Adhesive peel-forming formulations for dermal delivery of drugs and methods of using the same

• US 20050276842A1
• Filed: 06/06/2005
• Published: 12/15/2005
• Est. Priority Date: 06/07/2004
• Status: Active Grant

• Current Assignee: Crescita Therapeutics Inc.
• Original Assignee: Zars, Inc.
• Inventors: Rigby, Larry D., Zhang, Jie, Ashburn, Michael A., Warner, Kevin S., Niu, Suyi
• Granted Patent: US 8,907,153 B2
• Time in Patent Office: Days
• US Class Current: 424/448
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/7015 Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/22 for herpes viruses

Abstract

The present invention is drawn to adhesive peel-forming formulations for dermal delivery of a drug. The formulation can include a drug, a solvent vehicle, and a peel-forming agent. The solvent vehicle can include a volatile solvent system having one or more volatile solvent, and a non-volatile solvent system having one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility for the drug that is within a window of operable solubility for the drug such that the drug can be delivered at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system. When applied to the skin, the formulation can form a solidified peelable layer after at least a portion of the volatile solvent system is evaporated.

Claims

1. An adhesive peel-forming formulation for dermal delivery of a drug, comprising:

a) a drug;

b) a solvent vehicle, comprising;

i) a volatile solvent system including one or more volatile solvent, and

ii) a non-volatile solvent system including one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility with respect to the drug that is within a window of operable solubility such that the drug is deliverable at therapeutically effective rates over a sustained period of time; and

c) a peel-forming agent,

wherein the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface forms a solidified peelable layer after at least partial evaporation of the volatile solvent system, wherein the drug continues to be delivered after the volatile solvent system is substantially evaporated.

2. A formulation as in claim 1, wherein the non-volatile solvent system acts as a plasticizer for said peel-forming agent.

3. A formulation as in claim 1, wherein said volatile solvent system comprises water.

4. A formulation as in claim 1, wherein said volatile solvent system comprises at least one solvent more volatile than water, and is selected from the group consisting of ethanol, isopropyl alcohol, ethyl acetate, acetone, mixtures thereof, and mixtures with water thereof.

5. A formulation as in claim 1, wherein the non-volatile solvent system includes multiple non-volatile solvents admixed together which provide a solubility for the drug that is within the window of operable solubility.

6. A formulation as in claim 1, wherein the non-volatile solvent system comprises one or more solvents selected from the group consisting of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, oleyl alcohol, isostearic acid, fatty acids including medium chain fatty acids, and mixtures thereof.

7. A formulation as in claim 1, wherein the peel-forming agent is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, and mixtures thereof.

8. A formulation as in claim 1, wherein the peel-forming agent includes a member selected from the group consisting of dextrin, guar gum, xantham gum, polyethylene oxide having a weight average molecular weight greater than about 5,000 Mw, starch, cellulose derivatives, and mixtures thereof.

9. A formulation as in claim 8, wherein the peel-forming agent includes a cellulose derivative selected from the group consisting of hydroxyethylcellulose, ehtylcellulose, carboxymethylcellulose, hydroxypropylcellulose, copolymers of methyl vinyl ether and maleic anhydride, and mixtures thereof.

10. A formulation as in claim 1, wherein the peel-forming agent is selected from the group consisting of polyvinyl alcohol-polyethylene glycol co-polymers, methacrylic acid and methacrylate-based copolymers including poly(methacrylic acid) copolymers, methylmethacrylate copolymers, methyacrylic acid-ethyl acrylate copolymers, and mixtures thereof.

11. A formulation as in claim 1, wherein the drug includes multiple pharmaceutically active agents.

12. A formulation as in claim 1, wherein the peel-forming agent includes a methyacrylic polymer.

13. A formulation as in claim 1, wherein the peel-forming agent includes a methyacrylic acid-ethyl acrylate copolymer.

14. A formulation as in claim 1, wherein the peel-forming agent includes a polyvinyl alcohol-polyethylene glycol copolymer.

15. A formulation as in claim 1, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, penciclovir, famciclovir, valacyclovir steroids, and behenyl alcohol; and

combinations thereof.

16. A formulation as in claim 1, wherein the drug is ketoprofen.

17. A formulation as in claim 1, wherein the drug is a humectant or emollient.

18. A formulation as in claim 1, wherein the drug is a steroid for treating herpes infection.

19. A formulation as in claim 1, wherein the drug is a drug for treating a cold sore.

20. A formulation as in claim 1, wherein the drug is a drug for treating genital warts.

21. A formulation as in claim 1, wherein the drug is a drug for treating muscle skeletal pain.

22. A formulation as in claim 1, wherein the drug is diclofenac.

23. A formulation as in claim 1, wherein the drug is an antifungal drug.

24. A formulation as in claim 23, wherein the antifungal drug is selected from the group of ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives including butenafine, naftifine, and terbinafine, and combinations thereof.

25. A formulation as in claim 1, wherein the drug is an antiviral drug.

26. A formulation as in claim 25, wherein the antiviral drug is selected from the group of acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir, acyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and combinations thereof.

27. A formulation as in claim 1, wherein the drug is an anti-infective.

28. A formulation as in claim 1, wherein the solidified peelable layer is sufficiently flexible and adhesive to the skin such that when applied to the skin at a human joint, the solidified peelable layer will remain substantially intact on the skin upon bending of the joint.

29. A formulation as in claim 1, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 2 hours following the formation of said solidified peelable layer.

30. A formulation as in claim 1, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 4 hours following the formation of said solidified peelable layer.

31. A formulation as in claim 1, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 8 hours following the formation of said solidified peelable layer.

32. A formulation as in claim 1, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 12 hours following the formation of said solidified peelable layer.

33. A formulation as in claim 1, wherein the peel-forming agent is dispersed or solvated in the solvent vehicle.

34. A formulation as in claim 1, wherein the window of operable solubility is predetermined.

35. A formulation as in claim 1, wherein the weight ratio of the non-volatile solvent system to the peel-forming agent is from about 0.01:

1 to about 2;

1.

36. A formulation as in claim 1, wherein the weight ratio of the non-volatile solvent system to the peel-forming agent is from about 0.2:

1 to about 1.2;

1.

37. A formulation as in claim 1, wherein the volatile solvent system is capable of causing human skin irritation and at least one non-volatile solvent of said non-volatile solvent system is capable of reducing the skin irritation.

38. A formulation as in claim 37, wherein the non-volatile solvent capable of reducing skin irritation is selected from the group consisting of glycerin, propylene glycol, and honey.

39. A formulation as in claim 1, wherein the solidified peelable layer is formed within 15 minutes of application to the skin surface under standard skin and ambient conditions.

40. A formulation as in claim 1, wherein the solidified peelable layer is formed within 4 minutes of the application to the skin surface under standard skin and ambient conditions.

41. A formulation as in claim 1, wherein the formulation has an initial viscosity prior to skin application from about 100 to about 3,000,000 centipoises.

42. A formulation as in claim 1, wherein the formulation has an initial viscosity prior to skin application from about 1,000 to about 1,000,000 centipoises.

43. A formulation as in claim 1, wherein the weight percentage of the volatile solvent system is from about 2 wt % to about 50 wt %.

44. A formulation as in claim 1, wherein the weight percentage of the volatile solvent system is from about 4 wt % to about 30 wt %.

45. A formulation as in claim 1, wherein the non-volatile solvent system includes multiple non-volatile solvents, and at least one of the non-volatile solvents improves the compatibility of the non-volatile solvent system with the peel-forming agent.

46. A formulation as in claim 1, wherein the drug is a local anesthetic agent and the window of operable solubility is from about 50 μ

g/g to about 400 mg/g.

47. A formulation as in claim 1, wherein the drug is an antiviral agent and the window of operable solubility is from about 50 μ

g/g to about 400 mg/g.

48. A formulation as in claim 1, wherein the drug is a non-steroidal anti-inflammatory agent and the window of operable solubility is from about 200 μ

g/g to about 400 mg/g.

49. A formulation as in claim 1, wherein the drug is imiquimod and the window of operable solubility is from about 100 μ

g/g to about 400 mg/g.

50. A formulation as in claim 1, wherein the drug is testosterone and the window of operable solubility is from about 0.5 mg/g to about 400 mg/g.

51. A formulation as in claim 1, wherein the drug is an alpha-2 agonist and the window of operable solubility is from about 10 μ

g/g to about 400 mg/g.

52. A formulation as in claim 1, wherein the drug is an antibiotic and the window of operable solubility is from about 10 μ

g/g to about 400 mg/g.

53. A formulation as in claim 1, wherein the drug is capsaicin and the window of operable solubility is from about 10 μ

g/g to about 400 mg/g.

54. A formulation as in claim 1, wherein the drug is a retenoid and the window of operable solubility is from about 5 μ

g/g to about 400 mg/g.

55. A formulation as in claim 1, wherein the non-volatile solvent includes at least two non-volatile solvents, and wherein one of said at least two non-volatile solvents is included to improve compatibility with the peel-forming agent.

56. A method of dermally delivering a drug, comprising:

a) applying an adhesive peel-forming formulation to a skin surface of a subject, said adhesive peel-forming formulation, comprising;

i) a drug;

ii) a solvent vehicle, comprising;

a volatile solvent system including one or more volatile solvent, and

a non-volatile solvent system having one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility with respect to the drug that is within a window of operable solubility such that the drug can be delivered at therapeutically effective rates over a sustained period of time; and

iii) a peel-forming agent,

wherein the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface forms a solidified peelable layer after at least partial evaporation of the volatile solvent system, wherein the drug continues to be delivered after the volatile solvent system is substantially evaporated; and

b) dermally delivering the drug from the solidified peelable layer to the subject at therapeutically effective rates over a sustained period of time.

57. A method as in claim 56, wherein the step of applying includes applying the adhesive peel-forming formulation at a thickness from about 0.01 mm to about 2 mm.

58. A method as in claim 57, wherein the thickness is from about 0.05 mm to about 1 mm.

59. A method as in claim 56, wherein the non-volatile solvent system includes multiple non-volatile solvents admixed together to form a mixture, said mixture providing a solubility for the drug that is within the window of operable solubility.

60. A method as in claim 56, wherein the non-volatile solvent system comprises one or more solvent selected from the group consisting of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, isostearic acid, fatty acids and medium chain fatty acids, and mixtures thereof.

61. A method as in claim 56, wherein the peel-forming agent is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, and mixtures thereof.

62. A method as in claim 56, wherein the peel-forming agent includes a member selected from the group consisting of dextrin, guar gum, xantham gum, polyethylene oxide having a weight average molecular weight greater than about 5,000 Mw, starch, cellulose derivatives, and mixtures thereof.

63. A method as in claim 62, wherein the peel-forming agent includes a cellulose derivative selected from the group consisting of hydroxyethylcellulose, ehtylcellulose, carboxymethylcellulose, hydroxypropylcellulose, copolymers of methyl vinyl ether and maleic anhydride, and mixtures thereof.

64. A formulation as in claim 56, wherein the peel-forming agent is selected from the group consisting of polyvinyl alcohol-polyethylene glycol co-polymers, methacrylic acid and methacrylate-based copolymers including poly(methacrylic acid) copolymers, methylmethacrylate copolymers, methyacrylic acid-ethyl acrylate copolymers, and mixtures thereof.

65. A method as in claim 56, wherein the drug includes multiple pharmaceutically active agents.

66. A method as in claim 56, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, penciclovir, famciclovir, valacyclovir steroids, and behenyl alcohol; and

mixtures thereof.

67. A method as in claim 56, wherein the drug is a steroid for treating herpes infection.

68. A method as in claim 56, wherein the drug is for treating a cold sore.

69. A formulation as in claim 56, wherein the drug is a drug for treating genital warts.

70. A method as in claim 56, wherein the drug is for treating muscle skeletal pain.

71. A formulation as in claim 56, wherein the drug is an antifungal drug selected from the group consisting of ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives including butenafine, naftifine, terbinafine, and combinations thereof.

72. A formulation as in claim 56, wherein the drug is an antiviral drug selected from the group consisting of acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir, acyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and combinations thereof.

73. A method as in claim 56, wherein the solidified peelable layer is sufficiently flexible and adhesive to the skin such that when applied to the skin at a human joint, the solidified peelable layer will remain substantially intact on the skin upon bending of the joint.

74. A method as in claim 56, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 2 hours following the formation of said solidified peelable layer.

75. A method as in claim 56, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 4 hours following the formation of said solidified peelable layer.

76. A method as in claim 56, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 8 hours following the formation of said solidified peelable layer.

77. A method as in claim 56, wherein the peelable formulation is configured to deliver the drug at a substantially constant rate for at least 12 hours following the formation of said solidified peelable layer.

78. A method as in claim 56, wherein the weight ratio of the non-volatile solvent system to the peel-forming agent is from about 0.01:

1 to about 2;

1.

79. A method as in claim 56, wherein the weight ratio of the non-volatile solvent system to the peel-forming agent is from about 0.2:

1 to about 1.2;

1.

80. A method as in claim 56, wherein the solidified peelable layer is formed within 15 minutes of the application to the skin surface.

81. A method as in claim 56, wherein the solidified peelable layer is formed within 4 minutes of the application to the skin surface.

82. A method as in claim 56, wherein the formulation has an initial viscosity from about 100 to about 3,000,000 centipoises.

83. A method as in claim 56, wherein the formulation has an initial viscosity from about 1,000 to about 1,000,000 centipoises.

84. A method as in claim 56, wherein the step of applying includes applying the adhesive peelable formulation over an area of the skin surface that is sufficiently large to deliver a therapeutically effective amount of the drug.

85. A method of preparing an adhesive peel-forming formulation for dermal drug delivery, comprising:

a) selecting a drug suitable for dermal delivery;

b) selecting non-volatile solvent system consisting essentially of one non-volatile solvent that has a solubility with respect to the drug within a window of operable solubility; and

c) formulating the drug and the non-volatile solvent into an adhesive peel-forming formulation that further includes a peel-forming agent and a volatile solvent system including at least one volatile solvent, said adhesive peel-forming formulation having a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface forms a solidified peelable layer after at least a portion of the volatile solvent system is evaporated, and wherein the drug continues to be delivered at therapeutically effective rates after the volatile solvent system is substantially evaporated.

86. A method as in claim 85, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir, acyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and combinations thereof;

antifungal drugs including ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and the allylamine derivatives such as butenafine, naftifine, and terbinafine, and combinations thereof.

87. A method as in claim 85, wherein the non-volatile solvent is selected from the group consisting of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, oleyl alcohol, isostearic acid, fatty acids and medium chain fatty acids.

88. A method of preparing an adhesive peel-forming formulation for dermal drug delivery, comprising:

a) selecting a drug suitable for dermal delivery;

b) forming a non-volatile solvent system by selecting at least two non-volatile solvents according to a ratio that positions the solubility of the drug in the non-volatile solvent system within a window of operable solubility; and

c) formulating the drug and the non-volatile solvent system into an adhesive peel-forming formulation that further includes a peel-forming agent and a volatile solvent system including at least one volatile solvent, said adhesive peel-forming formulation having a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface forms a solidified peelable layer after at least a portion of the volatile solvent system is evaporated, and wherein the drug continues to be delivered at therapeutically effective rates after the volatile solvent system is substantially evaporated.

89. A method as in claim 88, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, penciclovir, famciclovir, valacyclovir steroids, and behenyl alcohol; and

combinations thereof.

90. A method as in claim 88, wherein the non-volatile solvent system includes a member selected from the group of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, isostearic acid, fatty acids and medium chain fatty acids, and mixtures thereof.

91. A method as in claim 88, wherein at least one of the non-volatile solvents is added to improve non-volatile solvent system compatibility with the peel-forming agent.

92. A solidified peelable layer for delivering a drug, comprising:

a) a drug;

b) a non-volatile solvent system having one or more non-volatile solvent,

wherein the non-volatile solvent system provides a window of operable solubility for the drug such that the drug is deliverable at therapeutically effective rates for at least 2 hours; and

c) a peel-forming agent,

wherein said peelable layer can be stretched in at least one direction by 10% without breaking or cracking.

93. A solidified peelable layer as in claim 92, wherein the non-volatile solvent system acts as a plasticizer for the peel-forming agent.

94. A solidified peelable layer as in claim 92, wherein solidified peelable layer is sufficiently adhesive and flexible to remain substantially intact on a skin surface adjacent to a joint or muscle group where regular skin stretching occurs.

95. A solidified peelable layer as in claim 92, wherein the non-volatile solvent system includes multiple solvents admixed together according to a ratio that positions the solubility of the drug within a window of operable solubility with respect to the non-volatile solvent system.

96. A solidified peelable layer as in claim 92, wherein the non-volatile solvent system includes a member selected from the group of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, isostearic acid, fatty acids and medium chain fatty acids, and mixtures thereof.

97. A solidified peelable layer as in claim 92, wherein the peel-forming agent includes at a member selected from the group consisting of dextrin, guar gum, xantham gum, polyethylene oxide having a weight average molecular weight greater than about 5,000 Mw, starch, cellulose derivatives, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, methyacrylic polymer, methyacrylic acid-ethyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, dextrin, guar gum, xantham gum, polyethylene oxide, starch, cellulose derivatives, copolymers of methyl vinyl ether and maleic anhydride, and mixtures thereof.

98. A solidified peelable layer as in claim 92, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, Cidofovir, Gancyclovir, valacyclovir, podofilox, podophyllotoxin,ribavirin, Abacavir, Delavirdine, Didanosine, Efavirenz, Lamivudine, Nevirapine, Stavudine, Zalcitabine, Zidovudine, Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Amantadine, Interferon, Oseltamivir, Ribavirin, Rimantadine, Zanamivir;

antifungal drugs including ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives including butenafine, naftifine, and terbinafine; and

combinations thereof.

99. An adhesive peel-forming formulation for dermal delivery of a drug comprising:

a) a drug;

b) a peel-forming agent; and

c) a solvent vehicle, comprising

i) a volatile solvent system including one or more volatile solvent, and

ii) a non-volatile solvent system including one or more non-volatile solvent,

wherein when said adhesive peel-forming formulation is applied to a skin surface, the adhesive peel-forming formulation forms a solidified peelable layer having a contact surface, said contact surface having a first area dimension, said solidified peelable layer being stretchable such that the first area dimension is capable of being stretched to a second area dimension that is 10% larger than the first area dimension without cracking, breaking, or separating from the skin surface; and

wherein after the formation of said solidified peelable layer and after the volatile solvent system is substantially evaporated the drug continues to be delivered at therapeutically effective rates.

100. A formulation as in claim 99, wherein said volatile solvent system includes a member selected from the group consisting of water, ethanol, isopropyl alcohol, ethyl acetate, acetone, and mixtures thereof.

101. A formulation as in claim 99, wherein the non-volatile solvent system comprises one or more solvents selected from the group consisting of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, isostearic acid, medium chain fatty acid and other fatty acids, and mixtures thereof.

102. A formulation as in claim 99, wherein the peel-forming agent includes a member selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, dextrin, guar gum, xantham gum, polyethylene oxide having a weight average molecular weight greater than about 5,000 Mw, starch, cellulose derivatives, and mixtures thereof.

103. A formulation as in claim 99, wherein the drug is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, and zanamivir;

antifungal drugs including ciclopirox, imidazole, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives including butenafine, naftifine, and terbinafine; and

combinations thereof.

104. A formulation as in claim 99, wherein the solidified peelable layer is sufficiently flexible and adhesive to the skin such that when applied to the skin at a human joint, the solidified peelable layer will remain substantially intact on the skin upon bending of the joint.

105. A formulation as in claim 99, wherein the weight ratio of the non-volatile solvent system to the peel-forming polymer is from about 0.01:

1 to about 2;

1.

106. A formulation as in claim 99, wherein the weight ratio of the non-volatile solvent system to the peel-forming polymer from about 0.2:

1 to about 1.2;

1.

107. A formulation as in claim 99, wherein the solidified peelable layer is formed within 15 minutes of the application to the skin surface under normal skin and ambient conditions.

108. A formulation as in claim 99, wherein the solidified peelable layer is formed within 4 minutes of the application to the skin surface.

109. An adhesive peel-forming formulation for dermal delivery of a drug, comprising:

a) a drug selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;

COX-2 selective NSAIDs and agents;

COX-3 selective NSAIDs and agents;

local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine;

steroids including dexamethasone;

antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants, emollients, antiviral drugs including acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, and zanamivir;

antifungal drugs including ciclopirox, imidazole, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives including butenafine, naftifine, and terbinafine; and

combinations thereof;

b) a solvent vehicle, comprising;

i) a volatile solvent system including one or more volatile solvent selected from the group of water, ethanol, isopropyl alcohol, ethyl acetate, acetone, mixtures thereof, and

ii) a non-volatile solvent system including one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility with respect to the drug that is within a window of operable solubility such that the drug is deliverable at therapeutically effective rates over a sustained period of time; and

said one or more non-volatile solvent is selected from the group consisting of glycerol, polyethylene glycol having a weight average molecular weight from about 200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate, essential oils including eugenol and rose oil, oleic acid, oleyl alcohol, isostearic acid, fatty acids including medium chain fatty acids, and mixtures thereof; and

c) a peel-forming agent, selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, dextrin, guar gum, xantham gum, polyethylene oxide, hydroxyethylcellulose, ehtylcellulose, carboxymethylcellulose, hydroxypropylcellulose, copolymers of methyl vinyl ether and maleic anhydride, polyvinyl alcohol-polyethylene glycol co-polymers, methacrylic acid and methacrylate-based copolymers including poly(methacrylic acid) copolymers, methylmethacrylate copolymers, methyacrylic acid-ethyl acrylate copolymers;

wherein the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface forms a solidified peelable layer after at least partial evaporation of the volatile solvent system, wherein the drug continues to be delivered after the volatile solvent system is substantially evaporated, wherein the formulation has a drying time of 5 minutes or shorter under standard skin and ambient conditions, wherein the weight ratio of the non-volatile solvent system to the peel-forming polymer is from about 0.2;

1 to about 1.2;

1, and wherein the solidified peelable layer can be stretched in at least one direction by 10% without cracking, breaking, or separating from the skin.