Method and Formulation for Improving Roflumilast Skin Penetration Lag Time

Abstract

Decreasing skin penetration lag times will improve the bioavailability of a topically administered roflumilast composition. A shorter skin penetration lag time provides quicker onset of disease relief and more consistent bioavailability as there is less transference to clothing or other people. The skin penetration lag time for roflumilast can be reduced by formulating a roflumilast composition to have a pH between 4.0-6.5 and/or combining roflumilast with an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate.

1 . A method of manufacturing a topical roflumilast pharmaceutical composition having reduced skin penetration lag time, said method comprising:
 adding an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate to a topical roflumilast composition,   wherein said composition has a pH less than 7.5.   
     
     
         2 . The method of  claim 1 , wherein said composition comprises roflumilast in an amount of 0.05%-1% w/w. 
     
     
         3 . The method of  claim 2 , wherein said composition has a pH between 4.0 and 6.5. 
     
     
         4 . The method of  claim 3 , wherein said composition has a pH between 5.0 and 6.0. 
     
     
         5 . The method of  claim 3 , wherein the composition is configured to achieve a skin penetration lag time of roflumilast of less than 1 hour. 
     
     
         6 . The method of  claim 5 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.1 ng/mL, 1 hour after administration of said composition. 
     
     
         7 . The method of  claim 6 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.3 ng/mL, 1 hour after administration of said composition. 
     
     
         8 . The method of  claim 4 , wherein the composition is configured to achieve a skin penetration lag time of roflumilast of less than 1 hour. 
     
     
         9 . The method of  claim 8 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.1 ng/mL, 1 hour after administration of said composition. 
     
     
         10 . The method of  claim 9 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.3 ng/mL, 1 hour after administration of said composition. 
     
     
         11 . The method of  claim 1 , wherein the emulsifier blend is present in an amount sufficient to reduce roflumilast skin penetration lag time relative to the same composition without said emulsifier blend. 
     
     
         12 . The method of  claim 6 , wherein the emulsifier blend is in an amount of 10% w/w. 
     
     
         13 . The method of  claim 2 , wherein said composition further comprises diethylene glycol monoethyl ether and water. 
     
     
         14 . The method of  claim 13 , wherein diethylene glycol monoethyl ether is in an amount of 25% w/w. 
     
     
         15 . The method of  claim 13 , wherein said composition has a pH between 4.0 and 6.5. 
     
     
         16 . The method of  claim 15 , wherein said composition has a pH between 5.0 and 6.0. 
     
     
         17 . The method of  claim 15 , wherein the composition is configured to achieve a skin penetration lag time of roflumilast of less than 1 hour. 
     
     
         18 . The method of  claim 17 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.1 ng/mL, 1 hour after administration of said composition. 
     
     
         19 . The method of  claim 18 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.3 ng/mL, 1 hour after administration of said composition. 
     
     
         20 . The method of  claim 16 , wherein the composition is configured to achieve a skin penetration lag time of roflumilast of less than 1 hour. 
     
     
         21 . The method of  claim 20 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.1 ng/mL, 1 hour after administration of said composition. 
     
     
         22 . The method of  claim 21 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.3 ng/mL, 1 hour after administration of said composition. 
     
     
         23 . A method of manufacturing a topical pharmaceutical composition comprising:
 preparing a topical pharmaceutical composition comprising roflumilast, diethylene glycol monoethyl ether and water,   wherein said composition has a pH between 5.0 and 6.0,   wherein the roflumilast is present in an amount sufficient to treat inflammatory skin conditions, and   wherein the composition is a cream.   
     
     
         24 . The method of  claim 23 , wherein the composition is configured to achieve a skin penetration lag time of roflumilast of less than 1 hour. 
     
     
         25 . The method of  claim 24 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.1 ng/mL, 1 hour after administration of said composition. 
     
     
         26 . The method of  claim 25 , wherein the roflumilast and emulsifier blend are in amounts sufficient to achieve a concentration of roflumilast in plasma of at least 0.3 ng/mL, 1 hour after administration of said composition.