Biodegradable polymer matrices for sustained delivery of local anesthetic agents

• US 6,214,387 B1
• Filed: 09/17/1997
• Issued: 04/10/2001
• Est. Priority Date: 09/10/1992
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Langer, Robert S., Berde, Charles B.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/932,550
• Time in Patent Office: 1,301 Days
• Field of Search: 424/501, 424/494, 424/486, 424/428, 514/818, 514/951-52
• US Class Current: 424/501
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Abstract

Biodegradable controlled release microspheres for the prolonged administration of a local anesthetic agent, and a method for the manufacture thereof are disclosed. The microspheres are formed of a biodegradable polymer degrading significantly within a month, with at least 50% of the polymer degrading into non-toxic residues which are removed by the body within a two week period. Useful polymers include polyanhydrides, polylactic acid-glycolic acid copolymers and polyorthoesters containing a catalyst; polylactic acid-glycolic acid copolymers are preferred. Local anesthetics are incorporated into the polymer using a method that yields a uniform dispersion, preferably solvent casting. Prolonged release is obtained by incorporation of a glucocorticoid into the polymeric matrix or by co-administration of the glucocorticoid with the microspheres. The type of anesthetic and the quantity are selected based on the known pharmaceutical properties of these compounds.

Claims

1. A method for prolonged nerve blockade, local numbness, or pain relief at a site in a patient comprising

administering at the site a multiparticulate unit dose of a local anesthetic selected from the group consisting of bupivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine and salts thereof incorporated into particles of a biocompatible, biodegradable polymer selected from the group consisting of polymers of lactic acid, glycolic acid, and copolymers thereof, the particles being selected from the group consisting of microparticles, microspheres, and microcapsules, wherein the local anesthetic is included in the unit dose in an amount effective to achieve nerve blockade, local numbness, or pain relief at the site and is incorporated into the particles in a percent loading of between 5 and 90% by weight, and an amount of a glucocorticoid effective to prolong the nerve blockade or pain relief provided by the local anesthetic for a time period greater than that obtained by the use of the local anesthetic incorporated in the polymer in the absence of the glucocorticoid.

2. The method of claim 1 wherein the polymer is selected from the group consisting of copolymers of lactic acid and glycolic acid degrading at least fifty percent in less than six months following implantation into the patient.

3. The method of claim 1 wherein the unit dose provides nerve blockade, local numbness, or pain relief for a time period from about one day to about one week.

4. The method of claim 1 wherein the anesthetic is bupivacaine and salts thereof.

5. The method of claim 1 wherein the anesthetic is incorporated into the polymer at a percent loading of between 20 and 75% by weight.

6. The method of claim 5 wherein the glucocorticoid is incorporated into the polymer at a percent loading of between 0.01 and 30% by weight.

7. The method of claim 1 wherein the glucocorticoid is administered in a solution with the unit dose.

8. The method of claim 2 wherein the particles are microspheres having a diameter of between 10 and 200 microns.

9. The method of claim 1 wherein the polymer dose not elicit inflammation following implantation into a patient.

10. The method of claim 1 further comprising administering the unit dose by injection.

22. The method of claim 1 wherein the local anesthetic is bupivacaine and the glucocorticoid is dexamethasone.

23. The method of claim 6 wherein the local anesthetic is bupivacaine and the glucocorticoid is dexamethasone.

11. A formulation for prolonged nerve blockade, local numbness, or pain relief at a site in a patient comprising

a unit dose of a local anesthetic selected from the group consisting of bupivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine and salts thereof incorporated into a biocompatible, biodegradable polymer selected from the group consisting of polymers of lactic acid, glycolic acid, and copolymers thereof, wherein the local anesthetic is included in the unit dose in an amount effective to achieve nerve blockade, local numbness, or pain relief at the site and is incorporated into the polymer in a percent loading of between 5 and 90% by weight, and

an amount of a glucocorticoid effective to prolong the nerve blockade, local numbness, or pain relief provided by the local anesthetic for a time period greater than that obtained by the use of the local anesthetic incorporated into the polymer in the absence of the glucocorticoid.

12. The formulation of claim 11 wherein the polymer is selected from the group consisting of copolymers of lactic acid and glycolic acid degrading at least fifty percent in less than six months following implantation into the patient.

13. The formulation of claim 11 wherein the formulation provides nerve blockade or pain relief for a time period from about one day to about one week.

14. The formulation of claim 11 wherein the anesthetic is selected from the group consisting of bupivacaine and salts thereof.

15. The formulation of claim 11 wherein the anesthetic is incorporated into the polymer at a percent loading of between 20 and 75%.

16. The formulation of claim 15 wherein the glucocorticoid is incorporated into the polymer at a percent loading of between 0.01 and 30% by weight.

17. The formulation of claim 12 wherein the formulation is microspheres having a diameter between 10 and 200 microns.

18. The formulation of claim 11 wherein the glucocorticoid is in a solution with the microspheres.

19. The formulation of claim 11 wherein the polymer does not elicit inflammation following implantation into a patient.

20. The formulation of claim 11 further comprising a pharmaceutically acceptable carrier for administering the formulation by injection.

21. The formulation of claim 11 wherein the polymer incorporating the local anesthetic is coated with a material preventing inflammation as a result of implantation of the polymer.

24. The formulation of claim 11 wherein the local anesthetic is bupivacaine and the glucocorticoid is dexamethasone.

25. A formulation for prolonged nerve blockade, local numbness, or pain relief at a site in a patient comprising

a unit dose of a local anesthetic incorporated into a biocompatible, biodegradable polymer in the form of microspheres, the local anesthetic being included in the unit dose in an amount effective to achieve nerve blockade, local numbness, or pain relief at the site and being incorporated into the polymer in a percent loading of 5 to 90% by weight, and

an amount of a glucocorticoid effective to prolong the nerve blockade, local numbness, or pain relief provided by the local anesthetic for a time period greater than that obtained by the use of the local anesthetic incorporated into the polymer in the absence of the glucocorticoid.

26. The formulation of claim 25 wherein the local anesthetic is in a form selected from the group consisting of the free base of the local anesthetic, a pharmaceutically acceptable salt of the local anesthetic, and mixtures thereof.

27. The formulation of claim 25 wherein the formulation provides nerve blockade or pain relief for a time period from about one day to about one week.

28. The formulation of claim 26 wherein the local anesthetic is bupivacaine.

29. The formulation of claim 28 wherein the polymer is selected from the group consisting of lactic acid, glycolic acid, and copolymers thereof.

30. The formulation of claim 29 which is incorporated into a pharmaceutically acceptable solution for injection.

31. The formulation of claim 25 wherein the microspheres are microcapsules.

32. The formulation of claim 31 wherein the local anesthetic is bupivacaine and the polymer is a copolymer of lactic acid and glycolic acid.