# US 12,005,067 B2 · JAK inhibitor with a vitamin D analog for treatment of skin diseases

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- Number: US 12,005,067 B2
- Document ID: US12005067B2
- Status: Granted
- Kind: B2
- Application number: 17/541,601
- Filed: 2021-12-03
- Published: 2022-06-30
- Granted: 2024-06-11
- Earliest claimed: 2020-12-04
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Paul Smith; Zheng Zhang; Melissa Parker; James Fidge
- Web page: https://patentgrep.com/patent/US12005067B2

## CPC

- A61K 31/593: 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
- 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 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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 disclosure relates to topical treatment of skin diseases, such as psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and a disorder of keratinization, using (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A pharmaceutical formulation for topical treatment of a skin disease, comprising (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor, or a pharmaceutically acceptable salt thereof, is a JAK1/2 inhibitor, which is ruxolitinib, or a pharmaceutically acceptable salt thereof; and the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is a compound of Formula (II):
wherein:
R1 is H or OH;
R2 and R3 are each H; or
R2 is O—R2A; and R3 is H; or
R2 and R3 are taken together to form a ═CH2 group;
R2A is —C1-4 alkylene-OH;
R4 and R5 are each H; or
R4 and R5 are taken together to form a ═CH2 group;
R6 and R7 are each H; or
R6 and R7 are taken together to form a ═CH2 group;
L is —CH2—CH2—CH(R12)—, —CH2—CH2—CH2—CH(R12)—, —CH═CH—CH(R12)—, —CH═CH—CH═CH—, —CH2—C≡C—, —O—CH2—CH2—, or —O—CH2—CH2—CH2—, wherein R12 is H or OH;
R9 is C1-3 alkyl or C1-4 haloalkyl;
R10 is C1-3 alkyl or C1-4 haloalkyl;
R11 is H or OH;
or, alternatively, R9 and R10 together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; and
R11 is H.

### Claim 2 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.

### Claim 3 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.

### Claim 5 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.

### Claim 6 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises from about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis.

### Claim 7 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.

### Claim 9 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.

### Claim 10 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w or from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.

### Claim 11 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.

### Claim 12 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation is a cream or a lotion.

### Claim 13 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation is an oil-in-water emulsion.

### Claim 14 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation comprises water, an oil component, and an emulsifier or stabilizer component.

### Claim 15 (depends on 14)

The pharmaceutical formulation of claim 14, wherein the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation.

### Claim 16 (depends on 14)

The pharmaceutical formulation of claim 14, wherein the oil component comprises from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 50%, or from about 5% to about 40% by weight of the pharmaceutical formulation.

### Claim 17 (depends on 14)

The pharmaceutical formulation of claim 14, wherein the emulsifier or stabilizer component comprises from about 1% to about 30% or from about 5% to about 25% by weight of the pharmaceutical formulation.

### Claim 18 (depends on 14)

The pharmaceutical formulation of claim 14, further comprising a solvent component for dissolving ruxolitinib, or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The pharmaceutical formulation of claim 18, wherein the solvent component comprises from about 5% to about 20%, from about 2% to about 30%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, or from about 10% to about 20% by weight of the pharmaceutical formulation.

### Claim 20 (depends on 1)

The pharmaceutical formulation of claim 1, wherein the formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.

### Claim 21 (depends on 20)

The pharmaceutical formulation of claim 20, wherein pH of the formulation is adjusted with trolamine.