Formulations and methods for providing prolonged local anesthesia

• US 6,921,541 B2
• Filed: 09/09/2002
• Issued: 07/26/2005
• Est. Priority Date: 06/09/1995
• Status: Expired due to Fees

• Current Assignee: Euroceltique SA
• Original Assignee: Euroceltique SA
• Inventors: Burch, Ronald M, Tigner, Joseph, Sackler, Richard, Goldenheim, Paul, Chasin, Mark
• Primary Examiner(s): Levy, Neil S.
• Application Number:
  US10/237,387
• Publication Number:
  US 20030185873A1
• Time in Patent Office: 1,051 Days
• Field of Search: 514/449, 514/330, 514/817, 514/818, 514171-177, 514/182, 514/279, 514/535, 514/229, 424422-437, 424484-486, 424/488, 424/490, 424/491, 424/493, 424497-499, 424/501, 424/502
• 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 31/14 Quaternary ammonium compounds, e.g. edrophonium, choline betaines A61K31/205
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• 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 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A formulation and methods for inducing sustained regional local anesthesia in a patient comprising a substrate comprising a local anesthetic and an effective amount of a biocompatible, biodegradable, controlled release material prolonging the release of the local anesthetic from the substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and a pharmaceutically acceptable, i.e., non-toxic, non-glucocorticoid augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable from the substrate without the augmenting agent.

Claims

1. A formulation for inducing sustained regional local anesthesia or analgesia in a patient comprising:

a plurality of substrates in a pharmaceutically acceptable medium, 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 to provide a controlled release of said local anesthetic when said formulation is implanted or injected in a patient, said biocompatible, biodegradable controlled release material being capable of degrading at least fifty percent in less than two years following implantation or injection into the patient and prolonging the release of said local anesthetic from said substrates in-vitro, when measured using the United States Pharmacopeia/National Formulary Paddle Method II, said substrates being included in said formulation in an amount sufficient to obtain reversible local numbness and/or analgesia when said formulation is implanted or injected in a patient, and

taxol in an amount effective to augment the local anesthetic, said taxol being (i) incorporated into and/or onto said substrates;

or (ii) incorporated into said pharmaceutically acceptable medium, or (iii) incorporated into said substrates and also incorporated into said pharmaceutically acceptable medium.

2. The formulation of claim 1, wherein said substrates are microspheres.

3. The formulation of claim 1, wherein said substrates are microcapsules.

4. The formulation of claim 1, wherein at least a portion of said taxol is incorporated in said substrates.

5. The formulation of claim 1, wherein said taxol is incorporated in the pharmaceutically acceptable medium in a concentration of from about 0.01% to about 1%, by weight.

6. The formulation of claim 1, wherein said taxol is incorporated in the pharmaceutically acceptable medium in a concentration of from about 0.05% to about 0.5%, by weight.

7. The formulation of claim 1, wherein the local anesthetic is incorporated into said controlled release material at a percent loading of 0.1% to about 90% by weight.

8. The formulation of claim 1, 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.

9. The formulation of claim 1, wherein the substrates are in a form selected from slabs, rods, beads, pellets, microparticles, spheroids and pastes.

10. The formulation of claim 1, wherein said substrates include from about 65% to about 80% local anesthetic, by weight.

11. The formulation of claim 1, wherein said formulation is injected.

12. The formulation of claim 1, wherein said formulation is implanted.

13. The formulation of claim 1, wherein the local anesthetic is bupivacaine.

14. The formulation of claim 1, wherein the taxol is incorporated in said substrates.

15. The formulation of claim 1, wherein a further amount of said taxol is on said substrates.

16. The formulation of claim 1, wherein the taxol is on said substrates.

17. The formulation of claim 1, wherein the substrates are in a pharmaceutically acceptable medium and wherein the taxol is incorporated in the pharmaceutically acceptable medium.

18. The formulation of claim 1, wherein the taxol is provided in an amount effective to prolong the duration of the local anesthetic effect for a time period greater than that possible by the use of the local anesthetic in controlled release form by itself.

19. A formulation for inducing sustained regional local anesthesia or analgesia in a patient comprising:

a plurality of substrates in a pharmaceutically acceptable medium, 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 to provide a controlled release of said local anesthetic when said formulation is implanted or injected in a patient, said biocompatible, biodegradable controlled release material being capable of degrading at least fifty percent in less than two years following implantation or injection into the patient, and prolonging the release of said local anesthetic from said substrates in-vitro, said substrates being included in said formulation in an amount sufficient to obtain reversible local numbness and/or analgesia when said formulation is implanted or injected in a patient; and

taxol in an amount effective to augment the local anesthetic, said taxol being (i) incorporated into and/or onto said substrates;

or (ii) incorporated into said pharmaceutically acceptable medium, or (iii) incorporated into said substrates and also incorporated into said pharmaceutically acceptable medium, said formulation providing an in vitro release of said local anesthetic using the United States Pharmacopeia/National Formulary Paddle Method II of from about 10 to about 60 percent after 24 hours, from about 20 to about 80 percent release after 48 hours and from about 40 to about 100 percent release after 72 hours, said formulation providing a reversible local anesthesia at the site when administered in vivo of at least about 24 hours.

20. The formulation of claim 19, 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.

21. The formulation of claim 19, wherein said Substrates are microspheres.

22. The formulation of claim 19, wherein said Substrates are microcapsules.

23. A formulation for inducing sustained regional local anesthesia or analgesia in a patient comprising a plurality of substrates comprising a local anesthetic, taxol in an amount effective to augment the 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 to provide a controlled release of said local anesthetic when said formulation is implanted or injected in a patient, said biocompatible, biodegradable controlled release material being capable of degrading at least fifty percent in less than two years following implantation or injection into the patient and prolonging the release of said local anesthetic from said substrates in vitro, when measured using the United States Pharmacopeia/National Formulary Paddle Method II, said substrates being included in said formulation in an amount sufficient to obtain reversible local numbness and/or analgesia when said formulation is implanted or injected in a patient.

24. The formulation of claim 23, 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.