Polymerizable biodegradable polymers including carbonate or dioxanone linkages

• US 6,083,524 A
• Filed: 10/06/1997
• Issued: 07/04/2000
• Est. Priority Date: 09/23/1996
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Focal PLLC
• Inventors: Sawhney, Amarpreet S., Yao, Fei, Goodrich, Stephen D., Avila, Luis Z., Weaver, Douglas, Nason, William C., Jarrett, Peter K., Enscore, David J., Rudowsky, Ronald S., Barman, Shikha P., Coury, Arthur J., Powell, Michelle D.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US08/944,739
• Time in Patent Office: 1,002 Days
• Field of Search: 424/426, 514/772.3
• 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
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

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 biodegradable, polymerizable macromer having a solubility of at least one gram/liter in an aqueous solution at a temperature in the range between about 0 and 50°

C. comprising at least one water-soluble region, at least one biodegradable region, and at least one reactive polymerizable group or region capable of crosslinking with other macromers, wherein the polymerizable regions are separated from each other by at least one biodegradable region, and wherein at least one biodegradable region comprises a carbonate or dioxanone linkage.

2. The macromer of claim 1 wherein the water soluble region is attached to a biodegradable region and at least one polymerizable group or region is attached to the biodegradable region.

3. The macromer of claim 1 wherein the water soluble region forms a central core, at least two biodegradable regions are attached to the core, and at least two polymerizable groups or regions are attached to the biodegradable regions.

4. The macromer of claim 1 wherein the biodegradable region is a central core, and at least one polymerizable group or region is attached to said core so that each polymerizable region is separated from each other polymerizable group or region by at least one biodegradable linkage or region.

5. The macromer of claim 1 wherein the water soluble region is a macromer backbone, the biodegradable region is a branch or graft attached to the macromer backbone, and at least two polymerizable groups or regions are attached to the biodegradable regions.

6. The macromer of claim 4 having two or more polymerizable groups or regions attached to the core.

7. The macromer of claim 1 wherein the water soluble region is a star backbone, the biodegradable region is a branch or graft attached to the water soluble star backbone, and at least two polymerizable groups or regions are attached to one or more biodegradable branch or graft, so that each polymerizable group or region is separated from each other polymerizable group or region by at least one biodegradable linkage or region.

8. The macromer of claim 1 wherein the biodegradable region is a star backbone, the water soluble region is a branch or graft attached to the biodegradable star backbone, and two or more polymerizable groups or regions are attached to the biodegradable backbone so that each polymerizable group or region is separated from each other polymerizable group or region by at least one biodegradable linkage or region.

9. The macromer of claim 1 wherein the water soluble region is also the biodegradable region.

10. The macromer of claim 1 wherein the water soluble region is also the biodegradable region, and one or more additional biodegradable regions are grafts or branches upon the water soluble region.

11. The macromer of claim 1 comprising a water-soluble core, at least two biodegradable extensions on the core, and an end cap on at least two extensions, wherein

the core comprises poly(ethylene glycol);

at least one of the extensions comprises a biodegradable carbonate or dioxanone linkage; and

each end cap comprises a group or region which is polymerizable by a free-radical reaction.

12. The macromer of claim 1 wherein at least one of the extensions comprises a biodegradable poly(hydroxy acid).

13. The macromer of claim 11 wherein the poly(ethylene glycol) has a molecular weight between about 400 and 40,000 Da;

the extensions have a molecular weight between about 200 and 2000 Da; and

the polymerizable group or region has a molecular weight between about 50 and 200 Da.

14. The macromer of claim 13 wherein the poly(ethylene glycol) oligomers have a molecular weight of about 20,000 Da;

the extensions have a molecular weight about 1000 Da; and

the polymerizable groups have a molecular weight of about 50 Da.

15. The macromer of claim 1 wherein the polymerizable groups contain a carbon-carbon double bond capable of cross-linking and polymerizing macromers.

16. The macromer of claim 1 wherein crosslinking and polymerization of the macromer are initiated by a light-sensitive free-radical polymerization initiator with or without a cocatalyst, further comprising a free radical polymerization initiator.

17. The macromer of claim 16 wherein the initiator is selected from the group consisting of xanthine dyes, acridine dyes, thiazine dyes, phenazine dyes, camphorquinone dyes, and acetophenone dyes.

18. The macromer of claim 17 wherein the initiator is selected from the group consisting of eosin, ethyl eosin, 2,2-dimethyl-2-phenyl acetophenone, and 2-methoxy-2-phenyl acetophenone.

19. The macromer of claim 1 wherein crosslinking or polymerizations are initiated in situ by light having a wavelength of 320 nm or longer.

20. The macromer of claim 1 wherein at least one biodegradable region is selected from the group consisting of poly (alpha-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters).

21. The macromer of claim 20 wherein the poly(alpha-hydroxy acid) is selected from the group consisting of poly(glycolic acid), poly(D,L-lactic acid) and poly(L-lactic acid).

22. The macromer of claim 20 wherein the poly(lactone) is selected from the group consisting of poly(epsilon-caprolactone), poly (delta-valerolactone) and poly(gamma-butyrolactone).

23. The macromer of claim 1 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.

24. The macromer of claim 1 further comprising a prophylactic, therapeutic or diagnostic agent.

25. The macromer of claim 1 comprising at least two water soluble regions linked to each other by at least one carbonate or dioxanone linkage.

26. The macromer of claim 1 comprising a core of two or more water soluble regions linked by carbonate or dioxanone linkages.

27. The macromer of claim 26 wherein at least two biodegradable groups or regions are attached to the core and at least two polymerizable groups are attached to the biodegradable groups or linkages.

28. The macromer of claim 1 wherein the carbonate linkage is prepared from a cyclic aliphatic carbonate.

29. The macromer of claim 1 wherein the carbonate linkage is prepared from trimethylene carbonate.

30. The macromer of claim 1, 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.

31. The macromer of claim 30, wherein the average number of polymer blocks in each macromer is two or more.

32. The macromer of claim 1, in which the one or more reactive polymerizable group(s) are selected from ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids and phosphate groups.

33. The macromer of claim 32, in which the one or more reactive polymerizable group(s) are selected from an ethylenically-unsaturated group.

34. The macromer of claim 33, in which the ethylenically-usaturated group is selected from vinyl groups, allyl groups, unsaturated monocarboxylic acids, diacrylates, oligoacrylates, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids.

35. The macromer of claim 32, in which the reactive polymerizable groups are found on more than one type of macromer.

36. The macromer of claim 35, in which a first macromer comprises a reactive group selected from an amine, an alcohol, and a thiol, and a second macromer comprises a reactive group selected from isocyanate, isothiocyanate, aldehyde, epoxide, oxirane (epoxide), succinimides, maleimides and cyclic imines.