Particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain, useful for pharmaceutical and other applications

• US 6,383,500 B1
• Filed: 06/27/1997
• Issued: 05/07/2002
• Est. Priority Date: 06/27/1996
• Status: Expired due to Term

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: Washington University In St Louis
• Inventors: Wooley, Karen L., Thurmond, K. Bruce II, Huang, Haiyong
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US08/902,614
• Time in Patent Office: 1,775 Days
• Field of Search: 424/781, 424/489, 424/401, 424/497, 424/490, 424/439, 424/408, 424/78.18, 428/407
• US Class Current: 424/401
• 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
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08J 3/246 Intercrosslinking of at least two polymers
• CPC Class Codes: Y10T 428/2998 including synthetic resin or polymer

Abstract

Provided are particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain. Also provided are compositions comprising such particles, including pharmaceutical compositions, methods of making the present particles, and methods of using such particles, for example for delivery of pharmaceutically active agents.

Claims

1. A particle comprising an amphiphilic copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, said shell comprising a region of said copolymer which differs in hydrophilicity and hydrophobicity from another region of said copolymer in said core, said copolymer being crosslinked in said region within said shell, said copolymer region in said shell having a degree of crosslinking ranging from about 1% to about 80%, said copolymer being selected from among amphiphilic copolymers physically conducive to forming micelles prior to crosslinking.

2. The particle of claim 1, wherein said crosslinked shell is permeable.

3. The particle of claim 1, wherein said crosslinked shell is hydrophilic and said core is hydrophobic.

4. The particle of claim 3, wherein said amphiphilic copolymer is crosslinked via functional groups within the hydrophilic region.

5. The particle of claim 3, wherein said hydrophobic core is also crosslinked.

6. The particle of claim 5, wherein said amphiphilic copolymer is crosslinked via functional groups within the hydrophobic region.

7. The particle of claim 1, wherein said crosslinked shell is hydrophobic and said core is hydrophilic.

8. The particle of claim 7, wherein said amphiphilic copolymer is crosslinked via functional groups within the hydrophobic region.

9. The particle of claim 7, wherein said hydrophilic core is also crosslinked.

10. The particle of claim 9, wherein said amphiphilic copolymer is crosslinked via functional groups within the hydrophilic region.

11. The particle of claim 1, where said amphiphilic copolymer is selected from the group consisting of amphiphilic diblock copolymers, amphiphilic triblock copolymers, amphiphilic multiblock copolymers, and amphiphilic graft copolymers.

12. The particle of claim 1, wherein copolymer blocks comprising said crosslinked shell are crosslinked by condensation reactions, chain polymerization reactions, or addition reactions.

13. The particle of claim 12, wherein the copolymer blocks comprising said crosslinked shell are crosslinked using a titrimetric crosslinking reagent.

14. The particle of claim 1, wherein the degree of crosslinking ranges from about 10% to about 50%.

15. The particle of claim 1, wherein said particle has an average molecular weight in the range of from about 10,000 to about 5,000,000.

16. The particle of claim 1, wherein said crosslinked shell has a positive or negative charge.

17. The particle of claim 1, wherein said core has a positive or negative charge.

18. The particle of claim 1, further comprising a pharmaceutically active agent.

19. The particle of claim 5, wherein said core comprises polyisoprene.

20. The particle of claim 1, wherein said crosslinked shell comprises an amphiphilic copolymer region selected from the group consisting of polyvinylpyridine-N-chloromethylstyrene, polyvinylpyridine-N-chloromethylstyrene-co-polyvinylpyridine-N-bromopolyethylene oxide monomethyl ether, and polyacrylic acid.

21. The particle of claim 20 wherein said crosslinked shell comprises polyacrylic acid crosslinked with 2,2′

-(ethylenedioxy)bis(ethylamine) or α

,ω

-(polyethyleneoxy)bis(ethylamine).

22. The particle of claim 1, wherein said core comprises an amphiphilic copolymer region selected from the group consisting of polystyrene, polyisoprene, poly(1,4-isoprene), and poly(6-hydroxycaproic acid).

23. The particle of claim 1 wherein said amphiphilic copolymer is a graft copolymer.

24. A pharmaceutical composition, comprising a particle comprising amphiphilic copolymers, wherein said particle has a crosslinked shell domain and an interior core domain, or

a pharmaceutically acceptable salt thereof, and

a pharmaceutically acceptable carrier, excipient, or diluent.

25. The pharmaceutical composition of claim 24, wherein said crosslinked shell domain is permeable.

26. A pharmaceutical composition, comprising a particle comprising amphiphilic copolymers, wherein said particle has a crosslinked shell domain and an interior core domain, or

a pharmaceutically acceptable salt thereof;

a pharmaceutically active agent; and

a pharmaceutically acceptable carrier, excipient, or diluent.

27. The pharmaceutical composition of claim 26, wherein said pharmaceutically active agent is present in or on said particle.

28. A method of producing a particle comprising an amphiphilic copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, the method comprising:

(a) preparing a micellar assembly comprising an amphiphilic copolymer having reactive functionalities, wherein an interior of said micellar assembly comprise regions of said copolymer that differ in hydrophobicity and hydrophilicity from other regions of said copolymer within a periphery of said assembly; and

(b) crosslinking regions of said copolymer in said periphery of said micellar assembly to produce a particle comprising amphiphilic copolymers having a core and a crosslinked shell.

29. The method of claim 28, wherein said micellar assembly is prepared by placing said amphiphilic copolymers at an appropriate concentration in a solvent system effective in orienting said amphiphilic copolymers into micelles.

30. The method of claim 29, wherein said appropriate concentration of said amphiphilic copolymers is in the range of from about 0.001 mg/mL to about 10 mg/mL.

31. The method of claim 29, wherein said solvent system predominantly comprises a hydrophilic solvent.

32. The method of claim 31, wherein said crosslinked shell is hydrophilic.

33. The method of claim 29, wherein said solvent system predominantly comprises a hydrophobic solvent.

34. The method of claim 33, wherein said crosslinked shell is hydrophobic.

35. The method of claim 28, wherein the regions of said copolymers in said periphery are crosslinked using a titrimetric crosslinking reagent.

36. The method of claim 28, further comprising crosslinking regions of said copolymers in said interior blocks of said micellar assembly to produce a particle having a crosslinked core.

37. A particle comprising an amphiphilic copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, said shell comprising a region of said copolymer which differs in hydrophilicity and hydrophobicity from another region of said copolymer in said core, said copolymer being crosslinked in said region within said shell, said copolymer region in said shell having a degree of crosslinking of at least about 10%, said copolymer being selected from among amphiphilic copolymers physically conducive to forming micelles prior to crosslinking.

38. The particle of claim 37 wherein said crosslinked shell is hydrophilic and said core is hydrophobic.

39. The particle of claim 38 wherein said hydrophobic core is also crosslinked.

40. The particle of claim 37 wherein said crosslinked shell is hydrophobic and said core is hydrophilic.

41. The particle of claim 40 wherein said hydrophilic core is also crosslinked.

42. The particle of claim 37 wherein said amphiphilic copolymer is selected from the group consisting of amphiphilic diblock copolymers, amphiphilic triblock copolymers, amphiphilic multiblock copolymers, and amphiphilic graft copolymers.

43. The particle of claim 37 wherein the degree of crosslinking ranges from about 10% to about 50%.

44. The particle of claim 37 wherein said crosslinked shell comprises an amphiphilic copolymer region selected from the group consisting of polyvinylpyridine-N-chloromethylstyrene, polyvinylpyridine-N-chloromethylstyrene-co-polyvinylpyridine-N-bromopolyethylene oxide monomethyl ether, and polyacrylic acid.

45. The particle of claim 44 wherein said crosslinked shell comprises polyacrylic acid crosslinked with 2,2′

-(ethylenedioxy)bis(ethylamine) or α

,ω

-(polyethyleneoxy)bis(ethylamine).

46. The particle of claim 37 wherein said core comprises an amphiphilic copolymer region selected from the group consisting of polystyrene, polyisoprene, poly(1,4-isoprene), and poly(6-hydroxycaproic acid).

47. The particle of claim 46 wherein said core comprises polyisoprene.

48. A formulation comprising the particle of claim 37 and a carrier, excipient or diluent which is (i) pharmaceutically acceptable, (ii) agronomically acceptable, (iii) gastronomically acceptable, and/or (iv) acceptable for use in foods or cosmetics.

49. The formulation of claim 48 comprising a pharmaceutically acceptable carrier, excipient or diluent and a pharmaceutically active agent.

50. The formulation of claim 49 wherein the pharmaceutically active agent is contained within the particle.

51. The formulation of claim 48 comprising an agronomically acceptable carrier, excipient or diluent and a pesticidally active agent.

52. The formulation of claim 51 wherein the pesticidally active agent is contained within the particle.

53. The formulation of claim 48 comprising a gastronomically acceptable carrier, excipient or diluent.

54. The formulation of claim 48 comprising a carrier, excipient or diluent acceptable for use in foods.

55. The formulation of claim 48 comprising a carrier, excipient or diluent acceptable for use in cosmetics.

56. A particle comprising an amphiphilic copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, said shell comprising a region of said copolymer which differs in hydrophilicity and hydrophobicity from another region of said copolymer in said core, said copolymer being crosslinked in said region within said shell, said copolymer being selected from among amphiphilic copolymers physically conducive to forming micelles prior to crosslinking, said particle having a mean particle diameter ranging from about 2 nm to about 1000 nm.

57. The particle of claim 56 wherein said particle has an aspect ratio ranging from about 0.5 to about 5000.

58. The particle of claim 56 wherein said particle has an aspect ratio ranging from about 1 to about 500.

59. The particle of claim 56 wherein said particle has a mean particle diameter ranging from about 5 to about 200.

60. The particle of claim 59 wherein said particle has an aspect ratio ranging from about 0.5 to about 5000.

61. The particle of claim 59 wherein said particle has an aspect ratio ranging from about 1 to about 500.

62. The particle of claim 56 wherein said crosslinked shell is hydrophilic and said core is hydrophobic.

63. The particle of claim 62 wherein said hydrophobic core is also crosslinked.

64. The particle of claim 56 wherein said crosslinked shell is hydrophobic and said core is hydrophilic.

65. The particle of claim 64 wherein said hydrophilic core is also crosslinked.

66. The particle of claim 56 wherein said amphiphilic copolymer is selected from the group consisting of amphiphilic diblock copolymers, amphiphilic triblock copolymers, amphiphilic multiblock copolymers, and amphiphilic graft copolymers.

67. The particle of claim 56 wherein said copolymer region comprised by said shell has a degree of crosslinking ranging from about 1% to about 80%.

68. The particle of claim 56 wherein said crosslinked shell comprises an amphiphilic copolymer region selected from the group consisting of polyvinylpyridine-N-chloromethylstyrene, polyvinylpyridine-N-chloromethylstyrene-co-polyvinylpyridine-N-bromopolyethylene oxide monomethyl ether, and polyacrylic acid.

69. The particle of claim 68 wherein said crosslinked shell comprises polyacrylic acid crosslinked with 2,2′

-(ethylenedioxy)bis(ethylamine) or α

,ω

-(polyethyleneoxy)bis(ethylamine).

70. The particle of claim 68 wherein said core comprises an amphiphilic copolymer region selected from the group consisting of polystyrene, polyisoprene, poly(1,4-isoprene), and poly(6-hydroxycaproic acid).

71. The particle of claim 70 wherein said core comprises polyisoprene.

72. A particle comprising an amphiphilic block copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, said shell comprising a block of said copolymer which differs in hydrophilicity and hydrophobicity from another block of said copolymer in said core, said copolymer being crosslinked in the block in said shell, said copolymer being selected from among amphiphilic block copolymers physically conducive to forming micelles prior to crosslinking.

73. The particle of claim 72 wherein said particle has mean particle diameter ranging from about 2 nm to about 1000 nm.

74. The particle of claim 73 wherein said particle has an aspect ratio ranging from about 0.5 to about 5000.

75. The particle of claim 72 wherein said crosslinked shell is hydrophilic and said core is hydrophobic.

76. The particle of claim 75 wherein said hydrophobic core is also crosslinked.

77. The particle of claim 72 wherein said crosslinked shell is hydrophobic and said core is hydrophilic.

78. The particle of claim 77 wherein said hydrophilic core is also crosslinked.

79. The particle of claim 72 wherein said amphiphilic block copolymer is selected from the group consisting of amphiphilic diblock copolymers, amphiphilic triblock copolymers, and amphiphilic multiblock copolymers.

80. The particle of claim 72 wherein said copolymer region comprised by said shell has a degree of crosslinking ranging from about 1% to about 80%.

81. The particle of claim 72 wherein said crosslinked shell comprises an amphiphilic copolymer region selected from the group consisting of polyvinylpyridine-N-chloromethylstyrene, polyvinylpyridine-N-chloromethylstyrene-co-polyvinylpyridine-N-bromopolyethylene oxide monomethyl ether, and polyacrylic acid.

82. The particle of claim 81 wherein said crosslinked shell comprises polyacrylic acid crosslinked with 2,2′

-(ethylenedioxy)bis(ethylamine) or α

,ω

-(polyethyleneoxy)bis(ethylamine).

83. The particle of claim 72 wherein said core comprises an amphiphilic copolymer region selected from the group consisting of polystyrene, polyisoprene, poly(1,4-isoprene), and poly(6-hydroxycaproic acid).

84. The particle of claim 83 wherein said core comprises polyisoprene.

85. A particle comprising an amphiphilic copolymer and having a core and a crosslinked shell which differs from said core in hydrophilicity and hydrophobicity, said shell comprising a region of said copolymer which differs in hydrophilicity and hydrophobicity from another region of said copolymer in said core, said copolymer being crosslinked in the region in said shell, said particle being derived from a micellar assembly of said amphiphilic copolymer.

86. The particle of claim 85 wherein said particle is derived from a shell crosslinked micellar assembly.

87. The particle of claim 85 wherein said particle has mean particle diameter ranging from about 2 nm to about 1000 nm.

88. The particle of claim 87 wherein said particle has an aspect ratio ranging from about 0.5 to about 5000.

89. The particle of claim 85 wherein said crosslinked shell is hydrophilic and said core is hydrophobic.

90. The particle of claim 89 wherein said hydrophobic core is also crosslinked.

91. The particle of claim 85 wherein said crosslinked shell is hydrophobic and said core is hydrophilic.

92. The particle of claim 91 wherein said hydrophilic core is also crosslinked.

93. The particle of claim 85 wherein said amphiphilic copolymer is selected from the group consisting of amphiphilic diblock copolymers, amphiphilic triblock copolymers, amphiphilic multiblock copolymers, and graft copolymers.

94. The particle of claim 85 wherein said copolymer region comprised by said shell has a degree of crosslinking ranging from about 1% to about 80%.

95. The particle of claim 85 wherein said crosslinked shell comprises an amphiphilic copolymer region selected from the group consisting of polyvinylpyridine-N-chloromethylstyrene, polyvinylpyridine-N-chloromethylstyrene-co-polyvinylpyridine-N-bromopolyethylene oxide monomethyl ether, and polyacrylic acid.

96. The particle of claim 95 wherein said crosslinked shell comprises polyacrylic acid crosslinked with 2,2′

-(ethylenedioxy)bis(ethylamine) or α

,ω

-(polyethyleneoxy)bis(ethylamine).

97. The particle of claim 85 wherein said core comprises an amphiphilic copolymer region selected from the group consisting of polystyrene, polyisoprene, poly(1,4-isoprene), and poly(6-hydroxycaproic acid).

98. The particle of claim 97 wherein said core comprises polyisoprene.