Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts

Abstract

Pharmaceutical formulations and methods for the topical or transdermal delivery of 1isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1H-imidazo[4,5 c]quinolin-4-amine, i.e., imiquimod, to treat genital/perianal warts with shorter durations of therapy than currently prescribed for the commercially available Aldara® 5% imiquimod cream, as now approved by the U.S. Food & Drug Administration (“FDA”), are disclosed and described. More specifically, lower dosage strength imiquimod formulations to deliver an efficacious dose of imiquimod for treating genital/perianal warts with an acceptable safety profile and dosing regimens that are shorter and more convenient for patient use than the dosing regimen currently approved by the U.S. Food & Drug Administration (“FDA”) for Aldara® 5% imiquimod cream to treat genital/perianal warts are also disclosed and described.

1 ) A method of treating a subject diagnosed with genital or perianal warts, said method comprising applying an effective amount of imiquimod to a treatment area diagnosed with the genital or perianal warts once a day for up to 8 weeks to achieve at least partial clearance of the genital warts. 
     
     
         2 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation, contains imiquimod in an amount by weight of between about 1% and about 4.25% w/w. 
     
     
         3 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25%. 
     
     
         4 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         5 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         6 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         7 ) A method of  claim 1 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod 
     
     
         8 ) A method of  claim 2 , wherein the lower dosage strength imiquimod formulation contains a fatty acid. 
     
     
         9 ) A method of  claim 2 , wherein the fatty acid is unrefined oleic acid. 
     
     
         10 ) A method of  claim 2 , wherein the fatty acid is refined oleic acid. 
     
     
         11 ) A method of  claim 2 , wherein the fatty acid is isostearic acid. 
     
     
         12 ) A method of  claim 2 , wherein the lower dosage strength imiquimod formulation is selected from a group of formulations listed in Table 9. 
     
     
         13 ) A method of treating a subject diagnosed with genital warts, said method comprising applying a lower dosage strength imiquimod formulation to a treatment area once a day for each day during a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         14 ) A method of treating a subject diagnosed with genital warts of  claim 13 , wherein the lower dosage strength imiquimod formulation is selected from the group consisting of lower dosage strength imiquimod formulations set forth in Example 23. 
     
     
         15 ) A method of treating a subject diagnosed with genital warts, said method comprising applying a lower dosage strength imiquimod formulation comprising about 3.75% imiquimod by weight to treatment area once a day for each day in accordance with a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         16 ) A method of treating a subject diagnosed with genital warts of  claim 15 , wherein the 3.75% imiquimod formulation is selected from the group consisting of the 3.75% imiquimod formulations set forth in Example 23. 
     
     
         17 ) A method of treating a subject diagnosed with genital warts, said method comprising applying a lower dosage strength imiquimod formulation comprising about 2.5% imiquimod by weight to a treatment area once a day for each day in accordance with a short duration of therapy to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         18 ) A method of treating a subject diagnosed with genital warts of  claim 17 , wherein the 2.5% imiquimod formulation is selected from the group consisting of 2.5% imiquimod formulations set forth in Example 23. 
     
     
         19 ) A method of treating a subject diagnosed with genital warts, said method comprises applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 3.75% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         20 ) A method of treating a subject diagnosed with genital warts of  claim 19 , wherein the 3.75% imiquimod formulation is selected from the group consisting of 3.75% imiquimod formulations set forth in Example 23. 
     
     
         21 ) A method of treating a subject diagnosed with genital warts of  claim 19 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, unrefined oleic acid, super refined oleic acid, stearic acid, isostearic acid and mixtures thereof. 
     
     
         22 ) A method of treating a subject diagnosed with genital warts, said method comprising applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 2.5% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         23 ) A method of treating a subject diagnosed with genital warts of  claim 22 , wherein the 2.5% imiquimod formulation is selected from the group consisting of the 2.5% imiquimod formulations set forth in Example 23. 
     
     
         24 ) A method of treating a subject diagnosed with genital warts, said method comprising applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 3.75% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises isostearic acid, to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         25 ) A method of treating a subject diagnosed with genital warts of  claim 24 , wherein the 3.75% imiquimod formulation is selected from the group consisting of the 3.75% imiquimod formulations set forth in Example 23. 
     
     
         26 ) A method of treating a subject diagnosed with genital warts, said method comprisings applying to a treatment area once a day for each day during a short duration of therapy a lower dosage strength formulation comprised of about 2.5% 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) by weight, and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises isostearic acid, to deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         27 ) A method of treating a subject diagnosed with genital warts of  claim 26 , wherein the 2.5% imiquimod formulation is selected from the group consisting of the 2.5% imiquimod formulations set forth in Example 23. 
     
     
         28 ) An imiquimod formulation for treating genital warts, said imiquimod formulation comprising: a lower dosage strength of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod), and a pharmaceutically acceptable vehicle for the imiquimod, which vehicle comprises a fatty acid, for application to a treatment area once a day for a short duration of therapy to topically or transdermally deliver an effective amount of imiquimod to the treatment area to treat genital warts. 
     
     
         29 ) An imiquimod formulation of  claim 28 , wherein the said application of said imiquimod formulation is without inducing significant local skin reactions or irritation in the treatment area or treatment limiting adverse events which could result in premature therapy termination or significant voluntary rest periods of several days that are generally associated with higher concentrations of imiquimod therapy. 
     
     
         30 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation is selected from a group of lower dosage strength of imiquimod formulations set forth in Table 9. 
     
     
         31 ) An imiquimod formulation of  claim 28 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         32 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength of imiquimod is about 3.75%. 
     
     
         33 ) An imiquimod formulation of  claim 32 , wherein the 3.75% imiquimod formulation is selected from a group consisting of the 3.75% imiquimod formulations in Example 23. 
     
     
         34 ) An imiquimod formulation of  claim 33 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         35 ) An imiquimod formulation of  claim 33 , wherein the fatty acid is isostearic acid. 
     
     
         36 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength of imiquimod is about 2.5%. 
     
     
         37 ) An imiquimod formulation of  claim 36 , wherein the 2.5% imiquimod formulation is selected from a group consisting of the 2.5% imiquimod formulations in Example 23. 
     
     
         38 ) An imiquimod formulation of  claim 37 , wherein the fatty acid is selected from the group consisting of palmitic acid, linoleic acid, stearic acid, isostearic acid, unrefined oleic acid, super refined oleic acid and mixtures thereof. 
     
     
         39 ) An imiquimod formulation of  claim 37 , wherein the fatty acid is isostearic acid. 
     
     
         40 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 1.0% and about 4.25%. 
     
     
         41 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25%. 
     
     
         42 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. 
     
     
         43 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. 
     
     
         44 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 2.5%. 
     
     
         45 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation contains imiquimod in an amount by weight of about 3.75% imiquimod. 
     
     
         46 ) An imiquimod formulation of  claim 28 , wherein the fatty acid is present in an amount of between about 5% and 30% by weight. 
     
     
         47 ) An imiquimod formulation of  claim 28 , wherein the lower dosage strength imiquimod formulation has dose proportionate release rates as to both the release rates of the imiquimod and the total amount of imiquimod released, relative to the Aidaro® 5% imiquimod cream. 
     
     
         48 ) An imiquimod formulation of  claim 46 , wherein the fatty acid is isostearic acid. 
     
     
         49 ) An imiquimod formulation of  claim 48 , wherein the imiquimod is present in an amount of about 3.75% by weight. 
     
     
         50 ) An imiquimod formulation of  claim 48 , wherein the imiquimod is present in an amount of about 2.5% by weight. 
     
     
         51 ) An imiquimod formulation of any one of  claims 28 - 50 , wherein the lower dosage strength imiquimod formulation is bioequivalent. 
     
     
         52 ) An imiquimod formulation of any one of  claims 28 - 50 , wherein the lower dosage strength imiquimod formulation is therapeutically equivalent. 
     
     
         53 ) An imiquimod formulation of any one of  claims 28 - 50 , wherein the lower dosage strength imiquimod formulation is pharmaceutically equivalent. 
     
     
         54 ) An imiquimod formulation of any one of  claims 28 - 50 , wherein the lower dosage strength imiquimod formulation is interchangeable. 
     
     
         55 ) An imiquimod formulation of any one of  claims 28 - 50 , wherein the lower dosage strength imiquimod formulation remains free of degradation products when stored at about 25° C./60% RH, about 30° C./65% RH and about 40° C./75/ORH over about one, about two, about three and about six months and when analyzed at about 318 nm wavelength.