Claims for Patent: 6,395,292

Summary for Patent: 6,395,292

Title:	Sustained delivery of an active agent using an implantable system
Abstract:	The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.
Inventor(s):	Peery; John R. (Stanford, CA), Dionne; Keith E. (Menlo Park, CA), Eckenhoff; James B. (Los Altos, CA), Landrau; Felix A. (Punta Gorda, FL), Lautenbach; Scott D. (San Mateo, CA), Magruder; Judy A. (Mountain View, CA), Wright; Jeremy C. (Los Altos, CA)
Assignee:	Alza Corporation (Mountain View, CA)
Application Number:	09/848,211
Patent Claims:	1. A fluid-imbibing device for delivering an active agent to a fluid environment of use, said device comprising a water-swellable semipermeable material that is received in sealing relationship with the interior surface of one end of an impermeable reservoir and an active agent to be displaced from the device when the water-swellable material swells. 2. The device of claim 1 wherein the semipermeable material is selected from the group consisting of plasticized cellulosic materials, polyurethanes and polyamides. 3. The device of claim 1 wherein the aspect ratio of the plug is 1:10 to 10:1 length to diameter. 4. The device of claim 1 wherein the semipermeable material is assembled into an open end of the reservoir. 5. The device of claim 1 wherein the semipermeable material is assembled into a cavity in said reservoir. 6. The device of claim 5 wherein the cavity is of a shape selected from the group consisting of a cylindrical, stepped, helical threaded and spaced configuration. 7. The device of claim 1 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent. 8. The device of claim 7 wherein the active agent is an LHRH agonist or antagonist. 9. The device of claim 7 wherein the active agent is leuprolide. 10. The device of claim 7 wherein the active agent is selected from the group consisting of Factor VIII and Factor IX. 11. The device of claim 1 wherein the active agent is delivered to a site remote from the device. 12. A device for storing an active agent in a fluid environment of use during a predetermined administration period, the device comprising a reservoir containing an active agent, wherein said device effectively seals the active agent chamber and isolates it from said fluid environment of use, said reservoir being formed at least in part from a metallic material, the portion of said reservoir contacting said active agent being non-reactive with the active agent, said metallic material in contact with active agent being formed of a material selected from the group consisting of titanium and its alloys. 13. The device of claim 12 wherein the titanium alloy is at least 60% titanium. 14. The device of claim 12 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent. 15. The device of claim 14 wherein the active agent is delivered to a site remote from the device. 16. A fluid-imbibing implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period, wherein the time to start-up is less than 10% of the predetermined administration period. 17. A method for preparing a fluid-imbibing implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period said method comprising injection molding a semipermeable plug into the end of an impermeable reservoir such that the semipermeable plug is protected by the reservoir. 18. The method of claim 17 wherein the semipermeable plug material is a polyurethane based material. 19. The method of claim 17 wherein the semipermeable plug material is a polyamide based material. 20. The method of claim 17 wherein the semipermeable plug material is a cellulosic based material. 21. A method of reducing testosterone to castrate levels comprising administering at least one fluid-imbibing device for delivering an active agent to a fluid environment of use, said device comprising a water-swellable semipermeable material that is received in sealing relationship with the interior surface of one end of an impermeable reservoir and an active agent to be displaced from the device when the water-swellable material swells, wherein said active agent is an LHRH agonist or antagonist. 22. The method of claim 21 wherein said active agent is leuprolide. 23. A method of reducing testosterone to castrate levels comprising administering at least one implantable delivery system comprising: a) an impermeable reservoir; b) a piston that divides the reservoir into a first and a second chamber, the first and second chambers each having an open end; c) a water-swellable agent formulation in the first chamber; d) a formulation of an active agent which is an LHRH agonist or antagonist in the second chamber; e) a semipermeable plug in the open end of the first chamber; and f) a back diffusion regulating outlet in the open end of the second chamber, wherein the system effectively seals the second chamber and isolates the active agent from the environment of use. 24. The method of claim 23 wherein said active agent is leuprolide. 25. The method of claims 23 wherein the reservoir is titanium or a titanium alloy. 26. The method of claim 23 wherein the piston is formed of a styrene-ethylene-butylene-copolymer. 27. The method of claim 23 wherein the water-swellable agent formulation contains at least about 64 mg NaCl. 28. The method of claim 23 wherein the water-swellable agent formulation contains NaCl, a gelling osmopolymer and granulation and processing aids. 29. The method of claim 23 further comprising an additive in the first chamber. 30. The method of claim 29 wherein said additive is PEG 400. 31. The method of claim 24 wherein the leuprolide formulation is leuprolide acetate dissolved in DMSO at an assay content of 37% leuprolide. 32. The method of claim 24 which contains 65 mg leuprolide. 33. The method of claim 23 wherein the semipermeable plug is formed of polyurethane material with 20% water uptake. 34. The method of claim 23 wherein the back-diffusion regulating outlet is made of polyethylene and has a flow path helical in shape with a diameter between 0.003 and 0.020 inches and a length of 2 to 7 centimeters. 35. The method of claim 23 which delivers about 0.35 .mu.L active agent formulation per day. 36. The method of claim 23 which provides continuous delivery of active agent formulation for about one year. 37. The method of claim 23 which reaches at least about 70% steady-state delivery by day 14. 38. The method of claim 24 which delivers about 150 .mu.g leuprolide per day. 39. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent. 40. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent, wherein said material is selected from the group consisting of plasticized cellulosic materials, enhanced polymethylmethacrylate, hydroxyethylmethacrylate, elastomeric materials, polyurethanes, polyamides, polyether-polyamide co-polymers and thermoplastic co-polymers. 41. The plug of claim 39 wherein said material is selected from the group consisting of polyamides and polyurethanes. 42. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent, which provides delivery of active agent for a period of one month. 43. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent, which provides delivery of active agent for a period of two months. 44. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent, which provides delivery of active agent for a period of three months. 45. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of uses, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, wherein selection of the material which forms the plug determines the rate of delivery of active agent, which provides delivery of active agent for a period of twelve months. 46. A method for controlling the delivery rate of an active agent delivery system for delivering an active agent to a fluid environment of uses, said delivery system comprising a plug, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use, said method comprising selecting a particular material to form the plug. 47. The method of claim 46 wherein said material is selected from the group consisting of plasticized cellulosic materials, enhanced polymethylmethacrylate, hydroxyethylmethacrylate, elastomeric materials, polyurethanes, polyamides, polyetherpolyamide co-polymers and thermoplastic co-polymers. 48. The method of claim 46 wherein said material is selected from the group consisting of polyamides and polyurethanes.