초록 ▼

A permeation enhancer composition is provided for increasing the permeability of skin or mucosal tissue to topically or transdermally administered pharmacologically or cosmeceutically active agents. The composition is comprised of a hydroxide-releasing agent and a lipophilic co-enhancer such as a fa

A permeation enhancer composition is provided for increasing the permeability of skin or mucosal tissue to topically or transdermally administered pharmacologically or cosmeceutically active agents. The composition is comprised of a hydroxide-releasing agent and a lipophilic co-enhancer such as a fatty alcohol, a fatty ether, or a fatty acid ester, including fatty acid esters of polyols such as propylene glycol and glycerol. Also provided are pharmaceutical formulations containing a therapeutically effective amount of an active agent in addition to the aforementioned enhancer composition, methods for administering active agents topically or transdermally with enhanced permeation, and drug delivery systems for application to an individual's skin or mucosal tissue, wherein the systems are formulated so as to contain an active agent to be administered and an effective permeation enhancing amount of an enhancer composition of the invention.

대표청구항 ▼

1. A method for enhancing the flux of a drug through a body surface, comprising administering the drug to a localized region of a human patient's body surface in combination with an effective permeation enhancing amount of permeation enhancer composition comprised of a hydroxide-releasing agent and

1. A method for enhancing the flux of a drug through a body surface, comprising administering the drug to a localized region of a human patient's body surface in combination with an effective permeation enhancing amount of permeation enhancer composition comprised of a hydroxide-releasing agent and a lipophilic co-enhancer, said lipophilic co-enhancer being selected from the group consisting of:(i) a compound having a molecular weight in the range of about 150 to 1000 and an aqueous solubility of less than about 1 wt %, and the structure (CH 3 —L—X) n R, wherein: n is 1 or 2; L is alkylene or alkenylene containing 1 to 3 double bonds, and from about 6 to about 22 carbon atoms; X is selected from the group consisting of—COO—, —CH2O—, and —CH 2 O—(CO)—; and R is selected from the group consisting of H, lower alkyl, and lower alkyl substituted with one or two hydroxyl groups, with the proviso that if R is H, X is necessarily —CH 2 O—, and wherein when n is 2, R contains at least two carbon atoms;(ii) a lower alkyl ester of a C 10 -C 18 fatty acid; and(iii) an esterified polyol selected from the group consisting of propylene glycol mono- or di-substituted with a C 10 -C 18 fatty acid and glycerol mono- or di-substituted with a C 10 -C 18 fatty acid;wherein the composition is effective to provide a pH in the range of approximately 8.0 to 13.0 at the localized region of the body surface, and the amount of hydroxide-releasing agent in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 25 wt % of the composition. 2. The method of claim 1, wherein the pH is in the range of approximately 8.0 to 11.5. 3. The method of claim 1, wherein the body surface is skin. 4. The method of claim 1, wherein the body surface is mucosal tissue. 5. The method of claim 1, wherein the composition is aqueous. 6. The method of claim 5, wherein the composition is selected from the group consisting of a cream, a gel, a lotion, and a paste. 7. The method of claim 1, wherein the composition is nonaqueous. 8. The method of claim 7, wherein the composition is an ointment. 9. The method of claim 1, wherein the hydroxide-releasing agent releases free hydroxide ions in the presence of an aqueous fluid. 10. The method of claim 1, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof. 11. The method of claim 10, wherein the hydroxide-releasing agent is an inorganic hydroxide. 12. The method of claim 11, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof. 13. The method of claim 12, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof. 14. The method of claim 13, wherein the inorganic hydroxide is sodium hydroxide. 15. The method of claim 13, wherein the inorganic hydroxide is potassium hydroxide. 16. The method of claim 11, wherein the amount of inorganic hydroxide in the composition is the total of(a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the composition. 17. The method of claim 16, wherein the amount of inorganic hydroxide in the composition is the total of(a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt. % to 3.0 wt. % of the composition. 18. The method of claim 17, wherein the amount of inorganic hydroxide in the composition is the total of(a) the amount required to neutralize any acidic species in the composition plus (b) an amou nt equal to approximately 0.75 wt. % to 2.0 wt. % of the composition. 19. The method of claim 10, wherein the hydroxide-releasing agent is an inorganic oxide. 20. The method of claim 19, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide, and mixtures thereof. 21. The method of claim 19, wherein the composition contains up to approximately 20 wt. % of the hydroxide-releasing agent. 22. The method of claim 10, wherein the hydroxide-releasing agent is a metal salt of a weak acid. 23. The method of claim 22, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, sodium borate, potassium carbonate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, sodium metaborate, and mixtures thereof. 24. The method of claim 22, wherein the composition contains up to approximately 20 wt. % of the hydroxide-releasing agent. 25. The method of claim 1, wherein L is alkylene. 26. The method of claim 25, wherein L has a total of from about 8 to about 12 carbon atoms. 27. The method of claim 1, wherein L is alkenylene. 28. The method of claim 27, wherein L has a total of from about 8 to about 18 carbon atoms. 29. The method of claim 28, wherein L has a total of from about 8 to about 16 carbon atoms. 30. The method of claim 1, wherein X is —COO—. 31. The method of claim 30, wherein n is 1 and R is lower alkyl. 32. The method of claim 30, wherein n is 1 and R is lower alkyl substituted with one or two hydroxyl groups. 33. The method of claim 30, wherein n is 2 and R is lower alkyl substituted with one or two hydroxyl groups. 34. The method of claim 30, wherein R is selected from the group consisting of 35. The method of claim 1, wherein X is —CH 2 O— and R is lower alkyl or lower alkyl substituted with one or two hydroxyl groups. 36. The method of claim 1, wherein X is —CH 2 O— and R is H. 37. The method of claim 1, wherein X is —CH 2 O—(CO)— and R is lower alkyl. 38. The method of claim 1, wherein X is —CH 2 O—(CO)— and R is lower alkyl substituted with one or two hydroxyl groups. 39. The method of claim 1, wherein the weight ratio of the hydroxide-releasing agent to the lipophilic co-enhancer is in the range of approximately 1:99 to approximately 99:1. 40. The method of claim 39, wherein the weight ratio of the hydroxide-releasing agent to the lipophilic co-enhancer is in the range of approximately 1:20 to approximately 20:1. 41. The method of claim 40, wherein the weight ratio of the hydroxide-releasing agent to the lipophilic co-enhancer is in the range of approximately 1:2 to approximately 2:1. 42. The method of claim 1, wherein the drug and the permeation enhancer composition are administered by applying a drug delivery device to the localized region of the patient's body surface thereby forming a body surface-delivery device interface, the device comprising the drug and the permeation enhancer composition, and having an outer backing layer that serves as the outer surface of the device during use. 43. The method of claim 1, wherein the drug is selected from the group consisting of: analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antibelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; calcium channel blockers; beta-blockers; antiarrhythmic agents; central nervous system stimulants; decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; ophthalmic drugs; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics; tranquilizers; vasodilators; and combinations thereof. 44. The method of claim 1, wherein the drug is an acid addition salt of a basic compound, and the amount in (a) is the amount required to neutralize the acid addition salt and any other acidic species in the composition. 45. The method of claim 1, wherein the drug is an acidic drug in the form of a free acid, and the amount in (a) is the amount required to neutralize the acidic drug and any other acidic species in the composition. 46. The method of claim 1, wherein the drug is a basic drug is the form of a free base. 47. The method of claim 1, wherein the drug is a basic addition salt of an acidic compound. 48. The method of claim 1, wherein the drug is nonionizable.