Claims
- 1. A transdermal composition comprising a pharmaceutically acceptable carrier, a drug, and a quaternary ammonium salt constituting from about 0.1% to about 4.5% by weight of the carrier.
- 2. The transdermal composition of claim 1, wherein said quaternary ammonium salt is a compound having the formula:
- 3. The transdermal composition of claim 1, wherein said quaternary ammonium salt is benzalkonium chloride; benzalkonium saccharinate; behenalkonium chloride; cetalkonium chloride; erucalkonium chloride; lauralkonium chloride; myristalkonium chloride; myristalkonium saccharinate (Quaternium-3); stearalkonium chloride; olealkonium chloride; tallowalkonium chloride; dodecylbenzyltrimethylammonium chloride (Quaternium-28); dodecylbenzyl trimethyl ammonium 2-ethylhexanoate; ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8); ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14); dodecylbenzyl dimethyl octadecyl ammonium chloride; dodecylbenzyl triethanol ammonium chloride (Quaternium-30); benzoxonium chloride; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride; benzethonium chloride; methylbenzethonium chloride; N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide); dodecarbonium chloride; babassuamidopropalkonium chloride; wheatgermamidopropalkonium chloride, or a mixture thereof.
- 4. The transdermal composition of claim 1, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.
- 5. The transdermal composition of claim 1, wherein the quaternary ammonium salt is benzethonium chloride.
- 6. The transdermal composition of claim 1, wherein the quaternary ammonium salt is methylbenzethonium chloride.
- 7. The transdermal composition of claim 1, wherein the quaternary ammonium salt is benzalkonium chloride.
- 8. The transdermal composition of claim 1, wherein the quaternary ammonium salt is olealkonium chloride.
- 9. The transdermal composition of claim 1, wherein the quaternary ammonium salt is phenoctide.
- 10. The transdermal composition of claim 2, wherein the quaternary ammonium salt is present in an amount sufficient to act as an anti-irritant.
- 11. The transdermal composition of claim 10, wherein said quaternary ammonium salt is a member selected from the group consisting of alkyl-, dimethyl benzenemethanaminium salts; acyl-, dimethyl benzenemethanaminium salts; mixed acyl-/alkyl-, dimethyl benzenemethanaminium salts; ethylbenzyl dodecyl dimethylammonium chloride, dodecylbenzyltrimethylammonium chloride, dodecylbenzyl triethanolammonium chloride, benzoxonium chloride, benzethonium chloride; methylbenzethonium chloride; phenoctide; dodecarbonium chloride; and mixed alkyl-/acyl-, amidopropalkonium salts.
- 12. The transdermal composition of claim 1, wherein said quaternary ammonium salt constitutes about 1% by weight of the pharmaceutically acceptable carrier.
- 13. The transdermal composition of claim 1, wherein said quaternary ammonium salt constitutes about 2% by weight of the pharmaceutically acceptable carrier.
- 14. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier is a biocompatible polymer.
- 15. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier is an adhesive.
- 16. The transdermal composition of claim 15, wherein said adhesive is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylene-vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-rubber block copolymers, and mixtures thereof.
- 17. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier comprises a viscous material suitable for inclusion in a liquid reservoir.
- 18. The transdermal composition of claim 17, wherein said viscous material forms a gel.
- 19. The transdermal composition of claim 2, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate. arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate, and a mixture thereof.
- 20. The transdermal composition of claim 1, further comprising a diluent, excipient, emollient, plasticizer, skin irritation reducing agent, or a mixture thereof.
- 21. The transdermal composition of claim 1, further comprising a co-enhancer that acts synergistically with the quaternary ammonium salt to enhance the penetration of the drug.
- 22. The transdermal composition of claim 21, wherein said co-enhancer comprises a compound represented by the formula:
- 23. The transdermal composition of claim 21, wherein said co-enhancer is a member selected from the group consisting of fatty acids and their salts, fatty alcohols, branched aliphatic alcohols, fatty acid alkyl esters, fatty acid monoesters of sorbitol and glycerol, fatty acid esters with glycolic acid and lactylic acid and their salts, fatty acid amides, alkylpyrrolidones and mixtures thereof.
- 24. The transdermal composition of claim 21, wherein said co-enhancer is a member selected from the group consisting of oleic acid; lauric acid; oleyl alcohol; lauryl alcohol; 2-butyl-octanol; 2-hexyl decanol; 2-octyl-decanol; 2-hexyldodecanol; 2-octyl-dodecanol; 2-decyl-tetradecanol; 2-tetradecyl-octadecanol; methyl and ethyl laurate; sorbitan monooleate and monolaurate; glycerol monooleate and monolaurate; lauric, myristic, capric, stearic, and oleic diethanolamide; lauric, myristic, capric, stearic, and oleic monoethanolamide; lauric, myristic, capric, stearic, and oleic monoisopropanolamide; caproyl, lauroyl and stearoyl lactylic acid and their salts; caproyl, lauroyl and stearoyl glycolic acid and their salts; N-n-octyl and N-n-dodecyl pyrrolidone.
- 25. The transdermal composition of claim 21, wherein said co-enhancer is oleic acid; lauric acid; oleyl alcohol; lauryl alcohol; 2-butyl-octanol; sorbitan monooleate; glycerol monooleate; lauric, stearic, and oleic diethanolamide; lauric monoisopropanolamide; caproyl lactylic acid; N-n-octyl pyrrolidone, or a mixture thereof.
- 26. The transdermal composition of claim 1, wherein said drug is a member selected from the group consisting of: antibiotics, neoplastic agents, agents affecting the immune response, blood calcium regulators, peptide and protein hormones, agents useful in glucose regulation, antithrombotics and hemostatics, antihyperlipidemic agents, thyromimetic and antithyroid drugs, anti-ulcer agents, histamine H2-receptor agonists and antagonists, inhibitors of allergic response, local anesthetics, analgesics and analgesic combinations, antipsychotics, anti-anxiety agents, antidepressants agents, anorexigenics, bone-active agents, diagnostic agents, antidiarrheals, antimigraine agents, antimotion sickness agents, antinauseants, antiparkinsonism agents, antipruritics, antipyretics, antispasmodics, anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular agents, central nervous system stimulants, decongestants, diagnostics, hormones, immunosuppressives, parasympatholytics, parasympathomimetics, sedatives, tranquilizers and mixtures thereof.
- 27. A transdermal composition comprising a pharmaceutically acceptable carrier, a drug, and a quaternary ammonium salt, wherein the quaternary ammonium salt constitutes an amount sufficient to enhance penetration of the drug with reduced skin irritation.
- 28. The transdermal composition of claim 27, wherein the quaternary ammonium salt is present in low concentration.
- 29. The transdermal composition of claim 28, wherein the low concentration represents no greater than 4.5% by weight of the carrier.
- 30. The transdermal composition of claim 28, wherein the low concentration represents no greater than 4.0% by weight of the carrier.
- 31. The transdermal composition of claim 28, wherein the low concentration represents no greater than 3.0% by weight of the carrier.
- 32. The transdermal composition of claim 28, wherein the low concentration represents no greater than 2.0% by weight of the carrier.
- 33. The transdermal composition of claim 28, wherein the low concentration represents no greater than 1.0% by weight of the carrier.
- 34. The transdermal composition of claim 28, wherein said quaternary ammonium salt is a compound having the formula:
- 35. The transdermal composition of claim 28, wherein said quaternary ammonium salt is benzalkonium chloride; benzalkonium saccharinate; behenalkonium chloride; cetalkonium chloride; erucalkonium chloride; lauralkonium chloride; myristalkonium chloride; myristalkonium saccharinate (Quaternium-3); stearalkonium chloride; olealkonium chloride; tallowalkonium chloride; dodecylbenzyltrimethylammonium chloride (Quaternium-28); dodecylbenzyl trimethyl ammonium 2-ethylhexanoate; ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8); ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14); dodecylbenzyl dimethyl octadecyl ammonium chloride; dodecylbenzyl triethanol ammonium chloride (Quaternium-30); benzoxonium chloride; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride; benzethonium chloride; methylbenzethonium chloride; N,N-(diethyl-N-[2-[4-( 1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide); dodecarbonium chloride; babassuamidopropalkonium chloride; wheatgermamidopropalkonium chloride, or a mixture thereof.
- 36. The transdermal composition of claim 28, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.
- 37. The transdermal composition of claim 28, wherein the quaternary ammonium salt is benzethonium chloride.
- 38. The transdermal composition of claim 28, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide , acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.
- 39. A method of reducing skin irritation of a transdermal composition comprising a pharmaceutically acceptable carrier,
comprising the step of incorporating a low concentration of a quaternary ammonium salt.
- 40. The method of claim 39, wherein the low concentration represents no greater than 4% by weight of the carrier.
- 41. The method of claim 39, wherein the low concentration represents no greater than 3% by weight of the carrier.
- 42. The method of claim 39, wherein the low concentration represents no greater than 2% by weight of the carrier.
- 43. The method of claim 39, wherein the low concentration represents no greater than 1% by weight of the carrier.
- 44. The method of claim 39, wherein the low concentration represents no greater than 0.8% by weight of the polymeric carrier.
- 45. The transdermal composition of claim 39, wherein said quaternary ammonium salt is a compound having the formula:
- 46. The transdermal composition of claim 39, wherein said quaternary ammonium salt is benzalkonium chloride; benzalkonium saccharinate; behenalkonium chloride; cetalkonium chloride; erucalkonium chloride; lauralkonium chloride; myristalkonium chloride; myristalkonium saccharinate (Quaternium-3); stearalkonium chloride; olealkonium chloride; tallowalkonium chloride; dodecylbenzyltrimethylammonium chloride (Quaternium-28); dodecylbenzyl trimethyl ammonium 2-ethylhexanoate; ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8); ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14); dodecylbenzyl dimethyl octadecyl ammonium chloride; dodecylbenzyl triethanol ammonium chloride (Quaternium-30); benzoxonium chloride; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride; benzethonium chloride; methylbenzethonium chloride; N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide); dodecarbonium chloride; babassuamidopropalkonium chloride; wheatgermamidopropalkonium chloride, or a mixture thereof.
- 47. The transdermal composition of claim 39, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.
- 48. The transdermal composition of claim 39, wherein the quaternary ammonium salt is benzethonium chloride.
- 49. The transdermal composition of claim 39, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.
- 50. A method of synergistically enhancing transdermal penetration of a drug in a transdermal composition comprising a carrier, a penetration enhancer, and a drug, comprising the step of incorporating a low concentration of a quaternary ammonium salt.
- 51. The method of claim 50, wherein the low concentration represents no greater than 4% by weight of the carrier.
- 52. The method of claim 50, wherein the low concentration represents no greater than 3% by weight of the carrier.
- 53. The method of claim 50, wherein the low concentration represents no greater than 2% by weight of the carrier.
- 54. The method of claim 50, wherein the low concentration represents no greater than 1% by weight of the carrier.
- 55. The method of claim 50, wherein the low concentration represents no greater than 0.8% by weight of the carrier.
- 56. The transdermal composition of claim 50, wherein said quaternary ammonium salt is a compound having the formula:
- 57. The transdermal composition of claim 50, wherein said quaternary ammonium salt is benzalkonium chloride; benzalkonium saccharinate; behenalkonium chloride; cetalkonium chloride; erucalkonium chloride; lauralkonium chloride; myristalkonium chloride; myristalkonium saccharinate (Quaternium-3); stearalkonium chloride; olealkonium chloride; tallowalkonium chloride; dodecylbenzyltrimethylammonium chloride (Quaternium-28); dodecylbenzyl trimethyl ammonium 2-ethylhexanoate; ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8); ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14); dodecylbenzyl dimethyl octadecyl ammonium chloride; dodecylbenzyl triethanol ammonium chloride (Quaternium-30); benzoxonium chloride; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide; benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride; benzethonium chloride; methylbenzethonium chloride; N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide); dodecarbonium chloride; babassuamidopropalkonium chloride; wheatgermamidopropalkonium chloride, or a mixture thereof.
- 58. The transdermal composition of claim 50, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.
- 59. The transdermal composition of claim 50, wherein the quaternary ammonium salt is benzethonium chloride.
- 60. The transdermal composition of claim 50, wherein the penetration enhancer comprises a compound represented by the formula:
- 61. The transdermal composition of claim 50, wherein said enhancer is a member selected from the group consisting of fatty acids and their salts, fatty alcohols, branched aliphatic alcohols, fatty acid alkyl esters, fatty acid monoesters of sorbitol and glycerol, fatty acid esters with glycolic acid and lactylic acid and their salts, fatty acid amides. alkylpyrrolidones and mixtures thereof.
- 62. The transdermal composition of claim 50, wherein said enhancer is a member selected from the group consisting of oleic acid; lauric acid; oleyl alcohol; lauryl alcohol; 2-butyl-octanol; 2-hexyl decanol; 2-octyl-decanol; 2-hexyldodecanol; 2-octyl-dodecanol; 2-decyl-tetradecanol; 2-tetradecyl-octadecanol; methyl and ethyl laurate; sorbitan monooleate and monolaurate; glycerol monooleate and monolaurate; lauric, myristic, capric, stearic, and oleic diethanolamide; lauric, myristic, capric, stearic, and oleic monoethanolamide; lauric, myristic, capric, stearic, and oleic monoisopropanolamide; caproyl, lauroyl and stearoyl lactylic acid and their salts; caproyl, lauroyl and stearoyl glycolic acid and their salts; N-n-octyl and N-n-dodecyl pyrrolidone.
- 63. The transdermal composition of claim 50, wherein said enhancer is oleic acid; lauric acid; oleyl alcohol; lauryl alcohol; 2-butyl-octanol; sorbitan monooleate; glycerol monooleate: lauric, stearic, and oleic diethanolamide; lauric monoisopropanolamide; caproyl lactylic acid ; N-n-octyl pyrrolidone, or a mixture thereof.
- 64. The transdermal composition of claim 50, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.
- 65. The transdermal composition of claim 1, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.
- 66. The transdermal composition of claim 27, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.
- 67. The transdermal composition of claim 39, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.
- 68. The transdermal composition of claim 50, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.
- 69. The method of claim 39, wherein the skin irritation manifests as erythema, papule, vesicle, or a combination thereof.
- 70. The method of claim 39, wherein the skin irritation is caused by microbial growth.
- 71. The method of claim 70, wherein the microbial comprises gram-positive bacteria.
- 72. The method of claim 50, wherein the penetration enhancement is from about 10-100% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.
- 73. The method of claim 50, wherein the penetration enhancement is from about 20-100% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.
- 74. The method of claim 50, wherein the penetration enhancement is from about 10-50% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.
- 75. A method of enhancing transdermal delivery of a drug and reducing skin irritation associated with the transdermal delivery comprising the step of:
applying a transdermal drug delivery system as recited in claim 1 to a selected skin surface.
- 76. A transdermal composition for reducing skin irritation, comprising a low concentration of a quaternary ammonium salt, wherein the composition results in no greater than mild skin irritation when applied to the skin.
PRIORITY INFORMATION
[0001] This application claims priority to U.S. Provisional Patent Applications Serial No: 60/153,001, Serial. No: 60/153,008, and Serial. No: 60/153,015 each of which was filed on Sep. 9, 1999. Each of these applications is hereby incorporated by reference.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60153001 |
Sep 1999 |
US |
|
60153008 |
Sep 1999 |
US |
|
60153015 |
Sep 1999 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09657080 |
Sep 2000 |
US |
Child |
10105032 |
Mar 2002 |
US |