High load formulations and methods for providing prolonged local anesthesia

• US 6,238,702 B1
• Filed: 07/12/1999
• Issued: 05/29/2001
• 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., Curley, Joanne, Berde, Charles B., Castillo, Jenny
• Primary Examiner(s): Spear, James M.
• Assistant Examiner(s): Bennett, Rachel M
• Application Number:
  US09/352,511
• Time in Patent Office: 687 Days
• Field of Search: 424/489, 424/426, 424/464, 424/484, 424/486, 424/488, 424/436, 424/400, 424/422
• US Class Current: 424/489
• 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

A formulation for inducing sustained local anesthesia in a patient comprising a substrate comprising a high load of local anesthetic by weight and an effective amount of a biocompatible, controlled release material to obtain a. reversible nerve blockade or anesthesia effect when implanted or injected in a patient, and a non-toxic glucocorticosteroid agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable from the substrate without the glucocorticosteroid agent.

Claims

1. A formulation for providing pain relief at a site in a patient comprising a local anesthetic in a biocompatible biodegradable controlled release form and a glucocorticosteroid in an amount effective to prolong the effect of the local anesthetic such that the duration of effect is greater than that obtained by use of the same dose of local anesthetic in controlled release form in the absence of the glucocorticosteroid.

2. The formulation of claim 1 wherein the controlled release form comprises a biocompatible polymer.

3. The formulation of claim 1 wherein at least a portion of the glucocorticosteroid is incorporated into a separate controlled release form.

4. The formulation of claim 2 wherein the polymer is selected the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, polyorthoesters, proteins, and polysaccharides.

5. The formulation of claim 2 wherein the polymer is a copolymer of lactic acid and glycolic acid.

6. The formulation of claim 5 wherein the copolymer comprises a ratio of lactic acid and glycolic acid ranging from about 75:

25 to about 50;

50 by weight.

7. The formulation of claim 1 wherein the glucocorticosteroid is selected from the group consisting of dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and mometasone and pharmaceutically acceptable mixtures and salts thereof.

8. The formulation of claim 1 wherein the glucocorticosteroid is incorporated at a loading between about 0.001 and about 30 percent by weight.

9. The formulation of claim 1 wherein the glucocorticosteroid is dexamethasone.

10. The formulation of claim 1 wherein the local anesthetic is in free base form.

11. The formulation of claim 1 wherein the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, and mixtures thereof.

12. The formulation of claim 1 wherein the local anesthetic is incorporated into the controlled release form at a percent loading of ranging from about 60% to about 85% by weight.

13. The formulation of claim 1 which is in the form selected from the group consisting of slabs, beads, pellets, microparticles, microspheres, microcapsules, and pastes.

14. The formulation of claim 13 which comprises a plurality of microparticles.

15. The formulation of claim 14, which comprises microspheres. suspended in a pharmaceutically acceptable carrier for administration by a method selected from the group consisting of injection, infiltration, infusion or topical application.

16. The formulation of claim 15 wherein at least a portion of the glucocorticosteroid is present in said pharmaceutically acceptable vehicle for injection.

17. The formulation of claim 15 further comprising an outer coating wherein the outer coating flier comprises a pharmaceutically active agent for immediate release selected from the group consisting of a glucocorticosteroid and a local anesthetic and mixtures thereof.

18. The formulation of claim 1 wherein the local anesthesia is effective from about 0.1 hour to about 200 hours after administration.

19. The formulation of claim 1 wherein the local anesthesia is effective from about 1 hour to about 150 hours after administration.

32. A formulation for sustained release of a local anesthetic according to claim 1, wherein the controlled release form comprises microcapsules comprising the local anesthetic, the glucocorticosteroid, and a biocompatible, biodegradable polymer, wherein the local anesthetic is present in said microcapsules at a weight percent ranging from about 70 to about 90%.

20. A formulation for sustained release of a local anesthetic at a site in a patient comprising a local anesthetic and a glucocorticosteroid incorporated into a biocompatible biodegradable polymer, the formulation including the local anesthetic in a concentration effective to provide pain relief at the site and the glucocorticosteroid in a concentration effective to prolong the effect of the local anesthetic such that the duration of effect is greater than that obtained by use of the same dose of local anesthetic in controlled release form in the absence of the glucocorticosteroid.

21. A method for providing pain relief at a site in a patient, comprising administering a local anesthetic in a controlled release form and administering a glucocorticosteroid at the site in an amount effective to substantially prolong the effect of the local anesthetic such that the duration of effect is greater than that obtained by use of the same dose of local anesthetic in controlled release form in the absence of the glucocorticosteroid.

22. The method of claim 21 wherein the controlled release form comprises a biocompatible polymer.

23. The method of claim 22 wherein the polymer is selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, polyorthoesters, proteins, and polysaccharides.

24. The method of claim 21 wherein at least a portion of the glucocorticosteroid is incorporated into a separate biocompatible polymer from the local anesthetic.

25. The method of claim 21 wherein the glucocorticosteroid is selected from the group consisting of dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and mometasone and pharmaceutically acceptable mixtures and salts thereof.

26. The method of claim 21 wherein the glucocorticosteroid is dexamethasone.

27. The method of claim 21 wherein the local anesthetic is in free base form.

28. The method of claim 21 wherein;

the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, and mixtures thereof.

29. The method of claim 21 wherein the anesthetic is incorporated into the polymer at a percent loading ranging from about 60 percent to about 90 percent by weight.

30. The method of claim 21 wherein the formulation is in the form selected from the group consisting of slabs, beads, pellets, microparticles, microspheres, microcapsules, and pastes.

31. The method of claim 30 wherein the formulation comprises a plurality of microparticles.

33. A formulation for providing prolonged pain relief at a site in a patient comprising a local anesthetic incorporated into a biocompatible, biodegradable controlled release form selected from the group consisting of slabs, beads, pellets, microparticles, microspheres, microcapsules, and pastes, said local anesthetic being contained in said controlled release form at a percent loading ranging from about 60 percent to about 90 percent by weight, said controlled release form further comprising a glucocorticosteroid in an amount effective to prolong the effect of local anesthetic such that the duration of effect is greater than that obtained by use of the same dose of local anesthetic in controlled release form in the absence of the glucocorticosteroid.

34. The formulation of claim 33 which comprises microcapsules.

35. The formulation of claim 34, which comprises microcapsules or microspheres suspended in a pharmaceutically acceptable carrier for administration by a method selected from the group consisting of injection, infiltration, infusion or topical application.

36. The formulation of claim 33 wherein the biocompatible, biodegradable controlled release form comprises a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, polyorthoesters, proteins, and polysaccharides.

37. The formulation of claim 36, wherein the biocompatible, biodegradable controlled release form comprises a copolymer of lactic acid and glycolic acid.

38. The formulation of claim 37, wherein the copolymer comprises a ratio of lactic acid and glycolic acid ranging from about 75:

25 to about 50;

50 by weight.