Prolonged anesthesia in joints and body spaces

• US 6,248,345 B1
• Filed: 07/02/1998
• Issued: 06/19/2001
• Est. Priority Date: 07/02/1997
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Sackler, Richard, Goldenheim, Paul, Chasin, Mark, Donigi-Gale, Donna, Lacouture, Peter
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/109,324
• Time in Patent Office: 1,083 Days
• Field of Search: 424/426
• US Class Current: 424/426
• 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 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 23/02 Local anaesthetics
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Sustained release local anesthetic formulations are administered intra articularly and/or into body spaces/cavities. The formulation is preferably a plurality of injectable microparticles including a local anesthetic and an effective amount of a biocompatible, biodegradable, sustained release material prolonging the release of the local anesthetic and optionally and a pharmaceutically acceptable, i.e., non-toxic, augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable without the augmenting agent.

Claims

1. A method of treating localized pain, comprising administering into an intra articular joint a formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release material prolonging the release of the local anesthetic from the formulation, and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, said intra articular joint being selected from the group consisting of knee, elbow hip, stemoclavicular, temporomandibular, carpal tarsal, wrist, ankle, and any other joint subject to arthritic conditions, to treat localized pain.

2. The method of claim 1, wherein at least a portion of said augmenting agent is incorporated into said microparticles.

3. The method of claim 1, wherein a plurality of microparticles are suspended in a pharmaceutically acceptable vehicle for injection.

4. The method of claim 1, wherein the formulation further comprises an active agent selected from the group consisting of an enzyme, an anti-infective agent, an antibody and combinations thereof.

5. The method of claim 4, wherein at least a portion of said further active agent is incorporated into said microparticles.

6. The method of claim 1, wherein said sustained release material is 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.

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

8. The method of claim 1, wherein the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof.

9. The method of claim 1, wherein the augmenting agent is a glucocorticosteriod.

10. The method of claim 1, wherein the local anesthetic is bupivacaine, the augmenting agent is dexamethasone, and the sustained release material is a poly(lactide co-glycolide).

11. The method of claim 9, wherein the glucocorticosteriod 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 mixtures thereof.

12. The method of claim 1, wherein the microparticles comprise local anesthetic in a percent loading between 0.1% and 90%, preferably between 65 and 80%, and the augmenting agent is a glucocorticosteroid present in a weight percent relative to the local anesthetic from 0.005% to 15%.

13. The method of claim 1, wherein the augmenting agent is an effective amount of a pharmaceutically acceptable vasoconstrictor agent.

14. The method of claim 1, for administration into intra articular joints selected from the group consisting of knee, elbow, hip, stemoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions, and which formulation provides pain relief for 3-5 days.

17. The method of claim 1, wherein the formulation provides pain relief for 3-5 days.

24. The method of claim 17, wherein said sustained release material is 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.

25. The method of claim 17, wherein the local anesthetic is incorporated into said microparticles at a percent loading of 0. 1% to 90% by weight.

26. The method of claim 17, wherein the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof.

27. The method of claim 17, wherein the augmenting agent is a glucocorticosteriod.

28. The method of claim 17, wherein the local anesthetic is bupivacaine, the augmenting agent is dexamethasone, and the sustained release material is a poly(lactide co-glycolide).

29. The method of claim 26, wherein the glucocorticoid agent 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 mixtures thereof.

30. The method of claim 17, wherein the microparticles comprise local anesthetic in a percent loading from about 65 to about 80%, and augmenting agent is a glucocorticosteroid agent present in a weight percent relative to the local anesthetic from about 0.005% to about 15%.

31. The method of claim 17, wherein the augmenting agent is a pharmaceutically acceptable vasoconstrictor agent.

15. A method of treating localized joint pain comprising administering into an intra articular joint a formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release polymer selected from polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof, providing an in-vitro release of said local anesthetic of from 10 to 60 percent after 24 hours, from 20 to 80 percent release after 48 hours, and from 40 to 100 percent release after 72 hours;

and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, for providing pain relief said intra articular joint being selected from the group consisting of knee, elbow, hip, stemoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions, and which formulation when administered in-vivo providing pain relief for at least about 24 hours to about 5 days.

16. The method of claim 15, which further comprises a second active agent selected from an enzyme, an anti-infective agent, an antibody, a diagnostic aid, a radio-opaque dye, a magnetic resonance imaging dye, a radiolabeled agent, and combinations thereof.

18. A method of treating localized pain comprising administering a formulation into a bursae to treat localized pain, said formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release material prolonging the release of the local anesthetic from the formulation, and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, said bursae selected from the group consisting of acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ishchiadica, and other bursa known to those skilled in the art to be subject to pain.

19. The method of claim 18, wherein the formulation provides pain relief for 3-5 days.

21. The method of claim 18, wherein a plurality of microparticles are suspended in a pharmaceutically acceptable vehicle for injection, and said formulation is injected into said bursae.

22. The method of claim 18, wherein the formulation fuirther comprises an active agent selected from the group consisting of an enzyme, an anti-infective agent, an antibody and combinations thereof.

23. The method of claim 21, wherein at least a portion of said further active agent is incorporated into said microparticles.

20. The method of claimed 18, wherein at least a portion of said augmenting agent is incorporated into said microparticles.

32. A method of treating localized joint pain in a mammal, comprising

injecting a formulation into an intra articular joint selected from the group consisting of knee, elbow, hip, stemoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions, said formulation comprising a pharmaceutically acceptable medium containing a plurality of microspheres comprising a local anesthetic and an effective amount of a biocompatible, biodegradable controlled release material said biocompatible, biodegradable controlled release material capable of degrading at least fifty percent in less than two years following injection of the formulation in vivo, said controlled release material being 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 formulation further comprising a non-toxic augmenting agent which is (i) incorporated into and/or onto said microspheres;

or (ii) incorporated into said pharmaceutically acceptable medium, or (iii) incorporated into said microspheres and also incorporated into said pharmaceutically acceptable medium;

said microspheres being included in said formulation in an amount sufficient to obtain reversible local numbness and/or analgesia for at least about 24 hours when said formulation is injected intra articularly.

33. The method of claim 32, wherein said microspheres are microcapsules.

34. The method of claim 32, wherein the diameter of the microspheres ranges in size from about 5 microns to about 200 microns.

35. The method of claim 32, wherein at least a portion of said local anesthetic is incorporated in said microspheres.

36. The method of claim 32, wherein the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, procaine, chloroprocaine, prilocaine, mepivacaine, mixtures thereof, and salts thereof.

37. The method of claim 36, wherein said augmenting agent is a glucocorticosteroid.

38. A method of treating localized joint pain comprising administering a formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release material prolonging the release of the local anesthetic from the formulation, and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, to treat localized joint pain.