Radio-opaque polymeric biomaterials

• US 6,852,308 B2
• Filed: 11/05/2002
• Issued: 02/08/2005
• 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:
  US10/288,076
• Publication Number:
  US 20040037778A1
• Time in Patent Office: 826 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.6, 424/78.01, 424/78.02, 424/78.03, 424/78.04, 424/78.05, 424/78.08, 424/78.17, 424/78.18, 528/176, 528/182, 528/196, 528/203, 528/204, 528/206, 528/272, 528/332, 525/432, 525/433, 525/434, 525/454, 525/467, 568/303, 568/700, 560/40
• US Class Current: 424/9.6
• 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-opacifying diphenol compound substituted with at least one bromine or iodine atom, and having the structure:

wherein X₁ and X₂ are independently iodine or bromine, Y1 and Y2 are independently 0, 1 or 2, and R₉ is an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms.

2. The diphenol of claim 1, wherein R₉ has the structure:

wherein R₀ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)m, and R₄ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_n, in which m and n are independently 0 to 8, inclusive, and J₁and J₂ are independently Br or I; and

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

3. The diphenol of claim 2, wherein R₄ is —

CH₂—

or —

CHJ₁—

CHJ₂— and

R₀ is —

CH₂—

or —

CH₂—

CH₂—

.

4. The diphenol of claim 2, wherein Z is a free carboxylic acid group or an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.

5. A radio-opaque polymeric biomaterial comprising a biocompatible polymer and the diphenol compound of claim 1, physically admixed, imbedded or dispersed in said polymer in an amount effective to radio-opacify said polymer.

17. A radio-opaque composition comprising a biocompatible or bioerodible matrix polymer having physically admixed, dispersed or embedded therein the radio-opaque compound of claim 1.

18. The radio-opaque composition of claim 17, wherein said radio-opaque compound is an analog of a monomer from which said matrix polymer is polymerized.

20. A radio-opaque microshpere, formed from the radio-opaque composition of claim 17.

23. An implantable, radio-opaque medical device comprising the radio-opaque composition of claim 17.

28. A drug delivery device, comprising a biologically or pharmaceutically active compound in combination with the radio-opaque composition of claim 17, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

29. The drug delivery device of claim 28, wherein said active compound is covalently bonded to said either of said radio-opaque compound or said matrix polymer.

30. The drug delivery device of claim 28, wherein 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.

37. A method for site-specific or systemic drug delivery comprising implanting in the body of a patient in need thereof the implantable drug delivery device of claim 28.

38. The method of claim 37, wherein said active compound is covalently bonded to said either of said radio-opaque compound or said matrix polymer.

39. The method of claim 37, wherein 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.

44. 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 18.

49. A pharmaceutical composition comprising (a) the composition of claim 18, 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.

6. A radio-opaque polymeric biomaterial comprising a monomeric repeating units substituted with at least one bromine or iodine atom, and having the structure:

wherein each X₁ and X₂ are independently iodine or bromine, each Y1 and Y2 are independently 0, 1 or 2, and R₉ is an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms.

7. The polymer of claim 6, wherein R₉ has the structure:

wherein R₀ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂)_m, and R₄ is selected from the group consisting of —

CH═

CH—

,—

CHJ₁—

CHJ₂— and

(—

CH₂—

)_n, in which m and n are independently 0 to 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 esters and amides thereof, said ester and amide being selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds.

8. The polymeric of claim 7, wherein R₄ is —

CH₂—

or —

CHJ₁—

CHJ₂—

, and R₀ is —

CH₂—

or —

CH₂—

CH₂—

.

9. The polymer of claim 7, wherein Z is a free carboxylic acid group of an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.

10. A radio-opaque biocompatible polymer comprising monomeric repeating units substituted with at least one bromine or iodine atom, and having the structure:

wherein each X₂ is independently I or Br;

each Y2 is 1 or 2;

each R₅ and R₆ are each independently selected from the group consisting of H, Br, I and straight and branched alkyl groups having up to 18 carbon atoms, each R₀ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁—

CHJ₂— and

(—

CH₂—

)_d and each R₁₅ is selected from the group consisting of —

CH═

CH—

, (—

CH₂—

)_m and —

CHJ₁—

CHJ₂—

, wherein each J₁ and J₂ are independently Br or I; and

d and m are independently between 0 and 8, inclusive; and

each Z is independently selected from the group consisting of hydrogen, a free carboxylic acid group or an ester or amide thereof, said ester or amide comprising straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds.

11. The radio-opaque polymer of claim 10, wherein R₁₅ is selected from the group consisting of —

CH₂— and

—

CHJ₁—

CHJ₂—

, and R₀ is selected from the group consisting of —

CH₂— and

—

CH₂—

CH₂—

.

12. The radio-opaque polymer of claim 10, wherein Z is a free carboxylic acid group of an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.

13. The radio-opaque polymer of claim 10, wherein R₁₅ is (—

CH₂—

)_c, C is 0 and R₅ and R₆ are independently hydrogen or a methyl group.

14. The radio-opaque polymer of claim 13 wherein R₅ and R₆ are both hydrogen.

15. The radio-opaque polymer of claim 13 wherein one of R₅ and R₆ is hydrogen and the other is a methyl group.

16. The radio-opaque polymer of claim 10, wherein R₀ is —

CH— and

Z is a carboxylic acid ethyl ester.

19. A radio-opaque composition comprising a biocompatible or bioerodible matrix polymer having physically admixed, or embedded therein the radio-opaque polymer of claim 6 or claim 10.

21. A radio-opaque microsphere, formed from the radio-opaque composition of claim 19.

22. A radio-opaque microshpere, formed from the radio-opaque polymer of claim 6 or claim 10.

24. An implantable, radio-opaque medical device comprising the radio-opaque composition of claim 19.

25. A drug delivery device, comprising a biologically or pharmaceutically active compound in combination with the polymer of claim 6 or claim 10, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

26. The drug delivery device of claim 25, wherein said active compound is covalently bonded to said polymer.

27. The drug delivery device of claim 25, wherein said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

31. A drug delivery device, comprising a biologically or pharmaceutically active compound in combination with the radio-opaque composition of claim 19, wherein said active compound is present in amounts effective for therapeutic site-specific or systemic drug delivery.

32. The drug delivery device of claim 26, wherein said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

33. The drug delivery device of claim 31, wherein 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.

34. A method for site-specific or systemic drug delivery comprising implanting in the body of a patient in need thereof the implantable drug delivery device of claim 25.

35. The method of claim 34, wherein said active compound is covalently bonded to said polymer.

36. The method of claim 34, wherein said active compound is physically admixed with said polymer or physically embedded or dispersed in a matrix formed by said polymer.

40. A method for site-specific or system drug delivery comprising implanting in the body of a patient in need thereof the implantable drug delivery device of claim 31.

41. The method of claim 40, wherein said active compound is covalently bonded to said either of said radio-opaque polymer or said matrix polymer.

42. The method of claim 40, wherein 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.

43. 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 6 or 10.

45. The method of claim 43 or 44, wherein said polymer being in the form of a coating on a medical implant.

46. The method of claim 43 or 44, wherein said polymer being in the form of a film.

47. The method of claim 43 or 44, wherein said polymer being in the form of a polymeric tissue scaffold.

48. A pharmaceutical composition comprising (a) the polymer of claim 6 or 10, comprising one or more side chains conjugated to a biologically or pharmaceutically active compound;

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

50. The pharmaceutical composition of claim 48 or 49 in the form of a tablet, capsule, suspension, solution, emulsion, liposome or aerosol.

51. The pharmaceutical composition of claim 50 in the form of an injectable suspension, solution or emulsion.

52. The pharmaceutical composition of claim 50 in the form of an injectable liposome composition.