COATINGS FOR IMPLANTABLE MEDICAL DEVICES FOR LIPOSOME DELIVERY

• US 20080181928A1
• Filed: 12/20/2007
• Published: 07/31/2008
• Est. Priority Date: 12/22/2006
• Status: Abandoned Application

• Current Assignee: MIV Scientific Holdings Ltd. (MIV THERAPEUTICS, INC.)
• Original Assignee: MIV THERAPEUTICS, INC.
• Inventors: Tsui, Manus, Landy, Mark, Tsetkov, Aleksy, Budzynski, Vlad, Hakimi-Mehr, Dorna
• Application Number:
  US11/960,974
• Publication Number:
  US 20080181928A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 2300/62 Encapsulated active agents, e.g. emulsified droplets
• CPC Class Codes: A61L 31/08 Materials for coatings
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Disclosed herein are medical devices, such as implantable medical devices (e.g., stents), comprising at least one coating covering at least a portion of the device comprising dry film. The dry film comprises at least one lipid bilayer and at least one pharmaceutically effective agent. Upon exposure to an aqueous fluid, liposomes are released comprising lipids from the dry film encapsulating the pharmaceutically effective agent. The film can contact the device directly or can be coated on a substrate, such as a ceramic.

Claims

1. A stent, comprising at least one coating covering at least a portion thereof, the at least one coating comprising a dry film comprising at least one lipid bilayer and at least one pharmaceutically effective agent.

2. The stent of claim 1, wherein the at least one coating is free of a polymer.

3. The stent of claim 1, wherein the at least one lipid bilayer comprises at least one lipid capable of forming a liposome encapsulating the pharmaceutically effective agent when exposed to an aqueous solution.

4. The stent of claim 1, wherein the at least one lipid bilayer comprises at least one lipid capable of forming a liposome encapsulating the pharmaceutically effective agent when released from the stent.

5. The stent of claim 1, wherein the coating further comprises a substrate covering at least a portion of the stent, and the dry film covers at least a portion of the substrate.

6. The stent of claim 5, wherein the substrate comprises a ceramic.

7. The stent of claim 6, wherein the ceramic is selected from at least one metal oxide and at least one calcium phosphate.

8. The stent of claim 7, wherein the at least one calcium phosphate comprises a hydroxyapatite.

9. The stent of claim 8, wherein the hydroxyapatite is a porous hydroxyapatite.

10. The stent of claim 5, wherein the substrate has a thickness of no more than 2 μ

m.

11. The stent of claim 5, wherein the substrate has a thickness of no more than 1 μ

m.

12. The stent of claim 5, wherein the substrate is porous.

13. The stent of claim 1, wherein the at least one pharmaceutically active agent is chosen from anti-inflammatory agents, anti-proliferatives, pro-healing agents, gene therapy agents, extracellular matrix modulators, anti-thrombotic agents, anti-platelet agents, antineoplastic agents, antisense agents, anti-angiogenic agents, anticoagulants, and antibiotics.

14. The stent of claim 1, wherein the at least one pharmaceutically active agent inhibits restenosis.

15. The stent of claim 1, wherein the at least one pharmaceutically active agent is selected from smooth muscle cell inhibitors, immunosuppressive agents, and anti-angiogenic agents.

16. The stent of claim 1, wherein the at least one pharmaceutically active agent is selected from sirolimus, paclitaxel, tacrolimus, heparin, pimecrolimus, imatinib mesylate, gentamycin, midostaurin, and bisphosphonates.

17. The stent of claim 16, wherein the bisphosphonates are selected from etidronate, clodronate, pamidronate, alendronate, risedronate, tiludronate, ibandronate, zoledronate, incadronate, olpadronate, neridronate, minodronate, YH 529, and EB-1053.

18. The stent of claim 1, wherein the film further comprises at least one anticoagulant.

19. The stent of claim 1, wherein the at least one lipid is selected from phospholipids and glycolipids.

20. The stent of claim 19, wherein the phospholipids are selected from phosphoglycerides.

21. The stent of claim 20, wherein the phosphoglycerides are selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, and phosphatidic acids, phosphatidylserines, and phosphatidylinositols.

22. The stent of claim 21, wherein the phosphatidylcholines are selected from 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphcholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine.

23. The stent of claim 21, wherein the phosphatidylethanolamines are selected from 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine.

24. The stent of claim 21, wherein the phosphatidylglycerols are selected from egg phosphatidylglycerol, 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, 1,2-distearoyl-sn-glycero-3-phosphoglycerol, and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol.

25. The stent of claim 21, wherein the phosphatidic acids are selected from 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, and 1,2-distearol-sn-glycero-3-phosphate.

26. The stent of claim 1, wherein the at least one lipid comprises a mixture of at least two lipids.

27. The stent of claim 26, wherein at least one of the at least two lipids is selected from cholesterol and derivatives thereof.

28. The stent of claim 27, wherein the cholesterol is selected from 7β

-hydroxycholesterol 7-ketocholesterol, 7-ketocholesteryl acetate, 25-hydroxycholesterol, 24,25-epoxycholesterol, diacetylenic cholesterol, cholest-4-ene-3,6-dione, cholest-4-en-3-one, cholesteryl behenate, cholesteryl benzoate, cholesteryl butyrate, cholesteryl caprate, cholesteryl caproate, cholesteryl caprylate, cholesteryl-3,5-dinitrobenzoate, cholesteryl formate, cholesteryl-β

-D-glucoside, cholesteryl hemisuccinate, cholesteryl heptylate, cholesteryl heptadecanoate, cholesteryl hydrogen phthalate, cholesteryl isobutyrate, cholesteryl isovalerate, cholesteryl laurate, cholesteryl linoleate, cholesteryl methyl succinates, cholesteryl myristate, cholesteryl nervonate, cholesteryl-p-nitrobenzoate, cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl palmitate, cholesteryl palmitelaidate, cholesteryl palmitoleate, cholesteryl phosphoryl choline, cholesteryl polyethylene glycols, cholesteryl propionate, cholesteryl N-propyl carbonate, cholesteryl 1-pyreecarbonate, cholesteryl (pyren-1-yl) hexanoate, cholesteryl stearate, cholesteryl-P-tosylate, cholesteryl valerate, and thiocholesterolcholesteryl sulfate.

29. The stent of claim 26, wherein the film comprises a phosphatidylcholine and a cholesterol or derivatives thereof.

30. The stent of claim 1, wherein the film further comprises at least one anticoagulant.

31. A method of preparing a coating for a stent, comprising:

combining at least one lipid with at least one pharmaceutically active agent to form a composition comprising at least one lipid bilayer; and

coating at least a portion of the stent with the composition.

32. The method of claim 31, further comprising depositing a substrate on at least a portion of the stent, and the coating of the composition is performed on at least a portion of the substrate.

33. The method of claim 32, wherein the depositing comprises depositing the substrate from a solution or suspension.

34. The method of claim 32, wherein the depositing comprises at least one method selected from electrochemical deposition, electrophoretic deposition (EPD), sol gel processes, aero-sol gel processes, biomimetic (BM) processes, spraying, and dipping.

35. A method of preparing a coating for an implantable medical device, comprising:

coating at least a portion of the device with a substrate by at least one method selected from electrochemical deposition, electrophoretic deposition (EPD), sol gel processes, aero-sol gel processes, biomimetic (BM) processes, spraying, and dipping;

combining at least one lipid with at least one pharmaceutically active agent to form a composition comprising at least one lipid bilayer; and

coating at least a portion of the substrate with the composition.

36. The method of claim 35, wherein the coating step comprises electrochemical deposition.

37. The method of claim 35, wherein the combining comprises forming a solution comprising the at least one lipid with at least one pharmaceutically active agent.

38. The method of claim 37, wherein the at least one pharmaceutically active agent is hydrophobic or amphipathic.

39. The method of claim 35, wherein the combining comprises forming a water-in-oil emulsion comprising the pharmaceutically active agent in the aqueous phase within a non-aqueous phase comprising the at least one lipid.

40. The method of claim 39, wherein the at least one pharmaceutically active agent is hydrophilic or amphipathic.

41. The method of claim 39, wherein the emulsion further comprises at least one additional surfactant.

42. The method of claim 41, wherein the at least one additional surfactant is selected from chitosan, didodecyldimethylammonium bromide, dextrans, dextran salts, polyoxyethylene castor oil, polyoxyethylene 35 soybean glycerides, glyceryl monooleate, triglyceryl monoleate, glyceryl monocaprylate, glycerol monocaprylocaprate, propylene glycol monolaurate, triglycerol monooleate, stearic glycerides, sorbitane monostearate, sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylenesorbitan tristearate, and polyoxyethylene sorbitan monooleate.

43. A method of preparing a coating for an implantable medical device, comprising:

coating at least a portion of the device by depositing a substrate from a solution or suspension;

combining at least one lipid with at least one pharmaceutically active agent to form a composition comprising at least one lipid bilayer; and

coating at least a portion of the substrate with the composition.

44. A method of treating at least one disease or condition comprising:

implanting in a subject in need thereof a medical device comprising a coating covering at least a portion of the device, the coating comprising at least one lipid bilayer and a therapeutically effective amount of at least one pharmaceutically active agent, and

releasing from the device the at least one pharmaceutically active agent encapsulated in a liposome comprising lipids from the lipid bilayer.

45. The method of claim 44, wherein the releasing comprises contacting the coating with an aqueous or physiological medium.

46. The method of claim 44, wherein the device is implanted in a mammalian lumen.

47. The method of claim 46, wherein the at least one disease or condition is associated with narrowing or obstruction of the mammalian lumen.

48. The method of claim 44, wherein the at least one disease or condition is a proliferative disorder.

49. The method of claim 48, wherein the proliferative disorder is restenosis.

50. The method of claim 48, wherein the proliferative disorder is a tumor.

51. The method of claim 48, wherein the proliferative disorder comprises the proliferation of smooth muscle cells.

52. The method of claim 44, wherein the at least one disease or condition is an inflammatory disease.

53. The method of claim 44, wherein the at least one disease or condition is thrombosis.

54. A medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising:

a porous substrate;

a composition contacting the porous substrate, the composition comprising at least one lipid and at least one pharmaceutically effective agent wherein the at least one lipid does not form a lipid bilayer film; and

a dry lipid bilayer film contacting the porous substrate and/or the composition, the dry film comprising at least one pharmaceutically effective agent that can be the same or different from the agent in the composition.

55. The device of claim 54, wherein the at least one pharmaceutically effective agent in the composition acts primarily as an anti-proliferative agent and the agent in the dry bilayer film acts primarily as an anti-inflammatory agent.

56. A medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising:

a porous substrate;

a composition impregnating the porous substrate, the composition comprising at least one lipid and at least one pharmaceutically effective agent;

a film overcoating the composition, the film comprising at least one pharmaceutically effective agent and at least one lipid.

57. The device of claim 56, wherein the film comprises the at least one lipid in the form of a lipid bilayer.

58. The device of claim 56, wherein the at least one pharmaceutically effective agent in the composition is the same as the agent in the film.

59. The device of claim 58, wherein the at least one pharmaceutically effective agent in the composition acts primarily as an anti-proliferative agent and the agent in the film acts primarily as an anti-inflammatory agent.

60. The device of claim 56, wherein the at least one pharmaceutically effective agent in the composition is the different from the agent in the film.

61. A medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising:

a porous substrate;

at least one pharmaceutically effective agent impregnating the porous substrate; and

a film overcoating the porous substrate, the film comprising at least one pharmaceutically effective agent and at least one lipid.

62. The device of claim 61, wherein the film comprises the at least one lipid in the form of a lipid bilayer.

63. The device of claim 61, wherein the at least one pharmaceutically effective agent impregnating the porous substrate is the same as the agent in the film.

64. The device of claim 61, wherein the at least one pharmaceutically effective agent impregnating the porous substrate acts primarily as an anti-proliferative agent and the agent in the film acts primarily as an anti-inflammatory agent.

65. The device of claim 61, wherein the at least one pharmaceutically effective agent in the composition is the different from the agent in the layer.

66. A medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising:

a porous substrate;

a film deposited on the substrate comprising at least one lipid and at least one pharmaceutically active agent; and

at least one pharmaceutically active agent contacting the porous substrate and free of contact with the film.

67. The device of claim 66, wherein the porous substrate is a ceramic.

68. The device of claim 66, wherein the at least one pharmaceutically effective agent contacting the ceramic is primarily an anti-proliferative agent and the agent in the film is primarily an anti-inflammatory agent.

69. The device of claim 66, wherein the at least one coating is free of a polymer.

70. The device of claim 66, wherein the ceramic is bioresorbable and releases the at least one pharmaceutically active agent contacting the ceramic upon resorption of the ceramic.

71. A method of treating at least one disease or condition comprising:

implanting in a subject in need thereof a medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising;

a composition comprising at least one lipid and at least one pharmaceutically active agent, the composition covering at least a portion of the device; and

releasing from the device the least one pharmaceutically active agent encapsulated in the at least one lipid.

72. The method of claim 71, wherein the at least one coating further comprises a substrate and the composition covers at least a portion of the substrate.

73. The method of claim 71, wherein the at least one lipid is present as a lipid bilayer, and the at least one agent is encapsulated in the liposome.

74. The method of claim 73, wherein the liposomes have a particle size distribution, wherein 25% or less of the particles have an average diameter of less than 1 μ

m, and at least 25% of the particles have an average diameter of greater than 1 μ

m.

75. The method of claim 74, wherein at least 50% of the particles have an average diameter of greater than 2 μ

m.

76. The method of claim 74, wherein the liposomes having a particle size greater than 1 μ

m are anti-inflammatory agents.

77. The method of claim 74, wherein the liposomes having a particle size less than 1 μ

m and any drug released in molecular form are anti-proliferative agents.

78. The method of claim 71, wherein the at least one disease or condition is associated with restenosis.