Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

Abstract

A method for altering the PK profile of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike in Cmax. The spike in Cmax is reduced by topically administering the PDE-4 inhibitor in combination with one or more phosphate ester surfactants. Reducing the spike in Cmax will reduce gastrointestinal side effects and result in better patient compliance.

1 . A method for reducing gastrointestinal side effects in a patient suffering from gastrointestinal side effects or likely to suffer from gastrointestinal side effects due to administration of a PDE-4 inhibitor drug, comprising administering to said patient, a composition comprising a PDE-4 inhibitor drug at a concentration sufficient to provide a systemic effect of the drug in combination with a phosphate ester surfactant comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate. 
     
     
         2 . The method of  claim 1  wherein the composition is administered topically. 
     
     
         3 . The method of  claim 1  wherein the PDE-4 inhibitor drug is selected from the group consisting of apremilast, cilomilast, crisaborole, ibudilast, piclamilast, roflumilast, and rolipram. 
     
     
         4 . The method of  claim 3  wherein the PDE-4 inhibitor drug is roflumilast. 
     
     
         5 . The method of  claim 1  wherein the composition is in the form of a semisolid. 
     
     
         6 . The method of  claim 1  wherein the composition further comprises diethylene glycol monoethyl ether. 
     
     
         7 . The method according to  claim 4 , wherein said roflumilast is in an amount of 0.005-2% w/w. 
     
     
         8 . The method according to  claim 7 , wherein said roflumilast is in an amount of 0.05-1% w/w. 
     
     
         9 . The method according to  claim 8 , wherein said roflumilast is in an amount of 0.1-0.5% w/w. 
     
     
         10 . The method according to  claim 3 , wherein said roflumilast is in an amount of 0.3% w/w. 
     
     
         11 . The method according to  claim 1 , wherein said composition is selected from the group consisting of an oil in water emulsion, a thickened aqueous gel, a thickened hydroalcoholic gel, a hydrophilic gel, and a hydrophilic or hydrophobic ointment. 
     
     
         12 . The method according to  claim 1 , wherein said roflumilast composition further comprises at least one additional component selected from the group consisting of a solvent, moisturizer, surfactant or emulsifier, polymer or thickener, anti-foaming agent, preservative, antioxidant, sequestering agent, stabilizer, buffer, pH adjusting solution, skin penetration enhancer, film former, dye, pigment, and fragrance. 
     
     
         13 . The method according to  claim 1 , wherein said roflumilast composition further comprises an additional active agent selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), Apremilast, JAK inhibitors, leukotriene inhibitors, mast cell stabilizers, Anthralin, Azathioprine, Tacrolimus, Coal tar, Methotrexate, Methoxsalen, Salicylic acid, Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids, Corticotropin, Vitamin D analogues, Acitretin, Tazarotene, Cyclosporine, Resorcinol, Colchicine, bronchodialators, and antibiotics. 
     
     
         14 . The method according to  claim 1 , wherein said patient is suffering from asthma or chronic obstructive pulmonary disease (COPD). 
     
     
         15 . The method according to  claim 1 , wherein said patient is suffering from an inflammatory condition. 
     
     
         16 . The method according to  claim 13 , wherein said patient is suffering from atopic dermatitis. 
     
     
         17 . The method according to  claim 1 , wherein the composition is administered in a semi-solid or a liquid form. 
     
     
         18 . The method according to  claim 17 , wherein the composition is administered in a form selected from the group consisting of an emulsion, suspension, ointment, oil, cream, gel, paste, transdermal patch, spray, and foam. 
     
     
         19 . The method according to  claim 18 , wherein the composition is administered in the form of a foam. 
     
     
         20 . A method for reducing a spike in Cmax resulting from administration of a PDE-4 inhibitor drug, comprising administering to said patient, a composition comprising a PDE-4 inhibitor drug at a concentration sufficient to provide a systemic effect of the drug in combination with a phosphate ester surfactant, wherein said phosphate ester surfactant comprises cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate. 
     
     
         21 . A composition comprising a PDE-4 inhibitor drug in combination with a phosphate ester surfactant comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate. 
     
     
         22 . The composition according to  claim 21 , wherein the composition is in a form selected from the group consisting of an emulsion, suspension, ointment, oil, cream, gel, paste, transdermal patch, spray, and foam. 
     
     
         23 . The method according to  claim 22 , wherein the composition is in the form of a cream or a foam.