Radio-opaque polymer biomaterials

• US 6,475,477 B1
• Filed: 07/03/2000
• Issued: 11/05/2002
• Est. Priority Date: 11/07/1997
• Status: Expired due to Term

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Pendharkar, Sanyog M., Bolikal, Durgadas, Kohn, Joachim B.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/554,027
• Time in Patent Office: 855 Days
• Field of Search: 424/78.01, 424/78.02, 424/78.03, 424/78.04, 424/78.05, 424/78.08, 424/78.17, 424/78.18, 424/78.31, 424/78.35, 424/78.37, 424/1.11, 424/1.65, 424/9.1, 560/40, 568/303, 568/700, 525/432, 525/433, 525/434, 525/454, 525/467, 528/176, 528/182, 528/196, 528/203, 528/204, 528/206, 528/272, 528/332
• US Class Current: 424/78.08
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 49/0438 Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• CPC Class Codes: A61K 49/0442 Polymeric X-ray contrast-enhancing agent comprising a halogenated group
• CPC Class Codes: A61K 49/0447 Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 31/18 Materials at least partially X-ray or laser opaque
• CPC Class Codes: C08G 63/672 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/6826 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/6856 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 64/10 containing halogens
• CPC Class Codes: C08G 64/12 containing nitrogen
• CPC Class Codes: C08G 64/1633 containing halogens
• CPC Class Codes: C08G 64/1641 containing nitrogen
• CPC Class Codes: C08G 64/183 containing polyether sequences
• CPC Class Codes: C08G 65/3317 phenolic
• CPC Class Codes: C08G 69/44 Polyester-amides
• CPC Class Codes: C08K 5/13 Phenols; Phenolates
• CPC Class Codes: C08K 5/20 : Carboxylic acid amides

Abstract

Iodinated and/or brominated derivatives of aromatic dihydroxy monomers are prepared and polymerized to form radio-opaque polymers. The monomers may also be copolymerized with other dihydroxy monomers. The iodinated and brominated aromatic dihydroxy monomers can be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials. Radio-opaque medical implants and drug delivery devices for implantation prepared from the polymers of the present invention are also disclosed.

Claims

1. A radio-opaque polymer characterized by having the structure:

wherein X₁ and X₂ are independently I or Br, Y1 and Y2 are independently 0, 1 or 2, R₇ is independently an alkylene group containing up to 4 carbon atoms;

R₉ and R₁₂ are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms;

A is;

wherein R₈ is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms;

k is between about 5 and about 3,000, and f and g are independently between 0 and 0.99, inclusive.

2. The polymer of claim 1, characterized in that f and g are both 0.

3. The polymer of claim 1, characterized in that R₉ has the structure:

wherein R⁰ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_m, R₄ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_a, wherein a and m are independently between 0 and 8, inclusive; and

J₁ and J₂ are independently Br or I; and

Z is selected from the group consisting of hydrogen, a free carboxylic acid group, and carboxylic acid esters and amides, wherein said esters and amides are selected from the group consisting of esters and amides of straight and branched alkyl and alkyl aryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compound.

4. The polymer of claim 3, characterized in that g is greater than 0 and R₁₂ has the structure:

wherein R₀ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_m, R₄ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_a, wherein a and m are independently between 0 and 8, inclusive; and

J₁ and J₂ are independently Br or I; and

Z is selected from the group consisting of hydrogen, a free carboxylic acid group, and carboxylic acid esters and amides, wherein said esters and amides are selected from the group consisting of esters and amides of straight and branched alkyl and alkyl aryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds.

5. The polymer of claim 4, characterized in that R₉ has the structure:

and R₁₂ has the structure;

wherein a and c are two and b and d are one.

6. The polymer of claim 4, characterized in that each Z of R₉ and R₁₂ is an ester of a carboxylic acid;

wherein each ester group is independently selected from the group consisting of ethyl, butyl, hexyl, octyl and benzyl groups.

13. The polymer of claim 1 or 7, characterized in that f is greater than 0.

14. The polymer of claim 13, characterized in that each R₇ group is ethylene.

15. The polymer of claim 13, characterized in that f is between about 0.05 and about 0.95.

16. The polymer of claim 1 or 7, characterized in that A is:

17. The polymer of claim 1 or 7, characterized in that A is:

18. The polymer of claim 17, characterized in that R₈ is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl groups containing up to 8 carbon atoms.

19. The polymer of claim 18, characterized in that R₈ is selected from the group consisting of —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH— and

(—

CH₂—

)_Q, wherein Q is between 0 and 8, inclusive.

20. The polymer of claim 17, characterized in that R₈ is selected from the group consisting of substituted and unsubstituted aryl and alkylaryl groups containing from 13 to 20 carbon atoms.

21. A radio-opaque composition characterized by a biocompatible or bioerodible matrix polymer having physically admixed, or embedded therein the radio-opaque polymer of claim 1 or claim 7.

22. A radio-opaque composition characterized by a biocompatible or bioerodible matrix polymer having physically admixed, or embedded therein the radio-opaque polymer of claim 13.

23. A radio-opaque microsphere, characterized by being formed from the radio-opaque composition of claim 21.

24. A radio-opaque microsphere, characterized by being formed from the radio-opaque composition of claim 22.

25. A radio-opaque microsphere, characterized by being formed from the radio-opaque polymer of claim 1 or claim 7.

26. A radio-opaque microsphere, characterized by being formed from the radio-opaque polymer of claim 13.

27. An implantable, radio-opaque medical device characterized by the radio-opaque composition of claim 21.

28. An implantable, radio-opaque medical device characterized by being coated with the radio-opaque composition of claim 22.

29. An implantable, radio-opaque medical device characterized by the radio-opaque polymer of claim 13.

30. An implantable, radio-opaque medical device characterized by being coated with the radio-opaque polymer of claim 13.

31. A film for use as a barrier to prevent the formation of surgical adhesions, characterized by the radio-opaque polymer of claim 13.

32. A film for use as a barrier to prevent the formation of surgical adhesions, characterized by the radio-opaque composition of claim 22.

33. A drug delivery device, characterized by a biologically or pharmaceutically active compound in combination with the polymer of claim 1 or claim 7, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

34. The drug delivery device of claim 33, characterized in that said active compound is covalently bonded to said polymer.

35. The drug delivery device of claim 33, characterized in that said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

36. A drug delivery device, characterized by a biologically or pharmaceutically active compound in combination with the polymer of claim 13, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

37. The drug delivery device of claim 36, characterized in that said active compound is covalently bonded to said polymer.

38. The drug delivery device of claim 36, characterized in that said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

39. A drug delivery device, characterized by a biologically or pharmaceutically active compound in combination with the radio-opaque composition of claim 21, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

40. The drug delivery device of claim 39, characterized in that said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

41. The drug delivery device of claim 39, characterized in that said active compound is physically admixed with said radio-opaque composition or physically embedded or dispersed in the polymer matrix of said radio-opaque composition.

42. A drug delivery device, characterized by a biologically or pharmaceutically active compound in combination with the radio-opaque composition of claim 22, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

43. The drug delivery device of claim 42, characterized in that said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

44. The drug delivery device of claim 42, characterized in that said active compound is physically admixed with said radio-opaque composition or physically embedded or dispersed in the polymer matrix of said radio-opaque composition.

45. A method for site-specific or systemic drug delivery characterized by implanting in the body of a patient in need thereof the implantable drug delivery device of claim 33.

46. The method of claim 45, characterized in that said active compound is covalently bonded to said polymer.

47. The method of claim 45, characterized in that said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

48. A method for site-specific or systemic drug delivery characterized by implanting in the body of a patient in need thereof the implantable drug delivery device of claim 36.

49. The method of claim 48, characterized in that said active compound is covalently bonded to said polymer.

50. The method of claim 48, characterized in that said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

51. A method for site-specific or systemic drug delivery characterized by implanting the body of a patient in need thereof the implantable drug delivery device of claim 39.

52. The method of claim 51, characterized in that said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

53. The method of claim 51, characterized in that said active compound is physically admixed with said radio-opaque composition or physically embedded or dispersed in the polymer matrix of said radio-opaque composition.

54. A method for site-specific or systemic drug delivery characterized by implanting in the body of a patient in need thereof the implantable drug delivery device of claim 42.

55. The method of claim 54, characterized in that said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

56. The method of claim 54, characterized in that said active compound is physically admixed with said radio-opaque composition or physically embedded or dispersed in the polymer matrix of said radio-opaque composition.

57. A method for treating injured tissues with an adhesion formation barrier characterized by inserting as a barrier between said injured tissues a sheet or film consisting essentially of the polymer of claim 13.

58. A method for treating injured tissues with an adhesion formation barrier characterized by inserting as a barrier between said injured tissues a sheet or film consisting essentially of the polymer of claim 22.

59. A method of regulating cellular attachment, migration and proliferation on a polymeric substrate, comprising contacting living cells, tissues or biological fluids containing living cells with the polymer of claim 1 or 7.

60. A method of regulating cellular attachment, migration and proliferation on a polymeric substrate, comprising contacting living cells, tissues or biological fluids containing living cells with the composition of claim 22.

61. The method of claim 59, characterized by said polymer being in the form of a coating on a medical implant.

62. The method of claim 59, characterized by said polymer being in the form of a film.

63. The method of claim 59, characterized by said polymer being in the form of a polymeric tissue scaffold.

64. A pharmaceutical composition characterized by (a) the polymer of claim 1 or 7 comprising one or more side chains conjugated to a biologically or pharmaceutically active compound;

and (b) a pharmaceutically acceptable carrier for said polymer conjugate.

65. A pharmaceutical composition characterized by (a) the composition of claim 22, wherein one or more of the polymer side chains is conjugated to a biologically or pharmaceutically active compound;

and (b) a pharmaceutically acceptable carrier for said polymer conjugate composition.

66. The pharmaceutical composition of claim 64, characterized by being in the form of a tablet, capsule, suspension, solution, emulsion, liposome or aerosol.

67. The pharmaceutical composition of claim 66, characterized by being in the form of an injectable suspension, solution or emulsion.

68. The pharmaceutical composition of claim 66, characterized by being in the form of an injectable liposome composition.

69. A method of regulating cellular attachment, migration and proliferation on a polymeric substrate, comprising contacting living cells, tissues or biological fluids containing living cells with the polymer of claim 13.

70. A method of regulating cellular attachment, migration and proliferation on a polymeric substrate, comprising contacting living cells, tissues or biological fluids containing living cells with the composition of claim 21.

71. The method of claim 69, characterized by said polymer being in the form of a coating on a medical implant.

72. The method of claim 70, characterized by said polymer being in the form of a coating on a medical implant.

73. The method of claim 69, characterized by said polymer being in the form of a film.

74. The method of claim 70, characterized by said polymer being in the form of a film.

75. The method of claim 69, characterized by said polymer being in the form of a polymeric tissue scaffold.

76. The method of claim 70, characterized by said polymer being in the form of a polymeric tissue scaffold.

77. A pharmaceutical composition characterized by (a) the polymer of claim 13, comprising one or more side chains conjugated to a biologically or pharmaceutically active compound;

and (b) a pharmaceutically acceptable carrier for said polymer conjugate.

78. A pharmaceutical composition characterized by (a) the composition of claim 21, wherein one or more of the polymer side chains is conjugated to a biologically or pharmaceutically active compound;

and (b) a pharmaceutically acceptable carrier for said polymer conjugate composition.

79. The pharmaceutical composition of claim 77, characterized by being in the form of a tablet, capsule, suspension, solution, emulsion, liposome or aerosol.

80. The pharmaceutical composition of claim 78, characterized by being in the form of a tablet, capsule, suspension, solution, emulsion, liposome or aerosol.

7. A radio-opaque polymer characterized by the structure:

wherein;

(a) R₅ and R₆ are independently selected from the group consisting of H, Br, I, and straight and branched alkyl groups having up to 18 carbon atoms; and

R₁₆ and R₁₇ are independently selected from the group consisting of H and straight and branched alkyl groups having up to 18 carbon atoms, provided that when g is zero, R₁ and R₂ are independently Br or I unless R₁₅ is —

CJ₁—

CJ₂—

or Z is a carboxylic acid amide;

(b) R₁₅ is selected from the group consisting of (—

CH₂—

)_c, —

CH═

CH— and

—

CHJ₁—

CHJ₂—

, wherein J₁ and J₂ are independently Br or I and c is between 0 and 8, inclusive;

(c) X₂ is Br or I and Y2is 1 or 2;

(d) Z is selected from the group consisting of H, a free carboxylic acid group or an ester or amide thereof;

(e) each R₇ is an alkylene group containing up to four carbon atoms, with k being between about 5 and about 3000;

(f) A is;

wherein R₈ is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms;

(g) each R⁰ is independently —

CH═

CH—

or (—

CH₂—

)_d, wherein d is between 0 and 8, inclusive; and

(h) f and g independently range from 0 to less than 1.

8. The polymer of claim 7, characterized in that R₀ or R₁₅ are (—

CH₂—

)_d or (—

CH₂—

)_c, respectively, wherein c or d are 0, and R₅, R₆, R₁₆ and R₁₇ are independently hydrogen or a methyl group.

9. The polymer of claim 8, characterized in that R₅, R₆, R₁₆ and R₁₇ are all hydrogen.

10. The polymer of claim 9, characterized in that one of R₅ and R₆ or R₁₆ and R₁₇ is hydrogen and the others are methyl.

11. The polymer of claim 7, characterized in that each Z is an ester of a carboxylic acid, wherein each ester group is independently selected from the group consisting of ethyl, butyl, hexyl, octyl and benzyl groups.

12. The polymer of claim 11, characterized in that both R₀ and R₁₅ are (—

CH₂—

) and each Z is an ethyl ester of a carboxylic acid.