# US 2021/0275509 A1 · Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

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- Number: US 2021/0275509 A1
- Document ID: US20210275509A1
- Status: Published application
- Kind: A1
- Application number: 17/327,236
- Filed: 2021-05-21
- Published: 2021-09-09
- Earliest claimed: 2018-11-16
- Assignees: Arcutis Biotherapeutics, Inc.
- Applicants: Arcutis Biotherapeutics, Inc.
- Inventors: Howard WELGUS; Archie W. THURSTON, JR.; David W. Osborne
- Web page: https://patentgrep.com/patent/US20210275509A1

## 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 in a patient suffering from gastrointestinal side effects or likely to suffer from gastrointestinal side effects due to administration of a PDE-4 (phosphodiesterase-4) inhibitor drug, comprising
a) determining whether a patient is suffering from diarrhea, nausea, and/or abdominal pain or is likely to suffer from diarrhea, nausea, and/or abdominal pain due to administration of a PDE-4 inhibitor, and
b) 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the composition is administered topically.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

The method of claim 3, wherein the PDE-4 inhibitor drug is roflumilast.

### Claim 5 (depends on 1)

The method of claim 1, wherein the composition is in the form of a semisolid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the composition further comprises diethylene glycol monoethyl ether.

### Claim 7 (depends on 4)

The method according to claim 4, wherein said roflumilast is in an amount of 0.005-2% w/w.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said roflumilast is in an amount of 0.05-1% w/w.

### Claim 9 (depends on 8)

The method according to claim 8, wherein said roflumilast is in an amount of 0.1-0.5% w/w.

### Claim 10 (depends on 3)

The method according to claim 3, wherein said roflumilast is in an amount of 0.3% w/w.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

The method according to claim 1, wherein said 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.

### Claim 13 (depends on 1)

The method according to claim 1, wherein said 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.

### Claim 14 (depends on 1)

The method according to claim 1, wherein said patient is suffering from asthma or chronic obstructive pulmonary disease (COPD).

### Claim 15 (depends on 1)

The method according to claim 1, wherein said patient is suffering from an inflammatory condition.

### Claim 16 (depends on 13)

The method according to claim 13, wherein said patient is suffering from atopic dermatitis.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the composition is administered in a semi-solid or a liquid form.

### Claim 18 (depends on 17)

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.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the composition is administered in the form of a foam.

### Claim 20

A method for reducing a spike in Cmax resulting from administration of a PDE-4 (phosphodiesterase-4) inhibitor drug, comprising topically 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, wherein said PDE-4 inhibitor is selected from the group consisting of apremilast, cilomilast, crisaborole, ibudilast, piclamilast and rolipram.

### Claim 21

A composition comprising a PDE-4 (phosphodiesterase-4) inhibitor drug in combination with a phosphate ester surfactant comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate, wherein said PDE-4 inhibitor is selected from the group consisting of apremilast, cilomilast, crisaborole, ibudilast, piclamilast and rolipram.

### Claim 22 (depends on 21)

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.

### Claim 23 (depends on 22)

The composition according to claim 22, wherein the composition is in the form of a cream or a foam.