Claims for Patent: 12,042,487

Summary for Patent: 12,042,487

Title:	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.
Inventor(s):	David W. Osborne
Assignee:	Arcutis Biotherapeutics Inc
Application Number:	US18/353,870
Patent Claims:	1. A pharmaceutical composition for topical administration comprising: (i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% w/w; (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate, wherein the phosphate ester surfactant blend is in an amount of 1.0-25% w/w; and (iii) water; wherein the Cmax of roflumilast from the topical composition is reduced relative to an oral roflumilast formulation marketed under the trademark DALIRESP®. 2. The composition of claim 1, wherein said composition further comprises diethylene glycol monoethyl ether. 3. The composition of claim 1, wherein said roflumilast is in an amount of 0.3% w/w. 4. The composition of claim 1, wherein said roflumilast is in an amount of 0.15% w/w. 5. The composition of claim 1, wherein said roflumilast is in an amount of 0.05% w/w. 6. The composition of claim 1, wherein said phosphate ester surfactant blend is in an amount sufficient to decrease a slope of the plasma concentration curve of the roflumilast between administration of said composition and Cmax. 7. The composition of claim 1, wherein the plasma concentration curve of the roflumilast has no spike at Cmax. 8. The composition of claim 1, wherein said roflumilast is in an amount of 0.3% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 9. The composition of claim 1, wherein said roflumilast is in an amount of 0.15% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 10. The composition of claim 1, wherein said roflumilast is in an amount of 0.05% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 11. A pharmaceutical composition for topical administration comprising: (i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% w/w; (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate, wherein the phosphate ester surfactant blend is in an amount of 1.0-25% w/w; wherein the peak to trough ratio of roflumilast blood plasma concentration is less than 2 at steady state. 12. The composition of claim 11, wherein the difference in a trough and an adjacent peak of the plasma concentration curve of the roflumilast at steady state is between about 4% and about 7%. 13. The composition of claim 11, wherein the plasma concentration of the roflumilast plateaus after Cmax for 24 hours following administration. 14. The composition of claim 11, wherein the peak to trough ratio is approximately 1 at steady state. 15. The composition of claim 11, wherein said phosphate ester surfactant blend is in an amount of 5% to 15% w/w. 16. The composition of claim 15, wherein said phosphate ester surfactant blend is in an amount of about 10% w/w. 17. The composition of claim 11, wherein said composition comprises diethylene glycol monoethyl ether. 18. The composition of claim 17, wherein said diethylene glycol monoethyl ether is in an amount of 10% to 40% w/w. 19. The composition of claim 11, wherein said roflumilast is in an amount of 0.3% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 20. The composition of claim 11, wherein said roflumilast is in an amount of 0.15% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 21. The composition of claim 11, wherein said roflumilast is in an amount of 0.05% w/w, wherein said phosphate ester surfactant blend is in an amount of about 5% to about 15% w/w, and wherein said composition comprises diethylene glycol monoethyl ether in an amount of 10% to 40% w/w. 22. A pharmaceutical composition for topical administration comprising: (i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% w/w; (ii) at least one phosphate ester surfactant, wherein the total amount of phosphate ester surfactant in the composition is 1.0-25% w/w; (iii) at least one pharmaceutically acceptable solvent; and (iv) water, wherein the Cmax of the roflumilast from the topical composition is reduced relative to an oral roflumilast formulation marketed under the trademark DALIRESP®; and wherein said phosphate ester surfactant comprises: potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, ceteth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10-phosphate, DEA-oleth-3 phosphate, DEA C8-18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate, tristearyl phosphate, or a combination thereof. 23. The composition of claim 22, wherein said pharmaceutically acceptable solvent comprises diethylene glycol monoethyl ether. 24. The composition of claim 23, wherein said diethylene glycol monoethyl ether is in an amount of 10%-40% w/w. 25. The composition of claim 22, wherein the plasma concentration curve of the roflumilast has no spike at Cmax. 26. The composition of claim 22, wherein said roflumilast is in an amount of 0.05% w/w, 0.15% w/w, or 0.3% w/w, and wherein said composition is a foam or a cream. 27. A pharmaceutical composition for topical administration comprising: (i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% w/w; (ii) at least one phosphate ester surfactant, wherein the total amount of phosphate ester surfactant in the composition is 1.0-25% w/w; and (i at least one pharmaceutically acceptable solvent, wherein the peak to trough ratio of roflumilast blood plasma concentration is less than 2 at steady state; and wherein said phosphate ester surfactant comprises: potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, ceteth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10-phosphate, DEA-oleth-3 phosphate, DEA C8-18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate, tristearyl phosphate, or a combination thereof. 28. The composition of claim 27, wherein said pharmaceutically acceptable solvent comprises diethylene glycol monoethyl ether in an amount of 10%-40% w/w. 29. The composition of claim 28, wherein said roflumilast is in an amount of 0.05% w/w, 0.15% w/w, or 0.3% w/w, and wherein said composition is a foam or a cream. 30. The composition of claim 27, wherein the plasma concentration of the roflumilast plateaus after Cmax for 24 hours following administration.