Injectable sustained release delivery devices

• US 20040176341A1
• Filed: 11/13/2003
• Published: 09/09/2004
• Est. Priority Date: 05/07/2002
• Status: Active Grant

• Current Assignee: EyePoint Pharmaceuticals, Inc.
• Original Assignee: pSivida US, Inc
• Inventors: Guo, Hong, Ashton, Paul, Shimizu, Robert W., Watson, David A., Chou, Kang-Jye
• Granted Patent: US 8,871,241 B2
• Time in Patent Office: Days
• US Class Current: 514/179
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• 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: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/284 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209

Abstract

An injectable drug delivery device includes a core containing one or more drugs and one or more polymers. The core may be surrounded by one or more polymer outer layers (referred to herein as “coatings,” “skins,” or “outer layers”). In certain embodiments, the device is formed by extruding or otherwise preforming a polymeric skin for a drug core. The drug core may be co-extruded with the skin, or inserted into the skin after the skin has been extruded, and possibly cured. In other embodiments, the drug core may be coated with one or more polymer coatings. These techniques may be usefully applied to fabricate devices having a wide array of drug formulations and skins that can be selected to control the release rate profile and various other properties of the drugs in the drug core in a form suitable for injection using standard or non-standard gauge needles. The device may be formed by combining at least one polymer, at least one drug, and at least one liquid solvent to form a liquid suspension or solution wherein, upon injection, such suspension or solution under goes a phase change and forms a gel. The configuration may provide for controlled release of the drug(s) for an extended period.

Claims

1. A drug delivery device shaped and sized for injection comprising:

a core including one or more drugs; and

a polymeric skin at least partially surrounding the core, the skin comprising a first one or more polymers.

2. The device of claim 1 wherein the core comprises a matrix of the one or more drugs and a second one or more polymers.

3. The device of claim 2 wherein at least one of the second one or more polymers is bioerodible.

4. The device of claim 2 wherein the second one or more polymers comprises at least one ofpoly(vinyl acetate) (PVAC), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), ethylene vinyl acetate polymer (EVA), poly(vinyl acetate) (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacralate, polyurethane, or nylon, or a copolymer thereof.

5. The device of claim 1 wherein the one or more drugs includes at least one of a codrug or a prodrug.

6. The device of claim 1, wherein the core comprises a biocompatible gelling formulation.

7. The device of claims 1 wherein the one or more drugs includes a steroid.

8. The device of claim 7 wherein the steroid comprises at least one of loteprednol etabonate, triamcinolone acetonide (TA), fluocinolone acetonide, or anacortave acetate.

9. The device of claim 1 wherein at least one of the one or more drugs comprises an anti-metabolite.

10. The device of claim 9 wherein the anti-metabolite comprises 5-fluorouracil (5-FU).

11. The device of claim 1 wherein at least one of the one or more drugs comprises an adrenergic agent.

12. The device of claim 11 wherein the adrenergic agent comprises brimonidine.

13. The device of claims 1 wherein at least one of the one or more drugs comprises a carbonic anhydrase inhibitor.

14. The device of claim 13 wherein the carbonic anhydrase inhibitor comprises at least one of acetazolamide, methazolamide, ethoxzolamide, dichlorphenamide, dorzolamide, or brinzolamide.

15. The device of claim 1 wherein at least one of the one or more drugs comprises an antiviral agent.

16. The device of claim 15 wherein the antiviral agent comprises neviripine.

17. The device of claim 1 wherein the polymeric skin is one of impermeable, semi-permeable, or permeable to at least one of the one or more drugs.

18. The device of claims 1 wherein the polymeric skin comprises at least one of PVAC, PCL, PEG, PLGA, EVA, PVA, PLA, PGA, polyalkyl cyanoacralate, polyurethane, or nylon, or a copolymer thereof.

19. The device of claim 2 wherein at least one of the first one or more polymers and the second one or more polymers is bioerodible.

20. The device of claim 2 wherein at least one of the first one or more polymers and the second one or more polymers is radiation curable.

21. The device of claim 2 wherein at least one of the first one or more polymers and the second one or more polymers is heat curable.

22. The device of claim 2 wherein at least one of the first one or more polymers and the second one or more polymers is evaporation curable.

23. The device of claim 2 wherein at least one of the first one or more polymers and the second one or more polymers is curable by catalyzation.

24. The device of claim 1 wherein the polymeric skin further comprises at least one drug.

25. The device of claim 1 further comprising an anchor, wherein the device is shaped and sized for injection through at least one of a needle having a size from about 30 gauge to about 15 gauge or a cannula having a size from about 30 gauge to about 15 gauge.

26. The device of claim 1 wherein the device is shaped and sized for injection through at least one of a cannula having a size from about 30 gauge to about 15 gauge or a needle having a size from about 30 gauge to about 15 gauge.

27. The device of claim 1 wherein the device is shaped and sized for at least one of periocular or intraocular injection.

28. The device of claim 1 further comprising an anchor for securing the device after injection.

29. The device of claim 1 wherein the device provides sustained release of the one or more drugs when exposed to a biological medium.

30. The device of claim 2 further comprising a second polymeric skin.

31. The device of claim 30 wherein the polymeric skin has a different permeability to the one or more drugs than the second polymeric skin, and the core is completely covered by a combination of the polymeric skin and the second polymeric skin.

32. The device of claim 30 wherein at least one of the polymeric skin, or the second polymeric skin is bioerodible.

33. The device of claim 32 wherein a release rate of at least one of the one or more drugs is influenced by an erosion of at least one of the polymeric skin or the second polymeric skin.

34. The device of claim 32 wherein a release rate of at least one of the one or more drugs is independent of an erosion of at least one of the polymeric skin or the second polymeric skin.

35. The device of claim 31 wherein each of the core, the polymeric skin, and the second polymeric skin is bioerodible.

36. The device of claim 31 wherein a release rate of at least one of the one or more drugs is controlled by at least one of the permeability of the second polymeric skin to the at least one of the one or more drugs and a surface area of the core that is not covered by the polymeric skin.

37. The device of claim 31 wherein at least one of the polymeric skin and the second polymeric skin prevent direct interaction of biological fluids with the core.

38. The device of claim 31 wherein a release rate of at least one of the one or more drugs is controlled by a surface area of the core.

39. The device of claim 31 wherein a release rate of at least one of the one or more drugs is not substantially influenced by diffusion of the at least one drug through the core.

40. The device of claim 31 wherein a release rate of at least one of the one or more drugs is significantly influenced by diffusion of the at least one drug through the core.

41. The device of claim 31 wherein a release rate of at least one of the one or more drugs is significantly influenced by a solubility of the at least one drug within the core.

42. The device of claim 31 wherein at least one of the one or more drugs is more stable within the device than in a biological medium.

43. The device of claim 31 wherein the device provides increased stability of at least one of the one or more drugs to a curing process.

44. The device of claim 31 wherein the device provides increased stability of at least one of the one or more drugs to storage.

45. The device of claim 31 further comprising an anchor.

46. A method comprising:

extruding a polymeric skin;

extruding within the polymeric skin a core containing one or more drugs to provide a co-extruded mass having a core that includes the one or more drugs; and

forming the co-extruded mass into at least one drug delivery device shaped and sized for injection.

47. The method of claim 46 wherein the polymeric skin includes at least one curable polymer, the method further comprising at least partially curing the polymeric skin.

48. The method of claim 47 wherein the at least one curable polymer is radiation curable, the method further comprising applying radiation to the polymeric skin.

49. The method of claim 47 wherein the polymeric skin is cured at a curing station.

50. The method of claim 46 wherein forming the co-extruded mass includes segmenting the co-extruded mass into a plurality of segments.

51. The method of claim 50 further comprising coating the plurality of segments with one or more layers including at least one of a layer that is permeable to the one or more drugs, a layer that is semi-permeable to the one or more drugs, or a layer that is bioerodible.

52. The method of claim 50 further comprising coating the plurality of segments using at least one of dip coating or film coating.

53. The method of claim 50 wherein a segmenting station is provided for segmenting the co-extruded mass.

54. The method of claim 46 wherein forming the co-extruded mass includes segmenting the co-extruded mass into a plurality of tubular segments.

55. The method of claim 46 wherein the polymeric skin includes at least one drug.

56. The method of claim 46 further comprising attaching an anchor to one of the at least one drug delivery devices, the anchor adapted to secure the drug delivery device after injection.

57. The method of claim 56 wherein attaching an anchor comprises:

applying an ultraviolet curable adhesive to the drug delivery device;

contacting the anchor to the ultraviolet curable adhesive; and

exposing the ultraviolet curable adhesive to ultraviolet radiation.

58. A device comprising:

a drug core containing one or more drugs, the drug core having a substantially cylindrical shape with a side wall, a first end, and a second end;

a polymeric skin surrounding the side wall of the drug core and extending beyond at least the first end of the drug core to create a reservoir;

an adhesive within the reservoir; and

an anchor adapted to secure the device after injection, the anchor partially embedded within the adhesive.

59. The device of claim 58 wherein the adhesive is a curable adhesive.

60. The device of claim 59 wherein the adhesive is a radiation curable adhesive.

61. The device of claim 59 wherein the adhesive is an ultraviolet curable adhesive.

62. A method for forming an injectable drug delivery device comprising:

forming a polymeric skin having an interior region;

inserting a mixture into the interior region of the polymeric skin, the mixture including at least one drug;

segmenting the polymeric skin and mixture into one or more segments to provide one or more drug cores, each having a first end and a second end;

placing one of the drug cores into a polymeric sleeve that extends beyond at least the second end of the drug core to provide a reservoir; and

creating a diffusion membrane over the first end of the drug core, the diffusion membrane permeable to the at least one drug.

63. The method of claim 62 further comprising:

inserting a curable adhesive into the reservoir at the second end of the drug core;

placing a first portion of an anchor into the curable adhesive, a second portion of the anchor adapted to secure a drug delivery device in vivo; and

curing the curable adhesive.

64. The method of claim 62 further comprising sterilizing the drug delivery device.

65. The method of claim 62 further comprising packaging the drug delivery device for shipment.

66. A method comprising:

extruding a polymeric skin having an interior region;

inserting one or more drugs into the interior region to provide a substantially cylindrical mass having a core that includes the one or more drugs; and

forming the cylindrical mass into at least one drug delivery device shaped and sized for injection.

67. The method of claim 66 further comprising at least partially curing the polymeric skin before inserting one or more drugs.

68. The method of claim 66 further comprising at least partially curing the cylindrical mass before forming the cylindrical mass.

69. The method of claim 66 further comprising coating the at least one drug delivery device with a polymeric layer.

70. A method comprising:

inserting a wire into an uncured polymer;

curing the polymer;

withdrawing the wire from the polymer to obtain a polymeric skin surrounding a portion of the wire;

removing the polymeric skin from the wire;

inserting one or more drugs into an interior region of the polymeric skin to provide a substantially cylindrical mass having a core that includes the one or more drugs; and

forming the cylindrical mass into at least one drug delivery device shaped and sized for injection.

71. The method of claim 70 wherein the polymer is polyimide.

72. The method of claim 70 wherein the wire is a Nitinol wire.

73. The method of claim 70 wherein the one or more drugs comprises a drug matrix of at least one drug and at least one polymer.

74. A method for treating or reducing the risk of retroviral or lentiviral infection comprising injecting a sustained release drug delivery system including an antiviral agent in a patient in need of treatment wherein a dose of said agent is released for at least 7 days.

75. A method for treating or reducing the risk of retroviral or lentiviral infection comprising injecting a sustained release drug delivery system including an antiviral agent in a patient in need of treatment wherein release of said agent maintains a desired concentration of said agent in blood plasma for at least 7 days.

76. A method comprising:

forming a core including a drug;

coating the core with a polymeric skin; and

forming the core and polymeric skin into a device shaped and sized for injection.

77. The method of claim 76 wherein the core comprises a plurality of drugs.

78. The method of claim 76 wherein forming the core comprises extruding the core.

79. The method of claim 76 wherein forming the core comprises compressing a mixture including the drug into the shape of the core.

80. The method of claim 76 wherein coating the core comprises spraying the polymeric skin onto the core.

81. The method of claim 76 wherein coating the core comprises dip coating the core into an uncured polymer.

82. The method of claim 76 wherein coating the core comprises leaving at least one surface of the core uncoated.

83. The method of claim 76 wherein the device is cylindrical.

84. The method of claim 76 further comprises attaching an anchor to the device.