# US 12,005,051 B2 · Topical roflumilast formulation having improved delivery and plasma half life

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- Number: US 12,005,051 B2
- Document ID: US12005051B2
- Status: Granted
- Kind: B2
- Application number: 17/402,051
- Filed: 2021-08-13
- Published: 2021-12-16
- Granted: 2024-06-11
- Earliest claimed: 2017-06-07
- Assignees: Arcutis Biotherapeutics, Inc.
- Applicants: ARCUTIS BIOTHERAPEUTICS, inc.
- Inventors: David W. Osborne
- Web page: https://patentgrep.com/patent/US12005051B2

## 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 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 9/12: Aerosols; Foams {(A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015)}
- A61K 9/122: {Foams; Dry foams (edible foams A61K9/0056)}
- A61K 9/7015: {Drug-containing film-forming compositions, e.g. spray-on}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61P 17/06: Antipsoriatics
- 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

The present invention is directed to methods for improving the therapeutic outcome of treatment with roflumilast. The therapeutic outcome is improved by consistent delivery and/or a longer plasma half-life of a topically administered roflumilast composition. The roflumilast composition preferably includes dicetyl phosphate, ceteth-10 phosphate, diethylene glycol monoethyl ether, and/or hexylene glycol.

## Claims

### Claim 1

A method for improving the therapeutic outcome of treatment with roflumilast, comprising topically administering once daily a composition comprising diethylene glycol monoethyl ether, cetearyl alcohol, dicetyl phosphate, ceteth-10 phosphate and roflumilast to a patient in need of such treatment, wherein said patient misses at least one dose but no more than two consecutive doses, and the plasma concentration of roflumilast decreases by less than 50%.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said patient is suffering from atopic dermatitis.

### Claim 3 (depends on 1)

The method according to claim 1, wherein after three days of missed dosing, the plasma concentration of roflumilast decreases by less than 50%.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the composition comprises:
roflumilast
0.3% w/w
white petrolatum
10.0% w/w
isopropyl palmitate
5.0% w/w
cetearyl alcohol, dicetyl phosphate
10.0% w/w
and ceteth-10 phosphate
diethylene glycol monoethyl ether
25.0% w/w
methylparaben
0.2% w/w
propylparaben
0.05% w/w, and
purified water q.s.
ad 100,
wherein the pH is
adjusted to 5.5.

### Claim 5 (depends on 1)

The method according to claim 1, wherein said patient misses two consecutive doses and the plasma concentration of roflumilast decreases by less than 50%.

### Claim 6 (depends on 1)

The method according to claim 1, wherein said roflumilast has a half-life of about 81-89 hours.

### Claim 7 (depends on 1)

The method according to claim 1, wherein said patient is a human.

### Claim 8 (depends on 1)

The method according to claim 1, further comprising an additional active agent selected from the group consisting of Anthralin (dithranol), 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, and antibiotics.

### Claim 9 (depends on 8)

The method according to claim 8, wherein said Corticosteroids are selected from the group consisting of Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, and Prednisone; and/or said vitamin D analogue is selected from the group consisting of calcipotriene and calcitriol.

### Claim 10 (depends on 1)

The method according to claim 1, wherein said composition is selected from the group consisting of an oil in water emulsion and a foam.

### Claim 11 (depends on 1)

The method according to claim 1, wherein said roflumilast is in an amount of 0.05-1% w/w.

### Claim 12 (depends on 1)

The method according to claim 1, wherein said roflumilast is in an amount of 0.1-0.5% w/w.

### Claim 13 (depends on 1)

The method according to claim 1, wherein said patient is suffering from psoriasis.

### Claim 14 (depends on 1)

The method according to claim 1, wherein said diethylene glycol monoethyl ether is in an amount of 10-30% w/w.

### Claim 15

A method for improving the therapeutic outcome of treatment with roflumilast, comprising topically administering once daily a composition comprising diethylene glycol monoethyl ether, a phosphate ester surfactant blend comprising dicetyl phosphate, ceteth-10 phosphate and cetearyl alcohol, and roflumilast to a patient in need of such treatment once daily, wherein when said patient misses at least one dose but no more than two consecutive doses, the plasma concentration of roflumilast decreases by less than 50%.

### Claim 16 (depends on 15)

The method according to claim 15, wherein said phosphate ester surfactant blend is in an amount of 1-25% w/w.

### Claim 17 (depends on 16)

The method according to claim 16, wherein said phosphate ester surfactant blend is in an amount of 2.5-20% w/w.

### Claim 18 (depends on 17)

The method according to claim 17, wherein said phosphate ester surfactant blend is in an amount of 5-15% w/w.

### Claim 19 (depends on 15)

The method according to claim 15, wherein said diethylene glycol monoethyl ether is in an amount of 10-30% w/w.

### Claim 20 (depends on 4)

The method according to claim 4, wherein the purified water is in an amount of 49.45%.