Poly(lactic acid) copolymer hydrogels and related methods of drug delivery

• US 20060018872A1
• Filed: 06/16/2005
• Published: 01/26/2006
• Est. Priority Date: 06/16/2004
• Status: Abandoned Application

• Current Assignee: University Of Massachusetts
• Original Assignee: University Of Massachusetts
• Inventors: Tew, Gregory N., Bhatia, Surita
• Application Number:
  US11/154,308
• Publication Number:
  US 20060018872A1
• Time in Patent Office: Days
• US Class Current: 424/78.370
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42
• CPC Class Codes: C08J 2367/04 Polyesters derived from hydroxy carboxylic acids, e.g. lactones C08J2367/06 takes precedence
• CPC Class Codes: C08J 3/075 Macromolecular gels

Abstract

A-B-A triblock copolymers tailored to produce certain embodiments that have specific properties, such as relatively high elastic modulus. Also provided are methods of designing and synthesizing such a triblock copolymer having desired properties, such non-limiting copolymers comprising a poly(ethylene oxide) block and a block selected from at least one of poly(L-lactic acid) and poly(D,L-lactic acid).

Claims

1. An A-B-A triblock copolymer compound comprising A blocks comprising about 17-about 58 weight percent of said compound, each said A block of a formula (II),

where R¹, R², R³ and R⁴ are moieties independently selected from hydrogen, C₁-about C₆ alkyl, aryl, and X, where X is selected from Cl, Br, F, and I, a is an integer from 0 to about 6 and n is an integer from about 10 to about 300;

and a B block comprising about 42-about 83 weight percent poly(ethylene oxide), wherein the elastic modulus at 0.1 Hz of a hydrogel formed from an aqueous medium comprising about 10-about 50 wt % of said compound is about 0.1-about 1,000 kPa.

2. The triblock copolymer of claim 1 wherein said A block is selected from poly(lactic acid), poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(caprolactone), poly(valerolactone) and combinations thereof.

3. The triblock copolymer of claim 2 wherein said A block is selected from poly(L-lactic acid), poly(D,L-lactic acid) and a combination thereof.

4. The triblock copolymer of claim 1 wherein the elastic modulus at 0.1 Hz of a hydrogel formed from an aqueous solution of about 10-about 30 weight percent of said compound is about 0.1-about 10 kPa.

5. The copolymer of claim 1 wherein said A block comprises poly(lactic acid), and said compound is a hydrogel in an aqueous medium, said hydrogel comprising a hydrophobic therapeutic agent.

6. The copolymer of claim 5 wherein said A block of said hydrogel compound is at least partially crystalline.

7. An A-B-A triblock copolymer compound comprising poly(lactic acid) A blocks, each said A block comprising (C(O)CH(CH₃)O)_m, wherein n is an integer ranging from about 10 to about 50;

and a B block comprising poly(ethylene oxide), wherein the ratio of the degree of polymerization of poly(ethylene oxide) to the degree of polymerization of poly(lactic acid) ranges from about 2.0 to about 8.0.

8. The compound of claim 7 wherein said degree of polymerization of poly(lactic acid) ranges from about 25 to about 75.

9. The compound of claim 7 wherein the molecular weight of poly(ethylene oxide) ranges from about 4,000 to about 16,000.

10. The compound of claim 7 where said A block at least partially comprises poly(L-lactic acid).

11. The compound of claim 7 comprising a hydrogel in an aqueous medium, said hydrogel with an elastic modulus ranging from about 0.1 to about 50 kPa.

12. The compound of claim 7 comprising a hydrogel in an aqueous medium, said hydrogel comprising a therapeutic agent with an affinity for said A block.

13. The compound of claim 12 wherein said A block of said hydrogel is at least partially crystalline.

14. The compound of claim 12 wherein said hydrogel comprises an agent selected from sulindac and tetracaine.

16. The method of claim 14 wherein selection of a copolymer molecular weight comprises evaluating PEO weight percent, and selecting overall copolymer elastic modulus.

15. A method of a designing and synthesizing a biodegradable A-B-A triblock copolymer having desired properties, comprising the steps of:

selecting a copolymer molecular weight;

selecting a poly(ethylene oxide) B block length;

selecting a ratio of the degree of polymerization of poly(ethylene oxide) to the degree of polymerization of poly(lactic acid);

selecting an A block comprising at least one of poly(L-lactic acid) and poly(D,L-lactic acid) and

synthesizing the triblock copolymer.

17. The method of claim 15 wherein selection of a ratio of the degree of polymerization of poly(ethylene oxide) to the degree of polymerization of poly(lactic acid) comprises determining the weight percent of each polymer block for a desired elastic modulus.

18. The method of claim 15 wherein selection of at least one of poly(L-lactic acid) or poly(D,L-lactic acid) comprises selecting a desired drug release rate, and selecting a desired percent of crystallinity.

19. A method of using crystallinity to affect drug release from a poly(lactic acid)-poly(ethylene oxide)-poly(lactic acid) triblock copolymer, said method comprising:

providing a poly(lactic acid)-poly(ethylene oxide)-poly(lactic acid) triblock copolymer compound, said compound comprising a poly(lactic acid) block comprising at least one of L-lactic acid monomers, D-lactic acid monomers and a combination thereof, said poly(lactic acid) block having a crystallinity, said compound in an aqueous medium and in an amount at partially sufficient for gel formation; and

contacting said compound with a therapeutic agent having an affinity for said poly(lactic acid) block.

20. The method of claim 19 wherein said poly(lactic acid) block comprises poly(L-lactic acid).

21. The method of claim 20 wherein an increase in poly(L-lactic acid) content of said compound increases the rate of release of said agent.

22. The method of claim 19 wherein said poly(lactic acid) block comprises a combination of L- and D-lactic acid monomers.

23. The method of claim 22 wherein increasing the D-lactic acid content of said poly(lactic acid) block decreases the rate of release of said agent.

24. The method of claim 19 wherein said agent is selected from sulindac and tetracaine.