Formulations and methods for providing prolonged local anesthesia

• US 6,426,339 B1
• Filed: 04/03/2000
• Issued: 07/30/2002
• Est. Priority Date: 09/16/1996
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Curley, Joanne, Berde, Charles B., Castillo, Jenny, Langer, Robert S.
• Primary Examiner(s): Criares, Theodore J.
• Assistant Examiner(s): KIM, JENNIFER M
• Application Number:
  US09/541,928
• Time in Patent Office: 848 Days
• Field of Search: 514/180, 514/330, 514/818
• US Class Current: 514/180
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 23/02 Local anaesthetics

Abstract

The use of glucocorticosteroids in methods and formulations for prolonging and/or reactivating local anesthesia or local anesthesia previously induced by a local anesthetic agent, is disclosed.

Claims

1. A method for providing prolonged local analgesia at a site in a patient in need thereof, comprising

administering a local anesthetic in controlled release form at a site in a patient at which local analgesia is desired, and thereafter

administering at the site a glucocorticosteroid agent, in an amount effective to reactivate or prolong local analgesia, said glucocorticosteroid agent being administered at least one hour after said local anesthetic is administered.

2. The method according to claim 1, wherein said local anesthetic is administered by a method selected from the group consisting of topical application, implantation, infiltration, injection, infusion and any combination thereof, at or adjacent to the site requiring local analgesia.

3. The method according to claim 1, wherein said glucocorticosteroid agent is administered by a method selected from the group consisting of topical application, implantation, infiltration, injection, infusion and systemic administration and any combination thereof, at or adjacent to the site requiring reactivated analgesia.

4. The method of claim 1, wherein at least a portion of said glucocorticosteroid agent is administered at a time period ranging from about 1 to about 6 hours after said previous local anesthetic was administered.

5. The method of claim 1 wherein at least a portion of said glucocorticosteroid is in controlled release form.

6. The method of claim 5 further comprising preparing said controlled release form as a plurality of microspheres comprising said glucocorticosteroid, suspending said microspheres in a pharmaceutically acceptable medium for injection, and injecting said microspheres at the site requiring reactivated analgesia.

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

8. The method of claim 7 wherein the local anesthetic is bupivacaine.

9. The method of claim 1 wherein the reactivated local analgesia ranges in duration from about 1.1 to about 14 fold or more of the duration of local analgesia induced by controlled release local anesthetic without restoration.

10. The method of claim 1, wherein the reactivated local analgesia ranges in duration from about 1 to about 72 hours, measured from the time of administration of said effective amount of said glucocorticosteroid agent.

11. The method 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 thereof and salts thereof.

12. The method of claim 11 wherein the glucocorticosteroid is dexamethasone.

13. The method of claim 8 wherein the bupivacaine is administered in a dose ranging from about 0.5 to about 1000 mg at a site in the patient.

14. The method of claim 1, wherein said local anesthetic in controlled release form comprises microparticles that are suspended in a medium that is pharmaceutically acceptable for administration by a method selected from the group consisting of injection, instillation and topical application.

15. The method of claim 1, wherein the local anesthetic in controlled release form comprises a polymer selected from the group consisting of polyanhydrides, copolymers of acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, and polysaccharides.

16. The method of claim 1, wherein the local anesthetic is incorporated into said controlled release form at a percent loading of 0.1% to 90% by weight.

17. The method according to claim 1, wherein said glucocorticosteroid agent is administered at a time ranging from about 4 to about 24 hours after said local anesthetic was administered.

18. The method according to claim 14, wherein said microparticles are microspheres ranging in size from about 5 microns to about 200 microns in diameter.

19. The method according to claim 1 wherein said local anesthetic is incorporated into said controlled release form at a percent loading of about 75% by weight.

20. The method of claim 15 wherein said local anesthetic is incorporated into microspheres in an amount from about 45% to about 70% by weight, the copolymer being PLGA in a 50:

50 ratio, said copolymer having a molecular weight ranging from about 5000 to about 200,000.

21. The method according to claim 17, wherein said local anesthetic is bupivacaine.

22. The method of claim 1, wherein said controlled release form is liposomes.

23. The method of claim 1, wherein said local anesthetic in controlled release form comprises microcapsules.

24. The method of claim 1 wherein said local anesthetic is bupivacaine and said glucocorticosteroid is dexamethasone.

33. The method of claim 15 wherein said local anesthetic is incorporated into microspheres in an amount from about 60% to about 85% by weight, the copolymer being PLGA in a 50:

50 ratio, said copolymer having a molecular weight ranging from about 5000 to about 200,000.

34. The method of claim 15 wherein said local anesthetic is incorporated into microspheres in an amount from about 60% to about 85% by weight, the copolymer being PLGA in a 65:

35 ratio, said copolymer having a molecular weight ranging from about 5000 to about 200,000.

35. The method of claim 15 wherein said local anesthetic is incorporated into microspheres in an amount from about 60% to about 85% by weight, the copolymer being PLGA in a 75:

25 ratio, said copolymer having a molecular weight ranging from about 5000 to about 200,000.

36. The method of claim 15 wherein said local anesthetic is incorporated into microspheres in an amount from about 60% to about 85% by weight, the copolymer being PLGA in a 85:

15 ratio, said copolymer having a molecular weight ranging from about 5000 to about 200,000.

25. A method for providing prolonged local analgesia at a site in a patient in need thereof, comprising

administering bupivacaine or a salt thereof in controlled release form at a site in a patient at which local analgesia is desired, and thereafter

administering at the site dexamethasone or a salt thereof, in an amount effective to reactivate or prolong local analgesia, said dexamethasone or salt thereof being administered at least one hour after said bupivacaine or a salt thereof was administered.

26. The method of claim 25 wherein said bupivacaine or salt thereof in controlled release form comprises microcapsules.

27. The method of claim 25 wherein said bupivacaine or salt thereof in controlled release form comprises microspheres.

28. The method of claim 25 wherein said bupivacaine or salt thereof in controlled release form comprises a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides, and combinations thereof.

29. The method of claim 25 wherein said bupivacaine or salt thereof in controlled release form is administered in the form of

a plurality of substrates in a pharmaceutically acceptable medium for injection, said substrates comprising said bupivacaine or salt thereof and an effective amount of a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof.

30. The method of claim 27 wherein said microspheres are incorporated into a pharmaceutically acceptable solution or suspension for injection.

31. The method of claim 27, wherein said microspheres are in a reconstitutable form.

32. The method of claim 31 further comprising reconstituting said microspheres using a pharmaceutically acceptable solution or suspension for injection.

37. A method for providing local anesthesia or analgesia at a site in a patient in need thereof, comprising administering an amount of a local anesthetic effective to induce local anesthesia or analgesia at a site in a patient and an amount of a glucocorticosteroid effective to reactivate or prolong said local anesthesia or analgesia, said local anesthetic and said glucocorticosteroid being provided in controlled release form such that an amount of said glucocorticosteroid effective to reactivate or prolong the desired local anesthesia or analgesia is provided at the site at least one hour after the local anesthetic has been administered.

38. The method of claim 37, wherein the amount of said glucocorticosteroid that is effective to reactivate or prolong the desired local anesthesia or analgesia is provided from about one hour to about 72 hours after the local anesthetic has been administered.

39. The method of claim 37, wherein the amount of said glucocorticosteroid that is effective to reactivate or prolong the desired local anesthesia or analgesia is provided from about one hour to about 24 hours after the local anesthetic has been administered.

40. The method of claim 37, wherein the amount of said glucocorticosteroid that is effective to reactivate or prolong the desired local anesthesia or analgesia is provided from about one hour to about 6 hours after the local anesthetic has been administered.

41. The method of claim 37, wherein the local anesthetic is bupivacaine.

42. The method of claim 37, wherein the glucocorticosteroid is dexamethasone.

43. The method of claim 37, wherein said controlled release form comprises a plurality of substrates in a pharmaceutically acceptable medium for injection, said substrates comprising a local anesthetic and an effective amount of a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly (glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof, said biocompatible, biodegradable controlled release material being capable of prolonging the release of said local anesthetic from said substrates in vitro.

44. The method of claim 37, wherein said controlled release form is liposomes.

45. The method of claim 43, wherein said plurality of substrates comprises microcapsules, microspheres or microparticles.

46. The method of claim 37 wherein said local anesthetic is incorporated into said controlled release form at a percent loading of about 30% to about 90% by weight.

47. The method of claim 37, wherein said local anesthetic is incorporated into said controlled release form at a percent loading of about 60% to about 85% by weight.

48. The method of claim 40, wherein the glucocorticosteroid is dexamethasone.

49. The method of claim 37, wherein said controlled release form comprises an outer layer of controlled release local anesthetic agent coated on a substrate comprising a glucocorticosteroid in controlled release form.

50. The method of claim 37, wherein the controlled release form comprises a mixture of microspheres formed of polymers having different release rates.

62. The method of claim 37, 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 thereof and salts thereof.

64. The method of claim 39, wherein said local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and mixtures and salts thereof.

51. A method for reactivating a previously induced local anesthesia or analgesia, comprising administering a pharmaceutically acceptable composition comprising an effective amount of a local anesthetic and a glucocorticosteroid agent in an amount effective to prolong local anesthesia or analgesia at a site in a patient in need thereof, and thereafter administering a further dose of glucocorticosteroid effective to reactivate the anesthesia or analgesia, said further dose of glucocorticosteroid agent being administered at least one hour after said local anesthetic is administered.

52. The method of claim 51, wherein the local anesthetic is bupivacaine.

53. The method of claim 51, wherein the glucocorticosteroid is dexamethasone.

54. The method of claim 51, wherein said local anesthetic is in controlled release form.

55. The method of claim 54, wherein said local anesthetic is administered in the form of

a plurality of substrates in a pharmaceutically acceptable medium for injection, said substrates comprising a local anesthetic and an effective amount of a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly (glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof, said biocompatible, biodegradable controlled release material being capable of prolonging the release of said local anesthetic from said substrates in vitro.

56. The method of claim 54, wherein said controlled release form is liposomes.

57. The method of claim 55, wherein said plurality of substrates comprises microcapsules, microspheres or microparticles.

58. The method of claim 54 wherein said local anesthetic is incorporated into said controlled release form at a percent loading of about 30% to about 90% by weight.

59. The method of claim 54, wherein said local anesthetic is incorporated into said controlled release form at a percent loading of about 60% to about 85% by weight.

60. The method of claim 54, wherein said controlled release form comprises an outer layer of controlled release local anesthetic agent coated on a substrate comprising a glucocorticosteroid in controlled release form.

61. The method of claim 54, wherein the controlled release form comprises a mixture of microspheres formed of polymers having different release rates.

63. The method of claim 51, 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 thereof and salts thereof.

65. The method of claim 51, wherein said local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and mixtures and salts thereof.