# US 11,992,480 B2 · Method for reducing side effects from administration of phosphodiesterase-4 inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,992,480 B2 - Document ID: US11992480B2 - Status: Granted - Kind: B2 - Application number: 17/327,236 - Filed: 2021-05-21 - Published: 2021-09-09 - Granted: 2024-05-28 - Earliest claimed: 2018-11-16 - Assignees: Arcutis Biotherapeutics, Inc. - Applicants: Arcutis Biotherapeutics, Inc. - Inventors: David W. Osborne; Howard Welgus - Web page: https://patentgrep.com/patent/US11992480B2 ## CPC - A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof - A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)} - A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} - A61K 9/122: {Foams; Dry foams (edible foams A61K9/0056)} - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids - A61P 11/06: Antiasthmatics - A61P 11/08: Bronchodilators - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 A method for reducing gastrointestinal side effects of roflumilast relative to an oral roflumilast formulation marketed under the trademark DALIRESP®, comprising topically administering to said patient, a composition comprising (i) roflumilast in an amount of 0.05%-1% w/w and (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate in an amount of 1.0-25% w/w. ### Claim 2 (depends on 1) The method of claim 1, wherein the patient is suffering from an inflammatory dermatoses. ### Claim 3 (depends on 2) The method of claim 2, wherein said roflumilast is in an amount of 0.05% w/w. ### Claim 4 (depends on 2) The method of claim 2, wherein said roflumilast is present in an amount of 0.15% w/w. ### Claim 5 (depends on 2) The method according to claim 2, wherein said roflumilast is in an amount of 0.3% w/w. ### Claim 6 (depends on 2) The method of claim 2, wherein said composition is a foam, wherein said roflumilast is present in an amount 0.3% w/w, wherein said phosphate surfactant blend is present in an amount of 1.0%-10% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water. ### Claim 7 (depends on 6) The method of claim 6, wherein said patient is suffering from atopic dermatitis. ### Claim 8 (depends on 6) The method of claim 6, wherein said patient is suffering from psoriasis. ### Claim 9 (depends on 6) The method of claim 6, wherein said patient is suffering from seborrheic dermatitis. ### Claim 10 (depends on 2) The method of claim 2, wherein said composition is a cream, wherein said roflumilast is present in an amount 0.3% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from psoriasis. ### Claim 11 (depends on 10) The method of claim 10, wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w. ### Claim 12 (depends on 11) The method of claim 11, wherein said phosphate surfactant blend is present in an amount of 10% w/w. ### Claim 13 (depends on 2) The method of claim 2, wherein said composition is a cream, wherein said roflumilast is present in an amount 0.15% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from atopic dermatitis. ### Claim 14 (depends on 13) The method of claim 13, wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w. ### Claim 15 (depends on 14) The method of claim 14, wherein said phosphate surfactant blend is present in an amount of 10% w/w. ### Claim 16 (depends on 2) The method of claim 2, wherein said composition is a cream, wherein said roflumilast is present in an amount 0.05% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from atopic dermatitis. ### Claim 17 (depends on 16) The method of claim 16, wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w. ### Claim 18 (depends on 17) The method of claim 17, wherein said phosphate surfactant blend is present in an amount of 10% w/w. ### Claim 19 (depends on 1) The method of claim 1, wherein said composition is a cream or a foam. ### Claim 20 (depends on 19) The method of claim 19, wherein said composition further comprises hexylene glycol in an amount of 0.1-20% w/w. ### Claim 21 (depends on 1) The method of claim 1, wherein said composition further comprises at least one additional component selected from the group consisting of a solvent, moisturizer, preservative, pH adjusting solution, and skin penetration enhancer. ### Claim 22 (depends on 1) The method of claim 1, wherein said phosphate ester surfactant blend is in an amount of 10% w/w. ### Claim 23 (depends on 1) The method of claim 1, wherein said composition further comprises diethylene glycol monoethyl ether and water. ### Claim 24 (depends on 23) The method of claim 23, wherein said composition comprises diethylene glycol monoethyl ether in an amount of 25% w/w. ### Claim 25 (depends on 1) The method of claim 1, wherein said patient is suffering from psoriasis, atopic dermatitis or seborrheic dermatitis. ### Claim 26 (depends on 25) The method of claim 25, wherein said patient is suffering from atopic dermatitis. ### Claim 27 (depends on 25) The method of claim 25, wherein said patient is suffering from psoriasis. ### Claim 28 (depends on 1) The method of claim 1, wherein said composition further comprises diethylene glycol monoethyl ether in an amount of 10-40% w/w. ### Claim 29 A method for reducing gastrointestinal side effects of roflumilast relative to an oral roflumilast formulation marketed under the trademark DALIRESP®, comprising topically administering to said patient a composition comprising (i) roflumilast in an amount of 0.05%-1% w/w and (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate in an amount of 1.0-25% w/w, wherein the peak to trough ratio of roflumilast blood plasma concentration is less than 2 after multiple daily administrations, and wherein the patient is suffering from an inflammatory dermatoses. ### Claim 30 (depends on 29) The method of claim 29, wherein the peak to trough ratio is less than 2 at steady state. ### Claim 31 (depends on 29) The method of claim 29, wherein the peak to trough ratio is approximately 1 at steady state. ### Claim 32 (depends on 29) The method of claim 29, wherein said composition is a cream, and said phosphate ester surfactant blend is in an amount of 10% w/w. ### Claim 33 (depends on 29) The method of claim 29, wherein said composition is a foam, and said phosphate ester surfactant blend is in an amount of 2% w/w. ### Claim 34 (depends on 29) The method of claim 29, wherein said composition further comprises diethylene glycol monoethyl ether and water. ### Claim 35 (depends on 34) The method of claim 34, wherein said diethylene glycol monoethyl ether is in an amount of 10-40% w/w. ### Claim 36 (depends on 35) The method of claim 35, wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w. ### Claim 37 (depends on 29) The method of claim 29, wherein said patient is suffering from psoriasis, atopic dermatitis or seborrheic dermatitis. ### Claim 38 A method for reducing gastrointestinal side effects of a topical roflumilast composition, comprising adding a phosphate ester surfactant blend in an amount of 1.0-25% w/w to a composition comprising roflumilast in an amount of 0.05%-1% w/w and a pharmaceutically acceptable solvent, wherein the phosphate ester surfactant blend comprises cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate. ### Claim 39 (depends on 38) The method of claim 38, wherein said composition is a cream, and said phosphate ester surfactant blend is in an amount of 10% w/w. ### Claim 40 (depends on 38) The method of claim 38, wherein said pharmaceutically acceptable solvent comprises diethylene glycol monoethyl ether. ### Claim 41 (depends on 40) The method of claim 40, wherein said diethylene glycol monoethyl ether is in an amount of 10-40% w/w. ### Claim 42 (depends on 41) The method of claim 41, wherein said diethylene glycol monoethyl ether is in an amount of 15-30% w/w. ### Claim 43 (depends on 42) The method of claim 42, wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w.