US20040111080A1 - Methods and implantable devices and systems for long term delivery of a pharmaceutical agent - Google Patents

Abstract

Implantable devices and osmotic pump and catheter systems for delivering a pharmaceutical agent to a patient at selectable rates include an impermeable pump housing and a moveable partition disposed within the housing, the partition dividing the housing into an osmotic driving compartment having an open end and a pharmaceutical agent compartment having a delivery orifice. A plurality of semi permeable membranes may be disposed in the open end of the osmotic driving compartment and a number of impermeable barriers may seal selected ones of the plurality of semi permeable membranes from the patient until breached. Breaching one or more of the impermeable barriers increases the surface area of semi permeable membrane exposed to the patient and controllably increases the delivery rate of the pharmaceutical agent through the delivery orifice and catheter. Each of the plurality of semi permeable membranes may have a selected surface area, composition and/or thickness, to allow a fine-grained control over the infusion rate while the pump is implanted in the patient.

Description

BACKGROUND OF THE INVENTION
• 1. Field of the Invention[0001]
• This invention relates to the field of drug delivery. In particular, the present invention relates to methods, devices and systems adapted to sub-chronic implantation (less than or equal to 12 months and typically less or equal to about 6 months) in the patient's body to deliver a drug or other pharmaceutical agent at a sustained rate.[0002]
• 2. Description of the Related Art[0003]
• Since the beginning of modem 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 often reduce the efficacy of medication; furthermore, medications delivered systemically sometimes cause undesirable side effects. Over the course of the past few decades, drug delivery technology and administration has evolved from oral delivery to site-specific delivery. In addition to the oral route of administration, drugs are also routinely administered via the vascular system (intravenous or IV). Intravenous drug delivery has 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.[0004]
• The next step in the evolution of drug delivery was the implanted pump. The implanted pump is a device that is completely implanted under the skin of a patient, thereby negating the need for a percutaneous catheter. These implanted pumps provide the patient with a drug at a constant or a programmed delivery rate. Constant rate or programmable rate pumps are based on either phase-change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-rate pump is well suited for long-term implanted drug delivery. If changes to the infusion rate are expected, a programmable pump may be used in place of the constant rate pump. Fully implanted constant rate and programmable rate infusion pumps have been sold in the United States for human use since the late 1970s and early 1980s, respectively. Two problems associated with such 1970s and 1980s vintage constant rate and programmable rate infusion pumps relate to their size and their cost. Current implantable constant rate and programmable pumps are about the size and shape of hockey pucks, and they typically are sold to the hospital for $5,000-$9,000. The current implantable pumps must be implanted in the Operating Room under general anesthesia, which further increases costs, as well as the risk, and discomfort to the patient. The size and cost of such pumps has proven to be a substantial barrier to their use, and they are rarely used to deliver medication. An added drawback of phase-change and peristaltic pumps is that they must be refilled with drug every 3-8 weeks. Refills constitute an added burden to the caregiver, and add further costs to an already overburdened healthcare system. The burden associated with such refills, therefore, further limits the use of phase-change and peristaltic pumps.[0005]
• In the 1970s, a new approach toward implanted pump design was commercialized for animal use only. The driving force of the pumps based upon this new approach utilized the principle of osmosis. Osmotic pumps may be much smaller than other constant rate or programmable pumps, because their infusion rate can be very low. An 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 an impermeable reservoir that is divided into a water-swellable agent chamber and a drug chamber. Fluid from the body is imbibed through a semi permeable plug into the water-swellable agent chamber and the drug is released through a diffusion outlet at a substantially constant rate.[0006]
• 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. Implanted 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 either replace the current implant or implant an additional pump to replace or supplement the system. 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. For such patients for whom the implantable pump no longer delivers an adequate dosage of medication, the physician may opt to supplement the dosage delivered by the implantable device by other means, such as by intravenous delivery, in which case the same side effects discussed above may again occur.[0007]
• Pain management medications are only one example of medications that need to be increased in dosage over time. Other applications may include but are not limited to hypertensive medications, other cardiovascular medications, and medications to treat disorders of the brain and endocrine system.[0008]
SUMMARY OF THE INVENTION
• An object of the present invention, therefore, is to provide methods and implantable devices and systems for long-term delivery of a pharmaceutical agent at selectable rates. It is another object of the present invention to provide implantable devices and systems for long term delivery of a drug that are small in size and that may be readily implanted in a physician's procedure room or a radiology suite.[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 comprises a pump housing; a moveable partition disposed within the housing, the partition dividing the housing into an osmotic driving compartment having an open end and a pharmaceutical agent compartment having a delivery orifice; a first semi permeable membrane disposed in the open end of the osmotic driving compartment, the first semi permeable membrane being exposed to the patient; a second semi permeable membrane disposed in the open end of the osmotic driving compartment, and a first impermeable barrier disposed over the second semi permeable membrane, the second semi permeable membrane being sealed from the patient until the first barrier is breached, wherein breaching the first barrier increases the surface area of semi permeable membrane exposed to the patient and increases a delivery rate of the pharmaceutical agent through the delivery orifice.[0010]
• According to further embodiments, the first impermeable barrier may include titanium and/or stainless steel. A saturated solution including NaCl may be present between the first impermeable barrier and the second semi permeable membrane. The first and second semi permeable membranes may the same composition and/or may have the same thickness. Alternatively, the first and second semi permeable membranes may have mutually different compositions and/or mutually different thickness. The pump may further include a third semi permeable member, and a second impermeable barrier may be nested within the first impermeable barrier. The second impermeable barrier may be disposed over the third semi permeable membrane and may seal the third semi permeable membrane from the patient until the second impermeable barrier is breached. Breaching the second barrier increases the surface area of semi permeable membrane exposed to the patient and increases the delivery rate of the pharmaceutical agent through the delivery orifice.[0011]
• A saturated solution including NaCl may be present between the second barrier and the third semi permeable membrane. The pharmaceutical agent compartment may contain sufentanil, for example, and may also contain other medications. The sufentanil may be at a concentration selected between about 200 μg/mL and about 15,000 μg/mL. The daily delivery rate of the pharmaceutical agent through the delivery orifice may be selected from about 0.5 micrograms per day to about 25 micrograms per day when the pump is configured to be implanted intraventricularly; about 0.5 micrograms per day to about 50 micrograms per day when the pump is configured to be implanted intrathecally; about 5 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted epidurally; about 10 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted subcutaneously.[0012]
• The first and second semi permeable membranes may include cellulose acetate. The first semi permeable membrane may be shaped as a torus and may be disposed adjacent the outer periphery of the first impermeable barrier. The second semi permeable membrane may be disposed in the center opening of the torus.[0013]
• A catheter may be coupled to the delivery orifice and the catheter may have an inner diameter of between about 0.001 inches and about 0.010 inches. The catheter may include a guidewire lumen and a pharmaceutical agent infusion lumen. The pharmaceutical agent infusion lumen may have an inner diameter selected between about 0.001 inches to about 0.010 inches. The catheter and the pump may be dimensioned to infuse a volume of pharmaceutical agent of between about 1 μL/day and about 10 μL/day over a treatment period. The catheter and the pump may be dimensioned to infuse a dose of pharmaceutical agent of between about 0.5 μg/day and about 300 μg/day over a treatment period.[0014]
• At least a portion of the catheter may be radiopaque. The guidewire lumen may include a valve to prevent back flow of fluid into the guidewire lumen.[0015]
• The present invention is also a method for achieving an analgesic effect in a patient. The method comprises the step of administering a therapeutically effective dose of a sufentanil-containing analgesic to the patient using a device that is fully implanted in the patient. The dose may be administered intravascularly, subcutaneously, epidurally, intrathecally or intraventricularly. A step of selectively increasing the dose in a stepwise manner over a treatment period without removing the device from the patient may also be carried out. The dose may be administered using an implanted osmotic pump that includes a first semi permeable membrane exposed to the patient and a second semi permeable membrane initially not exposed to the patient and wherein the increasing step may include a step of exposing the second semi permeable membrane to the patient. The second semi permeable membrane exposing step may include a step of breaching an impermeable barrier sealing the second semi permeable membrane from the patient. The breaching step may include a step of puncturing the impermeable barrier using a lancet while the pump remains implanted in the patient. The therapeutically effective dose may be selected within the range of about 0.5 μg/day to about 300 μg/day.[0016]
• According to another embodiment, the present invention may also be viewed as a method for achieving an analgesic effect in a patient, the method comprising intraspinal administration of a therapeutically-effective dose of an analgesic to the patient by an osmotic pump and catheter integrated combination, the pump including a first semi permeable membrane across which an osmotic pressure gradient develops when the pump is implanted in the patient.[0017]
• The method may also include the step of selectively increasing a surface area of semi permeable membrane exposed to the patient in a stepwise manner. The analgesic may include sufentanil and/or other medication(s). A second semi permeable membrane may be provided, and the surface area of semi permeable membrane exposed to the patient may be increased by breaching an impermeable barrier initially sealing the second semi permeable membrane from the patient. For example, the impermeable barrier may be breached by puncturing the impermeable barrier. The dose may be increased in a stepwise manner by sequentially breaching one of a plurality of nested impermeable barriers disposed over a corresponding plurality of the semi permeable membranes, each sequential breach exposing additional surface area of semi permeable membrane to the patient. Each of the plurality of nested barriers may be configured to be breached by a lancet, an outer diameter of the lancet determining which of the plurality of nested barriers is breached. The analgesic may be administered intravascularly, subcutaneously, epidurally or intrathecally. The second semi permeable membrane may have the same or a different composition as the first semi permeable membrane. Similarly, the second semi permeable membrane may have the same or a different thickness as the first semi permeable membrane.[0018]
• The present invention is also an integrated implantable pump and catheter system for delivering a dose of sufentanil to a patient over a treatment period, comprising a pump housing; a moveable partition disposed within the housing, the partition dividing the housing into an driving engine compartment and a pharmaceutical agent compartment having a delivery orifice; a catheter coupled to the delivery orifice, and a preloaded amount of sufentanil in the pharmaceutical agent compartment.[0019]
• The pump and the catheter may be dimensioned to deliver sufentanil at an infusion rate of about 0.5 μg/day to about 300 μg/day over a treatment period. The system further may further include a mechanical infusion rate selection structure configured to allow the infusion rate of the pump to be increased while the system is implanted in the patient. The infusion rate selection feature may include a plurality of semi permeable membranes across each of which osmotic pressure develops when selectively and sequentially exposed to the patient. Each of the plurality of semi permeable membranes may have the same or a different thickness, composition and surface area, the selected thickness, composition and surface area contributing to a rate at which the sufentanil is infused into the patient.[0020]
• The present invention also encompasses a kit comprising an osmotic pump; sufentanil preloaded in the osmotic pump, and a delivery catheter configured to be coupled to the osmotic pump. The osmotic pump may include a mechanical infusion rate selection structure. The kit may further include a lancet configured to act upon the infusion rate selection structure to increase an infusion rate of the sufentanil through the delivery catheter. The pump may be configured to deliver sufentanil at an infusion rate of a bout 0.5 μg/day to about 300 μg/day over a treatment period. The catheter may include a guidewire lumen and a sufentanil delivery lumen. The kit may further include a guidewire. The kit may also include a guidewire, a needle and a splittable introducer. According to still further embodiments, the needle may be a hypodermic needle or a non-coring needle, for example.[0021]
• The present invention is also a kit comprising an osmotic pump that includes a mechanical infusion rate selection structure; an amount of pharmaceutical agent preloaded into the pump, and a delivery catheter. The pharmaceutical agent may include sufentanil and/or other medication(s). The infusion rate selection structure may be configured to allow the infusion rate to be increased while the pump is implanted into a patient. The infusion rate selection structure may include a plurality of semi permeable membranes, each of which being selectably exposable to the patient to increase a dose of pharmaceutical agent delivered to the patient. Each of the plurality of semi permeable membranes may have an individually selected thickness, composition and/or surface area.[0022]
• According to a still further embodiment thereof, the present invention is a method of delivering a pharmaceutical agent to a patient, comprising the steps of implanting an osmotic pump within the patient, the osmotic pump including the pharmaceutical agent and a plurality of semi permeable membranes across which osmotic pressure develops when exposed to the patient, and controlling a surface area of semi permeable membrane exposed to the patient to control an infusion rate of the pharmaceutical agent analgesic to the patient. A step of controlling the thickness and/or a composition of each of the plurality of semi permeable membranes may also be carried out.[0023]
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:[0024]
• FIG. 1 is a schematic diagram illustrating a conventional drug delivery osmotic pump.[0025]
• FIG. 2 is a block diagram illustrating an implantable pump for long-term delivery of a pharmaceutical agent at selectable rates according to an embodiment of the present invention, wherein an impermeable barrier is disposed across an underlying central semi permeable membrane.[0026]
• FIG. 3 is a block diagram illustrating the implantable device of FIG. 2, illustrating the breaching of the impermeable barrier.[0027]
• FIG. 4 is a block diagram illustrating the implantable device of FIG. 3, wherein the impermeable barrier is breached, thereby increasing the aggregate surface area of semi permeable membrane exposed to the patient.[0028]
• FIG. 5 is a block diagram of an implantable pump for long-term delivery of a pharmaceutical agent at selectable rates according to another embodiment of the present invention, wherein the pump includes a plurality of nested impermeable barriers disposed over and sealing respective underlying semi permeable membranes.[0029]
• FIG. 6 is a block diagram of the implantable pump of FIG. 5, wherein an outermost impermeable barrier is breached, thereby increasing the aggregate surface area of semi permeable membrane exposed to the patient.[0030]
• FIG. 7 is a block diagram of the implantable pump of FIG. 6, wherein the middle impermeable barrier is breached; thereby further increasing the aggregate surface area of semi permeable membrane exposed to the patient.[0031]
• FIG. 8 is a block diagram of the implantable pump of FIG. 7, wherein the innermost impermeable barrier is breached; thereby still further increasing the aggregate surface area of semi permeable membrane exposed to the patient.[0032]
• FIG. 9A is a diagram of a complete implantable pump and catheter system for long-term delivery of a pharmaceutical agent at selectable rates, according to an embodiment of the present invention.[0033]
• FIG. 9B is a cross-sectional view of the catheter portion of the implantable pump of FIG. 9A, taken along lines AA′.[0034]
• FIG. 9C is a perspective view of the distal end of the catheter portion of the implantable pump of FIG. 9A, according to an embodiment of the present invention.[0035]
• FIG. 10 is a cross-sectional side view of an implantable pump according to an embodiment of the present invention.[0036]
• FIG. 11 shows a proximal portion of the implantable pump of FIG. 10, showing the manner in which the pharmaceutical agent (e.g., drug) delivery rate of the pump may be increased, according to an embodiment of the present invention.[0037]
• FIG. 12A shows a cross section of the proximal portion of the implantable pump of FIG. 11 after the impermeable barrier has been breached.[0038]
• FIG. 12B shows an end view of the implantable pump of FIG. 12A.[0039]
• FIG. 13 shows a cross-sectional side view of an embodiment of a lancet that may be utilized to breach the impermeable barrier of the implantable pump, according to an embodiment of the present invention.[0040]
• FIG. 14A depicts the proximal portion of an implantable pump for long-term delivery of a drug at selectable rates, wherein the end-cap portion thereof is removed, according to another embodiment of the present invention.[0041]
• FIG. 14[0042]bis a perspective view of the end-cap portion of the implantable pump of FIG. 14A.
• FIG. 15 is a cross-sectional diagram of tissue surrounding the spinal fluid wherein the implantable pump according to the present invention may infuse one or more pharmaceutical agents.[0043]
• FIG. 16 is a cross-sectional diagram illustrating the first steps in introducing the implantable pump into the tissue of FIG. 15, according to the present invention.[0044]
• FIG. 17 is a cross-sectional diagram of further steps to be carried out in introducing the implantable pump system of the present invention into the tissue of FIG. 15.[0045]
• FIG. 18 illustrates a pump for long-term delivery of a pharmaceutical agent at selectable rates according to the present invention, fully implanted into the tissue of FIG. 15.[0046]
• FIG. 19A is a cross-sectional diagram of a split introducer and needle used to insert the catheter into the patient, according to an embodiment of the present invention.[0047]
• FIG. 19B shows a longitudinal cross section of a non-coring needle that may be utilized in combination with the split introducer of FIG. 19A to insert the catheter into the patient, according to another embodiment of the present invention.[0048]
DESCRIPTION OF THE INVENTION
• FIG. 1 shows a schematic diagram of a conventional osmotic pump. The pump includes a[0049]housing100. Thehousing100 may be shaped as a cylinder and may be divided into adrug reservoir102 and anosmotic engine compartment106. Apiston104 separates thedrug reservoir102 and theosmotic engine compartment106. The movement of thepiston104 toward thedelivery orifice112 provides the driving force to effuse the drug contained within thedrug reservoir102. A semipermeable membrane108 is disposed at one end of the pump, covering the opening thereof opposite thedelivery orifice112. The semipermeable membrane108 is permeable to water. Therefore, when the pump is placed within the patient's body or other aqueous medium, water tends to cross the semipermeable membrane108 into theosmotic engine compartment106. The osmotic engine within thecompartment106 is the driving force that maintains the solution inside the pump (but outside the reservoir102) at a fully saturated state. A fully saturated state ensures that the osmotic pressure differential between the body tissue and the inside of the pump remains constant. The pressure differential is maintained constant by a block of osmotic agent (e.g., a salt block) inside of theosmotic agent compartment106. In operation, thepiston104 slides within the housing toward thedelivery orifice112 as water from the patient's body crosses the semipermeable membrane108. In turn, the slidingpiston104 causes the drug within thereservoir102 to effuse from thedelivery orifice112.
• FIG. 2 is a block diagram illustrating an implantable pump for long-term delivery of a pharmaceutical agent (such as a drug or drugs, for example) at selectable rates, according to an embodiment of the present invention. The present invention achieves such selectable effusion rates by exploiting the property of osmotic pumps that the effusion rate of the drug from the pump of is substantially proportional to the surface area (among other factors, such as composition and thickness) of the semi permeable membrane (such as cellulose acetate, for example) exposed to the patient or other aqueous solution. The implantable pump according to an embodiment of the present invention, as shown in FIG. 2, includes an impermeable rigid (and cylindrical, for example, although other shapes are also possible) pump[0050]housing200 that is internally divided into apharmaceutical agent compartment202 and anosmotic driving compartment206. A piston or othermoveable partition204 separates thepharmaceutical agent compartment202 from theosmotic driving compartment206. Thepharmaceutical agent compartment202 includes adelivery orifice212 through which the pharmaceutical agent is delivered. Thedelivery orifice212 may be coupled to a catheter (not shown in FIG. 2) to deliver the pharmaceutical agent from thedelivery orifice212 to a selected location (subcutaneously, epidurally, subdurally, in the subarachnoid space or thecal sac, intravenously or intraventricularly, for example) within the patient. Theosmotic driving compartment206 includes an open end within which a plurality of semi permeable membranes (two such semipermeable membranes214a,214bbeing shown in FIG. 2) is disposed. At least a portion of a peripheral semipermeable membrane214ais initially exposed to the patient, thereby allowing a net influx of water from the patient's body through the exposed peripheral semipermeable membrane214ato the osmotic driving engine within the osmoticdriving engine compartment206. As water from the patient's body crosses the exposed peripheral semi permeable membrane214, themoveable partition204 is driven toward thedelivery orifice212, constrained in its motion by thepump housing200. As thepump housing200 is rigid, a volume of pharmaceutical agent substantially equal to the increase in volume of the osmotic engine is displaced and pushed out of the pump through thedelivery orifice212.
• A plurality of semi permeable membranes may be disposed across the open end of the[0051]osmotic driving compartment206. At least one of these semi permeable membranes may be covered by an impermeable barrier, such as shown at220 in FIG. 2. Thebarrier220 may be formed of a biologically inert material that is impermeable to water and/or other bodily fluids that may be found in the patient's body at the location wherein the pump is implanted. For example, theimpermeable barrier220 may include titanium and/or stainless steel. As shown in FIG. 2, theimpermeable barrier220 may be disposed away from the surface of the semi permeable membranes by aspacer218. Thespacer218 may be shaped as a cylinder supporting theimpermeable barrier220 above the central semipermeable membrane214bunderlying thebarrier220. Theimpermeable barrier220 may be sealed to thespacer218 such as to seal the central semipermeable membrane214bfrom the patient. Indeed, as long as theimpermeable barrier220 is intact, there is no (or substantially no) net influx of water from the patient into the osmotic engine through the central semipermeable membrane214b. When theimpermeable barrier220 is intact, however, water reaches the osmotic engine only through a plurality ofopenings216 aligned with the peripheral semipermeable membrane214a, theopenings216 being defined in the structure supporting thespacer218 across the open end of theosmotic driving compartment206. Theinterstitial space224 between theimpermeable barrier220 and the surface of the central semipermeable membrane214bmay include a saturated saline solution, to prevent the underlying semipermeable membrane214bfrom drying out and to maintain solutions of equal osmolarity on either side of the central semipermeable membrane214b. The peripheral semipermeable membrane214amay be a torus-shaped (doughnut-shaped) membrane disposed adjacent an outer periphery ofspacer218 sealing the underlying central semipermeable membrane214bfrom the patient. The spacer218 (and thus the central semipermeable membrane214b) may be disposed in the center opening of the torus-shaped peripheralpermeable membrane214a. The underlying central semipermeable membrane214b, therefore, may be concentric with the peripheralpermeable membrane214a.
• There are occasions when the physician may wish to increase the dose of the pharmaceutical agent initially delivered to the patient, such as when the level of pain experienced by the patient increases, as a result of the progression of the patient's disease or habituation, for example. Previously, increasing the infusion dose of an osmotic pump entailed subjecting the patient to a further procedure to remove the previously implanted pump to substitute therefor a new pump that delivers a larger dose. According to an embodiment of the present invention, however, the physician may increase the dose of pharmaceutical agent delivered while the pump disclosed herein remains implanted within the patient through a simple and short procedure that may be carried out within the physician's office or in a radiology suite, for example. Indeed, when the physician wishes to increase the delivery rate of the pharmaceutical agent through the delivery orifice[0052]212 (or a catheter coupled thereto), theimpermeable barrier220 may be breached percutaneously by a thin, elongated and rigid member222 (hereafter lancet), as shown in FIG. 3. Preferably, the outer diameter of thelancet222 is somewhat greater than the inner diameter of thespacer218. These relative dimensions prevent thelancet222 from being inserted too far. That is, the relative dimensions of thelancet222 and thespacer218 are such that when thelancet222 is percutaneously inserted in the patient to breach theimpermeable barrier220, thespacer218 prevents thelancet222 from damaging the underlying central semipermeable membrane214b, breaching theosmotic driving compartment206 or otherwise damaging the pump. Preferably, thelancet222 is inserted only as far as to breach theimpermeable barrier220 and to allow a free influx of water from the patient's body into the previously sealedinterstitial space224 between the underlying central semipermeable membrane214band theimpermeable barrier220.
• When the[0053]impermeable barrier220 is breached and thelancet222 is retracted from thespacer218, water from the patient's body reaches the central semipermeable membrane214b, as indicated by the arrows pointing within thespacer218 shown in FIG. 4. The effect of breaching theimpermeable barrier220 and allowing water to reach the central semipermeable membrane214bis to increase the net surface area of semi permeable membrane exposed to the patient. Indeed, once theimpermeable barrier220 is breached, the aggregate surface area of semi permeable membrane exposed to the patient is substantially equal to the sum of the surface areas of the peripheral and central semipermeable membranes214aand214b. When thebarrier220 is breached, water from the patient also reaches the osmotic engine throughopenings217 aligned with the semipermeable membrane214b. Increasing the surface area of semi permeable membrane exposed to the patient, therefore, increases the influx of water therethrough, which in turn increases the delivery rate of the pharmaceutical agent through thedelivery orifice212. Thus, the effusion rate of the pump according to the present invention has been increased without removing the pump from the patient, thereby affording the patient an increased dose of pharmaceutical agent (such as an analgesic, for example). The surface area, thickness and/or composition of the semipermeable membranes214aand214bmay be manipulated to achieve a fine-grained control over the effusion rate of the pharmaceutical agent from theorifice212 and any catheter coupled thereto.
• The embodiment of the present invention shown in FIGS. 2 through 4 allows a one step increase in the dose of pharmaceutical agent delivered to the patient, from a first initial dose to a subsequent second, larger dose. However, the present invention is not limited to a one step increase in the dose of pharmaceutical agent delivered to the patient. Indeed, FIGS.[0054]5 though8 illustrate another embodiment of the present invention wherein the dose delivered to the patient may be increased in situ three times, from a first initial dose to a fourth dose, each subsequent dose being larger than the previous dose. The present invention may also readily be configured for a lesser or greater number of physician-selectable effusion rates. Turning first to FIG. 5,reference numerals200,202,204,206 and212 denote structures finding exact counterparts in FIGS. 2 through 4. The description above of the structures referenced by these numerals is, therefore, incorporated herein by reference.
• Rather than the[0055]single spacer218 supporting a singleimpermeable barrier220 as illustrated in FIGS.2-4, the embodiment of FIGS. 5 through 8 includes three such spacers, each of which supports a separate and distinct impermeable barrier. Indeed, the pump of FIGS. 5 through 8 includes afirst spacer518athat supports a firstimpermeable barrier520a. Nested within thefirst spacer518a, according to the embodiment shown in FIGS. 5 through 8, is asecond spacer518bthat supports a secondimpermeable barrier520b. In turn, nested within thesecond spacer518bis athird spacer518cthat supports a thirdimpermeable barrier520c. Each of thebarriers520a,520band520cis sealed to itsrespective spacer518a,518band518c. Disposed within the open end of theosmotic driving compartment206 is a plurality of separate semi permeable membranes. As shown in FIG. 5, a peripheral semipermeable membrane514pis disposed adjacent an outer periphery of the base of thefirst spacer518a. At least a portion of the peripheral semipermeable membrane514pis exposed to the patient environment when the pump is initially implanted into the patient. Therefore, water or other aqueous fluid from the patient that has traveled through the peripheral semipermeable membrane514pmay reach the osmotic driving engine within thecompartment206 through theopenings516 facing the peripheral semipermeable membrane514p. Theopenings516 are defined by thepump housing200 and the structure supporting thespacer518aacross the open end of theosmotic driving compartment206. In the state of the pump illustrate in FIG. 5, the patient receives an initial first dose of pharmaceutical agent, the dose being proportional to the surface area (and/or composition and/or thickness) of the peripheral semipermeable membrane514pexposed to the patient.
• Turning now to FIG. 6, a[0056]first lancet522amay be used to breach the firstimpermeable barrier520a. The outer diameter of thelancet522ais preferably somewhat larger than the inner diameter of thefirst spacer518a, so as to cause thelancet522ato breach only the firstimpermeable barrier520a. Once thelancet522ais retracted from the pump, fluids from the patient may reach the first inner semipermeable membrane514a. Therefore, water or other aqueous fluid from the patient that has traveled through the first inner semipermeable membrane514amay reach the osmotic driving engine within thecompartment206 through theopenings517 facing the first inner semipermeable membrane514a. The aggregate surface area of semi permeable membrane exposed to the patient is, in the state of the pump shown in FIG. 6, the sum of the surface areas of the peripheral semipermeable membrane514pand the first inner semipermeable membrane514a. Therefore, the effusion rate of the pharmaceutical agent from thecompartment202 to the patient is now proportional to the increased area (and/or composition and/or thickness) of the semi permeable membrane exposed to the patient, resulting in the delivery of a second dose of pharmaceutical agent, the second dose being greater than the first dose administered when the pump is in the state illustrated in FIG. 5.
• As shown in FIG. 7, a[0057]second lancet522bmay be used to breach the secondimpermeable barrier520b. The outer diameter of thesecond lancet522bis preferably somewhat larger than the inner diameter of thesecond spacer518b(and smaller than the inner diameter of thelancet522a), so as to cause thelancet522bto breach only the secondimpermeable barrier520b. Once thelancet522bis retracted from the pump, fluids from the patient environment in which the pump is implanted may also reach the second inner semipermeable membrane514b. Therefore, water or other aqueous fluid from the patient that has traveled through the second inner semipermeable membrane514bmay reach the osmotic driving engine within thecompartment206 through theopenings518 facing the second semipermeable membrane514b. The surface area of semi permeable membrane exposed to the patient is, in the state of the pump shown in FIG. 7, the sum of the surface areas of the peripheral semipermeable membrane514p, the first inner semipermeable membrane514aand the second inner semipermeable membrane514b. Therefore, the effusion rate of the pharmaceutical agent from thecompartment202 to the patient is now proportional to this increased area (and/or composition and/or thickness) of semi permeable membrane exposed to the patient, thereby resulting in the delivery of a third dose of pharmaceutical agent, the third dose being greater than either of the first and second doses administered when the pump is in the states illustrated in FIGS. 5 and 6.
• Similarly, as shown in FIG. 8, a[0058]third lancet522cmay be used to breach the thirdimpermeable barrier520c. The outer diameter of thelancet522bis preferably somewhat larger than the inner diameter of thethird spacer518c(and smaller than the inner diameter of the first or second effusion pens522a,522b), so as to cause the lancet to breach only the thirdimpermeable barrier520cwithout, however, damaging the third semipermeable membrane514c. Once thelancet522cis retracted from the pump, fluids from the patient environment in which the pump is implanted may also reach the third inner semipermeable membrane514c. Therefore, water or other aqueous fluid from the patient that has traveled through the third inner semipermeable membrane514cmay reach the osmotic driving engine within thecompartment206 through theopenings519 facing the third inner semipermeable membrane514c. The surface area of semi permeable membrane exposed to the patient is, in the state of the pump shown in FIG. 8, the sum of the surface areas of the peripheral semipermeable membrane514p, the first semipermeable membrane514a, the second semipermeable membrane514band the third semipermeable membrane514c. Therefore, the effusion rate of the pharmaceutical agent from thecompartment202 to the patient is now proportional to this increased area (and/or composition and/or thickness) of semi permeable membrane exposed to the patient, thereby resulting in the delivery of a fourth dose of pharmaceutical agent, the fourth dose being greater than the first, second or third doses administered when the pump is in the states illustrated in FIGS. 5, 6 and7. A saturated saline solution is present in each of the interstitial spaces shown atreference numerals524a,524band524c.
• The peripheral semi[0059]permeable membrane514pmay be a torus-shaped membrane disposed adjacent the outer periphery of thefirst spacer518a. Likewise, the first semipermeable membrane514amay be a torus-shaped membrane disposed adjacent an outer periphery of thesecond spacer518b. Similarly, the second semipermeable membrane514bmay be a torus-shaped membrane disposed adjacent an outer periphery of thethird spacer518c. The third semipermeable membrane514cmay be shaped as a right cylinder or a disk disposed within the open end of theosmotic driving compartment206, aligned with thethird spacer518c. The semipermeable membranes514p,514a,514band514cmay, therefore, be concentrically disposed relative to one another. Moreover, each of the semipermeable membranes514p,514a,514band514cmay have a different surface area and/or thickness and/or composition, thereby allowing a high degree of control over the effusion rate of the pharmaceutical agent to the patient.
• Various modifications to the above-described pump may occur to those of skill in this art. For example, the[0060]pump housing200 may be extended at least as far as to cause the proximal edge thereof (the proximal end of the pump being defined as that end of the pump that is closest to the semi permeable membranes and the distal end thereof being defined as that end that is closest to the delivery orifice212) to be coplanar with the firstimpermeable barrier520a, to protect the nestedspacers518a,518band518cand to provide additional rigidity to the pump. Also, thelancets522a,522band522cmay be combined in a single adjustable device, wherein structural characteristics of the lancet such as the diameter of the device and/or the length to which it penetrates within the nestedspacer structures518a,518band518cmay be selectively adjusted by the physician depending upon the dose of pharmaceutical agent to be delivered. For example, such structural characteristics may be selected on such a lancet by “dialing” the selected dose increase on the lancet on an adjusting wheel or dial integrated in the pen.
• FIG. 9A is a diagram of a complete fully implantable pump and[0061]catheter assembly600 for long-term delivery of a pharmaceutical agent at selectable rates, according to an embodiment of the present invention. As shown, the implantable pump includes two major portions: thepump610 and thecatheter650. Thepump610 and thecatheter650, according to an embodiment of the present invention, are preferably coupled together, so that the physician needs not perform any assembly before implanting the device into the patient. Moreover, the pharmaceutical agent may be preloaded into the compartment202 (see FIGS. 2 through 8) ofpump610 to allow immediate use of the pump andcatheter assembly600 upon unpacking thereof in the physician's procedure room or radiology suite. Thepump610 may include the structures and functionality of the pumps discussed above relative to FIGS.2-4 and/or FIGS.5-8. According to an embodiment of the present invention, thecatheter650 may be a dual-lumen catheter. FIG. 9B is a cross-sectional view of such a dual-lumen catheter650, taken along lines AA′ of FIG. 9A. As shown therein, thecatheter650 includes aninfusion lumen652 that is proximately attached to theosmotic pump610, such as to itsdelivery orifice212, as shown in FIGS.2-8. The pharmaceutical agent, therefore, flows from thepump610 to the distal end of the catheter650 (the end thereof farthest away from the pump610) to be released within the patient (such as within the patient's epidural and/or intrathecal space, for example). Thecatheter650 may also include aguidewire lumen654 through which may be inserted aguidewire656. Theguidewire656 may be equipped with aguidewire torque658, to facilitate manipulation of theguidewire656 within the patient. Theguidewire lumen654 may span at least a portion of the length of thecatheter650. Theguidewire656 may be inserted into theguidewire lumen654 of thecatheter650 through aguidewire port660. Theguidewire port660 may be formed, for example, as a slit in thecatheter650.
• FIG. 9C is a perspective view of the distal end of the[0062]catheter650 of the implantable pump and catheter assembly of FIG. 9A, according to an embodiment of the present invention. As shown therein, the infusion lumen may terminate as an open lumen, to allow the pharmaceutical agent to exit thecatheter650. Theguidewire lumen654, according to an embodiment of the present invention, may include adistal valve662, such as a plug of elastomeric material (such as silicone or polyurethane, for example) with a slit therein. Thedistal valve662 prevents back flow of the pharmaceutical agent released into the patient through theguidewire lumen654. Such back flow may occur due to the pressure differential between the patient environment (such as the spinal fluid) and theguidewire port660. That is, the spinal fluid may be at a higher pressure than the pressure in theguidewire lumen654 and the outside. In the absence of adistal valve662 or other means for preventing back flow, the pharmaceutical agent effluent and spinal fluid may tend to flow back proximally toward thepump610 through guidewire lumen654 (once implanted). Such adistal valve662 allows theguidewire656 to be pushed therethrough but prevents back flow of the pharmaceutical agent or bodily fluids (such as spinal fluid) through theguidewire lumen654 when theguidewire656 is removed.
• The distal end of the[0063]catheter650, as shown in FIG. 9C, may include a radioopaque marker664 to allow the distal tip of thecatheter650 to be clearly visible through fluoroscopy. Suchdistal marker664 facilitates the insertion of thecatheter portion650 of theimplantable pump600 and catheter assembly under fluoroscopic guidance in a radiology suite, for example. To further aid implantation of thepump600 under fluoroscopic guidance, radioopaque length markers666 may be disposed on or incorporated within the length of thecatheter650. This allows the physician to gauge the length ofcatheter650 inserted into the patient. Alternatively, the entire length of thecatheter650 may include a radio opaque material.
• Alternatively still, the[0064]distal valve662 may be omitted, as may be the distal radioopaque marker664. Instead, thecatheter650 according to the present invention may be radio opaque over at least a portion of its entire length and include aproximal guidewire valve668 disposed within theguidewire lumen654 at or adjacent to theguidewire port660. The combination of a radioopaque catheter650 and aproximal guidewire valve668 allows the physician to adjust the length of thecatheter650 by trimming the distal end thereof according to the needs of the procedure at hand and/or the patient's anatomy. Any suitable radio opaque material may be used to render all or a portion or selected portions of thecatheter650 radio opaque. For example, thecatheter650 may be formed of silicone or polyurethane and may be doped with barium sulfate, for example. The length of thecatheter650 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 from thedelivery orifice212 to the free distal end of theinfusion lumen652. For example, thecatheter650 may be about 5 cm to about 100 cm in length. More preferably, thecatheter650 may be about 10 cm to about 30 cm in length. More preferably still, thecatheter650 may be about 15 cm to about 25 cm in length. For example, thecatheter650 may be about 20 cm in length. Theguidewire656 may be about 0.014 inches to about 0.038 inches in diameter. The internal diameter (ID) of theinfusion lumen652 may be selected within the range of about 0.001 inches to about 0.010 inches. The walls of thecatheter650 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 thecatheter650 may be selected between about 0.024 inches and about 0.066 inches in thickness.
• Tables 1 and 2 show the time required to infuse the dead space volume of the catheter of the implantable pump system according to the present invention, for an infusion rate of 1.75 and 5 microliters/day (μL/day), respectively.[0065]

  TABLE 1
  1.75 Microliter/Day infusion Rate
  Time To Infuse Dead Space Volume of Catheter (in hours)

  Catheter
  Diameter	Catheter Length (cm)

  (in.)	10	15	20	40

  0.001	0.7	1.0	1.4	2.8
  0.002	2.8	4.2	5.6	11.1
  0.005	17.4	26.1	34.7	69.5
  0.010	69.5	104.2	139.0	278.0

• [0066]

  TABLE 2
  5 Microliter/Day infusion Rate
  Time To Infuse Dead Space Volume of Catheter (in hours)

  Catheter
  Diameter	Catheter Length (cm)

  (in.)	10	15	20	40

  0.001	0.2	0.4	0.5	1.0
  0.002	1.0	1.5	2.0	3.9
  0.005	6.1	9.1	12.1	24.3
  0.010	24.3	36.5	48.7	97.3

• FIG. 10 is a cross-sectional view of an[0067]implantable pump700, according to a further embodiment of the present invention. Thepump700 of FIG. 10 includes arigid pump housing702. Thepump housing702 encloses amoveable partition704 that separates apharmaceutical agent compartment706 for enclosing apharmaceutical agent708 from anosmotic driving compartment710 for enclosing an osmotic engine712 (salt block). At the proximal end of theosmotic driving compartment710 is disposed a pair of semipermeable polymer membranes728,730, such as cellulose acetate membranes. Thepump700 may include a peripheral torus-shaped semi permeable membrane (or a plurality of such peripheral semi permeable membranes)728 and a central semipermeable membrane730, the latter being surrounded and sealed from the patient by thespacer718. The peripheral torus-shaped semipermeable membrane728 is in fluid communication with the osmotic engine throughopenings736 and the central semipermeable membrane730 is in fluid communication with theosmotic engine712 throughopenings738. Thespacer718 supports animpermeable barrier716 away from the underlying central semipermeable membrane730. Theimpermeable barrier716 may be formed of titanium and/or stainless steel, for example. The interstitial space between theimpermeable barrier716 and the underlying central semipermeable membrane730 includes a saturatedsaline solution720. According to the embodiment of FIG. 10, the distal end of thepump700 defines a threadedopening732. Anipple722 may be screwed onto the threadedopening732. Thenipple722 may include a centrally-disposednipple infusion lumen734. Thenipple infusion lumen734 may be seen as functionally equivalent to thedelivery orifice212 of FIGS. 2 through 8. Thenipple722 may have a shape that tapers distally and may include a proximal recessedfeature736 that allows an elastomericstrain relief element724 to be snapped and secured thereon. The proximal region of the strain relief element may be flush with thepump housing702, while the distal end thereof may taper to allow thecatheter726 to be sealed or press-fitted thereto. The distal portion of thecatheter726 is not shown in FIG. 10. The catheter may have a structure similar to that disclosed relative tocatheter650 in FIG. 9. Alternatively, as shown in FIG. 10, thecatheter726 may include asingle effusion lumen738.
• FIG. 11 shows a cross section (taken along line AA″ of FIG. 12B) of the proximal portion of the[0068]implantable pump700 of FIG. 10, showing the manner in which the pharmaceutical agent delivery (infusion) rate of thepump700 may be increased, according to an embodiment of the present invention, whereas FIG. 12A shows a cross section (also taken along line AA″ of FIG. 12B) of the proximal portion of the implantable pump of FIG. 11 after theimpermeable barrier716 has been breached. When theimplantable pump700 is initially implanted into the patient, only the peripheral semipermeable membrane728 is exposed to the patient's bodily. The surface area of the torus-shaped (for example) peripheral semipermeable membrane728 establishes the initial effusion rate of the pharmaceutical agent(s) from thecompartment706. When thelancet740 breaches theimpermeable barrier716, the surface area of semi permeable membrane exposed to the patient is increased to include the surface area of the central semipermeable membrane730 as well. According to the present invention, the relative ratio between the surface areas of the semi permeable membranes exposed and not exposed to the patient controls the effusion rate of the pharmaceutical agent from thepump700. Additionally, by varying the composition and/or thickness (in place of or in addition to the surface areas thereof) of the semi permeable membranes of the present invention, different step effusion rate functions may readily be achieved upon breaching the impermeable barrier(s) of the pump.
• FIG. 13 shows an embodiment of a[0069]lancet740 that may be utilized to breach theimpermeable barrier716 of the implantable pump according to the present invention. Thelancet740 may include a hollowcylindrical portion742 sharpened at its distal end and areservoir744. Thereservoir744 may be formed of an elastomeric material (such as silicone, for example), to allow the physician to squeeze the reservoir between his or her fingers. Thereservoir744 may contain water or a saturated saline solution, collectively referenced by the numeral746 in FIG. 13. When the physician wishes to increase the dose of pharmaceutical agent delivered to the patient, he or she may breach (puncture) theimpermeable barrier716 of thepump700 using an appropriately dimensionedlancet740. Thereafter, thereservoir744 may be squeezed to flush the saline solution contained therein into theinterstitial space720 between the centralsemipermeable membrane730 and theimpermeable barrier716. Thelancets222,522a,522band/or522cor FIGS. 2 through 8 may be configured as shown in FIG. 13a. Alternatively, the aforementioned lancets may include appropriately dimensioned hollow or solid needles, such as hypodermic needles, for example.
• FIG. 14A is a perspective view of the proximal portion of an implantable pump for long-term delivery of a pharmaceutical agent at selectable rates, wherein an end-cap portion thereof is removed, to illustrate a further embodiment of the present invention. FIG. 14B is a detail view of an end-cap portion configured to fit on the proximal portion of the pump shown in FIG. 14A. The implantable pump shown in FIG. 14A includes a[0070]pump housing800 that encloses a pharmaceutical agent compartment (not shown in FIG. 14b), a moveable partition or piston (also not shown in FIG. 14a), as well as an osmotic driving compartment enclosing anosmotic engine804. Semi permeable membranes are disposed adjacent the free end of the osmotic driving engine compartment802; namely a peripheral semipermeable membrane806 and a central semipermeable membrane808. Separating the two semipermeable membranes806 and808 is aspacer810. Thespacer810, as shown in FIG. 14A, may be shaped as a right cylinder, although other spacer shapes are possible. The peripheral semipermeable membrane806 may be disposed about the base of thespacer810 that is, in the distal portion thereof. Indeed, the peripheral semipermeable membrane806 may be disposed adjacent thespacer810 and around its outer periphery, thereby forming a generally toroidal shape. The central semipermeable membrane808 may be disposed within thespacer810, also toward the distal end thereof. The peripheral semipermeable membrane806 and the central semipermeable membrane808 may be approximately and mutually co-planar, albeit separated by at least the thickness of the wall of thespacer810. The generally disc-shaped structure forming the distal base of thespacer810 defines a plurality ofopenings816 aligned with the peripheral semipermeable membrane806 and a plurality ofopenings817 aligned with the central semipermeable membrane808. Theopenings816 allow the influx of water that has traveled from the patient's body through the peripheral semipermeable membrane806 to reach the osmotic driving compartment802 and thus to reach theosmotic engine804. According to an embodiment of the present invention, theimpermeable barrier822 may be fitted onto the freeproximal end818 of thespacer810. Alternatively, the proximal portion of thespacer810 may define a threading812 adapted to receive a mating threaded end-cap820, as shown in FIG. 14B. As shown in FIG. 14B, the end-cap820 may fit over and screw on the freeproximal end818 of thespacer810. Theimpermeable barrier822 may be disposed across the end-cap820. When the end-cap820 is screwed onto the freeproximal end818 of thespacer810, the underlying central semipermeable membrane808 is sealed from the patient's bodily fluids until and if theimpermeable barrier822 is breached.Struts824 attached to the end-cap820 may span the distance between the end-cap820 and the proximal edge of thepump housing800 to lend additional support and stability to the assembly including the end-cap820 and thepump housing800. According to an embodiment of the present invention, theend cap820 may be welded to thespacer810 and pumphousing800. As shown, the proximal edge of thepump housing800 may be approximately coplanar with the proximalfree end818 of thespacer810. The interstitial space between the end-cap820 and the underlyingcentral portion808 of the semi permeable membrane is preferably filled with a saturated solution of relatively high osmolarity, such as sodium chloride NaCl). When theimpermeable barrier822 is breached, the openings817 (FIG. 14A) allow the influx of water that has traveled from the patient's body through the central semipermeable membrane808 to reach the osmotic driving compartment802 and thus to reach theosmotic engine804.
• FIGS. 15 through 18 illustrate a method of and kits for implanting an implantable pump for long-term delivery of a pharmaceutical agent at selectable rates, according to the present invention. One method of introducing the pump and catheter combination according to the present invention (shown in FIG. 9[0071]a, for example) is known as the “Seldinger Technique” often used to insert catheters through patients' vasculatures. FIGS. 15 through 18 illustrate a method of implanting the pump subcutaneously so the distal free distal end of the integrated catheter lies in the intraspinal space which contains cerebrospinal fluid (hereafter CSF). The integrated catheter may also be inserted epidurally; that is, adjacent the dura matter surrounding the brain and spinal cord. Returning now to FIG. 15, the CSF is contained within thedura matter910, over which lies asuperficial tissue layer900. FIG. 15 does not show the spinal cord or any of the bony structures thereof.
• As shown in FIG. 16, to insert the integrated pump and catheter assembly according to the present invention, a[0072]split introducer930 andhypodermic needle932 is inserted through thesuperficial tissue layer900 and thedura910. Thepreferred split introducer930 according to the present invention is shown in cross section in FIG. 19. As shown therein, thesplit introducer930 has a conical tapered shape to facilitate blunt dissection of thesuperficial tissue900 and thedura matter910, thereby easing the introduction of the catheter (such as shown at650 in FIG. 9A) therethrough and into theCSF920. Thesplit introducer930 may be shaped so as to be in intimate contact with a needle932 (such as the hypodermic needle shown in FIGS. 16 and 19 or thenon-coring needle932 shown in cross section in FIG. 19, for example), and may become larger towards its proximal end. As thedura matter910 is very elastic, it tends to recoil as thesplit introducer930 is inserted therethrough. Thesplit introducer930 may blunt dissects thedura matter910 and may tear it somewhat as it enlarges the passageway through which it tunnels. Alternatively, a non-coring needle (an example of which is shown in cross-section in FIG. 19B) may be used in place of the hypodermic needle shown in FIGS. 16 and 19A. Returning to FIG. 16, aneedle932 is then inserted through thesplit introducer930. Theneedle932 may be formed of metal, such as stainless steel. Alternatively, theneedle932 may be inserted into thesplit introducer930, and the assembly introduced through thesuperficial tissue900, thedura matter910 and into theCSF920. Aguidewire656 is then introduced through theneedle932 and theguidewire656 is then left in place. Theneedle932 is then removed, leaving thesplit introducer930 and guidewire656 in place. The catheter610 (see FIG. 9A) is then introduced over theguidewire656 as shown in FIG. 17, theguidewire656 traveling within the guidewire lumen (reference numeral654 in FIG. 9A). Once thecatheter650 is in place, thesplit introducer930 may be peeled off and removed. As shown in FIG. 18, asubcutaneous pocket934 may then be formed between thesuperficial tissue900 and thedura matter910, and thepump610 may then be tunneled therein and thepocket934 sutured close at935a. Alternatively, thedura matter910 may sutured close aroundcatheter650 at935bbefore thesuperficial tissue900 is sutured. As shown in FIG. 18, the distal end of thecatheter650 is disposed at the desired location within theCSF920 where thepharmaceutical agent936 may be released.
• Electromechanical implantable pumps are rather large devices and are designed to deliver relatively large volumes of drugs to the patient, whether intravenously, epidurally or intrathecally. The implantable pump system for long-term delivery of a pharmaceutical agent at selectable rates according to the present invention, however, is a smaller device able to deliver a minute, continuous and step-wise selectable flow of a pharmaceutical agent for a long period of time, such as about 6 or 12 months. Consequently, the procedure required to implant the pump system according to the present invention is a less traumatic and simpler procedure than is traditionally required to implant relatively larger electromechanical devices.[0073]
• For illustrative purposes only and with particular reference to FIGS. 9A and 10, the length of the[0074]pump610,700 may be about 1.25 inches and the diameter thereof may be about 0.14 inches. The pharmaceutical agent compartment (seereference202 in FIGS. 2 through 8 andreference708 in FIG. 10) of such apump610,700 may contain about 0.32 milliliters (ml) of drug or other pharmaceutical agent. Continuing with the same example, the length of thecatheter650 may be about 12 inches with an ID of 0.0025 inches, for a dead space volume (primer volume) therein of about 0.001 ml. A small dead space volume means that the time required for the pharmaceutical agent to reach its destination from the pharmaceutical agent compartment is short. Such an osmotic pump-catheter assembly according to the present invention may infuse about 1.75 microliters (μL) of a drug per day for about 180 days, or about 6 months. For a larger infusion rate of about, for example, 5 μL per day for a period of about 180 days, the length of thepump610,700 may be about 1.25 inches and the diameter thereof may be about 0.24 inches. The pharmaceutical agent compartment (seereference202 in FIGS. 2 through 8 andreference708 in FIG. 10) of such apump610,700 may contain about 0.9 ml of drug or other pharmaceutical agent. The length of thecatheter650 may be about 12 inches with an ID of 0.005 inches, for a dead space volume therein of about 0.0038 ml. To offer significant pain relief while delivering only about 1 to about 5 μL per day (defined as a 24 hour period), the pharmaceutical agent contained in thecompartment202,708 must be a potent analgesic agent. The opioids (morphine, for example) conventionally used in implantable pumps would not be therapeutically effective in controlling pain at the above-cited infusion rates. According to the present invention, thepharmaceutical agent compartment202,708 may contain sufentanil (such as sufentanil citrate), an opioid that is about 700 to 1,000 times more potent than morphine. This greater potency allows a small volume of drug to alleviate significant pain.
• Table 3 is provided to allow a comparison of the dosage needed to achieve a same analgesic effect, across different modes of delivery using the implantable pump system according to the present invention.[0075]

  	TABLE 3
  		Equianalgesic
  		Conversion
  		factor

  	Oral	300
  	Intravascular	100
  	Subcutaneou	100
  	Epidural	10
  	Intrathecal	1

• As can be seen, delivering an analgesic within the intrathecal space requires a dosage that is 300 hundred times smaller than the dosage needed to achieve the same analgesic effect when the drug is given orally. There is, however, not a direct correlation in the equianalgesic conversion chart for the intravascular and subcutaneous routes. Indeed, as the patient's need for more medication increases, they will be converted to other modes of delivery.[0076]
• Table 4 illustrates the starting and expected maximum dosage range of sufentanil using the implantable pump system of the present invention, as the system is implanted intravascularly, subcutaneously, epidurally, intrathecally and intraventricularly, according to further embodiments of the present invention.[0077]

  	TABLE 4
  		Starting	Expected
  		Dosage	Maximum
  		Range	Dosage
  		(μg/day)	(μg/day)

  	Intravascular	10-100	300
  	Subcutaneous	10-100	300
  	Epidural	5.0-50	300
  	Intrathecal	0.5-5.0	50
  	Intraventricular	0.5-2.5	25

• 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. Moreover, 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.[0078]

Claims (59)

What is claimed is:

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

a pump housing;

a moveable partition disposed within the housing, the partition dividing the housing into an osmotic driving compartment having an open end and a pharmaceutical agent compartment having a delivery orifice;

a first semi permeable membrane disposed in the open end of the osmotic driving compartment, the first semi permeable membrane being exposed to the patient;

a second semi permeable membrane disposed in the open end of the osmotic driving compartment, and

a first impermeable barrier disposed over the second semi permeable membrane, the second semi permeable membrane being sealed from the patient until the first barrier is breached, wherein breaching the first barrier increases the surface area of semi permeable membrane exposed to the patient and increases a delivery rate of the pharmaceutical agent through the delivery orifice.

2. The pump ofclaim 1, wherein the first impermeable barrier includes at least one of titanium and stainless steel.

3. The pump ofclaim 1, further comprising a saturated solution including NaCl between the first impermeable barrier and the second semi permeable membrane.

4. The pump ofclaim 1, wherein the first and second semi permeable membranes have a same composition.

5. The pump ofclaim 1, wherein the first and second semi permeable membranes have a same thickness.

6. The pump ofclaim 1, wherein the first and second semi permeable membranes have mutually different compositions.

7. The pump ofclaim 1, wherein the first and second semi permeable membranes have mutually different thickness.

8. The pump ofclaim 1, further including:

a third semi permeable member, and

a second impermeable barrier nested within the first impermeable barrier, the second impermeable barrier being disposed over the third semi permeable membrane, the third semi permeable membrane being sealed from the patient until the second impermeable barrier is breached, wherein breaching the second barrier increases the surface area of semi permeable membrane exposed to the patient and increases a delivery rate of the pharmaceutical agent through the delivery orifice.

9. The pump ofclaim 8, further comprising a saturated solution including NaCl between the second barrier and the third semi permeable membrane.

10. The pump ofclaim 1, wherein the pharmaceutical agent compartment contains sufentanil.

11. The pump ofclaim 10, wherein the sufentanil is at a concentration selected between about 200 μg/mL and about 15,000 μg/mL.

12. The pump ofclaim 1, wherein the daily delivery rate of the pharmaceutical agent through the delivery orifice is selected from about:

0.5 micrograms per day to about 25 micrograms per day when the pump is configured to be implanted intraventricularly;

0.5 micrograms per day to about 50 micrograms per day when the pump is configured to be implanted intrathecally;

5 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted epidurally, and 10 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted subcutaneously.

13. The pump ofclaim 1, wherein the first and second semi permeable membranes include cellulose acetate.

14. The pump ofclaim 1, wherein the first semi permeable membrane is shaped as a torus and is disposed adjacent an outer periphery of the first impermeable barrier and wherein the second semi permeable membrane is disposed in a center opening of the torus.

15. The pump ofclaim 1, further comprising a catheter coupled to the delivery orifice.

16. The pump ofclaim 15, wherein the catheter has an inner diameter of between about 0.001 inches and about 0.010 inches.

17. The pump ofclaim 15, wherein the catheter includes a guidewire lumen and a pharmaceutical agent infusion lumen.

18. The pump ofclaim 17, wherein the pharmaceutical agent infusion lumen has an inner diameter selected between about 0.001 inches to about 0.010 inches.

19. The pump ofclaim 15, wherein the catheter and the pump are dimensioned to infuse a volume of pharmaceutical agent of between about 1 μL/day and about 10 μL/day over a treatment period.

20. The pump ofclaim 15, wherein the catheter and the pump are dimensioned to infuse a dose of pharmaceutical agent of between about 0.5 μg/day and about 300 μg/day over a treatment period.

21. The pump ofclaim 15, wherein at least a portion of the catheter is radiopaque.

22. The pump ofclaim 17, wherein the guidewire lumen includes a valve to prevent back flow of fluid into the guidewire lumen.

23. A method for achieving an analgesic effect in a patient, the method comprising the step of administering a therapeutically effective dose of a sufentanil-containing analgesic to the patient using a device that is fully implanted in the patient.

24. The method ofclaim 23, wherein the dose is administered one of intravascularly, subcutaneously, epidurally, intrathecally and intraventricularly.

25. The method ofclaim 23, further comprising the step of selectively increasing the dose in a stepwise manner over a treatment period without removing the device from the patient.

26. The method ofclaim 25, wherein the dose is administered using an implanted osmotic pump that includes a first semi permeable membrane exposed to the patient and a second semi permeable membrane initially not exposed to the patient and wherein the increasing step includes a step of exposing the second semi permeable membrane to the patient.

27. The method ofclaim 26, wherein the second semi permeable membrane exposing step includes a step of breaching an impermeable barrier sealing the second semi permeable membrane from the patient.

28. The method ofclaim 27, wherein the breaching step includes a step of puncturing the impermeable barrier using a lancet while the pump remains implanted in the patient.

29. The method ofclaim 23, wherein the therapeutically effective dose is selected within the range of about 0.5 μg/day to about 300 μg/day.

30. A method for achieving an analgesic effect in a patient, the method comprising intraspinal administration of a therapeutically-effective dose of an analgesic to the patient by an osmotic pump and catheter integrated combination, the pump including a first semi permeable membrane across which an osmotic pressure gradient develops when the pump is implanted in the patient.

31. The method ofclaim 30, further including the step of selectively increasing a surface area of semi permeable membrane exposed to the patient in a stepwise manner.

32. The method ofclaim 30, wherein the analgesic includes sufentanil.

33. The method ofclaim 30, further including a second semi permeable membrane and wherein the surface area of semi permeable membrane exposed to the patient is increased by breaching an impermeable barrier initially sealing the second semi permeable membrane from the patient.

34. The method ofclaim 33, wherein the impermeable barrier is breached by puncturing the impermeable barrier.

35. The method ofclaim 31, wherein the dose is increased in a stepwise manner by sequentially breaching one of a plurality of nested impermeable barriers disposed over a corresponding plurality of the semi permeable membranes, each sequential breach exposing additional surface area of semi permeable membrane to the patient.

36. The method ofclaim 35, wherein each of the plurality of nested barriers is configured to be breached by a lancet, an outer diameter of the lancet determining which of the plurality of nested barriers is breached.

37. The method ofclaim 30, wherein the analgesic is administered one of intravascularly, subcutaneously, epidurally and intrathecally.

38. The method ofclaim 33, wherein the second semi permeable membrane has one of a same and different composition as the first semi permeable membrane.

39. The method ofclaim 33, wherein the second semi permeable membrane has one of a same and different thickness as the first semi permeable membrane.

40. An integrated implantable pump and catheter system for delivering a dose of sufentanil to a patient over a treatment period, comprising:

a pump housing;

a moveable partition disposed within the housing, the partition dividing the housing into an driving engine compartment and a pharmaceutical agent compartment having a delivery orifice;

a catheter coupled to the delivery orifice, and a preloaded amount of sufentanil in the pharmaceutical agent compartment.

41. The system ofclaim 40, wherein the pump and catheter are dimensioned to deliver sufentanil at an infusion rate of about 0.5 μg/day to about 300 μg/day over a treatment period.

42. The system ofclaim 40, wherein the system further includes a mechanical infusion rate selection structure configured to allow the infusion rate of the pump to be increased while the system is implanted in the patient.

43. The system ofclaim 40, wherein the infusion rate selection feature includes a plurality of semi permeable membranes across each of which osmotic pressure develops when selectively and sequentially exposed to the patient.

44. The system ofclaim 43, wherein each of the plurality of semi permeable membranes has a selected thickness, composition and surface area, the selected thickness, composition and surface area contributing to a rate at which the sufentanil is infused into the patient.

45. A kit comprising:

an osmotic pump;

sufentanil preloaded in the osmotic pump, and

a delivery catheter configured to be coupled to the osmotic pump.

46. The kit ofclaim 45, wherein the osmotic pump includes a mechanical infusion rate selection structure.

47. The kit ofclaim 45, and further comprising a lancet configured to act upon the infusion rate selection structure to increase an infusion rate of the sufentanil through the delivery catheter.

48. The kit ofclaim 45, wherein the pump is configured to deliver sufentanil at an infusion rate of a bout 0.5 μg/day to about 300 μg/day over a treatment period.

49. The kit ofclaim 45, wherein the catheter includes a guidewire lumen and a sufentanil delivery lumen.

50. The kit ofclaim 49, further comprising a guidewire.

51. The kit ofclaim 49, further comprising:

a guidewire;

a needle, and

a splittable introducer.

52. The kit ofclaim 51, wherein the needle is one of a hypodermic needle and a non-coring needle.

53. A kit comprising:

an osmotic pump that includes a mechanical infusion rate selection structure;

an amount of pharmaceutical agent preloaded into the pump, and

a delivery catheter.

54. The kit ofclaim 53, wherein the pharmaceutical agent includes sufentanil.

55. The kit ofclaim 53, wherein the infusion rate selection structure is configured to allow the infusion rate to be increased while the pump is implanted into a patient.

56. The kit ofclaim 53, wherein the infusion rate selection structure includes a plurality of semi permeable membranes, each of which being selectably exposable to the patient to increase a dose of pharmaceutical agent delivered to the patient.

57. The kit ofclaim 56, wherein each of the plurality of semi permeable membranes has an individually selected thickness, composition and surface area.

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

implanting an osmotic pump within the patient, the osmotic pump including the pharmaceutical agent and a plurality of semi permeable membranes across which osmotic pressure develops when exposed to the patient, and

controlling a surface area of semi permeable membrane exposed to the patient to control an infusion rate of the pharmaceutical agent analgesic to the patient.

59. The method ofclaim 58, further comprising the step of controlling at least one of a thickness and a composition of each of the plurality of semi permeable membranes.

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