Prolonged anesthesia in joints and body spaces

• US 6,534,081 B2
• Filed: 04/02/2001
• Issued: 03/18/2003
• Est. Priority Date: 07/02/1997
• Status: Expired due to Fees

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Donigi-Gale, Donna, Lacouture, Peter, Sackler, Richard, Goldenheim, Paul, Chasin, Mark
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/824,465
• Publication Number:
  US 20020054915A1
• Time in Patent Office: 715 Days
• Field of Search: 424/426, 424/501, 424/502, 514/772.3, 264/4.33, 428/402
• 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 a formulation into a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, said formulation comprising (a) a local anesthetic incorporated in an effective amount of a biocompatible, biodegradable sustained release material, which prolongs 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 pain arising from said body space.

3. The method of claim 1, wherein the formulation 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.

5. The method of claim 3, wherein at least a portion of said second active agent is incorporated into said microparticles.

6. 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).

2. A method of treating localized pain, comprising administering a formulation into a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, said 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 and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, said formulation when administered providing pain relief to said body space, said formulation when administered in-vivo providing local anesthesia or analgesia or numbness or pain relief for at least about 24 hours.

4. The method of claim 2, wherein said bursae is selected from the group consisting of acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ishchiadica, and any other bursae subject to pain.

7. The method of claim 2, wherein said formulation when administered in-vivo provides local anesthesia or analgesia or numbness or pain relief for at least about 3-5 days.

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

9. The method of claim 2, wherein said augmenting agent is a glucocorticosteriod.

10. The method claim 2, wherein said microparticles comprise local anesthetic in a percent loading between 65 and 80%, and said augmenting agent is a glucocorticosteroid present in a weight percent relative to the local anesthetic from 0.005% to 15%.

11. The method of claim 9, wherein said 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 2, wherein a plurality of said microparticles are suspended in a pharmaceutically acceptable vehicle for injection.

13. The method of claim 2, wherein said local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof.

14. A method of treating localized pain arising from a body space in a mammal, comprising injecting a formulation into a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, 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 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 anesthesia or analgesia or numbness or pain relief or anti-inflammatory effect for at least about 24 hours when said formulation is injected into said body space.

15. The method of claim 14, wherein said augmenting agent is a glucocorticosteriod.

16. A method of prolonging the effect of a local anesthetic agent in body spaces, comprising injecting a formulation into a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, 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 anesthesia or analgesia or numbness or pain relief or anti-inflammatory effect for at least about 24 hours when said formulation is injected into said body space.

17. The method of claim 16, wherein said local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof.

18. The method of claim 16, wherein said formulation when administered in-vivo provides local anesthesia or analgesia or numbness or pain relief for at least about 3 to about 5 days.

19. The method claim 16, wherein said microspheres are microcapsules.

20. The method of claim 16, wherein the diameter of the microspheres ranges in size from about 5 microns to about 200 microns.

21. The method of claim 16, wherein at least a portion of said local anesthetic is incorporated in said microspheres.

22. The method of claim 16, wherein said augmenting agent is a glucocorticosteriod.

23. A method of prolonging the effect of a local anesthetic agent in body spaces, comprising administering a formulation into a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, said 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;

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 to a body space selected from the group consisting of pleura, peritoneum, cranium, mediastinum, pericardium, bursae, epidural space, intrathecal space, and intraocular space, said bursae selected from the group consisting of acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, and ishchiadica, and said formulation when administered in-vivo provides local anesthesia or analgesia or numbness or pain relief for at least about 24 hours.

24. The method of claim 23, wherein said augmenting agent is a glucocorticosteriod.

25. A method of treating localized pain, comprising administering a formulation into an intra-articular joint selected from the group consisting of knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to pain, said formulation comprising (a) a local anesthetic incorporated in an effective amount of a biocompatible, biodegradable sustained release material, which prolongs 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 pain arising from said intra-articular joint.

26. The method of claim 25, wherein said augmenting agent is a glucocorticosteriod.

27. A method of treating localized pain, comprising administering a formulation into a space selected from the group consisting of a pleural space, mediastinum, and pericardium, said formulation comprising (a) a local anesthetic incorporated in an effective amount of a biocompatible, biodegradable sustained release material, which prolongs 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 pain arising from said space.

28. A method of treating localized pain, comprising administering a formulation into a space selected from the group consisting of a pleural space, mediastinum, and pericardium, said 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;

and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, said formulation when administered providing pain relief to said space, said formulation when administered in-vivo providing local anesthesia or analgesia or numbness or pain relief for at least about 24 hours.

29. A method of treating localized pain arising from a space in a mammal, comprising injecting a formulation into a space selected from the group consisting of a pleural space, mediastinum, and pericardium, 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 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 anesthesia or analgesia or numbness or pain relief or anti-inflammatory effect for at least about 24 hours when said formulation is injected into said space.

30. A method of prolonging the effect of a local anesthetic agent in spaces, comprising injecting a formulation into a space selected from the group consisting of a pleural space, mediastinum, and pericardium, said formulation comprising a pharmaceutically acceptable medium containing a plurality of micro spheres 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 anesthesia or analgesia or numbness or pain relief or anti-inflammatory effect for at least about 24 hours when said formulation is injected into said space.

31. A method of prolonging the effect of a local anesthetic agent in spaces, comprising administering a formulation into a space selected from the group consisting of a pleural space, mediastinum, and pericardium, said 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;

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 to a space selected from the group consisting of a pleural space, mediastinum, and pericardium, and said formulation when administered in-vivo provides local anesthesia or analgesia or numbness or pain relief for at least about 24 hours.