Polymer micelle as monolayer or layer-laminated surface

• US 20050079197A1
• Filed: 09/02/2003
• Published: 04/14/2005
• Est. Priority Date: 11/04/1999
• Status: Active Grant

• Current Assignee: Johnson & Johnson Vision Care Incorporated (Johnson & Johnson)
• Original Assignee: Johnson & Johnson Vision Care Incorporated (Johnson & Johnson)
• Inventors: Iijima, Michihiro, Kataoka, Kazunori, Nagasaki, Yukio, Emoto, Kazunori
• Granted Patent: US 7,674,478 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61F 2/14 Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
• CPC Class Codes: A61F 2/16 Intraocular lenses
• CPC Class Codes: A61F 2250/0056 differing in wettability, e.g. in hydrophilic or hydrophobic behaviours
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence

Abstract

The present invention is directed to a coated biomedical device said micelle having a hydrophilic outer shell and a hydrophobic inner core, or a hydrophobic outer shell and a hydrophilic inner core said micelle comprised of a block copolymer having a HLB value ranging from about 1 to about 40. The medical device may have one coating thereon or multiple coatings. The present invention is also directed to the use of the micelle as a drug carrier.

Claims

1. A coated biomedical device wherein the coating comprises at least one polymeric micelle immobilized to the surface of said biomedical device, said micelle having either a hydrophilic core and hydrophobic shell or a hydrophobic core and a hydrophilic shell, said micelle comprised of a block copolymer having a HLB value ranging from about 1 to about 40.

2. The coated biomedical device according to claim 1 wherein the HLB value of said block copolymer ranges from about 4 to about 20.

3. The coated biomedical device according to claim 1 wherein the micelle has an outer hydrophilic shell and an inner hydrophobic core.

4. The coated biomedical device according to claim 1 wherein the micelle has an outer hydrophobic shell and an inner hydrophilic core.

5. The coated biomedical device according to claim 1 wherein the micelle is covalently bonded to the surface of the biomedical device.

6. The coated biomedical device according to claim 5 wherein the micelle is bonded to the surface of the biomedical device through a covalent bond selected from the group consisting of

7. The coated biomedical device according to claim 1 wherein the micelle has a hydrophilic outer shell and a hydrophobic inner core and the hydrophilic outer shell is covalently bonded to the surface of the biomedical device.

8. The coated biomedical device according to claim 1 wherein the micelle has a hydrophobic outer shell and a hydrophilic inner core and the hydrophobic outer shell is covalently bonded to the surface of said biomedical device.

9. The coated biomedical device according to claim 7 wherein the hydrophilic shell consists essentially of a polyethylene glycol, polyacrylamide, polymethacrylamide, polyvinyl pyrrolidone, or polyvinyl alcohol.

10. The coated biomedical device according to claim 9 wherein the hydrophilic shell is a polyethylene glycol.

11. The coated biomedical device according to claim 7 wherein the hydrophobic inner core is methylmethacrylate, silicone, poly(α

-hydroxycarboxylic acid) or poly(ω

-hydroxycarboxylic acid).

12. The coated biomedical device according to claim 11 wherein the hydrophobic inner core comprises poly(α

-hydroxycarboxylic acid) or poly(ω

-hydroxycarboxylic acid) or methylmethacrylate.

13. The coated biomedical device according to claim 1 wherein the hydrophobic core has at its terminus a free radical reactive group.

14. The coated biomedical device according to claim 13 wherein said hydrophobic shell has at its terminus an ethyleneically polymerizable group.

15. The coated biomedical device according to claim 14 wherein the ethyleneically unsaturated polymerizable group is a free radical reactive polymerizable acrylate, free radical reactive polymerizable styryl, free radical reactive polymerizable methacrylate or a free radical polymerizable vinyl ethyl ether.

16. The coated biomedical device according to claim 1 wherein said hydrophilic core has at its terminus end a free radical reactive group.

17. The coated biomedical device according to claim 16 wherein said hydrophilic shell has at its terminus end an ethyleneically unsaturated polymerizable group.

18. The coated biomedical device according to claim 17 wherein the ethyleneically unsaturated polymerizable group is a free radical reactive polymerizable acrylate, free radical reactive polymerizable styryl, free radical reactive polymerizable methacrylate or a free radical polymerizable vinyl ethyl ether.

19. The coated biomedical device according to claim 1 wherein the biomedical device is coated with a monolayer of said micelle.

20. The coated biomedical device according to claim 1 wherein the biomedical device is coated with a multi-layer of said micelle.

21. The coated biomedical device of claim 20 wherein the biomedical device is coated with at most six layers of said micelle.

22. The coated biomedical device according to claim 20 wherein the multi-layer comprises at least one set of covalently bonded layers comprised of two polymer micelles and a second polymer sandwiched therebetween, said second polymer having a molecular weight greater than 8000 daltons, having a plural number of functional groups thereon selected from the group consisting of an amino group, a carboxyl group, and a sulfo group.

23. The coated biomedical device according to claim 22 wherein the second polymer is polyallylamine, polyvinylamine, polylysine, chitosan, polyethyleneimine, poly(meth)acrylic acid, carboxymethylcellulose, alginic acid, heparin, or polystyrene sulfonic acid.

24. The coated biomedical device according to claim 20, wherein at least two micelle layers are crosslinked to one another.

25. The coated biomedical device according to claim 20 wherein the biomedical device is coated with a multi-layer polymer micelle wherein the multi-layer comprises at least one set of covalently bonded layers comprised of two polymer micelles and sandwiched therebetween is a low molecular weight molecule selected from the group consisting of lower alkylene diamine, glutaraldehyde and ethanedithiol.

26. The coated biomedical device according to claim 1 wherein the block copolymer has the formula:

27. The coated biomedical device according to claim 1 wherein the block copolymer has the formula:

X—

O

CH₂CH₂O

_m

Y

_nZ 

 

(II)

wherein

X denotes an alkyl group having 1 to 10 carbon atoms which has an amino group, a carboxyl group or a mercapto group;

Y denotes moieties of the following formula;

wherein

R¹¹ and R¹² independently denote a hydrogen atom or a C_1-5 alkyl;

R³ denotes a hydrogen atom or a methyl group;

R⁴ denotes a C_1-5 alkyl substituted by a hydroxyl group which may be protected; and

q denotes an integer of 2-5, and

wherein

Z denotes acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl;

m denotes an integer of 2-10,000; and

n denotes an integer of 2-10,000.

28. The coated biomedical device according to claim 1 wherein the block copolymer has the formula:

29. The coated biomedical device according to claim 1 wherein the biomedical device is a contact lens or intraocular lens.

72. The coated biomedical device according to claim 1 which substantially prevents the permeation of dextran therethrough.

30. A method for reducing protein contamination of a biomedical device after insertion in an animal, said method comprises coating said biomedical device with a protein adsorption inhibiting effective amount of polymeric micelle immobilized on the surface of said biomedical device, said micelle having a hydrophilic outer shell and a hydrophobic inner core or a hydrophobic outer shell and a hydrophilic inner core, said micelle comprised of a block copolymer having a HLB value ranging from about 1 to about 40.

31. The method according to claim 30 wherein the HLB value of said block copolymer ranges from about 4 to about 20.

32. The method according to claim 30 wherein the micelle has an outer hydrophilic shell and an inner hydrophobic core.

33. The method according to claim 30 wherein the micelle has an outer hydrophobic shell and an inner hydrophilic core.

34. The method according to claim 30 wherein the micelle is covalently bonded to the surface of the biomedical device.

35. The coated biomedical device according to claim 34 wherein the hydrophilic core is bonded to the surface of the biomedical device through covalent bonds selected from the group consisting of

36. The method according to claim 30 wherein the micelle has a hydrophilic outer shell and a hydrophobic inner core and the hydrophilic outer shell is covalently bonded to the surface of the biomedical device.

37. The method according to claim 30 wherein the micelle has a hydrophobic outer shell and a hydrophilic inner core and the hydrophobic outer shell is covalently bonded to the surface of said biomedical device.

38. The method according to claim 36 wherein the hydrophilic outer shell consists essentially of a polyethylene glycol, polyacrylamide, polymethacrylamide, polyvinyl pyrrolidone, polyvinyl alcohol or polymethacrylate or polyacrylic ester.

39. The method according to claim 38 wherein the hydrophilic outer shell is a polyethylene glycol.

40. The method according to claim 36 wherein the hydrophobic core is methylmethacrylate, silicone, poly(α

-hydroxycarboxylic acid), poly(ω

-hydroxy-carboxylic acid).

41. The method according to claim 40 wherein the hydrophobic core comprises poly(α

-hydroxycarboxylic acid), poly(ω

-hydroxycarboxylic acid) or methylmethacrylate.

42. The method according to claim 33 wherein the outer hydrophobic shell has on its terminus a free radical reactive group.

43. The method according to claim 42 wherein said outer hydrophobic shell has on its terminus an ethylenically unsaturated polymerizable group.

44. The method according to claim 43 wherein said ethylenically unsaturated polymerizable group is a free radical reactive polymerizable acrylate, free radical reactive polymerizable styryl, free radical reactive polymerizable methacrylate or a free radical polymerizable vinyl ethyl ether.

45. The method according to claim 32 wherein

said hydrophilic outer shell has at its terminus end a free radical reactive group.

46. The method according to claim 45 wherein

said hydrophilic outer shell has at its terminus end an ethylenically unsaturated polymerizable group.

47. The method according to claim 46 wherein the ethyleneically unsaturated polymerizable group is a free radical reactive polymerizable acrylate, free radical reactive polymerizable styryl, free radical reactive polymerizable methacrylate or a free radical polymerizable vinyl ethyl ether.

48. The method according to claim 30 wherein the biomedical device is coated with one layer of micelle.

49. The method according to claim 30 wherein the biomedical device is coated with a multi-layer polymer micelle.

50. The method according to claim 49 wherein the biomedical device is coated with up to six layers of polymer micelle.

51. The method according to claim 49 wherein the multi-layer comprises at least one set of covalently bonded layers comprised of two polymer micelles and a second polymer sandwiched therebetween, said second polymer having a molecular weight greater than 8,000 daltons and having a plural number of functional groups selected from the group consisting of an amino group, a carboxyl group, and a sulfo group.

52. The method according to claim 51 wherein the second polymer is polyallylamine, polyvinylamine, polylysine, chitosan, polyethyleneimine, poly(meth)acrylic acid, carboxymethylcellulose, alginic acid, heparin, or polystyrene sulfonic acid.

53. The method according to claim 49 wherein the biomedical device is coated with a multi-layer polymer micelle wherein the multi-layer comprises at least one set of covalently bonded layers comprised of two polymer micelles and sandwiched therebetween is a low molecular weight molecule selected from the group consisting of lower alkylene diamine, glutaraldehyde and ethanedithiol.

54. The method according to claim 30 wherein the biomedical device is a contact lens or intraocular lens.

55. The method according to claim 30 wherein the block copolymer has the formula:

56. The method according to claim 30 wherein the block copolymer has the formula:

X—

O

CH₂CH₂O

_m

Y

_nZ 

 

(II)

wherein

X denotes an alkyl group having 1 to 10 carbon atoms which has an amino group, a carboxyl group or a mercapto group;

Y denotes a moiety of the following formula;

wherein

R¹¹ and R¹² independently denote a hydrogen atom or a C_1-5 alkyl;

R³ denotes a hydrogen atom or a methyl group;

R⁴ denotes a C_1-5 alkyl substituted by a hydroxyl group which may be protected; and

q denotes an integer of 2-5, and

wherein

Z denotes acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl;

m denotes an integer of 2-10,000; and

n denotes an integer of 2-10,000.

57. The method according to claim 30 wherein the block copolymer has the formula:

58. The method according to claim 30 wherein the biomedical device is a contact lens or intraocular lens.

70. The method according to claim 58 wherein the biomedical device is a contact lens.

71. The method according to claim 70 wherein the contact lens is comprised of poly(hydroxyethylmethacrylate).

59. (canceled)

60. (canceled)

61. (canceled)

62. (canceled)

63. (canceled)

64. (canceled)

65. (canceled)

66. (canceled)

67. A method for reducing microbial contamination of a biomedical device after insertion in an animal, said method comprises coating said biomedical device with an anti-microbial effective amount of a polymeric micelle, said micelle having either an hydrophilic outer shell and a hydrophobic inner core or a hydrophobic outer shell and a hydrophilic inner core, said micelle comprised of a block copolymer having a HLB value ranging from about 1 to about 40.

68. The method according to claim 67 wherein the HLB value of said block copolymer ranges from about 4 to about 20.

69. The method according to claim 67 wherein an anti-microbial agent is additionally present on the biomedical device.