Crosslinked hydrogel copolymers

• US 6,800,663 B2
• Filed: 10/18/2002
• Issued: 10/05/2004
• Est. Priority Date: 10/18/2002
• Status: Expired due to Fees

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Costantino, Henry R., Asgarzadeh, Firouz
• Primary Examiner(s): SELLERS, ROBERT E
• Application Number:
  US10/273,365
• Publication Number:
  US 20040077797A1
• Time in Patent Office: 718 Days
• Field of Search: 424/436, 424/501, 514/772.1, 514/772.2, 514/772.3, 516/102, 516/108, 524/599, 524/601, 524/604, 525/59, 525/404, 525/445, 525/450
• US Class Current: 516/108
• CPC Class Codes: C08G 2650/34 Oligomeric, e.g. cyclic oligomeric
• CPC Class Codes: C08G 2650/58 Ethylene oxide or propylene oxide copolymers, e.g. pluronics
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 65/14 Unsaturated oxiranes
• CPC Class Codes: C08G 65/3324 cyclic
• CPC Class Codes: C08J 3/16 by coagulating dispersions C08J3/122 takes precedence
• CPC Class Codes: C08L 2666/18 Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

The present invention relates to crosslinked polymers, synthesized through ring-opening polymerization of ethylenically unsaturated epoxides, in combination with α-hydroxy acids using a hydrophilic macroinitiator, such as poly(ethylene glycol), to form substituted copolymers having ethylenically unsaturated functionality randomly distributed along the polyester polymer backbone. That copolymer is subsequently crosslinked to form a hydrogel network. More particularly, the present invention relates to the synthesis of biodegradable poly(α-hydroxy acid-co-glycidyl methacrylate)-block-poly(ethylene glycol)-block-poly(α-hydroxy acid-co-glycidyl methacrylate) copolymers, which are subsequently crosslinked to form hydrogel networks. The invention also relates to the use of these hydrogel networks in various applications, in particular, for the controlled release of drugs and proteins.

Claims

1. A block copolymer comprising a poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide)-block-(hydrophilic segment)-block-poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide) copolymer, wherein the ring-opened ethylenically unsaturated epoxide is randomly distributed ring opened cyclic ester portion of the block copolymer.

2. The block copolymer of claim 1, wherein the hydrophilic segment is amphiphilic.

3. The block copolymer of claim 1, wherein the hydrophilic segment comprises poly(ethylene glycol).

4. The block copolymer of claim 1, wherein the hydrophilic segment comprises a hydroxy-terminated polyethylene oxide/polypropylene oxide block copolymer.

5. The block copolymer of claim 1, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, caprolactams, and copolymers of the foregoing.

6. The block copolymer of claim 5, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, and copolymers of the foregoing.

7. The block copolymer of claim 1, wherein the ethylenically unsaturated epoxide is glycidyl methacrylate.

8. The block copolymer of claim 1, wherein the copolymer is biodegradable.

9. A hydrogel comprising a crosslinked block copolymer, wherein said block copolymer comprises a poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide)-block-(hydrophilic segment)-block-poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide) copolymer, wherein the ring-opened ethylenically unsaturated epoxide is randomly distributed in the ring-opened cyclic ester portion of the block copolymer.

10. The hydrogel of claim 9, wherein the hydrophilic segment is amphiphilic.

11. The hydrogel of claim 9, wherein the hydrophilic segment comprises poly(ethylene glycol).

12. The hydrogel of claim 9, wherein the hydrophilic segment comprises a hydroxy-terminated polyethylene oxide/polypropylene oxide block copolymer.

13. The hydrogel of claim 9, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, caprolactams, and copolymers of the foregoing.

14. The hydrogel of claim 13, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, and copolymers of the foregoing.

15. The hydrogel of claim 9, wherein the ring-opened ethylenically unsaturated epoxide is glycidyl methacrylate.

16. The hydrogel of claim 9, wherein the block copolymer is biodegradable.

17. A method of making a block copolymer, comprising randomly polymerizing an ethylenically unsaturated epoxide and a cyclic ester using a macroinitiator to form a ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide)-block-hydrophilic(macroinitiator)-block-poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide) copolymer, wherein the ring-opened ethylenically unsaturated epoxide is randomly distributed in the ring-opened cyclic ester portion of the block copolymer.

18. The method of claim 17, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, caprolactone, 1,4-dioxan-2-one, cyclic carbonates, caprolactams, and copolymers of the foregoing.

19. The method of claim 18, wherein the ring-opened cyclic ester is selected from the group consisting of lactide, glycolide, and copolymers of the foregoing.

20. The method of claim 17, wherein the ethylenically unsaturated epoxide is glycidyl methacrylate.

21. The method of claim 17, wherein the hydrophilic macroinitiator is amphiphilic.

22. The method of claim 17, wherein the hydrophilic macroinitiator comprises poly(ethylene glycol).

23. The method of claim 17, wherein the hydrophilic macroinitiator comprises a hydroxy-terminated polyethylene oxide/polypropylene oxide block copolymer.

24. The method of claim 17, wherein block copolymer is biodegradable.

25. The method of claim 17, further comprising the step of crosslinking said block copolymer to form a hydrogel.

26. The block copolymer formed by the method of claim 17.

27. The crosslinked block copolymer formed by the method of claim 25.

28. A block copolymer comprising a poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide)-block-(hydrophilic sequence-block-poly(ring-opened cyclic ester-co-ring-opened ethylenically unsaturated epoxide) copolymer, wherein the ring-opened ethylenically unsaturated epoxide is randomly distributed in the ring-opened cylic ester portion of the block copolymer having the formula:

29. The copolymer of claim 28, wherein the hydrophilic segment is amphiphilic.

30. The block copolymer of claim 28, wherein the hydrophilic segment comprises poly(ethylene glycol).

31. The block copolymer of claim 28, wherein the hydrophilic segment comprises a hydroxy-terminated polyethylene oxide/polypropylene oxide block copolymer.

32. The block copolymer of claim 28, wherein R₄=—

CH₂—

O—

C(O)—

C(CH₃)═

CH₂.

33. The block copolymer of claim 28, wherein the copolymer is biodegradable.

34. The block copolymer as in claim 28, wherein the copolymer is crosslinked to form a hydrogel.

35. The hydrogel as in claims 9 or 34, wherein the hydrogel has a water content of at least about 85%.