being configured to exert a force on the piston to cause the piston to travel within the tube-shaped compartment and deliver the pharmaceutical agent when the pump is implanted in the patient, and a catheter configured to attach to the pump. The pump may further include a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted. The pump may further include a dose escalation assembly fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path. The kit may further include a dose escalation pen configured to breach the first and/or second impermeable membranes. The dose escalation pen may include a dose selection actuator that is adapted to re-configure the dose escalation pen to selectively breach one of the first and second impermeable membranes. The tube-shaped compartment may be pre-loaded with the pharmaceutical agent.[0018]
• The present invention is also a method of delivering a pharmaceutical agent to a patient, comprising steps of implanting a pump into the patient, the pump including a pump engine and a compartment adapted to store a pharmaceutical agent, the compartment defining at least a partial torus around the osmotic engine, and causing a piston to travel a distance within the compartment and to deliver a dose of pharmaceutical agent corresponding to the distance traveled out of the compartment. The implanting step may implant the pump (and/or portions thereof) intravascularly, subcutaneously, epidurally, intrathecally and/or intraventricularly, for example. A step of selectively increasing the dose in a stepwise manner over a treatment period without removing the pump from the patient may also be carried out. The pump engine may include an osmotic engine and the pump may include an initial dose semipermeable membrane initially exposed to the patient and at least one second semipermeable membrane initially not exposed to the patient. The increasing step may then include a step of selectively exposing the at least one second semipermeable membrane to the patient. The pump the engine may include an osmotic engine in fluid communication with the piston and the causing step may include a step of increasing a volume of the osmotic engine.[0019]
• The present invention is also a pump, comprising a pump engine; a tube coiled around the engine, the tube defining an inner tube-shaped compartment adapted to store a fluid, and a piston disposed within the tube-shaped compartment, the engine being adapted to cause the piston to travel within the tube-shaped compartment and to force a dose of the fluid out of the pump. The pump engine may include an osmotic engine. The fluid may include a pharmaceutical agent. A catheter may be coupled to the tube. The pump may be fully implantable in a body and the pump engine and the tube may be enclosed in a biocompatible pump housing. The pump may include a dose escalation assembly, the escalation assembly being configured to selectively increase the dose of fluid delivered. The dose escalation assembly may comprise means for increasing the dose delivered in a stepwise manner. The piston may include a sphere, an elastomeric cylinder and/or an elastomeric conical section, for example.[0020]
• According to another embodiment thereof, the present invention is an osmotic pump, comprising an osmotic engine and a pump housing enclosing the osmotic engine and defining a substantially toroidal space adapted to contain a volume of pharmaceutical agent. The pump housing may define a substantially circular outline. The substantially toroidal space may define an inner and an outer radius, and the osmotic engine may be disposed within the inner radius. The pump may include a tube disposed within the toroidal space, the tube defining an inner lumen adapted to contain the volume of pharmaceutical agent. Alternatively, the pump housing may include a first housing half and a second housing half, the first and second housing halves defining, when mated together, the substantially toroidal space, the substantially toroidal space being fluid tight. The pump may further include a semipermeable membrane enclosure and a semipermeable membrane fitted within the semipermeable membrane enclosure. A single semipermeable membrane may be fitted within the semipermeable membrane enclosure, in which case, the pump is a single stage pump. Alternatively, the pump may be an n-stage pump and the semipermeable membrane enclosure may be fitted with n semipermeable membranes, each of the n stages being configured to be selectively activated after implantation of the pump. The pump may also include an OFF switch mechanism configured to be selectively activated after implantation of the pump. The pump may also include a filter assembly to filter the pharmaceutical agent. The filter assembly may include a plug of porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns. For example, the filter assembly may include a plug of porous material, the porous material being hydrophilic or hydrophobic (or having hydrophilic or hydrophobic characteristics).[0021]
• The present invention is also an implantable osmotic pump, comprising a semipermeable membrane; a housing adapted to enclose a volume of pharmaceutical agent and a portion of the semipermeable membrane; an osmotic engine adapted to cause the pharmaceutical agent to be delivered out of the pump as an osmotic pressure differential develops across the semipermeable membrane, and an OFF switch, the OFF switch being effective to reduce the osmotic pressure differential across the semipermeable membrane substantially to zero, and/or an ON switch, the ON switch being effective to enable the pump to begin to deliver the pharmaceutical agent out of the pump. The OFF switch may include an OFF switch impermeable membrane and the OFF switch may be configured to turn the pump OFF (reduce the osmotic pressure substantially to zero) only when the OFF switch impermeable membrane is breached. The OFF switch may define a lumen adapted to allow fluid to bypass the semipermeable membrane when the OFF switch impermeable membrane is breached. The ON switch may include an impermeable membrane disposed over the semipermeable membrane, the pump being turned ON (adapted to begin delivery of the pharmaceutical agent) only after the impermeable membrane is breached. A volume of saturated saline solution may be disposed between the semipermeable membrane and the impermeable membrane.[0022]
• The pharmaceutical agent compartment of the pump may contain Sufentanil, for example, and/or may contain other medications. The sufentanil may be at a concentration of up to about 500,000 μg/mL. The pharmaceutical agent may include Sufentanil and the pump may be configured for a daily delivery rate of Sufentanil of up to about 25 micrograms per day when the pump is configured to be implanted intraventricularly; a daily delivery rate of Sufentanil of up to about 50 micrograms per day when the pump is configured to be implanted intrathecally; a daily delivery rate of Sufentanil of up to about 500 micrograms per day when the pump is configured to be implanted epidurally; a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted subcutaneously, and a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted intravascularly. The catheter and the pump may be dimensioned to infuse a dose of pharmaceutical agent of up to about 1500 μg/day over a treatment period, for example.[0023]
• According to another embodiment thereof, the present invention is also a filter assembly for an osmotic pump, the filter defining a first end configured to mate with the osmotic pump a second end configured to be exposed, in use, to an aqueous environment and including a filter between the first and second ends. The filter may include a porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns. The plug of porous material may be hydrophilic or hydrophobic (or have hydrophobic or hydrophilic properties).[0024]
BRIEF DESCRIPTION OF THE DRAWINGS
• For a further understanding of the objects and advantages of the present invention, reference should be made to the following detailed description, taken in conjunction with the accompanying figures, in which:[0025]
• FIG. 1 is a perspective view of the osmotic pump according to an embodiment of the present invention.[0026]
• FIG. 2 is an exploded view of the osmotic pump according to an embodiment of the present invention, showing the major components thereof.[0027]
• FIG. 3 is a plan view of the osmotic pump according to an embodiment of the present invention in which the first half of the housing has been removed.[0028]
• FIG. 4 is a cross sectional view of the osmotic pump of FIG. 3, taken along lines BB′.[0029]
• FIG. 5 is a cross sectional view of the osmotic pump of FIG. 3, taken along lines AA′.[0030]
• FIG. 6 is a plan view of the second half of the osmotic pump housing, according to an embodiment of the present invention.[0031]
• FIG. 7 is a cross sectional view of the second half of the osmotic pump housing, taken along lines CC′.[0032]
• FIG. 8 is a perspective view of the first half of the osmotic pump housing according to an embodiment of the present invention.[0033]
• FIG. 9 is a plan view of the first half of the osmotic pump housing of FIG. 8.[0034]
• FIG. 10 is a cross-sectional view of the first half of the osmotic pump housing of FIG. 9, taken along lines DD′.[0035]
• FIG. 11 is a plan view of an embodiment of the membrane enclosure, according to an embodiment thereof.[0036]
• FIG. 12 is a perspective view of the membrane enclosure of FIG. 11, showing the semipermeable membrane wells in dashed lines.[0037]
• FIG. 13 is a plan view of an impermeable membrane can of an osmotic pump according to an embodiment of the present invention, showing the internal surface and through bore thereof in dashed lines.[0038]
• FIG. 14 shows a side view of the impermeable membrane can of FIG. 13.[0039]
• FIG. 15 is a plan view of the osmotic engine of the osmotic pump, according to an embodiment of the present invention.[0040]
• FIG. 16 is a side view of the osmotic engine of FIG. 15.[0041]
• FIG. 17 is a plan view of the coiled tube, according to an embodiment of the present invention.[0042]
• FIG. 18 is a cross-sectional view of the tube of FIG. 17, taken along line EE′.[0043]
• FIG. 19 is a cross-sectional view of the coiled tube of FIG. 17, taken along line FF′.[0044]
• FIG. 20 illustrates the tube coupled to a catheter, according to an embodiment of the present invention.[0045]
• FIG. 21 illustrates the distal tip of the catheter of FIG. 20, according to an embodiment of the present invention.[0046]
• FIG. 22 illustrates the proximal end of the catheter of FIG. 20, according to an embodiment of the present invention.[0047]
• FIG. 23 shows an embodiment of a piston within the coiled pharmaceutical agent compartment, according to an embodiment of the present invention.[0048]
• FIG. 24 shows a further embodiment of a piston within the coiled pharmaceutical agent compartment, according to an embodiment of the present invention.[0049]
• FIG. 25 shows a further embodiment of still another piston within the coiled pharmaceutical agent compartment, according to an embodiment of the present invention.[0050]
• FIG. 26 shows a first step of a method by which the impermeable membrane of the first impermeable membrane may be breached so as to escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0051]
• FIG. 27 shows a second step of a method by which the impermeable membrane of the first impermeable membrane may be breached so as to escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0052]
• FIG. 28 shows a third step of a method by which the impermeable membrane of the first impermeable membrane can may be breached so as to escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0053]
• FIG. 29 shows a fourth step of a method by which the impermeable membrane of the second impermeable membrane can may be breached so as to further escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0054]
• FIG. 30 shows a fifth step of a method by which the impermeable membrane of the second impermeable membrane can may be breached so as to further escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0055]
• FIG. 31 shows a sixth step of a method by which the impermeable membrane of the second impermeable membrane can may be breached so as to further escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention.[0056]
• FIG. 32 is a plan view of another embodiment of the membrane enclosure, according to the present invention, showing the OFF feature of the present invention.[0057]
• FIG. 33 is a perspective view of the membrane enclosure of FIG. 32, showing the semipermeable membrane wells in dashed lines and the OFF switch feature of the present invention.[0058]
• FIG. 34 is an exploded view of another embodiment of an osmotic pump according to the present invention.[0059]
• FIG. 35 is an exploded view of a three-stage osmotic pump, according to another embodiment of the present invention.[0060]
• FIG. 36[0061]ais a top view of a three stage osmotic pump according to the present invention, showing the internal structure thereof in dashed lines.
• FIG. 36[0062]bis a reduced-size (relative to FIG. 36a) top view of a three stage osmotic pump, showing selected exemplary dimensions thereof.
• FIG. 37 is a cross-sectional view of a three stage osmotic pump according to the present invention, taken along cross-sectional line BB′ of FIG. 36.[0063]
• FIG. 38 is a cross-sectional view of a three stage osmotic pump according to the present invention, taken along cross-sectional line AA′ of FIG. 36.[0064]
• FIG. 39 is a cross-sectional view of the[0065]filter assembly312 of FIG. 35.
• FIG. 40 is a front view of the[0066]filter assembly312 of FIG. 35.
• FIG. 41 is a cross-sectional view of a piston, according to an embodiment of the present invention.[0067]
• FIG. 42 is a perspective view of a single stage osmotic pump according to another embodiment of the present invention.[0068]
• FIG. 43 is an exploded view of a single stage osmotic pump according to the present invention.[0069]
• FIG. 44 is a top view of a single stage osmotic pump according to the present invention, showing internal components thereof in dashed lines.[0070]
DESCRIPTION OF THE INVENTION
• FIG. 1 is a perspective view and FIG. 2 shows an exploded view of the[0071]pump100 according to an embodiment of the present invention. Considering FIGS. 1 and 2 collectively, thepump100 includes apump engine108 and a substantially toroidal compartment around theengine108. The toroidal compartment is bounded by aninner radius207 and anouter radius208 and is adapted to contain a fluid, such as a pharmaceutical agent. According to an embodiment of the present invention, the pharmaceutical agent compartment is tube-shaped and is defined by aninner lumen110 of atube109 that may be coiled at least partially around theosmotic engine108. Thetube109 has aproximal end184 and adistal end186. Thetube109 may include or be formed of, for example, polyimid. Apiston162 is disposed in the tube-shapedcompartment110. The piston is adapted to travel (in the direction from theproximal end184 to thedistal end186 of the tube109) within the tube-shapedcompartment110 and to cause a volume of fluid to be forced out of thedistal end186 of thetube109. As shown in FIG. 1, acatheter102 may be coupled to thedistal end186 of thetube109, to enable the fluid forced out thedistal end186 of thetube109 to be delivered to the intended delivery site within the patient. In one embodiment of the present invention, thepump engine108 includes an osmotic engine. Thepump100 may further include apump housing101 that is configured to enclose (at least) thepump engine108 and thetube109. As shown in FIG. 2, thepump housing101 may include afirst housing half106 and a matingsecond housing half104. According to an embodiment of the present invention, the first and secondpump housing halves106,104 mate to one another like a clamshell, in a fluid-tight fashion. As shown, the first andsecond housing halves106,104 may each have a generally circular outline (as may the entire pump100) and have a generally define a saucer shape. Thefirst housing half106 may further define anopening140, which may be circular in shape.
• The present invention will now be described in terms of an implantable osmotic pump for delivering a pharmaceutical agent to a patient, although the present invention is not so limited. The pump and/or the[0072]catheter102 may be implanted intravascularly, subcutaneously, epidurally, intrathecally and/or intraventricularly, for example. As shown in FIG. 2 as well as in FIGS. 15 and 16, the pump engine108 (referred to hereafter asosmotic engine108, although the present invention is not limited to osmotic-type pump engines) may be shaped like hollow, open-ended right cylinder. Theosmotic engine108 is hygroscopic and may include a salt block or a “salt wafer” and/or may include an absorbent polymer, such as poly(acrylic acid), potassium salt; poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide), potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethylene oxide); poly (2-hydroxethyl methacrylate) and/or poly(2-hydroxypropyl methacrylate) and poly(isobutylene-co-maleic acid). Suitable absorbent polymers are available from Aldrich, Inc. of Milwaukee, Wis., for example. Theosmotic engine108 may include a base that may be disposed in a correspondingly shaped depression defined in thesecond housing half104 and a cylindrical wall attached to the base.
• According to an embodiment of the present invention, the[0073]pump100 may include a generally cylindrical-shapedmembrane enclosure112. Themembrane enclosure112 may be fitted within and partially surrounded by thepump engine108. Themembrane enclosure112 is dimensioned to closely fit theopening140 defined in thefirst housing half106. Themembrane enclosure112 may include an initial dose semipermeable membrane (formed of or including cellulose acetate, for example), as shown in FIG. 5, to create a fluid path for water through the initialwater access port130 defined in themembrane enclosure112 to theosmotic engine108. The initialwater access port130 may be spanned by a thinimpermeable membrane182, thereby defining an interstitial space between the initial dose semipermeable membrane and the impermeable membrane. This interstitial space may be filled with a saturated saline solution, to keep the initial dose semipermeable membrane fully hydrated prior to implantation of thepump100 in a patient (not shown). Prior to implantation, the physician may breach theimpermeable membrane182 spanning the initialwater access port130 to allow water from the patient to enter the initial dose semipermeable membrane well150 (see FIG. 12) and migrate across the initial dose semipermeable membrane134 (see FIG. 5) to reach theosmotic engine108. In this manner, the initialwater access port130, the thinimpermeable membrane182 and the saturated saline solution effectively form a pump ON switch. Indeed, after implantation of the pump but before breaching the thinimpermeable membrane182, thepump100 does not deliver any pharmaceutical agent to the patient. It is only after breaching the thinimpermeable membrane182 that the pump becomes effective to initiate delivery of the contained pharmaceutical agent to the patient. The saturated saline solution between theimpermeable membrane182 and the underlying initial dosesemipermeable membrane150 insures that the onset of delivery of the pharmaceutical agent is not delayed by the time required for the initial dosesemipermeable membrane150 to hydrate.
• The[0074]membrane enclosure112 may also define a primarywater access port132 that may be (but need not be) concentric with the circumference of themembrane enclosure112. A dose escalation assembly may fit within the primarywater access port132. The dose escalation assembly, according to the present invention, is adapted to selectively increase the amount of water from implantation site within the patient that reaches theosmotic engine108. The dose escalation assembly may include one or more impermeable membrane cans fitted within the primarywater access port132 of themembrane enclosure112. In the embodiment of FIG. 2, the dose escalation includes a first impermeable membrane can114 stacked upon a second impermeable membrane can116 whose structure and function is described hereunder.
• Reference is now made to FIGS.[0075]3-5, in which FIG. 3 is a plan view of the osmotic pump according to an embodiment of the present invention in which the first half of the housing has been removed, FIG. 4 is a cross sectional view of the osmotic pump of FIG. 3, taken along lines BB′ of FIG. 3 and FIG. 5 is a cross sectional view of the osmotic pump of FIG. 3, taken along lines AA′. FIG. 3 shows thetube109 coiled around theosmotic engine108 from theproximal end184 to the distal end thereof, shown at186. Thedistal end186 of the coiledtube109 may be fitted with acatheter ID tube118 that facilitates the coupling of thecatheter102 to thedistal end186 of thetube109. As shown in FIG. 5, the initialwater access port130 may lead to an initial dosesemipermeable membrane134 within themembrane enclosure112. Themembrane enclosure112 is configured to enable water from the patient to flow into the initialwater access port130, to migrate across the initial dosesemipermeable membrane134 to reach theosmotic engine108. As the water reaches theosmotic engine108, theengine108 swells in volume and increases the osmotic pressure differential across the initial dosesemipermeable membrane134 and pushes thepiston160 within the tube-shaped compartment defined by thetube109 toward thedistal end186 thereof, as the expansion of theosmotic engine108 is constrained to within the tube-shapedcompartment110. In so doing, thepiston160 displaces a volume of pharmaceutical agent within the tube-shapedcompartment110, which displaced volume of pharmaceutical agent is delivered out of thedistal end186 of thetube109. The pharmaceutical agent is delivered at a selected initial infusion rate that is related to the thickness, composition and surface area of the initial dosesemipermeable membrane134. In the case wherein the initial dosesemipermeable membrane134 is implanted in a fully hydrated state, the pharmaceutical agent within the tube-shaped compartment is quickly delivered to the patient at the selected initial infusion rate. If the initial dosesemipermeable membrane134 is not pre-hydrated, the delivery of the pharmaceutical agent may be delayed until themembrane134 becomes at least partially hydrated from water from the patient implant site. Until at least the firstimpermeable membrane cans114 is breached, the only water that reaches theosmotic engine108 enters thepump100 through the initialwater access port130 to cross the initial dosesemipermeable membrane134.
• As shown in FIG. 4, the[0076]membrane assembly112 includes a firstsemipermeable membrane120 and a secondsemipermeable membrane124. The diameter of thesemipermeable membranes120,124 is directly proportional to the flow rate of the pump of the present invention. As shown, the firstsemipermeable membrane120 may be (but need not be) vertically offset from the secondsemipermeable membrane124 in themembrane enclosure112. Reference is now made to FIGS. 13 and 14, of which FIG. 13 is a plan view of an impermeable membrane can114,116 and of which FIG. 14 is a side view of the impermeable membrane can114,116 of FIG. 13. As shown therein, thecans114,116 include acylindrical sidewall154 and a through bore defined therein. Specifically, the sidewall of the first impermeable membrane can114 defines a first throughbore122 and the sidewall of the second impermeable membrane can116 defines a second throughbore126. An impermeable membrane152 (shown in FIGS. 13 and 14 in its intact state) spans one of the free ends of each of thecans114,116. Theimpermeable membranes152, according to the present invention, are impermeable at least to water from the patient implant site and are configured to be easily breached by the physician, as is detailed below. Theimpermeable membranes152 may include or be formed of most any water impermeable material that is biologically inert, such as titanium and/or stainless steel, coated platinum or platinum-iridium for radiopacity, for example. Theimpermeable membranes152 of the first andsecond cans114,116 may be surface ground to a thickness of about 1 or 2 thousandths of an inch, for example. Theimpermeable membranes152 may alternatively include polyethylene, PET, PETG or PETE, for example. Preferably, theimpermeable membranes152 are radiopaque, so as to be visible under fluoroscopy, once thepump100 is implanted. For example, a layer of radiopaque material may be sputtered or otherwise deposited on theimpermeable membranes152, to render them visible under fluoroscopy. Preferably, theimpermeable membranes110 are adapted to be breached by the physician or clinician, using a dose escalation pen (or a lancet or stylet as shown in FIGS.26-31), or some other functionally similar device. Theimpermeable membranes152 of the first and secondimpermeable membrane cans114,116 initially seal the first and secondsemipermeable membranes120,124 to prevent any water originating from the patient's implant site from crossing thesemipermeable membranes120,124 until the impermeable membrane(s)152 is breached, as shown at176 in FIGS.28-31.
• Returning now to FIGS.[0077]3-5, the first and secondimpermeable membrane cans114,116 are stacked within themembrane enclosure112 such that the respective throughbores122,126 thereof are aligned with the first and secondsemipermeable membranes120,122, respectively. Specifically, the first throughbore122 defined in the first impermeable membrane can114 is aligned with the firstsemipermeable membrane120 and the second throughbore126 defined in the second impermeable membrane can116 is aligned with the secondsemipermeable membrane124. Moreover, theimpermeable membrane152 of the first impermeable membrane can114 is disposed adjacent the primarywater access port132, whereas the secondimpermeable can116 is disposed under the first impermeable membrane can114 and oriented such that the impermeable membrane thereof is immediately adjacent the first impermeable membrane can114. Although the present figures show thepump100 of the present invention equipped with twoimpermeable membrane cans114,116, the present invention is not limited thereto, as a single or a greater number of impermeable membrane cans may be used along with a corresponding number of semipermeable membranes.
• FIG. 6 is a plan view of the[0078]second half104 of theosmotic pump housing101, according to an embodiment of the present invention and FIG. 7 is a cross sectional view thereof, taken along lines CC′. As shown therein, thesecond half104 of thepump housing101 may have a generally saucer-like shape. Indeed, thesecond half104 of thehousing101 may have a generally circular outline and may define abulge136 therein to accommodate a portion of theosmotic engine108 therein. The rim of the second half104 (See FIG. 10) of thepump housing101 also defines anindentation138 adapted to mate with a corresponding feature defined by the rim of thefirst half106 of thepump housing101. FIG. 8 is a perspective view of thefirst half106 of theosmotic pump housing101 according to an embodiment of the present invention, whereas FIG. 9 is a plan view and FIG. 10 is a cross-sectional view thereof, taken along lines DD′. As shown in the perspective view of FIG. 10, anopening140 is defined in the also generally saucer-shapedfirst half106 of theosmotic pump housing101. Theopening140 may be centered in thehousing half106 and concentric with the generally circular outline thereof, as shown in FIG. 9. Theopening140 is preferably dimensioned so as to closely fit themembrane enclosure112. As shown in FIG. 10, thefirst half106 of thepump housing101 may define abulge144 that increases the interior volume of thepump100 when the first andsecond housing halves106,104 are mated to one another.
• FIG. 11 is a plan view of an embodiment of the[0079]membrane housing112, according to an embodiment thereof, whereas FIG. 12 is a perspective view of the membrane housing of FIG. 11, showing the semipermeable membrane wells in dashed lines. Considering now FIGS. 11 and 12 collectively, themembrane enclosure112 may be shaped as a cylinder dimensioned to fit within theosmotic engine108 and theopening140 in thefirst housing half106. The primarywater access port132 may be a bore partially through themembrane enclosure112. However, to best control the flow of water form the patient implant site to theosmotic engine108, the bore defined within themembrane enclosure112 should not run the entire length of themembrane enclosure112. Indeed, the only water paths from the implant site to the osmotic engine should be through the initial dose semipermeable membrane well150, through the first semipermeable membrane well146 and/or through the secondsemipermeable membrane well150. In contrast, the combination of the initialwater access port130 and the initial dose semipermeable well150 runs the entire length of themembrane enclosure112, as also shown in FIG. 5. Indeed, once thepump100 is implanted in the patient and any impermeable membrane that may span the initialwater access port130 is breached, a water path to theosmotic engine108 may be defined straight through themembrane enclosure112, as the water from the implant site migrates across the initial dose semipermeable membrane (shown at134 in FIG. 5) fitted within the initial dosesemipermeable membrane well150.
• First and second[0080]semipermeable membranes120,124 (shown in FIG. 4) are fitted within the first and secondsemipermeable membrane wells146,148, respectively. According to the present invention, when theimpermeable membrane152 of the first impermeable membrane can114 is breached (as shown at176 in FIGS. 28, 29 and31), water from the implant site may enter theprimary access port132 and travel through the first throughbore122 of the first impermeable membrane can114. From there, the water may travel through afirst passageway188, defined between primarywater access port132 and firstsemipermeable membrane well146. After crossing the firstsemipermeable membrane120 disposed in the well146, the water reaches theosmotic engine108. This first water path is shown at178 in FIGS. 28, 29 and31. As the water reaches theosmotic engine108, theengine108 swells in volume due to the osmotic pressure differential across the firstsemipermeable membrane120 and pushes thepiston160,162 within the tube-shapedcompartment110 defined within thetube109 toward thedistal end186 thereof. In so doing, thepiston160,162 displaces a volume of pharmaceutical agent within the tube-shapedcompartment110, which displaced volume of pharmaceutical agent is delivered out of thedistal end186 of thetube109. The pharmaceutical agent is delivered at a selected first infusion rate that is related to the thickness, composition and surface area of the firstsemipermeable membrane120 and that of the initial dosesemipermeable membrane134.
• Similarly, when the[0081]impermeable membrane152 of the second impermeable membrane can116 is breached (as shown at177 in FIGS. 28, 29 and31), water from the implant site may enter theprimary access port132 and travel through the second throughbore126 of the second impermeable membrane can116. From there, the water may travel through asecond passageway190, defined within theenclosure112 between the primarywater access port132 and the secondsemipermeable membrane well148. After crossing the secondsemipermeable membrane124 disposed in the well148, the water reaches theosmotic engine108. This water path is shown at180 in FIG. 31. As the water reaches theosmotic engine108, theengine108 swells in volume due to the osmotic pressure differential across the secondsemipermeable membrane124 and pushes thepiston160,162 within the tube-shapedcompartment110 defined by thetube109 toward thedistal end186 thereof. In so doing, thepiston160 displaces a volume of pharmaceutical agent within the tube-shapedcompartment110, which displaced volume of pharmaceutical agent is delivered out of thedistal end186 of thetube109. The pharmaceutical agent is delivered at a selected second infusion rate that is related to the thickness, composition and surface area of the secondsemipermeable membrane124, the thickness, composition and surface area of the firstsemipermeable membrane120 and the thickness, composition and surface area of the initial dosesemipermeable membrane134. Indeed, the infusion rate of thepump100 is related to which of thesemipermeable membranes134,120 and/or124 are currently exposed to the patient. If only the initial dosesemipermeable membrane134 is exposed to the patient, the infusion rate may be related only to the characteristics of the initial dosesemipermeable membrane134. If both the initial dosesemipermeable membrane134 and the firstsemipermeable membrane120 are exposed to the patient, the pump infusion rate may be related to the characteristics of both the initial dose and firstsemipermeable membranes134,120. In other words, the total infusion rate of thepump100 of the present invention in the state wherein both the initial dosesemipermeable membrane134 and the firstsemipermeable membrane120 are breached, may be approximated as the sum of the individual infusion rates contributed by each of thesemipermeable membranes134 and120. If the initial dosesemipermeable membrane134, the firstsemipermeable membrane120 and the secondsemipermeable membrane124 are exposed to the patient, the pump infusion rate may be related to the characteristics of the initial dose, the first and the secondsemipermeable membranes134,120 and124. In other words, the total infusion rate of the pump of the present invention in the state wherein theimpermeable membranes134,120 and124 are breached, may be approximated as the sum of the individual infusion rates contributed by each of thesemipermeable membranes134,120 and124.
• FIG. 17 is a plan view of the coiled[0082]tube109, according to an embodiment of the present invention, FIG. 18 is a cross-sectional view of thetube109 of FIG. 17, taken along line EE′ and FIG. 19 is a cross-sectional view thereof, taken along line FF′. According to the present invention, thepiston160 may initially (upon implantation) be disposed within the tube-shapedcompartment110 near theproximal end184 of thetube109. As the osmotic engine expands in volume, the only available volume for such expansion is within the tube-shapedcompartment110. Therefore, the expansion of theosmotic engine108 forces thepiston160 to travel through the coiledtube109 in the direction ofarrow166, which causes a volume of pharmaceutical agent to be delivered to the patient out of thedistal end186 of thetube109. A catheter ID (inner diameter)tube118 may be fitted onto thedistal end186 of thetube109, which facilitates coupling thecatheter102 thereto. As shown, thetube109 may be coiled a number of times around themembrane enclosure112. In the embodiment shown in FIGS.17-19, thetube109 is coiled four times around the membrane enclosure112 (not shown in FIGS.17-19), although a lesser or greater number of coils may readily be implemented.
• FIG. 20 illustrates the[0083]tube109 coupled to acatheter102, according to an embodiment of the present invention. FIG. 21 illustrates the distal tip of the catheter of FIG. 20, according to an embodiment of the present invention and FIG. 22 illustrates the manner in which the catheter may couple to thecatheter ID tube118. In FIG. 20, the outline of thepump housing101 is shown for reference purposes. Thecatheter102 is used to deliver the pharmaceutical agent from thecatheter ID tube118 to the target area within the patient's body. Thecatheter102 may be visible under fluoroscopy over its length, thereby enabling the physician to trim the catheter to the desired length. Alternatively, thecatheter102 may include distal radiopaque markers, for example. As shown in FIG. 21, thedistal tip158 of thecatheter102 may included a rounded, atraumatic tip. A plurality ofpharmaceutical agent openings158 may be defined through the catheter wall, from the internal lumen thereof to the patient. As shown in FIG. 22, the catheter ID may be fitted over thecatheter ID tube118 using a friction fit and/or suitable biocompatible adhesive(s), for example. Any suitable radio opaque material may be used to render all or a portion or selected portions of thecatheter102 radio opaque. For example, thecatheter102 may be formed of silicone or polyurethane and may be doped with barium sulfate, for example. The length of thecatheter102 may be most any therapeutically effective length. A longer length, however, increases the dead space therein and delays the effusion of the pharmaceutical agent into the patient, as it will take longer for the agent to travel the length thereof. For example, thecatheter102 may be about 5 cm to about 100 cm in length. More preferably, thecatheter102 may be about 10 cm to about 30 cm in length. More preferably still, the catheter012 may be about 15 cm to about 25 cm in length. For example, thecatheter102 may be about 20 cm in length. The internal diameter (ID) of the infusion lumen of thecatheter102 may be selected within the range of about 0.001 inches to about 0.010 inches. The walls of thecatheter102 may be about 0.001 inches to about 0.006 inches in thickness. According to an embodiment of the present invention, the outer diameter (OD) of thecatheter102 may be selected between about 0.024 inches and about 0.066 inches in thickness, for example.
• FIGS.[0084]23-25 are cross sections of thetube109, showing various designs for the piston within the tube shapedcompartment110. Considering now FIGS.23-25 collectively, the piston of theosmotic pump100 of the present invention may be spherical, as shown at160, cylindrical as shown at162 or may approximate a conical section as shown at163, although other shapes are possible. A spherical shape minimizes the contact points of thepiston160 with the tube-shapedcompartment110, thereby enabling thepiston160 to travel through thecompartment110, even as the radius of curvature thereof changes form theproximal end184 to the distal end of thetube109.Reference170 represents slurry from theosmotic engine108. Indeed,reference170 may be considered to be an extension of theosmotic engine108, as it swells with water from the patient implant site through thesemipermeable membranes134,120 and/or124. As theosmotic engine108 swells in volume, it exerts aforce168 on thepiston160,162 or163, forcing it to travel within the tube-shapedcompartment110 in the direction ofarrow166. In so doing, thepiston160,162,163 displaces a corresponding volume ofpharmaceutical agent164. Thepiston160,162,163 may include stainless steel, nylon or an elastomer, for example. When the piston has a cylindrical shape, as shown on FIG. 24 at162, thepiston162 may be formed of an elastomeric substance, such as butyl rubber, for example. Such acylindrical piston162 may then deform to match the radius of curvature of the tube-shapedcompartment110. The inner diameter of the tube109 (that is, the diameter of the tube-shaped compartment110) may be constant over the length of thetube109 or may become larger or smaller over its length. In the latter case, thepiston163 may assume a truncated conical shape, in which a proximal end thereof is smaller than a distal end thereof (or vice-versa), to match the change in inner diameter of the tube-shapedcompartment110. To prevent thetube109 from compressing, binding and/or kinking as theosmotic engine108 swells, thecoiled tube109 may be encased in a hard substance, such as epoxy, for example.
• FIG. 26-[0085]28 shows steps of a method by which theimpermeable membrane152 of the first impermeable membrane can114 may be breached so as to escalate a dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention. FIG. 29-31 shows further steps of the method by which theimpermeable membrane152 of the second impermeable membrane can116 may be breached so as to further escalate the dose of pharmaceutical agent delivered to the patient, according to an embodiment of the present invention. While any device may be used to breach theimpermeable membranes152, a dose escalation pen orstylet172 similar to that shown in FIGS.26-31 may be advantageously used. Anactuator192, such as a thumb actuated wheel, may be coupled to a pointedextendible portion200 of thepen172. Actuating theactuator192 may cause the pointed andextendible portion200 to extend in length from afirst length202 shown in FIGS.26-28, to asecond length204 shown in FIGS.29-31. At some time after implantation of thepump100, the patient may require a greater dose of pharmaceutical agent than provided by the initial dose, which initial dose is driven by theosmotic engine108 swelling in response to water entering the initialwater access port132. Without removing thepump100 from the patient, the physician may, according to the present invention, use a dose escalation pen or stylet to increase the effusion rate of the pharmaceutical agent from thepump100 in a simple office or outpatient procedure.
• For clarity of illustration, only the first and second[0086]impermeable membrane cans114,116 of thepump100 are shown in FIGS.26-31. In the state illustrated in FIG. 26, theimpermeable membranes152 prevent any water from the patient implant site from reaching the first and secondsemipermeable membranes120,124. When the physician wishes to increase the dose of pharmaceutical agent delivered to the patient, he or she may use thedose escalation pen172 in a configuration wherein the pointedextendible portion200 thereof is extended only to thefirst length202. By inserting theportion200 through the patient's skin under fluoroscopic, ultrasonic or manual (palpation) guidance, for example, the physician may breach theimpermeable membrane152 of the first impermeable membrane can114, as shown at FIG. 27. Preferably, thefirst length202 of theextendible portion200 is selected so as to breach only theimpermeable membrane152 of thefirst can114, and not that of thesecond can116. Preferably, the outer diameter of theextendible portion200 is slightly smaller than the outer diameter of thecans114,116, to enable thedose escalation pen172 to create a wide opening when breaching theimpermeable membranes152. Similarly, thehandle portion206 of thepen172 should have a diameter that is slightly larger than the outer diameter of thecans114,116, to limit the travel of theextendible portion200 within thecans114,116. As shown in FIG. 28, once thedose escalation pen172 is retracted after the impermeable membrane of thefirst can114 is breached, afirst water path178 is created, from the patient implant site through the first impermeable membrane can114, through the first throughbore122 thereof, across the firstsemipermeable membrane120 to theosmotic engine108. In this state of thepump100, water may now reach theosmotic engine108 through the initialwater access port132 and through the first impermeable membrane can114.
• Turning now to FIGS.[0087]29-31, when the patient requires an even greater dose of pharmaceutical agent, the physician may actuate theactuator192 to change the length of theextendible portion200 to thesecond length204, whichsecond length204 is sufficient to penetrate thefirst can114 and breach theimpermeable membrane152 of the second impermeable membrane can116, as shown at177 FIG. 31. After thedose escalation pen172 is retracted as shown at FIG. 31, asecond water path180 is created. Thesecond water path180 runs from the patient implant site through the first impermeable membrane can114, through the breachedimpermeable membrane152 of thesecond can116, through the second throughbore126 of thesecond can116, across the secondsemipermeable membrane124 to theosmotic engine108. In this state of thepump100, water may now reach theosmotic engine108 through the initialwater access port132, through the first impermeable membrane can114 as well as through the second impermeable membrane can116.
• The tube-shaped[0088]compartment110 of thepump100 may be pre-loaded with one or more pharmaceutical agents.30. For example, the pharmaceutical agent may be therapeutically effective for one or more of the following therapies: pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy, allergy therapy, hypertension therapy, antibiotic therapy, bronchodilation therapy, asthmatic therapy, arrhythmia therapy, nootropic therapy, cytostatic and metastasis inhibition therapy, migraine therapy, gastrointestinal therapy and/or other pharmaceutical therapies.
• For example, the pharmaceutical agent may include an opioid, a morphine-like agonist, a partial agonist, an agonist-antagonist and/or an alpha 2-adrenoreceptor agonist. Advantageously, the pharmaceutical agent may include morphine, hydromorphone, levorphanol, methadone, fentanyl, sufentanil, buprenorphine, pentazocine and/or butorphanol, for example. The pharmaceutical agent may, for example, include an analgesic agent such as Dihydrocodeine, Hydromorphone, Morphine, Diamorphine, Levorphanol, Butorphanol, Alfentanil, Pentazocine, Buprenorphine, Nefopam, Dextropropoxyphene, Flupirtine, Tramadol, Oxycodone, Metamizol, Propyphenazone, Phenazone, Nifenazone, Paracetamol, Phenylbutazone, Oxyphenbutazone, Mofebutazone, Acetyl Salicylic Acid, Diflunisal, Flurbiprofen, Ibuprofen, Diclofenac, Ketoprofen, Indomethacin, Naproxen, Meptazinol, Methadone, Pethidine, Hydrocodone, Meloxicam, Fenbufen, Mefenamic Acid, Piroxicam, Tenoxicam, Azapropazone, Codein, Bupivacaine, Ketamine, Meperidine and/or [D-Ala2,D-Leu5]enkephalin (DADL). The pharmaceutical agent may also include analgesic that is an alpha-2 adrenergetic agonist such as Clonidine, Tizadine, ST-91, Medetomidine, Dexmedetomidine and/or related alpha-2 adrenergetic agonists. The analgesic may also include an N-methyl-D-aspartate (NMDA) receptor agonist including Dexmethorphan, Ifenprodil, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK-801), and/or related NMDA agonists. The analgesic may also include a somatostatin analog selected including Octreotide, Sandostatin, Vapreotide, Lanreotide, and/or related Somatostatin analogs, for example. Alternatively, the pharmaceutical agent may include a non-opioid analgesic such as Ketorolac, super oxide dismutase, baclofen, calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin, omega-conopeptides, and/or related non-opioid analgesics, for example. The pharmaceutical agent in the[0089]compartment310 may be dissolved in an aqueous solution.
• For pain therapy, a preferred pharmaceutical agent is Sufentanil. In that case wherein the pharmaceutical agent is (or includes) Sufentanil that is dissolved in an aqueous medium, it has been found that the solubility of the Sufentanil within the aqueous solution increases with increasing acidity of the medium. For example, the pumps according to the present invention may be configured to deliver Sufentanil at up to about 1500 μg/day, at a concentration of up to about 500,000 μg/ml, when the Sufentanil is dissolved in an acidic aqueous medium.[0090]
EXAMPLE
• A pump according to the present invention may include a[0091]pharmaceutical agent compartment310 having a volume of 500 μl (microliters). Acompartment310 of this volume may contain 500 μl of pharmaceutical agent solution, the solution including 250,000 μg of Sufentanil dissolved in an acidic aqueous medium. Therefore, about 1500 μg/day of such pharmaceutical agent solution may be delivered to the patient over a treatment period spanning about 167 days. Implanted into a patient, such a pump would deliver about 3 μl of pharmaceutical agent solution to the patient per day, each such 3 μl of pharmaceutical agent solution containing about 1500 μl of Sufentanil.
• The pharmaceutical agent may also include an anti-allergic agent including Pheniramine, Dimethindene, Terfenadine, Astemizole, Tritoqualine, Loratadine, Doxylamine, Mequitazine, Dexchlorpheniramine, Triprolidine and/or Oxatomide, for example. The pharmaceutical agent may include one or more anti-hypertensive agents, such as Clonidine, Moxonidine, Methyldopa, Doxazosin, Prazosin, Urapidil, Terazosin, Minoxidil, Dihydralalzin, Deserpidine, Acebutalol, Alprenolol, Atenolol, Metoprolol, Bupranolol, Penbutolol, Propranolol, Esmolol, Bisoprolol, Ciliprolol, Sotalol, Metipranolol, Nadolol, Oxprenolol, Nifedipine, Nicardipine, Verapamil, Diltiazim, Felodipine, Nimodipine, Flunarizine, Quinapril, Lisinopril, Captopril, Ramipril, Fosinoprol and/or Enalapril, for example. Alternatively, the pharmaceutical agent may include an antibiotic agent such as Democlocycline, Doxycycline, Lymecycline, Minocycline, Oxytetracycline, Tetracycline, Sulfametopyrazine, Ofloaxcin, Ciproflaxacin, Aerosoxacin, Amoxycillin, Ampicillin, Becampicillin, Piperacillin, Pivampicillin, Cloxacillin, Penicillin V, Flucloxacillin, Erythromycin, Metronidazole, Clindamycin, Trimethoprim, Neomycin, Cefaclor, Cefadroxil, Cefixime, Cefpodoxime, Cefuroxine, Cephalexin and/or Cefradine, for example. Bronchodialotors and anti-asthmatic agents may also be pre-loaded into the tube-shaped[0092]compartment110, including Pirbuterol, Orciprenaline, Terbutaline, Fenoterol, Clenbuterol, Salbutamol, Procaterol, Theophylline, Cholintheophyllinate, Theophylline-ethylenediamine and/or Ketofen, for example. Anti-arrhythmic agents may also be pre-loaded into thepump100, including Viquidil, Procainamide, Mexiletine, Tocainide, Propafenone and/or Ipratropium, for example. The pharmaceutical agent may alternatively include a centrally acting substance such as Amantadine, Levodopa, Biperiden, Benzotropine, Bromocriptine, Procyclidine, Moclobemide, Tranylcypromine, Tranylpromide, Clomipramine, Maprotiline, Doxepin, Opipramol, Amitriptyline, Desipramine, Imipramine, Fluroxamin, Fluoxetin, Paroxetine, Trazodone, Viloxazine, Fluphenazine, Perphenazine, Promethazine, Thioridazine, Triflupromazine, Prothipendyl, thiothixene, Chlorprothixene, Haloperidol, Pipamperone, Pimozide, Sulpiride, Fenethylline, Methylphenildate, Trifluoperazine, Oxazepam, Lorazepam, Bromoazepam, Alprazolam, Diazepam, Clobazam, Buspirone and/or Piracetam, for example. Cytostatics and metastasis inhibitors may also be pre-loaded within thepump100 of the present invention, including Melfalan, Cyclophosphamide, Trofosfamide, Chlorambucil, Busulfan, Prednimustine, Fluororacil, Methotrexate, Mercaptopurine, Thioguanin, Hydroxycarbamide, Altretamine and/or Procarbazine, for example. Other pharmaceutical agents that may be pre-loaded include anti-migrane agents such as Lisuride, Methysergide, Dihydroergotamine, Ergotamine and/or Pizotifen or gastrointestinal agents such as Cimetidine, Famotidine, Ranitidine, Roxatidine, Pirenzipine, Omeprazole, Misoprostol, Proglumide, Cisapride, Bromopride and/or Metoclopramide.
• The present invention is also a kit, including an implantable[0093]osmotic pump100, acatheter102 configured to attach to thepump100 and/or dose escalation pen(s)172 configured to breach theimpermeable membranes152 of the first and/orsecond cans114,116.
• There may be instances wherein it is desired to shut the pump down. For example, an adverse reaction to the pharmaceutical agent may have occurred. FIGS. 32 and 33 are plan and perspective views, respectively, of a[0094]membrane enclosure112, according to embodiment of the present invention that addresses this need. As shown therein, themembrane enclosure112 of FIGS. 32 and 33 is identical to the membrane enclosure of FIGS. 11 and 12, but for the presence of the structure referenced at209.Reference209 denotes an OFF switch that is configured to enable the physician to nullify or substantially nullify the osmotic pressure differential across any and all semipermeable membranes such as shown at120 or124. TheOFF switch209 includes an OFF switchimpermeable membrane210 and an OFF switchimpermeable lumen211. When and if the OFF switchimpermeable membrane210 is breached, fluid from the patient's implant site flows into theOFF switch lumen211, bypasses the semipermeable membranes, and flows directly to theosmotic engine108. Thus, any existing osmotic pressure that may have developed across such semipermeable membranes is reduced to zero or substantially zero, which correspondingly reduces the pump's driving force and reduces the delivery rate of the pharmaceutical agent to zero or about zero. The pump may then be explanted from the patient at will or may simply be left in place.
• FIG. 34 is an exploded view of another embodiment of an osmotic pump according to the present invention. FIG. 34 is similar to FIG. 1, but for the[0095]osmotic engine108. Accordingly, the description of the structures in FIG. 1 that are identical to structures in FIG. 34 is incorporated herein by reference. In FIG. 34, at least a portion of the osmotic engine is disposed within thetube109, at or near theproximal end184 thereof. The tube, in this case, is preferably rigid and may be formed of, for example, stainless steel or titanium. In this manner, the expansion of theosmotic engine108 may be entirely constrained within thetube109, thereby pushing thepiston162 within thetube109 toward theproximal end186 thereof.
• FIG. 35 is an exploded view of a three-stage[0096]osmotic pump300, according to another embodiment of the present invention. FIG. 36 is a top view of a three stage osmotic pump according to the present invention, showing the internal structure thereof in dashed lines. FIGS. 37 and 38 are cross-sectional views of a three stage osmotic pump according to the present invention, taken along cross-sectional line BB′ and AA′ of FIG. 36. Considering now FIGS.35-38 collectively, the constituent elements of thepump300 that are similar to corresponding elements in FIG. 2 are identified by the same reference numerals and the detailed description thereof is omitted here. As shown, theosmotic pump300 includes a substantially saucer-shaped housing that includes afirst housing half302 and asecond housing half304 that mates with thefirst housing half302. In contradistinction to the embodiment shown in FIG. 2, theosmotic pump300 of FIG. 35 does not include a tube, such astube109. Instead, when mated together, the first andsecond halves302,304 of the pump housing together define a tube-shaped and fluid-tight compartment310 that is adapted to enclose a pharmaceutical agent. Thecompartment310 is substantially toroidal in shape, in that it resembles a tube that curves around theosmotic engine306, following the outer curvature of the pump housing throughout most of its length. The tube-shapedcompartment310 defines afirst end330 that is in fluid communication with theosmotic engine306 through apassageway332 and asecond end334 adjacent thecompartment outlet314 that is formed when the first andsecond halves302,304 of the housing are joined together.
• The[0097]pump300 includes apiston316 that is configured and adapted to travel within thecompartment310 in response to the force exerted thereon by theosmotic engine306. As thepiston316 travels within thecompartment310, it displaces a volume of pharmaceutical agent. Thepiston316, when thepump300 is first implanted, is located adjacent thefirst end330 of thecompartment310 and thereafter travels from thefirst end330 toward thesecond end334, displacing a volume of pharmaceutical agent as it travels. FIG. 41 shows a cross-section of an exemplary embodiment of apiston316. As shown therein, thepiston316 may define aleading end322 and a trailingend324. Additionally, to reduce the surface area of thepiston316 that contacts the wall of thepharmaceutical agent compartment310, the outer surface of the piston may define one ormore throughs328 andridges326, thereby further facilitating the travel of thepiston316 through thecompartment310.
• Returning now to FIG. 35, the[0098]pump300, when configured for systemic delivery of a pharmaceutical agent (as is the case wherein the pump is implanted subcutaneously, for example), may include afilter assembly312. Thefilter assembly312 is configured to fit within thecompartment outlet314, so as to maintain the substantially circular footprint of thepump300, as shown most clearly in FIG. 36. The structure of thefilter assembly312 is further described below, with reference to FIGS. 39 and 40. Functionally, thefilter assembly312 filters the flow of the pharmaceutical agent from thepump300 to the implant site within the patient or to the aqueous environment in which the pump is deployed. Thefilter assembly312 prevents the passage of crystallized pharmaceutical agents to the patient. Crystallized pharmaceutical agents present a danger to the patient, in that the crystallized portion may contain an excess amount of agent and may cause an overdose.
• Assuming that the tube-shaped[0099]compartment310 is substantially circular in cross-section, the volume of pharmaceutical agent that may be contained therein may be estimated by:
• n/360[¼I]²(a+b)(b−a)²
• where, as shown in FIG. 36[0100]b(which figure is not shown to the same scale as FIG. 36a), a is the inner radius of thecompartment310, b is the outer radius of thecompartment310 and n represents the number of degrees that thecompartment310 is coiled around thepump300, as shown byarrow350. As shown in the embodiment illustrated in FIG. 36b, n is about 270°, as the portion of thecompartment310 that is free to enclose pharmaceutical agent (i.e., from theleading edge317 of thepiston316 to theproximal edge313 of the filter assembly312) spans about ¾ of the circumference of thepump300.
• The[0101]pump300 may also include aring308. Thering308 is preferably formed of the same material as the first andsecond housing halves302,304 such as stainless steel, titanium or alloys thereof, for example. To assemble thepump300, thepiston316 may be placed adjacent thefirst end330 of thecompartment310 and theosmotic engine306 may be centered between the first andsecond housing halves302,304. The first andsecond housing halves302,304 may then be welded together, along the circumferential seam thereof. The first and secondimpermeable membrane cans114,116 may then be inserted into the membrane enclosure, properly aligned therein and secured thereto. Thering308 may then be inserted into the central opening formed by the first andsecond housing halves302,304 and thesemipermeable membrane enclosure112, complete with the first and secondimpermeable cans114,116 may then be dropped into the central opening of thering308, taking care to align the first throughbore124 with the first semipermeable membrane well146 and the second throughbore124 with the secondsemipermeable membrane well148. Theenclosure112 may then be welded to thering308 and thering308 may be welded to thefirst half302 of the pump housing (not necessarily in that order). Thecompartment310 may then be filled with pharmaceutical agent (not shown in FIG. 35) and thefilter assembly312 may thereafter be fitted within thecompartment outlet314 and secured therein. Note that the initial dose semipermeable membrane fitted within the initial dose semipermeable membrane well336 is not shown in FIGS.35-38, nor is the first semipermeable membrane fitted within the first semipermeable membrane well146 or the second semipermeable membrane fitted within the secondsemipermeable membrane well148. Themembrane enclosure112 may also incorporate the OFF switch features shown in FIGS. 32 and 33. According to the embodiment of the present invention shown in FIGS.35-38, thepump300 is adapted to deliver a pharmaceutical agent or agents at three distinct rates. The first or initial rate occurs when thepump300 is implanted within the patient and only the initialwater access port130 is in fluid communication with the fluid environment of the pump's implant site within the patient. In this configuration, water from the implant site enters the pump at130, crosses the initial dose semipermeable membrane in the semipermeable membrane well336 and comes into contact with theosmotic engine306, causing theengine306 to swell and to push thepiston316 toward thesecond end334 of thecompartment310 at an initial first rate. Thereafter, the physician may puncture the impermeable membrane of thefirst can114, thereby causing water form the implant site to enter therein, cross the first semipermeable membrane within the first semipermeable membrane well146 and reach theosmotic engine306. The delivery rate of thepump300 is now increased from its first, initial rate to a second, larger rate, as more water from the patient implant site is reaching theosmotic engine306, causing it to swell at a faster rate, thereby causing topiston316 to travels within thecompartment310 at a corresponding second, faster rate. When the second impermeable membrane can116 is breached, water from the implant site enters therein, crosses the second semipermeable membrane within the second semipermeable membrane well148 and reaches theosmotic engine306. The delivery rate of thepump300 is now increased from its second rate to a third, even greater rate, as more water from the patient implant site reaches theosmotic engine306, causing it to swell at a faster rate, thereby causing topiston316 to travel within thecompartment310 at a third, faster rate, thus displacing a greater amount of pharmaceutical agent than either the initial or second rates.
• FIG. 39 is a cross-sectional view of the[0102]filter assembly312 of FIG. 35 and FIG. 40 is a front view of thefilter assembly312 of FIG. 35. As shown in FIGS. 35 and 39-40, thefilter assembly312 may be (but need not be) shaped as a slanted and truncated circular cylinder. Thefilter assembly312 defines aproximal end313 and adistal end315. Theassembly312 further defines apharmaceutical agent inlet321 that emerges at theproximal end313 and apharmaceutical agent outlet320 that emerges at the distal end of thefilter assembly312. Between theinlet321 and theoutlet320, the filter assembly includes afilter318. According to the present invention, thefilter318 may include a plug of porous material, that defines a plurality of pores. The pores, according to an embodiment of the present invention, may range from about 2 microns in average pore size to about 80 microns in average pore size, for example. For example, the average pore size of the porous material of thefilter318 may be selected within the range of about 5 microns to about 20 microns.
• The porous material of the[0103]filter318 may be selected to be hydrophilic or hydrophobic, depending upon, for example, the nature of the pharmaceutical agent contained in thepump300. The pharmaceutical agent in thecompartment310 may be dissolved in an aqueous solution. Alternatively, the pharmaceutical agent in thecompartment310 of thepump300 may be dissolved in a non-aqueous solution, such as alcohol (benzyl alcohol, for example). In such a case, thefilter assembly318 may include a filter that is substantially hydrophobic in nature, which would allow the passage of a hydrophobic solution, but would not admit the passage of a (or a substantial amount of a hydrophilic solution such as water. Water (or substantial amounts thereof) from the patient implant site, therefore, could not get into thepump300 and only the pharmaceutical agent could get out, into the patient. Alternatively, theporous material318 may have hydrophilic characteristics. When theporous material318 of thefilter assembly312 is hydrophilic, reliance is made on the pressure differential across the porous material318 (higher on theproximal end313 than on thedistal end315 end thereof, due to the pressure exerted by the osmotic engine306) as well as on the pore size of theporous material318 to limit the diffusion into thepump300. The pore size may be selected depending upon the magnitude of the pressure differential across thefilter assembly312, the length of thefilter318, the nature of the pharmaceutical agent to be delivered (for example, some pharmaceutical agent including large-sized protein molecules such contained in many pain medications may require afilter318 defining relatively large size pores) and the aspect ratio of the filter318 (ratio of aggregate pore size to length of filter318), among other factors. Suitable materials for the porous material of thefilter318 may be obtained from, for example Millipore Corp. (http://www.millipore.com), Porex Corp. (http//:www.porex.com) and others.
• FIGS. 42, 43 and[0104]44 show a perspective view, an exploded view and a top view of a single stage osmotic pump according to another embodiment of the present invention, with the top view of FIG. 44 showing internal components thereof in dashed lines. Thepump400 includes first andsecond housing halves302,304,filter assembly312,piston316,osmotic engine306 andring308, each of which being similar or identical to those structures in FIGS.35-38 referenced by the same numerals. A detailed description of these structures is, therefore, omitted here. The single-stage pump400 may include asemipermeable membrane enclosure412. Thesemipermeable membrane enclosure412 may define awater access port430 through which water from the patient implant site enters thepump400. Theenclosure412 also defines awater outlet port438, thorough which water comes into contact with theosmotic engine306. Between thewater inlet port430 and thewater outlet port438 is disposed a semipermeable membrane. Thewater inlet port430 may be covered by an impermeable membrane of stainless steel or titanium, for example. Moreover, a saturated saline solution may be present between the impermeable membrane covering thewater inlet port430 and the semipermeable membrane within theenclosure412. Such a saturated saline solution maintains the semipermeable membrane in a hydrated state, and speeds up the initial delivery of the pharmaceutical agent contained in thecompartment310 of thepump400 once the (optional) impermeable membrane covering thewater inlet port430 is breached. Such an impermeable membrane would be included in thepump400 only if it was desired to implant thepump400 in an inactive state and, at some later time, activate it so as to initiate the delivery of the pharmaceutical agent contained therein. Thesingle stage pump400 may also include the OFF switch features shown in FIGS. 32 and 33.
• The pharmaceutical agent compartment of the pumps according to the present invention, as noted above, may contain sufentanil, for example, and may also contain other medications. Depending upon the clinical indication, the pumps according to the present invention may be configured for intravascular, subcutaneous, epidural, intrathecal or intraventricular use. Table 1 below details exemplary maximum expected dosages of Sufentanil for above-listed uses.[0105]

  	TABLE 1
  	Expected Maximum Dosage of
  	Sufentanil (μg/day)

  	Intravascular	1500
  	Subcutaneous	1500
  	Epidural	500
  	Intrathecal	50
  	Intraventricular	25

• Table 2 below shows exemplary delivery schedules for pumps according to the present invention having a diameter of 1.8 cm and a[0106]compartment310 having a capacity of 200 mg, a diameter of 2.8 cm and acompartment310 having a capacity of 500 mg and a diameter of 5.0 cm and acompartment310 having a capacity of 2000 mg over selected delivery rates (in mg/day) ranging from 0.50 mg/day to 20.0 mg/day.

  Exemplary Delivery Schedule

  Months of Delivery

  	1.8 cm diameter	2.8 cm diameter	5.0 cmdiameter
  Delivery Rate
  	200 mg capacity	500 mg capacity	2000 mg capacity
  (mg/day)	(Without dose escalation)	(With dose escalation)	(With dose escalation)

  0.50	12	—	—
  0.75	8	12	—
  2.00	3.3	6	—
  5.00	—	3.3	12
  10.0	—	—	6
  20.0	—	—	3.3

• The present invention may be implanted under the patient's skin in an outpatient setting. The implantation procedure may be performed with a local anesthetic and may be carried out in as little as 15-20 minutes, for example. Depending upon the implant site, a small 0.5 to 0.75 inch incision may be all that is required, which incision may later be closed with one or more STERI-STRIP® skin closure devices or sutures, for example. The thin, circular shape of the pumps according to the present invention facilitates placement thereof in a number of locations throughout the patient's body, including the chest wall, the lower back, the arms and legs, the neck and even under the scalp, to identify a few exemplary locations. It is to be understood, however, that the above list of possible implant sites is not to be construed as limiting the locations at which the present pumps may be implanted, as those of skill in this art may recognize. The present invention has been presented within the context of pain management and of drugs of a potency comparable to Sufentanil. However, the present invention may be scaled appropriately to deliver any volume of drug at any potency level.[0107]
• While the foregoing detailed description has described preferred embodiments of the present invention, it is to be understood that the above description is illustrative only and not limiting of the disclosed invention. Those of skill in this art will recognize other alternative embodiments and all such embodiments are deemed to fall within the scope of the present invention. Thus, the present invention should be limited only by the claims as set forth below.[0108]

Claims (103)

What is claimed is:

1. An implantable osmotic pump for delivering a pharmaceutical agent to a patient, comprising:

an osmotic engine;

a substantially toroidal compartment adapted to store a pharmaceutical agent, and

a piston disposed within the compartment, the osmotic engine being configured to cause the piston to travel within the compartment and deliver the pharmaceutical agent when the pump is implanted in the patient.

2. The pump ofclaim 1, further including a tube coiled at least partially around the osmotic engine, an inner lumen of the tube defining the pharmaceutical agent compartment.

3. The pump ofclaim 2, wherein the tube includes at least one material selected from a group including metals, polymers and polyimid.

4. The pump ofclaim 1, wherein the compartment is disposed at least partially around the osmotic engine.

5. The pump ofclaim 2, wherein tube is rigid and wherein the osmotic engine is disposed within the tube.

6. The pump ofclaim 1, wherein the osmotic engine includes a base, a cylindrical wall attached to the base and a free end opposite the base.

7. The pump ofclaim 2, further including a housing configured to enclose at least the osmotic engine and the tube.

8. The pump ofclaim 7, wherein the housing includes a first housing half and a second housing half that mates with the first housing half.

9. The pump ofclaim 8, wherein each of the first and second housing halves define a saucer shape.

10. The pump ofclaim 8, wherein each of the first and the second housing halves are substantially circular in shape.

11. The pump ofclaim 8, wherein the first housing half defines a substantially circular opening.

12. The pump ofclaim 1, further including a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and including an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted.

13. The pump ofclaim 12, wherein the pump is configured to deliver an initial dose of the pharmaceutical agent to the patient at a selected initial infusion rate, the selected initial infusion rate being related to at least one of a thickness, a composition and a surface area of the initial dose semipermeable membrane.

14. The pump ofclaim 12, wherein the initial dose semipermeable membrane is fitted with an initial dose impermeable membrane that initially seals the initial dose semipermeable membrane.

15. The pump ofclaim 14, further including a volume of a saturated saline solution between the initial dose semipermeable membrane and the initial dose semipermeable membrane.

16. The pump ofclaim 12, further including a dose escalation assembly fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted.

17. The pump ofclaim 16, wherein the dose escalation assembly includes a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached.

18. The pump ofclaim 16, wherein the dose escalation assembly includes:

a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and

a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path.

19. The pump ofclaim 18, wherein the first and second impermeable membranes are disposed in the membrane enclosure in a stacked configuration wherein the first impermeable membrane must be breached before the second impermeable membrane can be breached.

20. The pump ofclaim 18, wherein the first fluid path includes a first semipermeable membrane and wherein the second fluid path includes a second semipermeable membrane that is distinct from the first semipermeable membrane.

21. The pump ofclaim 20, wherein the pump is configured to deliver a first dose of the pharmaceutical agent to the patient at a selected first infusion rate and a second dose of the pharmaceutical agent to the patient at a selected second infusion rate that is greater than the first infusion rate, the selected first and second infusion rates being related to at least one of a thickness, a composition and a surface area of the first and second semipermeable membranes, respectively.

22. The pump ofclaim 1, wherein the osmotic engine includes a hygroscopic salt.

23. The pump ofclaim 1, wherein the osmotic engine includes an absorbent polymer.

24. The pump system ofclaim 23, wherein the absorbent polymer includes a material selected from a group including poly(acrylic acid), potassium salt; poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide), potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethylene oxide); poly (2-hydroxethyl methacrylate); poly(2-hydroxypropyl methacrylate) and poly(isobutylene-co-maleic acid) or derivatives thereof.

25. The pump ofclaim 1, wherein the compartment has a substantially constant inner diameter over a length thereof.

26. The pump ofclaim 1, wherein the compartment has a non-constant inner diameter over a length thereof.

27. The pump ofclaim 2, wherein the tube is coiled at least twice around the osmotic engine.

28. The pump ofclaim 1, further comprising an epoxy layer encasing at least the tube.

29. The pump ofclaim 2, wherein the tube includes polyimid.

30. The pump ofclaim 2, wherein the tube defines a proximal end adjacent the osmotic engine and a distal end at an end opposite the proximal end, and wherein the pump further includes a catheter coupled to the distal end.

31. The pump ofclaim 30, wherein the catheter and the pump are dimensioned to infuse a volume of up to about 20 μL/day over a treatment period.

32. The pump ofclaim 30, wherein the catheter and the pump are dimensioned to infuse a dose of Sufentanil of up to 1500 μg/day over a treatment period.

33. The pump ofclaim 30, wherein the catheter includes a radiopaque tip.

34. The pump ofclaim 1, wherein the piston includes one of a sphere, an elastomeric cylinder and an elastomeric conical section.

35. The pump ofclaim 34, wherein the piston includes at least one of stainless steel, a refractory metal, plastic, nylon and rubber.

36. The pump ofclaim 1, wherein the compartment is pre-loaded with a volume of the pharmaceutical agent.

37. The pump ofclaim 36, wherein the pharmaceutical agent is therapeutically effective for at least one therapy selected from pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy, allergy therapy, hypertension therapy, antibiotic therapy, bronchodilation therapy, asthmatic therapy, arrhythmia therapy, nootropic therapy, cytostatic and metastasis inhibition therapy, migraine therapy, gastrointestinal therapy, schizophrenia therapy, depression therapy, stress therapy and/or other pharmaceutical therapies.

38. The pump ofclaim 36, wherein the pharmaceutical agent includes an opioid.

39. The pump ofclaim 36, wherein the pharmaceutical agent includes at least one of a morphine-like agonist, a partial agonist, an agonist-antagonist and an alpha 2-adrenoreceptor agonist.

40. The pump ofclaim 36, wherein the pharmaceutical agent includes at least one agent selected from a group including morphine, hydromorphone, levorphanol, methadone, fentanyl, sufentanil, buprenorphine, pentazocine and butorphanol.

41. The pump ofclaim 40, wherein the sufentanil is at a concentration up to about 500,000 μg/mL.

42. The pump ofclaim 36, wherein the pharmaceutical agent includes an agent selected from a group including Dihydrocodeine, Hydromorphone, Morphine, Diamorphine, Levorphanol, Butorphanol, Alfentanil, Pentazocine, Buprenorphine, Nefopam, Dextropropoxyphene, Flupirtine, Tramadol, Oxycodone, Metamizol, Propyphenazone, Phenazone, Nifenazone, Paracetamol, Phenylbutazone, Oxyphenbutazone, Mofebutazone, Acetyl Salicylic Acid, Diflunisal, Flurbiprofen, Ibuprofen, Diclofenac, Ketoprofen, Indomethacin, Naproxen, Meptazinol, Methadone, Pethidine, Hydrocodone, Meloxicam, Fenbufen, Mefenamic Acid, Piroxicam, Tenoxicam, Azapropazone, Codein, Bupivacaine, Ketamine, Meperidine and DADL.

43. The pump ofclaim 36, wherein the pharmaceutical agent includes an agent that is an alpha-2 adrenergetic agonist selected from a group including Clonidine, Tizadine, ST-91, Medetomidine, Dexmedetomidine and related alpha-2 adrenergetic agonists.

44. The pump ofclaim 36, wherein the pharmaceutical agent includes an agent that is an NMDA receptor agonist selected from a group including Dexmethorphan, Ifenprodil, MK-801, and related NMDA agonists.

45. The pump ofclaim 36, wherein the pharmaceutical agent includes an agent that is a somatostatin analog selected from a group including Octreotide, Sandostatin, Vapreotide, Lanreotide, and related Somatostatin analogs.

46. The pump ofclaim 36, wherein the pharmaceutical agent includes an agent that is a non-opioid analgesic selected from a group including Ketorolac, super oxide dismutase, baclofen, calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin, omega-conopeptides, and related non-opioid analgesics.

47. The pump ofclaim 36, wherein the pharmaceutical agent includes an anti-allergic agent selected from a group including Pheniramine, Dimethindene, Terfenadine, Astemizole, Tritoqualine, Loratadine, Doxylamine, Mequitazine, Dexchlorpheniramine, Triprolidine and Oxatomide.

48. The pump ofclaim 36, wherein the pharmaceutical agent includes an anti-hypertensive agent selected from a group including Clonidine, Moxonidine, Methyldopa, Doxazosin, Prazosin, Urapidil, Terazosin, Minoxidil, Dihydralalzin, Deserpidine, Acebutalol, Alprenolol, Atenolol, Metoprolol, Bupranolol, Penbutolol, Propranolol, Esmolol, Bisoprolol, Ciliprolol, Sotalol, Metipranolol, Nadolol, Oxprenolol, Nifedipine, Nicardipine, Verapamil, Diltiazim, Felodipine, Nimodipine, Flunarizine, Quinapril, Lisinopril, Captopril, Ramipril, Fosinoprol and Enalapril.

49. The pump ofclaim 36, wherein the pharmaceutical agent includes an antibiotic agent selected from a group including Democlocycline, Doxycycline, Lymecycline, Minocycline, Oxytetracycline, Tetracycline, Sulfametopyrazine, Ofloaxcin, Ciproflaxacin, Aerosoxacin, Amoxycillin, Ampicillin, Becampicillin, Piperacillin, Pivampicillin, Cloxacillin, Penicillin V, Flucloxacillin, Erythromycin, Metronidazole, Clindamycin, Trimethoprim, Neomycin, Cefaclor, Cefadroxil, Cefixime, Cefpodoxime, Cefuroxine, Cephalexin and Cefradine.

50. The pump ofclaim 36, wherein the pharmaceutical agent includes a bronchodialotors and anti-asthmatic agents selected from a group including: Pirbuterol, Orciprenaline, Terbutaline, Fenoterol, Clenbuterol, Salbutamol, Procaterol, Theophylline, Cholintheophyllinate, Theophylline-ethylenediamine and Ketofen.

51. The pump ofclaim 36, wherein the pharmaceutical agent includes an anti-arrhythmic agent selected from a group including Viquidil, Procainamide, Mexiletine, Tocainide, Propafenone and Ipratropium.

52. The pump ofclaim 36, wherein the pharmaceutical agent includes a centrally acting substance selected from a group including Amantadine, Levodopa, Biperiden, Benzotropine, Bromocriptine, Procyclidine, Moclobemide, Tranylcypromine, Tranylpromide, Clomipramine, Maprotiline, Doxepin, Opipramol, Amitriptyline, Desipramine, Imipramine, Fluroxamin, Fluoxetin, Paroxetine, Trazodone, Viloxazine, Fluphenazine, Perphenazine, Promethazine, Thioridazine, Triflupromazine, Prothipendyl, thiothixene, Chlorprothixene, Haloperidol, Pipamperone, Pimozide, Sulpiride, Fenethylline, Methylphenildate, Trifluoperazine, Oxazepam, Lorazepam, Bromoazepam, Alprazolam, Diazepam, Clobazam, Buspirone and Piracetam.

53. The pump ofclaim 36, wherein the pharmaceutical agent includes a cytostatics and metastasis inhibitor selected from a group including Melfalan, Cyclophosphamide, Trofosfamide, Chlorambucil, Busulfan, Prednimustine, Fluororacil, Methotrexate, Mercaptopurine, Thioguanin, Hydroxycarbamide, Altretamine and Procarbazine.

54. The pump ofclaim 36, wherein the pharmaceutical agent includes an anti-migrane agent selected from a group including Lisuride, Methysergide, Dihydroergotamine, Ergotamine and Pizotifen.

55. The pump ofclaim 36, wherein the pharmaceutical agent includes a gastrointestinal agents selected from a group including Cimetidine, Famotidine, Ranitidine, Roxatidine, Pirenzipine, Omeprazole, Misoprostol, Proglumide, Cisapride, Bromopride and Metoclopramide.

56. The pump ofclaim 16, wherein the dose escalation assembly includes:

a first saturated saline solution between the first impermeable membrane and the first semipermeable membrane, and

a second saturated saline solution between the second impermeable membrane and the second semipermeable membrane.

57. The pump ofclaim 1, wherein the pharmaceutical agent includes Sufentanil and wherein the pump is configured for:

a daily delivery rate of Sufentanil of up to about 25 micrograms per day when the pump is configured to be implanted intraventricularly;

a daily delivery rate of Sufentanil of up to about 50 micrograms per day when the pump is configured to be implanted intrathecally;

a daily delivery rate of Sufentanil of up to about 500 micrograms per day when the pump is configured to be implanted epidurally;

a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted subcutaneously, and

a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted intravascularly.

58. A kit, comprising:

an implantable osmotic pump for delivering a pharmaceutical agent to a patient, including an osmotic engine, a tube coiled around the osmotic engine, the tube defining an inner tube-shaped compartment adapted to store a pharmaceutical agent, and a piston disposed within the tube-shaped compartment, the osmotic engine being configured to exert a force on the piston to cause the piston to travel within the tube-shaped compartment and deliver the pharmaceutical agent when the pump is implanted in the patient, and

a catheter configured to attach to the pump.

59. The kit ofclaim 58, wherein the catheter and the pump are dimensioned to infuse a volume of up to about 20 μL/day over a treatment period.

60. The kit ofclaim 58, wherein the catheter and the pump are dimensioned to infuse a dose of Sufentanil of up to about 1500 μg/day over a treatment period.

61. The kit ofclaim 58, wherein pump further includes a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and including an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted.

62. The kit ofclaim 61, further including a dose escalation assembly fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted.

63. The kit ofclaim 62, wherein the dose escalation assembly includes:

a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and

a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path.

64. The kit ofclaim 63, further including a dose escalation pen configured to breach at least one of the first and second impermeable membranes.

65. The kit ofclaim 65, wherein the dose escalation pen includes a dose selection actuator that is adapted to re-configure the dose escalation pen to selectively breach one of the first and second impermeable membranes.

66. The kit ofclaim 58, wherein the tube-shaped compartment is pre-loaded with the pharmaceutical agent.

67. A method of delivering a pharmaceutical agent to a patient, comprising steps of:

implanting a pump into the patient, the pump including a pump engine and a compartment adapted to store a pharmaceutical agent, the compartment defining at least a partial torus around the osmotic engine, and

causing a piston to travel a distance within the compartment and to deliver a dose of pharmaceutical agent out of the compartment, the dose corresponding to the distance traveled by the piston within the compartment.

68. The method ofclaim 67, wherein the implanting step implants the pump one of intravascularly, subcutaneously, epidurally, intrathecally and intraventricularly.

69. The method ofclaim 68, wherein the pharmaceutical agent includes Sufentanil and wherein the pump is configured for:

a daily delivery rate of Sufentanil of up to about 25 micrograms per day when the pump is configured to be implanted intraventricularly;

a daily delivery rate of Sufentanil of up to about 50 micrograms per day when the pump is configured to be implanted intrathecally;

a daily delivery rate of Sufentanil of up to about 500 micrograms per day when the pump is configured to be implanted epidurally;

a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted subcutaneously, and

a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted intravascularly.

70. The method ofclaim 68, wherein travel of the piston within the compartment causes a delivery of a volume up to about 20 μL/day over a treatment period.

71. The method ofclaim 67, further comprising the step of selectively increasing the dose in a stepwise manner over a treatment period without removing the pump from the patient.

72. The method ofclaim 71, wherein the pump engine includes an osmotic engine and wherein the pump includes an initial dose semipermeable membrane initially exposed to the patient and at least one second semipermeable membrane initially not exposed to the patient and wherein the increasing step includes a step of selectively exposing the at least one second semipermeable membrane to the patient.

73. The method ofclaim 67, wherein the pump the engine includes an osmotic engine in fluid communication with the piston and wherein the causing step includes a step of increasing a volume of the osmotic engine.

74. A pump, comprising:

a pump engine;

a tube coiled around the engine, the tube defining an inner tube-shaped compartment adapted to store a fluid, and

a piston disposed within the tube-shaped compartment, the engine being adapted to cause the piston to travel within the tube-shaped compartment and to force a dose of the fluid out of the pump.

75. The pump ofclaim 74, wherein the pump engine includes an osmotic engine.

76. The pump ofclaim 74, wherein the fluid includes a pharmaceutical agent.

77. The pump ofclaim 74, further including a catheter coupled to the tube.

78. The pump ofclaim 74, wherein the pump is fully implantable in a body and wherein pump engine and the tube are enclosed in a biocompatible pump housing.

79. The pump ofclaim 74, further including a dose escalation assembly, the escalation assembly being configured to selectively increase the dose of fluid delivered.

80. The pump ofclaim 74, wherein the dose escalation assembly comprises means for increasing the dose delivered in a stepwise manner.

81. The pump ofclaim 74, wherein the piston includes one of a sphere, an elastomeric cylinder and an elastomeric conical section.

82. An osmotic pump, comprising:

an osmotic engine, and

a pump housing enclosing the osmotic engine and defining a substantially toroidal space adapted to contain a volume of pharmaceutical agent.

83. The osmotic pump ofclaim 82, wherein the pump housing defines a substantially circular outline.

84. The osmotic pump ofclaim 82, wherein the substantially toroidal space defines an inner and an outer radius, and wherein the osmotic engine is disposed within the inner radius.

85. The osmotic pump ofclaim 82, further comprising a tube disposed within the toroidal space, the tube defining an inner lumen adapted to contain the volume of pharmaceutical agent.

86. The osmotic pump ofclaim 82, wherein the pump housing includes a first housing half and a second housing half, the first and second housing halves defining, when mated together, the substantially toroidal space, the substantially toroidal space being fluid tight.

87. The osmotic pump ofclaim 82, further comprising a semipermeable membrane enclosure and a semipermeable membrane fitted within the semipermeable membrane enclosure.

88. The osmotic pump ofclaim 87, wherein a single semipermeable membrane is fitted within the semipermeable membrane enclosure and wherein the pump is a single stage pump.

89. The osmotic pump ofclaim 87, wherein the pump is an n-stage pump and wherein the semipermeable membrane enclosure is fitted with n semipermeable membranes, each of the n stages being configured to be selectively activated after implantation of the pump.

90. The osmotic pump ofclaim 82, further comprising an OFF switch mechanism configured to be selectively activated after implantation of the pump.

91. The osmotic pump ofclaim 82, further comprising a filter assembly to filter the pharmaceutical agent.

92. The osmotic pump ofclaim 91, wherein the filter assembly includes a plug of porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns.

93. The osmotic pump ofclaim 91, wherein the filter assembly includes a plug of porous material, the porous material being hydrophilic.

94. The osmotic pump ofclaim 91, wherein the filter assembly includes a plug of porous material, the porous material being hydrophobic.

95. An implantable osmotic pump, comprising:

a semipermeable membrane;

a housing adapted to enclose a volume of pharmaceutical agent and a portion of the semipermeable membrane;

an osmotic engine adapted to cause the pharmaceutical agent to be delivered out of he pump as an osmotic pressure differential develops across the semipermeable membrane, and

at least one of:

an OFF switch, the OFF switch being effective to reduce the osmotic pressure differential across the semipermeable membrane substantially to zero, and

an ON switch, the ON switch being effective to enable the pump to begin to deliver the pharmaceutical agent out of the pump.

96. The pump ofclaim 95, wherein the OFF switch includes an OFF switch impermeable membrane and wherein the OFF switch is configured to reduce the osmotic pressure substantially to zero only when the OFF switch impermeable membrane is breached.

97. The pump ofclaim 96, wherein the OFF switch defines a lumen adapted to allow fluid to bypass the semipermeable membrane when the OFF switch impermeable membrane is breached.

98. The pump ofclaim 95, wherein the ON switch includes an impermeable membrane disposed over the semipermeable membrane, the pump being adapted to begin delivery of the pharmaceutical agent only after the impermeable membrane is breached.

99. The pump ofclaim 98, further including a volume of saturated saline solution disposed between the semipermeable membrane and the impermeable membrane.

100. A filter assembly for an osmotic pump, the filter assembly defining a first end configured to mate with the osmotic pump a second end configured to be exposed, in use, to an aqueous environment and including a filter between the first and second ends.

101. The filter assembly ofclaim 100, wherein the filter includes a porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns.

102. The filter assembly ofclaim 100, wherein the filter includes a plug of porous material, the porous material being hydrophilic.

103. The filter assembly ofclaim 100, wherein the filter includes a plug of porous material, the porous material being hydrophobic.

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