TRANSDERMAL DRUG DELIVERY COMPOSITIONS AND TOPICAL COMPOSITIONS FOR APPLICATION ON THE SKIN

• US 20090053290A1
• Filed: 03/08/2007
• Published: 02/26/2009
• Est. Priority Date: 03/08/2006
• Status: Abandoned Application

• Current Assignee: Nuviance, Inc.
• Original Assignee: Nuviance, Inc.
• Inventors: Babich, Michael, Sand, Bruce J., Haghighi, Ali Zendedel
• Application Number:
  US12/281,768
• Publication Number:
  US 20090053290A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 8/34 Alcohols
• CPC Class Codes: A61K 8/553 Phospholipids, e.g. lecithin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: A61Q 19/02 for chemically bleaching or whitening the skin
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: A61Q 5/006 Antidandruff preparations

Abstract

Transdermal delivery compositions and topical compositions for application to the skin are provided. The transdermal delivery composition includes at least two penetrants working synergistically but by disparate biochemical pathways. In one embodiment, the transdermal delivery system includes benzyl alcohol and lecithin organogel. The transdermal delivery compositions are used in a variety of topical compositions as a means of transdermally delivering and topically administering different drugs and agents, including compositions promoting collagen biosynthesis, retinoids and skin lighteners, chemical denervation agents such as BOTOX®, anti-fungal agents, anesthetics and non-steroidal anti-inflammatory drugs (NSAIDs). In addition, these topical compositions may be used in combination with non-ablative treatment modalities, such as microdermabrasion, laser-based skin remodeling and radio-frequency-based skin remodeling.

Claims

1. A transdermal delivery composition for topical application on skin, the transdermal delivery composition comprising first and second penetrants, the first and second penetrants working synergistically and following disparate biochemical pathways, wherein the composition has a pH ranging from about 3.0 to about 7.4.

2. The transdermal delivery composition according to claim 1, wherein each of the first and second penetrants is independently selected from the group consisting of:

lower alkyl diols,

C₁₀-C₂₀ fatty acids and esters thereof,

C₄-C₂₀ substituted aliphatic alcohols,

C₄-C₂₀ unsubstituted aliphatic alcohols,

lecithin organogel in isopropyl palrnitate organic solvent,

pluronic lecithin organogel in isopropyl palmitate organic solvent,

a formulation comprising Fe (iron) and Ca (calcium) peptide,

a mixture of 1-dodecylazacycloheptan-2-one with a diol compound or a second N-substituted alkyl-azacycloalkyl-2-one (a “

cycloketo”

compound), wherein the diol compound is selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, and 2,3-butanediol,

aminopolysaccharides,

diisopropyl adipate,

dimethyl isosorbide,

propylene glycol,

1,2,6-hexanetriol,

dioctyl maleate,

propylene carbonate, and

diisopropyl sebacate.

3. The transdermal delivery composition according to claim 1, wherein the first penetrant comprises benzyl alcohol.

4. The transdermal delivery composition according to claim 3, wherein the benzyl alcohol is present in an amount ranging from about 1% to about 20% by weight.

5. The transdermal delivery composition according to claim 3, wherein the benzyl alcohol is present in an amount ranging from about 1.5% to about 2.5% by weight.

6. The transdermal delivery composition according to claim 1, wherein the second penetrant comprises a lecithin organogel.

7. The transdermal delivery composition according to claim 6, wherein the lecithin organogel is pluronic lecithin organogel.

8. The transdermal delivery composition according to claim 6, wherein the lecithin organogel is present in an amount ranging from about 0.5% to about 20% by weight.

9. The transdermal delivery composition according to claim 6, wherein the lecithin organogel is present in an amount ranging from about 0.5% to about 0.6% by weight.

10. The transdermal delivery composition according to claim 1, wherein the first penetrant is benzyl alcohol and the second penetrant is lecithin organogel.

11. The transdermal delivery composition according to claim 1, further comprising at least two metallic cations.

12. The transdermal delivery composition according to claim 11, wherein the at least two metallic cations are selected from the group consisting of Fe, Ca and Cu.

13. The transdermal delivery composition according to claim 11, wherein the at least two metallic cations comprise metal cation peptides.

17. A topical composition for topical application to skin, the topical composition comprising:

the transdermal delivery composition according to claim 1;

an active ingredient selected from the group consisting of drugs, agents or compositions; and

a topical pharmaceutically acceptable carrier.

18. The topical composition according to claim 17, wherein the topical pharmaceutically acceptable carrier comprises:

dimethyl sulfoxide;

lecithin;

ethanol;

an isopropyl ester of a long-chain fatty acid selected from the group consisting of isopropyl palmitate, isopropyl stearate and isopropyl myristate; and

a nonionic surfactant comprising at least one free hydroxyl group.

19. The topical composition according to claim 17, wherein the topical pharmaceutically acceptable carrier comprises:

water;

propylene glycol;

carbopol;

an octyl ester of a long-chain fatty aid selected from the group consisting of octyl palmitate, octyl stearate, and octyl myristate;

silicone fluid;

cetearyl alcohol;

a buffer for buffering the pH of the composition to a value ranging from about 3.0 to about 7.4; and

at least one non-sensitizing preservative.

20. The topical composition according to claim 17, wherein the topical pharmaceutically acceptable carrier comprises:

propylene glycol;

carbopol;

a surface coated starch polymer;

octyl palmitate;

isopropyl palmitate;

silicone fluid;

glyceryl stearate or PEG-100 stearate;

cetearyl alcohol;

stearic acid;

triethanolamine;

caprylic or capric triglyceride;

caprylic or capric stearyl triglyceride; and

water.

21. The topical composition according to claim 17, wherein the active ingredient comprises a composition comprising:

methionine;

cysteine;

a mixture of amino acids comprising leucine, lysine, phenylalanine, threonine, tryptophan, valine, histidine and arginine;

at least one antioxidant;

at least one cross-linking agent; and

at least one metallic catalyst.

22. The topical composition according to claim 21, wherein the methionine is present in the active ingredient composition in an amount ranging from about 0.0005% to about 0.02% by weight.

23. The topical composition according to claim 21, wherein the cysteine is present in the active ingredient composition in an amount ranging from about 0.01% to about 0.4% by weight.

24. The topical composition according to claim 21, wherein the mixture of amino acids comprises from about 0.005% to about 0.5% by weight of the active ingredient composition.

25. The topical composition according to claim 21, wherein the at least one antioxidant is selected from the group consisting of lipoic acid, lipoic acid derivatives or analogues, ascorbic acid, and ascorbic acid derivatives.

26. The topical composition according to claim 25, wherein the at least one antioxidant is selected from the group consisting of dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid and salts of dihydrolipoic acid.

27. The topical composition according to claim 25, wherein the at least one antioxidant is α

-lipoic acid.

28. The topical composition according to claim 27, wherein the α

-lipoic acid is present in the active ingredient composition in an amount ranging from about 0.3% to about 2.0% by weight.

29. The topical composition according to claim 25, wherein the at least one antioxidant is selected from the group consisting of ascorbyl palmitate, ascorbyl myristate, ascorbyl stearate, and ascorbyl isotetrapalmitate.

30. The topical composition according to claim 29, wherein the at least one antioxidant is ascorbyl isotetrapalmitate, and the ascorbyl isotetrapalmitate is present in the active ingredient composition in an amount ranging from about 0.1% to about 0.6% by weight.

31. The topical composition according to claim 25, wherein the at least one antioxidant is a derivative of ginkgo selected from the group consisting of ginkgolide A, ginkgolide B, ginkgolide C and bilobalide.

32. The topical composition according to claim 25, wherein the at least one antioxidant is an isoflavone selected from the group consisting of genistein, genistin, 6″

-0-malonylgenistin, 6″

-0-acetylgenistin, daidzein, daidzin, 6″

-0-malonyldaidzin, 6″

-0-acetylgenistin, glycitein, glycitin, 6″

-0-malonylglycitin, and 6-0-acetylglycitin.

33. The topical composition according to claim 21, wherein the metallic catalyst is copper in a form selected from the group consisting of cuprous ionic forms, cupric ionic forms, peptide forms, and salt forms selected from the group consisting of cupric acetate, cuprous acetate, cuprous chloride, cupric chloride, cuprous sulfate, and cupric sulfate.

34. The topical composition according to claim 21, wherein the mixture of essential amino acids comprises:

from about 5% to about 20% of leucine;

from about 10% to about 25% of lysine;

from about 5% to about 20% of phenylalanine;

from about 5% to about 25% of threonine;

from about 5% to about 20% of tryptophan;

from about 10% to about 25% of valine;

from about 5% to about 20% of histidine; and

from about 5% to about 20% of arginine.

35. The topical composition of claim 21, wherein the cross-linking agent is a bioflavonoid selected from the group consisting of quercetin, quercitrin, kaempferol, kaempferol 3-rutinoside, 3′

-methoxy kaempferol 3-rutinoside, 5,8,4′

-trihydroxyl-6,7-dimethoxyflavone, catechin, epicachetin, epicachetin gallate, epigallocachetin gallate, hesperidin, naringin, rutin, vixetin, proanthocyanidin, apigenin, myricetin, tricetin, quercetin, naringin, kaempferol, luteolin, biflavonyl, silybin, silydianin, and silychristin.

36. The topical composition according to claim 35, wherein the bioflavonoid is selected from the group consisting of proanthocyanidin and silybin, and the bioflavonoid is present in an amount ranging from about 0.3% to about 2.0% by weight.

37. The topical composition according to claim 21 wherein the cross-linking agent is decorin.

38. The topical composition according to claim 21, wherein the active ingredient composition further comprises a chaotropic agent.

39. The topical composition according to claim 38, wherein the chaotropic agent is Ca(OH)₂.

40. The topical composition according to claim 21, wherein the active ingredient composition further comprises a long-chain fatty acid ester of tocopherol selected from the group consisting of tocopheryl palmitate, tocopheryl myristate, and tocopheryl stearate.

41. The topical composition according to claim 17, wherein the active ingredient comprises a skin lightener selected from the group consisting of hydroquinone, kojic acid, azelaic acid, glycolic acid and artocarpin.

42. The topical composition according to claim 41, wherein the skin lightener comprises hydroquinone, and the hydroquinone is present in an amount ranging from about 1.5% to about 4.0% by weight.

43. The topical composition according to claim 17, wherein the active ingredient comprises a retinoid selected from the group consisting of isotretinoin, retinal, retinol, retinoic acid, retinyl acetate, retinyl palmitate, retinyl propionate, synthetic retinoid mimics and tretinoin.

44. The topical composition according to claim 43, wherein the active ingredient is tretinoin and the tretinoin is present in an amount ranging from about 0.005% to about 1.0% by weight.

45. The topical composition according to claim 17, wherein the active ingredient comprises:

a retinoid selected from the group consisting of isotretinoin, retinal, retinol, retinoic acid, retinyl acetate, retinyl palmitate, retinyl propionate, synthetic retinoid mimics and tretinoin; and

a skin lightener selected from the group consisting of hydroquinone, kojic acid, azelaiz acid, glycolic acid and artocarpin.

46. The topical composition according to claim 45, wherein the retinoid is tretinoin and is present in an amount ranging from about 0.005% to about 1.0% by weight, and wherein the skin lightener is hydroquinone and is present in an amount ranging from about 1.5% to about 4.0% by weight.

47. The topical composition according to claim 17, wherein the active ingredient comprises a chemical denervation agent.

48. The topical composition according to claim 47, wherein the chemical denervation agent is selected from the group consisting of botulinium type A toxins and botulinium type B toxins.

49. The topical composition according to claim 17, wherein the active ingredient is an anti-fungal agent.

50. The topical composition according to claim 49, wherein the anti-fungal agent is selected from the group consisting of fungicidal agents and fungistatic agents.

51. The topical composition according to claim 50, wherein the anti-fungal agent is selected from the group consisting of terbinafine, itraconazole, micronazole nitrate, thiapendazole, tolnaftate, clotrimazole and griseofulvin.

52. The topical composition according to claim 49, wherein the anti-fungal is present in an amount ranging from about 0.05% to about 3% by weight.

53. The topical composition according to claim 17, wherein the active ingredient is at least one local anesthetic.

54. The topical composition according to claim 53, wherein the at least one local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxine, prilocalne, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propxycaine, choroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pyrrocaine, risocaine, rodocaine, pharmaceutically acceptable derivatives and bioisoteres thereof, and mixtures thereof.

55. The topical composition according to claim 53, wherein the at least one anesthetic comprises benzocaine, lidocaine and tetracaine.

56. The topical composition according to claim 55, wherein the benzocaine is present in an amount ranging from about 10% to about 30% by weight, the lidocaine is present in an amount ranging from about 3% to about 12% by weight, and the tetracaine is present in an amount ranging from about 2% to about 8% by weight.

57. The topical composition according to claim 53, further comprising a therapeutic agent selected from the group consisting of analgesics, antianxiety agents, antiarryhthmics, antibacterials, antibiotics, anticoagulants, anticonvulsants, antifungals, antihistamines, antiinflammatories, antivirals, antipruritics, bronchodilators, calcium channel blockers, cytotoxic agents, anticancer agents, cytokines, growth factors, immunosuppressants, muscle relaxants, psychotherapeutics, sympathomimetics, vasodilators, and vitamins.

58. The topical composition according to claim 57, wherein the therapeutic agent is an antihistamine selected from the group consisting of bromphenphiramine maleate, chlorpheniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, carbinoxamine, clemastine fumarate, pyrilamine maleate, promethazine hydrochloride, cyproheptadine hydrochloride, astemazole, loratidine, fexofenadine and cetirizine.

59. The topical composition according to claim 57, wherein the therapeutic agent is an antibiotic selected from the group consisting of streptomycin, neomycin, gentamycin, cephalothin, cefazolin, cefalexin, cefuroxime, cefamandole, cefoxitin, cefaclor, vancomycin, clindamycin, erythromycin, tinidazole, penicillin, azocillin, nafcillin, methicillin, ampicillin, amoxicillin, sulfonamides, tetracyclines, bacitracin, polymyxin and ciprofloxacin.

60. The topical composition according to claim 17, wherein the active ingredient is a non-steroidal anti-inflammatory drug.

61. The topical composition according to claim 60, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, oxaprozin, and celecoxib.

62. The topical composition according to claim 60, wherein the non-steroidal anti-inflammatory drug is present in an amount ranging from about 0.1% to about 80% by weight.

63. A topical composition for topical application to skin, the topical composition comprising:

an active ingredient selected from the group consisting of drugs, agents or compositions;

the transdermal delivery composition according to claim 1; and

an anhydrous delivery system.

64. The topical composition according to claim 63, wherein the anhydrous delivery system comprises:

a volatile organic co-solvent;

menthol;

propylene glycol;

2,2′

-ethoxyethoxyethanol;

a gelling agent;

a preservative; and

a dispersing agent.

65. The topical composition according to claim 64, wherein the volatile organic co-solvent is isopropyl alcohol.

66. The topical composition according to claim 64, wherein the gelling agent is selected from the group consisting of hydroxypropylcellulose, methylcellulose, and hydroxypropylmethylcellulose.

67. The topical composition according to claim 64, wherein the dispersing agent is glycerin.

68. The topical composition according to claim 64, wherein the preservative is selected from the group consisting of butylated hydroxytoluene and EDTA.

69. The topical composition according to claim 64, wherein the anhydrous delivery system further comprises a fragrance.

70. The topical composition according to claim 64, wherein the anhydrous delivery system further comprises a vasoconstrictor selected from the group consisting of phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, tramazoline, and salts thereof.

71. A method of treating skin comprising:

applying the transdermal delivery composition of claim 1 to the skin; and

applying an active ingredient to the skin, the active ingredient being selected from the group consisting of drugs, agents or compositions.

72. The method according to claim 71, wherein the transdermal delivery composition is applied to the skin before, after or simultaneously with application of the active ingredient.

73. The method according to claim 71, further comprising treating the skin with a non-ablative modality.

74. The method according to claim 73, wherein the non-ablative modality is selected from the group consisting of mechanical and radiation-based therapies.

75. The method according to claim 73, wherein the non-ablative modality is selected from the group consisting of microdermabrasion, laser based skin remodeling and radio-frequency-based skin remodeling.

76. The method according to claim 73, wherein the skin is treated with the active ingredient before, after or before and after the skin is treated with the non-ablative treatment modality.

77. The method according to claim 71, wherein the active ingredient comprises an active ingredient composition comprising:

methionine;

cysteine;

a mixture of amino acids comprising leucine, lysine, phenylalanine, threonine, tryptophan, valine, histidine and arginine;

at least one antioxidant;

at least one cross-linking agent; and

at least one metallic catalyst.

78. The method according to claim 71, wherein the active ingredient comprises a retinoid.

79. The method according to claim 71, wherein the active ingredient comprises a skin lightener.

80. The method according to claim 71, wherein the active ingredient comprises a retinoid and a skin lightener.

81. The method according to claim 71, wherein the active ingredient comprises a chemical denervation agent.

82. The method according to claim 71, wherein the active ingredient comprises an anti-fungal agent.

83. The method according to claim 71, wherein the active ingredient comprises at least one local anesthetic.

84. The method according to claim 71, wherein the active ingredient comprises a non-steroidal anti-inflammatory drug.

85. A method of treating skin comprising:

applying the transdermal delivery composition of claim 1 to the skin;

applying an active ingredient to the skin, the active ingredient being selected from the group consisting of drugs, agents or compositions; and

treating the skin with a non-ablative treatment modality.

86. The method according to claim 85, wherein the non-ablative treatment modality is selected from the group consisting of mechanical and radiation-based therapies.

87. The method according to claim 85, wherein the non-ablative treatment modality is selected from the group consisting of microdermabrasion, laser-based skin remodeling and radio-frequency based skin remodeling.

88. The method according to claim 85, wherein the skin is treated with a non-ablative treatment modality before, after or before and after the skin is treated with the active ingredient.

89. A method of rejuvenating and repairing damage to skin, the method comprising topically applying the composition according to claim 21 to the skin.

90. A method of promoting collagen biosynthesis in skin, the method comprising topically applying the composition according to claim 21 to the skin.

91. A method of treating hyperpigmentation of skin, the method comprising topically applying the topical composition according to claim 41 to the skin.

92. A method of treating a skin condition selected from the group consisting of acne, actinic damage, dandruff, eczema, fine lines, psoriasis, warts and wrinkles, the method comprising topically applying the topical composition according to claim 44 to the skin.

93. A method of treating a skin condition selected from the group consisting of acne, actinic damage, dandruff, eczema, fine lines, psoriasis, warts and wrinkles, the method comprising topically applying the topical composition according to claim 46 to the skin.

94. A method of increasing permeation of a chemical denervation agent through skin, the method comprising topically applying the topical composition according to claim 48 to the skin.

95. A method of treating rhytides caused by muscular contraction, the method comprising topically applying the topical composition according to claim 47 to the skin.

96. A method of treating a fungal infection comprising topically applying the topical composition according to claim 49 to an affected area.

97. A method of treating onychomycosis comprising topically applying the topical composition according to claim 49 to an affected area.

98. A method of administering a local anesthetic through skin, the method comprising topically administering the topical composition according to claim 53 to the skin.

99. A method of administering a non-steroidal anti-inflammatory drug through skin, the method comprising topically applying the topical composition according to claim 60 to the skin.

100. A system for administering an active ingredient through skin, the system comprising:

a drug reservoir comprising the active ingredient and the transdermal delivery composition according to claim 1; and

means for sustaining contact between the drug reservoir and the skin.

101. The system according to claim 100, wherein the drug reservoir is selected from the group consisting of sponges, pads, patches, polymer matrices, bandages, and swabs.

102. The system according to claim 100, wherein the means for sustaining contact between the drug reservoir and the skin is an adhesive.

108. The method according to claim 89, wherein the non-ablative treatment modality is selected from the group consisting of mechanical and radiation-based therapies.

112. The method according to claim 110, wherein the transdermal delivery agent comprises the composition according to claim 1.

14. A transdermal delivery composition for topical application to skin, the transdermal delivery composition comprising benzyl alcohol and lecithin organogel, wherein the benzyl alcohol is present in an amount greater than an amount of the lecithin organogel.

15. The transdermal delivery composition according to claim 14, wherein the transdermal delivery composition has a pH ranging from about 3.0 to about 7.4.

16. The transdermal delivery composition according to claim 14, wherein the benzyl alcohol is present in an amount of about 2% by weight and the lecithin organogel is present in an amount of about 0.6% by weight.

103. A topical composition for promotion of collagen synthesis, the composition comprising:

methionine;

cysteine;

a mixture of amino acids comprising leucine, lysine, phenylalanine, threonine, tryptophan, valine, histidine and arginine;

at least one antioxidant;

at least one cross-linking agent; and

at least one metallic catalyst.

104. The topical composition according to claim 103, wherein the at least one antioxidant is selected from the group consisting of lipoic acid, lipoic acid derivatives or analogues, ascorbic acid, and ascorbic acid derivatives.

105. The topical composition of claim 103, wherein the cross-linking agent is a bioflavonoid selected from the group consisting of quercetin, quercitrin, kaempferol, kaempferol 3-rutinoside, 3′

-methoxy kaempferol 3-rutinoside, 5,8,4′

-trihydroxyl-6,7-dimethoxyflavone, catechin, epicachetin, epicachetin gallate, epigallocachetin gallate,

106. The topical composition according to claim 103, wherein the cross-linking agent is decorin.

107. A method of treating skin, the method comprising:

applying the composition according to claim 103 to the skin; and

treating the skin with a non-ablative treatment modality.

109. The method according to claim 103, wherein the non-ablative treatment modality is selected from the group consisting of microdermabrasion, laser-based skin remodeling and radio-frequency based skin remodeling.

110. The method according to claim 103, further comprising applying a transdermal delivery agent to the skin.

111. The method according to claim 110, wherein the transdermal delivery agent is applied to skin before, after or simultaneously with the composition according to claim 103