Treatment of Inflammatory Lesions of Rosacea with Ivermectin

Abstract

Methods for safe and effective treatment of inflammatory lesions of rosacea in a subject are described. The methods involve once daily topically applying to an affected skin area a topical composition containing ivermectin and a pharmaceutically acceptable carrier. It has been demonstrated that once daily topical treatment with ivermectin is significantly superior than twice-daily topical treatment with metronidazole in reducing inflammatory lesion counts.

I/We claim: 
     
         1 . A method of treating inflammatory lesions of rosacea in a subject in need thereof, comprising topically administering, once daily, to a skin area affected by the inflammatory lesions of rosacea an emulsion comprising 1% by weight ivermectin and a pharmaceutically acceptable carrier, without co-administration of another active pharmaceutical ingredient. 
     
     
         2 . The method of  claim 1 , wherein the treatment results in more reduction in inflammatory lesion count in the subject in comparison to that achieved by topically administering to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight metronidazole. 
     
     
         3 . The method of  claim 1 , wherein the treatment results in longer relapse-free time of the inflammatory lesions of rosacea in the subject in comparison to that achieved by twice daily topically administering to the subject a second pharmaceutical composition comprising 0.75% by weight metronidazole. 
     
     
         4 . The method of  claim 1 , wherein the treatment has a median time to first relapse of 110 days or longer. 
     
     
         5 . The method of  claim 1 , wherein the subject has moderate to severe papulopustular rosacea before the treatment. 
     
     
         6 . The method of  claim 5 , wherein the subject has 15 or more of the inflammatory lesions before the treatment. 
     
     
         7 . The method of  claim 1 , wherein a steady state of plasma concentration of ivermectin is reached in the subject as early as 2 weeks after the initial administration of the emulsion to the subject, wherein the steady state has a C max  of ivermectin of 0.5-10 ng/mL, and an AUC 0-24hr  of 10-100 ng·hr/mL in the subject. 
     
     
         8 . The method of  claim 1 , wherein an improvement from the baseline in an investigator's global assessment (IGA) of rosacea severity, and/or a significant reduction in inflammatory lesion count, is observed 8 weeks after the initial administration of the emulsion. 
     
     
         9 . The method of  claim 1 , wherein an improvement from the baseline in an investigator's global assessment (IGA) of rosacea severity, and/or a significant reduction in inflammatory lesion count, is observed 12 weeks after the initial administration of the emulsion. 
     
     
         10 . The method of  claim 1 , wherein the emulsion is a cream that further comprises one or more ingredients selected from the group consisting of an oily phase comprising dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the oily phase further comprising fatty substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; at least one surfactant-emulsifier selected from the group consisting of glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a mixture of solvents and/or propenetrating agents selected from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; one or more gelling agents selected from the group consisting of carbomers, cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and modified starches; and water. 
     
     
         11 . The method of  claim 1 , wherein the topical administration of the emulsion to the subject results in a mean terminal half-life of ivermectin of about 145 hours in the subject. 
     
     
         12 . A method of treating inflammatory lesions of rosacea in a subject in need thereof, comprising topically administering, once daily, to a skin area affected by the inflammatory lesions a cream comprising 1% by weight ivermectin and a pharmaceutically acceptable carrier, without co-administration of another active pharmaceutical ingredient, wherein the pharmaceutically acceptable carrier comprises an oily phase, a surfactant-emulsifier, a mixture of solvents and/or propenetrating agents, a gelling agent, and water, and wherein an improvement from the baseline in an investigator's global assessment (IGA) of rosacea severity, and/or a significant reduction in inflammatory lesion count, is observed 12 weeks after the initial administration of the emulsion. 
     
     
         13 . The method of  claim 12 , wherein an improvement from the baseline in an investigator's global assessment (IGA) of rosacea severity, and/or a significant reduction in inflammatory lesion count, is observed 8 weeks after the initial administration of the emulsion. 
     
     
         14 . The method of  claim 12 , wherein the subject has moderate to severe papulopustular rosacea before the treatment. 
     
     
         15 . The method of  claim 14 , wherein the subject has 15 or more of the inflammatory lesions before the treatment. 
     
     
         16 . The method of  claim 12 , wherein the oily phase comprises dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the oily phase further comprises fatty substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; the surfactant-emulsifier is selected from the group consisting of glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; the mixture of solvents and/or propenetrating agents is selected from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; the gelling agent is selected from the group consisting of carbomers, cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and modified starches. 
     
     
         17 . The method of  claim 12 , wherein the cream comprises carbomer copolymer type B; cetyl alcohol; citric acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin; isopropyl palmitate; methyl paraben; oleyl alcohol; phenoxyethanol; polyoxyl 20 cetostearyl ether; propylene glycol; propyl paraben; purified water; sodium hydroxide; sorbitan monostearate and stearyl alcohol. 
     
     
         18 . The method of  claim 17 , wherein an improvement from the baseline in an investigator's global assessment (IGA) of rosacea severity, and/or a significant reduction in inflammatory lesion count, is observed 8 weeks after the initial administration of the emulsion. 
     
     
         19 . The method of  claim 17 , wherein the subject has moderate to severe papulopustular rosacea before the treatment. 
     
     
         20 . The method of  claim 17 , wherein the subject has 15 or more of the inflammatory lesions before the treatment.