HK1070829A - Osmotic implant with membrane and membrane retention means - Google Patents

Description

Osmotic implant with membrane and membrane retention mechanism

This application claims priority to U.S. application serial No.60/300,575, filed on day 22/6/2001, which is incorporated herein by reference.

Technical Field

The present invention relates to osmotically controlled implantable delivery devices, and more particularly to a delivery system having a membrane material capable of controlling the rate of delivery of beneficial agents from the delivery system, wherein the membrane material is cast, calendered or extruded and then machined (i.e., die cut or otherwise cut to shape), while the membrane material is retained within the delivery device by a retaining mechanism.

Background

Controlled delivery of beneficial agents, such as drugs, in the medical and veterinary fields has been accomplished by a variety of methods, including implantable delivery devices, such as implantable osmotic delivery devices, and implantable diffusion controlled delivery systems. Osmotic delivery systems are very reliable in delivering a beneficial agent over an extended period of time, referred to as the administration period. Typically, osmotic delivery systems operate by imbibing fluid from the external environment to release a corresponding beneficial agent amount from the delivery system.

Representative examples of various types of delivery devices are disclosed in U.S. patent nos.3,732,865; 3,987,790; 4,865,845; 5,059,423; 5,112,614; 5,137,727; 5,213,809, respectively; 5,234,692; 5,234,693; 5,308,348, respectively; 5,413,572; 5,540,665, respectively; 5,728,396; 5,985,305, all of which are incorporated herein by reference. All of the above-referenced patents generally include certain types of capsules having at least a portion of a wall that allows water to selectively pass into the interior of the capsule containing a water-attracting agent (also referred to as an osmotic agent, osmopolymer, or osmotic agent). The absorption of water by the water-absorbing agent within the capsule reservoir creates an osmotic pressure within the capsule that causes the beneficial agent within the capsule to be released. The hydrating agent may be a beneficial agent that is delivered to the patient. However, in most cases, a separate agent is used exclusively which is capable of introducing water into the capsule.

When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the capsule by a movable divider such as a piston. The components of the capsule are substantially rigid such that when the osmotic agent imbibes water to swell, the capsule does not swell. When the osmotic agent expands, the agent moves the movable partition member, causing the beneficial agent to be expelled through an orifice or outlet passage of the capsule. The beneficial agent is expelled through the outlet passage at a volumetric rate equal to the volumetric rate of water entering the osmotic agent through the semipermeable wall portion of the capsule.

The rate at which the beneficial agent is expelled from the delivery device is determined by a number of factors, including the type of bibulous or osmotic agent, the permeability of the semi-permeable membrane wall, and the size and shape of the outlet channel. One way to control the back diffusion of ambient fluid into the beneficial agent reservoir is through a flow regulator in the capsule outlet passage, which typically consists of a tubular passage of a specific cross-sectional area and length.

In known osmotic delivery systems, an osmotic tablet, such as saline, is placed in the capsule, and a membrane plug is placed in the open end of the capsule to provide a semipermeable barrier. The membrane plug seals the interior of the capsule from the external environment, allowing only certain liquid molecules from the environment to permeate through the membrane plug into the interior of the capsule. The membrane plug is impermeable to the contents of the capsule, including the osmotic agent and the beneficial agent. The rate at which the liquid penetrates the membrane plug and enters the capsule varies with the type of membrane material and the size and shape of the membrane plug. Second, the rate at which the liquid passes through the membrane plug controls the rate at which the osmotic agent expands to drive the beneficial agent from the delivery system through the outlet channel. Thus, by varying the permeability coefficient of the membrane plug and/or the size of the membrane plug, the delivery rate of the beneficial agent from the osmotic delivery system can be controlled.

Some known osmotic delivery systems use an injection molded membrane plug featuring a protruding circumferential sealing member that fits into a mating circumferential groove on the inside of the capsule (U.S. Pat. No.6,113,938, which is incorporated herein by reference). The membrane plug is held in the capsule by a retaining rib, which typically requires insertion of the membrane from the membrane end of the well. Injection molded semipermeable membranes can be difficult to manufacture without internal stress; the performance may vary slightly with the peg. Another disadvantage of known osmotic delivery systems is the requirement that the membrane plug itself be able to withstand the pressure generated by the expansion of the osmotic engine. Other known osmotic delivery systems use membrane plugs having raised circumferential sealing ribs that do not engage circumferential grooves on the inside of the membrane. Still other known osmotic delivery systems use membrane plugs having non-circumferential sealing ribs that are encapsulated by a friction fit. Other known osmotic delivery systems use membrane plugs that do not have any circumferential sealing ribs but have holes in the capsule into which the membrane plug can expand (WO 99/33446, incorporated herein by reference). Known delivery systems do not use capsules having pre-installed retaining features that cover or partially cover the membrane plug of the capsule in order to retain the membrane plug sealed in place. Thus, in these systems, if a retaining detail is used which is not a capsule groove and mating membrane peg rib, the retaining detail must be fitted to the capsule body after insertion of the membrane peg. This requirement tends to increase the cost and complexity of a high pressure osmotic delivery system.

Accordingly, there is a need to provide a delivery device that improves the performance and consistency of the membrane material while providing a retaining feature that retains the membrane material in the capsule under high pressure.

Summary of The Invention

In accordance with the present invention, a delivery system for controlled delivery of a beneficial agent includes an implantable capsule having a beneficial agent delivery end and a fluid uptake end. The capsule also includes a beneficial agent reservoir disposed within the capsule for storing the beneficial agent. A membrane member is disposed in the fluid uptake end of the capsule, and a fluid permeable barrier is disposed between the interior and exterior of the capsule. A membrane material retaining means is disposed at the fluid uptake end of the capsule and includes at least one aperture for allowing passage of fluid. The membrane material retaining means also prevents the membrane material from being expelled from the fluid uptake end of the capsule.

In another aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent, wherein the membrane material retaining means comprises a retaining flange disposed along a distal end of the fluid uptake end of the capsule.

According to another aspect, the invention resides in a delivery system wherein the membrane material retaining means comprises a screen, grid, perforated disc, frit or sintered powder metal member containing porous capillaries. If the membrane material retaining means comprises porous capillaries, the capillaries may have a diameter of about 0.5 to about 10 microns. The membrane material retaining means may be planar or have a rounded or profiled surface on at least one surface thereof.

In yet another aspect, the present invention resides in a delivery system for controlled delivery of a beneficial agent wherein the membrane has a substantially smooth cylindrical or disc shape.

In yet another aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent wherein the membrane material is extruded, cast or calendered and then machined (i.e., die cut or otherwise cut to shape).

In yet another aspect, the present invention pertains to a delivery system for controlled delivery of a beneficial agent, wherein the capsule comprises one or more inwardly projecting ridges, and wherein the inwardly projecting ridges securely grip an outer surface of the membrane material. Note that the word "ridge" as used herein may refer to a ridge or a plurality of ridges. Furthermore, the shape of the inwardly projecting ridge or ridges accommodates insertion of the membrane material from the beneficial agent delivery end of the capsule while preventing withdrawal of the membrane material from the beneficial agent delivery end of the capsule.

In yet another aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent, wherein an osmotic engine is positioned between the beneficial agent delivery end and the membrane material.

In yet another aspect, the invention pertains to a delivery system for controlled delivery of a beneficial agent and includes a piston disposed between a beneficial agent delivery end and an osmotic engine for transmitting a pushing force generated by the osmotic engine to the beneficial agent.

In accordance with yet another aspect of the invention, a method of forming an advantageous agent delivery device includes the steps of: providing an implantable capsule having an open delivery end, an open fluid uptake end and a membrane retaining mechanism; inserting a membrane member into the capsule from the open reagent delivery end and positioning the membrane member with an end surface thereof in contact with the inner surface of the membrane member retaining means; inserting the osmotic engine into the capsule followed by a movable partition or piston; the capsule is then filled with a beneficial agent and the agent delivery end is closed while providing a controlled exit for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent.

In yet another aspect, the present invention resides in an osmotic system for controlled delivery of a beneficial agent including an implantable capsule having a beneficial agent delivery end and a fluid uptake end. The capsule includes a beneficial agent reservoir disposed adjacent the beneficial agent delivery end for placement of the beneficial agent. A piston is disposed between the beneficial agent reservoir and the fluid uptake end. An osmotic engine is disposed between the piston and the fluid uptake end. The osmotic engine may be expanded at a controlled rate and, when expanded, exerts a pushing force on the piston which exerts a pushing force on the beneficial agent such that the beneficial agent is released at a predetermined rate through the beneficial agent delivery end. A membrane member is positioned at the fluid uptake end and forms a fluid permeable barrier between the interior and exterior of the capsule. A membrane retaining means is disposed at the fluid uptake end, the membrane retaining means comprising at least one aperture for allowing passage of fluid. The membrane material retaining means simultaneously prevents the membrane material from being discharged from the fluid uptake end by osmotic pressure.

The present invention provides the advantage of predictable and consistent delivery rates of beneficial agents by allowing the use of extruded, cast or calendered and then machined (i.e., die cut or otherwise cut into shape) membrane pieces that are more uniform when produced on a highly controlled machining or extrusion line when compared to the part-to-part consistency of injection molded plugs.

The present invention also provides the advantage that a cast, calendered or extruded, machined (i.e., die cut or otherwise cut) membrane can be sealed in place within an implantable osmotic delivery device while reducing the expulsion of the membrane from the implantable device under high pressure conditions (greater than 1,000psi) as encountered in the case of a blocked outlet channel.

Furthermore, the invention allows the membrane material retaining means to be integrally formed with the implantable capsule or attached to the capsule during assembly of the delivery device.

Brief Description of Drawings

The present invention will be described in more detail below with reference to the attached drawing figures, wherein like reference numerals refer to like parts, and wherein:

FIG. 1 is a side cross-sectional view of an osmotic drug delivery device including a capsule, a piston, an osmotic engine, a membrane member, and an outlet passage;

FIG. 2 is a side cross-sectional view of a portion of an implantable capsule;

FIG. 3 is a front view taken along line 3-3 of the implantable capsule of FIG. 2;

FIG. 4 is a side view of a membrane plug;

FIG. 5 is a front view taken along line 5-5 of the membrane plug of FIG. 4;

FIG. 6 is a side cross-sectional view of a portion of an implantable capsule in accordance with a second embodiment of the present invention;

FIG. 7 is a front view taken along line 7-7 of the implantable capsule of FIG. 6;

FIG. 8 is a side cross-sectional view of a portion of an implantable capsule in accordance with a third embodiment of the present invention;

FIG. 9 is a front view taken along line 9-9 of the implantable capsule of FIG. 8;

FIG. 10 is an enlarged view of detail A of FIG. 1;

FIG. 11 is a side cross-sectional view of a portion of an implantable capsule in accordance with a fourth embodiment of the present invention; and

fig. 12 is a side cross-sectional view of a portion of an implantable capsule in accordance with a fifth embodiment of the present invention.

Description of the preferred embodiments

The present invention is directed to an osmotic delivery system 10 having a membrane material 30 for controlling the delivery rate of a beneficial agent from the osmotic delivery system.

Definition of

The term "effective agent" or "beneficial agent" refers to an effective agent optionally in combination with a pharmaceutically acceptable carrier and optional additional ingredients such as antioxidants, stabilizers, penetration enhancers, and the like.

The term "impermeable" means that the material is sufficiently impermeable to ambient fluids and to the components contained in the dispensing device such that movement of such substances into and out of the device through the impermeable device is very small so as to have substantially no adverse effect on the function of the device during transport.

The term "semi-permeable" means that the material is permeable to external fluids but substantially impermeable to other components contained within the dispensing device and the environment of use.

The term "membrane" means that the semi-permeable membrane is in the form of a sheet or a plug. The membrane preferably has a diameter of about 0.040 "to about 0.250" and preferably has a length or thickness of about 0.010 "to about 0.350". The diameter and thickness of the membrane material is determined by such considerations as the desired beneficial agent delivery rate, the desired beneficial agent delivery lifetime, the device size, the material used for the semi-permeable membrane, the retention mechanism used for the semi-permeable membrane, the formulation of the beneficial agent, and/or the osmotic pressure generated during operation of the device.

FIG. 1 shows that the osmotic delivery system 10 generally includes a first chamber 50 containing a beneficial agent, a piston 54, and a second chamber 40 containing an osmotic agent, all of which are enclosed in an elongated, substantially cylindrical capsule 12.

The capsule 12 must be sufficiently robust to ensure that it does not leak, rupture, break or deform so as to expel its effective reagent contents under the pressure to which it is subjected during use. In particular, it should be designed to withstand the maximum osmotic pressure that may be generated by the osmotic agent in chamber 40. The capsule 12 must also be chemically inert, biocompatible and impermeable, i.e., it must be unreactive with the active agent formulation and the body, and must isolate the beneficial agent during the delivery process. Suitable materials generally include a non-reactive polymer or a biocompatible metal or alloy. The polymer includes acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer and the like; halogenated polymers such as polytetrafluoroethylene, polychlorotrifluoroethylene, tetrafluoroethylene, and hexafluoropropylene copolymers; a polyimide; polysulfones; a polycarbonate; polyethylene; polypropylene; polyvinyl chloride-acrylate copolymers; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; polyetheretherketone (PEEK); liquid Crystal Polymers (LCP), and the like. J.Pharm.Sci. (J.Pharm.Sci.) (J.Pharma., Vol.29, pp.1634-37 (1970)); ind. eng.chem. (industrial and engineering chemistry), vol.45, pp.2296-2306 (1953); materials Engineering, Vol.5, pp.38-45 (1972); ann.book of ASTM Stds (American society for testing and materials standards annual book), Vol.8.02, pp.208-211, and pp.584-587 (1984); and Ind. Eng. chem. (Industrial and engineering chemical), Vol.49, pp.1933-1936 (1957), reported the water vapor transmission rate through the composition used to form the beneficial agent reservoir. The metallic materials used in the present invention include stainless steel, titanium, platinum, tantalum, gold and their alloys, as well as gold-plated iron alloys, platinum-plated iron alloys, cobalt-chromium alloys, and titanium oxide-plated stainless steel. Particularly preferred is an advantageous reagent bath made of titanium or a titanium alloy of greater than 60% titanium (often greater than 85% titanium).

The capsule 12 has a beneficial agent delivery end 70 with an outlet passage 72 and an aperture 62 at its fluid uptake end. The outlet passage 72 may take any convenient form, such as straight, circular, spiral, etc. The outlet passage 72 is made of an inert, biocompatible material selected from the group consisting of, but not limited to, metals including, but not limited to, titanium, stainless steel, platinum and alloys thereof, and cobalt chromium alloys, and polymers including, but not limited to, polyethylene, polypropylene, polycarbonate, and polymethyl-methacrylate.

The fluid uptake end 60 of the capsule 12 is closed with the membrane material 30. In fig. 2 the membrane is in the form of a plug. The membrane material is made of a semi-permeable material that conforms to the shape of the capsule 12 when wetted and sealed to the hard surface of the capsule. The semipermeable membrane material expands when exposed to a fluid environment to create a seal between the mating surfaces of the membrane material and the capsule. The diameter of the membrane member is such that when it is in sealing contact over one or more circumferential or axial zones, the membrane member will sealingly engage the inner face of the basin prior to hydration and will expand in position to form an even tighter seal with the capsule when wetted. The membrane must be capable of penetrating about 0.1% to 200% by weight of water. Polymeric materials that can be used to make the semipermeable membrane vary according to the draw rate and device configuration requirements and include, without limitation, plasticized cellulosic materials, reinforced polymethylmethacrylate such as hydroxyethyl methyl acrylate (HEMA), and elastomeric materials such as polyurethanes and polyamides, polyetheramide copolymers, thermoplastic copolyesters, and the like.

The membrane material 30 closes off the fluid uptake end 60 from the second chamber 40 containing the osmotic agent.

The osmotic agent or osmotic engine may, for example, include a non-volatile, water-soluble osmotic agent, an osmotic polymer capable of swelling upon contact with water, or a mixture of the two. Osmotic agents such as NaCl with suitable tableting agents (lubricants and binders) and viscosity modifiers such as sodium carboxymethylcellulose or sodium polyacrylate are preferred water-swellable agents. Other osmotic agents that may be used as water-swellable agents include osmopolymers and osmotic agents and are described, for example, in U.S. Pat. No.5,413,572, which is incorporated herein by reference. The water-swellable agent may be a slurry, a tablet, a molded or extruded substance, or other forms known in the art. A liquid or gel additive or filler may be added to the chamber 40 to expel air from the space surrounding the osmotic engine.

Fluid flows from the exterior of the capsule 12 through the membrane material 30 into the second chamber 40, while the membrane material 30 prevents the composition within the capsule from flowing out of the capsule.

As can be seen in fig. 1, the first chamber 50 containing the beneficial agent is separated from the second chamber 40 containing the osmotic agent by a separating member, such as a movable piston 54. The movable piston 54 is a substantially cylindrical member configured to fit within the inner diameter of the capsule 12 in a sealing manner and to slide along the longitudinal axis within the capsule. The piston 54 forms an impermeable barrier between the beneficial agent contained in the first chamber 50 and the osmotic agent contained in the second chamber 40. The material from which the piston is made is preferably an impermeable elastomeric material including, but not limited to, polypropylene, rubbers such as EPDM, silicone rubber, butyl rubber, and the like, perfluoroelastomers such as Kalrez^And Chemrez^Fluorocarbons such as Viton^Andthermoplastic elastomers such as plasticized polyvinyl chloride, polyurethane, Santoprene^、C-Flex^TPE, a styrene-ethylene-butylene-styrene copolymer (compression polymer technology), and the like.

As can be seen in fig. 2 and 3, the capsule 12 comprises a smooth, generally cylindrical shape having a hollow interior. The capsule 12 is provided with a membrane retaining means having a retaining flange 20 disposed along the outer periphery of the fluid uptake end 60 and includes an aperture 62 to allow fluid to pass into the capsule. The membrane retaining flange 20 may have a flat rounded or contoured surface on its outside. The retaining flange 20 of the membrane retaining mechanism should be long enough to retain the membrane under full osmotic pressure, but the holes 62 need to maximize the exposed surface of the membrane. The capsule 12 also includes one or more inwardly projecting annular ribs or ridges 14 that form a fluid seal between the inner surface of the capsule 12 and the surface of the membrane material 30 and prevent fluid from leaking around the membrane material. The ribs or ridges 14 are also formed to grippingly engage the outer surface of the membrane material 30 and prevent the membrane material from flowing laterally toward the beneficial agent delivery end 70. In this regard, the diameter of the membrane material 30 is substantially equal to the inner diameter of the capsule 12. Also, the diameter of the membrane material 30 is larger than the inner diameter of the ribs or ridges 14. The capsule may be provided with about 1-8 ribs or ridges, but preferably about 1-4 ribs or ridges. Any reference to the term rib is intended to include a single rib as well as a plurality of ribs. Any reference to the word ridge is intended to be a reference to the word rib and vice versa.

Although fig. 2 shows the retaining flange 20 as being integrally formed with the capsule 12, it will be appreciated that the retaining flange may be a separate component attached to the capsule. For example, the membrane retention mechanism flange 20 may be welded, pressed, screwed, etc. to the end of the capsule 12.

The aperture 62 is sufficiently small that the membrane material 30 cannot deform through the aperture under high operating pressures, such as about 5000 psi.

As seen in fig. 4 and 5, the diaphragm member 30 includes a substantially smooth cylindrical body. As seen in fig. 4 and 5, the membrane material 30 is free of any protrusions, ribs or voids. The membrane element 30 is therefore simpler to produce than known membrane plugs. The membrane material 30 may be produced by casting, calendering or extrusion followed by machining (i.e., die cutting or other cut forming), thereby producing a membrane that is highly uniform compared to injection molded membrane materials of known systems. The membrane 30 may be made of any suitable biocompatible membrane material.

As seen in fig. 10, the inwardly projecting ridge 14 includes an inclined wall 16 and a vertical wall 18. The ridge 14 extends from the inner wall 22 of the capsule 12 a distance around the entire circumference of the inner wall. The height h of the vertical wall 18 is preferably about 0.002 "to about 0.020". Furthermore, the inclined wall 16 is at an angle α to the inner wall 22. The angle of release of the sloped wall 16 may be selected to be any suitable angle that allows the membrane material 30 to be easily inserted over the ridge 14. The vertical walls 18 of the ridges 14 prevent the membrane material 30 from moving laterally toward the delivery end of the beneficial agent. In use, the ridge 14 and the membrane retaining mechanism flange 20 act together to limit any lateral movement of the membrane material 30.

Although fig. 10 does not show any clearance between the ridges 14 of the membrane material 30, it is within the scope of the invention that there may be a gap between the membrane material 30 and the ridges 14 and between the inner wall 22 of the capsule 12 and the membrane material 30.

Fig. 6 and 7 illustrate a portion of a second preferred embodiment of an osmotic delivery system 150. In this embodiment, the membrane retaining mechanism comprises a perforated disc 120. The perforated disc 120 includes a plurality of apertures 122 which allow fluid to pass therethrough and subsequently through the membrane material 30 into the interior of the capsule. As also seen in fig. 6, the perforated disc 120 acts in conjunction with the ridges 114 to limit lateral movement of the membrane material 30 within the capsule 112. Thus, the ridge 114 functions in the same manner as the ridge 14 of the first embodiment. In this embodiment, the perforated disc 120 is secured to the fluid uptake end of the capsule 112 by welding, pressing, screwing, or the like.

Fig. 8 and 9 illustrate a portion of a third preferred embodiment of an osmotic delivery system 250. In this embodiment, a screen or grate 220 having a plurality of apertures 222 is secured to the fluid uptake end 60 (see FIG. 2) of the capsule 212. As in the previous embodiment, the screen or grate 220 may be welded, pressed, screwed or otherwise secured to the fluid uptake end 60 (see fig. 2) of the capsule 212. The screen or grill 220 may be secured to the capsule 212 before or after insertion of the membrane material 230. Although a screen or grate 220 is illustrated, other means of allowing water to pass through while preventing drainage of the membrane 230 may be used.

As also seen in FIG. 8, the capsule 212 is provided with a plurality of inwardly projecting, circumferentially extending sealing ribs or ridges 214 having an inner diameter that is less than the inner diameter of the capsule 212. The ridge 214 includes an inclined wall 16 and a vertical wall 18 (see fig. 10). The inclined wall 16 allows for easy insertion of the membrane material 230 into the capsule 212, while the vertical wall 18 prevents the membrane material 30 from moving laterally in the direction of the beneficial agent delivery end 70 (see fig. 1).

FIG. 11 illustrates a portion of a fourth preferred embodiment of an osmotic delivery system 350. In this embodiment, the fluid uptake end 160 includes the membrane retaining mechanism 120 and a sintered or sintered metal powder component 320. The frit 320 comprises a plurality of capillaries having a diameter of about 0.5 to 10 microns that allow fluid to pass therethrough and subsequently through the membrane material 30 into the interior of the capsule. In fig. 11, the membrane material 30 is long enough to include at least one rib or ridge 314. As can also be seen in fig. 11, the frit 320 acts with the ridge 314 to limit lateral movement of the membrane material 30 in the capsule 112. Thus, the ridge 314 functions in the same manner as the ridge 14 in the first embodiment. In this embodiment, the frit 320 is fixed to the membrane material holding mechanism 120 of the capsule 112 by welding, pressing, screwing, or the like.

FIG. 12 illustrates a portion of a fifth preferred embodiment of an osmotic delivery system 350. This embodiment is similar to the embodiment shown in FIG. 11, except that the membrane material is disposed between the first ribs or ridges 314 and the membrane material retaining mechanism 120. The movement of the membrane material 30 is restricted within the capsule 112 by the ridges 114 and the membrane material retaining means 120.

The membrane may be prepared by casting, calendering or extrusion. Casting involves pouring the film member onto a flat surface. Calendering includes forming a piece of film by pressing or rolling. Extrusion involves pushing the membrane through a die form to form a rod shape. Once prepared into a sheet or rod, the sheet or rod is cut or machined to produce a plug or disc shape. The cutting or machining may be accomplished by, for example, die cutting or punching the shape.

The devices of the present invention can be used to deliver a wide variety of beneficial agents. These agents include, but are not limited to, pharmacologically active peptides and proteins, genes and gene products, other gene therapy agents, and other small molecules. The polypeptides may include, but are not limited to, growth hormone analogs, somatomedin-C, gonadotropin-releasing hormone, follicle stimulating hormone, luteinizing hormone, LHRH analogs such as gonadotropin-releasing hormone analogs, nafarelin and gonadotropin-releasing hormone, LHRH voluntary and pre-voluntary muscles (antoagonists), growth hormone releasing factor, calcitonin, colchicine, gonadotropins such as chorionic gonadotropin, oxytocin, octreotide, growth hormone plus an amino acid, vasopressin, corticotropin, epidemic growth factor, prolactin, growth hormone inhibitors, growth hormone plus a protein, corticotropin, lysine vasopressin, polypeptides such as thyroid stimulating hormone releasing hormone, thyroid stimulating hormone, secretin, enkephalin, glucagon, endocrine agents that secrete internally and utilize the blood flow distribution, and the like. Other agents that may be delivered include alpha₁Antitrypsin, factor VIII, factor IX and other coagulation factors, insulin and other peptide hormones, adrenocorticotropic hormone, thyroid stimulating hormone and other pituitary hormones, interferons (e.g., α -, β -, γ -, Ω -), erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, pancreatin, lactase, cytokinin, interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor suppressor protein, cytotoxic protein, recombinant antibodies and antibody fragments, and the like.

The above agents are useful in the treatment of a variety of diseases including, but not limited to hemophilia and other hematological diseases, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, genetic diseases such as cerbrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, graves 'disease, systemic lupus erythematosus and homatrophid arthritis, shock and wasting disorders, cystic fibrosis, lactose intolerance, crohn's disease, inflammatory bowel disease, gastrointestinal cancer and other cancers.

The beneficial agent or agents may be an anhydrous or aqueous solution, suspension or complex with a pharmaceutically acceptable container or carrier, such that a flowable formulation is produced, which may be stored on a shelf or in a refrigerator for extended periods of time, and in an implanted delivery system. The formulation may include pharmaceutically acceptable truncations and additional inert ingredients. The effective agent may be in various forms, such as uncharged molecules, components of molecular complexes or pharmaceutically acceptable salts. Also, simple derivatives of the agent (e.g., prodrugs, ethers, esters, amides, etc.) that are easily hydrolyzed by body fluid pH, enzymes, etc. can be utilized.

It will also be understood that more than one active agent may be included in the active agent formulation of the device of the present invention, and that the use of the term "agent" in no way excludes the use of two or more such agents. The dispensing device of the present invention may be used, for example, with humans or other animals. The environment of use is a fluid environment and can include any subcutaneous location or body cavity, such as the peritoneum or uterus. The final delivery may or may not be systemic delivery of the beneficial agent, which may or may not be systemic. A single dispensing body or several dispensing devices may be administered to a subject during a treatment procedure. These devices are designed to remain implanted for a predetermined period of time. If the devices are not removed after administration, they may be designed to withstand the maximum osmotic pressure of the water-swellable agent, or they may be designed to have a bypass to relieve the pressure generated within the device.

The device of the present invention is preferably sterilized prior to use, particularly when such use is implantation. This can be done by sterilizing each device separately, for example by gamma irradiation, steam sterilization or sterile filtration, and then aseptically assembling the final system. Alternatively, the devices may be assembled first, then terminally sterilized by any suitable method.

The assembly of the osmotic delivery device is described below with reference to the embodiments of FIGS. 1-3, however, it should be understood that the embodiments of FIGS. 6-9 and 11 and 12 may be assembled in a similar manner.

According to a preferred embodiment, the capsule is flange-mounted with membrane holding means fixed to the capsule. The membrane material 30 is preferably inserted from the beneficial agent delivery end 70 of the capsule 12. The membrane material 30 is then slid through the length of the capsule 12 in the direction of the fluid uptake end of the capsule until it abuts the membrane material retaining means 20. The membrane material 30 may be inserted by compressed gas, for example. Further, as seen in FIG. 1, after the membrane material 30 is fully inserted, the osmotic agent or osmotic agent may then be inserted into the chamber 40 from the beneficial agent delivery end 70. Once the osmotic agent has been inserted, the piston 54 may be inserted into the capsule. After insertion of the piston 54, the beneficial agent may be inserted into the beneficial agent reservoir 50. Finally, the outlet channel or diffusion block is inserted into the beneficial agent delivery end 70.

Alternatively, the membrane retention mechanism 20 may be attached to the capsule after one or more of the membrane material 30, the permeation tool 42, the piston 54, or the beneficial agent is inserted into the capsule.

If a screen, grate, or frit is present in the holes 62, the screen, grate, or frit may be attached to the capsule 12 before or after the membrane material 30 is placed in the capsule 12.

Once the components of the osmotic delivery system 10 have been assembled, the beneficial agent delivery tip 70 may be closed in a known manner, such as by providing a cap with a delivery channel 72. For example, the beneficial agent delivery tip can be closed in the manner disclosed in commonly owned and designed U.S. Pat. No.5,728,396, issued to Peer et al, which is incorporated herein by reference.

Thus, the present invention provides a more consistent and predictable delivery rate of beneficial agent by allowing the use of cast, calendered or extruded membrane materials that are machined (e.g., die cut or otherwise cut into shape), wherein the permeability of the membrane material is more uniform because the membrane material is produced on a highly controlled extrusion or machining line as compared to the part-to-part uniformity of the injection molded plugs.

According to other embodiments of the invention, the delivery system may take different forms. For example, the piston may be replaced in a flexible manner, such as a diaphragm, spacer, pad, plate, sphere, or rigid metal alloy, and may be made of any number of other materials and, secondly, the osmotic device may function without the piston, with only one interface between the osmotic agent/fluid additive and the beneficial agent or with the osmotic agent included in the beneficial agent. Furthermore, the capsule of the present invention may have a more rounded shape along its edges in order to make insertion of the capsule into the patient easier.

The above-described exemplary embodiments are intended to be illustrative in all respects, rather than restrictive, of the present invention. Thus, the present invention is capable of many variations and detailed implementation that can be derived from the description contained herein by a person skilled in the art. All such variations and modifications are considered to be within the spirit and scope of the invention as defined by the following claims.

Claims (35)

1. A delivery system for controlled delivery of a beneficial agent, the system comprising:

an implantable capsule having a beneficial agent delivery end and a fluid uptake end;

a beneficial agent reservoir located within the capsule for delivering the beneficial agent at a predetermined delivery rate;

a membrane member disposed in the fluid uptake end of the capsule and providing a fluid permeable barrier between the interior and exterior of the capsule;

one or more inwardly projecting ridges circumferentially aligned adjacent the fluid uptake end of the capsule for fixedly retaining the outer surface of the membrane material; and

a membrane material retaining means disposed at the fluid uptake end of said capsule, said retaining means comprising at least one aperture for allowing passage of fluid, the membrane material retaining means preventing expulsion of the membrane material from the fluid uptake end of the capsule.

2. A delivery system for controlled delivery of a beneficial agent, the system comprising:

an implantable capsule having a beneficial agent delivery end and a fluid uptake end;

a beneficial agent reservoir located within the capsule for delivering the beneficial agent at a predetermined delivery rate;

a membrane member disposed in the fluid uptake end of the capsule and providing a fluid permeable barrier between the interior and exterior of the capsule;

one or more inwardly projecting ridges circumferentially aligned adjacent the fluid uptake end of the capsule for fixedly retaining the outer surface of the membrane material; and

a membrane material retaining means disposed at the fluid uptake end of said capsule, said retaining means comprising a flange with a sintered or sintered powder metal member containing a porous capillary tube, the membrane material retaining means preventing the membrane material from being expelled from the fluid uptake end of the capsule.

3. An osmotic system for controlled delivery of a beneficial agent, comprising:

an implantable capsule having a beneficial agent delivery end and a fluid uptake end;

a beneficial agent reservoir disposed adjacent said beneficial agent delivery end for containing the beneficial agent;

a piston disposed between said beneficial agent reservoir and said fluid uptake end;

an osmotic engine disposed between said piston and said fluid uptake end;

a membrane member disposed in the fluid uptake end and providing a fluid permeable barrier between the interior and exterior of the capsule;

one or more inwardly projecting ridges circumferentially aligned adjacent the fluid uptake end of the capsule for fixedly retaining the outer surface of the membrane material; and

a membrane material retaining means disposed at the fluid uptake end, said membrane material retaining means comprising at least one aperture for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being expelled from the fluid uptake end of the capsule; and

wherein the osmotic engine is expandable at a controlled rate and, when expanded, the osmotic engine applies a pushing force to the piston which in turn applies a pushing force to the beneficial agent such that the beneficial agent is dispensed through the beneficial agent delivery end at a predetermined rate.

4. A delivery system according to claim 1 or claim 3, wherein said membrane material retaining means comprises a retaining flange disposed along the outer periphery of said fluid uptake end.

5. A delivery system according to claim 2 or 4, wherein the retaining flange and the capsule are integrally formed.

6. A delivery system according to claim 2 or 4, wherein the retaining flange is a separate component attached to the capsule.

7. A delivery system according to claim 6, wherein the flange is attached to the capsule by welding.

8. The delivery system according to claim 6, wherein said flange is attached to said capsule by press fitting.

9. A delivery system according to claim 6, wherein the flange is attached to the capsule by a screw mechanism.

10. A delivery system according to claim 1, 2 or 3, wherein the membrane retaining means comprises a screen or a grate.

11. A delivery system according to claim 1 or claim 3, wherein the membrane retaining means comprises a perforated disc, sintered or sintered powder metal member containing porous capillaries.

12. The delivery system of claim 11, wherein said membrane material retention means comprises a frit.

13. The delivery system of claim 11, wherein said membrane retention mechanism comprises a perforated disc.

14. A delivery system according to claim 11, wherein said membrane material retaining means comprises a sintered powder metal structure including a porous capillary tube.

15. A delivery system according to claim 2 or 14, wherein the porous capillaries of the sintered powder metal article have a diameter of about 0.5 to about 10 microns.

16. A delivery system according to claim 1, 2 or 3, wherein the retaining means may have a flat, rounded or profiled surface on at least one surface.

17. A delivery system according to claim 1, 2 or 3, wherein the membrane member comprises a substantially smooth cylindrical shape.

18. A delivery system according to claim 1, 2 or 3, wherein said membrane member has a diameter of about 0.040-0.250 inches.

19. A delivery system according to claim 1, 2 or 3, wherein said membrane has a thickness of from about 0.010 to about 0.350 inches.

20. A delivery system according to claim 1, 2 or 3, wherein the membrane material is extruded, cast or calendered.

21. A delivery system according to claim 20, wherein the membrane material is machined after extrusion, casting or calendering.

22. A delivery system according to claim 1, 2 or 3, wherein the membrane material is machined.

23. A delivery system according to claim 22, wherein the membrane material is die cut.

24. A delivery system according to claim 1, 2 or 3, wherein the plurality of inwardly projecting ridges are shaped to accommodate insertion of the membrane material while preventing withdrawal of the membrane material from the capsule.

25. The delivery system of claim 1 or 2, further comprising an osmotic agent disposed between the beneficial agent delivery end and the membrane material.

26. The delivery system of claim 25 further comprising a piston disposed between said beneficial agent delivery end and said osmotic engine for transmitting a pushing force generated by said osmotic engine to said beneficial agent.

27. A method of forming a beneficial agent delivery device comprising the steps of:

providing an insertable capsule having an open reagent delivery end and a fluid uptake end with membrane retaining means;

inserting a membrane into said capsule from the open reagent delivery end;

positioning the membrane material such that an end surface thereof contacts an inner surface of the membrane material holding mechanism;

filling a cavity of the capsule with a beneficial agent; and

the reagent delivery end is closed while providing a controlled exit for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent.

28. The method of forming a beneficial agent delivery device of claim 27, wherein the membrane material is formed by extrusion.

29. The method of forming a beneficial agent delivery device of claim 27, wherein the membrane material is machined.

30. The method of forming a beneficial agent delivery device of claim 27, wherein the membrane material is die cut.

31. The method of forming a beneficial agent delivery device of claim 27, wherein the membrane member comprises a smooth cylindrical shape.

32. A method of forming a beneficial agent delivery device according to claim 27, wherein the capsule includes a plurality of inwardly projecting ridges, and wherein the step of positioning the membrane material with an end surface thereof in contact with an inner surface of the membrane material retention means includes the step of positioning the membrane material over the plurality of inwardly projecting ridges such that the plurality of inwardly projecting ridges securely retain the membrane material within the capsule.

33. A method of forming a beneficial agent delivery device comprising the steps of:

providing an implantable capsule having an open agent delivery end and a fluid uptake end, one or more inwardly projecting ridges adjacent the fluid uptake end, and a membrane retaining mechanism at the fluid uptake end;

inserting a membrane member into said capsule from the open reagent delivery end with one end surface thereof contacting the inner surface of the membrane member retaining means, said membrane member being seated on said inwardly projecting ridges such that said inwardly projecting ridges securely retain said membrane member in said capsule;

positioning the film member so that one end surface thereof is in contact with the inner surface of the film member holding mechanism;

filling a cavity of the capsule with a beneficial agent; and

the reagent delivery end is closed while providing a controlled exit for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent.

34. A method of forming a beneficial agent delivery device comprising the steps of:

providing an implantable capsule having an open agent delivery end and a fluid uptake end, a membrane retaining means and one or more inwardly projecting ridges adjacent the fluid uptake end;

inserting a membrane into said capsule from the open reagent delivery end;

positioning the membrane material with one end surface thereof in contact with the inner surface of the membrane material retaining means, said membrane material being positioned on said inwardly projecting ridges such that said inwardly projecting ridges securely retain said membrane material in said capsule;

inserting an osmotic tool into the capsule;

inserting a piston into the capsule;

filling a cavity of the capsule with a beneficial agent; and

the reagent delivery end is closed while providing a controlled exit for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent.

35. A method of forming a beneficial agent delivery device comprising the steps of:

providing an implantable capsule having an open agent delivery end and a fluid uptake end and one or more inwardly projecting ridges;

inserting one or more of:

(a) inserting a membrane member into the capsule from the open reagent delivery end such that an end face of the membrane member will contact a surface of a membrane member retaining mechanism, seating the membrane member on the inwardly projecting ridge such that the inwardly projecting ridge securely retains the membrane member in the capsule;

(b) inserting an osmotic tool into the capsule;

(c) inserting a piston into the capsule; or

(d) Filling a cavity of the capsule with a beneficial agent;

attaching a film holding mechanism;

inserting any one of (a), (b), (c), or (d) which is not inserted before attaching the film holding mechanism; and

the reagent delivery end is closed while providing a controlled exit for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent.