Slow release of organic salts of local anesthetics for pain relief

Abstract

Particles of an organic acid salt of an amino acid amide or ester local anesthetic are employed as agents for the improved alleviation of pain. Particularly, the particles find use with surgically created wounds, where the particles may be administered directly into the bed of the wound or topically for transdermal transport.

What is claimed is: 
     
       1. A method for alleviating pain associated with a surgical wound of a mammal, said method comprising:
 administering to the area of said surgical wound a therapeutically effective amount of particles consisting essentially of (a) an organic acid salt of a caine anesthetic or (b) an organic acid salt of a caine anesthetic and the organic acid, wherein the organic acid has at least 6 carbon atoms, provided that said particles do not comprise a polymeric matrix or a wax matrix which controls the release of the caine anesthetic, and wherein the particles are of median size in the range of 50 to 2000 μm;
 whereby said caine anesthetic is released by dissolution of said salt and provides alleviation of pain. 
 
 
     
     
       2. The method according to  claim 1 , wherein said caine anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine. 
     
     
       3. The method according to  claim 1 , wherein said particles are prepared by dissolving said caine anesthetic and said organic acid in a solvent; and
 precipitating the organic acid salt of said caine anesthetic from said solvent as particles or forming particles from said precipitate. 
 
     
     
       4. A method according to  claim 1 , wherein said organic acid is an aliphatic organic acid and said particles comprise up to 50% equivalent excess of said aliphatic organic acid. 
     
     
       5. A method according to  claim 1 , wherein said organic acid is an aromatic organic acid and said particles comprise up to 50% equivalent excess of said aromatic organic acid. 
     
     
       6. A method according to  claim 1 , wherein said caine anesthetic is an amino acid amide. 
     
     
       7. A method according to  claim 1 , wherein said caine anesthetic is an amino acid ester. 
     
     
       8. The method according to  claim 1 , wherein said particles are introduced into the bed of said wound. 
     
     
       9. The method according to  claim 8 , wherein said particles are sprayed into said bed. 
     
     
       10. The method according to  claim 1 , wherein said particles are administered topically in a gel or liquid medium. 
     
     
       11. A method for alleviating pain associated with a surgically created wound of a human, said method comprising:
 administering particles consisting essentially of an organic acid and a caine anesthetic, to the bed of said wound, wherein said organic acid is of from 6 to 30 carbon atoms, provided that said particles do not comprise a polymeric matrix or a wax matrix which controls the release of the caine anesthetic, and wherein the particles are of median size in the range of 50 to 2000 μm; 
 whereby said caine anesthetic is released by dissolution of said salt and alleviates said pain. 
 
     
     
       12. A method according to  claim 11 , wherein said particles are sprayed into the bed of said wound. 
     
     
       13. A method according to  claim 12 , wherein said particles are dispersed in a vehicle to form a dispersion. 
     
     
       14. A method according to  claim 10 , wherein said particles are painted in the area of said wound. 
     
     
       15. A method for alleviating pain associated with a surgically created wound of a human said method comprising:
 topically administering to the skin in proximity to said wound particles consisting essentially of an aliphatic organic acid salt of a caine selected from the group consisting of ropivicaine, bupivicaine or lidocaine and 0 to 50% equivalent excess of the aliphatic organic acid, wherein said aliphatic organic acid is of from 6 to 30 carbon atoms and said particles are of median size in the range of 100 to 1200 μm, provided that said particles do not comprise a polymeric matrix of a wax matrix which controls the release of the caine anesthetic; 
 whereby said caine is released by dissolution of said salt and transported dermally over at least one day at a therapeutically effective amount and alleviates said pain. 
 
     
     
       16. The method of  claim 1 , wherein the organic acid is a sulfonic acid. 
     
     
       17. The method of  claim 11 , wherein the organic acid is a carboxylic acid. 
     
     
       18. The method of  claim 16 , wherein the sulfonic acid is benzenesulfonic acid; N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid; naphthalene sulfonic acid; octane-2-sulfonic acid; or toluene sulfonic acid. 
     
     
       19. The method of  claim 17 , wherein the acid is an aliphatic carboxylic acid. 
     
     
       20. The method of  claim 17 , wherein the acid is an aliphatic carboxylic acid of 12 to 24 carbon atoms. 
     
     
       21. A method for alleviating pain associated with a surgically created wound of a mammal, said method comprising:
 administering particles consisting essentially of an organic acid and a caine anesthetic, to the bed of said wound, wherein said organic acid is of from 6 to 30 carbon atoms, provided that said particles do not comprise a polymeric matrix or a wax matrix which controls the release of the caine anesthetic;   wherein the caine anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine;   wherein the particles are prepared by dissolving said caine anesthetic and said organic acid in a solvent and precipitating a precipitate and, optionally, forming particles from the precipitate;   wherein the particles are in a size range of about 50 to 2000 μm;   whereby said caine anesthetic is released by dissolution and alleviates said pain.   
     
     
       22. The method of claim 21 wherein the precipitate comprises an ionic species. 
     
     
       23. The method of claim 21 wherein the precipitate is characterized by a differential scanning calorimetry that confirms the presence of a new peak not identified in a differential scanning calorimetry of the caine anesthetic and organic acid. 
     
     
       24. The method of claim 21 wherein the solvent is an organic solvent. 
     
     
       25. The method of claim 24 wherein the caine anesthetic comprises a free base of the caine anesthetic. 
     
     
       26. The method of claim 25 wherein the organic acid is an aliphatic carboxylic acid. 
     
     
       27. The method of claim 25 wherein the organic acid is an aliphatic carboxylic acid having from about 12 to 24 carbon atoms. 
     
     
       28. The method of claim 25 wherein the organic acid is selected from the group consisting of capric, caproic, caprylic, lauric, myristic, palmitic, stearic, oleic, linoleic, linolenic, and arachidonic acids. 
     
     
       29. The method of claim 21 wherein the solvent is an aqueous solvent. 
     
     
       30. The method of claim 29 wherein the caine anesthetic dissolved in the aqueous solvent comprises a hydrochloride salt of the caine anesthetic. 
     
     
       31. The method of claim 28, wherein the precipitate comprises an ionic species. 
     
     
       32. The method of claim 21, wherein said particles have a median size in the range of 50 to 1500 μm. 
     
     
       33. The method of claim 21, wherein said particles have a median size in the range of 100 to 1200 μm. 
     
     
       34. A method for alleviating pain associated with a surgically created wound of a mammal, said method comprising:
 administering particles consisting essentially of an organic acid and a caine anesthetic, to the bed of said wound, provided that said particles do not comprise a polymeric matrix or a wax matrix which controls the release of the caine anesthetic;   wherein the caine anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine;   wherein the organic acid is an aliphatic carboxylic acid having from about 12 to 24 carbon atoms;   wherein the particles are prepared by dissolving said caine anesthetic and said organic acid in a solvent and precipitating a precipitate and, optionally, forming particles from the precipitate;   whereby said caine anesthetic is released by dissolution and alleviates said pain.   
     
     
       35. A pharmaceutical product comprising particles consisting essentially of an aliphatic organic acid and bupivacaine;
 wherein the aliphatic organic acid has from 6 to 30 carbon atoms, provided that said particles do not comprise a polymeric matrix or wax matrix which controls the release of the bupivicaine;   wherein the particles are prepared by dissolving bupivicaine and said aliphatic organic acid in a solvent and precipitating a precipitate and, optionally, forming particles from the precipitate.   
     
     
       36. The product of claim 35, wherein said precipitate comprises an ionic species. 
     
     
       37. The product of claim 35, wherein said particles have a median size in the range of 50 to 2000 μm. 
     
     
       38. The product of claim 35, wherein said particles have a median size in the range of 50 to 1500 μm.