Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents

Abstract

The low aqueous solubility of roflumilast in parenteral preparations and topical emulsions, suspensions, gels or solutions can be improved by including a blend of water-miscible solvents in the pharmaceutical composition. The blend of water-miscible solvents can include diethylene glycol monoethyl ether (Tradename Transcutol®; abbreviated DEGEE) and water. The ratio of diethylene glycol monoethyl ether to water is from 1:10 to 20:1. The resulting composition has improved bioavailability and efficacy and can be used to inhibit phosphodiesterase 4 in a patient in need of such treatment.

1 . A topical, pharmaceutical, oil in water emulsion comprising roflumilast and a blend of water-miscible, pharmaceutically acceptable solvents, wherein said blend comprises diethylene glycol monoethyl ether and water in a weight ratio which increases the solubility of said roflumilast relative to the solubility in water, wherein said diethylene glycol monoethyl ether is in an amount sufficient to keep said roflumilast dissolved after one month of storage, wherein said roflumilast is in an amount of 0.05-0.5% by weight of the total composition, wherein said composition does not contain undissolved roflumilast before or after storage, and wherein said weight ratio of diethylene glycol monoethyl ether to water is 1:4 to 9:1. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein said diethylene glycol monoethyl ether is in an amount of 15-20% w/w. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein said roflumilast is in an amount of 0.05-0.3% w/w. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical 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. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition further comprises at least one additional component selected from the group consisting of a solvent, moisturizer, surfactant or emulsifier, polymer or thickener, antifoaming agent, preservative, antioxidant, sequestering agent, stabilizer, buffer, pH adjusting solution, skin penetration enhancer, film former, dye, pigment, and fragrance. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition further comprises an additional active agent selected from the group consisting of 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, Adalimumab, Ustekinumab, Infliximab, bronchodialators, and antibiotics. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition comprises carriers suitable for topical, parenteral or pulmonary administration. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein said pharmaceutical composition comprises carriers suitable for topical administration. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition further comprises hexylene glycol in an amount of 0.1-20% w/w. 
     
     
         10 . A method for overcoming low aqueous solubility of a roflumilast formulation, comprising combining diethylene glycol monoethyl ether and water in a composition comprising roflumilast, wherein said diethylene glycol monoethyl ether is in an amount of 10-30% (w/w), said water is in an amount of 20-90% (w/w) and said roflumilast is at a saturation concentration. 
     
     
         11 . The method according to  claim 10 , wherein the ratio of diethylene glycol monoethyl ether to water is from 1:10 to 20:1. 
     
     
         12 . The method according to  claim 11 , wherein said ratio of diethylene glycol monoethyl ether to water is 1:4 to 9:1. 
     
     
         13 . The method according to  claim 10 , wherein said diethylene glycol monoethyl ether is in an amount of 15-20% (w/w). 
     
     
         14 . The method according to  claim 10 , wherein said roflumilast composition comprises 0.005-2% roflumilast. 
     
     
         15 . A method of inhibiting phosphodiesterase 4 in a patient, comprising administering a composition comprising roflumilast and diethylene glycol monoethyl ether to said patient. 
     
     
         16 . The method according to  claim 15 , wherein said patient is suffering from an inflammatory condition. 
     
     
         17 . The method according to  claim 16 , wherein said patient is suffering from atopic dermatitis.