Transdermal anesthetic and vasodilator composition and methods for topical administration

• US 20020006435A1
• Filed: 01/26/2001
• Published: 01/17/2002
• Est. Priority Date: 01/27/2000
• Status: Abandoned Application

• Current Assignee: Dawn Sweeney, Paul J. Samuels
• Original Assignee: Dawn Sweeney, Paul J. Samuels
• Inventors: Samuels, Paul J., Sweeney, Dawn
• Application Number:
  US09/770,344
• Publication Number:
  US 20020006435A1
• Time in Patent Office: Days
• US Class Current: 424/449
• 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 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

A composition for topical application comprising a therapeutically effective amount of a topical anesthetic, a safe and effective amount of a pharmaceutically acceptable topical vasodilator and a pharmaceutically acceptable carrier and a method of administering the composition to a mammal are disclosed.

Claims

1. A local, topical transdermal anesthetic and vasodilator formulation comprising a therapeutically safe and effective amount of:

a. at least one pharmaceutically active topical anesthetic;

b. at least one pharmaceutically active topical vasodilator; and

c. a pharmaceutically acceptable carrier.

2. The formulation of claim 1, wherein the topical anesthetic is selected from the group consisting of benzocaine, bupivacaine, butamben, butambenpicrate, chloroprocaine hydrochloride, chlorprocaine, cocaine, cocaine hydrochloride, dibucaine, dibucaine hydrochloride, dimethisoquin hydrochloride, diperodon, diphenhydramine, dyclonine, dyclonine hydrochloride, etidocaine, hexylcaine, ketamine, lidocaine, lidocaine hydrochloride, mepivacaine, methapyriline, oxyprocaine hydrochloride, p-buthylaminobenzoic acid 2-(die-ethylamino) ethyl ester hydrochloride, phenol, piperocaine hydrochloride, pramoxine, pramoxine hydrochloride., procaine, procaine hydrochloride, tetracaine, tetracaine hydrochloride, tripelennamine, and pharmaceutically acceptable acids, bases, and salts thereof.

3. The formulation of claim 1, wherein the topical anesthetic is at least one pharmaceutically active anesthetic selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, butanilicaine, prilocaine, tetracaine and trimecaine and their salts thereof.

4. The formulation of claim 1, wherein the topical anesthetic is at least one pharmaceutically active anesthetic selected from the group consisting of lidocaine, dibucaine, tetracaine, and prilocaine and their salts thereof.

5. The formulation of claim 2, wherein the topical anesthetic agent comprises a eutectic mixture.

6. The formulation of claim 5, wherein the topical anesthetic agent comprises a eutectic mixture of lidocaine and prilocaine.

7. The formulation of claim 1, wherein the anesthetic agent comprises a eutectic mixture consisting essentially of prilocaine in the form of its base in admixture with lidocaine, in the form of its base in a weight ratio of from about 1:

4 to about 4;

1.

8. The formulation of claim 1, wherein the topical vasodilator is at least one pharmaceutically active anesthetic selected from the group consisting of organic nitrates, glyceryl trinitrate, adenine, arginine, phentolamine, nicotinates, prostaglandins (eicosanoids), calcium antagonists, papaverine, nimodipine, hydralazine, nitric oxide, epoprostenol, tolazoline, aminone, milrinone, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, erythritol tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazep, trapidil, trimetazidine, and their substituted derivatives.

9. The formulation of claim 8, wherein the organic nitrate is selected from the group consisting of nitroglycerine, tetranitroerythritol, hexanitroinositol, tetranitropentaerythritol, propatyl nitrate, isosorbide 5-mononitrate (IS-5-MN), isosorbide dinitrate, isosorbide 2-mononitrate (IS-2-MN), isomannide 2-nitrate, 1,4:

3,6-dianhydrohexitol nitrates, and trinitrotriethanolamine, and their substituted derivatives.

10. The formulation of claim 9, wherein the organic nitrate is nitroglycerine.

11. The formulation of claim 8, wherein the topical anesthetic comprises from about 0.5 to about 30% and the vasodilator comprises from about 0.01 to about 5% by weight based upon the total weight of the formulation.

12. The formulation of claim 8, wherein the topical anesthetic comprises from about 0.5 to about 20% and the vasodilator comprises from about 0.01 to about 2% by weight based upon the total weight of the formulation.

13. The formulation of claim 8, wherein the topical anesthetic comprises from about 0.5 to about 10% and the vasodilator comprises from about 0.01 to about 1% by weight based upon the total weight of the formulation.

14. The formulation of claim 1 or 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of a gel, paste, foam, ointment, cream, lotion, liquid suspension, solution, spray, emulsion, liposomes, film, laminate, and transdermal treatment system.

15. The formulation of claim 1 or 14, wherein the formulation further comprises at least one dermatologically acceptable ingredient selected from the group consisting of emollients, emulsifiers, thickening agents, buffers, solvents, mixed solvents, preservatives, coloring agents, fragrances, anti-oxidants, preservatives antimicrobial and antifangal actives, anti-inflammatory actives, lower alcohols, polyols, esters of fatty acids, oils, and waxes, silicones, antifoam agents, hydrating agents, stabilizers, surfactants, fillers, sequestrants, anionic, cationic, nonionic and amphoteric polymers, propellants, alkalifying and acidifying agents and mixtures thereof.

16. The formulation of claim 14, wherein the formulation further comprises a emollient.

17. The formulation of claim 14, wherein the formulation further comprises from about 1% to about 20% of emollient and from about 50% to about 90% water.

18. The formulation of claim 14, wherein the formulation further comprises from about 5% to about 10%, of emollient and from about 60% to about 80%, water.

19. The formulation of claim 14, wherein the formulation further comprises from about 5% to about 50% of emollient and from about 45% to about 85% water.

20. The formulation of claim 14, wherein the formulation further comprises from about 10% to about 20% of emollient and from about 50% to about 75%, water.

21. The formulation of claim 14, wherein the formulation further comprises a pharmaceutically acceptable thickening agent.

22. The formulation of claim 14, wherein the formulation is an ointment further comprising from about 2% to about 10% of an emollient, and from about 0.1% to about 2% of a thickening agent.

23. The formulation of claim 14, wherein the formulation further comprises a pharmaceutically acceptable thickening agent.

24. The formulation of claim 23, wherein the thickening agent is selected from the group consisting of CARBOPOL, HYPAN, NATROSOL, KLUCEL, STABILEZE, carboxypolymethylene, hydroxyethylcellulose, cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, block copolymers of polyoxyethylene and polyoxypropylene, or combinations thereof.

25. The formulation of claim 24, wherein the thickening agent concentration of the formulation is from about 0.1% to about 10%.

26. The formulation of claim 24, wherein the thickening agent concentration of the formulation is from about 0.1% to about 5%.

27. The formulation of claim 24, wherein the thickening agent concentration of the formulation is from about 0.2% to about 3%.

28. The formulation of claim 14, wherein the formulation further comprises a pharmaceutically acceptable emulsifier.

29. The formulation of claim 28, wherein the emulsifier is selected from the group consisting of alkylene oxide esters of fatty acids, alkylene oxide diesters of fatty acids, alkylene oxide ethers of fatty alcohols, the condensation products of alkylene oxides with both fatty acids and fatty alcohols, sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated ethers of C1-C30 fatty alcohols, polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters of polyols, C1-C30 ethers of polyols, alkyl phosphates, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates, and mixtures thereof.

30. The formulation of claim 28, wherein the emulsifier is selected from the group consisting of decyl polyglucoside and lauryl polyglucoside, ceteth-6, ceteth-10, ceteth-12, ceteareth-6, ceteareth-10, ceteareth-12, steareth-6, steareth-10, steareth-12, PEG-6 stearate, PEG-10 stearate, PEG-100 stearate, PEG-12 stearate, PEG-20 glyceryl stearate, PEG-80 glyceryl tallowate, PEG-10 glyceryl stearate, PEG-30 glyceryl cocoate, PEG-80 glyceryl cocoate, PEG-200 glyceryl tallowate, PEG-8 dilaurate, PEG-10 distearate, polyethylene glycol 20 sorbitan monolaurate (Polysorbate 20), polyethylene glycol 5 soya sterol, Steareth-20, Ceteareth-20, PPG-2 methyl glucose ether distearate, Ceteth-10, Polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, Polysorbate 60, glyceryl stearate, polyoxyethylene 20 sorbitan trioleate (Polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate, hexyl laurate, PPG-2 methyl glucose ether distearate, PEG-100 stearate, and mixtures thereof.

31. The formulation of claim 28, wherein the emulsifier concentration of the formulation is from about 0.05% to about 10%.

32. The formulation of claim 28, wherein the emulsifier concentration of the formulation is from about 0.1% to about 6%.

33. The formulation of claim 28, wherein the emulsifier concentration of the formulation is from about 0.1% to about 3% of at least one surfactant.

34. A local, topical transdernal anesthetic and vasodilator formulation, comprising a eutectic mixture of at least one first pharmaceutically active anesthetic, at least one second pharmaceutically active anesthetic in a ratio of from about 15:

1 to about 15;

1, and at least one pharmaceutically active vasodilator, in a suitable pharmaceutically acceptable carrier, wherein

(a) said at least one first pharmaceutically active anesthetic is selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilicaine and trimecaine

(b) said at least one second pharmaceutically active anesthetic is selected from the group consisting of prilocaine, tetracaine, butanilicaine and trimecaine, and

(c) said at least one first pharmaceutically active anesthetic is different than said at least one second pharmaceutically active anesthetic.

35. The formulation of claim 34, wherein the topical vasodilator is at least one pharmaceutically active anesthetic selected from the group consisting of organic nitrates, glyceryl trinitrate, adenine, arginine, phentolamine, nicotinates, prostaglandins (eicosanoids), calcium antagonists, papaverine, nimodipine, hydralazine, nitric oxide, epoprostenol, tolazoline, arninone, milrinone, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, erythritol tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazep, trapidil, trimetazidine, and their substituted derivatives.

36. The formulation of claim 35, wherein the organic nitrate is selected from the group consisting of nitroglycerine, tetranitroerythritol, hexanitroinositol, tetranitropentaerythritol, propatyl nitrate, isosorbide 5-mononitrate (IS-5-MN), isosorbide dinitrate, isosorbide 2-mononitrate (IS-2-MN), isomannide 2-nitrate, 1,4:

3,6-dianhydrohexitol nitrates, and trinitrotriethanolamine, and their substituted derivatives.

37. The formulation of claim 36, wherein the organic nitrate is nitroglycerine.

38. The formulation of claim 34, wherein the eutectic mixture of at least one first pharmaceutically active anesthetic and at least one second pharmaceutically active anesthetic are present in a ratio of from about 10:

1 to about 1;

10.

39. The formulation of claim 34, wherein the eutectic mixture of at least one first pharmaceutically active anesthetic and at least one second pharmaceutically active anesthetic are present in a ratio of from about 4:

1 to about 1;

4.

40. The formulation of claim 34, wherein the eutectic mixture comprises lidocaine and prilocaine in a lipophilic base.

41. The formulation of claim 40, wherein said lipophilic base is a petroleum product comprises from about 30% to about 90% by weight of the formulation.

42. The formulation of claim 41, wherein said lipophilic base is a higher aliphatic alcohol of 8-18 carbon atoms, or an ester thereof.

43. The formulation of claim 41, wherein said lipophilic base is a paraffin.

44. The formulation of claim 35, wherein the eutectic mixture comprises lidocaine and prilocaine in a weight ratio of from about 15:

1 to about 1;

15.

45. The formulation of claim 35, wherein the eutectic mixture comprises lidocaine and prilocaine in a weight ratio of from about 4:

1 to about 1;

4.

46. The formulation of claim 35, wherein the topical anesthetic comprises from about 0.5 to about 30% and the vasodilator comprises from about 0.01 to about 5% by weight based upon the total weight of the formulation.

47. The formulation of claim 35, wherein the topical anesthetic comprises from about 0.5 to about 20% and the vasodilator comprises from about 0.01 to about 2% by weight based upon the total weight of the formulation.

48. The formulation of claim 35, wherein the topical anesthetic comprises from about 0.5 to about 10% and the vasodilator comprises from about 0.01 to about 1% by weight based upon the total weight of the formulation.

49. The formulation of claim 35, further comprising dibucaine from 0.2 to 2% by weight of the total formulation.

50. The formulation of claim 35, wherein the pharmaceutically acceptable carrier is selected from the group consisting of a gel, paste, foam, ointment, cream, lotion, liquid suspension, solution, spray, emulsion, liposomes, film and laminate.

51. The formulation of claim 50, wherein the formulation further comprises at least one dermatologically acceptable ingredient selected from the group consisting of emollients, emulsifiers, thickening agents, buffers, solvents, mixed solvents, preservatives, coloring agents, fragrances, anti-oxidants, preservatives antimicrobial and antifungal actives, anti-inflammatory actives, lower alcohols, polyols, esters of fatty acids, oils, and waxes, silicones, antifoam agents, hydrating agents, stabilizers, surfactants, fillers, sequestrants, anionic, cationic, nonionic and amphoteric polymers, propellants, alkalifying and acidifying agents and mixtures thereof.

52. The formulation of claim 51, wherein the formulation further comprises an emollient.

53. The formulation of claim 52, wherein the formulation further comprises from about 1% to about 20% of emollient and from about 50% to about 90% water.

54. The formulation of claim 52, wherein the formulation further comprises from about 5% to about 10%, of emollient and from about 60% to about 80%, water.

55. The formulation of claim 52, wherein the formulation further comprises from about 5% to about 50% of emollient and from about 45% to about 85% water.

56. The formulation of claim 52, wherein the formulation further comprises from about 10% to about 20% of emollient and from about 50% to about 75%, water.

57. The formulation of claim 52, wherein the formulation further comprises a pharmaceutically acceptable thickening agent.

58. The formulation of claim 57, wherein the formulation is an ointment further comprising from about 2% to about 10% of an emollient, and from about 0.1% to about 2% of a thickening agent.

59. The formulation of claim 57, wherein the formulation further comprises a pharmaceutically acceptable thickening agent.

60. The formulation of claim 57, wherein the thickening agent is selected from the group consisting of CARBOPOL, HYPAN, NATROSOL, KLUCEL, STABILEZE, carboxypolymethylene, hydroxyethylcellulose, cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, block copolymers of polyoxyethylene and polyoxypropylene, or combinations thereof.

61. The formulation of claim 57, wherein the thickening agent concentration of the formulation is from about 0.1% to about 10%.

62. The formulation of claim 57, wherein the thickening agent concentration of the formulation is from about 0.1% to about 5%.

63. The formulation of claim 57, wherein the thickening agent concentration of the formulation is from about 0.2% to about 3%.

64. The formulation of claim 50, wherein the formulation further comprises a pharmaceutically acceptable emulsifier.

65. The formulation of claim 64, wherein the emulsifier is selected from the group consisting of alkylene oxide esters of fatty acids, alkylene oxide diesters of fatty acids, alkylene oxide ethers of fatty alcohols, the condensation products of alkylene oxides with both fatty acids and fatty alcohols, sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated ethers of C1-C30 fatty alcohols, polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters of polyols, C1-C30 ethers of polyols, alkyl phosphates, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates, and mixtures thereof.

66. The formulation of claim 64, wherein the emulsifier is selected from the group consisting of decyl polygluco side and lauryl polyglucoside, ceteth-6, ceteth-10, ceteth-12, ceteareth-6, ceteareth-10, ceteareth-12, steareth-6, steareth-10, steareth-12, PEG-6 stearate, PEG-10 stearate, PEG-100 stearate, PEG-12 stearate, PEG-20 glyceryl stearate, PEG-80 glyceryl tallowate, PEG-10 glyceryl stearate, PEG-30 glyceryl cocoate, PEG-80 glyceryl cocoate, PEG-200 glyceryl tallowate, PEG-8 dilaurate, PEG-10 distearate, polyethylene glycol 20 sorbitan monolaurate (Polysorbate 20), polyethylene glycol 5 soya sterol, Steareth-20, Ceteareth-20, PPG-2 methyl glucose ether distearate, Ceteth-10, Polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, Polysorbate 60, glyceryl stearate, polyoxyethylene 20 sorbitan trioleate (Polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate, hexyl laurate, PPG-2 methyl glucose ether distearate, PEG-100 stearate, and mixtures thereof.

67. The formulation of claim 64, wherein the emulsifier concentration of the formulation is from about 0.05% to about 10%.

68. The formulation of claim 64, wherein the emulsifier concentration of the formulation is from about 0.1% to about 6%.

69. The formulation of claim 64, wherein the emulsifier concentration of the formulation is from about 0.01% to about 3%.

70. The formulation of claim 52, wherein the topical anesthetic comprises a third anesthetic selected from the group consisting of benzocaine, bupivacaine, butamben, butambenpicrate, chloroprocaine hydrochloride, chlorprocaine, cocaine, cocaine hydrochloride, dibucaine, dibucaine hydrochloride, dimethisoquin hydrochloride, diperodon, diphenhydramine, dyclonine, dyclonine hydrochloride, etidocaine, hexylcaine, ketamine, lidocaine, lidocaine hydrochloride, mepivacaine, methapyriline, oxyprocaine hydrochloride, p-buthylaminobenzoic acid 2-(die-ethylamino) ethyl ester hydrochloride, phenol, piperocaine hydrochloride, pramoxine, pramoxine hydrochloride., procaine, procaine hydrochloride, tetracaine, tetracaine hydrochloride, tripelennamine, and pharmaceutically acceptable acids, bases, and salts thereof.

71. A method of administering topical anesthetic agents along with a vasodilator comprising the steps of:

(a) providing a composition comprising a therapeutically safe and effective amount of at least one topical anesthetic;

a therapeutically safe and effective amount of at least one vasodilator; and

a pharmaceutically acceptable carrier; and

(b) contacting an area of skin of a subject with the composition thereby administering the topical anesthetic and vasodilator, preferably at the site of insertion of an intravenous device.

72. The method of claim 71, wherein the method further comprises waiting an appropriate time for the composition to provide its anesthetic and vasodilation effect.

73. The method of claim 72, wherein the method further comprises inserting a medical device through the skin or dermis at the site of application.

74. The method of claim 71, wherein the composition is allowed to act from about 5 to about 90 minutes.

75. The method of claim 71, wherein the composition is allowed to act from about 15 to about 90 minutes.

76. The method of claim 71, wherein the composition is allowed to act from about 30 to about 60 minutes.

77. The method of claim 73, wherein the medical device is an intravenous or intravascular device selected from the group consisting of a needle, catheter, cannula, tube, syringe, stint or other insertable medical device that pierces the skin or dermis.