Biodegradable copolymer hydrogels

• US 8,211,959 B2
• Filed: 09/30/2009
• Issued: 07/03/2012
• Est. Priority Date: 12/31/2008
• Status: Active Grant

• Current Assignee: Industrial Technology Research Institute
• Original Assignee: Industrial Technology Research Institute
• Inventors: Shen, Hsin-Hsin, Chen, Chin-Fu, Hsieh, Meng-Yow, Lee, Wen-Fu, Chen, Miao-Tzu
• Primary Examiner(s): Schultz, Doug
• Application Number:
  US12/570,588
• Publication Number:
  US 20100166863A1
• Time in Patent Office: 1,007 Days
• Field of Search: None
• US Class Current: 523/522
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 63/668 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08G 63/91 Polymers modified by chemical after-treatment
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids

Abstract

Biodegradable copolymer hydrogels are provided. The biodegradable copolymer hydrogels have a structure of Formula (I) or Formula (II)
A-B—BOX—B-A  Formula (I)
B-A-B—(BOX—B-A-B)n-BOX—B-A-B  Formula (II),

• • wherein, A comprises a hydrophilic polyethylene glycol polymer (A); B comprises a hydrophobic polyester polymer (B); BOX is bifunctional group monomer of 2,2′-Bis(2-oxazoline) and used for coupling the blocks A-B or B-A-B; and n is an integer, equal to or greater than 0.

Claims

1. A biodegradable copolymer hydrogel, comprising a copolymer represented by Formula (I):

A-B—

BOX—

B-A,

wherein A comprises a hydrophilic polyethylene glycol polymer, B comprises a hydrophobic polyester polymer, and BOX comprises a bifunctional group monomer of 2,2′

-Bis(2-oxazoline) for coupling the di-blocks A-B, wherein the hydrophobic polyester polymer (B) has a molecular weight of 500-5000 Da.

2. The biodegradable copolymer hydrogel as claimed in claim 1, wherein an end of the hydrophobic polyester polymer (B) which is not bonded with the hydrophilic polyethylene glycol polymer (A) has an end capping/coupling functional group.

3. The biodegradable copolymer hydrogel as claimed in claim 2, wherein the hydrophobic polyester polymer (B) is bonded with the BOX via the end capping/coupling functional group.

4. The biodegradable copolymer hydrogel as claimed in claim 2, wherein the end capping/coupling functional group is derived from an end capping/coupling agent, and the end capping/coupling agent comprises an anhydride.

5. The biodegradable copolymer hydrogel as claimed in claim 4, wherein the end capping/coupling agent comprises succinic anhydride, maleic anhydride, phthalic anhydride, or sebacic anhydride.

6. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the hydrophilic polyethylene glycol polymer (A) comprises methoxy-poly(ethylene glycol) (mPEG).

7. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the hydrophilic polyethylene glycol polymer (A) has a molecular weight of 300-3000 Da.

8. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the hydrophobic polyester polymer (B) comprises polymers or copolymers derived from D,L-Lactide, D-Lactide, L-Lactide, D,L-Lactic acid, D-Lactic acid, L-Lactic acid, glycolide, β

-propiolactone, δ

-valerolactone, or ε

-caprolactone.

9. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the hydrophobic polyester polymer (B) comprises poly(lactide-co-glycolide) (PLGA), poly(propionic-co-lactic (PPLA), poly(valeric-co-lactic) (PVLA), or poly(caproic-co-lactic) (PCLA).

10. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the hydrophobic polyester polymer (B) comprises the copolymer of poly(lactic acid) (PLA) and poly(glycolide acid) (PGA).

11. The biodegradable copolymer hydrogel as claimed in claim 10, wherein the poly(lactic acid) has a mole percent of 50-90 mol %, based on the total mole percent of poly(lactic acid) and poly(glycolide acid).

12. The biodegradable copolymer hydrogel as claimed in claim 10, wherein the poly(glycolide acid) has a mole percent of 10-50 mol %, based on the total mole percent of poly(lactic acid) and poly(glycolide acid).

13. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the di-block A-B is reacted with 2,2′

-Bis(2-oxazoline) via ring-opening polymerization to form the copolymer represented by Formula (I).

14. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the biodegradable copolymer hydrogel has no cytotoxicity after degradation.

15. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the biodegradable copolymer hydrogel has a low critical solution temperature (LCST) of 10-90°

C.

16. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the biodegradable copolymer hydrogel is applied for drug release, cells delivery, growth factors delivery, nucleic acids delivery, tissue engineering, repair of soft and hard tissues, or bioadhesion.

17. The biodegradable copolymer hydrogel as claimed in claim 16, wherein the biodegradable copolymer hydrogel serves as a bioadhesion for adhering interfaces of cells, tissues, and implants, repair of soft and hard tissues, or implant fillers.

18. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the biodegradable copolymer hydrogel is further mixed with a biological activity compound, ceramics, polymer, or metal.

19. The biodegradable copolymer hydrogel as claimed in claim 1, wherein the biodegradable copolymer hydrogel serves as a carrier of an injection, pastille, powder, gel or oral liquid.

20. A biodegradable copolymer hydrogel, comprising a copolymer represented by Formula (II) of

B-A-B—

(BOX—

B-A-B)n-BOX—

B-A-B,

wherein A comprises a hydrophilic polyethylene glycol polymer, B comprises a hydrophobic polyester polymer, BOX comprises a bifunctional group monomer of 2,2′

-Bis(2-oxazoline) for coupling the tri-blocks B-A-B, and n is an integer, equal to or greater than 0, wherein the hydrophobic polyester polymer (B) has a molecular weight of 500-5000 Da.

21. The biodegradable copolymer hydrogel as claimed in claim 20, wherein an end of the hydrophobic polyester polymer (B) which is not bonded with the hydrophilic polyethylene glycol polymer (A) has an end capping/coupling functional group.

22. The biodegradable copolymer hydrogel as claimed in claim 21, wherein the hydrophobic polyester polymer (B) is bonded with the BOX via the end capping/coupling functional group.

23. The biodegradable copolymer hydrogel as claimed in claim 21, wherein the end capping/coupling functional group is derived from an end capping/coupling agent, wherein the end capping/coupling agent comprises an anhydride.

24. The biodegradable copolymer hydrogel as claimed in claim 23, wherein the end capping/coupling agent comprises succinic anhydride, maleic anhydride, phthalic anhydride, or sebacic anhydride.

25. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the hydrophilic polyethylene glycol polymer (A) comprises poly(ethylene glycol) (PEG).

26. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the hydrophilic polyethylene glycol polymer (A) has a molecular weight of 300-3000 Da.

27. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the hydrophobic polyester polymer (B) comprises polymers or copolymers derived from D,L-Lactide, D-Lactide, L-Lactide, D,L-Lactic acid, D-Lactic acid, L-Lactic acid, glycolide, β

-propiolactone, δ

-valerolactone, or ε

-caprolactone.

28. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the hydrophobic polyester polymer (B) comprises poly(lactide-co-glycolide) (PLGA), poly(propionic-co-lactic (PPLA), poly(valeric-co-lactic) (PVLA), or poly(caproic-co-lactic) (PCLA).

29. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the hydrophobic polyester polymer (B) comprises the copolymer of poly(lactic acid) (PLA) and poly(glycolide acid) (PGA).

30. The biodegradable copolymer hydrogel as claimed in claim 29, wherein the poly(lactic acid) has a mole percent of 50-90 mol %, based on the total mole percent of poly(lactic acid) and poly(glycolide acid).

31. The biodegradable copolymer hydrogel as claimed in claim 29, wherein the poly(glycolide acid) has a mole percent of 10-50 mol %, based on the total mole percent of poly(lactic acid) and poly(glycolide acid).

32. The biodegradable copolymer hydrogel as claimed in claim 29, wherein the tri-block B-A-B is reacted with 2,2′

-Bis(2-oxazoline) via ring-opening polymerization to form the copolymer represented by Formula (II).

33. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the biodegradable copolymer hydrogel has no cytotoxicity after degradation.

34. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the biodegradable copolymer hydrogel has a low critical solution temperature (LCST) of 10-90°

C.

35. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the biodegradable copolymer hydrogel is applied for drug release, cells delivery, growth factors delivery, nucleic acids delivery, tissue engineering, repair of soft and hard tissues, or bioadhesion.

36. The biodegradable copolymer hydrogel as claimed in claim 35, wherein the biodegradable copolymer hydrogel serves as a bioadhesion for adhering interfaces of cells, tissues, and implants, repair of soft and hard tissues, or implant fillers.

37. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the biodegradable copolymer hydrogel is further mixed with a biological activity compound, ceramics, polymer, or metal.

38. The biodegradable copolymer hydrogel as claimed in claim 20, wherein the biodegradable copolymer hydrogel serves as a carrier of an injection, pastille, powder, gel or oral liquid.