Functionalized degradable polymers

• US 20030050426A1
• Filed: 06/22/2001
• Published: 03/13/2003
• Est. Priority Date: 06/22/2001
• Status: Active Grant

• Current Assignee: Venkatram P. Shastri
• Original Assignee: Venkatram P. Shastri
• Inventors: Shastri, Venkatram P.
• Granted Patent: US 6,730,772 B2
• Time in Patent Office: Days
• US Class Current: 528/92
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 65/22 Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring
• CPC Class Codes: C08L 2205/05 containing polymer components which can react with one another
• CPC Class Codes: C08L 2666/18 Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

The present invention relates to degradable polymers having increased functionality, synthesized through ring-opening polymerization of functionalized epoxides alone or in combination with cyclic esters under mild, controlled conditions.

Claims

1. A homopolymer comprising a ring-opened functionalized epoxide formed by polymerization using an initiating system permitting polymerization under mild conditions.

2. The homopolymer of claim 1 wherein the epoxide is functionalized before polymerization.

3. The homopolymer of claim 1 wherein the epoxide is functionalized after polymerization.

4. The homopolymer of claim 1, wherein the functionalized epoxide is an epoxide having the composition E—

CHR—

G, wherein E=(CH₂OCH)—

, R is hydrogen or alkyl, and G comprises a derivatizable group.

5. The epoxide of claim 4, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

6. The epoxide of claim 4, wherein the derivatizable group G comprises unsaturated functionality.

7. The homopolymer of claim 1 wherein the epoxide is an epoxide of an ester of 2-methyl-pent-4-enoic acid.

8. The homopolymer of claim 7 wherein the ester of 2-methyl-pent-4-enoic acid is ethyl-2-methyl-pent-4-enoate [EMP].

9. The homopolymer of claim 7 wherein the ester of 2-methyl-pent-4-enoic acid is monomethyl polyethylene oxide-2-methyl-pent-4-enoate [PEG-MP].

10. The homopolymer of claim 7 wherein the ester of 2-methyl-pent-4-enoic acid is (2′

-methacryloyl)ethyl-2-methyl-pent-4-enoate [HEMA-MP].

11. The homopolymer of claim 1 wherein the initiating system comprises a stannous catalyst and an alcohol-containing species.

12. The homopolymer of claim 11 wherein the stannous catalyst comprises stannous (2-ethyl hexanoate).

13. A homopolymer formed by ring-opening polymerization of a functionalized epoxide using an initiating system permitting polymerization under mild conditions.

14. The homopolymer of claim 13 wherein the epoxide is functionalized before polymerization.

15. The homopolymer of claim 13 wherein the epoxide is functionalized after polymerization.

16. The homopolymer of claim 13, wherein the functionalized epoxide is an epoxide having the composition E—

CHR—

G, wherein E=(CH₂OCH)—

, R is hydrogen or alkyl, and G comprises a derivatizable group.

17. The epoxide of claim 16, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

18. The epoxide of claim 16, wherein the derivatizable group G comprises unsaturated functionality.

19. The homopolymer of claim 13 wherein the epoxide is an epoxide of an ester of 2-methyl-pent-4-enoic acid.

20. The homopolymer of claim 19 wherein the ester of 2-methyl-pent-4-enoic acid is ethyl-2-methyl-pent-4-enoate [EMP].

21. The homopolymer of claim 19 wherein the ester of 2-methyl-pent-4-enoic acid is monomethyl polyethylene oxide-2-methyl-pent-4-enoate [PEG-MP].

22. The homopolymer of claim 19 wherein the ester of 2-methyl-pent-4-enoic acid is (2′

-methacryloyl)ethyl-2-methyl-pent-4-enoate [HEMA-MP].

23. The homopolymer of claim 13 wherein the initiating system comprises a stannous catalyst and an alcohol-containing species.

24. The homopolymer of claim 23 wherein the stannous catalyst comprises stannous (2-ethyl hexanoate).

25. A copolymer comprising randomly distributed units of a ring-opened epoxide and a ring-opened cyclic ester.

26. The copolymer of claim 25 wherein the epoxide is functionalized before ring-opening.

27. The copolymer of claim 25 wherein the epoxide is functionalized after polymerization.

28. The copolymer of claim 25, wherein the epoxide is an epoxide having the composition E—

CHR—

G, wherein E=(CH₂OCH)—

, R is hydrogen or alkyl, and G comprises a derivatizable group.

29. The epoxide of claim 28, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

30. The epoxide of claim 28, wherein the derivatizable group G comprises unsaturated functionality.

31. The copolymer of claim 25 wherein the epoxide is an epoxide of an ester of 2-methyl-pent-4-enoic acid.

32. The copolymer of claim 31 wherein the ester of 2-methyl-pent-4-enoic acid is ethyl-2-methyl-pent-4-enoate [EMP].

33. The copolymer of claim 31 wherein the ester of 2-methyl-pent-4-enoic acid is monomethyl polyethylene oxide-2-methyl-pent-4-enoate [PEG-MP].

34. The copolymer of claim 31 wherein the ester of 2-methyl-pent-4-enoic acid is (2′

-methacryloyl)ethyl-2-methyl-pent-4-enoate [HEMA-MP].

35. The copolymer of claim 25 wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, and copolymers of the foregoing.

36. The copolymer of claim 25 wherein the copolymer is degradable.

95. The polymer as in claims 25, 51, 79, or 88, formed by ring-opening copolymerization of a functionalized epoxide and a cyclic ester.

96. The polymer of claim 95, wherein the functionalized epoxide acts as a solvent for the cyclic ester.

97. A method of using the polymer as in claims 25, 51, 79, or 88 for delivery of active agents to a body.

98. A method of using the polymer as in claims 25, 51, 79, or 88 as polymer scaffolds for tissue engineering.

99. A method of using the polymer as in claims 25, 51, 79, or 88 for making articles that possess shaped memories.

100. The polymer as in claims 25, 5179, or 88 wherein the polymers each have a polydispersity (M_w/M_n) of less than about 3.5.

101. The polymer as in claims 25, 51, 79, or 88 wherein the polymers each have a polydispersity (M_w/M_n) of less than about 3.0.

102. The polymer as in claims 25, 51, 79, or 88 wherein the polymers each have a polydispersity (M_w/M_n) of less than about 2.5.

103. The polymer as in claims 25, 51, 79, or 88 wherein the polymers each have a polydispersity (M_w/M_n) of less than about 2.0.

37. A method of making a homopolymer, comprising polymerizing a functionalized epoxide using an initiating system that permits polymerization under mild conditions.

38. The method of claim 37 wherein the initiating system comprises a stannous catalyst and an alcohol-containing species.

39. The method of claim 38 wherein the stannous catalyst comprises stannous (2-ethyl hexanoate).

40. The method of claim 37 wherein polymerizing comprises ring-opening the epoxide.

41. The homopolymer formed by the method of claim 37.

42. A method of making a homopolymer, comprising polymerizing a functionalized epoxide using an initiating system that permits polymerization at a temperature of less than about 100°

C.

43. A method of making a homopolymer according to claim 42, wherein the temperature is from about 50°

C. to about 75°

C.

44. A method of making a copolymer comprising randomly polymerizing an epoxide and a cyclic ester.

45. The method of claim 44 wherein polymerizing is initiated by an initiating system permitting polymerization under mild conditions.

46. The method of claim 45 wherein the initiating system comprises a stannous catalyst and an alcohol-containing species.

47. The method of claim 45 wherein the stannous catalyst used to initiate polymerization comprises stannous (2-ethyl hexanoate).

48. The method of claim 44 wherein polymerizing comprises ring-opening the epoxide and the cyclic ester.

49. The method of claim 44 wherein the cyclic ester is selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, and copolymers of the foregoing.

50. The method of claim 44 wherein the copolymer is degradable.

51. The copolymer formed by the method of claim 44.

52. A method of making a copolymer, comprising randomly polymerizing an epoxide and a cyclic ester using an initiating system that permits polymerization at a temperature of less than about 100°

C.

53. A method making a copolymer according to claim 52, wherein the temperature is from about 50°

C. to about 75°

C.

54. A method for preparing particulates, comprising:

(a) preparing a first phase, the first phase comprising an active agent, a copolymer which comprises a ring-opened epoxide and a ring-opened cyclic ester, and a solvent;

(b) preparing a second phase, wherein the first phase is substantially immiscible with the second phase;

(c) combining the first phase and the second phase to form an emulsion; and

(d) extracting solvent from the emulsion using an extraction liquid to thereby form particulates containing the active agent.

55. A method for preparing particulates, comprising:

(a) preparing an emulsion comprising an active agent, and a copolymer, which comprises a ring-opened epoxide and a ring-opened cyclic ester, dissolved in a solvent;

(b) combining the emulsion with a coacervating agent that is free from solvents for the copolymer to form a combined phase;

(c) extracting solvent from the combined phase in an extraction medium that is a non-solvent for the copolymer and a solvent for the solvent and the coacervating agent, whereby particulates precipitate out of the extraction medium.

56. A method of preparing particulates, comprising:

(a) freezing droplets of a polymer solution, which comprises a ring-opened epoxide and a ring-opened cyclic ester, by atomizing the droplets into a liquefied gas, having a temperature below the freezing point of the polymer solution effective to immediately freeze the atomized polymer solution upon contact, said liquefied gas overlaying a layer of frozen liquid non-solvent for the polymer, wherein the polymer solvent is miscible in the liquid non-solvent;

(b) thawing the polymer solvent in the frozen droplets of polymer solution; and

(c) extracting the solvent from the droplets into a liquid non-solvent to form polymeric particulates.

57. The method of claim 56 wherein the particulates additionally comprise an active agent.

59. The method of claim 57 wherein the polymeric material comprises an active agent.

58. A method for forming particulates of a polymeric material, which comprises a ring-opened epoxide and a ring-opened cyclic ester, from droplets of a solution of the polymeric material and a solvent, comprising the steps of:

(a) directing the droplets into a freezing section containing a liquefied gas, whereby the droplets freeze; and

(b) contacting the frozen droplets in an extraction section with a liquid non-solvent to extract the solvent into the non-solvent thereby forming said particulates;

wherein the freezing section and extraction section are separated and the non-solvent is in the liquid state throughout the method.

60. A method of using -2-methyl-pent-4-enoic acid [MPA], which comprises a carboxylic acid group and a labile proton adjacent thereto, comprising the step of functionalizing the labile proton of MPA adjacent to the carboxylic acid group.

61. A method of using X-2-methyl-pent-4-enoate [X-MP], wherein X=alkyl, which comprises an alkyl ester group and a labile proton adjacent thereto, comprising the step of functionalizing the labile proton of X-MP adjacent to the carboxylic acid group.

62. The compound monomethyl polyethylene oxide-2-methyl-pent-4-enoate [PEG-MP].

63. The compound (2′

-methacryloyl)ethyl-2-methyl-pent-4-enoate [HEMA-MP].

64. The compound X-2-methyl-pent-4-enoate oxide [X-MPO], wherein X=alkyl.

65. The compound ethyl-2-methyl-pent-4-enoate oxide [EMPO].

66. The compound monomethyl polyethylene oxide-2-methyl-pent-4-enoate oxide [PEG-MPO].

67. The compound (2′

-methacryloyl)ethyl-2-methyl-pent-4-enoate oxide [HEMA-MPO].

68. An epoxide having the composition E—

CHR—

G, wherein E=(CH₂OCH)—

, R is hydrogen or alkyl, and G comprises a derivatizable group.

69. The epoxide of claim 68, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

70. The epoxide of claim 68, wherein the derivatizable group G comprises unsaturated functionality.

71. The epoxide of claim 68, wherein the derivatizable group G comprises a degradable linkage.

72. A polymer having the formula —

[O—

(CHR)—

(CHG)]—

, wherein R is hydrogen or alkyl, and G comprises a derivatizable group.

73. The polymer of claim 72, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

74. The polymer of claim 72, wherein the derivatizable group G comprises unsaturated functionality.

75. The polymer of claim 74, wherein the unsaturated functionality is chemically or photochemically cured.

76. The polymer of claim 72, wherein the derivatizable group G comprises a degradable linkage.

77. The polymer of claim 72 further comprising a linkage —

[O—

(CHR)—

(CHG′

)]—

, wherein R is hydrogen or alkyl, and G′

is different from G and is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

78. The polymer of claim 77 further comprising an ester linkage derived from one or more of the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, and cyclic carbonates.

79. A degradable polymer comprising a backbone comprised of ether and ester linkages, having the formula:

—

{[O—

(CR₁R₂)_a—

C(O)]_x—

[O—

(CHR)—

(CHG)]_y}—

,

wherein R=H or alkyl;

R₁=H, alkyl or substituted alkyl;

R₂=H, alkyl, or substituted alkyl; and

G comprises a derivatizable group; and

wherein a=1 to 5;

x is greater or equal to one; and

y is greater or equal to one.

80. The degradable polymer of claim 79, wherein the derivatizable group G is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

81. The degradable polymer of claim 79, wherein the derivatizable group G comprises unsaturated functionality.

82. The degradable polymer of claim 79, wherein the unsaturated functionality is chemically or photochemically cured.

83. The degradable polymer of claim 79, wherein the derivatizable group G comprises a degradable linkage.

84. The degradable polymer of claim 79, wherein the derivatizable group G comprises an ester and unsaturated functionality.

85. The degradable polymer of claim 79, wherein the ester linkage, [O—

(CR₁R₂)_a—

C(O)]_x, is derived from one or more of the group consisting of lactide, glycolide, and caprolactone.

86. The degradable polymer of claim 79 wherein the ester and ethoxy linkages are randomly distributed in the polymer backbone.

87. The degradable polymer of claim 79 wherein the ether linkage, —

[O—

(CHR)—

(CHG)]_y is repeated no more than 7 times sequentially.

88. A degradable polymer comprising a backbone of randomly distributed ether and ester linkages, wherein the ether linkages comprise a derivatizable group and the ester linkages are derived from lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, and derivatives thereof.

89. The degradable polymer of claim 88, wherein the derivatizable group is selected from the group consisting of alkyl groups or chains, esters, ethers, sulfonates, carbonates, amino carbonates, carbamates, amides, imides, anhydrides, peptides, lipids, cationic charge carriers, anionic charge carriers, pluronics, PEG, PEO, PPO, urethanes, fatty acids, fatty alcohols, cholesterol, N,N alkyl amines, sugars, and polysaccharides.

90. The degradable polymer of claim 88, wherein the derivatizable group comprises unsaturated functionality.

91. The degradable polymer of claim 90, wherein the unsaturated functionality is chemically or photochemically cured.

92. The degradable polymer of claim 88, wherein the derivatizable group G comprises a degradable linkage.

93. The degradable polymer of claim 88, wherein the derivatizable group comprises an ester and unsaturated functionality.

94. A copolymer comprising randomly distributed units of a ring-opened epoxide and a ring-opened cyclic ester, wherein the ring-opened epoxide unit is repeated no more than 7 times sequentially.