POLYMERIC COMPOSITIONS AND METHODS OF MAKING AND USING THEREOF

• US 20100285094A1
• Filed: 04/20/2007
• Published: 11/11/2010
• Est. Priority Date: 04/20/2006
• Status: Abandoned Application

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Gupta, Kavita
• Application Number:
  US12/226,547
• Publication Number:
  US 20100285094A1
• Time in Patent Office: Days
• US Class Current: 424/429
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 15/60 Liquid-swellable gel-forming materials, e.g. super-absorbents
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: C08F 222/36 Amides or imides
• CPC Class Codes: C08F 232/00 Copolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system
• CPC Class Codes: C08G 2190/00 Compositions for sealing or packing joints

Abstract

Described herein are polymeric compositions that comprise at least one polymer residue and at least one crosslinking moiety, wherein the polymer residue is crosslinked by the crosslinking moiety and wherein the crosslinking moiety is formed from a reaction between a boronic acid moiety and a hydroxamic acid moiety. Also, described are methods of making and using such polymeric compositions.

Claims

1. A polymeric composition comprising at least one polymer residue and at least one crosslinking moiety, wherein the polymer residue is crosslinked by the crosslinking moiety and wherein the crosslinking moiety is formed from a reaction between a boronic acid moiety and a hydroxamic acid moiety.

2. The polymeric composition of claim 1, wherein the boronic acid moiety comprises an alkylboronic acid moiety.

3. The polymeric composition of claim 2, wherein the alkylboronic acid moiety comprises Formula IV:

4. The polymeric composition of claim 3, wherein J¹ and J² are hydrogen and one of J³ and J⁴ is hydrogen and the other is hydroxy, alkoxy, nitro, amino, or halide.

5. The polymeric composition of claim 3, wherein J³ and J⁴ are hydrogen and one of J¹ and J² is hydrogen and the other is hydroxy, alkoxy, nitro, amino, or halide.

6. The polymeric composition of claim 1, wherein the boronic acid moiety comprises an arylboronic acid moiety.

7. The polymeric composition of claim 6, wherein the arylboronic acid moiety comprises a moiety having Formula V:

8. The polymeric composition of claim 1, wherein the boronic acid moiety comprises a phenylboronic acid moiety.

9. The polymeric composition of claim 1, wherein the boronic acid moiety further comprises a bioactive agent.

10. The polymeric composition of claim 1, wherein the hydroxamic acid moiety comprises an alkylhydroxamic acid moiety.

11. The polymeric composition of claim 10, wherein the alkylhydroxamic acid moiety comprises Formula VI:

12. The polymeric composition of claim 11, wherein Q¹ and Q² are hydrogen and one of Q³ and Q⁴ is hydrogen and the other is hydroxy, alkoxy, nitro, amino, or halide.

13. The polymeric composition of claim 11, wherein Q³ and Q⁴ are hydrogen and one of Q¹ and Q² is hydrogen and the other is hydroxy, alkoxy, nitro, amino, or halide.

14. The polymeric composition of claim 1, wherein the hydroxamic acid moiety comprises an arylhydroxamic acid moiety.

15. The polymeric composition of claim 14, wherein the arylhydroxamic acid moiety comprises a phenylhydroxamic acid moiety having Formula VII:

16. The polymeric composition of claim 15, wherein the arylhydroxamic acid moiety comprises a phenylhydroxamic acid moiety having Formula VIIIa:

17. The polymeric composition of claim 15, wherein the arylhydroxamic acid moiety comprises a phenylhydroxamic acid moiety having Formula VIIIb:

18. The polymeric composition of claim 1, wherein the hydroxamic acid moiety comprises a salicylhydroxamic acid moiety.

19. The polymeric composition of claim 1, wherein the hydroxamic acid moiety further comprises a bioactive agent.

20. The polymeric composition of claim 1, wherein the crosslinking moiety comprises a boronate ester.

21. The polymeric composition of claim 1, wherein the crosslinking moiety comprises a bioactive agent.

22. The polymeric composition of claim 1, wherein at least one polymer residue comprises a homopolymer.

23. The polymeric composition of claim 1, wherein at least one polymer residue comprises a block, graft, or graft comb copolymer.

24. The polymeric composition of claim 1, wherein at least one polymer residue comprises a multi-armed polymer.

25. The polymeric composition of claim 1, wherein at least one polymer residue has a molecular weight of from about 2,000 Da to about 2,000,000 Da.

26. The polymeric composition of claim 1, wherein at least one of the polymer residues comprises a residue of polyethylene oxide or polypropylene oxide.

27. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a homopolymer or copolymer of poly(ortho ester), poly(ether-ester), poly(ester-amide), poly(ester-urethane), polyphosphonate ester, polyphosphoester, polyanhydride, or polyphosphazene.

28. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a homopolymer or copolymer of polyacrylic acid, poly(2-sulfoethyacrylamide), poly(sulfostyrene), poly(meth)acrylate, polyvinyl alcohol, polyethylene vinylalcohol), polyacrylonitrile, poly(alkylcyanoacrylate), poly(N-isopropyl acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyglucuronic acid, polyaspartic acid, polytartaric acid, polyglutamic acid, polyfumaric acid, polylactide, polyglycolide, polyethyleneimine, polylysine, polyhydroxyalkanoates, poly(propylene fumarate), polyvinylpyrrolidone, polyvinyl polypyrrolidone, or polyvinyl N-methylpyrrolidone.

29. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a homopolymer or copolymer of poly(2-hydroxypropyl)(meth)acrylamide or poly(meth)acrylamide.

30. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a homopolymer or copolymer of aminodextran, dextran, DEAE-dextran, chondroitin, chondroitin sulfate, chitosan, dermatan, dermatan sulfate, heparin, heparan, heparan sulfate, carrageenan, alginic acid, sodium alginate, gelatin, acid-hydrolytically-degraded gelatin, agarose, starch, glycogen, pectin, cellulose, methylcellulose, hydroxypropylcellulose, carboxymethylamylose, carboxypolymethylene, carboxymethylcellulose, hyaluronic acid, hyaluronan, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, or calcium hyaluronate.

31. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a homopolymer or copolymer of polyethyethelene, polypropylene, polybutylene, polystyrene, polyester, or polyurethane.

32. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of poly(hydroxymethyl methacrylate), or poly(hydroxyethyl methacrylate).

33. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a siloxane.

34. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue of a sulphonamide or sulphonamide derivative.

35. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue containing anioinic groups.

36. The polymeric composition of claim 1, wherein at least one polymer residue comprises a residue containing cationic groups.

37. The polymeric composition of claim 1, wherein the polymeric composition comprises one or more moieties having Formula I:

R¹—

(Z)_n—

R² 

 

I

wherein R¹ and R² are polymer residues, Z is the crosslinking moiety, and n is at least 1.

38. The polymeric composition of claim 37, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, or greater than 10.

39. The polymeric composition of claim 37, wherein R¹ and R² are residues of the same polymer.

40. The polymeric composition of claim 37, wherein R¹ and R² are residues of different polymers.

41. The polymeric composition of claim 37, wherein R¹ is derived from a polymer comprising at least one boronic acid moiety and R² is derived from a polymer comprising at least one hydroxamic acid moiety.

42. The polymeric composition of claim 37, wherein R¹ is derived from a polymer comprising at least one boronic acid moiety or hydroxamic acid moiety and R² is derived from a polymer comprising at least one hydroxamic acid moiety and at least one boronic acid moiety.

43. The polymeric composition of claim 37, wherein the ratio of R¹ to R² is about 1:

1.

44. The polymeric composition of claim. 1, wherein the polymeric composition comprises one or more moieties having Formula II:

L-(Z—

R¹)_m 

 

II

wherein R¹ is the polymer residue, L is a residue of a linker agent, Z is the crosslinking moiety, and n is at least 2.

45. The polymeric composition of claim 44, wherein m is 2, 3, 4, 5, 6, 7, 8, 9, 10, or greater than 10.

46. The polymeric composition of claim 44, wherein R¹ is derived from a polymer comprising one or more boronic acid moieties and L is derived from a linker agent comprising two or more hydroxamic acid moieties.

47. The polymeric composition of claim 44, wherein R¹ is derived from a polymer comprising one or more hydroxamic acid moieties and L is derived from a linker agent comprising two or more boronic acid moieties.

48. The polymeric composition of claim 44, wherein L is derived from a linker agent comprising hydroxamic acid moieties and boronic acid moieties.

49. The polymeric composition of claim 44, wherein L is a residue of a di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, or deca-valent linker agent.

50. The polymeric composition of claim 44, wherein L comprises a C₁-C₆ branched or straight-chain alkyl or alkoxy.

51. The polymeric composition of claim 44, wherein L comprises a methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, propylaminomethyl, propylaminoethyl, methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, or methoxymethoxyethyl.

52. The polymeric composition of claim 44, wherein L comprises the formula —

(OCH₂CH₂)_m—

, wherein m is from 2 to 10.

53. The polymeric composition of claim 1, wherein the polymeric composition comprises a laminate, a gel, a bead, a sponge, a film, a mesh, or a matrix.

54. The polymeric composition of claim 1, wherein the polymeric composition comprises a hydrogel.

55. The polymeric composition of claim 1, wherein the polymeric composition further comprises one or more sugars.

56. The polymeric composition of claim 1, wherein the polymeric composition further comprises one or more bioactive agents.

57. The polymeric composition of claim 56, wherein the bioactive agent comprises a growth factor, an anti-inflammatory agent, an anti-cancer agent, an analgesic, an anti-infection agent, an anti-viral agent, a hormone, an antibody, or a therapeutic protein.

58. The polymeric composition of claim 1, wherein the polymeric composition further comprises one or more prodrugs.

59. The polymeric composition of claim 1, wherein the polymeric composition is coupled to an anti-adhesion compound.

60. The polymeric composition of claim 59, wherein the anti-adhesion compound comprises an anti-cancer drug, anti-proliferative drug, PKC inhibitor, ERK or MAPK inhibitor, cdc inhibitor, antimitotic, DNA intercalator, inhibitor of PI3 kinase, or anti-inflammatory drug.

61. The polymeric composition of claim 1, wherein the polymeric composition is coupled to a prohealing compound.

62. The polymeric composition of claim 61, wherein the prohealing compound comprises a protein, synthetic polymer, polysaccharide, or growth factor.

63. The polymeric composition of claim 1, wherein the polymeric composition is biodegradable.

64. The polymeric composition of claim 63, wherein the biodegradable composition comprises a peptide.

65. The polymeric composition of claim 63, wherein the biodegradable composition comprises an orthoester, alpha-hydroxy ester, phosphazene, or polymer thereof.

87. A pharmaceutical composition comprising a bioactive agent and the polymeric composition in any of claim 1-65 or 86.

88. A method for improving wound healing in a subject in need of such improvement, comprising contacting the wound of the subject with the polymeric composition of any of claim 1-65 or 86-87.

89. A method for delivering at least one bioactive agent to a subject in need of such delivery, comprising contacting at least one tissue of the subject capable of receiving the bioactive compound with the polymeric composition of any of claim 1-65 or 86-87.

90. The method of claim 89, wherein the bioactive compound comprises a growth factor, an anti-inflammatory agent, an anti-cancer agent, an analgesic, an anti-infection agent, an anti-cell attachment agent, an anti-viral agent, a hormone, an antibody, or a therapeutic protein.

91. A method for delivering at least one bioactive agent in an acidic environment, comprising contacting the acidic environment with the polymeric composition of any of claim 1-65 or 86-87.

92. A method of repairing a tympanic membrane perforation, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

93. A method of preventing sinus osteum closure during or after FESS, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

94. A method of promoting healing after FESS or of reducing scarring after FESS, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

95. A method of preventing adhesion after a surgical procedure, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

96. The use of claim 95, wherein the surgical procedure comprises cardiosurgery and articular surgery, abdominal surgery, a surgical procedure performed in the urogenital region, a surgical procedure involving a tendon, laparascopic surgery, pelvic surgery, ontological surgery, sinus and craniofacial surgery, ENT surgery, or a procedure involving spinal dura repair.

97. A method of preventing airway stenosis, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

98. A method of repairing a vocal fold, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

99. A method of supporting the growth of primary cells or immortalized cells, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

100. A method of support the growth of tumor cells, fibroblasts, chondrocytes, stem cells, epithelial cells, neural cells, cells derived from the liver, endothelial cells, cardiac cells, muscle cells, or osteoblasts, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

101. A method for repairing bone or tilage, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

102. A method of extending the viability of skin, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

103. A method of promoting scar-free wound healing after a surgical procedure, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to a subject in need thereof.

104. A method of delivering a bioactive agent, comprising administering the polymeric composition of any of claim 1-65 or 86-87 and a bioactive agent to the vagina mucosa of a subject.

105. A method of promoting satiety in a subject, comprising administering the polymeric composition of any of claim 1-65 or 86-87 to the subject.

106. The method of claim 104, wherein the bioactive agent comprises a microbicide, a spermicide, an anti-inflamatory agent, or mixture thereof.

107. The method of claim 104, wherein the polymeric composition is contained in or coated on a vaginal device.

108. The method of claim 107, wherein vaginal device comprises a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal cup, vaginal film, or vaginal sponge.

109. The method of claim 104, wherein the polymeric composition is applied directly to the vaginal mucosa in the form of a cream, lotion, or foam.

110. An article coated with the polymeric composition of any of claim 1-65 or 86-87.

111. The article of claim 110, wherein the article is a suture, a clap, stent, a prosthesis, a catheter, a metal screw, a bone plate, a pin, or a bandage.

112. A liposome comprising the polymeric composition of any of claim 1-65 or 86-87.

113. A foodstuff comprising the polymeric composition of any of claim 1-65 or 86-87.

114. A particle comprising the polymeric composition of any of claim 1-65 or 86-87.

115. A filament comprising the polymeric composition of any of claim 1-65 or 86-87.

116. A nanoparticle comprising the polymeric composition of any of claim 1-65 or 86-87.

117. A soft contact lense comprising the polymeric composition of any of claim 1-65 or 86-87.

118. An intra-ocular lense comprising the polymeric composition of any of claim 1-65 or 86-87.

119. A shock-absorbant gel or foam comprising the polymeric composition of any of claim 1-65 or 86-87.

123. A method for the fabrication of an article, comprising electrospinning the polymeric composition of any of claim 1-65 or 86-87.

124. A method for the preparation of an article, comprising injection molding the polymeric composition of any of claim 1-65 or 86-87.

125. A method for the preparation of an article, comprising melt processing the polymeric composition of any of claim 1-65 or 86-87.

126. A method for the preparation of an article, comprising thermally extruding the polymeric composition of any of claim 1-65 or 86-87.

66. A method of making a polymeric composition comprising:

contacting a first polymer comprising one or more hydroxamic acid moieties and a second polymer comprising one or more boronic acid moieties under conditions where the hydroxamic acid and boronic acid moieties undergo a reaction to provide a boronate ester.

69. The method of claims 66-68, wherein the polymers and linker agent are contacted at a pH of from about 4 to about 14.

70. The method of claims 66-68, wherein the polymers and linker agent are contacted at a pH of from about 4 to about 8.

71. The method of claims 66-68, wherein the polymers and linker agent are contacted in aqueous media or in biological fluids.

72. The method of claims 66-68, wherein the polymers and linker agent are contacted in a non-aqueous media.

73. The method of claims 66-68, wherein the polymers and linker agent are contacted in the presence of a sugar.

74. The method of claims 66-68, wherein the polymers and linker agent are contacted at from about minus 4°

C. to about 90°

C.

75. The method of claims 66-68, wherein the polymers and linker agent are contacted at from about 25°

C. to about 37°

C.

76. The method of claims 66-68, wherein the polymers and linker agent are contacted in the presence of cells, biomolecules, tissues, or salts.

77. The method of claims 66-68, wherein the polymers and linker agent are contacted in the presence of a bioactive agent, a microbicide, an anti-adhesion compound, or a prohealing compound.

78. The method of claims 66-68, wherein the boronic acid moiety comprises a phenylboronic acid moiety and wherein the hydroxamic acid moiety comprises a salicylhydroxamic acid moiety.

79. The method of claims 66-68, wherein the polymer comprising one or more boronic acid moieties or the linker agent comprising two or more boronic acid moieties further comprises a primary or secondary amine.

80. The method of claims 66-68, further comprising contacting the polymeric composition with a bioactive agent, a prodrug, an anti-adhesion compound, or a prohealing compound.

81. The method of claims 66-68, further comprising lowering the pH of the polymeric composition to less than about 4.

82. The method of claim 81, further comprising raising the pH of the polymeric composition to about 4 or above.

83. The method of claims 66-68, further comprising forming the polymeric composition into a filament.

84. The method of claim 83, wherein the filament is formed by electrospinning.

85. The method of claim 83, wherein filaments is formed by extrusion.

86. A polymeric composition prepared by the method of any of claims 66-85.

67. A method of making a polymeric composition comprising:

contacting a polymer comprising one or more boronic acid moieties with a linker agent comprising two or more hydroxamic acid moieties under conditions where the hydroxamic acid and boronic acid moieties undergo a reaction to provide a boronate ester.

68. A method of making a polymeric composition comprising:

contacting a polymer comprising one or more hydroxamic acid moieties with a linker agent comprising two or more boronic acid moieties under conditions where the hydroxamic acid and boronic acid moieties undergo a reaction to provide a boronate ester.

120. A kit comprising a polymer comprising at least one hydroxamic acid moiety and a polymer comprising at least one boronic acid moiety.

121. A kit comprising a polymer comprising at least one hydroxamic acid moiety and a linking agent comprising at least two boronic acid moieties.

122. A kit comprising a polymer comprising at least one boronic acid moiety and a linking agent comprising at least two hydroxamic acid moieties.