Zero-order prolonged release coaxial implants

• US 20030007992A1
• Filed: 06/21/2002
• Published: 01/09/2003
• Est. Priority Date: 06/22/2001
• Status: Active Grant

• Current Assignee: DURECT Corporation
• Original Assignee: Southern Biosystems, Inc. (DURECT Corporation)
• Inventors: Holl, Richard J., Gibson, John W., Tipton, Arthur J., Meador, Stacey
• Granted Patent: US 8,263,108 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

A coaxial implant has been developed using entirely biodegradable polymeric materials. As referred to herein, a coaxial implant is a device having a core containing drug, surrounded by a semi-permeable membrane that controls the rate of release of material from the core. The device is formed by extrusion, using a pre-milling and extruding step to maximize uniformity of drug dispersion within the polymeric material. In one embodiment, the polymer is processed to yield a semi-crystalline polymer, rather than an amorphous polymer. The core containing the drug and the polymer membrane(s) can be the same or different polymer. The polymer can be the same or different composition (i.e., both polycaprolactone, or both poly(lactide-co-glycolide) of different monomer ratios, or polycaprolactone outside of a core of poly(lactide)), of the same or different molecular weights, and of the same or different chemical structure (i.e., crystalline, semi-crystalline or amorphous). The core acts as a reservoir of drug, which partitions from the core polymer to form a saturated solution of at least 10% drug at the polymer membrane.

Claims

1. A completely biodegradable coaxial implant comprising a core containing active agent to be delivered and a rate-controlling membrane, wherein the implant does not degrade completely until all the active agent is released.

2. The implant of claim 1 wherein the active agent is released for at least 30 days.

3. The implant of claim 1 wherein the core of the implant is formed of a biodegradable polymer having active agent incorporated therein.

4. The implant of claim 1 wherein the membrane is a microporous membrane.

5. The implant of claim 1 wherein the membrane is a semi-permeable membrane.

6. The implant of claim 1 wherein the core is formed by dry blending of active agent and polymer, followed by extrusion.

7. The implant of claim 1 wherein the core is formed by a double extrusion process.

8. The implant of claim 1 wherein the core is a liquid.

9. The implant of claim 1 wherein the core is pure drug.

10. The implant of claim 1 wherein the polymer forming the membrane or core is semi-crystalline, crystalline or amorphous.

11. The implant of claim 1 wherein the polymer forming the membrane and the core is the same polymer.

12. The implant of claim 1 releasing active agent with zero order release kinetics.

13. The implant of claim 1 wherein the implant comprises active agent in or abutting the membrane.

14. The implant of claim 1 formed into a device selected from a matrix, prosthetic, graft, or coating.

15. The implant of claim 1 wherein the core composition further comprises concentric layers having different compositions.

16. The implant of claim 1 wherein the core comprises excipient.

17. The implant of claim 1 wherein the rate-controlling membrane comprises pore forming agents.

18. The implant of claim 1 wherein the implant comprises a polymer selected from the group consisting of polyethylene glycol, polyhydroxyacid, caprolactone, or copolymer thereof.

19. The implant of claim 1 wherein the implant has sealed ends.

20. The implant of claim 1 wherein the implant is further process post-extrusion by drawing or annealing.

21. The implant of claim 1 wherein the active agent is water soluble.

22. The implant of claim 1 wherein the active agent is a protein or peptide.

32. The implant of claim 1 wherein the core contains a non-polymeric, non-water soluble liquid and an active agent.

33. The implant of claim 1 formed by filling a preformed membrane with a liquid, drug-containing formulation.

35. The implant of claim 34 wherein the analgesic or antagonist is selected from the group consisting of sufentanil, fentanyl, naltrexone, and naloxone.

36. The implant of claim 34 wherein the polymer is biodegradable.

37. The implant of claim 34 wherein the implant is a coaxial implant comprising a core containing the analgesic or antagonist and a rate-controlling membrane.

38. The implant of claim 34 releasing the analgesic or antagonist over a period of at least thirty days with zero order release kinetics.

39. The implant of claim 34 formed into a device selected from a matrix, prosthetic, graft, or coating.

40. The implant of claim 39 wherein the device is suitable for implantation intravascularly.

41. The implant of claim 40 wherein the device comprises an active agent selected from the group consisting of heparin, taxol and other drugs for use in treating or preventing restenosis.

42. The implant of claim 39 suitable for implantation into a body lumen.

43. The implant of claim 39 suitable for implantation adjacent to a nerve plexus.

44. The implant of claim 34 wherein the core composition further comprises concentric layers having different compositions.

45. The implant of claim 34 wherein the core comprises excipient.

46. The implant of claim 37 wherein the rate-controlling membrane comprises pore forming agents.

47. The implant of claim 34 wherein the implant comprises a polymer selected from the group consisting of polyethylene glycol, polyhydroxyacid, caprolactone, or copolymer thereof.

48. The implant of claim 34 wherein the implant has sealed ends.

49. The implant of claim 34 wherein the implant is further process post-extrusion by drawing or annealing.

50. A method administering a drug to a patient comprising implanting the implant of claim 1 in the patient.

51. A method of administering a narcotic analgesic or antagonist thereof to a patient in need thereof comprising implanting the implant of claim 34 in the patient.

34. A polymeric implant for delivery of a thereof comprising a monolithic or coaxial implant.

52. A method of making a coaxial implant comprising the steps of twice extruding active agent and polymer to form the core of the coaxial implant.

53. The method of claim 52 wherein the active agent and the polymer are dry blended before the first extrusion step.