Title of Invention	A DELIVERY SYSTEM FOR CONTROLLED DELIVERY OF A BENEFICIAL AGENT
Abstract	A delivery system for controlled delivery of a beneficial agent, said system comprising: an implantable capsule having a beneficial agent delivery end and a fluid uptake end; a beneficial agent reservoir positioned within the capsule for delivery of the beneficial agent at a predetermined delivery rate; a membrane material received in the fluid uptake end of the capsule and providing a fluid permeable barrier between an interior and an exterior of the capsule; one or a plurality of inwardly protruding ridges circumferentially arrayed near the fluid uptake end of the capsule to securingly grip the outer surface of the membrane material; and a membrane material retaining means positioned at the fluid uptake end of said capsule, said retaining means including at least one opening for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being ejected out of the fluid uptake end of the capsule.

Title of Invention

A DELIVERY SYSTEM FOR CONTROLLED DELIVERY OF A BENEFICIAL AGENT

Abstract

A delivery system for controlled delivery of a beneficial agent, said system comprising: an implantable capsule having a beneficial agent delivery end and a fluid uptake end; a beneficial agent reservoir positioned within the capsule for delivery of the beneficial agent at a predetermined delivery rate; a membrane material received in the fluid uptake end of the capsule and providing a fluid permeable barrier between an interior and an exterior of the capsule; one or a plurality of inwardly protruding ridges circumferentially arrayed near the fluid uptake end of the capsule to securingly grip the outer surface of the membrane material; and a membrane material retaining means positioned at the fluid uptake end of said capsule, said retaining means including at least one opening for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being ejected out of the fluid uptake end of the capsule.

Full Text	OSMOTIC IMPLANT WITH MEMBRANE AND MEMBRANE RETENTION MEANS [0001] This application claims the priority of U.S. Application Serial No. 60/300,575 filed June 22, 2001, which is incorporated herein by reference. BACKGROUND OF THE INVENTION Field of the Invention [0002] The present invention relates to osmotically controlled implantable delivery devices, and more particularly to a delivery system having a membrane material that controls the delivery rate of a beneficial agent from the delivery system, in which the membrane material is cast, calendered or extruded then machined (i.e. stamped, die cut or otherwise cut to shape), and the membrane material is maintained within the delivery device by a retaining means. Description of the Related Art [0003] 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 called an administration period. In general, osmotic delivery systems operate by imbibing fluid from an outside environment and releasing corresponding amounts of beneficial agent from the delivery system. [0004] 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; 5,234,692; 5,234,693; 5,308.348; 5.413,572; 5,540,665; 5,728,396; and 5,985,305, all of which are incorporated herein by reference. All of the above-cited patents generally include some type of capsule having at least a portion of a wall that selectively passes water into the interior of the capsule containing a water-attracting agent (also called an osmotic agent, an osmopolymer or osmoagent). The absorption of water by the water-attracting agent within the capsule reservoir creates an osmotic pressure within the capsule which causes a beneficial agent within the capsule to be delivered. The water attracting agent may be the beneficial agent being delivered to the patient. However, in most cases, a separate agent is used specifically for its ability to draw water into the capsule. [0005] When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the capsule by a movable dividing member such as a piston. The structure of the capsule is generally rigid such that as the osmotic agent takes in water and expands, the capsule does not expand. As the osmotic agent expands, the agent causes the movable dividing member to move, discharging the beneficial agent through an orifice or exit passage of the capsule. The beneficial agent is discharged through the exit passage at the same volumetric rate that water enters the osmotic agent through the semipermeable wall portion of the capsule. [0006] The rate at which the beneficial agent is discharged from the delivery device is determined by many factors, including the type of water-attracting agent or osmotic agent, the permeabiity of the semipermeabie membrane wall, and the size and shape of the exit passage. One manner in which the back diffusion of environmental fluid into the beneficial agent reservoir is controlled is by a flow moderator in the exit passage of the capsule, with the flow moderator generally consisting of a tubular passage having a particular cross-sectional area and length. [0007] In known osmotic delivery systems, an osmotic tablet, such as salt, is placed inside the capsule and a membrane plug is placed in an open end of the capsule to provide a semipermeable barrier. The membrane plug seals the interior of the capsule from the exterior environment, permitting only certain liquid molecules from the environment to permeate through the membrane plug and into the interior of the capsule. The membrane plug is impermeable to items within the capsule including the osmotic agent and the beneficial agent. The rate at which the liquid permeates the membrane plug and enters the capsule varies depending upon the type of membrane material and the size and shape of the membrane plug. Further, the rate at which the liquid passes through the membrane plug controls the rate at which the osmotic agent expands to thereby drive the beneficial agent from the delivery system through the exit passage. Accordingly, the rate of delivery of the beneficial agent from the osmotic delivery system is controllable by varying the permeability coefficient of the membrane plug and/or the size of the membrane plug. [0008] Some known osmotic delivery systems use injection molded membrane plugs featuring protruding circumferential sealing ribs that fit into matching circumferential grooves on the inside of the capsule (U.S. Patent No. 6,113,938, which is incorporated herein by reference). The membrane plug is retained in the capsule by the sealing ribs, which usually requires the membrane to be inserted from the membrane end of the reservoir. Injection molded semipermeable membranes may be difficult to manufacture without internal stresses; thus performance may vary slightly from plug to plug. An additional drawback of known osmotic delivery systems is that the membrane plug itself is required to withstand the pressures created by the expansion of the osmotic engine. Other known osmotic delivery systems use membrane plugs with protruding circumferential sealing ribs but no matching circumferential grooves inside of the capsule. Still other known osmotic delivery systems use membrane plugs with no circumferential sealing ribs that fit into the capsule by friction fit. Still other known osmotic delivery systems use membrane plugs without any circumferential sealing ribs but with holes in the capsule into which the membrane plug can expand (WO 99/33446, which is incorporated herein by reference). Known delivery systems preclude the use of a capsule having a pre- installed retaining feature covering or partially covering the membrane plug end of the capsule for keeping the membrane plug sealed in position. Consequently, in these systems, if a retaining feature other than the capsule grooves and matching ribs of the membrane plug is to be used, it must be assembled to the main capsule body, after the membrane plug is inserted. This requirement tends to increase the cost and complexity of a high pressure osmotic delivery system. [0009] Accordingly, it is desirable to provide a delivery device that provides improved consistency and performance of the membrane material and also provides a feature for retaining the membrane material within the capsule under high pressure. SUMMARY OF THE INVENTION [00010] 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 positioned within the capsule for housing the beneficial agent. A membrane material is received in the fluid uptake end of the capsule and provides a fluid permeable barrier between an interior and an exterior of the capsule. A membrane material retaining means is positioned at the fluid uptake end of the capsule and includes at least one opening for allowing passage of fluid. The membrane material retaining means also prevents the membrane material from being ejected out of the fluid uptake end of the capsule. [00011] In another aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent in which the membrane material retaining means includes a retention flange positioned along a proximal end of the fluid uptake end of the capsule. [00012] In accordance with another aspect, the present invention pertains to a delivery system, in which the membrane material retaining means includes a screen, a grate, a perforated disk, a frit, or a sintered powdered metal structure including porous capillaries. If the membrane material retaining means includes porous capillaries, the capillaries can have diameters between about 0.5 and about 10 microns. The membrane material retaining means can be flat or have a rounded or contoured surface on at least one surface thereof. [00013] In a further aspect, the present invention pertains to a delivery system for controlled delivery of a beneficial agent in which the membrane material has a generally smooth, cylindrical or disc shape. [00014] In yet another aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent, in which the membrane material is extruded, cast, or calendered and then machined (i.e. die-cut, stamped, or otherwise cut into shape). [00015] In another aspect, the present invention pertains to a delivery system for controlled delivery of a beneficial agent, in which the capsule includes one or a plurality of inward protruding ridges and in which the inward protruding ridges securely grip an outer surface of the membrane material. Note that the word ridges as used herein can indicate one or more ridges. Additionally, the inwardly protruding ridge or plurality of inwardly protruding ridges are shaped to accommodate insertion of the membrane material from the beneficial agent delivery end of the capsule while inhibiting withdrawal of the membrane material from the beneficial agent delivery end of the capsule. [00016] In a further aspect, the present invention is directed to a delivery system for controlled delivery of a beneficial agent, in which an osmotic engine is positioned between the beneficial agent delivery end and the membrane material. [00017] In a further aspect, the present invention pertains to a delivery system for controlled delivery of a beneficial agent and includes a piston positioned between the beneficial delivery end and the osmotic engine for transmitting a pushing force created by the osmotic engine to the beneficial agent. [00018] According to a further aspect of the present invention, a method of forming a beneficial agent delivery device includes the steps of providing an implantable capsule having an open delivery end, an open fluid uptake end and a membrane material retaining means. A membrane material is inserted into the capsule from the open agent delivery end and positioned such that an end surface thereof is in contact with an inside surface of the membrane material retaining means. The osmotic agent is inserted into the capsule, followed by a movable dividing means or piston. The capsule is then filled with a beneficial agent, and the agent delivery end is closed while providing a controlled outlet for the beneficial agent to escape when sufficient pressure is applied to the beneficial agent. [00019] In a further aspect, the present invention pertains to 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 positioned adjacent the beneficial agent delivery end for housing the beneficial agent. A piston is positioned between the beneficial agent reservoir and the fluid uptake end. An osmotic engine is positioned between the piston and the fluid uptake end. The osmotic engine is expandable at a controlled rate and when expanding, applies a pushing force against the piston which applies a pushing force against the beneficial agent, such that, the beneficial agent is released through the beneficial agent delivery end at a predetermined rate. A membrane material is received in the fluid uptake end and provides a fluid permeable barrier between an interior and an exterior of the capsule. A membrane material retaining means is positioned at the fluid uptake end, with the membrane material retaining means including at least one opening for allowing passage of fluid. The membrane material retaining means also prevents the membrane material from being ejected out of the fluid uptake end of the capsule by osmotic pressure. [00020] The present invention provides the advantage of consistent and predictable delivery rate of a beneficial agent by allowing the use of extruded, cast, or calendered and then machined (i.e. die cut, stamped or otherwise cut to shape) membrane materials, whose consistency is more homogeneous when produced on a highly controlled machining or extrusion line as compared to the part-to-part consistency of injection molded membrane plugs. [00021] The present invention also provides the advantage of allowing the sealing of a cast, calendered, or extruded membrane material that has been machined (i.e. die cut stamped or otherwise cut to shape) in place in an implantable osmotic delivery device while reducing the expulsion of the membrane from the implantable device under high pressure conditions (greater than 1,000 psi), such as those encountered in the case of a blocked exit passage. [00022] In addition, the present invention allows for the membrane retaining means to be formed integrally with the implantable capsule or attached thereto during assembly of the delivery device. BRIEF DESCRIPTION OF THE DRAWINGS [00023] The invention will be described in greater detail with reference to the accompanying drawings in which like elements bear like reference numerals, and wherein: FIG. 1 is a cross-sectional side view of an osmotic drug delivery device including a capsule, a piston, an osmotic engine, a membrane, and an exit passage; FIG. 2 is a cross-sectional side view of a portion of an implantable capsule; FIG. 3 is a front view 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 along line 5-5 of the membrane plug of FIG. 4; FIG. 6 is a cross-sectional side view of a portion of an implantable capsule according to a second embodiment of the invention; FIG. 7 is a front view taken along line 7-7 of the implantable capsule of FIG. 6; FIG. 8 is a cross-sectional side view of a portion of an implantable capsule according to a third embodiment of the invention; FIG. 9 is a front view taken along line 9-9 of the implantable capsule of FIG. 8; and FIG. 10 is an enlarged view of the detail A of FIG. 1. FIG. 11 is a cross-sectional side view of a portion of an implantable capsule according to a fourth embodiment of the invention. FIG. 12 is a cross-sectional side view of a portion of an implantable capsule according to a fifth embodiment of the invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS [00024] The present invention relates to an osmotic delivery system 10 having a membrane material 30 for controlling a delivery rate of a beneficial agent from the osmotic delivery system. [00025] Definitions [00026] The term “active agent" or “beneficial agent" intends the active agent(s) optionally in combination with pharmaceutically acceptable carriers and optionally additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. [00027] The term “impermeable' intends that the material is sufficiently impermeable to environmental fluids as well as ingredients contained within the dispensing device such that the migration of such materials into or out of the device through the impermeable device is so low as to have substantially no adverse impact on the function of the device during the delivery period. [00028] The term "semipermeable" intends that the material is permeable to external fluids but substantially impermeable to other ingredients contained within the dispensing device and the environment of use. [00029] The term “membrane material" intends that the semipermeable membrane is in the form of a sheet or plug. The membrane material preferably has a diameter between about 0.040" and about 0.250” and preferably has a length or thickness between about 0.010” and about 0.350". The diameter and thickness of the membrane material are determined by such considerations as desired rate of delivery of the beneficial agent, desired duration of delivery of the beneficial agent, the device size, the material used for the semipermeable membrane, the retention means for the semipermeable membrane, the beneficial agent formulation, and/or the osmotic pressure generated during operation of the device. [00030] FIG. 1 shows that the osmotic delivery system 10 generally includes a first chamber 50 which contains a beneficial agent, a piston 54 and a second chamber 40 containing an osmotic agent, all of which are enclosed within -an elongated substantially cylindrical capsule 12. [00031] The capsule 12 must be sufficiently strong to ensure that it will not leak, crack, break or distort so as to expel its active agent contents under stresses it would be subjected to during use. In particular, it should be designed to withstand the maximum osmotic pressure that could be generated by the osmotic agent in chamber 40. Capsule 12 must also be chemically inert, biocompatible, and impermeable, that is, it must be non-reactive with the active agent formulation as well as the body and must isolate the beneficial agent during the delivery process. Suitable materials generally comprise a non- reactive polymer or a biocompatible metal or alloy. The polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer, and the like; halogenated polymers such as polytetrafluorethylene, polychoiortrifluoro- ethylene, copolymer tetrafluoroethylene and hexafluoropropytene; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; polyether ether ketone (PEEK); liquid crystal polymer (LCP); and the like. The water vapor transmission rate through compositions useful for forming the reservoir are reported in J. Pharm. Sci., Vol 29, pp. 1634-37 (1970); Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1963); Materials Engineering, Vol 5, pp. 38-45 (1972); Ann. Book of ASTM Stds., Vol 8.02, pp 208-211 and pp. 584-587 (1984); and Ind. and Eng. Chem., Vol 49, pp. 1933-1936 (1957). Metallic materials useful in the invention include stainless steel, titanium, platinum, tantalum, gold and their alloys as well as gold-plated ferrous alloys, platinum-plated ferrous alloys, cobalt-chromium alloys and titanium nitride coated stainless steel. A reservoir made from titanium or a titanium alloy having greater than 60%, often greater than 85% titanium is particularly preferred. [00032] The capsule 12 has a delivery end 70 with an exit passage 72 in it at the beneficial agent delivery end 70 and an opening 62 at the fluid uptake end of the capsule 12. The exit passage 72 may take any convenient form such as straight circular, spiral,etc. The exit passage 72 is made of an inert and biocompatible material selected from but not limited to metals including but not limited to titaniium, stainless steel, platinum and their alloys and cobalt-chromium alloys and the like, and polymers including but not limited to polyethylene, polypropylene, polycarbonate and polymethyl-methacrylate and the like. [00033] The fluid uptake end 60 of the capsule 12 is closed by the membrane material 30. In FIG. 2 the membrane material is in the form of a plug. Materials from which the membrane materials are made are those that are semipermeable and that can conform to the shape of the capsule 12 upon wetting and sealing to the rigid surface of the capsule. The semipermeable membrane material expands as it hydrates when placed in a fluid environment so that a seal is generated between the mating surfaces of the membrane material and the capsule. The diameter of the membrane material is such that it will sealingly fit inside the reservoir prior to hydration as a result of sealing contact at one or more circumferential or axial zones and will expand in place upon wetting to form an even tighter seal with the capsule. The membrane material must be able to imbibe between about 0.1% and 200% by weight of water. The polymeric materials from which the semipermeable membrane material may be made vary based on the pumping rates and the device configuration requirements and include but are not limited to plasticized ceflulosic materials, enhanced polymethylmethacrylate such as hydroxyethylmethacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, polyether- polyamide copolymers, thermoplastic copolyesters and the like. [00034] The membrane material 30 closes the fluid uptake end 60 from the second chamber 40 containing the osmotic agent. [00035] The osmotic agent or osmotic engine may include, for example, a non-volatile water soluble osmoagent, an osmopolymer which swells on contact with water, or a mixture of the two. Osmotic agents, such as NaCI with appropriate tabletting agents (lubricants and binders) and viscosity modifying agents, such as sodium carboxymethylcellulose or sodium polyacrylate are preferred water-swellable agents. Other osmotic agents useful as the water- swellable agent include osmopolymers and osmoagents and are described, for example, in U.S. Pat. No. 5.413,572, which is incorporated by reference herein. The water-swellable agent formulation can be a slurry, a tablet, a molded or extruded material or other form known in the art. A liquid or gel additive or filler may be added to chamber 40 to exclude air from spaces around the osmotic engine. [00036] Fluid passes through the membrane material 30 from an exterior of the capsule 12 and into the second chamber 40, while the membrane material 30 prevents the compositions within the capsule from passing out of the capsule. [00037] As 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 interior diameter of the capsule 12 in a sealing manner and to slide along a longitudinal axis inside the capsule. The piston 54 provides an impermeable barrier between the beneficial agent contained in the first chamber 50 and the osmotic agent contained in the second chamber 40. The materials from which the piston are made are preferably elastomeric materials that are impermeable and include but are not limited to polypropylene, rubbers such as EPDM, silicone rubber, butyl rubber, and the like, perfluoro-elastomers such as Kalrez® and Chemrez®, fluorocarbons such as Viton®, and thermoplastic elastomers such as plasticized polyvinylchloride, polyurethanes, Santoprene®, C-Flex® TPE, a styrene- ethylene-butylene-styrene copolymer (Consolidated Polymer Technologies Inc.), and the like. [00038] As seen in FIGS. 2 and 3, the capsule 12 includes a smooth, generally cylindrical shape having a hollow interior. The capsule 12 is provided with a membrane retaining means having a retention flange 20 positioned along an outer periphery of the fluid uptake end 60 and includes an opening 62 to allow for the passage of fluid into the capsule. The membrane retaining flange 20 can have a flat rounded, or contoured surface on the exterior side. The retention flange 20 of the membrane retaining means should be long enough to retain the membrane material under full osmotic pressure, yet the opening 62 needs to maximize the exposed surface of the membrane material. The capsule 12 also includes one or a plurality of inwardly protruding annular ribs or ridges 14 which provide fluid sealing between the interior surface of the capsule 12 and the outer 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 30 from moving in a lateral direction towards the beneficial agent delivery end 70. In this respect, the diameter of the membrane material 30 is substantially equal to the inner diameter of the capsule 12. Moreover, 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 between about 1 to 8 ribs or ridges, but is preferably provided with about 1 to 4 ribs or ridges. Any reference to the word ribs is intended to include a single rib as well as a plurality of ribs. Any reference to the word ridge or ridges is intended to be a reference to the word rib or ribs, and vice versa. [00039] Although FIG. 2 depicts the retention flange 20 as being formed integrally with the capsule 12, it will be understood that the retention flange may alternatively be a separate member attached to the capsule. For example, the membrane retaining means flange 20 may be welded, pressed, screwed or the like to the end of the capsule 12. [00040] The opening 62 is sufficiently small that the membrane material 30 cannot distort and pass through the opening under high operating pressures, such as about 5000 psi. [00041] The membrane material 30, as seen in FIGS. 4 and 5 includes a substantially smooth cylindrical body. As seen in FIGS. 4 and 5, the membrane material 30 is devoid of any protrusions, ribs, or abscesses. Thus, the membrane material 30 is simpler to manufacture than known membrane plugs. The membrane material 30 may be produced by casting, calendering, or extrusion, then machining (i.e. die-cutting, stamping or otherwise cutting to shape), thereby yielding a membrane of superior consistency compared with injection molded membrane materials of known systems. The membrane material 30 may be made of any suitable biocompatible membrane material. [00042] As seen in FIG. 10, the inwardly protruding ridges 14 include a sloped wall 16 and a vertical wall 18. The ridges 14 extend a distance from the inner wall 22 of the capsule 12, about the entire circumference of the inner wall. The height h of vertical wall 18 preferably is about 0.002" to about 0.020'. In addition, the sloped wall 16 is provided at an angle a from the inner wall 22. The angle of the sloped wall 16 can be chosen to be any suitable angle that allows for the membrane material 30 to be easily inserted over the ridges 14. The vertical wall 18 of the ridges 14 prevents the membrane material 30 from moving laterally towards the beneficial agent delivery end. In use the ridges 14 and the membrane retaining means flange 20 act together to restrict any lateral movement of the membrane material 30. [00043] Although FIG. 10 does not show any clearance between the membrane material 30 and the ridges 14, it is within the scope of the present invention that gaps may exist there between and between the inner wall 22 of the capsule 12 and the membrane material 30. [00044] FIGS. 6 and 7 show a portion of a second preferred embodiment of an osmotic delivery system 150. In this embodiment, the membrane material retaining means comprises a perforated disk 120. The perforated disk 120 includes a plurality of openings 122 which allow fluid to pass therethrough and subsequently through the membrane material 30 and into the interior of the capsule. As can also be seen in FIG. 6, the perforated disk 120 acts together with the ridges 114 to restrict the lateral movement of the membrane material 30 within the capsule 112. Thus, ridges 114 function in the same manner as the ridges 14 of the first embodiment. In this embodiment, the perforated disk 120 is affixed by welding, pressing, screwing or the tike, to the fluid uptake end of the capsule 112. [00045] FIGS. 8 and 9 illustrate a portion of a third preferred embodiment of an osmotic delivery device 250. In this embodiment, a screen or a grate 220 having a plurality of openings 222 is affixed 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 affixed to the fluid uptake end 60 (see Fig. 2) of the capsule 212. The screen or grate 220 may be affixed to the capsule 212 either before or after insertion of the membrane material 230. Although a screen or grate 220 has been illustrated, other structures that allow passage of water and prevent the membrane material 230 from being expelled may also be used. [00046] As also seen in FIG. 8, the capsule 212 is provided with a plurality of inward protruding, circumferentially extending, sealing ribs or ridges 214 having a smaller inner diameter than the inner diameter of the capsule 212. The ridges 214 include sloped walls 16 and vertical walls 18 (see Fig. 10). The sloped walls 16 allow for the easy insertion of the membrane material 230 into the capsule 212 while the vertical walls 18 prevent the transverse movement of the membrane material 30 in the direction of the beneficial agent delivery end 70 (see Fig. 1). [00047] FIG. 11 shows a portion of a fourth preferred embodiment of an osmotic delivery system 350. In this embodiment, the fluid uptake end 160 comprises the membrane material retaining means 120 and a frit or sintered powdered metal structure 320. The frit 320 includes a plurality of capillaries having diameters between about 0.5 and 10 microns which 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 of sufficient length to include at least one rib or ridge 314. As can also be seen in FIG. 11, the frit 320 acts together with the ridges 314 to restrict the lateral movement of the membrane material 30 within the capsule 112. Thus, ridges 314 function in the same manner as the ridges 14 of the first embodiment In this embodiment, the frit 320 is affixed, by welding, pressing, screwing or the like, to the membrane material retaining means 120 of the capsule 112. [00048] FIG. 12 shows a portion of a fifth preferred embodiment of an osmotic delivery system 350. The embodiment is similar to the embodiment shown in FIG. 11 except that the membrane material 30 is located between the first rib or ridge 314 and the membrane material retaining means 120. Movement of the membrane material 30 is restricted within the capsule 112 by both the ridge 114 and the membrane material retaining means 120. [00049] The membrane material can be prepared by casting, calendering, or extrusion. Casting comprises pouring the membrane material onto a flat surface. Calendering comprises forming a sheet of membrane material by pressing or rolling. Extrusion comprises pushing the membrane material through a die form to form a rod shape. Once the sheet or rod is prepared the plug or disc shape is prepared by cutting or machining the sheet or rod. The cutting or machining can be accomplished for example by die-cutting or stamping the shape. [00050] The devices of the invention are useful to deliver a wide variety of active 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, somatotropin analogues, somatomedin-C, Gonadotropic releasing hormone, follicle stimulating hormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide, nafarelin and goserelin, LHRH agonists and antoagonists, growth hormone releasing factor, calcitonin, colchicine, gonadotropins such a chorionic gonadotropin, oxytocin, octreotide, somatotropin plus an amino acid, vasopressin, adrenocorticotriphic hormone, epidermal growth factor, prolactin, somatostatin, somatotropin plus a protein, cosyntropin, typressin, polypeptides such as thyrotropin releasing hormone, thyroid stimulation hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine agents secreted internally and distributed by way of the bloodstream, and the like. Further agents that may be delivered include a1 antitrypsin, factor VIII, factor IX and other coagulation factors, insulin and other peptide hormones, adrenal cortical stimulating hormone, thyroid stimulating hormone and other pituitary hormones, interferon (for example, alpha, beta, gamma, and omega), erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, pancreatic enzymes, lactase, cytokines, interieukin-1 receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor suppresser proteins, cytotoxic proteins, and recombinant antibodies and antibody fragments, and the like. [00051] The above agents are useful for the treatment of a variety of conditions including but not limited to hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary diseases such as cerbrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves disease, systemic lupus erythematosus and theumatoid arthritis, shock and wasting disorder, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, gastrointestinal and other cancers. [00052] The active or beneficial agents may be anhydrous or aqueous solutions, suspensions or complexes with pharmaceutically acceptable vehicles or carriers such that a flowable formulation is produced that may be stored for long periods on the shelf or under refrigeration, as well as stored in an implanted delivery system. The formulations may include pharmaceutically acceptable carriers and additional inert ingredients. The active agents may be in various forms, such as uncharged molecules, components of molecular complexes or pharmacologically acceptable salts. Also, simple derivatives of the agents (such as prodrugs, ethers, esters, amides, etc.) which are easily hydrolyzed by body pH, enzymes, etc. can be employed. [00053] It is to be understood that more than one active agent may be incorporated into the active agent formulation in a device of this invention and that the use of the term "agent" in no way excludes the use of two or more such agents. The dispensing devices of the invention find use, for example, in humans or other animals. The environment of use is a fluid environment and can comprise any subcutaneous position or body cavity, such as the peritoneum or uterus. Ultimate delivery may be systemic or targeted and may or may not be systemic delivery of the beneficial agent A single dispensing device or several dispensing devices can be administered to a subject during a therapeutic program. The devices are designed to remain implanted during a predetermined administration period. If the devices are not removed following the administration, they may be designed to withstand the maximum osmotic pressure of the water-swellable agent or they may be designed with a bypass to release the pressure generated within the device. [00054] The devices of the present invention are preferably rendered sterile prior to use, especially when such use is implantation. This may be accomplished by separately sterilizing each component, e.g., by gamma radiation, steam sterilization or sterile filtration, then aseptically assembling the final system. Alternatively, the devices may be assembled, then terminally sterilized using any appropriate method. [00055] The assembly of the osmotic delivery device will be described below with reference to the embodiment 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. [00056] According to a preferred embodiment, the capsule is assembled with the membrane retaining means flange 20 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, towards the direction of the fluid uptake end of the capsule until it abuts a membrane material retaining means 20. The membrane material 30 may be inserted by, for example, compressed gas. In addition, as seen in FIG. 1, after the membrane material 30 has been fully inserted, the osmotic engine or osmotic agent may then be inserted into chamber 40 from the beneficial agent delivery end 70. Once the osmotic engine has been inserted, the piston 54 may then be inserted into the capsule. After insertion of the piston 54, the beneficial agent can be inserted into the beneficial agent reservoir 50. Finally, the exit passageway or diffusion moderator is inserted into the beneficial agent delivery end 70. [00057] Alternatively, the membrane retaining means 20 can be attached to the capsule after one or more of the membrane material 30, osmotic engine 42, piston 54, or beneficial agent has been inserted into the capsule 12. [00058] If a screen, grate, or frit is present in opening 62, such screen, grate, or frit can be attached to capsule 12 before or after the membrane material 30 is placed in capsule 12. [00059] Once all of the components of the osmotic delivery system 10 have been assembled, the beneficial agent delivery end 70 can be closed in a known manner, such as providing a cap with a delivery passage 72. For example, the beneficial agent delivery end may be closed in the manner disclosed in commonly owned and assigned U.S. Patent No. 5,728,396, issued to Peery et al., which is incorporated herein by reference. [00060] Thus, the present invention provides a more consistent and predictable delivery rate of a beneficial agent by allowing for the use of cast, calendered or extruded membrane materials that are machined (i.e. die-cut, stamped or otherwise cut to shape), in which the permeability of the membrane materials are more homogeneous because they are produced on a highly controlled extrusion or machining line as compared to the part-to-part homogeneity of injection molded plugs. [00061] According to other embodiments of the present invention, the delivery system may take different forms. For example, the piston may be replaced with a flexible member such as a diaphragm, partition, pad, flat sheet, spheroid, or rigid metal alloy, and may be made of any number of other materials. Furthermore, the osmotic device may function without the piston, having simply an interface between the osmotic agent/fluid additive and the beneficial agent or having the osmotic agent incorporated in the beneficial agent. In addition, the capsule of the present invention may be provided with a more rounded shape along its edges in order to make insertion of the capsule within the patient simpler. [00062] 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 scope and the spirit of the present invention as defined by the following claims. We Claim: 1. A delivery system for controlled delivery of a beneficial agent, said system comprising: an implantable capsule having a beneficial agent delivery end and a fluid uptake end; a beneficial agent reservoir positioned within the capsule for delivery of the beneficial agent at a predetermined delivery rate; a membrane material received in the fluid uptake end of the capsule and providing a fluid permeable barrier between an interior and an exterior of the capsule; one or a plurality of inwardly protruding ridges circumferentially arrayed near the fluid uptake end of the capsule to securingly grip the outer surface of the membrane material; and a membrane material retaining means positioned at the fluid uptake end of said capsule, said retaining means including at least one opening for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being ejected out of the fluid uptake end of the capsule. 2. 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 positioned adjacent said beneficial agent delivery end for housing the beneficial agent; a piston positioned between said beneficial agent reservoir and said fluid uptake end; an osmotic engine positioned between said piston and said fluid uptake end; a membrane material received in the fluid uptake end and providing a fluid permeable barrier between an interior and an exterior of the capsule; one or a plurality of inwardly protruding ridges circumferentially arrayed near the fluid uptake end of the capsule to securingly grip the outer surface of the membrane material; and a membrane material retaining means positioned at the fluid uptake end, said membrane material retaining means including at least one opening for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being ejected out of the fluid uptake end of the capsule; wherein said osmotic engine is expandable at a controlled rate and when expanded, applied a pushing force against said piston which applies a pushing force against said beneficial agent, such that said beneficial agent is released through said beneficial agent delivery end at a predetermined rate. The delivery system as claimed in claim 1 or 2, wherein said membrane material retaining means comprises a retention flange positioned along an outer periphery of said fluid uptake end. The delivery system as claimed in claim 3, wherein said membrane material retaining means comprises a retention flange. The delivery system as claimed in claim 4, wherein said retention flange and said capsule are formed integrally. The delivery system as claimed in claim 4, wherein said retention flange is a separate member attached to said capsule. The delivery system as claimed in claim 6 wherein the said flange is attached to the said capsule by welding. The delivery system as claimed in claim 6 wherein the said flange is attached to the said capsule by press fit. The delivery system as claimed in claim 6 wherein the said flange is attached to the said capsule by screw means. The delivery system as claimed in any one of claims 1 to 9, wherein said membrane material retaining means comprises a screen or a grate. The delivery system as claimed in any one of claims 1 or 9, wherein said membrane material retaining means comprises a perforated disc, frit or sintered powdered metal structure including porous capillaries. The delivery system as claimed in claim 11, wherein said membrane material retaining means comprises a frit. The delivery system as claimed in claim 11, wherein said membrane material retaining means comprises a perforated disc. The delivery system as claimed in claim 11, wherein said membrane material retaining means comprises a sintered powdered metal structure including porous capillaries. The delivery system as claimed in claim 14, wherein the diameter of said sintered powdered metal structure porous capillaries is between 0.5 and 10 µm. The delivery system as claimed in any one of claims 1 to 15, wherein the said retaining means can have a flat, rounded, or contoured surface on at least one surface. The delivery system as claimed in any one of claims 1 to 16, wherein said membrane material comprises a generally smooth, cylindrical shape. The delivery system as claimed in any of claims 1 to 17, wherein said membrane material has a diameter between 1,016 mm and 6,35 mm (0.040 inches 0.250 inches). The delivery system as claimed in any one of claims 1 to 18, wherein said membrane material has a length or thickness between 0.254 mm and 8.89 mm (0.010 inches and 0.350 inches). The delivery system as claimed in any one of claims 1 to 19, wherein the membrane material is extruded, cast or calendared. The delivery system as claimed in any one of claims 1 to 20, wherein the membrane material is machined, optionally followed extrusion, casting or calendaring. The delivery system as claimed in any one of claims 1 to 21, wherein the membrane material is die-cut. The delivery system as claimed in any one of claims 1 to 22, wherein the plurality of inward-protruding ridges are shaped to accommodate insertion of the membrane material, while preventing withdrawal of the membrane material from said capsule. The delivery system as claimed in any one of claims 1 to 23, further comprising an osmotic engine positioned between said beneficial agent delivery end and said membrane material. The delivery system as claimed in claim 24, further comprising a piston positioned between said beneficial agent delivery end and said osmotic engine for transmitting a pushing force created by said osmotic engine to said beneficial agent. 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 with a membrane material retaining means; inserting a membrane material into said capsule from the open agent delivery end; positioning the membrane material such that an end surface thereof is in contact with an inside surface of the membrane material retaining means; filing a chamber of the capsule with a beneficial agent; and closing the agent delivery end while providing a controlled outlet for said beneficial agent to escape when sufficient pressure is applied to said beneficial agent. The method as claimed in claim 26, wherein the membrane material is formed by extrusion. The method as claimed in claim 26, wherein the membrane material is machined. The method as claimed in claim 26, wherein the membrane material is die-cut. The method as claimed in any one of claims 27 to 29, wherein said membrane material comprises a smooth, cylindrical shape. The method as claimed in any one of claims 27 to 30, wherein said capsule comprises a plurality of inward-protruding ridges, and wherein the step of positioning the membrane material such that an end surface thereof is in contact with an inside surface of the membrane material retaining means includes the step of positioning said membrane material over said plurality of inward- protruding ridges such that said plurality of inward-protruding ridges hold said membrane material securely within said capsule. 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 inward-protruding ridge (s) near the fluid uptake end and a membrane material retaining means at the fluid uptake end; inserting a membrane material into said capsule from the open agent delivery end such that an end surface thereof is in contact with an inside surface of the membrane material retaining means, positioned said membrane material over said inward-protruding ridge(s) such that said inward-protruding ridge(s) hold said membrane material securely within said capsule; positioning the membrane material such that an end surface thereof is in contact with an inside surface of the membrane material retaining means; filing a chamber of the capsule with a beneficial agent; and closing the agent delivery end while providing a controlled outlet for said beneficial agent to escape when sufficient pressure is applied to said beneficial agent. 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 with a membrane material retaining means and one or more inward-protruding ridge (s) near the fluid uptake end; inserting a membrane material into said capsule from the open agent delivery end; positioning the membrane material such that an end surface thereof is in contact with an inside surface of the membrane material retaining means, positioning said membrane material over said inward-protruding ridge (s) such that said inward-protruding ridge (s) hold said membrane material securely within said capsule; inserting an osmotic engine into the capsule; inserting a piston into the capsule; filling a chamber of the capsule with a beneficial agent; and closing the agent delivery end while providing a controlled outlet for said beneficial agent to escape when sufficient pressure is applied to said beneficial agent. 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 inward-protruding ridge (s); inserting one or more of the following: (a) a membrane material into said capsule from the open agent delivery end such that an end surface of said membrane will be in contact with a surface of a membrane material retaining means, positioning said membrane material over said inward protruding ridge (s) such that said inward-protruding ridge (s) hold said membrane material securely within said capsule; (b)an osmotic engine into the capsule; (c) a piston into the capsule; or (d) filling a chamber of the capsule with a beneficial agent; attaching a membrane retention means; inserting any of (a), (b), (c) or (d) that were not inserted prior to attaching the membrane retention means; and closing the agent delivery end while providing a controlled outlet for said beneficial agent to escape when sufficient pressure in applied to said beneficial agent. A delivery system for controlled delivery of a beneficial agent, said system comprising: an implantable capsule having a beneficial agent delivery end and a fluid uptake end; a beneficial agent reservoir positioned within the capsule for delivery of the beneficial agent at a predetermined delivery rate; a membrane material received in the fluid uptake end of the capsule and providing a fluid permeable barrier between an interior and an exterior of the capsule; one or a plurality of inwardly protruding ridges circumferentially arrayed near the fluid uptake end of the capsule to securingly grip the outer surface of the membrane material; and a membrane material retaining means positioned at the fluid uptake end of said capsule, said retaining means including at least one opening for allowing passage of fluid, the membrane material retaining means preventing the membrane material from being ejected out of the fluid uptake end of the capsule.

Full Text

OSMOTIC IMPLANT WITH MEMBRANE AND MEMBRANE RETENTION MEANS
[0001] This application claims the priority of U.S. Application Serial No.
60/300,575 filed June 22, 2001, which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to osmotically controlled implantable
delivery devices, and more particularly to a delivery system having a membrane
material that controls the delivery rate of a beneficial agent from the delivery
system, in which the membrane material is cast, calendered or extruded then
machined (i.e. stamped, die cut or otherwise cut to shape), and the membrane
material is maintained within the delivery device by a retaining means.
Description of the Related Art
[0003] 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
called an administration period. In general, osmotic delivery systems operate by
imbibing fluid from an outside environment and releasing corresponding amounts
of beneficial agent from the delivery system.
[0004] 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; 5,234,692; 5,234,693; 5,308.348; 5.413,572;
5,540,665; 5,728,396; and 5,985,305, all of which are incorporated herein by
reference. All of the above-cited patents generally include some type of capsule
having at least a portion of a wall that selectively passes water into the interior of
the capsule containing a water-attracting agent (also called an osmotic agent, an
osmopolymer or osmoagent). The absorption of water by the water-attracting
agent within the capsule reservoir creates an osmotic pressure within the capsule
which causes a beneficial agent within the capsule to be delivered. The water
attracting agent may be the beneficial agent being delivered to the patient.
However, in most cases, a separate agent is used specifically for its ability to
draw water into the capsule.
[0005] When a separate osmotic agent is used, the osmotic agent may be
separated from the beneficial agent within the capsule by a movable dividing
member such as a piston. The structure of the capsule is generally rigid such
that as the osmotic agent takes in water and expands, the capsule does not
expand. As the osmotic agent expands, the agent causes the movable dividing
member to move, discharging the beneficial agent through an orifice or exit
passage of the capsule. The beneficial agent is discharged through the exit
passage at the same volumetric rate that water enters the osmotic agent through
the semipermeable wall portion of the capsule.
[0006] The rate at which the beneficial agent is discharged from the delivery
device is determined by many factors, including the type of water-attracting agent
or osmotic agent, the permeabiity of the semipermeabie membrane wall, and the
size and shape of the exit passage. One manner in which the back diffusion of
environmental fluid into the beneficial agent reservoir is controlled is by a flow
moderator in the exit passage of the capsule, with the flow moderator generally
consisting of a tubular passage having a particular cross-sectional area and
length.
[0007] In known osmotic delivery systems, an osmotic tablet, such as salt, is
placed inside the capsule and a membrane plug is placed in an open end of the
capsule to provide a semipermeable barrier. The membrane plug seals the
interior of the capsule from the exterior environment, permitting only certain liquid
molecules from the environment to permeate through the membrane plug and
into the interior of the capsule. The membrane plug is impermeable to items
within the capsule including the osmotic agent and the beneficial agent. The rate
at which the liquid permeates the membrane plug and enters the capsule varies
depending upon the type of membrane material and the size and shape of the
membrane plug. Further, the rate at which the liquid passes through the
membrane plug controls the rate at which the osmotic agent expands to thereby
drive the beneficial agent from the delivery system through the exit passage.
Accordingly, the rate of delivery of the beneficial agent from the osmotic delivery
system is controllable by varying the permeability coefficient of the membrane
plug and/or the size of the membrane plug.
[0008] Some known osmotic delivery systems use injection molded
membrane plugs featuring protruding circumferential sealing ribs that fit into
matching circumferential grooves on the inside of the capsule (U.S. Patent No.
6,113,938, which is incorporated herein by reference). The membrane plug is
retained in the capsule by the sealing ribs, which usually requires the membrane
to be inserted from the membrane end of the reservoir. Injection molded
semipermeable membranes may be difficult to manufacture without internal
stresses; thus performance may vary slightly from plug to plug. An additional
drawback of known osmotic delivery systems is that the membrane plug itself is
required to withstand the pressures created by the expansion of the osmotic
engine. Other known osmotic delivery systems use membrane plugs with
protruding circumferential sealing ribs but no matching circumferential grooves
inside of the capsule. Still other known osmotic delivery systems use membrane
plugs with no circumferential sealing ribs that fit into the capsule by friction fit.
Still other known osmotic delivery systems use membrane plugs without any
circumferential sealing ribs but with holes in the capsule into which the
membrane plug can expand (WO 99/33446, which is incorporated herein by
reference). Known delivery systems preclude the use of a capsule having a pre-
installed retaining feature covering or partially covering the membrane plug end
of the capsule for keeping the membrane plug sealed in position. Consequently,
in these systems, if a retaining feature other than the capsule grooves and
matching ribs of the membrane plug is to be used, it must be assembled to the
main capsule body, after the membrane plug is inserted. This requirement tends
to increase the cost and complexity of a high pressure osmotic delivery system.
[0009] Accordingly, it is desirable to provide a delivery device that provides
improved consistency and performance of the membrane material and also
provides a feature for retaining the membrane material within the capsule under
high pressure.
SUMMARY OF THE INVENTION
[00010] 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 positioned within the capsule for housing the beneficial
agent. A membrane material is received in the fluid uptake end of the capsule
and provides a fluid permeable barrier between an interior and an exterior of the
capsule. A membrane material retaining means is positioned at the fluid uptake
end of the capsule and includes at least one opening for allowing passage of
fluid. The membrane material retaining means also prevents the membrane
material from being ejected out of the fluid uptake end of the capsule.
[00011] In another aspect, the present invention is directed to a delivery
system for controlled delivery of a beneficial agent in which the membrane
material retaining means includes a retention flange positioned along a proximal
end of the fluid uptake end of the capsule.
[00012] In accordance with another aspect, the present invention pertains
to a delivery system, in which the membrane material retaining means includes a
screen, a grate, a perforated disk, a frit, or a sintered powdered metal structure
including porous capillaries. If the membrane material retaining means includes
porous capillaries, the capillaries can have diameters between about 0.5 and
about 10 microns. The membrane material retaining means can be flat or have a
rounded or contoured surface on at least one surface thereof.
[00013] In a further aspect, the present invention pertains to a delivery
system for controlled delivery of a beneficial agent in which the membrane
material has a generally smooth, cylindrical or disc shape.
[00014] In yet another aspect, the present invention is directed to a delivery
system for controlled delivery of a beneficial agent, in which the membrane
material is extruded, cast, or calendered and then machined (i.e. die-cut,
stamped, or otherwise cut into shape).
[00015] In another aspect, the present invention pertains to a delivery
system for controlled delivery of a beneficial agent, in which the capsule includes
one or a plurality of inward protruding ridges and in which the inward protruding
ridges securely grip an outer surface of the membrane material. Note that the
word ridges as used herein can indicate one or more ridges. Additionally, the
inwardly protruding ridge or plurality of inwardly protruding ridges are shaped to
accommodate insertion of the membrane material from the beneficial agent
delivery end of the capsule while inhibiting withdrawal of the membrane material
from the beneficial agent delivery end of the capsule.
[00016] In a further aspect, the present invention is directed to a delivery
system for controlled delivery of a beneficial agent, in which an osmotic engine is
positioned between the beneficial agent delivery end and the membrane
material.
[00017] In a further aspect, the present invention pertains to a delivery
system for controlled delivery of a beneficial agent and includes a piston
positioned between the beneficial delivery end and the osmotic engine for
transmitting a pushing force created by the osmotic engine to the beneficial
agent.
[00018] According to a further aspect of the present invention, a method of
forming a beneficial agent delivery device includes the steps of providing an
implantable capsule having an open delivery end, an open fluid uptake end and a
membrane material retaining means. A membrane material is inserted into the
capsule from the open agent delivery end and positioned such that an end
surface thereof is in contact with an inside surface of the membrane material
retaining means. The osmotic agent is inserted into the capsule, followed by a
movable dividing means or piston. The capsule is then filled with a beneficial
agent, and the agent delivery end is closed while providing a controlled outlet for
the beneficial agent to escape when sufficient pressure is applied to the
beneficial agent.
[00019] In a further aspect, the present invention pertains to 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 positioned adjacent the beneficial
agent delivery end for housing the beneficial agent. A piston is positioned
between the beneficial agent reservoir and the fluid uptake end. An osmotic
engine is positioned between the piston and the fluid uptake end. The osmotic
engine is expandable at a controlled rate and when expanding, applies a pushing
force against the piston which applies a pushing force against the beneficial
agent, such that, the beneficial agent is released through the beneficial agent
delivery end at a predetermined rate. A membrane material is received in the
fluid uptake end and provides a fluid permeable barrier between an interior and
an exterior of the capsule. A membrane material retaining means is positioned at
the fluid uptake end, with the membrane material retaining means including at
least one opening for allowing passage of fluid. The membrane material
retaining means also prevents the membrane material from being ejected out of
the fluid uptake end of the capsule by osmotic pressure.
[00020] The present invention provides the advantage of consistent and
predictable delivery rate of a beneficial agent by allowing the use of extruded,
cast, or calendered and then machined (i.e. die cut, stamped or otherwise cut to
shape) membrane materials, whose consistency is more homogeneous when
produced on a highly controlled machining or extrusion line as compared to the
part-to-part consistency of injection molded membrane plugs.
[00021] The present invention also provides the advantage of allowing the
sealing of a cast, calendered, or extruded membrane material that has been
machined (i.e. die cut stamped or otherwise cut to shape) in place in an
implantable osmotic delivery device while reducing the expulsion of the
membrane from the implantable device under high pressure conditions (greater
than 1,000 psi), such as those encountered in the case of a blocked exit
passage.
[00022] In addition, the present invention allows for the membrane retaining
means to be formed integrally with the implantable capsule or attached thereto
during assembly of the delivery device.
BRIEF DESCRIPTION OF THE DRAWINGS
[00023] The invention will be described in greater detail with reference to
the accompanying drawings in which like elements bear like reference numerals,
and wherein:
FIG. 1 is a cross-sectional side view of an osmotic drug delivery device including
a capsule, a piston, an osmotic engine, a membrane, and an exit passage;
FIG. 2 is a cross-sectional side view of a portion of an implantable capsule;
FIG. 3 is a front view 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 along line 5-5 of the membrane plug of FIG. 4;
FIG. 6 is a cross-sectional side view of a portion of an implantable capsule
according to a second embodiment of the invention;
FIG. 7 is a front view taken along line 7-7 of the implantable capsule of FIG. 6;
FIG. 8 is a cross-sectional side view of a portion of an implantable capsule
according to a third embodiment of the invention;
FIG. 9 is a front view taken along line 9-9 of the implantable capsule of FIG. 8;
and
FIG. 10 is an enlarged view of the detail A of FIG. 1.
FIG. 11 is a cross-sectional side view of a portion of an implantable capsule
according to a fourth embodiment of the invention.
FIG. 12 is a cross-sectional side view of a portion of an implantable capsule
according to a fifth embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[00024] The present invention relates to an osmotic delivery system 10
having a membrane material 30 for controlling a delivery rate of a beneficial
agent from the osmotic delivery system.
[00025] Definitions
[00026] The term “active agent" or “beneficial agent" intends the active
agent(s) optionally in combination with pharmaceutically acceptable carriers and
optionally additional ingredients such as antioxidants, stabilizing agents,
permeation enhancers, etc.
[00027] The term “impermeable' intends that the material is sufficiently
impermeable to environmental fluids as well as ingredients contained within the
dispensing device such that the migration of such materials into or out of the
device through the impermeable device is so low as to have substantially no
adverse impact on the function of the device during the delivery period.
[00028] The term "semipermeable" intends that the material is permeable to
external fluids but substantially impermeable to other ingredients contained within
the dispensing device and the environment of use.
[00029] The term “membrane material" intends that the semipermeable
membrane is in the form of a sheet or plug. The membrane material preferably
has a diameter between about 0.040" and about 0.250” and preferably has a
length or thickness between about 0.010” and about 0.350". The diameter and
thickness of the membrane material are determined by such considerations as
desired rate of delivery of the beneficial agent, desired duration of delivery of the
beneficial agent, the device size, the material used for the semipermeable
membrane, the retention means for the semipermeable membrane, the beneficial
agent formulation, and/or the osmotic pressure generated during operation of the
device.
[00030] FIG. 1 shows that the osmotic delivery system 10 generally
includes a first chamber 50 which contains a beneficial agent, a piston 54 and a
second chamber 40 containing an osmotic agent, all of which are enclosed within
-an elongated substantially cylindrical capsule 12.
[00031] The capsule 12 must be sufficiently strong to ensure that it will not
leak, crack, break or distort so as to expel its active agent contents under
stresses it would be subjected to during use. In particular, it should be designed
to withstand the maximum osmotic pressure that could be generated by the
osmotic agent in chamber 40. Capsule 12 must also be chemically inert,
biocompatible, and impermeable, that is, it must be non-reactive with the active
agent formulation as well as the body and must isolate the beneficial agent
during the delivery process. Suitable materials generally comprise a non-
reactive polymer or a biocompatible metal or alloy. The polymers include
acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer, and the
like; halogenated polymers such as polytetrafluorethylene, polychoiortrifluoro-
ethylene, copolymer tetrafluoroethylene and hexafluoropropytene; polyimide;
polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic
copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; polyether
ether ketone (PEEK); liquid crystal polymer (LCP); and the like. The water vapor
transmission rate through compositions useful for forming the reservoir are
reported in J. Pharm. Sci., Vol 29, pp. 1634-37 (1970); Ind. Eng. Chem., Vol. 45,
pp. 2296-2306 (1963); Materials Engineering, Vol 5, pp. 38-45 (1972); Ann. Book
of ASTM Stds., Vol 8.02, pp 208-211 and pp. 584-587 (1984); and Ind. and Eng.
Chem., Vol 49, pp. 1933-1936 (1957). Metallic materials useful in the invention
include stainless steel, titanium, platinum, tantalum, gold and their alloys as well
as gold-plated ferrous alloys, platinum-plated ferrous alloys, cobalt-chromium
alloys and titanium nitride coated stainless steel. A reservoir made from titanium
or a titanium alloy having greater than 60%, often greater than 85% titanium is
particularly preferred.
[00032] The capsule 12 has a delivery end 70 with an exit passage 72 in it
at the beneficial agent delivery end 70 and an opening 62 at the fluid uptake end
of the capsule 12. The exit passage 72 may take any convenient form such as
straight circular, spiral,etc. The exit passage 72 is made of an inert and
biocompatible material selected from but not limited to metals including but not
limited to titaniium, stainless steel, platinum and their alloys and cobalt-chromium
alloys and the like, and polymers including but not limited to polyethylene,
polypropylene, polycarbonate and polymethyl-methacrylate and the like.
[00033] The fluid uptake end 60 of the capsule 12 is closed by the
membrane material 30. In FIG. 2 the membrane material is in the form of a plug.
Materials from which the membrane materials are made are those that are
semipermeable and that can conform to the shape of the capsule 12 upon
wetting and sealing to the rigid surface of the capsule. The semipermeable
membrane material expands as it hydrates when placed in a fluid environment so
that a seal is generated between the mating surfaces of the membrane material
and the capsule. The diameter of the membrane material is such that it will
sealingly fit inside the reservoir prior to hydration as a result of sealing contact at
one or more circumferential or axial zones and will expand in place upon wetting
to form an even tighter seal with the capsule. The membrane material must be
able to imbibe between about 0.1% and 200% by weight of water. The polymeric
materials from which the semipermeable membrane material may be made vary
based on the pumping rates and the device configuration requirements and
include but are not limited to plasticized ceflulosic materials, enhanced
polymethylmethacrylate such as hydroxyethylmethacrylate (HEMA) and
elastomeric materials such as polyurethanes and polyamides, polyether-
polyamide copolymers, thermoplastic copolyesters and the like.
[00034] The membrane material 30 closes the fluid uptake end 60 from the
second chamber 40 containing the osmotic agent.
[00035] The osmotic agent or osmotic engine may include, for example, a
non-volatile water soluble osmoagent, an osmopolymer which swells on contact
with water, or a mixture of the two. Osmotic agents, such as NaCI with
appropriate tabletting agents (lubricants and binders) and viscosity modifying
agents, such as sodium carboxymethylcellulose or sodium polyacrylate are
preferred water-swellable agents. Other osmotic agents useful as the water-
swellable agent include osmopolymers and osmoagents and are described, for
example, in U.S. Pat. No. 5.413,572, which is incorporated by reference herein.
The water-swellable agent formulation can be a slurry, a tablet, a molded or
extruded material or other form known in the art. A liquid or gel additive or filler
may be added to chamber 40 to exclude air from spaces around the osmotic
engine.
[00036] Fluid passes through the membrane material 30 from an exterior of
the capsule 12 and into the second chamber 40, while the membrane material 30
prevents the compositions within the capsule from passing out of the capsule.
[00037] As 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 interior diameter of
the capsule 12 in a sealing manner and to slide along a longitudinal axis inside
the capsule. The piston 54 provides an impermeable barrier between the
beneficial agent contained in the first chamber 50 and the osmotic agent
contained in the second chamber 40. The materials from which the piston are
made are preferably elastomeric materials that are impermeable and include but
are not limited to polypropylene, rubbers such as EPDM, silicone rubber, butyl
rubber, and the like, perfluoro-elastomers such as Kalrez® and Chemrez®,
fluorocarbons such as Viton®, and thermoplastic elastomers such as plasticized
polyvinylchloride, polyurethanes, Santoprene®, C-Flex® TPE, a styrene-
ethylene-butylene-styrene copolymer (Consolidated Polymer Technologies Inc.),
and the like.
[00038] As seen in FIGS. 2 and 3, the capsule 12 includes a smooth,
generally cylindrical shape having a hollow interior. The capsule 12 is provided
with a membrane retaining means having a retention flange 20 positioned along
an outer periphery of the fluid uptake end 60 and includes an opening 62 to allow
for the passage of fluid into the capsule. The membrane retaining flange 20 can
have a flat rounded, or contoured surface on the exterior side. The retention
flange 20 of the membrane retaining means should be long enough to retain the
membrane material under full osmotic pressure, yet the opening 62 needs to
maximize the exposed surface of the membrane material. The capsule 12 also
includes one or a plurality of inwardly protruding annular ribs or ridges 14 which
provide fluid sealing between the interior surface of the capsule 12 and the outer
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 30 from moving in a lateral direction towards the beneficial agent
delivery end 70. In this respect, the diameter of the membrane material 30 is
substantially equal to the inner diameter of the capsule 12. Moreover, 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 between about 1 to 8 ribs or
ridges, but is preferably provided with about 1 to 4 ribs or ridges. Any reference
to the word ribs is intended to include a single rib as well as a plurality of ribs.
Any reference to the word ridge or ridges is intended to be a reference to the
word rib or ribs, and vice versa.
[00039] Although FIG. 2 depicts the retention flange 20 as being formed
integrally with the capsule 12, it will be understood that the retention flange may
alternatively be a separate member attached to the capsule. For example, the
membrane retaining means flange 20 may be welded, pressed, screwed or the
like to the end of the capsule 12.
[00040] The opening 62 is sufficiently small that the membrane material 30
cannot distort and pass through the opening under high operating pressures,
such as about 5000 psi.
[00041] The membrane material 30, as seen in FIGS. 4 and 5 includes a
substantially smooth cylindrical body. As seen in FIGS. 4 and 5, the membrane
material 30 is devoid of any protrusions, ribs, or abscesses. Thus, the
membrane material 30 is simpler to manufacture than known membrane plugs.
The membrane material 30 may be produced by casting, calendering, or
extrusion, then machining (i.e. die-cutting, stamping or otherwise cutting to
shape), thereby yielding a membrane of superior consistency compared with
injection molded membrane materials of known systems. The membrane
material 30 may be made of any suitable biocompatible membrane material.
[00042] As seen in FIG. 10, the inwardly protruding ridges 14 include a
sloped wall 16 and a vertical wall 18. The ridges 14 extend a distance from the
inner wall 22 of the capsule 12, about the entire circumference of the inner wall.
The height h of vertical wall 18 preferably is about 0.002" to about 0.020'. In
addition, the sloped wall 16 is provided at an angle a from the inner wall 22. The
angle of the sloped wall 16 can be chosen to be any suitable angle that allows for
the membrane material 30 to be easily inserted over the ridges 14. The vertical
wall 18 of the ridges 14 prevents the membrane material 30 from moving laterally
towards the beneficial agent delivery end. In use the ridges 14 and the
membrane retaining means flange 20 act together to restrict any lateral
movement of the membrane material 30.
[00043] Although FIG. 10 does not show any clearance between the
membrane material 30 and the ridges 14, it is within the scope of the present
invention that gaps may exist there between and between the inner wall 22 of the
capsule 12 and the membrane material 30.
[00044] FIGS. 6 and 7 show a portion of a second preferred embodiment of
an osmotic delivery system 150. In this embodiment, the membrane material
retaining means comprises a perforated disk 120. The perforated disk 120
includes a plurality of openings 122 which allow fluid to pass therethrough and
subsequently through the membrane material 30 and into the interior of the
capsule. As can also be seen in FIG. 6, the perforated disk 120 acts together
with the ridges 114 to restrict the lateral movement of the membrane material 30
within the capsule 112. Thus, ridges 114 function in the same manner as the
ridges 14 of the first embodiment. In this embodiment, the perforated disk 120 is
affixed by welding, pressing, screwing or the tike, to the fluid uptake end of the
capsule 112.
[00045] FIGS. 8 and 9 illustrate a portion of a third preferred embodiment of
an osmotic delivery device 250. In this embodiment, a screen or a grate 220
having a plurality of openings 222 is affixed 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 affixed to the fluid uptake end 60 (see
Fig. 2) of the capsule 212. The screen or grate 220 may be affixed to the
capsule 212 either before or after insertion of the membrane material 230.
Although a screen or grate 220 has been illustrated, other structures that allow
passage of water and prevent the membrane material 230 from being expelled
may also be used.
[00046] As also seen in FIG. 8, the capsule 212 is provided with a plurality
of inward protruding, circumferentially extending, sealing ribs or ridges 214
having a smaller inner diameter than the inner diameter of the capsule 212. The
ridges 214 include sloped walls 16 and vertical walls 18 (see Fig. 10). The
sloped walls 16 allow for the easy insertion of the membrane material 230 into
the capsule 212 while the vertical walls 18 prevent the transverse movement of
the membrane material 30 in the direction of the beneficial agent delivery end 70
(see Fig. 1).
[00047] FIG. 11 shows a portion of a fourth preferred embodiment of an
osmotic delivery system 350. In this embodiment, the fluid uptake end 160
comprises the membrane material retaining means 120 and a frit or sintered
powdered metal structure 320. The frit 320 includes a plurality of capillaries
having diameters between about 0.5 and 10 microns which 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 of sufficient
length to include at least one rib or ridge 314. As can also be seen in FIG. 11,
the frit 320 acts together with the ridges 314 to restrict the lateral movement of
the membrane material 30 within the capsule 112. Thus, ridges 314 function in
the same manner as the ridges 14 of the first embodiment In this embodiment,
the frit 320 is affixed, by welding, pressing, screwing or the like, to the membrane
material retaining means 120 of the capsule 112.
[00048] FIG. 12 shows a portion of a fifth preferred embodiment of an
osmotic delivery system 350. The embodiment is similar to the embodiment
shown in FIG. 11 except that the membrane material 30 is located between the
first rib or ridge 314 and the membrane material retaining means 120. Movement
of the membrane material 30 is restricted within the capsule 112 by both the
ridge 114 and the membrane material retaining means 120.
[00049] The membrane material can be prepared by casting, calendering,
or extrusion. Casting comprises pouring the membrane material onto a flat
surface. Calendering comprises forming a sheet of membrane material by
pressing or rolling. Extrusion comprises pushing the membrane material through
a die form to form a rod shape. Once the sheet or rod is prepared the plug or
disc shape is prepared by cutting or machining the sheet or rod. The cutting or
machining can be accomplished for example by die-cutting or stamping the
shape.
[00050] The devices of the invention are useful to deliver a wide variety of
active 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, somatotropin analogues, somatomedin-C,
Gonadotropic releasing hormone, follicle stimulating hormone, luteinizing
hormone, LHRH, LHRH analogues such as leuprolide, nafarelin and goserelin,
LHRH agonists and antoagonists, growth hormone releasing factor, calcitonin,
colchicine, gonadotropins such a chorionic gonadotropin, oxytocin, octreotide,
somatotropin plus an amino acid, vasopressin, adrenocorticotriphic hormone,
epidermal growth factor, prolactin, somatostatin, somatotropin plus a protein,
cosyntropin, typressin, polypeptides such as thyrotropin releasing hormone,
thyroid stimulation hormone, secretin, pancreozymin, enkephalin, glucagon,
endocrine agents secreted internally and distributed by way of the bloodstream,
and the like. Further agents that may be delivered include a1 antitrypsin, factor
VIII, factor IX and other coagulation factors, insulin and other peptide hormones,
adrenal cortical stimulating hormone, thyroid stimulating hormone and other
pituitary hormones, interferon (for example, alpha, beta, gamma, and omega),
erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor
1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist,
tumor necrosis factor, pancreatic enzymes, lactase, cytokines, interieukin-1
receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor
suppresser proteins, cytotoxic proteins, and recombinant antibodies and antibody
fragments, and the like.
[00051] The above agents are useful for the treatment of a variety of
conditions including but not limited to hemophilia and other blood disorders,
growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection,
hereditary diseases such as cerbrosidase deficiency and adenosine deaminase
deficiency, hypertension, septic shock, autoimmune diseases such as multiple
sclerosis, Graves disease, systemic lupus erythematosus and theumatoid
arthritis, shock and wasting disorder, cystic fibrosis, lactose intolerance, Crohn's
disease, inflammatory bowel disease, gastrointestinal and other cancers.
[00052] The active or beneficial agents may be anhydrous or aqueous
solutions, suspensions or complexes with pharmaceutically acceptable vehicles
or carriers such that a flowable formulation is produced that may be stored for
long periods on the shelf or under refrigeration, as well as stored in an implanted
delivery system. The formulations may include pharmaceutically acceptable
carriers and additional inert ingredients. The active agents may be in various
forms, such as uncharged molecules, components of molecular complexes or
pharmacologically acceptable salts. Also, simple derivatives of the agents (such
as prodrugs, ethers, esters, amides, etc.) which are easily hydrolyzed by body
pH, enzymes, etc. can be employed.
[00053] It is to be understood that more than one active agent may be
incorporated into the active agent formulation in a device of this invention and
that the use of the term "agent" in no way excludes the use of two or more such
agents. The dispensing devices of the invention find use, for example, in
humans or other animals. The environment of use is a fluid environment and can
comprise any subcutaneous position or body cavity, such as the peritoneum or
uterus. Ultimate delivery may be systemic or targeted and may or may not be
systemic delivery of the beneficial agent A single dispensing device or several
dispensing devices can be administered to a subject during a therapeutic
program. The devices are designed to remain implanted during a predetermined
administration period. If the devices are not removed following the
administration, they may be designed to withstand the maximum osmotic
pressure of the water-swellable agent or they may be designed with a bypass to
release the pressure generated within the device.
[00054] The devices of the present invention are preferably rendered sterile
prior to use, especially when such use is implantation. This may be
accomplished by separately sterilizing each component, e.g., by gamma
radiation, steam sterilization or sterile filtration, then aseptically assembling the
final system. Alternatively, the devices may be assembled, then terminally
sterilized using any appropriate method.
[00055] The assembly of the osmotic delivery device will be described
below with reference to the embodiment 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.
[00056] According to a preferred embodiment, the capsule is assembled
with the membrane retaining means flange 20 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, towards the direction of the fluid uptake end of the
capsule until it abuts a membrane material retaining means 20. The membrane
material 30 may be inserted by, for example, compressed gas. In addition, as
seen in FIG. 1, after the membrane material 30 has been fully inserted, the
osmotic engine or osmotic agent may then be inserted into chamber 40 from the
beneficial agent delivery end 70. Once the osmotic engine has been inserted,
the piston 54 may then be inserted into the capsule. After insertion of the piston
54, the beneficial agent can be inserted into the beneficial agent reservoir 50.
Finally, the exit passageway or diffusion moderator is inserted into the beneficial
agent delivery end 70.
[00057] Alternatively, the membrane retaining means 20 can be attached to
the capsule after one or more of the membrane material 30, osmotic engine 42,
piston 54, or beneficial agent has been inserted into the capsule 12.
[00058] If a screen, grate, or frit is present in opening 62, such screen,
grate, or frit can be attached to capsule 12 before or after the membrane material
30 is placed in capsule 12.
[00059] Once all of the components of the osmotic delivery system 10 have
been assembled, the beneficial agent delivery end 70 can be closed in a known
manner, such as providing a cap with a delivery passage 72. For example, the
beneficial agent delivery end may be closed in the manner disclosed in
commonly owned and assigned U.S. Patent No. 5,728,396, issued to Peery et
al., which is incorporated herein by reference.
[00060] Thus, the present invention provides a more consistent and
predictable delivery rate of a beneficial agent by allowing for the use of cast,
calendered or extruded membrane materials that are machined (i.e. die-cut,
stamped or otherwise cut to shape), in which the permeability of the membrane
materials are more homogeneous because they are produced on a highly
controlled extrusion or machining line as compared to the part-to-part
homogeneity of injection molded plugs.
[00061] According to other embodiments of the present invention, the
delivery system may take different forms. For example, the piston may be
replaced with a flexible member such as a diaphragm, partition, pad, flat sheet,
spheroid, or rigid metal alloy, and may be made of any number of other
materials. Furthermore, the osmotic device may function without the piston,
having simply an interface between the osmotic agent/fluid additive and the
beneficial agent or having the osmotic agent incorporated in the beneficial agent.
In addition, the capsule of the present invention may be provided with a more
rounded shape along its edges in order to make insertion of the capsule within
the patient simpler.
[00062] 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
scope and the spirit of the present invention as defined by the following claims.
We Claim:
1. A delivery system for controlled delivery of a beneficial agent,
said system comprising:
an implantable capsule having a beneficial agent delivery end and
a fluid uptake end;
a beneficial agent reservoir positioned within the capsule for
delivery of the beneficial agent at a predetermined delivery rate;
a membrane material received in the fluid uptake end of the
capsule and providing a fluid permeable barrier between an interior
and an exterior of the capsule;
one or a plurality of inwardly protruding ridges circumferentially
arrayed near the fluid uptake end of the capsule to securingly grip
the outer surface of the membrane material; and
a membrane material retaining means positioned at the fluid
uptake end of said capsule, said retaining means including at least
one opening for allowing passage of fluid, the membrane material
retaining means preventing the membrane material from being
ejected out of the fluid uptake end of the capsule.
2. 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 positioned adjacent said beneficial
agent delivery end for housing the beneficial agent;
a piston positioned between said beneficial agent reservoir and said
fluid uptake end;
an osmotic engine positioned between said piston and said fluid
uptake end;
a membrane material received in the fluid uptake end and
providing a fluid permeable barrier between an interior and an
exterior of the capsule;
one or a plurality of inwardly protruding ridges circumferentially
arrayed near the fluid uptake end of the capsule to securingly grip
the outer surface of the membrane material; and
a membrane material retaining means positioned at the fluid uptake
end, said membrane material retaining means including at least one
opening for allowing passage of fluid, the membrane material
retaining means preventing the membrane material from being
ejected out of the fluid uptake end of the capsule;
wherein said osmotic engine is expandable at a controlled rate and
when expanded, applied a pushing force against said piston which
applies a pushing force against said beneficial agent, such that said
beneficial agent is released through said beneficial agent delivery
end at a predetermined rate.
The delivery system as claimed in claim 1 or 2, wherein said
membrane material retaining means comprises a retention flange
positioned along an outer periphery of said fluid uptake end.
The delivery system as claimed in claim 3, wherein said membrane
material retaining means comprises a retention flange.
The delivery system as claimed in claim 4, wherein said retention
flange and said capsule are formed integrally.
The delivery system as claimed in claim 4, wherein said retention
flange is a separate member attached to said capsule.
The delivery system as claimed in claim 6 wherein the said flange
is attached to the said capsule by welding.
The delivery system as claimed in claim 6 wherein the said flange
is attached to the said capsule by press fit.
The delivery system as claimed in claim 6 wherein the said flange
is attached to the said capsule by screw means.
The delivery system as claimed in any one of claims 1 to 9,
wherein said membrane material retaining means comprises a
screen or a grate.
The delivery system as claimed in any one of claims 1 or 9,
wherein said membrane material retaining means comprises a
perforated disc, frit or sintered powdered metal structure including
porous capillaries.
The delivery system as claimed in claim 11, wherein said
membrane material retaining means comprises a frit.
The delivery system as claimed in claim 11, wherein said
membrane material retaining means comprises a perforated disc.
The delivery system as claimed in claim 11, wherein said
membrane material retaining means comprises a sintered powdered
metal structure including porous capillaries.
The delivery system as claimed in claim 14, wherein the diameter
of said sintered powdered metal structure porous capillaries is
between 0.5 and 10 µm.
The delivery system as claimed in any one of claims 1 to 15,
wherein the said retaining means can have a flat, rounded, or
contoured surface on at least one surface.
The delivery system as claimed in any one of claims 1 to 16,
wherein said membrane material comprises a generally smooth,
cylindrical shape.
The delivery system as claimed in any of claims 1 to 17, wherein
said membrane material has a diameter between 1,016 mm and
6,35 mm (0.040 inches 0.250 inches).
The delivery system as claimed in any one of claims 1 to 18,
wherein said membrane material has a length or thickness between
0.254 mm and 8.89 mm (0.010 inches and 0.350 inches).
The delivery system as claimed in any one of claims 1 to 19,
wherein the membrane material is extruded, cast or calendared.
The delivery system as claimed in any one of claims 1 to 20,
wherein the membrane material is machined, optionally followed
extrusion, casting or calendaring.
The delivery system as claimed in any one of claims 1 to 21,
wherein the membrane material is die-cut.
The delivery system as claimed in any one of claims 1 to 22,
wherein the plurality of inward-protruding ridges are shaped to
accommodate insertion of the membrane material, while
preventing withdrawal of the membrane material from said
capsule.
The delivery system as claimed in any one of claims 1 to 23,
further comprising an osmotic engine positioned between said
beneficial agent delivery end and said membrane material.
The delivery system as claimed in claim 24, further comprising a
piston positioned between said beneficial agent delivery end and
said osmotic engine for transmitting a pushing force created by
said osmotic engine to said beneficial agent.
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 with a membrane material retaining
means;
inserting a membrane material into said capsule from the open
agent delivery end;
positioning the membrane material such that an end surface thereof
is in contact with an inside surface of the membrane material
retaining means;
filing a chamber of the capsule with a beneficial agent; and
closing the agent delivery end while providing a controlled outlet
for said beneficial agent to escape when sufficient pressure is
applied to said beneficial agent.
The method as claimed in claim 26, wherein the membrane
material is formed by extrusion.
The method as claimed in claim 26, wherein the membrane
material is machined.
The method as claimed in claim 26, wherein the membrane
material is die-cut.
The method as claimed in any one of claims 27 to 29, wherein said
membrane material comprises a smooth, cylindrical shape.
The method as claimed in any one of claims 27 to 30, wherein said
capsule comprises a plurality of inward-protruding ridges, and
wherein the step of positioning the membrane material such that an
end surface thereof is in contact with an inside surface of the
membrane material retaining means includes the step of
positioning said membrane material over said plurality of inward-
protruding ridges such that said plurality of inward-protruding
ridges hold said membrane material securely within said capsule.
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 inward-protruding ridge
(s) near the fluid uptake end and a membrane material retaining
means at the fluid uptake end;
inserting a membrane material into said capsule from the open
agent delivery end such that an end surface thereof is in contact
with an inside surface of the membrane material retaining means,
positioned said membrane material over said inward-protruding
ridge(s) such that said inward-protruding ridge(s) hold said
membrane material securely within said capsule;
positioning the membrane material such that an end surface thereof
is in contact with an inside surface of the membrane material
retaining means;
filing a chamber of the capsule with a beneficial agent; and
closing the agent delivery end while providing a controlled outlet
for said beneficial agent to escape when sufficient pressure is
applied to said beneficial agent.
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 with a membrane material retaining
means and one or more inward-protruding ridge (s) near the fluid
uptake end;
inserting a membrane material into said capsule from the open
agent delivery end;
positioning the membrane material such that an end surface thereof
is in contact with an inside surface of the membrane material
retaining means, positioning said membrane material over said
inward-protruding ridge (s) such that said inward-protruding ridge
(s) hold said membrane material securely within said capsule;
inserting an osmotic engine into the capsule;
inserting a piston into the capsule;
filling a chamber of the capsule with a beneficial agent; and
closing the agent delivery end while providing a controlled outlet
for said beneficial agent to escape when sufficient pressure is
applied to said beneficial agent.
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 inward-protruding
ridge (s);
inserting one or more of the following:
(a) a membrane material into said capsule from the open agent
delivery end such that an end surface of said membrane will be
in contact with a surface of a membrane material retaining
means, positioning said membrane material over said inward
protruding ridge (s) such that said inward-protruding ridge (s)
hold said membrane material securely within said capsule;
(b)an osmotic engine into the capsule;
(c) a piston into the capsule; or
(d) filling a chamber of the capsule with a beneficial agent;
attaching a membrane retention means;
inserting any of (a), (b), (c) or (d) that were not inserted prior to
attaching the membrane retention means; and
closing the agent delivery end while providing a controlled outlet
for said beneficial agent to escape when sufficient pressure in
applied to said beneficial agent.
A delivery system for controlled delivery of a beneficial agent, said system
comprising:
an implantable capsule having a beneficial agent delivery end and a fluid
uptake end;
a beneficial agent reservoir positioned within the capsule for delivery of the
beneficial agent at a predetermined delivery rate;
a membrane material received in the fluid uptake end of the capsule and
providing a fluid permeable barrier between an interior and an exterior of the
capsule;
one or a plurality of inwardly protruding ridges circumferentially arrayed
near the fluid uptake end of the capsule to securingly grip the outer surface
of the membrane material; and
a membrane material retaining means positioned at the fluid uptake end of
said capsule, said retaining means including at least one opening for
allowing passage of fluid, the membrane material retaining means
preventing the membrane material from being ejected out of the fluid uptake
end of the capsule.

Documents:

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Patent Number

225200

Indian Patent Application Number

01625/KOLNP/2003

PG Journal Number

45/2008

Publication Date

07-Nov-2008

Grant Date

05-Nov-2008

Date of Filing

16-Dec-2003

Name of Patentee

ALZA CORPORATION

Applicant Address

1900 CHARLESTON ROAD, MOUNTAIN VIEW, CALIFORNIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SCOTT, GILBERT, J.	1275 AVY AVENUE, MENLO PARK CA 94025
2	PERRY, JOHN, R.	P.O. BOX 20528, STANDFORD, CA 94025
3	BROWN, JAMES, E.	126 BLUEBERRY HILL DRIVE, LOS GATOS, CA 95032

PCT International Classification Number

A61K 9/00

PCT International Application Number

PCT/US2002/19531

PCT International Filing date

2002-06-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/300,575	2001-06-22	U.S.A.