Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease

• US 20060257451A1
• Filed: 04/07/2006
• Published: 11/16/2006
• Est. Priority Date: 04/08/2005
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Fox Beeley, Nathan Robert, deJuan, Eugene, Varner, Signe E.
• Granted Patent: US 8,003,124 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61F 2/14 Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2430/16 for reconstruction of eye parts, e.g. intraocular lens, cornea
• CPC Class Codes: A61L 27/44 having a macromolecular matrix
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

The invention relates to sustained release implants and to methods for treating eyes, particularly the eyes of mammals having eye disorders or diseases. By using the implants and methods described herein, the delivery of the one or more bioactive agents can be localized at a desired treatment site, particularly the choroid and the retina.

Claims

1. A sustained release implant that is configured for placement in a subretinal area of an eye having a choroid, a retina, one or more tissue layers above the choroid, and a nerve fiber layer, the sustained release implant comprising:

a biocompatible core having a length and an outer surface area; and

a biocompatible coating layer comprising a polymer matrix and a bioactive agent that is applied over at least a portion of the outer surface area of the core.

2. The implant of claim 1 wherein the implant is configured to be positioned in one or more tissue layers above the choroid but below the nerve fiber layer of the eye.

3. The implant of claim 1 wherein the coating layer is applied over the entire length of the biocompatible core.

4. The implant of claim 1 wherein the coating layer is applied over a portion of the length of the biocompatible core and wherein one or more portions of the length of the biocompatible core are left uncoated.

5. The implant of claim 1 wherein the coating layer comprises a center portion, a proximal transition segment, and a distal transition segment.

6. The implant of claim 1 wherein at least one of the proximal transition segment or the distal transition segment are feathered.

7. The implant of claim 6 wherein both the proximal transition segment and the distal transition segment are feathered.

8. The implant of claim 1 wherein the biocompatible core or biocompatible coating layer comprises a biostable polymer.

9. The implant of claim 8 wherein the biostable polymer is selected from the group consisting of polyurethanes, silicones, polyesters, polyolefins, polyisobutylene, acrylic polymers, vinyl halide polymers, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polyvinyl esters, poly(alkyl(meth)acrylates, such as poly((methyl)methacrylate) or poly((butyl)methacrylate)), polyvinyl amides, polyamides, polycaprolactam, polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, copolymers thereof and blends thereof.

10. The implant of claim 1 wherein the biocompatible core or the biocompatible coating layer comprises a biodegradable polymer or a biodegradable material.

11. The implant of claim 10 wherein the biodegradable polymer is selected from the group consisting of poly(L-lactic acid), poly(caprolactone), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D,L lactic acid), poly(glycolic acid- co-trimethylene carbonate), poly(phosphate esters), polyphosphoester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonates), polycarbonates, poly(iminocarbonates), polyesters, copoly(ether-esters), polyalkylene oxalates, polyphosphazenes and copolymers and blends of the above polymers.

12. The implant of claim 10 wherein the biodegradable material is selected from the group consisting of fibrin, fibrinogen, cellulose, dextrans, polysaccharides, starch collagen, chromic gut, and hyaluronic acid.

13. The implant of claim 1 wherein the biocompatible core comprises a material selected from the group consisting of titanium-nickel alloy wire, titanium alloy, nickel-cobalt base alloys, stainless steel, cobalt-chromium alloy, and biodegradable magnesium alloys.

14. The implant of claim 1 wherein the implant has a total diameter that is no greater than about 1000 μ

m.

15. The implant of claim 1 wherein the implant has a length no greater than about 5 mm.

16. The implant of claim 1 wherien the implant has a total diameter that is no greater than about 200 μ

m to about 500 μ

m.

17. The implant of claim 1 wherein the implant has a total length that ranges from about 2.25 mm to about 2.75 mm.

18. The implant of claim 1 wherein the core has a cross-sectional shape that is circular.

19. The implant of claim 18 wherein the core has a diameter that is less than about 200 μ

m.

20. The implant of claim 1 wherein the biocompatible coating layer is covered with one or more additional coating layers of polymer material whereby the one or more additional coating layers of polymer material modify the release rate characteristics of the bioactive agents from the polymer matrix.

21. The implant of claim 20 wherein the one or more additional coating layers comprise poly(caprolactone), poly(methylmethacrylate), polyesters, chromic gut, polyorthoesters, polypropylene, polyethylene vinyl acetate or poly(butylmethacrylate).

22. The implant of claim 1 wherein the bioactive agent is selected from antiproliferative agent, anti-inflammatory agent, anti-angiogenic agent, antibiotic, neurotrophic factor, or a combination thereof.

23. The implant of claim 1 wherein the polymer matrix comprises a blend of (a) a first biodegradable polymer that is a copolymer of polyalkylene glycol terephthalate and an aromatic polyester;

and (b) a second biodegradable polymer;

wherein the second biodegradable polymer is selected to have a slower bioactive agent release rate relative to the first biodegradable polymer.

24. The implant of claim 23 wherein the polyalkylene glycol terephthalate is selected from the group of polyethylene glycol terephthalate, polypropylene glycol terephthalate, polybutylene glycol terephthalate, and combinations of these.

25. The implant of claim 23 wherein the aromatic polyester comprises polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate, and combinations thereof.

26. The implant of claim 23 wherein the first polymer comprises a copolymer of polyethylene glycol terephthalate and polybutylene terephthalate in relative amounts of 70-80% polyethylene glycol terephthalate and 5-20% polybutylene terephthalate.

27. The implant of claim 23 wherein the second biodegradable polymer comprises a polymer derived from monomers selected from lactic acid, glycolic acid, caprolactone, ethylene glycol, and ethyloxyphosphate.

28. The implant of claim 1 wherein the polymer matrix comprises a random block copolymer having the formula:

wherein R₁ is —

CH═

CH—

or (—

CH₂—

)_j, in which j is zero or an integer from one to eight;

R₂ is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and optionally containing at least one ether linkage, and derivatives of biologically or pharmaceutically active compounds covalently bonded to the copolymer;

each R₃ is independently selected from alkylene groups containing 1 to 4 carbon atoms;

y is between 5 and about 3000; and

f is the percent molar fraction of alkylene oxide in the copolymer.

29. The implant of claim 1 wherein the polymer matrix comprises a hydrogel.

67. A method for treating or preventing disorders or diseases of an eye having a choroid, a retina, a tissue layer above the choroid, and a nerve fiber layer, the method comprising the steps of:

(a) implanting the implant of claim 1 in the eye below the retina; and

(b) allowing the one or more bioactive agents to elute in order to deliver the one or more bioactive agents to a portion of the eye to be treated.

68. The method of claim 67 wherein the implant is positioned in the tissue layer above the choroid but below the nerve fiber layer.

69. The method of claim 67 further comprising implanting a second implant in the eye below the retina;

wherein two implants are located in the eye simultaneously.

70. The method of claim 67 wherein the implant is capable of piercing or penetrating the eye to achieve implantation.

71. The method of claim 67 further comprising using an instrument to insert the implant within the eye.

72. The method of claim 67 further comprising using an uncoated portion of the implant to grasp or dock the implant with a surgical instrument to insert the implant into the eye.

73. The method of claim 67 wherein at least 5% of the one or more bioactive agents eluted by the implant is delivered substantially only to the portion of the eye being treated.

74. The method of claim 67 wherein less than 95% of the one or more bioactive agents eluted by the implant is delivered to healthy tissue.

30. A sustained release implant configured for placement in a subretinal area of an eye that has a choroid, one or more tissue layers above the choroid, and a retina, the sustained release implant comprising one or more bioactive agents and a polymer matrix comprising:

(a) a first polymer selected from poly(alkyl(meth)acrylates), aromatic poly(meth)acrylates, and mixtures thereof; and

(b) a second polymer comprising a poly(ethylene-co-vinyl acetate) copolymer.

31. The implant of claim 30 wherein the implant is tapered at a proximal end, a distal end, or both the proximal and distal ends.

32. The implant of claim 30 wherein the implant is configured to be positioned in one or more tissue layers above a choroid but below a nerve fiber layer of an eye.

33. The implant of claim 30 wherein the implant has a total diameter of no greater than about 1000 μ

m and a length of no greater than about 5 mm.

34. The implant of claim 30 wherein the implant has a bioactive agent elution rate of at least about 0.0001 μ

g per day.

35. The implant of claim 30 wherein at least 5% of the bioactive agent eluted from the implant is delivered to the retina.

36. The implant of claim 30 wherein the first polymer comprises poly(alkyl(meth)acrylate).

37. The implant of claim 36 wherein the poly(alkyl(meth)acrylate) comprises poly(n-butylmethacrylate).

38. The implant of claim 30 wherein the first polymer comprises an aromatic poly(meth)acrylate.

39. The implant of claim 38 wherein the aromatic poly(meth)acrylate comprises a poly(aryl(meth)acrylate), poly(aralkyl(meth)acrylate), poly(aryloxyalkyl(meth)acrylate), or a mixture thereof.

40. The implant of claim 39 wherein the poly(aryl(meth)acrylate) comprises poly(9-anthracenylmethacrylate), poly(chlorophenylacrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthylacrylate), poly(napthylmethacrylate), poly(4-nitrophenylacrylate), poly(pentachlorophenylacrylate), poly(pentabromophenylacrylate), poly(pentafluorophenylacrylate), poly(pentachlorophenylmethacrylate), poly(pentabromophenylmethacrylate), poly(pentafluorophenylmethacrylate), poly(phenylacrylate), poly(phenylmethacrylate), and mixtures thereof.

41. The implant of claim 39 wherein the poly(aralkyl(meth)acrylate) comprises poly(benzylacrylate), poly(benzylmethacrylate), poly(2-phenethylacrylate), poly(2-phenethylmethacrylate), poly(1-pyrenylmethylmethacrylate), and mixtures thereof.

42. The implant of claim 39 wherein the poly(aryloxyalkyl(meth)acrylate) comprises poly(phenoxyethylacrylate), poly(phenoxyethylmethacrylate), poly(ethyleneglycolphenyletheracrylates), poly(ethyleneglycolphenylether methacrylates), and mixtures thereof.

43. The implant of claim 30 wherein the poly(ethylene-co-vinyl acetate) copolymer has a vinyl acetate concentration ranging from about 10% to about 90% wt. of the copolymer.

44. The implant of claim 30 wherein the first polymer comprises poly(n-butylmethacrylate) having a weight average molecular weight of 100 kD to about 1000 kD;

and wherein the second polymer comprises poly(ethylene-co-vinyl acetate) copolymer having a vinyl acetate content in the range of about 10% to about 90% wt. of the copolymer.

45. The implant of claim 30 further comprising a core, and wherein the polymer matrix and one or more bioactive agents are provided as a coating layer on a surface of the core.

46. The implant of claim 45 wherein the coating is provided on a portion of the surface of the core.

47. The implant of claim 45 wherein the coating is provided on an intermediate portion of the core.

48. The implant of claim 45 wherein the coating includes proximal a transition segment, a distal transition segment, or both a proximal and a distal transition segment.

49. The implant of claim 45 wherein the core is fabricated of a nondegradable material.

50. The implant of claim 49 wherein the nondegradable material is selected from titanium alloys, nickel-cobalt base alloys, stainless steel, cobalt-chromium alloys, and biodegradable magnesium alloys.

51. The implant of claim 49 wherein the nondegradable material comprises one or more polymers selected from poly(methyl methacrylate) and silicone.

52. The implant of claim 45 wherein the core is fabricated of a biodegradable material.

53. The implant of claim 52 wherein the biodegradable material is selected from polyglycolic acid, polydioxanone, surgical gut, polylactic acid, polyglyconate, polyglactin, and polyglecaprone.

54. The implant of claim 30 wherein the bioactive agent is selected from antiproliferative agent, anti-inflammatory agent, anti-angiogenic agent, antibiotic, neurotrophic factor, or a combination of any two or more of these.

75. A method for treating or preventing disorders or diseases of an eye having a choroid, a retina, a tissue layer above the choroid, and a nerve fiber layer, the method comprising the steps of:

(a) implanting the implant of claim 30 in the eye below the retina; and

(b) allowing the one or more bioactive agents to elute in order to deliver the one or more bioactive agents to a portion of the eye to be treated.

76. The method of claim 75 wherein the implant is positioned in the tissue layer above the choroid but below the nerve fiber layer.

77. The method of claim 75 further comprising implanting a second implant in the eye below the retina;

wherein two implants are located in the eye simultaneously.

78. The method of claim 75 wherein the implant is capable of piercing or penetrating the eye to achieve implantation.

79. The method of claim 75 further comprising using an instrument to insert the implant within the eye.

80. The method of claim 75 further comprising using an uncoated portion of the implant to grasp or dock the implant with a surgical instrument to insert the implant into the eye.

81. The method of claim 75 wherein at least 5% of the one or more bioactive agents eluted by the implant is delivered substantially only to the portion of the eye being treated.

82. The method of claim 75 wherein less than 95% of the one or more bioactive agents eluted by the implant is delivered to healthy tissue.

55. A method of making an implant for the sustained delivery of one or more bioactive agents to an eye, wherein the implant is implanted subretinally, comprising the steps of:

(a) dissolving one or more polymers in a solvent to form a complex fluid;

(b) adding at least one bioactive agent to the complex fluid to produce a homogeneous solution of the one or more bioactive agents or to produce a solution comprising a dispersed phase of the one or more bioactive agents;

(c) drying the solution to form a solid;

(d) heating the solid to a temperature below the melting point of the one or more polymers to form a semi-solid; and

(e) forming the implant device out of the solid of step (c).

56. The method of claim 55 wherein step (e) comprises melt-extrusion-drawing.

57. The method of claim 55 wherein the polymer is biodegradable poly(caprolactone).

58. The method claim 57 wherein the biodegradable polymer is comprised, in whole or in part, of repeating caprolactone monomer units.

59. The method of claim 55 wherein the temperature is no greater than about 100°

C.

60. The method of claim 55 wherein the one or more bioactive agents are selected from antiproliferative agent, anti-inflammatory agent, anti-angiogenic agent, antibiotic, neurotrophic factor, or a combination of any two or more of these.

61. An implant made by the method of claim 55.

62. The implant of claim 61 wherein the implant is tapered at a proximal end, a distal end, or both the proximal and distal ends.

63. The implant of claim 61 wherein the implant is configured to be positioned in one or more tissue layers above a choroid but below a nerve fiber layer of an eye.

64. The implant of claim 61 wherein the implant has a total diameter of no greater than about 1000 μ

m and a length of no greater than about 5 mm.

65. The implant of claim 55 wherein the implant has a bioactive agent elution rate of at least about 0.0001 μ

g per day.

66. The method of claim 55 wherein amount of bioactive agent the implant elutes is no more than 90% excess bioactive agent than an amount required to provide a therapeutic effect.