Polymerizable biodegradable polymers including carbonate or dioxanone linkages

• US RE39,713 E1
• Filed: 01/23/2003
• Issued: 07/03/2007
• Est. Priority Date: 09/23/1996
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Sawhney, Amarpreet S., Avila, Luis Z., Lyman, Michelle D., Jarrett, Peter K., Rudowsky, Ronald S., Barman, Shikha P., Yao, Fei, Goodrich, Stephen D., Weaver, Douglas, Nason, William C., Enscore, David J., Coury, Arthur J.
• Primary Examiner(s): Azpuru; Carlos A.
• Application Number:
  US10/351,930
• Time in Patent Office: 1,622 Days
• Field of Search: 424/426, 424/489, 424/490, 514/772.1, 514/772.3, 514/773, 514/777, 528/354, 528/361, 128/898, 525/54.1, 525/54.2, 525/408, 525413-415
• US Class Current: 424/426
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 26/0019 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: C08G 63/64 Polyesters containing both carboxylic ester groups and carbonate groups

Abstract

Water-soluble macromers including at least one hydrolysable linkage formed from carbonate or dioxanone groups, at least one water-soluble polymeric block, and at least one polymerizable group, and methods of preparation and use thereof are described. The macromers are preferably polymerized using free radical initiators under the influence of long wavelength ultraviolet light or visible light excitation. Biodegradation occurs at the linkages within the extension oligomers and results in fragments which are non-toxic and easily removed from the body. The macromers can be used to encapsulate cells, deliver prophylactic, therapeutic or diagnostic agents in a controlled manner, plug leaks in tissue, prevent adhesion formation after surgical procedures, temporarily protect or separate tissue surfaces, and adhere or seal tissues together.

Claims

1. A method for forming a polymeric, biocompatible coating on tissue comprising:

a) applying to the tissue surface a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization;

b) applying to the initiator-coated surface a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50°

C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and

c) polymerizing the macromer.

2. The method of claim 1, wherein the macromer solution further comprises a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization.

3. The method of claim 1, wherein the tissue is coated to prevent leakage of gases or bodily fluids from the tissue.

4. The method of claim 1, wherein the tissue is coated to prevent adhesion of the tissue to other tissue.

5. The method of claim 1, wherein the tissue is coated and adhered to other tissue during polymerization.

6. The method of claim 1 wherein the macromer solution further comprises a prophylactic, therapeutic or diagnostic agent.

7. The method of claim 1 wherein the initiator binds to the tissue, further comprising removing unbound initiator prior to application of the macromer solution.

8. A method for making a device for controlled release of a prophylactic, therapeutic or diagnostic agent comprising:

a) mixing a prophylactic, therapeutic or diagnostic agent with a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature between about 0 and 50°

C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and

b) polymerizing the macromer to incorporate the agent within the resulting polymer.

9. The method of claim 8 wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.

10. The method of claim 8 wherein the macromer is polymerized in situ in or on a living tissue.

11. The method of claim 8 wherein the controlled release device is formed on the surface of a medical device.

12. The method of claim 11 wherein the device is coated after implantation into the body.

13. The method of claim 11 wherein the device is coated prior to implantation.

14. A method for increasing the elasticity of a hydrophilic polymer gel comprising incorporating one or more carbonate linkages into a reactive polymer before gelation by reaction of the reactive groups, wherein the resulting polymer has a solubility in water of at least one gram/liter of an aqueous solution at a temperature in the range between about 0 and 50°

C., is biodegradable, and wherein each reactive group is separated from each other reactive group by at least one degradable linkage.

15. The method of claim 14 wherein the carbonate linkage is prepared from trimethylene carbonate.

16. The method of claim 14, wherein two or more polymer blocks are linked by linkages comprising carbonate groups to obtain a higher molecular weight of reactive macromer without compromise of biodegradability.

17. A method for improving the biodegradability of a carbonate-comprising chemically-reactive macromer, the method comprising:

a) reacting a carbonate with a biocompatible compound which has a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50°

C., wherein the biocompatible compound comprises at least two hydroxyl groups to form a carbonate-comprising precursor, the reaction continuing for a sufficient time to ensure completion of the reaction and attainment of equilibrium among reacting species, and the carbonate providing a first biodegradable linkage;

b) adding to the carbonate-comprising precursor an excess of a first reagent to form a second biodegradable linkage, wherein the first reagent comprises a biodegradable moiety other than a carbonate; and

then

c) adding to the carbonate-comprising precursor a second reagent which forms at least one chemically-reactive group, thereby forming the chemically-reactive macromer,

wherein the chemically reactive group of step c) is attached to the macromer via the biodegradable moiety of step b).

18. The method of claim 17, wherein the carbonate is a cyclic aliphatic carbonate.

19. The method of claim 17 in which the polymer is a polyalkylene glycol.

20. The method of claim 17 in which the first reagent comprises a residue of a hydroxycarboxylic acid.

21. The method of claim 20 which the hydroxycarboxylic acid residue is an alpha-hydroxy acid.

22. The method of claim 21 in which the acid is selected from lactic acid, lactide, and lactoyl chloride.

23. The method of claim 17 wherein the chemically-reactive group of step c) comprises at least one component selected from the group consisting of ethylenically unsaturated groups, acetylenically unsaturated groups, isocyanates, oxiranes, sulfhydryls, succinimides, maleimides, amines, imines, carboxylic acids, sulfonic acids, and phosphoric acids.

24. A polymer comprising a biodegradable macromer comprising at least one water soluble region, at least one degradable region, and at least one functional, polymerizable group, wherein the polymerizable groups are separated from each other by at least one degradable region, and wherein at least one degradable region is a carbonate

25. The polymer of claim 24, further comprising a prophylactic, therapeutic, or diagnostic agent.

26. The polymer of claim 24, wherein the polymer is a hydrogel.

27. The polymer of claim 24, wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.

28. The polymer of claim 24, wherein the polymer is a tissue sealant.

29. The polymer of claim 24, wherein the water soluble region is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.

30. The polymer of claim 29, wherein the water soluble region is poly(ethylene glycol).

31. The polymer of claim 24, wherein at least one biodegradable region is selected from the group consisting of poly(hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters).

32. The polymer of claim 31, wherein the biodegradable region is a poly(hydroxy acid) selected from the group consisting of poly(glycolic acid), poly(D,L-lactic acid) and poly(L-lactic acid).

33. The polymer of claim 31, wherein the biodegradable region is a poly(lactone) selected from the group consisting of poly(epsilon-caprolactone), poly(delta-valcrolactone) and poly(gamma-butyrolactone).

34. The polymer of claim 24, wherein the carbonate linkage is prepared from a cyclic aliphatic carbonate.

35. The polymer of claim 24, wherein the carbonate linkage is prepared from trimethylene carbonate.

36. The polymer of claim 24, wherein the one or more reactive polymerizable group(s) are selected from the group consisting of ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids, and phosphate groups.

37. The polymer of claim 36, wherein the one or more reactive polymerizable group(s) are ethylenically-unsaturated groups.

38. The polymer of claim 37, wherein the ethylenically-unsaturated group is selected from the group consisting of vinyl groups, allyl groups, unsaturated monocarboxylic acids, diacrylates, oligoacrylates, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids.

39. The polymer of claim 24, wherein the macromer comprises carbonate or dioxanone residues in range from about 0.3% to 20% (by weight).

40. The polymer of claim 24, wherein the water soluble region forms the core of the macromer.