(WO200334988) The present invention provides compositions and methods for extending the release times and lowering the toxicity of pharmacologically active compounds. The compounds comprise a salt of the pharmacologically active compound with a lipophilic counterion and a pharmaceutically acceptable water soluble solvent combined together to form an injectable composition. The lipophilic counterion may be a saturated or unsaturated C8-C22 fatty acid, and preferably may be a saturated or unsaturated C10-C18 fatty acid. When injected into a mammal, at least a portion of the composition precipitates and releases the active compound over time. Thus, the composition forms a slowly releasing drug depot of the active compound in the mammal. Therefore, the present invention enables one to provide a controlled dose administration of the active compound for a periods of up to 15 days or even longer. Many compounds can be administered according to the present invention including, but not limited to, tilmicosin, oxytetracycline, metoprolol, fluoxetine, roxithromycin, and turbinafine.
(WO200334988) 1. What is claimed is: 1. A composition for administration of a pharmacologically active compound to a mammal, comprising: a salt of the pharmacologically active compound with a lipophilic counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable composition that precipitates when injected into water; and wherein the composition releases the active compound over time when injected into the mammal. 2. The composition of claim 1 wherein the pharmaceutically acceptable solvent is a water miscible solvent. 3. The composition of claim 1 wherein the pharmacologically active compound is an antibiotic. 4. The composition of claim 1 wherein the pharmacologically active compound is tilmicosin, oxytetracycline, doxycycline, fluoxetine, roxithromycin, turbinafine or metoprolol. 5. The composition of claim 1 wherein the pharmacologically active compound is selected from the group consisting of: trimethoprim, neomycin, streptomycin, gentamycin, dibucaine, bupivacaine, benzocaine, tetracaine, acepromazine, itraconazole, tetracyclines, sulfonamides, and aminoglycosides. 6. The composition of claim 1 wherein the lipophilic counterion is a Cι0-C22saturated or un-saturated fatty acid. 7. The composition of claim 1 wherein the lipophilic counterion is a Cιo-Cι8saturated or unsaturated fatty acid. 8. The composition of claim 7 wherein the fatty acid selected from the group consisting of: lauric acid, decanoic acid, myristic acid, oleic acid and linoleic acid. 9. The method of claim 1 wherein the lipophilic counterion is a polycarboxylic acid. 10. The composition of claim 1 wherein the polycarboxylic acid is selected from the group consisting of: sebacic acid, polysebacic acid, polyaspartic acid, polyacrylic acid, and polybenzoic acid. 11. The composition of claim 1 wherein the pharmaceutically acceptable solvent is selected from the group consisting of one or a combination of: pyrrolidone, N- methyl pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, and tetrahydrofurfuryl alcohol. 12. The composition of claim 1 wherein the pharmaceutically acceptable solvent comprises 10% propylene glycol in glycerol formal with or without stabilizers. 13. The composition of claim 1 wherein the pharmaceutically acceptable solvent is triacetin. 14. The composition of claim 1 wherein the pharmacologically active compound is oxytetracycline, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 15. The composition of claim 1 wherein the pharmacologically active compound is tilmicosin, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 16. A method of administering a pharmacologically active compound to a mammal comprising: preparing a composition comprising a salt of the pharmacologically active compound and a lipophilic counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable formulation; and injecting the composition into the mammal; wherein at least a portion of the composition precipitates and releases the active compound over time when injected into the mammal. 17. The method of claim 16 wherein the pharmaceutically acceptable solvent is a water miscible solvent. 18. The method of claim 16 wherein the pharmacologically active compound is an antibiotic. 19. The method of claim 18 wherein the antibiotic is tilmicosin, tetracycline, or doxycycline. 20. The method of claim 18 wherein the antibiotic is selected from the group consisting of: trimethoprim, neomycin, streptomycin, gentamycin, tefracyclines, sulfonamides, and aminoglycosides. 21. The method of claim 16 wherein the lipophilic counterion is a fatty acid. 22. The method of claim 21 wherein the fatty acid is a C10-C22fatty acid. 23. The method of claim 22 wherein the fatty acid is selected from the group consisting of: lauric acid, decanoic acid, myristic acid, oleic acid and linoleic acid. 24. The method of claim 16 wherein the lipophilic counterion is sebacic acid. 25. The method of claim 16 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: pyrrolidone, N-methyl pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, and tetrahydrofurfuryl alcohol. 26. The method of claim 16 wherein the pharmaceutically acceptable carrier is triacetin. 27. The method of claim 16 wherein the pharmacologically active compound is oxytetracycline, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 28. The method of claim 16 wherein pharmacologically active compound is tilmicosin, the lipophilic counterion is decanoic acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 29. A method of extending the release time of a pharmacologically active compound administered to a mammal comprising, preparing a formulation comprising, a salt of the pharmacologically active compound and a lipophilic counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable formulation; and injecting the formulation into the mammal; wherein at least a portion of the formulation precipitates and releases the active compound over time when injected into the mammal, thereby extending the release time of the pharmacologically active compound. 30. The method of claim 29 wherein the pharmaceutically acceptable solvent is a water miscible solvent. 31. The method of claim 29 wherein the lipophilic counterion is a C 10-C \8 fatty acid. 32. The method of claim 31 wherein the antibiotic is tilmicosin, oxytetracycline, or doxycycline. 33. The composition of claim 32 wherein the fatty acid selected from the group consisting of: lauric acid, decanoic acid, and myristic acid. 34. The composition of claim 29 wherein the lipophilic counter ion is sebacic acid. 35. The composition of claim 29 wherein the pharmacologically active compound is oxytetracycline, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 36. The composition of claim 29 wherein the pharmacologically acceptable compound is tilmicosin, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 37. A method of manufacturing an injectable formulation for the administration of a pharmacologically active compound to a mammal comprising, providing a salt of the pharmacologically active compound with a lipophilic counterion; providing a pharmaceutically acceptable solvent; combining the salt and the solvent to form an injectable formulation; wherein at least a portion of the formulation precipitates and releases the active compound over time when injected into the mammal. 38. The method of claim 37 wherein the pharmaceutically acceptable solvent is a water miscible solvent. 39. The method of claim 37 wherein the pharmacologically active compound is an antibiotic. 40. The composition of claim 37 wherein the antibiotic is tilmicosin, oxytetracycline, or doxycycline. 41. The method of claim 37 wherein the lipophilic counterion is a Cι0-C18fatty acid. 42. The method of claim 41 wherein the fatty acid is selected from the group consisting of: lauric acid, decanoic acid, and myristic acid. 43. The method of claim 37 wherein the lipophilic counterion is sebacic acid. 44. The method of claim 37 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: pyrrolidone, N-methyl pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, and tetrahydrofurfuryl alcohol. 45. The method of claim 37 wherein the pharmaceutically acceptable carrier is triacetin. 46. The method of claim 37 wherein the pharmacologically active compound is oxytetracycline, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 47. The method of claim 37 wherein the pharmacologically active compound is tilmicosin, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 48. The method of claim 37 wherein the pharmacologically active compound is oxytetracycline, the lipophilic counterion is lauric acid, and the pharmaceutically acceptable solvent is selected from the group consisting of one or more of polyethylene glycol, propylene glycol, and glycerol formal. 49. A composition for administration of a pharmacologically active compound to a mammal, comprising: a salt of the pharmacologically active compound with a lipophilic counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable composition; and wherein at least a portion of the composition precipitates and releases the active compound over time when injected into an aqueous environment. 50. The composition of claim 49 wherein the pharmaceutically acceptable solvent is water miscible. 51. The composition of claim 49 wherein the antibiotic is tilmicosin, oxytetracycline, or doxycycline. 52. The composition of claim 49 wherein the pharmacologically active compound is selected from the group consisting of: trimethoprim, neomycin, streptomycin, gentamycin, dibucaine, bupivacaine, benzocaine, tetracaine, acepromazine, itraconazole, tetracyclines, sulfonamides, and aminoglycosides. 53. The composition of claim 49 wherein the lipophilic counterion is a do- Cι8fatty acid. 54. The composition of claim 53 wherein the fatty acid selected from the group consisting of: lauric acid, decanoic acid, and myristic acid. 55. The composition of claim 49 wherein the lipophilic counterion is sebacic acid. 56. The composition of claim 49 wherein the pharmaceutically acceptable solvent is selected from the group consisting of one or a combination of: pyrrolidone, N- methyl pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, and tetrahydrofurfuryl alcohol. 57. The composition of claim 49 wherein the pharmaceutically acceptable solvent is triacetin. 58. A composition for administration of a pharmacologically active compound to a mammal, comprising: a salt of the pharmacologically active compound with a lipophilic counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable composition; and wherein at least a portion of the pharmaceutically active compound and lipophilic counterion dissolves in the solvent and precipitates in vivo. 59. A composition for administration of a pharmacologically active compound to a mammal, comprising: a salt of the pharmacologically active compound with a polycarboxylic acid counterion; and a pharmaceutically acceptable solvent; combined together to form an injectable composition that precipitates when injected into water; and wherein the composition releases the active compound over time when injected into the mammal. 60. The composition of claim 58 wherein the polycarboxylic acid is selected from the group consisting of: polyaspartic acid, polyacrylic acid, sebacic acid, polysebacic acid, and polybenzoic acid. 61. The composition of claim 58 wherein the pharmaceutically acceptable solvent is a water miscible solvent. 62. The composition of claim 58 wherein the pharmacologically active compound is an antibiotic. 63. The composition of claim 58 wherein the pharmacologically active compound is tilmicosin, oxytetracycline, doxycycline, fluoxetine, roxithromycin, turbinafine or metoprolol. 64. The composition of claim 58 wherein the pharmacologically active compound is selected from the group consisting of: trimefhoprim, neomycin, streptomycin, gentamycin, dibucaine, bupivacaine, benzocaine, tetracaine, acepromazine, itraconazole, tefracyclines, sulfonamides, and aminoglycosides.
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