Formulations and methods for providing prolonged local anesthesia

• US 6,451,335 B1
• Filed: 07/02/1998
• Issued: 09/17/2002
• Est. Priority Date: 07/02/1998
• Status: Expired due to Fees

• Current Assignee: Euroceltique SA
• Original Assignee: Euroceltique SA
• Inventors: Burton, Kevin, Maskiewicz, Richard, Shameem, Mohammed, Ketkar, Amol, Goldenheim, Paul, Chasin, Mark, Donigi-Gale, Donna
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/109,323
• Time in Patent Office: 1,538 Days
• Field of Search: 424/426
• US Class Current: 424/426
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61M 19/00 Local anaesthesia syringes therefor A61M5/00; Hypothermia A61M5/42 takes precedence; cooling blood in a bypass of the arterial system A61M1/36

Abstract

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 the local anesthetic from the 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 the local anesthesia for a time period longer than that obtainable from the substrate without the augmenting agent. In preferred embodiments, the controlled release material is a low molecular weight, acid-terminated polymer. A further aspect of the invention is directed to such formulations which release the local anesthetic in two phases, the first a rapid “bolus” to initiate anesthesia and a second, slower release to maintain anesthesia.

Claims

1. 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 selected from the group consisting of alkalinizing agents, glucocorticoid steroids, non-glucocorticoid steroids, non-steroid modulators of GABA receptors, modulators of ionic transport across cell membranes, antipyretic agents, adrenergic receptor agonists, adrenergic receptor antagonists, osmotic polysaccharides, agonists of potassium ATP channels, antagonists of potassium ATP channels, Na/K-ATPase inhibitors, Na/K-ATPase enhancers, neurokinin antagonists PLC inhibitors, anti-convulsants, analeptics, tranquilizing agents, ataretics, antidepressants, anti-seizure agents, leukotriene agonists, leukotriene inhibitors, prostaglandin agonists, prostaglandin inhibitors, phosphodiesterase agonists, phosphodiesterase inhibitors, vasoconstrictors, and combinations of any of the foregoing, said augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo;

said sustained release material comprising a low molecular weight, acid-terminated PLGA polymer having a molecular weight from about 20 to about 50 kd.

2. The formulation of claim 1, wherein said polymer has an inherent viscosity from about 0.19 to about 0.7 dl/g.

3. The formulation of claim 1, wherein said polymer has an inherent viscosity from about 0.25 to about 0.43 dl/g.

4. The formulation of claim 1, wherein the polymer is acid-terminated with carboxylic acid.

5. The formulation of claim 1, wherein the polymer is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is from about 75:

25 to about 50;

50.

6. The formulation of claim 1, wherein the polymer is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is 65:

35.

15. The formulation of claim 1 wherein said augmenting agent is a non-glucocorticoid steroid selected from the group consisting of neuroactive steroids and steroid modulators of GABA receptors.

16. The formulation of claim 1 wherein said augmenting agent is a modulator of ionic transport across cell membranes selected from the group consisting of sodium channel blockers, calcium channel blockers and potassium channel blockers.

17. The formulation of claim 1 wherein said augmenting agent is α

2 receptor agonist.

7. 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 selected from the group consisting of alkalinizing agents, glucocorticoid steroids, non-glucocorticoid steroids, non-steroid modulators of GABA receptors, modulators of ionic transport across cell membranes, antipyretic agents, adrenergic receptor agonists, adrenergic receptor antagonists, osmotic polysaccharides, agonists of potassium ATP channels, antagonists of potassium ATP channels, Na/K-ATPase inhibitors, Na/K-ATPase enhancers, neurokinin antagonists, PLC inhibitors, anti-convulsants, analeptics, tranquilizing agents, ataretics, antidepressants, anti-seizure agents, leukotriene agonists, leukotriene inhibitors, prostaglandin agonists, prostaglandin inhibitors, phosphodiesterase agonists, phosphodiesterase inhibitors, vasoconstrictors, and combinations of any of the foregoing, said augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo;

said sustained release material providing an in-vitro release of said local anesthetic from said microparticles 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;

said formulation releasing the local anesthetic in-vivo in two phases, the first a rapid “

bolus”

to initiate anesthesia and a second, slower release to maintain local anesthesia and/or pain relief and/or local numbness for at least about 24 hours.

8. The formulation of claim 7, which maintains local anesthesia and/or pain relief and/or local numbness for a period of time from about 3 to about 5 days.

9. The formulation of claim 8, wherein said sustained release material comprises a low molecular weight, acid-terminated PLGA polymer having a molecular weight from about 20 to about 50 kd.

10. The formulation of claim 9, wherein said polymer has an inherent viscosity from about 0.19 to about 0.7 dl/g.

11. The formulation of claim 10, wherein said polymer has an inherent viscosity from about 0.25 to about 0.43 dl/g.

12. The formulation of claim 10, wherein the polymer is acid-terminated with carboxylic acid.

13. The formulation of claim 10, wherein the polymer is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is from about 75:

25 to about 50;

50.

14. The formulation of claim 13, wherein the polymer is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is 65:

35.

18. The formulation of claim 7 wherein said augmenting agent is a non-glucocorticoid steroid selected from the group consisting of neuroactive steroids and steroid modulators of GABA receptors.

19. The formulation of claim 7 wherein said augmenting agent is a modulator of ionic transport across cell membranes selected from the group consisting of sodium channel blockers, calcium channel blockers and potassium channel blockers.

20. The formulation of claim 7 wherein said augmenting agent is α

2 receptor agonist.