Formulations and methods for providing prolonged local anesthesia

• US 20030185873A1
• Filed: 09/09/2002
• Published: 10/02/2003
• Est. Priority Date: 06/09/1995
• Status: Active Grant

• Current Assignee: Joseph Tigner, Mark Chasin, Paul Goldenheim, Richard Sackler, Ronald M. Burch
• Original Assignee: Joseph Tigner, Mark Chasin, Paul Goldenheim, Richard Sackler, Ronald M. Burch
• Inventors: Sackler, Richard, Goldenheim, Paul, Chasin, Mark, Burch, Ronald M., Tigner, Joseph
• Granted Patent: US 6,921,541 B2
• Time in Patent Office: Days
• 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 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 said local anesthetic from said substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and

a non-toxic, augmenting agent effective to prolong the duration of said local anesthesia for a time period longer than that obtainable from the substrate without said augmenting agent, wherein said augmenting agent is not glucocorticosteroid agent.

2. The formulation of claim 1, wherein said substrate comprises microspheres and said microspheres are suspended in a pharmaceutically acceptable medium for injection.

3. The formulation of claims 1 and 2, wherein at least a portion of said augmenting agent is incorporated in said substrate.

4. The formulation of claims 1 and 2, wherein at least a portion of said augmenting agent is in immediate release form.

5. The formulation of claim 1, wherein the biocompatible material 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, polysaccharides and combinations thereof, capable of degrading at least fifty percent in less than two years following implantation into the patient.

6. The formulation of claim 1 wherein the substrate is in a form selected from the group consisting of slabs, rods, beads, pellets, microparticles, microspheres, microcapsules, spheroids and pastes.

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 90% by weight.

8. The formulation of claim 7 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 formulation of claim 1 wherein the augmenting agent is an effective amount of an agent selected from the group consisting of alphaxalone, allotetrahydrocortisone, aminopyrine, benzamil, clonidine, minoxidil, dehydroepiandrosterone, dextran, diazepam, diazoxide, ouabain, digoxin, spantide, taxol, tetraethylammonium, valproic acid, vincristine, a catecholamine in controlled release form, 1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-triene-17-yl]amino]hexl]-1-H-pyrrole-2,5-dione, and active derivatives, analogs and mixtures thereof.

10. The formulation of claim 1 wherein at least part of said augmenting agent is incorporated into said substrate at a percent loading ranging from about 0.001 to about 30% by weight, preferably from about 0.005% to about 15%, by weight.

11. The formulation of claim 14 wherein the augmenting agent is effective to prolong the duration of local anesthesia from about 15% to about 1400% of the duration of local anesthesia induced by controlled release local anesthetic without the augmenting agent.

12. The formulation of claim 14 wherein the augmenting agent is a neuroactive steroid, preferably alphaxalone and/or dehydroepiandrosterone.

14. A formulation according to claim 1 wherein the augmenting agent is an effective amount of a pharmaceutically acceptable vasoconstrictor agent in controlled release form.

15. A formulation according to claim 14 wherein the vasoconstrictor agent is selected from the group consisting of clonidine, guanfacine, guanabenz, dopa, methyldopa, ephedrine, amphetamine, methamphetamine, methylphenidate, ethylnorepinephrine, ritalin, pemoline, epinephrine, norepinephrine, dopamine, metaraminol, phenylephrine, methoxamine, mephentermine, ephedrine, methysergide, ergotamine, ergotoxine, dihydroergotamine, sumatriptan and analogs, including active metabolites, derivatives and mixtures of any of the foregoing.

13. The formulation of claim 21 wherein the augmenting agent is a dextran having a molecular weight ranging from about 20 kDa to about 200 kDa and is incorporated into said substrate at a percent loading of 0.01 to 30% by weight.

16. A formulation 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 said local anesthetic from said substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and

a non-toxic non-glucocorticoid augmenting agent effective to prolong the duration of said local anesthesia, said formulation providing an in vitro release of said local anesthetic 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.

17. A controlled release formulation for inducing sustained regional local anesthesia at a site in a patient comprising

a local anesthetic incorporated in a controlled release formulation consisting essentially of a biocompatible material, said material degrading at least fifty percent in less than six months following implantation into a patient, wherein the local anesthetic is present in a concentration effective to achieve local anesthesia in the patient, and an effective amount of a non-glucocorticoid augmenting agent effective to prolong the duration of the local anesthesia.

18. Lyophilized particles suitable for deposit at a site in a patient in need of local anesthesia comprising

a substrate comprising a local anesthetic and an effective amount of a biocompatible, biodegradable, controlled release material prolonging the release of said local anesthetic from said substrate to obtain a reversible local anesthesia when injected in a patient and a non-glucocorticoid augmenting agent effective to prolong the duration of said local anesthesia for a time period longer than that obtainable from the substrate without said augmenting agent, wherein said substrate is lyophilized.

19. A unit dosage form of the lyophilized particles according to claim 18 that is sterilized and is in a container comprising an amount of said lyophilized particles sufficient to induce prolonged local anesthesia in at least one patient upon suspension of said controlled release form in a solution acceptable for deposit into a patient.

20. A unit dosage form of the lyophilized particles according to claim 18 wherein an amount of said lyophilized particles sufficient to induce local anesthesia in at least one patient is sterile and provided in a sealed container ready for use.