JAK inhibitors containing vitamin D analogs for the treatment of skin diseases

Abstract

The present disclosure relates to the topical treatment of skin diseases such as psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and keratinization disorders 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.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 121,531, filed on 4 December 2020, and U.S. Provisional Application No. 63 / 199,876, filed on 29 January 2021, each of which is incorporated herein by reference in whole.

[0002] This disclosure relates to the topical treatment of skin diseases 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. [Background technology]

[0003] Inflammation mediated by Janus kinase (JAK) signaling transducers is a key characteristic of autoimmune skin diseases. JAK inhibitors have been developed as treatments for inflammatory skin diseases, including atopic dermatitis, alopecia areata, psoriasis, and vitiligo. However, like other therapeutic agents, JAK inhibitors are not equally effective in all subjects with inflammatory skin diseases. There is a need to develop more effective formulations containing JAK inhibitors to treat a broader range of subjects with various inflammatory skin diseases.

[0004] Given these limitations, there is a medical need for new treatment options. This disclosure addresses this need and other needs. [Overview of the project]

[0005] This disclosure provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient.

[0006] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) ruxolitinib or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0007] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) ruxolitinib or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient, and (b) calcipotriol or a pharmaceutically acceptable salt thereof to the patient.

[0008] This disclosure also provides JAK inhibitors or pharmaceutically acceptable salts thereof for use in combination with vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof for topical treatment of skin diseases described herein.

[0009] This disclosure also provides ruxolitinib or a pharmaceutically acceptable salt thereof for use in combination with vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof for topical treatment of the skin diseases described herein.

[0010] This disclosure also provides ruxolitinib or a pharmaceutically acceptable salt thereof for use in combination with calcipotriol or a pharmaceutically acceptable salt thereof for topical treatment of the skin diseases described herein.

[0011] This disclosure also provides the use of a JAK inhibitor or a pharmaceutically acceptable salt thereof for the preparation of agents for the topical treatment of skin diseases described herein in combination with vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0012] This disclosure also provides the use of ruxolitinib or a pharmaceutically acceptable salt thereof for the preparation of agents for the topical treatment of skin diseases described herein, in combination with vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0013] This disclosure also provides the use of ruxolitinib or a pharmaceutically acceptable salt thereof for the preparation of agents for the topical treatment of skin diseases described herein, in combination with calcipotriol or a pharmaceutically acceptable salt thereof.

[0014] In each of the embodiments described above, the patient is a human patient.

[0015] This disclosure further provides (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof for use in the topical treatment of skin disorders described herein, and (b) a topical formulation comprising vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0016] This disclosure further provides topical formulations for use in the topical treatment of skin disorders described herein, comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0017] This disclosure further provides ruxolitinib topical formulations for use in the topical treatment of skin disorders described herein, comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or a pharmaceutically acceptable salt thereof.

[0018] This disclosure also provides the use of topical formulations for use in the topical treatment of the skin disorders described herein, comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0019] This disclosure also provides the use of topical formulations comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for the manufacture of agents for use in the topical treatment of the skin disorders described herein.

[0020] This disclosure also provides the use of topical formulations comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or a pharmaceutically acceptable salt thereof, for the manufacture of agents for use in the topical treatment of the skin disorders described herein.

[0021] This disclosure further provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0022] The disclosure also further provides pharmaceutical formulations for the topical treatment of skin diseases, comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0023] This disclosure further provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) ruxolitinibrinate or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0024] Details of one or more embodiments of this disclosure are described below. Other features, purposes, and advantages of this disclosure will be apparent from the description and drawings, as well as the claims. [Brief explanation of the drawing]

[0025] [Figure 1]This study shows the multiplicative changes and p-values ​​of basal-treated IL-22 levels 24 hours after stimulation on normal (healthy) unirritated and stimulated human skin using various concentrations of ruxolitinib, calcipotriol, and combinations thereof. [Figure 2] This study shows the multiplicative changes and p-values ​​of basal-treated skin CXCL10 levels 24 hours after stimulation on normal (healthy) unirritated and stimulated human skin using various concentrations of ruxolitinib, calcipotriol, and combinations thereof. [Figure 3] This study shows the multiplicative changes and p-values ​​of basal MMP12 levels in treated skin 24 hours after stimulation on normal (healthy) unirritated and stimulated human skin using various concentrations of ruxolitinib, calcipotriol, and combinations thereof. [Figure 4] A schematic diagram of the Transwell® insert is shown. [Figure 5] The images show cream formulations #1 to #6. [Figure 6] The graphs show the absolute multiplicative changes in specific gene expression after treatment with calcipotriol and ruxolitinib combinations, compared to an untreated control after Th1 or Th17 stimulation (white indicates an absolute multiplicative change of <2, gray indicates an absolute multiplicative change of >2, and black indicates an absolute multiplicative change of >4). [Figure 7] The images show the multiplicative changes in IL-22 levels and CXCL10 levels (mean + SEM) 24 hours after stimulation on normal (healthy) unirritated and stimulated human skin, in skin treated basally with various concentrations of ruxolitinib, maxacalcitol, and combinations thereof (JAKi is ruxolitinib, Vit D is maxacalcitol, and Combo is a combination of ruxolitinib and maxacalcitol). [Figure 8]The images show the magnification changes (mean + SEM) of S100a12, Defb4, and Serpinb4, respectively, 24 hours after stimulation of skin topically treated with various concentrations of ruxolitinib, calcipotriol, and combinations thereof on normal (healthy) unirritated and stimulated human skin (JAKi is ruxolitinib, Vit D is calcipotriol, and Combo is the combination of ruxolitinib and calcipotriol). [Figure 9] The images show the magnification changes (mean + SEM) of MMP12, IL-22, and CXCL10 24 hours after stimulation on normal (healthy) unirritated and stimulated human skin, in skin topically treated with various concentrations of ruxolitinib, calcipotriol, and combinations thereof (JAKi is ruxolitinib, Vit D is calcipotriol, and Combo is the combination of ruxolitinib and calcipotriol). [Figure 10] This shows changes in ear thickness in an IL-23-induced psoriasis-like in vivo mouse model treated with a vehicle or a combination cream of ruxolitinib and calcipotriol (*** indicates p<0.001) (JAKi is ruxolitinib, Vit D is calcipotriol, and Combo is the combination of ruxolitinib and calcipotriol). [Modes for carrying out the invention]

[0026] This disclosure provides a method for treating a skin condition in a patient who requires treatment for a skin condition, comprising topically administering to the affected area of ​​the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.

[0027] This disclosure provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering to the affected area of ​​the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0028] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering to the affected area of ​​the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3 or a pharmaceutically acceptable salt thereof.

[0029] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering to the affected area of ​​the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0030] The disclosure also provides a method for treating a skin condition in a patient who requires treatment for the condition, comprising topically administering to the affected area of ​​the patient (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0031] This disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering to the affected area of ​​the patient (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3 or a pharmaceutically acceptable salt thereof.

[0032] The disclosure also provides a method for treating a skin condition in a patient who requires treatment for a skin condition, comprising topically administering to the affected area of ​​the patient (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0033] The disclosure also provides a method for treating a skin condition in a patient who requires treatment for the skin condition, comprising topically administering (a) ruxolitinibulinate and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient.

[0034] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) ruxolitinibulinate and (b) vitamin D3 or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient.

[0035] The disclosure also provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) ruxolitinibulinate and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient.

[0036] This disclosure also provides a method for treating a skin disease in a patient who requires treatment of the skin disease, comprising topically administering (a) ruxolitinibulinate and (b) calcipotriol or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient. In some embodiments, the skin disease is an autoimmune skin disease.

[0037] This disclosure also provides a method for treating a skin disease in a patient who requires treatment of the skin disease, comprising topically administering to the affected area of ​​the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or a pharmaceutically acceptable salt thereof. In some embodiments, the skin disease is an autoimmune skin disease.

[0038] In some embodiments, the skin disease is an inflammatory skin disease.

[0039] In some embodiments, skin diseases are associated with Th1 or Th2 cells. Th helper (Th)1 and / or Th helper (Th)17 cells are involved in many inflammatory and autoimmune skin diseases. For example, the following diseases are predominantly associated with Th17 cells: (i) psoriasis (Fletcher, et al., Clin Exp Immunol, 201(2):121-134(2020) PMID:32379344, Liu, et al., Front Immunol, 11:594735(2020) PMID:33281823), (ii) ichthyosis (Czarnowicki, et al., J Invest Dermatol, 138(10):2157-2167(2018) PMID:29660300, Paller, et al, J Allergy Clin Immunol, 139(1):152-165(2017) PMID:27554821), and (iii) Pityriasis pilaris (Liu, supra, PMID:33281823). Furthermore, the following diseases are predominantly associated with Th1: (i) alopecia areata (Zeberkiewicz, et al., Cent Eur J Immunol, 45(3):325-333 (2020) PMID:33437185, and (ii) vitiligo (Boniface, et al., Clin Rev Allergy Immunol, 54(1):52-67 (2018) PMID:28685247). Several diseases are associated with both Th1 and Th17, including: (i) hidradenitis suppurativa (Fletcher, above, PMID:32379344, Liu, above, PMID:33281823, Banerjee, et al., Immunol Invest, 46(2):149-158 (2017) PMID:27819528, Moran, et al., J Invest) Dermatol, 137(11):2389-2395 (2017) PMID: 28652108), and (ii) cutaneous lichen planus (Aghamajidi, et al., Scand J Immunol, e13000 (2020) PMID: 33190330).Furthermore, blocking inflammatory cytokines such as IL-22 and CXCL10, which are involved in the proliferation, survival, and function of Th1 or Th17 lymphocytes, may be useful in the treatment of Th1 or Th17-related diseases. For example, T helper (Th)17 cells are a distinct lineage of effector CD4+ T cells characterized by IL-17 production. See Liang, et al., J Exp Med, 203(10):2271-9 (2006) PMID:16982811. Th17 cells have been shown to express IL-22 in substantially higher amounts than Th1 or Th2 cells. Moreover, the expansion of IL-22-producing cells is dependent on IL-23. Subsequently, blocking IL-17 and IL-23 is a clinically validated approach in psoriasis. Examples of this approach in the treatment of psoriasis, a Th17-related disease, include secukinumab and guselkumab, which block IL-17 and IL-23, respectively. T helper (Th)1 cells are a distinct lineage of effector CD4+ T cells characterized by the production of IFN-gamma and T-bet transcription markers. See Szabo, et al., Cell, 100(6):655-69(2000) PMID:10761931. CXCL10, also known as interferon-gamma-inducible protein 10 (IP-10), attracts lymphocytes to the skin. Furthermore, CXCR3 is a receptor for the CXCL10 ligand. Diseases such as vitiligo are therefore considered Th1-related, as lymphocyte infiltration into vitiligo-affected skin is thought to be driven by CXCR3-positive Th1 cells that respond to the CXCL10 ligand.

[0040] In some embodiments, skin diseases are mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. In some embodiments, skin diseases are mediated by IL-22. In some embodiments, skin diseases are mediated by MMP12. In some embodiments, skin diseases are mediated by CXCL10.

[0041] In some embodiments, skin diseases are mediated by Defb4, S100a12, or Serpinb4. S100a12 is an important marker of psoriatic disease activity (Wilsmann-Theis, D, et al., J Eur Acad Dermatol Venereol, 30(7):1165-70(2016); doi:10.1111 / jdv.13269, which is incorporated herein by reference in its entirety). Defb4 encodes human beta-defensin 2 (hBD2), an antimicrobial peptide that plays an essential role in the inflammatory process of the skin and is important in the development of psoriasis (Johansen C, et al., J Invest Derm, 136(8):1608-1616(2016); doi:10.1016 / j.jid.2016.04.012, which is incorporated herein by reference in its entirety). Serpinb4 contributes to inflammation in patients with chronic skin diseases, including atopic dermatitis (Sivaprasad, U, et al., J Invest Derm 135(1):160-169(2015); DOI:10.1038 / jid.2014.353, which is incorporated herein by reference in its entirety).

[0042] In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital onychoplakia, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and keratinization disorders.

[0043] In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital onychoplakia, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.

[0044] In some embodiments, the skin disease is psoriasis. In some embodiments, psoriasis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The association between psoriasis and IL-22, CXCL10, and / or MMP12 can be found, for example, in IL-22, CXCL10, and / or MMP12, see He et al. “Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis” J Allergy Clin Immunol, 2020 Jul 9;S0091-6749(20)30824-1, PMID:32709423, which is incorporated herein by reference in its entirety. In some embodiments, psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, psoriasis is mediated by CXC-motif chemokine 10 (CXCL10). In some embodiments, psoriasis is mediated by matrix metallopeptidase 12 (MMP12). In some embodiments, psoriasis is selected from plaque psoriasis, onychopsoriasis, trigeminal psoriasis, palmoplantar psoriasis, and pustular psoriasis. In some embodiments, psoriasis is plaque psoriasis. In some embodiments, plaque psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, plaque psoriasis is mediated by CXC-motif chemokine 10 (CXCL10). In some embodiments, plaque psoriasis is mediated by matrix metallopeptidase 12 (MMP12).

[0045] In some embodiments, the skin disease is atopic dermatitis. In some embodiments, atopic dermatitis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The association between atopic dermatitis and IL-22 and / or MMP12 can be found, for example, in He et al. “Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis” J Allergy Clin Immunol, 2020 Jul 9;S0091-6749(20)30824-1, PMID:32709423. The association between atopic dermatitis and CXCL10 can be found, for example, in Brunner et al. “Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues” Allergy. 2017 Dec;72(12):2017-2025, PMID:28599078. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, atopic dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, atopic dermatitis is mediated by CXC motif chemokine 10 (CXCL10). In some embodiments, atopic dermatitis is mediated by matrix metallopeptidase 12 (MMP12).

[0046] In some embodiments, the skin disease is alopecia. In some embodiments, the skin disease is alopecia areata. The association between alopecia areata and IL-22 can be found, for example, in Loh et al. "Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients" J Eur Acad Dermatol Venereol. 2018 Jun;32(6):1028-1033., PMID:29283462. The association between alopecia areata and CXCL10 can be found, for example, in Duca et al. "Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing" Br J Dermatol. 2020 Mar 25, PMID:32215911. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, alopecia is mediated by interleukin-22 (IL-22). In some embodiments, alopecia is mediated by CXC motif chemokine 10 (CXCL10).

[0047] In some embodiments, the skin disease is vitiligo. The association between vitiligo and IL-22 can be found, for example, in Czarnowicki et al. "Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases" J Allergy Clin Immunol. 2019 Jun;143(6):2095-2107. PMID:30576756. The association between vitiligo and CXCL10 can be found, for example, in Abdallah et al. "CXCL-10 and Interleukin-6 are reliable serum markers for vitiligo activity: A multicenter cross-sectional study" Pigment Cell Melanoma Res. 2018 Mar;31(2):330-336. PMID:29094481. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, vitiligo is mediated by interleukin 22 (IL-22). In some embodiments, vitiligo is mediated by CXC motif chemokine 10 (CXCL10).

[0048] In some embodiments, the skin disorder is Reiter's syndrome. The association between Reiter's syndrome and IL-22 can be found, for example, in Zhao et al. "IL-22+CD4+T cells in patients with rheumatoid arthritis" Int J Rheum Dis. 2013 Oct;16(5):518-26, PMID:24164838. The association between Reiter's syndrome and CXCL10 can be found, for example, in Pandya et al. "Blood chemokine profile in untreated early rheumatoid arthritis:CXCL10 as a disease activity marker" Arthritis Res Ther. 2017 Feb 2;19(1):20, PMID:28148302. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, Reiter's syndrome is mediated by interleukin-22 (IL-22). In some embodiments, Reiter syndrome is mediated by CXC motif chemokine 10 (CXCL10).

[0049] In some embodiments, the skin disease is pityriasis rubra pilaris. The association between pityriasis rubra pilaris and IL-22 can be found, for example, in Feldmeyer et al. "Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris" JAMA Dermatol. 2017 Apr 1;153(4):304-308, PMID:28122069. The association between pityriasis rubra pilaris and CXCL10 can be found, for example, in Adnot-Desanlis et al. "Effectiveness of infliximab in pityriasis rubra pilaris is associated with pro-inflammatory cytokine inhibition" Dermatology 2013;226(1):41-6, PMID:23548788. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, pityriasis rubra pilaris is mediated by interleukin 22 (IL-22). In some embodiments, pityriasis rubra pilaris is mediated by CXC motif chemokine 10 (CXCL10).

[0050] In some embodiments, the skin disease is epidermolysis bullosa simplex. The association between epidermolysis bullosa simplex and IL-22 and / or CXCL10 can be found, for example, in Castela et al. “Epidermolysis bullosa simplex generalized severe induces a helper response and is improved by apremilast treatment” Br J Dermatol. 2019 Feb;180(2):357-364, PMID:29932457, which is incorporated herein by reference in its entirety. In some embodiments, epidermolysis bullosa simplex is mediated by interleukin 22 (IL-22). In some embodiments, epidermolysis bullosa simplex is mediated by CXC motif chemokine 10 (CXCL10).

[0051] In some embodiments, the skin disease is palmoplantar keratoderma. The association between palmoplantar keratoderma and IL-22 can be found, for example, in Druetz et al. “Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid” JAMA Dermatol. 2019 Feb 1;155(2):216-220, PMID:30484821, which is incorporated herein by reference in its entirety. In some embodiments, palmoplantar keratoderma is mediated by interleukin-22 (IL-22).

[0052] In some embodiments, the skin disease is congenital onychoplakia. The association between congenital onychoplakia and IL-22 can be found, for example, in Yang et al. “Keratin 17 in disease pathogenesis: from cancer to dermatoses” J Pathol. 2019 Feb;247(2):158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, congenital onychoplakia is mediated by interleukin 22 (IL-22).

[0053] In some embodiments, the skin disease is multiple sebaceous cysts. The association between multiple sebaceous cysts and IL-22 can be found, for example, in Yang et al. “Keratin 17 in disease pathogenesis: from cancer to dermatoses” J Pathol. 2019 Feb;247(2):158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, multiple sebaceous cysts are mediated by interleukin 22 (IL-22).

[0054] In some embodiments, the skin disease is cutaneous lichen planus. The association between cutaneous lichen planus and IL-22 can be found, for example, in Chen et al. "Immunoexpression of interleukin-22 and interleukin-23 in oral and cutaneous lichen planus lesions: a preliminary study" Mediators Inflamm. 2013;2013:801974, PMID:24376306. The association between cutaneous lichen planus and CXCL10 can be found, for example, in Domingues et al. “The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7 / TLR8 and TLR9 ligands in cutaneous lichen planus” Br J Dermatol. 2015 Jan;172(1):48-55, PMID:24976336, and Wenzel et al. “CXCR3<->ligand-mediated skin inflammation in cutaneous lichenoid graft-versus-host disease” J Am Acad Dermatol. 2008 Mar;58(3):437-42, PMID:18280341, each of which is incorporated herein by reference in whole. In some embodiments, cutaneous lichen planus is mediated by interleukin 22 (IL-22). In some embodiments, cutaneous lichen planus is mediated by CXC motif chemokine 10 (CXCL10).

[0055] In some embodiments, the skin disease is cutaneous T-cell lymphoma. In some embodiments, cutaneous T-cell lymphoma is mediated by interleukin-22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The association between cutaneous T-cell lymphoma and IL-22 and / or MMP12 can be found, for example, in Litvinov et al. "The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL)" Clin Cancer Res. 2015 Jun 15;21(12):2820-9, PMID:25779945. The association between cutaneous T-cell lymphoma and CXCL10 can be found, for example, in Mehul et al. “Proteomic analysis of stratum corneum in Cutaneous T-Cell Lymphomas and psoriasis” Exp Dermatol. 2019 Mar;28(3):317-321, PMID:30637808. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, cutaneous T-cell lymphoma is mediated by interleukin-22 (IL-22). In some embodiments, cutaneous T-cell lymphoma is mediated by CXC motif chemokine 10 (CXCL10). In some embodiments, cutaneous T-cell lymphoma is mediated by matrix metallopeptidase 12 (MMP12).

[0056] In some embodiments, the skin disease is hidradenitis suppurativa. The association between hidradenitis suppurativa and IL-22 can be found, for example, in Rumberger et al. “Transcriptomic analysis of hidradenitis suppurativa skin suggests roles for multiple inflammatory pathways in disease pathogenesis” Inflamm Res. 2020 Oct;69(10):967-973, PMID:32661800, which is incorporated herein by reference in its entirety. In some embodiments, hidradenitis suppurativa is mediated by interleukin-22 (IL-22).

[0057] In some embodiments, the skin condition is contact dermatitis. In some embodiments, contact dermatitis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The association between contact dermatitis and IL-22 can be found, for example, in Robb et al. "Prostaglandin E 2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis" J Allergy Clin Immunol. 2018 Jan;141(1):152-162, PMID:28583370. The association between contact dermatitis and CXCL10 can be found, for example, in Brans et al., “Stratum corneum levels of inflammatory mediators and natural moisturizing factor in patch test reactions to thiurams and fragrances and their possible role in discrimination between irritant and allergic reactions to hapten mixtures,” Contact Dermatitis. 2020 Nov 21, PMID:33222241. The causal relationship between contact dermatitis and MMP12 can be found, for example, in Meguro et al., “SOCS3 Expressed in M2 Macrophages Attenuates Contact Hypersensitivity by Suppressing MMP-12 Production,” J Invest Dermatol. 2016 Mar;136(3):649-657, PMID:27015453. Each reference cited herein is incorporated herein by reference in its entirety. In some embodiments, contact dermatitis is mediated by interleukin-22 (IL-22).In some embodiments, contact dermatitis is mediated by CXC motif chemokine 10 (CXCL10). In some embodiments, contact dermatitis is mediated by matrix metallopeptidase 12 (MMP12).

[0058] In some embodiments, the skin disease is ichthyosis. The association between ichthyosis and IL-22 can be found, for example, in Czarnowicki et al. “The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17 / Tc-17 / Th-22 / Tc-22 Polarization in Blood” J Invest Dermatol. 2018 Oct;138(10):2157-2167, PMID:29660300, which is incorporated herein by reference in its entirety. In some embodiments, ichthyosis is mediated by interleukin 22 (IL-22). In some embodiments, ichthyosis is ichthyosis vulgaris, x-linked recessive ichthyosis, bullous congenital ichthyosis-like erythroderma (BCIE), non-bullous congenital ichthyosis-like erythroderma (NBCIE), phyllodes ichthyosis, harlequin ichthyosis, ichthyosis syndrome, or acquired ichthyosis.

[0059] In general, keratin disorders are a group of disorders of keratinization. The association between keratin disorders and IL-22 can be found, for example, in Yang et al. “Keratin 17 in disease pathogenesis: from cancer to dermatoses” J Pathol. 2019 Feb;247(2):158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, keratin disorders are mediated by IL-22. In some embodiments, keratin disorders are selected from ichthyosis, palmoplantar keratosis, keratosis pilaris, and acantholytic dermatosis.

[0060] In some embodiments, the skin disease is rosacea, psoriatic arthritis, dermatofibrosis, morphea, nevus spitz, dermatophytosis, or acne vulgaris. In some embodiments, the skin disease is rosacea. In some embodiments, rosacea is mediated by interleukin 22 (IL-22) or CXC motif chemokine 10 (CXCL10), or a combination thereof. The association between rosacea and IL-22 and CXCL10 can be found, for example, in Buhl, et al., J. Invest. Derm., 135(9), pp. 2198-2208 (2015), PMID: 25848978, which is incorporated herein by reference in its entirety. In some embodiments, rosacea is mediated by interleukin 22 (IL-22). In some embodiments, psoriasis is rosacea mediated by CXC motif chemokine 10 (CXCL10). In some embodiments, the skin disease is psoriasis mediated by S100a12. In some embodiments, the skin disease is psoriatic arthritis mediated by S100a12. In some embodiments, the skin disease is dermatofibrosis mediated by S100a12. In some embodiments, the skin disease is morphea mediated by S100a12. In some embodiments, the skin disease is atopic dermatitis mediated by S100a12. In some embodiments, the skin disease is Spitz nevus mediated by S100a12.

[0061] In some embodiments, the skin disease is Defb4-mediated psoriasis. In some embodiments, the skin disease is Defb4-mediated psoriatic arthritis. In some embodiments, the skin disease is Defb4-mediated dermatophytosis. In some embodiments, the skin disease is Defb4-mediated acne vulgaris. In some embodiments, the skin disease is Defb4-mediated hidradenitis suppurativa.

[0062] In some embodiments, the skin disease is psoriasis mediated by Serpin b4. In some embodiments, the skin disease is psoriatic arthritis mediated by Serpin b4.

[0063] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered sequentially.

[0064] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered sequentially.

[0065] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered at least once daily.

[0066] In some embodiments, a JAK inhibitor or a pharmaceutically acceptable salt thereof is administered once daily.

[0067] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered twice daily.

[0068] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered once daily.

[0069] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered twice daily.

[0070] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as separate formulations.

[0071] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as a single formulation.

[0072] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered once daily.

[0073] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered twice daily.

[0074] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in synergistic amounts.

[0075] In some embodiments, there is a synergistic effect between a JAK inhibitor or a pharmaceutically acceptable salt thereof and vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0076] This disclosure provides a method for treating a skin condition in a patient who requires treatment of the skin condition, comprising topically administering (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof to the affected area of ​​the patient, and further comprising administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a corticosteroid.

[0077] In some embodiments, (b) is vitamin D3 or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the method described herein is provided, wherein (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0079] In some embodiments, the method described herein is provided, wherein (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0080] In each of the embodiments described above, the patient is a human patient.

[0081] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered once daily.

[0082] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least twice daily.

[0083] In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least twice daily.

[0084] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered in topical formulations. In some embodiments, each topical formulation is an ointment, cream, or lotion. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are contained in a single formulation. In some embodiments, the single formulation is a cream or lotion. In some embodiments, the formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.

[0085] Vitamin D3 and Vitamin D3 Analogues for Use in Methods and Topical Preparations In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (I). [Chemistry]

[0086] In some embodiments, R 1 is H or OH. In some embodiments, R 1 is H. In some embodiments, R 1 is OH.

[0087] In some embodiments, R 2 and R 3 are each H. In some embodiments, R 2 is H. In some embodiments, R 3 is H. In some embodiments, R 2 and R 3 are both H.

[0088] In some embodiments, R 2 is O-R 2A and R 3 is H.

[0089] In some embodiments, R 2 and R 3 together form a =CH2 group.

[0090] In some embodiments, R 2A is -C 1-4 alkylene-OH.

[0091] In some embodiments, R 4 and R 5 are each H. In some embodiments, R 4 is H. In some embodiments, R 5 is H. In some embodiments, R 4 and R 5 are both H.

[0092] In some embodiments, R 4 and R 5These combine to form a CH2 group.

[0093] In some embodiments, R 6 and R 7 These are H, respectively. In some embodiments, R 6 and R 7 Both are H. In some embodiments, R 6 H is H. In some embodiments, R 7 H is H.

[0094] In some embodiments, R 6 and R 7 These combine to form a CH2 group.

[0095] In some embodiments, L is -CH2-CH2-CH(R 12 )-,-CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-. In some embodiments, L is -CH2-CH2-CH(R 12 )-. In some embodiments, L is -CH2-CH2-CH2-CH(R 12 )-. In some embodiments, L is -CH=CH-CH(R 12 )-. In some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH2-C≡C-. In some embodiments, L is -O-CH2-CH2-. In some embodiments, L is -O-CH2-CH2-CH2-. In some embodiments, R 12 is H or OH. In some embodiments, R 12 is OH. In some embodiments, R 12 H is H.

[0096] In some embodiments, R 9 C 1-3 Alkyl or C1-4 In some embodiments, R 9 C 1-3 It is alkyl. In some embodiments, R 9 C 1-4 It is a haloalkyl group.

[0097] In some embodiments, R 10 C 1-3 Alkyl or C 1-4 In some embodiments, R 10 C 1-3 It is alkyl. In some embodiments, R 10 C 1-4 It is a haloalkyl group.

[0098] In some embodiments, R 11 is H or OH. In some embodiments, R 11 is OH. In some embodiments, R 11 H is H.

[0099] In some embodiments, R 9 and R 10 Together with the carbon atoms to which they bond, C 3-4 It forms a cycloalkyl ring. In some embodiments, R 11 H is H.

[0100] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (II). [ka]

[0101] In some embodiments, R 1 is H or OH. In some embodiments, R 1 H is H. In some embodiments, R 1 It is OH.

[0102] In some embodiments, R 2 and R 3 are each H. In some embodiments, R 2 is H. In some embodiments, R 3 is H. In some embodiments, R 2 and R 3 are both H.

[0103] In some embodiments, R 2 is O-R 2A and R 3 is H.

[0104] In some embodiments, R 2 and R 3 together form a =CH2 group.

[0105] In some embodiments, R 2A is -C 1-4 alkylene-OH.

[0106] In some embodiments, R 4 and R 5 are each H. In some embodiments, R 4 is H. In some embodiments, R 5 is H. In some embodiments, R 4 and R 5 are both H.

[0107] In some embodiments, R 4 and R 5 together form a =CH2 group.

[0108] In some embodiments, R 6 and R 7 are each H. In some embodiments, R 6 and R 7 are both H. In some embodiments, R 6 is H. In some embodiments, R 7 is H.

[0109] In some embodiments, R 6 and R 7 together form a =CH2 group.

[0110] In some embodiments, L is -CH2-CH2-CH(R 12 )-, -CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-. In some embodiments, L is -CH2-CH2-CH(R 12 )-. In some embodiments, L is -CH2-CH2-CH2-CH(R 12 )-. In some embodiments, L is -CH=CH-CH(R 12 )-. In some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH2-C≡C-. In some embodiments, L is -O-CH2-CH2-. In some embodiments, L is -O-CH2-CH2-CH2-. In some embodiments, R 12 is H or OH. In some embodiments, R 12 is OH. In some embodiments, R 12 is H.

[0111] In some embodiments, R 9 is C 1-3 alkyl or C 1-4 haloalkyl. In some embodiments, R 9 is C 1-3 alkyl. In some embodiments, R 9 is C 1-4 haloalkyl.

[0112] In some embodiments, R 10 is C 1-3 alkyl or C 1-4In some embodiments, R 10 C 1-3 It is alkyl. In some embodiments, R 10 C 1-4 It is a haloalkyl group.

[0113] In some embodiments, R 11 is H or OH. In some embodiments, R 11 is OH. In some embodiments, R 11 H is H.

[0114] In some embodiments, R 9 and R 10 Together with the carbon atoms to which they bond, C 3-4 It forms a cycloalkyl ring. In some embodiments, R 11 H is H.

[0115] In some embodiments, (b) is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1α-(OH)D3 analog or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1α,25(OH)2D3 analog, a vitamin 1α,24(OH)2D3 analog, or a vitamin 1α,26(OH)2D3 analog or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1α,25(OH)2D3 analog or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1α,24(OH)2D3 analog or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1α,26(OH)2D3 analog or a pharmaceutically acceptable salt thereof.

[0121] As used herein, “vitamin D3” (calcitol; cholecalciferol) has formula (i) having the numbering shown below. As used herein, “vitamin D derivative” means vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), and structural analogues of formula (i) that share a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, and 21, wherein the stereochemistry at carbon 20 may be (R) or (S). [ka]

[0122] In some embodiments, the phrase “vitamin D3 analog” refers to a structural analog of formula (i) that shares a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, and 21, where the stereochemistry at carbon 20 can be (R) or (S), the compound does not contain a methyl substituent at carbon 24, and the substitutions and bonds at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. In some embodiments, carbon 1 may have a hydroxyl group α relative to the hydroxyl group at carbon 3.

[0123] As used herein, the phrase “vitamin 1α-(OH)D3 analog” refers to a structural analog of formula (ii) that shares a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, and 21, where each dotted line may be a single, double, or triple bond within appropriate valence constraints, and the compound does not contain a methyl substituent at carbon 24, and substitutions at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. [ka]

[0124] As used herein, the phrase “vitamin 1α,25-(OH)2D3 analog” refers to a structural analog of formula (iii) that shares a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, and 25, where each dotted line may be a single, double, or triple bond within appropriate valence constraints, and the compound does not contain a methyl substituent at carbon 24, and substitutions at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. [ka]

[0125] As used herein, the phrase "vitamin 1α,24-(OH)2D3 analog" refers to a structural analog of structure (iv) that shares a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, and 24, where each dotted line can be a single bond, double bond, or triple bond within the appropriate valence constraints, the compound does not contain a methyl substituent at carbon 24, and the substitutions at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, there is no double bond at carbon 19. In some embodiments, there is a double bond at carbon 19.

Chem.

[0126] As used herein, the phrase "vitamin 1α,26-(OH)2D3 analog" refers to a structural analog of structure (v) that shares a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, and 26, where each dotted line can be a single bond, double bond, or triple bond within the appropriate valence constraints, the compound does not contain a methyl substituent at carbon 24, and the substitutions at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, there is no double bond at carbon 19. In some embodiments, there is a double bond at carbon 19.

Chem.

[0127] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (III).

Chem.

[0128] In some embodiments, R 2 and R 3 These are H, respectively. In some embodiments, R 2 H is H. In some embodiments, R 3 H is H. In some embodiments, R 2 and R 3 Both are H.

[0129] In some embodiments, R 2 is OR 2A And R 3 H is H.

[0130] In some embodiments, R 2A is -C 1-4 It is an alkylene-OH group.

[0131] In some embodiments, R 6 and R 7 These are H, respectively. In some embodiments, R 6 and R 7 Both are H. In some embodiments, R 6 H is H. In some embodiments, R 7 H is H.

[0132] In some embodiments, R 6 and R 7 These combine to form a CH2 group.

[0133] In some embodiments, L is -CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-. In some embodiments, L is -CH2-CH2-CH(R 12 )-. In some embodiments, L is -CH=CH-CH(R 12)- and in some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH2-C≡C-. In some embodiments, L is -O-CH2-CH2-. In some embodiments, L is -O-CH2-CH2-CH2-. In some embodiments, R 12 is H or OH. In some embodiments, R 12 is OH. In some embodiments, R 12 H is H.

[0134] In some embodiments, R 9 is CH3 or CF3. In some embodiments, R 9 is CH3. In some embodiments, R 9 This is CF3.

[0135] In some embodiments, R 10 is CH3 or CF3. In some embodiments, R 10 is CF3. In some embodiments, R 10 This is CH3.

[0136] In some embodiments, R 11 is H or OH. In some embodiments, R 11 H is H. In some embodiments, R 11 It is OH.

[0137] In some embodiments, R 9 and R 10 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring. In some embodiments, R 11 H is H.

[0138] In some embodiments, vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof are calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, phalecalcitriol, erdecalcitol, inesalcitol, theocalcitol, lexicalcitol, 20-epi-1α,25(OH)2D3, CD578(17-methyl-19-nor-21-nor-23-in-26,27-F6-1α,25(OH)2D 3) Selected from TX527 (19-nor-14,20-bisepi-23-yin-1α,25(OH)2D3), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)2D3), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)2D3), ILX23-7553 (16-ene-23-yin-1α,25(OH)2D3), and MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3).

[0139] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, phalecalcitriol, eldecalcitol, rice calcitol, theocalcitol, and lexicalcitol.

[0140] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is selected from calcipotriol, tacalcitol, maxacalcitol, and theocalcitol.

[0141] In some embodiments, the vitamin D3, vitamin D3 analogue, or pharmaceutically acceptable salt thereof is calcipotriol.

[0142] In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is maxacalcitol.

[0143] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is tacalcitol.

[0144] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is seocalcitol.

[0145] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is calcidiol.

[0146] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is calcitriol.

[0147] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is alfacalcidol.

[0148] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is falecalcitriol.

[0149] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is eldecalcitol.

[0150] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is ine calcitol.

[0151] In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is lexacalcitol.

[0152] Formulations of vitamin D3 or vitamin D3 analogs for use in a method In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation. In some embodiments, the topical formulation is a foam, ointment, lotion, or cream.

[0153] In some embodiments, vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof are administered as topical formulations containing approximately 0.0001% to approximately 0.1% of vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof on a free base basis by weight of the formulation. In some embodiments, vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof are administered as topical formulations containing approximately 0.0001% to approximately 0.02% of vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof on a free base basis by weight of the formulation. In some embodiments, vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof are administered as topical formulations containing approximately 0.0001% to approximately 0.005% of vitamin D3, vitamin D3 analogues, or pharmaceutically acceptable salts thereof on a free base basis by weight of the formulation. In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation containing approximately 0.0004% to approximately 0.005% of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis by weight of the formulation.

[0154] In some embodiments, the vitamin D3, vitamin D3 analogue, or pharmaceutically acceptable salt thereof is calcipotriol, which is administered as a topical formulation containing approximately 50 μg of calcipotriol per gram of formulation.

[0155] In some embodiments, the topical formulation is a foamy substance, an ointment, a lotion, or a cream. In some embodiments, the topical formulation further comprises betamethasone dipropionate. In some embodiments, betamethasone dipropionate is present in an amount of about 0.5 mg per gram of formulation.

[0156] In some embodiments, the vitamin D3 analog is tacalcitol, which is administered as a topical formulation containing approximately 4 μg of tacalcitol per gram of formulation. In some embodiments, the topical formulation is an ointment, cream, or lotion.

[0157] In some embodiments, the vitamin D3 analog is maxacalcitol, which is administered as a topical formulation containing approximately 6 μg, approximately 12.5 μg / g, approximately 25 μg, or approximately 50 μg per gram of formulation. In some embodiments, the topical formulation is an ointment.

[0158] JAK inhibitors for use in methods and topical formulations In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a compound that inhibits JAK1, JAK2, JAK3, and / or TYK2. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is selected from JAK1 inhibitors, JAK2 inhibitors, JAK3 inhibitors, TYK2 inhibitors, JAK1 / JAK2 inhibitors, pan-JAK inhibitors, JAK1 / TYK2 inhibitors, and JAK1 / JAK3 inhibitors, or any pharmaceutically acceptable salt of any of the above.

[0159] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is selected from ruxolitinib, baricitinib, oclacitinib, momerotinib, CTP-543, AH057, gandotinib, fedratinib, restaurtinib, pacritinib, CHZ868, upadacitinib, tofacitinib, filgotinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, celduratinib, desernotinib, BMS-986165, and ritrecitinib, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 inhibitor or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, JAK1 inhibitors are selective JAK1 inhibitors or pharmaceutically acceptable salts thereof. JAK1 plays a central role in several cytokine and growth factor signaling pathways that, in dysregulation, can lead to or contribute to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease that has been suggested to have adverse effects (see, e.g., Fonesca, et al., Autoimmunity Reviews, 8:538-42, 2009). This is because IL-6 signaling is at least partially mediated by JAK1, and IL-6 can be indirectly mediated through JAK1 inhibition, which may yield potential clinical benefits (see, e.g., Guschin, et al., Embo J 14:1421, 1995, and Smolen, et al., Lancet 371:987, 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to the disease and / or associated symptoms. Therefore, patients with such diseases may benefit from JAK1 inhibition. Selective inhibitors of JAK1 may be effective while avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases described herein. In some embodiments, JAK1 inhibitors are selective for JAK1 preferentially over JAK2 (e.g., JAK2 / JAK1 IC2 greater than 1). 50 (Having a ratio). In some embodiments, the compounds or salts provided and described herein are about 10 times more selective than JAK1 than JAK2. In some embodiments, the compounds or salts provided herein are IC2 at 1 mM ATP 50 As can be calculated by measuring, JAK2 is approximately 3 times, 5 times, 10 times, 15 times, or 20 times more selective than JAK1 (see, for example, Example 1).

[0162] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the JAK2 inhibitor is a selective JAK2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is IC2 with 1 mM ATP. 50 As can be calculated by measuring, JAK1, JAK3, and TYK2 are more selective than JAK2 by approximately 3 times, 5 times, 10 times, 15 times, or 20 times.

[0164] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK3 inhibitor or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the JAK3 inhibitor is a selective JAK3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK3 inhibitor is IC2 with 1 mM ATP. 50 As can be calculated by measuring, JAK1, JAK2, and TYK2 are more selective than JAK2 by approximately 3 times, 5 times, 10 times, 15 times, or 20 times.

[0166] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a TYK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the TYK2 inhibitor is a selective TYK2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the TYK2 inhibitor is IC2 with 1 mM ATP. 50 As can be calculated by measuring, TYK2 is approximately 3 times, 5 times, 10 times, 15 times, or 20 times more selective than JAK1, JAK2, and JAK3.

[0168] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the JAK1 / JAK2 inhibitor or a pharmaceutically acceptable salt thereof is more selective to JAK1 and JAK2 than to JAK3 and TYK2. In some embodiments, the JAK1 / JAK2 inhibitor or a pharmaceutically acceptable salt thereof is more selective to JAK1 and JAK2 than to JAK3. In some embodiments, the compound or salt is about 10 times more selective to JAK1 and JAK2 than to JAK3. In some embodiments, the compound or salt IC2 with 1 mM ATP 50 As can be calculated by measuring, JAK3 is more selective than JAK1 and JAK2 by approximately 3 times, 5 times, 10 times, 15 times, or 20 times.

[0170] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a pan-JAK inhibitor or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / TYK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, JAK1 / TYK2 inhibitors are used in IC50 with 1 mM ATP. 50 As can be calculated by measuring, JAK1 and TYK2 are more selective than JAK1 and TYK2 by approximately 3 times, 5 times, 10 times, 15 times, or 20 times compared to JAK2 and JAK3.

[0173] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / JAK3 inhibitor or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, JAK1 / JAK3 inhibitors are converted to IC50 with 1 mM ATP. 50 As can be calculated by measuring, JAK1 and JAK3 are approximately 3 times, 5 times, 10 times, 15 times, or 20 times more selective than JAK1 and JAK3 than JAK2 and TYK2.

[0175] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib or a pharmaceutically acceptable salt thereof. Ruxolitinib is a JAK1 / JAK2 inhibitor. Ruxolitinib has an IC50 of less than 10 nM at 1 mM ATP in JAK1 and JAK2. 50 Ruxolitinib can be manufactured by the procedure described in US7,598,257 (Example 67) of application filed December 12, 2006, which is incorporated herein by reference in its entirety. [ka]

[0176] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinibulinate. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is 1:1 ruxolitinib phosphate. The phosphate may be prepared as described in U.S. Patent No. 8,722,693, which is incorporated herein by reference in whole.

[0177] In some embodiments, ruxolitinib or a salt thereof is administered as a topical formulation. In some embodiments, the topical formulation contains, on a free base basis, about 0.05% to about 3.0% by weight, about 0.05% to about 1.5% by weight, about 0.05% to about 1% by weight, about 0.05% to about 0.5% by weight, about 0.1% to about 3.0% by weight, about 0.1% to about 2.0% by weight, about 0.1% to about 1.5% by weight, about 0.1% to about 1.0% by weight, about 0.1% to about 0.5% by weight, about 0.5% to about 2.0% by weight, about 0.5% to about 1.5% by weight, or about 0.5% to about 1.0% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation contains, on a free base basis, about 0.5% to about 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof of the formulation. In some embodiments, the topical formulation contains, on a free base basis, 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% Contains ruxolitinib or a pharmaceutically acceptable salt thereof in amounts of %, approximately 1.0 wt%, approximately 1.05 wt%, approximately 1.1 wt%, approximately 1.15 wt%, approximately 1.2 wt%, approximately 1.25 wt%, approximately 1.3 wt%, approximately 1.35 wt%, approximately 1.4 wt%, approximately 1.45 wt%, approximately 1.5 wt%, approximately 1.55 wt%, approximately 1.6 wt%, approximately 1.65 wt%, approximately 1.7 wt%, approximately 1.75 wt%, approximately 1.8 wt%, approximately 1.85 wt%, approximately 1.9 wt%, approximately 1.95 wt%, approximately 2.0 wt%, approximately 2.5 wt%, or approximately 3.0 wt%.

[0178] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib, where one or more hydrogen atoms are replaced by deuterium atoms or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is any of the compounds of U.S. Patent No. 9,249,149, which are incorporated herein by reference in whole, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is CTP-543 (having the following structure) or a pharmaceutically acceptable salt thereof. [ka]

[0179] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a compound of formula IV, [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 13 It is selected from H and D, Each R 14 Each R bonded to the common carbon is independent. 14 Selected from H and D, provided that they are identical. Each R 15 Each R bonded to the common carbon is independent. 15 Selected from H and D, provided that they are identical. R 16 It is selected from H and D, Each R 17 They are identical and selected from H and D, R 18 , R 19 , and R 20 Each is independently selected from H and D, except R 13 H is and each R 14 and each R 15 H is R 16 H is R 18 , R 19 , and R20 If each of them is H, then each R 17 It is D.

[0180] CTP-543 is a compound of formula IV that is a JAK1 / JAK2 inhibitor.

[0181] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a compound of formula IV (wherein R, R) selected from the following compounds 100-130 in the table below. 18 , R 19 , and R 20 R is a compound of formula IV (wherein R is H) selected from the following compounds 200-231 in the table below. 18 , R 19 , and R 20 Each of these is D) or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3]

[0182] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is baricitinib or a pharmaceutically acceptable salt thereof. Baricitinib is a JAK1 / JAK2 inhibitor.

[0183] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is baricitinib, where one or more hydrogen atoms are replaced by deuterium atoms or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is one of the compounds of U.S. Patent No. 9,540,367 (which is incorporated herein by reference in its entirety) or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is oclacitinib or a pharmaceutically acceptable salt thereof. Oclacitinib is a JAK1 / JAK2 inhibitor.

[0185] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is momerotinib or a pharmaceutically acceptable salt thereof. Momerotinib is a JAK1 / JAK2 inhibitor.

[0186] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is AH057 or a pharmaceutically acceptable salt thereof. AH057 is a JAK1 / JAK2 inhibitor.

[0187] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is gandotinib or a pharmaceutically acceptable salt thereof. Gandotinib is a JAK2 inhibitor.

[0188] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is fedratinib or a pharmaceutically acceptable salt thereof. Fedratinib is a JAK2 inhibitor.

[0189] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is restaurtinib or a pharmaceutically acceptable salt thereof. Restaurtinib is a JAK2 inhibitor.

[0190] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is pacritinib or a pharmaceutically acceptable salt thereof. Pacritinib is a JAK2 inhibitor and also inhibits fms-like tyrosine kinase 3 (FLT3).

[0191] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is CHZ868 or a pharmaceutically acceptable salt thereof. CHZ868 is a JAK2 inhibitor.

[0192] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is upadacitinib or a pharmaceutically acceptable salt thereof. Upadacitinib is a JAK1 inhibitor.

[0193] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is filgotinib or a pharmaceutically acceptable salt thereof. Filgotinib is a JAK1 inhibitor.

[0194] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is abrocitinib or a pharmaceutically acceptable salt thereof. Abrocitinib is a JAK1 inhibitor.

[0195] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is itacitinib or a pharmaceutically acceptable salt thereof. Itacitinib is a JAK1 inhibitor.

[0196] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 inhibitor or a pharmaceutically acceptable salt thereof, which is a compound listed in Table 1. The compounds in Table 1 are JAK1 selective inhibitors (e.g., more selective than JAK2, JAK3, and TYK2). IC obtained by the method of Example 1 with 1 mM ATP 50 The values ​​are shown in Table 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0197] In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidine-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidine-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile adipinate. The synthesis and preparation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidine-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile and its adipate can be found, for example, in U.S. Patent Publication No. 2011 / 0224190 filed on 9 March 2011, U.S. Patent Publication No. 2013 / 0060026 filed on 6 September 2012, and U.S. Patent Publication No. 2014 / 0256941 filed on 5 March 2014, each of which is incorporated herein by reference in whole.

[0198] In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate, which is the JAK1 inhibitor. In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrochloride. In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrobromide. In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide sulfate.The synthesis and preparation of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and its phosphates can be found, for example, in U.S. Patent Publication No. US2014 / 0343030, filed on 16 May 2014, which is incorporated herein by reference in its entirety.

[0199] In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate or a pharmaceutically acceptable salt thereof. The synthesis of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, and the characterization of their anhydrous and monohydrate forms, are described in U.S. Patent Publication No. 2014 / 0121198, filed October 31, 2013, and U.S. Patent Publication No. 2015 / 0344497, filed April 29, 2015, each of which is incorporated herein by reference in whole.

[0201] In some embodiments, the compounds in Table 1 are incorporated herein by reference in their entirety by U.S. Patent Publication No. 2011 / 0224190 filed March 9, 2011, U.S. Patent Publication No. 2014 / 0343030 filed May 16, 2014, U.S. Patent Publication No. 2014 / 0121198 filed October 31, 2013, U.S. Patent Publication No. 2010 / 0298334 filed May 21, 2010, and U.S. Patent Publication No. 201 It is prepared by the synthesis procedure described in U.S. Patent Publication No. 1 / 0059951, U.S. Patent Publication No. 2012 / 0149681 filed on November 18, 2011, U.S. Patent Publication No. 2012 / 0149682 filed on November 18, 2011, U.S. Patent Publication No. 2013 / 0018034 filed on June 19, 2012, U.S. Patent Publication No. 2013 / 0045963 filed on August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166 filed on May 17, 2013.

[0202] In some embodiments, the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is incorporated herein by whole reference, each of the following: U.S. Patent Publication No. 2011 / 0224190 filed March 9, 2011; U.S. Patent Publication No. 2014 / 0343030 filed May 16, 2014; U.S. Patent Publication No. 2014 / 0121198 filed October 31, 2013; U.S. Patent Publication No. 2010 / 0298334 filed May 21, 2010; and U.S. Patent Publication No. 2010 / 0298334 filed August 31, 2010. The compounds are selected from U.S. Patent Publication No. 2011 / 0059951, U.S. Patent Publication No. 2012 / 0149681 filed on November 18, 2011, U.S. Patent Publication No. 2012 / 0149682 filed on November 18, 2011, U.S. Patent Publication No. 2013 / 0018034 filed on June 19, 2012, U.S. Patent Publication No. 2013 / 0045963 filed on August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166 filed on May 17, 2013, or pharmaceutically acceptable salts thereof.

[0203] In some embodiments, the JAK inhibitor is brepocitinib or a pharmaceutically acceptable salt thereof. Brepocitinib is a JAK1 / JAK2 inhibitor.

[0204] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ATI-501 or a pharmaceutically acceptable salt thereof. ATI-501 (Aclaris) is a JAK1 / JAK3 inhibitor.

[0205] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ATI-1777 or a pharmaceutically acceptable salt thereof. ATI-1777 (Aclaris) is a JAK1 / JAK3 inhibitor.

[0206] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ATI-502 or a pharmaceutically acceptable salt thereof. ATI-502 (Aclaris) is a JAK1 / JAK3 inhibitor.

[0207] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is tofacitinib or a pharmaceutically acceptable salt thereof. Tofacitinib inhibits JAK1 and JAK3.

[0208] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is delgocitinib or a pharmaceutically acceptable salt thereof. Delgocitinib is a pan-JAK inhibitor.

[0209] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is peficitinib or a pharmaceutically acceptable salt thereof. Peficitinib is a pan-JAK inhibitor.

[0210] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is gusacitinib or a pharmaceutically acceptable salt thereof. Gusacitinib is a pan-JAK inhibitor that also inhibits SYK.

[0211] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is cucurbitacin I or a pharmaceutically acceptable salt thereof. Cucurbitacin I is a pan-JAK inhibitor that also inhibits STAT3.

[0212] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is celduratinib or a pharmaceutically acceptable salt thereof. Celduratinib is a pan-JAK inhibitor and also inhibits splenic tyrosine kinase (SYK).

[0213] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is desernotinib or a pharmaceutically acceptable salt thereof. Desernotinib is a JAK3 inhibitor.

[0214] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof has the following structure: [ka] It is BMS-986165 or a pharmaceutically acceptable salt thereof. BMS-986165 is a TYK2 inhibitor.

[0215] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is ritrecitinib or a pharmaceutically acceptable salt thereof. Ritrecitinib (Pfizer) is a JAK3 inhibitor that also inhibits TEC.

[0216] In some embodiments, the method described herein is provided in which the JAK inhibitor or a pharmaceutically acceptable salt thereof is selected from ruxolitinib, oclacitinib, baricitinib, momerotinib, and CTP-543, or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is selected from ruxolitinib, oclacitinib, baricitinib, momerotinib, CTP-543, gandotinib, fedratinib, restaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and celduratinib, or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is selected from ruxolitinib, oclacitinib, baricitinib, momerotinib, CTP-543, gandotinib, fedratinib, restaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and celduratinib, or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof may be an isotope-labeled compound or a pharmaceutically acceptable salt thereof. An “isotope-labeled” or “radio-labeled” compound is a compound in which one or more atoms are replaced or substituted by atoms having atomic masses or mass numbers different from those typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of this disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T as tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br,75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 This includes, but is not limited to, I. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms (e.g., -CD3 may be replaced by -CH3).

[0220] Therefore, in some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is a compound in which one or more hydrogen atoms are replaced by a deuterium atom or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the methods described herein are provided, wherein a JAK inhibitor or a pharmaceutically acceptable salt thereof is combined with any of the JAK inhibitors or pharmaceutically acceptable salts thereof described herein.

[0222] In some embodiments, the method described herein is provided, wherein (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0223] In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered as a topical formulation. In some embodiments, the topical formulation contains, on a free base basis, about 0.1% to about 3.0% by weight, about 0.1% to about 2.0% by weight, about 0.1% to about 1.5% by weight, about 0.1% to about 1.0% by weight, about 0.1% to about 0.5% by weight, about 0.5% to about 2.0% by weight, about 0.5% to about 1.5% by weight, or about 0.5% to about 1.0% by weight of the formulation, a JAK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation contains, on a free base basis, about 0.5% to about 1.5% by weight of the formulation, a JAK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation is free base-based and contains approximately 0.05% by weight, approximately 0.1% by weight, approximately 0.15% by weight, approximately 0.2% by weight, approximately 0.25% by weight, approximately 0.3% by weight, approximately 0.35% by weight, approximately 0.4% by weight, approximately 0.45% by weight, approximately 0.5% by weight, approximately 0.55% by weight, approximately 0.6% by weight, approximately 0.65% by weight, approximately 0.7% by weight, approximately 0.75% by weight, approximately 0.8% by weight, approximately 0.85% by weight, approximately 0.9% by weight, approximately 0.95% by weight, approximately 1.0% by weight, and approximately 1.05% by weight of the formulation. Contains approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.5% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight of a JAK inhibitor or a pharmaceutically acceptable salt thereof.

[0224] Ruxolitinib cream formulation In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is administered as a cream formulation containing ruxolitinib or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is administered as a cream formulation containing ruxolitinibrine salt.

[0226] In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is in the form of a cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion. In some embodiments, the cream formulation is described in whole in U.S. Patent No. 10,758,543, which is incorporated herein by reference. In particular, Examples 3–6 of U.S. Patent No. 10,758,543 (in particular Tables 3–5 and the accompanying text) are incorporated herein by reference. In some embodiments, the cream is free base-based, with an emulsion concentration of about 0.1% to about 3.0% by weight, about 0.1% to about 3.0% by weight, about 0.1% to about 1.5% by weight, about 0.1% to about 1.0% by weight, about 0.1% to about 0.5% by weight, about 0.5% to about 2.0% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 1.4% by weight, about 0.5% to about 1.3% by weight, about 0.5% to about 1.2% by weight, about 0.5% to about 1.1% by weight, about 0.6% to about 2.0% by weight, about 0.6% to about 1.5% by weight, about 0.6% to about 1.4% by weight, about 0.6% to about 1.3% by weight, about 0.6% by weight Weight% to about 1.2% by weight, about 0.6% to about 1.1% by weight, about 0.7% to about 2.0% by weight, about 0.7% to about 1.5% by weight, about 0.7% to about 1.4% by weight, about 0.7% to about 1.3% by weight , about 0.7% to about 1.2% by weight, about 0.7% to about 1.1% by weight, about 0.8% to about 2.0% by weight, about 0.8% to about 1.5% by weight, about 0.8% to about 1.4% by weight, about 0.8% to about 1% by weight .3% by weight, about 0.8% to about 1.2% by weight, about 0.8% to about 1.1% by weight, about 0.9% to about 2.0% by weight, about 0.9% to about 1.5% by weight, about 0.9% to about 1.4% by weight, about 0.9% by weight Contains ruxolitinib or a pharmaceutically acceptable salt thereof in amounts of approximately 1.3 wt% to 1.3 wt%, approximately 0.9 wt% to 1.2 wt%, approximately 0.9 wt% to 1.1 wt%, approximately 1.0 wt% to 2.0 wt%, approximately 1.0 wt% to 1.5 wt%, approximately 1.0 wt% to 1.4 wt%, approximately 1.0 wt% to 1.3 wt%, approximately 1.0 wt% to 1.2 wt%, approximately 1.0 wt% to 1.1 wt%, or approximately 0.5 wt% to 1.0 wt%.In some embodiments, the oil-in-water emulsion contains, on a free base basis, about 0.5% to about 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof of the emulsion. In some embodiments, the oil-in-water emulsion contains, on a free base basis, about 0.05%, 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%, and about 1.0% by weight of the emulsion. The product contains ruxolitinib or a pharmaceutically acceptable salt thereof in amounts of approximately 1.05% by weight, approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.5% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, or 2.0% by weight. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0227] In some embodiments, the cream formulation has a pH of about 6.5 to about 7.0.

[0228] In some embodiments, the cream formulation has a pH of about 2.8 to about 3.9.

[0229] In some embodiments, the cream formulation has a pH of about 2.8 to about 3.6.

[0230] In some embodiments, the cream comprises an oil-in-water emulsion containing ruxolitinib.

[0231] In some embodiments, the cream comprises an oil-in-water emulsion containing ruxolitinibrinate. In some embodiments, the cream is an oil-in-water emulsion described in US2015 / 0250790, which is incorporated herein by reference in whole. In particular, Examples 3–6 of US2015 / 0250790 (in particular Tables 3–5 and the accompanying text) are incorporated herein by reference.

[0232] In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.

[0233] In some embodiments, the oil component is present in an amount of about 10% to about 24% by weight of the emulsion.

[0234] In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the emulsion.

[0235] In some embodiments, the oil component is present in an amount of about 18% to about 24% by weight of the emulsion.

[0236] In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

[0237] In some embodiments, the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone.

[0238] In some embodiments, the oil component includes an occlusive agent component.

[0239] In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.

[0240] In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.

[0241] In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolinic acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., bee wax).

[0242] In some embodiments, the occlusive agent component comprises one or more substances selected from lanolinic acid fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and bee wax.

[0243] In some embodiments, the occlusive agent component includes petrolatum.

[0244] In some embodiments, the occlusive agent component includes white petrolatum.

[0245] In some embodiments, white petrolatum is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0246] In some embodiments, white petrolatum is present in an amount of about 7% by weight of the emulsion.

[0247] In some embodiments, the oil component includes a curing agent component.

[0248] In some embodiments, the curing agent component is present in an amount of about 2% to about 8% by weight of the emulsion.

[0249] In some embodiments, the curing agent component is present in an amount of about 3% to about 6% by weight of the emulsion.

[0250] In some embodiments, the curing agent component is present in an amount of about 4% to about 7% by weight of the emulsion.

[0251] In some embodiments, the curing agent component comprises one or more substances independently selected from fatty alcohols.

[0252] In some embodiments, the curing agent component is C 12-20 It contains one or more substances independently selected from fatty alcohols.

[0253] In some embodiments, the curing agent component is C 16-18 It contains one or more substances independently selected from fatty alcohols.

[0254] In some embodiments, the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

[0255] In some embodiments, cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0256] In some embodiments, the amount of cetyl alcohol is about 3% by weight of the emulsion.

[0257] In some embodiments, stearyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0258] In some embodiments, stearyl alcohol is present in an amount of about 1.75% by weight of the emulsion.

[0259] In some embodiments, the curing agent component comprises one or more substances independently selected from cetyl alcohol, stearyl alcohol, oleyl alcohol, and cetostearyl alcohol.

[0260] In some embodiments, cetostearyl alcohol is present in an amount of about 0.1% to about 30% by weight of the emulsion.

[0261] In some embodiments, cetostearyl alcohol is present in an amount of about 1% to about 20% by weight of the emulsion.

[0262] In some embodiments, the oil component includes a softening component.

[0263] In some embodiments, the softening component is present in an amount of about 5% to about 15% by weight of the emulsion.

[0264] In some embodiments, the softening component is present in an amount of about 7% to about 13% by weight of the emulsion.

[0265] In some embodiments, the softening component comprises one or more substances independently selected from mineral oils and triglycerides.

[0266] In some embodiments, the softening component comprises one or more substances independently selected from light mineral oils and medium-chain triglycerides.

[0267] In some embodiments, light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0268] In some embodiments, light mineral oil is present in an amount of about 4% by weight of the emulsion.

[0269] In some embodiments, the softening component comprises one or more substances independently selected from light mineral oils, medium-chain triglycerides, and dimethicone.

[0270] In some embodiments, dimethicone is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0271] In some embodiments, dimethicone is present in an amount of about 1% by weight of the emulsion.

[0272] In some embodiments, the amount of medium-chain triglycerides is about 0.1% to about 15% by weight of the emulsion.

[0273] In some embodiments, the amount of medium-chain triglycerides is about 7.0% by weight of the emulsion.

[0274] In some embodiments, water is present in an amount of about 35% to about 65% by weight of the emulsion.

[0275] In some embodiments, water is present in an amount of about 40% to about 60% by weight of the emulsion.

[0276] In some embodiments, water is present in an amount of about 45% to about 55% by weight of the emulsion.

[0277] In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the emulsion.

[0278] In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.

[0279] In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.

[0280] In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the emulsion.

[0281] In some embodiments, the emulsion comprises an emulsifier component and a curing agent component, the total amount of the emulsifier component and curing agent component being at least about 8% by weight of the emulsion.

[0282] In some embodiments, the emulsifying component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0283] In some embodiments, the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0284] In some embodiments, glyceryl stearate is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0285] In some embodiments, glyceryl stearate is present in an amount of about 3% by weight of the emulsion.

[0286] In some embodiments, the polysorbate 20 is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0287] In some embodiments, polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.

[0288] In some embodiments, the emulsifying component includes a nonionic surfactant.

[0289] In some embodiments, the nonionic surfactant is cetomacrogol 1000 or poloxamer 407.

[0290] In some embodiments, cetomacrogol 1000 is present in an amount of about 0.01% to about 15% by weight of the emulsion.

[0291] In some embodiments, cetomacrogol 1000 is present in an amount of about 0.1% to about 10% by weight of the emulsion.

[0292] In some embodiments, the poloxamer is poloxamer 407.

[0293] In some embodiments, poloxamer 407 is present in an amount of about 0.01% to about 15% by weight of the emulsion.

[0294] In some embodiments, the emulsifying component further comprises glyceryl stearate and PEG-100 stearate, for example, Arlacel® 165.

[0295] In some embodiments, glyceryl stearate and PEG-100 stearate are present in amounts ranging from about 0.1% to about 15% by weight of the emulsion.

[0296] In some embodiments, the emulsion further comprises a stabilizing component.

[0297] In some embodiments, the stabilizing component is present in an amount of about 0.05% to about 5% by weight of the emulsion.

[0298] In some embodiments, the stabilizing component is present in an amount of about 0.1% to about 2% by weight of the emulsion.

[0299] In some embodiments, the stabilizing component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.

[0300] In some embodiments, the stabilizing component comprises one or more substances independently selected from polysaccharides.

[0301] In some embodiments, the stabilizing component includes xanthan gum.

[0302] In some embodiments, xanthan gum is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0303] In some embodiments, xanthan gum is present in an amount of about 0.2% to about 0.6% by weight of the emulsion.

[0304] In some embodiments, xanthan gum is present in an amount of about 0.4% by weight of the emulsion.

[0305] In some embodiments, the emulsion further comprises a solvent component.

[0306] In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the emulsion.

[0307] In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the emulsion.

[0308] In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the emulsion.

[0309] In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0310] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0311] In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, and propylene glycol.

[0312] In some embodiments, the solvent components include PEG300 and propylene glycol.

[0313] In some embodiments, PEG300 is present in an amount of about 7% by weight of the emulsion.

[0314] In some embodiments, the solvent is a combination of PEG400 and propylene glycol.

[0315] In some embodiments, PEG400 is present in an amount of about 7% w / w of the emulsion.

[0316] In some embodiments, propylene glycol is present in about 6.5% by weight of the emulsion. In some embodiments, the solvent component includes diethylene glycol monoethyl ether, for example, Transcutol® P. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 30% w / w of the emulsion. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 20% w / w of the emulsion.

[0317] In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Emulsion containing 10% to approximately 40% by weight of oil components. Emulsifier components making up approximately 1% to 9% by weight of the emulsion, Approximately 10% to 35% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.05% to 5% by weight of stabilizer components.

[0318] In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 10% to 40% by weight of oil components in the emulsion. Emulsifier components making up approximately 1% to 9% by weight of the emulsion, Approximately 10% to 35% by weight of the solvent component in the emulsion; Approximately 0.05% to 5% by weight of stabilizer components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0319] In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 10% to 24% by weight of oily components in the emulsion. Emulsifier components making up approximately 1% to 9% by weight of the emulsion, Approximately 10% to 35% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.05% to 5% by weight of stabilizer components.

[0320] In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 10% to 24% by weight of oily components in the emulsion. Emulsifier components making up approximately 1% to 9% by weight of the emulsion, Approximately 10% to 35% by weight of solvent components in the emulsion. Stabilizer components in the emulsion: approximately 0.05% to approximately 5% by weight. The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0321] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 15% to 30% by weight of oil components in the emulsion. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 15% to 30% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.1% to 2% by weight of stabilizing agents.

[0322] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 15% to 30% by weight of oil components in the emulsion. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 15% to 30% by weight of solvent components in the emulsion. Approximately 0.1% to 2% by weight of stabilizer components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0323] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 15% to 30% by weight of oil components in the emulsion. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 15% to 24% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.1% to 2% by weight of stabilizing agents.

[0324] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 15% to 30% by weight of oil components in the emulsion. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 15% to 24% by weight of solvent components in the emulsion. Approximately 0.1% to 2% by weight of stabilizer components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0325] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 15% to 24% by weight of oil components in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 20% to 25% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.3% to 0.5% by weight of stabilizing agents.

[0326] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 15% to 24% by weight of oil components in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 20% to 25% by weight of solvent components in the emulsion. Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion. The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0327] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 15% to 24% by weight of oil components in the emulsion. Emulsifier component making up approximately 4% to 7% by weight of the emulsion, Approximately 20% to 25% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.3% to 0.5% by weight of stabilizing agents.

[0328] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 15% to 24% by weight of oil components in the emulsion. Emulsifier component making up approximately 4% to 7% by weight of the emulsion, Approximately 20% to 25% by weight of solvent components in the emulsion. Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0329] In some embodiments, The oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oil, triglycerides, and dimethicone. The emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters. The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols. The stabilizing agent component comprises one or more substances independently selected from polysaccharides.

[0330] In some embodiments, The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone. The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20. The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol. The stabilizing agent component includes xanthan gum.

[0331] In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 2% to 15% by weight of the occlusive agent component in the emulsion. Approximately 2% to 8% by weight of the curing agent component in the emulsion. Approximately 5% to 15% by weight of the softening agent in the emulsion. Approximately 1% to 9% by weight of emulsifier components in the emulsion, and Stabilizer components in the emulsion: approximately 0.05% to approximately 5% by weight. The emulsion further contains 10% to about 35% by weight of a solvent component. In some embodiments, the emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 2% to 15% by weight of the occlusive agent component in the emulsion. Approximately 2% to 8% by weight of the curing agent component in the emulsion. Approximately 5% to 15% by weight of the softening agent in the emulsion. Emulsifier components making up approximately 1% to 9% by weight of the emulsion, Stabilizer components in the emulsion: approximately 0.05% to approximately 5% by weight. Approximately 10% to 35% by weight of solvent components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0332] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. Approximately 2% to 8% by weight of the curing agent component in the emulsion. Approximately 7% to 12% by weight of the emulsion contains softening agents. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 0.1% to 2% by weight of stabilizers in the emulsion, and The emulsion further contains approximately 15% to 30% by weight of solvent components.

[0333] In some embodiments, the emulsion is Approximately 40% to 60% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. Approximately 2% to 8% by weight of the curing agent component in the emulsion. Approximately 7% to 12% by weight of the emulsion contains softening agents. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 0.1% to 2% by weight of stabilizer in the emulsion. Approximately 15% to 30% by weight of solvent components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0334] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. The emulsion contains approximately 3% to 6% by weight of the hardening agent component. Approximately 7% to 13% by weight of the softening agent in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion, and The emulsion further contains approximately 20% to 25% by weight of solvent components.

[0335] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. The emulsion contains approximately 3% to 6% by weight of the hardening agent component. Approximately 7% to 13% by weight of the softening agent in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion. Approximately 20% to 25% by weight of solvent components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0336] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. The emulsion contains approximately 4% to 7% by weight of the hardening agent component. Approximately 7% to 13% by weight of the softening agent in the emulsion. Emulsifier component making up approximately 4% to 7% by weight of the emulsion, Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion, and The emulsion further contains approximately 20% to 25% by weight of solvent components.

[0337] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 5% to 10% by weight of the emulsion contains the occlusive agent component. The emulsion contains approximately 4% to 7% by weight of the hardening agent component. Approximately 7% to 13% by weight of the softening agent in the emulsion. Emulsifier component making up approximately 4% to 7% by weight of the emulsion, Approximately 0.3% to 0.5% by weight of stabilizer components in the emulsion. Approximately 20% to 25% by weight of solvent components in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0338] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 7% by weight of the emulsion is the occlusive agent component. The emulsion contains approximately 4.5% to 5% by weight of the hardening agent component. Approximately 10% by weight of the emulsion contains softening agents. Emulsifier component in approximately 4% to 4.5% by weight of the emulsion, Approximately 0.4% by weight of the emulsion is a stabilizing agent component, and The emulsion further contains approximately 22% by weight of solvent components.

[0339] In some embodiments, the emulsion is Approximately 45% to 55% by weight of water in the emulsion. Approximately 7% by weight of the emulsion is the occlusive agent component. The emulsion contains approximately 4.5% to 5% by weight of the hardening agent component. Approximately 10% by weight of the emulsion contains softening agents. Emulsifier component in approximately 4% to 4.5% by weight of the emulsion, Approximately 0.4% by weight of the stabilizer component in the emulsion. Approximately 22% by weight of the solvent component in the emulsion, and The emulsion contains 0.5% to 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt, on a free base basis.

[0340] In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof exists as ruxolitinibulinate.

[0341] In some embodiments, the emulsion comprises 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the emulsion contains 1.5% by weight of ruxolitinibrinate salt.

[0343] In some embodiments, the emulsion comprises 1.1% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0344] In some embodiments, the emulsion contains 1.1% by weight of ruxolitinibrinate salt.

[0345] In some embodiments, the emulsion comprises 0.75% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the emulsion contains 0.75% by weight of ruxolitinibrinate salt.

[0347] In some embodiments, the total amount of the curing agent component and the emulsifier component is at least about 8% by weight of the emulsion.

[0348] In some embodiments, The occlusive drug component includes petrolatum. The curing agent component comprises one or more substances independently selected from one or more fatty alcohols. The softening component comprises one or more substances independently selected from mineral oils and triglycerides. The emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters. The stabilizing agent component comprises one or more substances independently selected from polysaccharides. The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0349] In some embodiments, The occlusive agent component contains white petrolatum. The curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol. The softening component comprises one or more substances independently selected from light mineral oil, medium-chain triglycerides, and dimethicone. The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20. The stabilizing agent component contains xanthan gum. The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0350] In some embodiments, the emulsion further comprises an antimicrobial preservative component.

[0351] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the emulsion.

[0352] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the emulsion.

[0353] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.

[0354] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.

[0355] In some embodiments, the antimicrobial preservative component includes methylparaben and propylparaben.

[0356] In some embodiments, methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0357] In some embodiments, methylparaben is present in an amount of about 0.1% by weight of the emulsion.

[0358] In some embodiments, propylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0359] In some embodiments, propylparaben is present in an amount of about 0.05% by weight of the emulsion.

[0360] In some embodiments, phenoxyethanol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0361] In some embodiments, phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.

[0362] In some embodiments, phenoxyethanol is present in an amount of about 0.1% to about 10% by weight of the emulsion.

[0363] In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, or about 7.0.

[0364] In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, about 6.5, or about 7.0.

[0365] In some embodiments, the pH of the cream is adjusted to a range of approximately 6.5 to approximately 7.0.

[0366] In some embodiments, the pH of the cream is adjusted with trolamine and / or phosphoric acid. In some embodiments, the pH of the cream is adjusted with trolamine. In some embodiments, the pH of the cream is adjusted with phosphoric acid. In some embodiments, the pH of the cream is adjusted with trolamine and phosphoric acid.

[0367] In some embodiments, the emulsion further comprises an antioxidant.

[0368] In some embodiments, the antioxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof.

[0369] In some embodiments, the emulsion further comprises a chelating agent component.

[0370] In some embodiments, the chelating agent component includes disodium edetate.

[0371] In some embodiments, disodium edetate is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0372] In some embodiments, disodium edetate is present in an amount of about 0.001% to about 1% by weight of the emulsion.

[0373] In some embodiments, the emulsion further comprises a calcipotriol stabilizer.

[0374] In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, or citric acid, or a combination thereof.

[0375] In some embodiments, the emulsion further comprises a humectant.

[0376] In some embodiments, the humectant is glycerol.

[0377] In some embodiments, glycerol is present in an amount of about 0.01% to about 20% by weight of the emulsion.

[0378] In some embodiments, glycerol is present in an amount of about 0.1% to about 20% by weight of the emulsion.

[0379] In some embodiments, the emulsion further comprises a surfactant.

[0380] In some embodiments, the surfactant is polysorbate 80. In some embodiments, polysorbate 80 is present in an amount of about 0.01% to about 15% by weight of the emulsion.

[0381] Ruxolitinib may be prepared as described in U.S. Patent No. 7,598,257 and U.S. Patent Publication No. 2009 / 0181959, respectively, which are incorporated herein by reference in whole. A 1:1 phosphate of ruxolitinib may be prepared as described in U.S. Patent Publication No. 2008 / 0312259, which are incorporated herein by reference in whole.

[0382] As can be understood, some components of the creams (emulsifies) described herein may have multiple functions. For example, a given substance may act as both an emulsifier and a stabilizer. In some such cases, the function of a given component can be considered to be one, even though its properties may enable multiple functions. In some embodiments, each component of the formulation comprises a different substance or a mixture of substances.

[0383] Pharmaceutical preparations (combinations of fixed doses) The pharmaceutical preparations provided and described herein may be used in the manner described herein.

[0384] Concentrations of JAK inhibitors, vitamin D3, or vitamin D3 analogues, or pharmaceutically acceptable salts of any of the foregoing, may also be used in the fixed-dose combination formulations described below. Where used herein, “Pharmaceutical formulations for the topical treatment of skin diseases” and “Topical formulations” are interchangeable.

[0385] This disclosure further provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.

[0386] The disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.

[0387] This disclosure further provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) ruxolitinibrinate or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.

[0388] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0389] This disclosure further provides pharmaceutical formulations for the topical treatment of skin diseases, comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.3% by weight, about 0.35% by weight, about 0.4% by weight, about 0.45% by weight, about 0.5% by weight, about 0.55% by weight, about 0.6% by weight, about 0.65% by weight, about 0.7% by weight, about 0.75% by weight, about 0.8% by weight, and about 0.85% by weight, on a free base basis. It exists in amounts of approximately 0.9% by weight, approximately 0.95% by weight, approximately 1.0% by weight, approximately 1.05% by weight, approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.5% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight.

[0390] The Disclosure also provides pharmaceutical formulations for the topical treatment of skin diseases, comprising (a) ruxolitiniburinate or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. The Disclosure also provides pharmaceutical formulations for the topical treatment of skin diseases, comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitiniburinate.

[0391] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0392] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0393] The disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 1.1% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0394] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 1 μg / mL to about 50 μg / mL. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0395] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0396] The disclosure also provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0397] The disclosure also provides pharmaceutical formulations for topical treatment of skin diseases, comprising (a) about 1.1% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analogue, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0398] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 1 μg / mL. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0399] This disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 10 μg / mL. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0400] The disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 50 μg / mL. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0401] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL on a free base basis vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0402] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0403] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0404] The disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL on a free base basis vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0405] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.1% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL on a free base basis vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0406] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0407] The disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 1.1% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0408] The Disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate. The Disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.01% w / w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis.

[0409] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 0.0001% w / w to about 0.005% w / w. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0410] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0411] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.1% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0412] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analogue, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0413] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof in a free base of about 0.005% w / w.

[0414] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0415] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0416] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.1% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0417] The formulation described in the preceding paragraph, wherein vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof. In some embodiments, the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, phalecalcitriol, eldecalcitol, inesalcitol, theocalcitol, lexicalcitol, 20-epi-1α,25(OH)2D3, CD578(17-methyl-19-nor-21-nor-23-in-26,27-F6-1α,25(OH) 2D3The following are selected: TX527 (19-nor-14,20-bisepi-23-in-1α,25(OH)2D3), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)2D3), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)2D3), ILX23-7553 (16-ene-23-in-1α,25(OH)2D3), and MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3). In some embodiments, the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol. In some embodiments, the vitamin D3 analog or a pharmaceutically acceptable salt thereof is tacalcitol. In some embodiments, the vitamin D3 analog or a pharmaceutically acceptable salt thereof is maxacalcitol.

[0418] This disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) calcipotriol in a free base of about 0.005% w / w. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0419] This disclosure also provides a pharmaceutical formulation for the topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0420] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0421] The disclosure also provides a pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.1% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0422] In some embodiments, the pharmaceutical formulation described herein is a cream. In some embodiments, the cream formulation of ruxolitinib described above may also be used in the fixed-dose combination formulations described below.

[0423] In some embodiments, the pharmaceutical formulation described herein is a lotion.

[0424] In some embodiments, the pharmaceutical formulations described herein further contain water. In some embodiments, water constitutes about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 10% to about 80% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 10% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 10% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 20% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 20% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 20% to about 50% by weight of the pharmaceutical formulation. In some embodiments, water constitutes about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the pharmaceutical formulation.

[0425] In some embodiments, the pharmaceutical formulations described herein have a pH of about 3.6 or less. In some embodiments, the pharmaceutical formulations described herein have a pH of about 2.7 to about 3.9. In some embodiments, the pharmaceutical formulations described herein have a pH of about 2.7 to about 3.6. In some embodiments, the pharmaceutical formulations described herein have a pH of about 4 to about 8. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.0 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.5 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.5 to about 7.5.

[0426] In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions.

[0427] In some embodiments, the oil-in-water emulsion comprises water, an oil component, and an emulsifier or stabilizer component.

[0428] In some embodiments, water constitutes about 5% to about 90% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 10% to about 80% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 10% to about 70% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 10% to about 60% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 20% to about 70% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 20% to about 60% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 20% to about 50% by weight of the pharmaceutical preparation. In some embodiments, water constitutes about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the pharmaceutical formulation.

[0429] In some embodiments, the oil component constitutes about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 80% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 50% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the oil component constitutes about 5% to about 90% by weight, about 5% to about 80% by weight, about 5% to about 70% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, or about 5% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the oil component includes fatty alcohols, nut oils, and / or mineral oils. In some embodiments, the oil component includes one of the oil components described herein, which includes a blunting agent, a curing agent, or other oil component.

[0430] In some embodiments, the emulsifier or stabilizer component constitutes about 1% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component constitutes about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component constitutes about 1% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component constitutes about 1% to about 30% by weight or about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier component includes a nonionic surfactant. In some embodiments, the emulsifier or stabilizer component includes polysorbate, poloxamer, fatty alcohol, polyethylene glycol fatty acid ether, glyceryl fatty acid ester, and / or polyethylene glycol fatty acid ester. In some embodiments, the emulsifier or stabilizer component includes one of the emulsifiers, stabilizers, or surfactants described herein.

[0431] In some embodiments, the emulsifier or stabilizer component includes a nonionic surfactant. In some embodiments, the nonionic surfactant is cetomacrogol 1000 or poloxamer 407.

[0432] In some embodiments, the pharmaceutical formulation further comprises a solvent component for dissolving ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the solvent component constitutes about 1% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 2% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 5% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 5% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 10% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component constitutes about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component includes diethylene glycol monoethyl ether, e.g., Transcutol® P. In some embodiments, the solvent component includes one of the solvent components described herein. In some embodiments, propylene glycol is present in about 6.5% by weight of the emulsion. In some embodiments, the solvent component includes diethylene glycol monoethyl ether, e.g., Transcutol® P. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 30% by weight of the emulsion. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 20% by weight of the emulsion.

[0433] In some embodiments, the pharmaceutical formulation further comprises an antioxidant. In some embodiments, the antioxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof. In some embodiments, the antioxidant constitutes about 0.01% to about 10% by weight, about 0.01% to about 5% by weight, about 0.01% to about 2% by weight, about 0.01% to about 1% by weight, or about 0.1% to about 10% by weight of the pharmaceutical formulation.

[0434] In some embodiments, the pH is adjusted to about 6.0 to about 7.0, or about 6.5 to about 7.0. In some embodiments, the pH is adjusted with trolamine.

[0435] In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.

[0436] In some embodiments, the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.

[0437] In some embodiments, the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.

[0438] In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

[0439] In some embodiments, the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone.

[0440] In some embodiments, the oil component includes an occlusive agent component.

[0441] In some embodiments, the occlusive agent is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0442] In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.

[0443] In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.

[0444] In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolinic acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., bee wax).

[0445] In some embodiments, the occlusive agent component comprises one or more substances selected from lanolinic acid fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and bee wax.

[0446] In some embodiments, the occlusive agent component includes petrolatum.

[0447] In some embodiments, the occlusive agent component includes white petrolatum.

[0448] In some embodiments, white petrolatum is present in an amount of about 7% by weight of the emulsion.

[0449] In some embodiments, the oil component includes a curing agent component.

[0450] In some embodiments, the curing agent component is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0451] In some embodiments, the curing agent component is present in an amount of about 2% to about 8% by weight of the emulsion.

[0452] In some embodiments, the curing agent component is present in an amount of about 3% to about 6% by weight of the emulsion.

[0453] In some embodiments, the curing agent component comprises one or more substances independently selected from fatty alcohols.

[0454] In some embodiments, the curing agent component comprises one or more substances independently selected from C12-20 fatty alcohols.

[0455] In some embodiments, the curing agent component comprises one or more substances independently selected from C16-C18 fatty alcohols.

[0456] In some embodiments, the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol. In some embodiments, cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0457] In some embodiments, the amount of cetyl alcohol is about 3% by weight of the emulsion.

[0458] In some embodiments, stearyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0459] In some embodiments, stearyl alcohol is present in an amount of about 1.75% by weight of the emulsion.

[0460] In some embodiments, the oil component includes a softening component.

[0461] In some embodiments, the softening component is present in an amount of about 0.1% to about 20% by weight of the emulsion.

[0462] In some embodiments, the softening component is present in an amount of about 5% to about 20% by weight of the emulsion.

[0463] In some embodiments, the softening component is present in an amount of about 10% to about 15% by weight of the emulsion.

[0464] In some embodiments, the softening component comprises one or more substances independently selected from mineral oils, triglycerides, and silicone oils.

[0465] In some embodiments, the softening component comprises one or more substances independently selected from light mineral oils, medium-chain triglycerides, and dimethicone.

[0466] In some embodiments, light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0467] In some embodiments, light mineral oil is present in an amount of about 4% by weight of the emulsion.

[0468] In some embodiments, dimethicone is present in an amount of about 1% by weight of the emulsion.

[0469] In some embodiments, the amount of medium-chain triglycerides is about 7% by weight of the emulsion.

[0470] In some embodiments, the amount of medium-chain triglycerides is about 10% by weight of the emulsion.

[0471] In some embodiments, the softening component comprises one or more substances independently selected from mineral oils, triglycerides, silicone oils, and nut oils.

[0472] In some embodiments, the nut oil is almond oil. In some embodiments, the almond oil is sweet almond oil. In some embodiments, the sweet almond oil is present in an amount of about 0.1% to about 15% by weight of the emulsion. In some embodiments, the sweet almond oil is present in an amount of about 0.1% to about 10% by weight of the emulsion.

[0473] In some embodiments, water is present in an amount of about 20% to about 80% by weight of the emulsion.

[0474] In some embodiments, water is present in an amount of about 35% to about 65% by weight of the emulsion.

[0475] In some embodiments, water is present in an amount of about 45% to about 65% by weight of the emulsion.

[0476] In some embodiments, the emulsifier component is present in an amount of about 0.5% to about 15% by weight of the emulsion.

[0477] In some embodiments, the emulsifier component is present in an amount of about 1% to about 10% by weight of the emulsion.

[0478] In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.

[0479] In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.

[0480] In some embodiments, the emulsion comprises an emulsifier component and a curing agent component, the total amount of the emulsifier component and curing agent component being at least about 8% by weight of the emulsion.

[0481] In some embodiments, the emulsifier component comprises one or more nonionic emulsifiers.

[0482] In some embodiments, the emulsifying component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0483] In some embodiments, the emulsifying component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0484] In some embodiments, glyceryl stearate is present in an amount of about 3% by weight of the emulsion.

[0485] In some embodiments, polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.

[0486] In some embodiments, the emulsion further comprises a stabilizing component.

[0487] In some embodiments, the stabilizing component is present in an amount of about 0.05% to about 5% by weight of the emulsion.

[0488] In some embodiments, the stabilizing component is present in an amount of about 0.1% to about 2% by weight of the emulsion.

[0489] In some embodiments, the stabilizing component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.

[0490] In some embodiments, the stabilizing component comprises one or more substances independently selected from polysaccharides.

[0491] In some embodiments, the stabilizing component includes xanthan gum.

[0492] In some embodiments, the emulsion further comprises a solvent component. In some embodiments, the solvent component is a solvent for a JAK inhibitor (e.g., ruxolitinib) or a pharmaceutically acceptable salt thereof.

[0493] In some embodiments, the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.

[0494] In some embodiments, the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.

[0495] In some embodiments, the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.

[0496] In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0497] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0498] In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, and propylene glycol.

[0499] In some embodiments, the solvent components include PEG300 and propylene glycol.

[0500] In some embodiments, PEG300 is present in an amount of about 7% by weight of the emulsion.

[0501] In some embodiments, the solvent is a combination of PEG400 and propylene glycol.

[0502] In some embodiments, PEG400 is present in an amount of about 7% by weight of the emulsion.

[0503] In some embodiments, propylene glycol is present in an amount of about 6.5% by weight of the emulsion.

[0504] In some embodiments, the oil-in-water emulsion is Approximately 20% to 80% by weight of water in the emulsion. Approximately 10% to 40% by weight of oil components in the emulsion. Emulsifier component of approximately 1% to 10% by weight of emulsion, Approximately 1% to 35% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.05% to 5% by weight of stabilizer components.

[0505] In some embodiments, the oil-in-water emulsion is Approximately 35% to 65% by weight of water in the emulsion. Approximately 15% to 35% by weight of oil components in the emulsion. Emulsifier component, approximately 2% to 6% by weight of the emulsion. Approximately 5% to 25% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.05% to 5% by weight of stabilizer components.

[0506] In some embodiments, the oil-in-water emulsion is Approximately 40% to 65% by weight of water in the emulsion. Approximately 20% to 28% by weight of oil components in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 10% to 20% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.1% to 2% by weight of stabilizing agents.

[0507] In some embodiments, the oil-in-water emulsion is Approximately 40% to 65% by weight of water in the emulsion. Approximately 20% to 28% by weight of oil components in the emulsion. Emulsifier component, approximately 3% to 5% by weight of the emulsion Approximately 10% to 20% by weight of solvent components in the emulsion, and The emulsion further contains approximately 0.3% to 0.5% by weight of stabilizing agents.

[0508] In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising an oil-in-water emulsion, the oil-in-water emulsion comprising water, an oil component, and an emulsifier component. The oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oil, triglycerides, and dimethicone. The emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters. The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols. The stabilizing agent component comprises one or more substances independently selected from polysaccharides.

[0509] In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising an oil-in-water emulsion, the oil-in-water emulsion comprising water, an oil component, and an emulsifier component. The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone. The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20. The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol. The stabilizing agent component includes xanthan gum.

[0510] In some embodiments, the emulsion further comprises an antimicrobial preservative component.

[0511] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the emulsion.

[0512] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the emulsion.

[0513] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.

[0514] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.

[0515] In some embodiments, the antimicrobial preservative component includes methylparaben and propylparaben.

[0516] In some embodiments, methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0517] In some embodiments, methylparaben is present in an amount of about 0.1% by weight of the emulsion.

[0518] In some embodiments, propylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.

[0519] In some embodiments, propylparaben is present in an amount of about 0.05% by weight of the emulsion.

[0520] In some embodiments, phenoxyethanol is present in an amount of about 0.1% to about 15% by weight of the emulsion.

[0521] In some embodiments, phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.

[0522] In some embodiments, the pH of the cream is approximately 4 to 8.

[0523] In some embodiments, the pH of the cream is approximately 6.5 to 7.0.

[0524] In some embodiments, the emulsion further comprises an antioxidant.

[0525] In some embodiments, the antioxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof.

[0526] In some embodiments, butylated hydroxytoluene is present in an amount of about 0.01% to about 15% by weight of the emulsion. In some embodiments, butylated hydroxytoluene is present in an amount of about 0.1% to about 10% by weight of the emulsion. In some embodiments, butylated hydroxytoluene is present in an amount of about 0.1% to about 5% by weight of the emulsion.

[0527] In some embodiments, butylhydroxyanisole is present in an amount of about 0.001% to about 5% by weight of the emulsion. In some embodiments, butylhydroxyanisole is present in an amount of about 0.01% to about 1% by weight of the emulsion.

[0528] In some embodiments, the emulsion further comprises a calcipotriol stabilizer.

[0529] In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, fumaric acid, or citric acid, or a combination thereof.

[0530] In some embodiments, the Disclosure also provides a pharmaceutical formulation (or, alternatively, a method according to any one of Embodiments 1 to 75) for topical treatment of a skin disease, wherein the formulation, on a free base basis, comprises about 1.5% w / w ruxolitinibulinate, about 0.005% w / w calcipotriol, about 55% w / w purified water, about 0.05% w / w disodium EDTA, about 7% w / w PEG300, about 6.5% w / w propylene glycol, and about 0.1% w / w methylparaben. It is an oil-in-water emulsion containing approximately 0.05% w / w propylparaben, approximately 0.4% w / w xanthan gum, approximately 7% w / w white petrolatum, approximately 4% w / w light mineral oil, approximately 3% w / w glycerol stearate SE, approximately 3% w / w cetyl alcohol, approximately 1.75% w / w stearyl alcohol, approximately 1% w / w dimethicone, approximately 7% w / w medium-chain triglycerides, approximately 1.25% w / w polysorbate 20, and approximately 0.5% w / w phenoxyethanol.

[0531] In some embodiments, the Disclosure also provides a pharmaceutical formulation (or, alternatively, a method according to any one of Embodiments 1 to 75) for topical treatment of skin diseases, the formulation comprising, on a free base basis, about 1.5% w / w ruxolitinibulinate, about 0.005% w / w calcipotriol, about 55% w / w purified water, about 0.05% w / w disodium EDTA, about 7% w / w PEG400, about 6.5% w / w propylene glycol, and about 0.1% w / w methylparaben. This is an oil-in-water emulsion containing approximately 0.05% w / w propylparaben, approximately 0.4% w / w xanthan gum, approximately 7% w / w white petrolatum, approximately 4% w / w light mineral oil, approximately 3% w / w glycerol stearate SE, approximately 3% w / w cetyl alcohol, approximately 1.75% w / w stearyl alcohol, approximately 1% w / w dimethicone, approximately 7% w / w medium-chain triglycerides, approximately 1.25% w / w polysorbate 20, and approximately 0.5% w / w phenoxyethanol.

[0532] In some embodiments, the pH of the pharmaceutical formulations described herein is adjusted with trolamine (triethanolamine). In some embodiments, the pH of the pharmaceutical formulations described herein is adjusted with phosphoric acid.

[0533] In some embodiments, the emulsified formulation of ruxolitinib described above may also be used in the fixed-dose combination formulations described below. The topical formulations described above can utilize any preferred combination of the vitamin D derivatives, vitamin D3 analogs, and JAK inhibitors described above.

[0534] When used in the context of "topical treatment of skin diseases," "topical" means administration to the skin.

[0535] Pharmaceutical formulations for topical administration to the skin may include solutions, suspensions, foams, ointments, lotions, creams, gels, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, etc., may be essential or desirable. In some embodiments, compositions are formulated for topical administration as solutions, suspensions, gels, creams, ointments, lotions, sprays, foams, liquids, and powders.

[0536] For the treatment of skin diseases described herein, topical drugs that can penetrate the skin barrier and provide limited systemic effects are of particular importance.

[0537] Topical (cutaneous / intradermal) formulations are typically solutions, suspensions, gels, creams, ointments, lotions, sprays, and foams. Preferred topical formulations should be physically and chemically stable, not cause skin irritation, and deliver the active ingredient to the appropriate layer of skin at a concentration that produces a therapeutic response with limited systemic exposure.

[0538] In some embodiments, the administration is topical and consists of a formulation having one or more pharmaceutically (e.g., dermatologically) acceptable excipients. Examples of dermatologically acceptable excipients include, but are not limited to, pH adjusters, chelating agents, preservatives, cosolvents, penetration enhancers, humectants, thickeners, gelling agents, viscosity builders, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof. In some embodiments, the topical formulation is administered topically to the patient (e.g., at the site of the lesion).

[0539] In some embodiments, the pH adjuster is selected from acids, acid salts, bases, base salts, and buffers, or any mixture thereof. Exemplary acids include, but are not limited to, lactic acid, acetic acid, citric acid, and benzoic acid, as well as their salts. Exemplary buffers include, but are not limited to, citrate / citric acid, acetate / acetic acid, edetate / edetic acid, and lactate / lactic acid.

[0540] In some embodiments, the chelating agent is a single excipient. In some embodiments, the chelating agent is a mixture of two or more chelating agents. Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or its salts. In some embodiments, the chelating agent comprises a mixture of a chelating agent and an antioxidant, the chelating agent and antioxidant preventing, minimizing, or reducing oxidative degradation reactions in the composition. Exemplary antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, and propyl gallate.

[0541] In some embodiments, the composition comprises one or more preservatives. In some embodiments, the composition comprises a mixture of two or more preservatives. In some embodiments, the composition comprises one to five preservatives. Exemplary preservatives include, but are not limited to, benzyl alcohol, phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben, and imidazolidinyl urea.

[0542] In some embodiments, the composition comprises one or more cosolvents. In some embodiments, the composition comprises a mixture of two or more cosolvents. In some embodiments, the composition comprises one to five cosolvents. Exemplary solvents include, but are not limited to, water, propylene glycol, diethylene glycol monoethyl ether, dimethyl isosorbide, ethyl alcohol, isopropyl alcohol, benzyl alcohol, propanediol, propylene glycol, and polyethylene glycol (e.g., polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, etc.). In some embodiments, the solvent is a water-insoluble agent. Exemplary water-insoluble agents include, but are not limited to, diethyl sebacate, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, and medium-chain triglycerides.

[0543] In some embodiments, the composition comprises one or more penetration accelerators. In some embodiments, the composition comprises a mixture of two or more penetration accelerators. In some embodiments, the composition comprises one to five penetration accelerators. Penetration accelerators can act as both solvents and penetration accelerators. Exemplary penetration accelerators include, but are not limited to, fatty acids, fatty acid esters, fatty alcohols, pyrrolidones, sulfoxides, alcohols, diols, and polyols, or any mixture thereof. In some embodiments, the cosolvent provided herein is a penetration accelerator.

[0544] In some embodiments, the composition comprises one or more thickeners, gelling agents, or viscosity builders. In some embodiments, the composition comprises a mixture of two or more thickeners, gelling agents, or viscosity builders. In some embodiments, the composition comprises one to five thickeners, gelling agents, or viscosity builders. Exemplary thickeners, gelling agents, or viscosity builders include, but are not limited to, cellulose derivatives (e.g., hydroxyethylcellulose (HEC), carboxymethylcellulose, hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC)) and polyvinylpyrrolidone (PVP).

[0545] A surfactant is a compound that reduces the interfacial tension between two liquids, or between a liquid and a solid. A surfactant can be a mixture of two or more surfactants. Exemplary surfactants include, but are not limited to, ethoxylated fatty alcohol ethers (e.g., steareth-2, steareth-10, steareth-20, ceteareth-2, ceteareth-10, etc.), PEG esters (e.g., PEG-4 dilaurate, PEG-20 stearate, etc.), glyceryl esters or their derivatives (e.g., glyceryl dioleate, glyceryl stearate, etc.), polymer ethers (e.g., poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 407, etc.), sorbitan derivatives (e.g., polysorbate 80, sorbitan monostearate, etc.), fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol, etc.), and emulsifying waxes (e.g., emulsifying wax NF, a mixture of cetearyl alcohol and polysorbate 60, etc.).

[0546] Topical (e.g., intradermal) administration, as described herein, offers the advantages of treating skin diseases and / or disorders locally, minimizing potential adverse events associated with systemic exposure, and, if necessary, allowing for easier discontinuation of treatment. Furthermore, some topical dosage forms, such as creams, ointments, and gels, have the advantage of excipients that can act as emollients or occlusive agents, which can improve patient health and compliance during the course of treatment. Other routes of administration, such as oral, parenteral, and inhalation, may lead to systemic drug levels exceeding therapeutic doses, an increased likelihood of adverse events, drug interactions, and the generation of active / toxic metabolites, which may result in treatment discontinuation and poor patient compliance.

[0547] Topical formulations intended for skin delivery are typically solutions, suspensions, gels, creams, ointments, lotions, sprays, and foams, and may contain one or more conventional carriers as described herein. The formulation composition should be prepared to deliver the active ingredient to the appropriate layer(s) of the skin, minimize systemic exposure, and prevent skin irritation. Furthermore, the pharmaceutical composition must be physically and chemically stable. Depending on the selected dosage form, one or more additional excipients as described herein may be required, such as pH adjusters, chelating agents, preservatives, cosolvents, penetration enhancers, humectants, thickeners, gelling agents, viscosity builders, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof.

[0548] In some embodiments, topical formulations may contain one or more conventional carriers described herein. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Carrier compositions for creams may be based on a combination of water, glycerol, and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethylcellulose, etc.

[0549] The compositions administered to the patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or aseptically filtered. Aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier before administration.

[0550] The subject matter compositions described in these claims may further comprise one or more additional pharmaceuticals, examples of which are listed above.

[0551] Combination therapy The methods described herein may further include administering one or more additional therapeutic agents. These additional therapeutic agents may be administered to the patient simultaneously or sequentially.

[0552] In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, erythromycin, metronidazole, rifampin, moxifloxacin, dapsone, or a combination thereof. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, or erythromycin in combination with metronidazole. In some embodiments, the antibiotic is a combination of rifampin, moxifloxacin, and metronidazole. In some embodiments, the antibiotic is a combination of moxifloxacin and rifampin.

[0553] In some embodiments, the additional therapeutic agent is a retinoid. In some embodiments, the retinoid is adapalene, etretinate, acitretin, or isotretinoin.

[0554] In some embodiments, the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the steroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or flumetholone.

[0555] In some embodiments, the additional therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate or cyclosporine A. In some embodiments, the immunosuppressant is mycophenolate mofetil or mycophenolate sodium.

[0556] In some embodiments, the additional therapeutic agent is azelaic acid.

[0557] In some embodiments, the additional therapeutic agent is for topical treatment. In some embodiments, the additional therapeutic agent is for treating psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital onychoplakia, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis. In some embodiments, the additional therapeutic agent is for treating atopic dermatitis. In some embodiments, the additional therapeutic agent is pimecrolimus. In some embodiments, the additional therapeutic agent is for treating psoriasis. In some embodiments, the additional therapeutic agent is for treating alopecia. In some embodiments, the additional therapeutic agent is for treating vitiligo. In some embodiments, the additional therapeutic agent is for treating Reiter's syndrome. In some embodiments, the additional therapeutic agent is for treating pityriasis rubra pilaris. In some embodiments, the additional therapeutic agent is for treating epidermolysis bullosa simplex. In some embodiments, the additional therapeutic agent is for treating palmoplantar keratosis. In some embodiments, the additional therapeutic agent is for treating congenital onychoplakia. In some embodiments, the additional therapeutic agent is for treating multiple sebaceous cysts. In some embodiments, the additional therapeutic agent is for treating cutaneous lichen planus. In some embodiments, the additional therapeutic agent is for treating cutaneous T-cell lymphoma. In some embodiments, the additional therapeutic agent is for treating hidradenitis suppurativa. In some embodiments, the additional therapeutic agent is for treating contact dermatitis. In some embodiments, the additional therapeutic agent is for treating ichthyosis.

[0558] In some embodiments, the additional therapeutic agent is crisabolol.

[0559] In some embodiments, the additional therapeutic agent is tacrolimus.

[0560] In some embodiments, the additional therapeutic agent is pimecrolimus.

[0561] kit This disclosure also includes a pharmaceutical kit useful in the treatment and / or prevention of skin conditions described herein, such as psoriasis, alopecia, and vitiligo, which includes one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof as described herein. As will be readily apparent to those skilled in the art, such a kit may further include one or more of various conventional pharmaceutical kit components, such as additional containers, for example, containers containing one or more pharmaceutically acceptable carriers, if desired. Instructions indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit, either as inserts or labels.

[0562] For clarity, it is further understood that certain features of the subject matter described in these claims, as described in relation to separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the subject matter described in these claims, as described in relation to a single embodiment, may also be provided separately or as any preferred subcombination.

[0563] definition As used herein, “affected skin area” refers to an area of ​​skin in a patient having a skin disease as described herein.

[0564] As used herein, “ruxolitinibulinate” means ruxolitinib phosphate, where ruxolitinib and phosphate are in a 1:1 ratio.

[0565] As used herein, “cream” means an emulsion, semi-solid dosage form intended for application to the skin.

[0566] When used herein, "C" is used alone or in combination with other terms.3-4 The term "cycloalkyl" refers to a non-aromatic monocyclic hydrocarbon moiety having 3 to 4 carbon atoms and optionally containing one or more alkenylene groups as part of its ring structure. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form a carbonyl bond. An example is C 3-4 Examples of cycloalkyl groups include cyclopropyl and cyclobutyl. In some embodiments, the cycloalkyl group is cyclopropyl. In some embodiments, the cycloalkyl group is cyclobutyl.

[0567] As used herein, the terms “synergistic effect” or “combined effect” mean any measured effect of a combination of drugs or compounds that is greater than the effect predicted from the sum of the effects of the individual drugs or compounds, when used in connection with a description of the effectiveness of such a combination. For example, as described herein, there is a synergistic effect of inhibiting IL-22, MMP12, and CXCL10 between (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, vitamin D3 analogue, or a pharmaceutically acceptable salt thereof, meaning that the total inhibitory effect of the combination of (a) and (b) is greater than the sum of the inhibitory effects of (a) and (b) individually.

[0568] As used herein, “statistically significant” means a p-value of <0.05 (preferably <0.001, most preferably <0.0001).

[0569] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with human and animal tissues. In some embodiments, “pharmaceutically acceptable” means that it is approved by a federal or state regulatory agency or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more specifically in humans.

[0570] The subject matter described in these claims also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. pharmaceutically acceptable salts of the subject matter described in these claims include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. pharmaceutically acceptable salts of the subject matter described in these claims can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two, generally in non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN). A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. In some embodiments, pharmaceutically acceptable salts are phosphates, sulfates, or maleates.

[0571] As used herein, the term “emulsifier component” refers, in one embodiment, to a substance or mixture of substances that maintains elements or particles in a suspension in a fluid medium. In some embodiments, the emulsifier component, when combined with water, allows the oil phase to form an emulsion. In some embodiments, the emulsifier component refers to one or more nonionic surfactants.

[0572] As used herein, the term “occlusive agent” refers to a hydrophobic agent or a mixture of hydrophobic agents that forms an occlusive film on the skin that reduces transepidermal water loss (TEWL) by preventing the evaporation of water from the stratum corneum.

[0573] As used herein, the term “curing agent component” refers to a substance or mixture of substances that increases the viscosity and / or consistency of a cream or improves the rheology of a cream.

[0574] As used herein, the term “softening agent” refers to an agent that softens or soothes the skin, or soothes an irritated interior.

[0575] As used herein, the term “stabilizing component” refers to a substance or mixture of substances that improve the stability of a cream and / or the compatibility of components in a crumb. In some embodiments, the stabilizing component prevents the aggregation of an emulsion and stabilizes droplets in an oil-in-water emulsion.

[0576] As used herein, the term “solvent component” refers to a liquid substance or mixture of liquid substances capable of dissolving the JAK inhibitors described herein, such as ruxolitinib or a pharmaceutically acceptable salt thereof, or other substances in the cream. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which ruxolitinib or a pharmaceutically acceptable salt thereof has reasonable solubility. For example, the solubility of ruxolitinib (free base) or its phosphate (1:1 salt) is reported in Table 1. In some embodiments, the solvent is a substance or mixture thereof in which ruxolitinib or a pharmaceutically acceptable salt thereof (either of which is used) has a solubility of at least about 10 mg / mL, at least about 15 mg / mL, or at least about 20 mg / mL.

[0577] As used herein, the term “antimicrobial preservative ingredient” refers to a substance or mixture of substances that inhibit microbial growth in a cream.

[0578] As used herein, the term "chelating agent" refers to a compound or mixture of compounds that has the ability to strongly bind to metal ions.

[0579] As used herein, “wt% of emulsion” means that the percentage of the concentration of an ingredient in the emulsion is on a weight / weight basis. For example, 1% w / w of ingredient A = [(mass of ingredient A) / (total mass of emulsion)] × 100.

[0580] When used herein, “free base basis, wt% of emulsion” for JAK inhibitors described herein, such as ruxolitinib or any pharmaceutically acceptable salt thereof, means that the %w / w is calculated based on the weight of ruxolitinib in the total emulsion. For example, “1.5% w / w, free base basis” of ruxolitinibulinate means that for 100 grams of the total formulation, there are 1.98 grams of ruxolitinibulinate in the emulsion (this corresponds to 1.5 grams of free base, ruxolitinib).

[0581] When used herein, “free base basis, weight % of the formulation” for JAK inhibitors described herein, such as ruxolitinib or any pharmaceutically acceptable salt thereof, means that the %w / w is calculated based on the weight of ruxolitinib in the total formulation. For example, “free base basis, 1.5% w / w” of ruxolitinibulinate means that for 100 grams of the total formulation, there are 1.98 grams of ruxolitinibulinate in the formulation (this corresponds to 1.5 grams of free base, ruxolitinib).

[0582] As used herein, the term “component” may mean one substance or a mixture of substances.

[0583] As used herein, the term “fatty acid” refers to saturated or unsaturated fatty acids. In some embodiments, the fatty acid is a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about 8 to about 30 carbon atoms. In some embodiments, the fatty acid has an average of about 12 to 20, 14 to 20, or 16 to 18 carbon atoms. Suitable fatty acids include, but are not limited to, cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof.

[0584] As used herein, the term “fatty alcohol” refers to saturated or unsaturated aliphatic alcohols. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has, on average, about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbon atoms. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidone alcohol, behenyl alcohol, isobehenyl alcohol, ceratyl alcohol, chymyl alcohol, and linoleyl alcohol, or mixtures thereof.

[0585] As used herein, the term “polyalkylene glycol,” when used alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units, or a copolymer of different oxyalkylene monomer units, where the alkylene group has 2-6, 2-4, or 2-3 carbon atoms. As used herein, the term “oxyalkylene,” when used alone or in combination with other terms, refers to a group of the formula -O-oxyalkylene-. In some embodiments, polyalkylene glycol is polyethylene glycol.

[0586] As used herein, the term “sorbitan fatty acid ester” includes sorbitan or sorbitol and fatty acids, and optionally products derived from poly(ethylene glycol) units, and includes sorbitan esters and polyethoxylated sorbitan esters. In some embodiments, the sorbitan fatty acid ester is a polyethoxylated sorbitan ester.

[0587] As used herein, the term “sorbitan ester” refers to a compound or mixture of compounds derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for deriving sorbitan esters are, but are not limited to, those listed herein. Preferred sorbitan esters include, but are not limited to, the Span® series (available from Uniqema), which includes Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). Other preferred sorbitan esters are listed in RCRowe and PJShesky, Handbook of Pharmaceutical Excipients (2006), 5th ed., which are incorporated herein by reference in their entirety.

[0588] As used herein, the term “polyethoxylated sorbitan ester” refers to a compound or mixture thereof derived from the ethoxylation of a sorbitan ester. The polyoxyethylene portion of the compound may be present between the fatty acid ester and the sorbitan portion. As used herein, the term “sorbitan ester” refers to a compound or mixture thereof derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for the derivation of polyethoxylated sorbitan esters are, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to, the Tween® series (available from Uniqema), which includes Tween 20 (POE(20) sorbitan monolaurate), 21 (POE(4) sorbitan monolaurate), 40 (POE(20) sorbitan monopalmitate), 60 (POE(20) sorbitan monostearate), 60K (POE(20) sorbitan monostearate), 61 (POE(4) sorbitan monostearate), 65 (POE(20) sorbitan tristearate), 80 (POE(20) sorbitan monooleate), 80K (POE(20) sorbitan monooleate), 81 (POE(5) sorbitan monooleate), and 85 (POE(20) sorbitan trioleate). As used herein, the abbreviation "POE" refers to polyoxyethylene. The number following the POE abbreviation indicates the number of oxyethylene repeating units in the compound.Other suitable polyethoxylated sorbitan esters include the polyoxyethylene sorbitan fatty acid esters listed in R.C. Rowe and P.J. Shesky, Handbook of Pharmaceutical Excipients (2006), 5th ed., which are incorporated herein by reference in their entirety. In some embodiments, the polyethoxylated sorbitan ester is a polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

[0589] As used herein, the term “glyceryl fatty acid ester” refers to a mono, di, or triglyceride of a fatty acid. Glyceryl fatty acid esters may optionally be substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids for derivation of fatty acid glycers are, but are not limited to, those described herein. In some embodiments, the glyceryl fatty acid ester is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceryl fatty acid ester is glyceryl stearate.

[0590] As used herein, the term “triglyceride” refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium-chain triglyceride.

[0591] As used herein, the term "alkylene glycol" refers to a group of the formula -O-alkylene-, where the alkylene group has 2-6, 2-4, or 2-3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).

[0592] As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Preferred polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or one or more hydroxyl groups etherified with lower alkyl groups, such as methyl groups. Derivatives of polyethylene glycol having esterifiable carboxyl groups are also preferred. Polyethylene glycols useful in this disclosure may be polymers of any chain length or molecular weight and may include branching. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number after the dash in the name refers to the average molecular weight of the polymer.

[0593] As used herein, “contains” is equivalent to “includes.”

[0594] As used herein, the terms “subject,” “individual,” or “patient,” used interchangeably, refer to a human being. In some embodiments, the “subject,” “individual,” or “patient” is the one requiring the treatment.

[0595] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts, or their pharmaceutical formulations, or their topical formulations, are administered in therapeutically effective amounts. As used herein, the term “therapeutably effective amount” means the amount of the active compound or pharmaceutical product that elicits a desired biological or pharmacological response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician.

[0596] As used herein, the terms “to treat” or “to cure” mean one or more of the following: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or overall symptoms of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or overall symptoms); (2) relieving a disease, e.g., reducing the severity of the disease, or reversing a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or overall symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or overall symptoms); or (3) preventing a disease, condition, or disorder in an individual who is predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or overall symptoms of the disease. In some embodiments, treating means inhibiting or relieving a disease. In some embodiments, treating means preventing a disease.

[0597] In some embodiments, the components are exactly within a specified range (for example, the term "approximately" does not exist). In some embodiments, the term "approximately" means ±10% of the value.

[0598] This disclosure also provides the following non-limiting embodiments.

[0599] Examples are provided below to allow for a more efficient understanding of the embodiments disclosed herein. These examples are for illustrative purposes only and should not be construed as limiting the embodiments in any way.

[0600] In some embodiments, the following embodiments are provided.

[0601] 1. A method for treating a skin disease in a patient who requires treatment for a skin disease, comprising topically administering to the patient the following to the affected area: (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof; and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0602] 2. The method according to Embodiment 1, wherein the skin disease is an autoimmune skin disease.

[0603] 3. The method according to Embodiment 1 or 2, wherein the skin disease is an inflammatory skin disease.

[0604] 4. The method according to any one of Embodiments 1 to 3, wherein the skin disease is a Th1 or Th17-related skin disease.

[0605] 5. The method according to any one of Embodiments 1 to 4, wherein the skin disease is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof.

[0606] 6. The method according to any one of Embodiments 1 to 5, wherein the skin disease is mediated by IL-22.

[0607] 7. The method according to any one of Embodiments 1 to 5, wherein the skin disease is mediated by MMP12.

[0608] 8. The method according to any one of Embodiments 1 to 5, wherein the skin disease is mediated by CXCL10.

[0609] 9. The method according to any one of Embodiments 1 to 8, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital onychoplakia, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.

[0610] 10. The method according to Embodiment 9, wherein the skin disease is psoriasis.

[0611] 11. The method according to Embodiment 9, wherein the skin disease is alopecia.

[0612] 12. The method according to Embodiment 11, wherein the alopecia is alopecia areata.

[0613] 13. The method according to Embodiment 9, wherein the skin disease is vitiligo.

[0614] 14. The method according to any one of Embodiments 1 to 13, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0615] 15. The method according to any one of Embodiments 1 to 13, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered sequentially.

[0616] 16. The method according to any one of Embodiments 1 to 15, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered at least once a day.

[0617] 17. The method according to any one of Embodiments 1 to 15, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered once daily.

[0618] 18. The method according to any one of Embodiments 1 to 15, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered twice daily.

[0619] 19. The method according to any one of Embodiments 1 to 18, wherein the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered once daily.

[0620] 20. The method according to any one of Embodiments 1 to 18, wherein the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered twice daily.

[0621] 21. The method according to any one of Embodiments 1 to 20, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as separate formulations.

[0622] 22. The method according to any one of Embodiments 1 to 14, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as a single formulation.

[0623] 23. The method according to Embodiment 22, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered once daily.

[0624] 24. The method according to Embodiment 22, wherein (a) the JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered twice daily.

[0625] 25. The method according to any one of Embodiments 1 to 24, wherein the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in a synergistic amount.

[0626] 26. The method according to any one of Embodiments 1 to 24, wherein a synergistic effect exists between the JAK inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0627] 27. The method according to any one of embodiments 1 to 26, further comprising administering an additional therapeutic agent.

[0628] 28. The method according to Embodiment 27, wherein the additional therapeutic agent is a corticosteroid.

[0629] 29. The method according to any one of Embodiments 1 to 28, wherein the patient is a human patient.

[0630] 30. The vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof is a compound having formula (I), [ka] During the ceremony, R 1 However, it is either H or OH, R 2 and R 3 However, each of them is H, or R 2 However, OR 2A And R 3 However, is it H, or R 2 and R 3 However, together they form a CH2 group, R 2A However, -C 1-4 It is alkylene-OH, R 4 and R 5 However, each of them is H, or R 4and R 5 However, together they form a CH2 group, R 6 and R 7 However, each of them is H, or R 6 and R 7 However, together they form a CH2 group, L is -CH2-CH2-CH(R 12 )-,-CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-, where R 12 However, it is either H or OH, R 9 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 10 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 11 However, is it H or OH? Alternatively, R 9 and R 10 However, together with the carbon atoms to which they bond, C 3-4 Forming a cycloalkyl ring, R 11 The method according to any one of Embodiments 1 to 29, wherein H.

[0631] 31. The vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof is a compound having formula (II), [ka] During the ceremony, R 1 However, it is either H or OH, R 2 and R 3 However, each of them is H, or R 2 However, OR 2A And R3 However, is it H, or R 2 and R 3 However, together they form a CH2 group, R 2A However, -C 1-4 It is alkylene-OH, R 4 and R 5 However, each of them is H, or R 4 and R 5 However, together they form a CH2 group, R 6 and R 7 However, each of them is H, or R 6 and R 7 However, together they form a CH2 group, L is -CH2-CH2-CH(R 12 )-,-CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-, where R 12 However, it is either H or OH, R 9 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 10 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 11 However, is it H or OH? Alternatively, R 9 and R 10 However, together with the carbon atoms to which they bond, C 3-4 Forming a cycloalkyl ring, R 11 The method according to any one of Embodiments 1 to 29, wherein H.

[0632] The method according to any one of Embodiments 1 to 29, wherein 32.(b) is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0633] 33. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is a vitamin 1α-(OH)D3 analog or a pharmaceutically acceptable salt thereof.

[0634] 34. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is a vitamin 1α,25(OH)2D3 analog, a vitamin 1α,24(OH)2D3 analog, or a vitamin 1α,26(OH)2D3 analog or a pharmaceutically acceptable salt thereof.

[0635] 35. The vitamin D3 analog or the pharmaceutically acceptable salt thereof is a compound having formula (III), [ka] During the ceremony, R 2 and R 3 However, each of them is H, or R 2 However, OR 2A And R 3 However, H is, R 2A However, -C 1-4 It is alkylene-OH, R 6 and R 7 However, each of them is H, or R 6 and R 7 However, together they form a CH2 group, L is -CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, -O-CH2-CH2-CH2-, and in the formula, R 12 However, it is either H or OH, R 9However, it is either CH3 or CF3. R 10 However, it is either CH3 or CF3. R 11 However, it is either H or OH. Alternatively, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a cyclopropyl ring, R 11 The method according to embodiment 32, wherein H is the same.

[0636] 36. The vitamin D3 analog or the pharmaceutically acceptable salt thereof is calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, phalecalcitriol, eldecalcitol, rice calcitol, theocalcitol, lexicalcitol, 20-epi-1α,25(OH)2D3, CD578(17-methyl-19-nor-21-nor-23-in-26,27-F6-1α,25(OH) 2D3 The method according to Embodiment 32, selected from ), TX527 (19-nor-14,20-bisepi-23-yin-1α,25(OH)2D3), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)2D3), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)2D3), ILX23-7553 (16-ene-23-yin-1α,25(OH)2D3), and MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3).

[0637] 37. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is calcipotriol.

[0638] 38. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is maxacalcitol.

[0639] 39. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is tacalcitol.

[0640] 40. The method according to any one of Embodiments 32 to 39, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is administered by topical formulation.

[0641] 41. The method according to Embodiment 40, wherein the topical preparation is a foam, ointment, lotion, or cream.

[0642] 42. The method according to Embodiment 40 or 41, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is administered as a topical formulation containing about 0.0001% to about 0.1% of the vitamin D3 analog based on the weight of the formulation.

[0643] 43. The method according to Embodiment 40 or 41, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is administered as a topical formulation containing about 0.0004% to about 0.005% of the vitamin D3 analog based on the weight of the formulation.

[0644] 44. The method according to Embodiment 32, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is calcipotriol or a pharmaceutically acceptable salt thereof administered as a topical preparation containing about 50 μg of calcipotriol per gram of the preparation.

[0645] 45. The method according to Embodiment 44, wherein the topical preparation is a foam, ointment, lotion, or cream.

[0646] 46. ​​The method according to Embodiment 44 or 45, wherein the topical formulation further comprises betamethasone dipropionate.

[0647] 47. The method according to Embodiment 46, wherein the betamethasone dipropionate is present in an amount of about 0.5 mg per gram of the preparation.

[0648] 48. The method according to Embodiment 33, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is tacalcitol administered as a topical preparation containing about 4 μg of tacalcitol per gram of the preparation.

[0649] 49. The method according to Embodiment 48, wherein the topical preparation is an ointment, cream, or lotion.

[0650] 50. The method according to Embodiment 33, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is maxacalcitol, administered as a topical preparation containing about 6 μg, about 12.5 μg, about 25 μg, or about 50 μg per gram of the preparation.

[0651] 51. The method according to Embodiment 50, wherein the topical preparation is an ointment.

[0652] 52. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is selected from JAK1 inhibitors, JAK2 inhibitors, JAK3 inhibitors, TYK2 inhibitors, JAK1 / JAK2 inhibitors, JAK1 / JAK3 inhibitors, pan-JAK inhibitors, and JAK1 / TYK2 inhibitors, or pharmaceutically acceptable salts.

[0653] 53. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a JAK1 inhibitor or a pharmaceutically acceptable salt thereof.

[0654] 54. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0655] 55. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a JAK1 / JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0656] 56. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a JAK1 / JAK3 inhibitor or a pharmaceutically acceptable salt thereof.

[0657] 57. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a pan-JAK inhibitor or a pharmaceutically acceptable salt thereof.

[0658] 58. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is a JAK1 / TYK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0659] 59. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is selected from ruxolitinib, baricitinib, oclacitinib, momerotinib, CTP-543, AH057, gandotinib, fedratinib, restaurtinib, pacritinib, CHZ868, upadacitinib, tofacitinib, filgotinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, celduratinib, desernotinib, BMS-986165, and ritrecitinib, or a pharmaceutically acceptable salt thereof.

[0660] 60. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is selected from ruxolitinib, oclacitinib, baricitinib, momerotinib, CTP-543, gandotinib, fedratinib, restaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and celduratinib, or a pharmaceutically acceptable salt thereof.

[0661] 61. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0662] 62. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0663] 63. The method according to Embodiment 61 or 62, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered as a cream formulation.

[0664] 64. The method according to Embodiment 63, wherein the cream formulation is an oil-in-water emulsion.

[0665] 65. The method according to Embodiment 63 or 64, wherein the cream formulation has a pH of about 2.8 to about 3.9.

[0666] 66. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is delgocitinib or a pharmaceutically acceptable salt thereof.

[0667] 67. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is tofacitinib or a pharmaceutically acceptable salt thereof.

[0668] 68. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is ATI-1777 or a pharmaceutically acceptable salt thereof.

[0669] 69. The method according to any one of Embodiments 1 to 51, wherein the JAK inhibitor or the pharmaceutically acceptable salt thereof is brepocitinib or a pharmaceutically acceptable salt thereof.

[0670] 70. The method according to any one of Embodiments 1 to 69, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0671] 71. (b) The method according to any one of Embodiments 1 to 70, wherein the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0672] 72. A method for treating a skin disease in a patient who requires treatment for a skin disease, comprising topically administering to the affected area of ​​the patient (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0673] 73. A method for treating a skin disease in a patient who requires treatment for a skin disease, comprising topically administering to the affected area of ​​the patient (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0674] 74. The method according to Embodiment 73, wherein the vitamin D3 analog or the pharmaceutically acceptable salt thereof is calcipotriol or a pharmaceutically acceptable salt thereof.

[0675] 75. The method according to any one of embodiments 72 to 74, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0676] 76. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof).

[0677] 77. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof).

[0678] 78. The ruxolitinib or the pharmaceutically acceptable salt thereof, on a free base basis, is present in amounts of about 0.1% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.3% by weight, about 0.35% by weight, about 0.4% by weight, about 0.45% by weight, about 0.5% by weight, about 0.55% by weight, about 0.6% by weight, about 0.65% by weight, about 0.7% by weight, about 0.75% by weight, about 0.8% by weight, about 0.85% by weight, about 0.9% by weight, about 0.95% by weight, about 1.0% by weight, and about 1.05% by weight of the formulation. Formulations of Embodiment 77 (or, alternatively, methods) present in amounts of 1.5% by weight, approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.5% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight.

[0679] 79. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) ruxolitinib or a pharmaceutically acceptable salt thereof in a free base of about 0.75% w / w to about 1.5% w / w, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof).

[0680] 80. A pharmaceutical formulation for topical treatment of a skin disease comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof).

[0681] 81. A pharmaceutical formulation for topical treatment of a skin disease comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof).

[0682] 82. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0683] 83. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL to about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0684] 84. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0685] 85. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis). A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0686] 86. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0687] 87. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0688] 88. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0689] 89. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 1 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0690] 90. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 10 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0691] 91. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 50 μg / mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0692] 92. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.01% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.01% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis.

[0693] 93. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0694] 94. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0695] 95. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.0001% w / w to about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0696] 96. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0697] 97. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0698] 98. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof on a free base basis).

[0699] 99. The formulation according to any one of Embodiments 77 to 98, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is ruxolitinibulinate (or, alternatively, the method according to any one of Embodiments 77 to 98).

[0700] 100. The formulation according to any one of Embodiments 76 to 99, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof (or, alternatively, the method according to any one of Embodiments 76 to 99).

[0701] 101. The vitamin D3 analogs or their pharmaceutically acceptable salts include calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, phalecalcitriol, eldecalcitol, inesalcitol, theocalcitol, lexicalcitol, 20-epi-1α,25(OH)2D3, CD578(17-methyl-19-nor-21-nor-23-in-26,27-F6-1α,25(OH) 2D3 A formulation (or, alternatively, a method) according to Embodiment 100, selected from TX527 (19-nor-14,20-bisepi-23-in-1α,25(OH)2D3), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)2D3), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)2D3), ILX23-7553 (16-ene-23-in-1α,25(OH)2D3), and MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3).

[0702] 102. The formulation (or, alternatively, the method) according to Embodiment 100, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol.

[0703] 103. The formulation (or, alternatively, the method) according to Embodiment 100, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is tacalcitol.

[0704] 104. The formulation (or, alternatively, the method) according to Embodiment 100, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is maxacalcitol.

[0705] 105. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w of calcipotriol (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w of calcipotriol).

[0706] 106. A pharmaceutical formulation for topical treatment of a skin disease comprising (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 0.75% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol).

[0707] 107. A pharmaceutical formulation for topical treatment of a skin disease comprising (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol (or, alternatively, the method according to any one of Embodiments 1 to 75, wherein the formulation comprises (a) about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, and (b) about 0.005% w / w calcipotriol).

[0708] 108. A formulation (or, alternatively, a method) according to any one of Embodiments 105 to 107, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0709] 109. The formulation (or, alternatively, the method) according to any one of Embodiments 76 to 108, wherein the formulation is a cream.

[0710] 110. The formulation (or, alternatively, the method) according to any one of Embodiments 76 to 108, wherein the formulation is a lotion.

[0711] 111. The formulation according to any one of Embodiments 76 to 110 (or, alternatively, the method), wherein the formulation further comprises water.

[0712] 112. The formulation according to any one of Embodiments 76 to 111 (or, alternatively, the method), wherein the formulation has a pH of approximately 3.6 or less.

[0713] 113. The formulation according to any one of Embodiments 76 to 111, wherein the formulation has a pH of about 2.7 to about 3.9 (or, alternatively, the method).

[0714] 114. The formulation according to any one of Embodiments 76 to 111 (or, alternatively, the method), wherein the formulation has a pH of about 2.7 to about 3.6.

[0715] 115. The formulation according to any one of Embodiments 76 to 111, wherein the formulation has a pH of about 4 to about 8.

[0716] 116. The formulation (or, alternatively, the method) according to any one of Embodiments 76 to 115, wherein the formulation is an oil-in-water emulsion.

[0717] 117. The formulation (or, alternatively, the method) according to Embodiment 116, wherein the oil-in-water emulsion comprises water, an oil component, and an emulsifier component.

[0718] 118. The formulation (or, alternatively, the method) according to Embodiment 117, wherein the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.

[0719] 119. The formulation (or, alternatively, the method) according to Embodiment 117, wherein the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.

[0720] 120. The formulation (or, alternatively, the method) according to Embodiment 117, wherein the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.

[0721] 121. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 120, wherein the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

[0722] 122. The formulation (or, alternatively, the method) according to any one of Embodiments 117 to 120, wherein the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone.

[0723] 123. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 120, wherein the oil component includes an occlusive agent component.

[0724] 124. The formulation (or, alternatively, the method) according to Embodiment 123, wherein the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.

[0725] 125. The formulation (or, alternatively, the method) according to Embodiment 123, wherein the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.

[0726] 126. A formulation (or, alternatively, a method) according to any one of Embodiments 123 to 125, wherein the occlusive agent component comprises white petrolatum.

[0727] 127. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 126, wherein the oil component comprises a curing agent component.

[0728] 128. The formulation (or, alternatively, the method) according to Embodiment 127, wherein the curing agent component is present in an amount of about 2% to about 8% by weight of the emulsion.

[0729] 129. The formulation (or, alternatively, the method) according to Embodiment 127, wherein the curing agent component is present in an amount of about 3% to about 6% by weight of the emulsion.

[0730] 130. The formulation (or, alternatively, the method) according to Embodiment 127, wherein the curing agent component is present in an amount of about 4% to about 7% by weight of the emulsion.

[0731] 131. A formulation (or, alternatively, a method) according to any one of Embodiments 127 to 130, wherein the curing agent component comprises one or more substances independently selected from fatty alcohols.

[0732] 132. The curing agent component is C 12~20 A formulation (or alternatively, a method) according to Embodiment 131, comprising one or more substances independently selected from fatty alcohols.

[0733] 133. The curing agent component is C 16~18 A formulation (or, alternatively, a method) according to Embodiment 131, comprising one or more substances independently selected from fatty alcohols.

[0734] 134. A formulation (or, alternatively, a method) according to any one of Embodiments 127 to 130, wherein the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

[0735] 135. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 134, wherein the oil component contains a softening component.

[0736] 136. The formulation (or, alternatively, the method) according to Embodiment 135, wherein the softening component is present in an amount of about 0.1% to about 20% by weight of the emulsion.

[0737] 137. The formulation (or, alternatively, the method) according to Embodiment 135, wherein the softening component is present in an amount of about 5% to about 20% by weight of the emulsion.

[0738] 138. The formulation (or, alternatively, the method) according to Embodiment 135, wherein the softening component is present in an amount of about 10% to about 15% by weight of the emulsion.

[0739] 139. A formulation (or, alternatively, a method) according to any one of Embodiments 135 to 138, wherein the softening component comprises one or more substances independently selected from mineral oil, triglycerides, and silicone oil.

[0740] 140. A formulation (or, alternatively, a method) according to any one of Embodiments 135 to 138, wherein the softening component comprises one or more substances independently selected from light mineral oil, medium-chain triglycerides, and dimethicone.

[0741] 141. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 140, wherein the water is present in an amount of about 20% to about 80% by weight of the emulsion.

[0742] 142. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 140, wherein the water is present in an amount of about 35% to about 65% by weight of the emulsion.

[0743] 143. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 140, wherein the water is present in an amount of about 40% to about 65% by weight of the emulsion.

[0744] 144. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 143, wherein the emulsifier component is present in an amount of about 0.5% to about 15% by weight of the emulsion.

[0745] 145. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 143, wherein the emulsifier component is present in an amount of about 1% to about 10% by weight of the emulsion.

[0746] 146. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 143, wherein the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.

[0747] 147. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 143, wherein the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.

[0748] 148. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 147, wherein the emulsifying agent component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0749] 149. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 147, wherein the emulsifying agent component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0750] 150. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 149, wherein the emulsion further comprises a stabilizing component.

[0751] 151. The formulation (or, alternatively, the method) according to Embodiment 150, wherein the stabilizing agent component is present in an amount of about 0.05% to about 5% by weight of the emulsion.

[0752] 152. The formulation (or, alternatively, the method) according to Embodiment 150, wherein the stabilizing component is present in an amount of about 0.1% to about 2% by weight of the emulsion.

[0753] 153. The formulation (or, alternatively, the method) according to Embodiment 150, wherein the stabilizing component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.

[0754] 154. A formulation (or, alternatively, a method) according to any one of Embodiments 150 to 153, wherein the stabilizing agent component comprises one or more substances independently selected from polysaccharides.

[0755] 155. A formulation (or, alternatively, a method) according to any one of Embodiments 150 to 153, wherein the stabilizing component comprises xanthan gum.

[0756] 156. A formulation (or, alternatively, a method) according to any one of Embodiments 117 to 155, wherein the emulsion further comprises a solvent component.

[0757] 157. The formulation (or, alternatively, the method) according to Embodiment 156, wherein the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.

[0758] 158. The formulation (or, alternatively, the method) according to Embodiment 156, wherein the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.

[0759] 159. The formulation (or, alternatively, the method) according to Embodiment 156, wherein the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.

[0760] 160. A formulation (or, alternatively, a method) according to any one of Embodiments 156 to 159, wherein the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0761] 161. A formulation (or, alternatively, a method) according to any one of Embodiments 156 to 159, wherein the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0762] 162. A pharmaceutical preparation for topical treatment of skin diseases comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0763] 163. The pharmaceutical formulation according to Embodiment 162, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0764] 164. The pharmaceutical formulation according to Embodiment 163, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0765] 165. The pharmaceutical formulation according to Embodiment 165, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinibrinate.

[0766] 166. The vitamin D3 analog or a pharmaceutically acceptable salt thereof is a compound having formula (II), [ka] During the ceremony, R 1 However, it is either H or OH, R 2 and R 3 However, each of them is H, or R 2 However, OR 2A And R 3 However, is it H, or R 2 and R 3 However, together they form a CH2 group, R 2A However, -C 1-4 It is alkylene-OH, R 4 and R 5 However, each of them is H, or R 4 and R 5 However, together they form a CH2 group, R 6 and R 7 However, each of them is H, or R 6 and R 7 However, together they form a CH2 group, L is -CH2-CH2-CH(R 12 )-,-CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-, where R 12 However, it is either H or OH, R 9 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 10 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 11 However, is it H or OH? Alternatively, R 9 and R 10 However, together with the carbon atoms to which they bond, C 3-4 Forming a cycloalkyl ring, R 11 A pharmaceutical preparation according to any one of embodiments 162 to 165, wherein is H.

[0767] 167. A pharmaceutical preparation according to any one of Embodiments 162 to 166, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol, maxacalcitol, or a pharmaceutically acceptable salt thereof.

[0768] 168. The pharmaceutical preparation according to actual form 163, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.

[0769] 169. The pharmaceutical formulation according to Embodiment 163, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.

[0770] 170. A pharmaceutical formulation according to any one of Embodiments 164 to 169, wherein the formulation comprises, on a free base basis, about 0.05% to about 3.0% or about 0.05% to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0771] 171. The formulation, on a free base basis, contains approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight, approximately 0.1% by weight, approximately 0.15% by weight, approximately 0.2% by weight, approximately 0.25% by weight, approximately 0.3% by weight, approximately 0.35% by weight, approximately 0.4% by weight, approximately 0.45% by weight, approximately 0.5% by weight, approximately 0.55% by weight, approximately 0.6% by weight, approximately 0.65% by weight, approximately 0.7% by weight, approximately 0.75% by weight, approximately 0.8% by weight, approximately 0.85% by weight, approximately 0.9% by weight, approximately 0.95% by weight, approximately 1.0% by weight, and approximately 1.05% by weight. A pharmaceutical formulation according to any one of Embodiments 164 to 169, comprising approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight of the ruxolitinib or a pharmaceutically acceptable salt thereof.

[0772] 172. A pharmaceutical preparation according to any one of Embodiments 163 to 171, wherein the preparation comprises, on a free base basis, about 0.0001% w / w to about 0.01% w / w of the vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0773] 173. The pharmaceutical formulation according to any one of Embodiments 163 to 171, wherein the formulation comprises, on a free base basis, about 0.0001% w / w to about 0.005% w / w of the vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0774] 174. A pharmaceutical preparation according to any one of Embodiments 163 to 171, wherein the preparation comprises, on a free base basis, about 0.0001% w / w to about 0.01% w / w or about 0.0001% w / w to about 0.005% w / w of the vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0775] 175. A pharmaceutical preparation according to any one of Embodiments 163 to 171, wherein the preparation comprises, on a free base basis, about 0.005% w / w of the vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0776] 176. The pharmaceutical preparation according to any one of embodiments 162 to 175, wherein the preparation is a cream or a lotion.

[0777] 177. The pharmaceutical preparation according to any one of embodiments 162 to 176, wherein the preparation is an oil-in-water emulsion.

[0778] 178. A pharmaceutical preparation according to any one of Embodiments 162 to 177, wherein the preparation comprises water, an oil component, and an emulsifier or stabilizer component.

[0779] 179. The pharmaceutical preparation according to Embodiment 178, wherein the water constitutes about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the pharmaceutical preparation.

[0780] 180. The pharmaceutical preparation according to Embodiment 178 or 179, wherein the oil component constitutes about 5% to about 90% by weight, about 5% to about 80% by weight, about 5% to about 70% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, or about 5% to about 40% by weight of the pharmaceutical preparation.

[0781] 181. Any one of embodiments 178 to 180, wherein the emulsifier or the stabilizing component constitutes about 1% to about 30% by weight, or about 5% to about 25% by weight, of the pharmaceutical preparation.

[0782] 182. A pharmaceutical formulation according to any one of Embodiments 178 to 180, further comprising a solvent component for dissolving ruxolitinib or a pharmaceutically acceptable salt thereof.

[0783] 183. The pharmaceutical preparation according to Embodiment 182, wherein the solvent component constitutes about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the pharmaceutical preparation.

[0784] 184. The pharmaceutical preparation according to any one of Embodiments 163 to 183, wherein the preparation has a pH of approximately 6.0 to approximately 8.0, approximately 6.5 to approximately 7.5, or approximately 6.5 to approximately 7.0.

[0785] 185. The pharmaceutical preparation according to Embodiment 184, wherein the pH of the preparation is adjusted with trolamine.

[0786] 186. A method for treating a skin disease in a patient who requires treatment for a skin disease, comprising topically administering to a trunk of the patient (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.

[0787] 187. The method according to Embodiment 186, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0788] 188. The method according to Embodiment 187, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0789] 189. The method according to Embodiment 187, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinibrinate.

[0790] 190. The vitamin D3 analog or a pharmaceutically acceptable salt thereof is a compound having formula (II), [ka] During the ceremony, R 1 However, it is either H or OH, R 2 and R 3 However, each of them is H, or R 2 However, OR 2A And R 3 However, is it H, or R 2 and R 3 However, together they form a CH2 group, R 2A However, -C 1-4 It is alkylene-OH, R 4 and R 5 However, each of them is H, or R 4 and R 5 However, together they form a CH2 group, R 6 and R 7 However, each of them is H, or R 6and R 7 However, together they form a CH2 group, L is -CH2-CH2-CH(R 12 )-,-CH2-CH2-CH2-CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH2-C≡C-, -O-CH2-CH2-, or -O-CH2-CH2-CH2-, where R 12 However, it is either H or OH, R 9 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 10 However, C 1-3 Alkyl, or C 1-4 It is a haloalkyl, R 11 However, it is either H or OH, Alternatively, R 9 and R 10 However, together with the carbon atoms to which they bond, C 3-4 Forming a cycloalkyl ring, R 11 The method according to any one of embodiments 187 to 189, wherein H.

[0791] 191. The method according to any one of Embodiments 187 to 189, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.

[0792] 192. The method according to Embodiment 187, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.

[0793] 193. The method according to Embodiment 187, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.

[0794] 194. The method according to any one of embodiments 187 to 193, wherein the skin disease is an autoimmune or inflammatory skin disease.

[0795] 195. The method according to any one of embodiments 187 to 193, wherein the skin disease is a Th1 or Th17-related skin disease.

[0796] 196. The method according to any one of Embodiments 187 to 193, wherein the skin disease is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof.

[0797] 197. The method according to any one of embodiments 187 to 193, wherein the skin disease is mediated by Defb4, S100a12, or Serpinb4.

[0798] 198. The method according to any one of Embodiments 187 to 193, wherein the skin disease is mediated by filaggrin / FLG, loricin / LOR, IL-31, TSLP, CAMP, CCL17, CCL22, DefB4a, interferon-gamma, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF18.

[0799] 199. The method according to any one of Embodiments 187 to 193, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, simple bullous epidermal lysis, palmoplantar keratosis, congenital onychoplakia, multiple lipocysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.

[0800] 200. The method according to any one of Embodiments 187 to 193, wherein the skin disease is rosacea, psoriatic arthritis, dermatofibrosis, morphea, nevus spitz, dermatophytosis, or acne vulgaris.

[0801] 201. The method according to any one of Embodiments 187 to 200, wherein there is a synergistic effect between the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3 analog or a pharmaceutically acceptable salt thereof.

[0802] 202. The method according to any one of Embodiments 187 to 201, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least once daily.

[0803] 203. The method according to any one of Embodiments 187 to 201, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least twice a day.

[0804] 204. The method according to any one of Embodiments 187 to 203, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0805] 205. The method according to any one of Embodiments 187 to 203, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered sequentially.

[0806] 206. The method according to any one of Embodiments 187 to 205, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered as separate formulations.

[0807] 207. The method according to any one of Embodiments 187 to 204, wherein (a) the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered in a single formulation.

[0808] 208. The method according to Embodiment 206, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are each administered as a topical formulation.

[0809] 209. The method according to Embodiment 207, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered in a single topical formulation.

[0810] 210. The method according to Embodiment 208, wherein each topical preparation is an ointment, cream, or lotion.

[0811] 211. The method according to Embodiment 209, wherein the single topical formulation is an ointment, a cream, or a lotion.

[0812] 212. The method according to Embodiment 211, wherein the single topical formulation is a cream or lotion.

[0813] 213. The method according to Embodiment 211, wherein the single topical formulation is a cream formulation.

[0814] 214. The method according to any one of Embodiments 211 to 213, wherein the single topical formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.

[0815] 215. The method according to any one of embodiments 187 to 214, further comprising administering an additional therapeutic agent.

[0816] 216. The method according to embodiment 215, wherein the additional therapeutic agent is a corticosteroid.

[0817] 217. The method according to Embodiment 216, wherein the corticosteroid is betamethasone dipropionate. [Examples]

[0818] The subject matter described in these claims will be illustrated in more detail by specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the subject matter described in these claims in any way. Those skilled in the art will readily recognize a variety of non-essential parameters that can be changed or modified to produce essentially the same results.

[0819] All statistical analyses of in vivo experiments were performed using GraphPad prism software (version 7) with the Kruskal-Wallis test and the Mann-Whitney U test. Gene expression was analyzed using Welch's t-test with Partek Flow genome analysis software and Subio Platform software v1.22.5266. Confidence intervals were determined at 95%. P<0.05 was considered "significant" (*), and p<0.01 was considered "very significant" (**). The KEGG pathway was mapped to differentially expressed genes using DAVID v6.8 (Database for Annotation, Visualization and Integrated Discovery).

[0820] Example 1. In vitro JAK kinase assay JAK1 inhibitors that may be used for the treatment of cytokine-related diseases or disorders will be tested for their inhibitory activity against JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (aa837-1142), JAK2 (aa828-1132), and JAK3 (aa781-1124) with an N-terminal His tag were expressed and purified using baculovirus in insect cells. The catalytic activity of JAK1, JAK2, or JAK3 was assayed by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). IC of the compound50 This is measured for each kinase in a 40 μL reaction mixture containing the enzyme, ATP, and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg / mL (0.01%) BSA. 1 mM IC50 50 For the measurement, the ATP concentration in the reactant was 1 mM. The reaction was carried out at room temperature for 1 hour, and then terminated with 20 μL of 45 mM EDTA, 300 nM SA-APC, and 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the europium-labeled antibody occurred for 40 minutes, and the HTRF signal was measured on a fusion plate reader (Perkin Elmer, Boston, MA). The compounds in Table 1 were tested in this assay, and the IC values ​​in Table 1 were measured. 50 It was shown to have a value.

[0821] Example 2: Ex vivo dermatopharmacological experiments on the combination of a JAK inhibitor and a vitamin D3 analog. Materials and methods The pharmacodynamic assays described herein involve a paradigm similar to that used to induce the TH17 response, as published in February 2016 by Susan H. Smith, et al., Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PlosOne. (which is incorporated herein by reference in its entirety), for inducing Th1, Th2, and Th17 responses. Using this paradigm, the therapeutic potential of active compounds in topical formulations for dermatological conditions (i.e., psoriasis, vitiligo, and alopecia) was evaluated.

[0822] Healthy human skin recently excised in cosmetic reduction surgery can be excised to a thickness of approximately 750 ± 100 μm using an Integra® dermatome. The excised skin is then further sectioned into 7 mm biopsies for basal or topical administration, taking care to avoid areas of variable thickness or striated skin. The biopsies are placed in a 6.5 mm permeable Transwell® insert for basal or topical administration. The human skin is placed in the Transwell® insert with a stratum corneum-side tip, containing a small amount of collagen between the basal skin tissue and the permeable membrane. A schematic diagram of the Transwell® insert is shown in Figure 4. Full-scale experiments were conducted with eight individual skin donors, n=4 for basal administration, or 2 individual skin donors for topical administration. Each donor can be utilized at the desired concentration according to Method A for basal administration or Method B for topical administration, for each combination of JAK inhibitor and vitamin D3 analogue.

[0823] Method A (Basal administration) (i) Approximately 0.33cm 2 A Transwell® permeable insert (n=4 per treatment) with an average surface area and a volume of 0.5 mL is used.

[0824] (ii) The skin prepared as described herein is placed in a Transwell® insert with a stratum corneum-side tip having a small amount of collagen between the basal skin tissue and the permeable membrane.

[0825] (iii) Fill the base chamber with 0.5 mL of culture medium added to the culture medium at the specified final concentration and the drug (JAK inhibitor and / or vitamin D3 analog), and pre-treat it in a humidified incubator overnight at 37°C (approximately 16 hours).

[0826] (iv) The following day, the contents of the basal chambers from each insert were vacuum-aspirated and replaced with 0.5 mL of pre-warmed (approximately 37°C) cornification media containing the test compound and a fresh irritant cocktail.

[0827] (v) The cultures can be stored in a humidified incubator at a temperature of 37°C.

[0828] (vi) Tissue grafts may be collected 24 hours after stimulation. Half of the tissue is placed in RNALater and cytokine production is assayed by RT-qPCR.

[0829] (vii) Tissue homogenization: The tissue tubes were placed in the Omni homogenizer and performed for 30 seconds over 3 cycles at 5 m / s with a 10-second dwell time setting. Homogenization was repeated 4 times over a total of 12 cycles, with 1 minute 30 seconds on ice between each run to cool the samples. After the final run, the tissue tubes were cooled on ice for the same period.

[0830] (viii) Using GAPDH as a housekeeping gene, RT-PCR was performed repeatedly on the sample using the Applied Biosystems Quant6 standard RT-qPCR program with a threshold of 40 cycles.

[0831] The appropriate concentrations of JAK inhibitors and vitamin D3 analogs are determined by the IC of the compound. 50 It can be determined based on the following. For example, the JAK inhibitor, ruxolitinib, inhibits IL-23-stimulated IL-22 production in human T cells. 50 It has an IC50 of 50 nM and an IC50 of 281 nM in the human whole blood TPO-induced STAT3 phosphorylation assay (Fridman, et al., J Invest Dermatol, 2011 Sep;131(9):1838-44 (PMID:21677670), and Fridman, et al., J Immunol, 2010 May 1;184(9):5298-307 (PMID:20363976). Similarly, tacalcitol, calcipotriol, and maxacalcitol have an IC50 of 50 nM. 50At concentrations of approximately 10-100 nM, it reduced keratinocyte cell line proliferation in a concentration-dependent manner (Takahasi, et al., J Dermatol Sci, 2003 Feb;31(1):21-8 (PMID:12615360)). JAK inhibitors (e.g., ruxolitinib, delgocitinib, etc.) and vitamin D3 analogs (e.g., tacalcitol, calcipotriol, and maxacalcitol) showed IC54. 50 Concentration less than (0 or less) and IC 50 It is possible to use concentrations exceeding the specified limit.

[0832] Method B (Local administration) (i) Approximately 0.33cm 2 A Transwell® permeable insert (n=4 per treatment) with an average surface area and a volume of 0.5 mL is used.

[0833] (ii) The skin prepared as described herein is placed in a Transwell® insert having a small amount of collagen between the basal skin tissue and the permeable membrane, on the stratum corneum side and the basal side.

[0834] (iii) Fill the base chamber with 0.5 mL of culture medium. Add the drug (JAK inhibitor and / or vitamin D3 analog) to the apical side of the excised skin (approximately 18 ul / cm²) for 16 or 24 hours in a humidified incubator at 37°C overnight to pre-treat. 2 It was applied locally to the area.

[0835] (iv) The following day, the contents of the basal chambers from each insert were vacuum-aspirated. The culture medium was replaced with 0.5 mL of pre-warmed (approximately 37°C) keratinizing medium containing a fresh stimulant cocktail.

[0836] (v) The cultures can be stored in a humidified incubator at a temperature of 37°C.

[0837] (vi) Tissue grafts may be collected 24 hours after stimulation. Half of the tissue is placed in RNALater and cytokine production is assayed by RT-qPCR.

[0838] (vii) Tissue homogenization: The tissue tubes were placed in the Omni homogenizer and performed for 30 seconds over 3 cycles at 5 m / s with a 10-second dwell time setting. Homogenization was repeated 4 times over a total of 12 cycles, with 1 minute 30 seconds on ice between each run to cool the samples. After the final run, the tissue tubes were cooled on ice for the same period.

[0839] (viii) Using GAPDH as a housekeeping gene, RT-PCR was performed repeatedly on the sample using the Applied Biosystems Quant6 standard RT-qPCR program with a threshold of 40 cycles.

[0840] Ruxolitinib and calcipotriol - basal administration (Method A) Experiments with ruxolitinibulinate and calcipotriol were carried out as described in the Materials and Methods (Method A) section of Example 2. A list of treatment conditions for donors 2 and 3 with Th1 or Th17 stimulation to which ruxolitinibulinate (calculated on a free base basis) and / or calcipotriol is shown in Tables 2 and 3, respectively. [Table 3] [Table 4]

[0841] The levels of biomarkers such as IL-22, CXCL10, and MMP12 were quantified for the test compounds and their combinations, and the multiplicative change in gene expression compared to an untreated control was calculated. Unexpectedly and surprisingly, the combination of calcipotriol and ruxolitinib showed a synergistic effect in lowering the levels of IL-22, CXCL10, and MMP12, as shown in Figures 1–3. For example, the tested combination significantly lowered IL-22 levels, and such a reduction was statistically significant. The tested combination also effectively lowered CXCL10 levels, and such a reduction was statistically significant. The tested combination effectively lowered MMP12 levels, and such a reduction was statistically significant. These results are unexpected and surprising for several reasons. One reason is that the primary source of vitamin D in humans is cutaneous synthesis in the presence of sunlight, and it is generally known in the art that the anti-inflammatory effects of JAK inhibitors on skin diseases have not been associated with geographical location or sun exposure. Another reason is that the clinical efficacy of vitamin D3 analogs is thought to be primarily driven by their ability to normalize the regulation of keratinocyte hyperproliferation and epidermal differentiation, and these mechanisms are independent of inflammatory cytokines that utilize the JAK pathway. See Hu et al. “Reciprocal role of vitamin D receptor on β-catenin regulated keratinocyte proliferation and differentiation” J Steroid Biochem Mol Biol. 2014 Oct;144 Pt A:237-41, PMID:24239508, which is incorporated herein by reference in its entirety. Furthermore, recent studies on psoriasis have shown that skin biopsies from psoriasis patients treated with topical calcipotriol show a significant decrease in CD8(+)IL-17(+) T cells, but no change in the frequency of IL-22(+) or IFN-γ(+) cells in psoriatic lesions.See Dyring-Andersen et al. “The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+IL-17+T Cells in Psoriasis Lesions. Scand J Immunol” 2015 Jul;82(1):84-91, PMID:25904071, which is incorporated herein by reference in its entirety. Thus, the synergistic effect between calcipotriol and ruxolitinib in reducing IL-22, CXCL10, and MMP12 levels is unexpected and surprising.

[0842] Furthermore, levels of other genetic markers were quantified for the test compounds (ruxolitinib and calcipotriol) and their combinations. The absolute fold change in gene expression was calculated relative to the untreated control. Figures 6A-6B show that the combination of calcipotriol and ruxolitinib caused an absolute fold change of >2 or >4 in certain genes compared to the untreated control (white indicates an absolute fold change of <2, gray indicates an absolute fold change of >2, and black indicates an absolute fold change of >4). Among the genes with the highest absolute fold changes, barrier function genes (filaggrin / FLG and loricin / LOR) are involved in many skin diseases; IL-31 and TSLP are involved in itching prevalent in many skin diseases; and CAMP and DefB4 are antimicrobial peptides involved in skin diseases with barrier disruption (which can increase infection).

[0843] Ruxolitinib and maxacalcitol - basal administration (Method A) Experiments with ruxolitinibulinate and maxacalcitol were carried out as described in the Materials and Methods (Method A) section of Example 2. A list of treatment conditions for donors 2 and 3 with Th1 or Th17 stimulation to which ruxolitinibulinate (calculated on a free base basis) and / or maxacalcitol is shown in Tables 4 and 5, respectively. [Table 5] [Table 6]

[0844] The levels of biomarkers such as IL-22 and CXCL10 for the test compounds and their combinations were quantified, and the multiplicative change in gene expression was calculated relative to the untreated control. Unexpectedly and surprisingly, the combination of maxacalcitol and ruxolitinib showed a synergistic effect in reducing IL-22 and CXCL10 levels, as shown in Figures 7A–7B.

[0845] Ruxolitinib and calcipotriol - Topical administration (Method B) Aqueous solutions of ruxolitinibrinate and calcipotriol were prepared individually and in combination using ruxolitinibrinate and calcipotriol according to the following procedure (see Table 6):

[0846] (i) BHT was first added to Transcutol P in amber-colored Duran and stirred at 500 RPM until visually homogeneous.

[0847] (ii) The solution from step (i) was added to the remaining polar phase excipient in the amber-colored Duran and stirred with a magnetic stirring rod at 500 RPM until visually homogeneous.

[0848] (iii) Ruxolitinibulinate was added to the final phase from step (ii) and stirred at 500 RPM for 5 minutes, but the ruxolitinibulinate did not completely dissolve in this step.

[0849] (iv) The suspension from step (iii) was adjusted to pH 6.5-7.0 with trolamine, and ruxolitinibrinate was dissolved in this step.

[0850] (v) Calcipotriol monohydrate was added to the polar phase from step (iv), stirred at 500 RPM at 65°C for 1 hour, and then stirred overnight at ambient laboratory temperature to dissolve.

[0851] (vi) Dilute a sufficient amount with water to make 100%. [Table 7]

[0852] The aqueous solutions shown in Table 6 were tested as described in the Materials and Methods (Method B) section of Example 2 for ruxolitinibulinate and calcipotriol. A list of treatment conditions for donors 1 and 2 with Th1 or Th17 stimulation to which ruxolitinibulinate (calculated on a free base basis) and / or calcipotriol is shown in Tables 7 and 8, respectively. [Table 8] [Table 9]

[0853] The levels of biomarkers such as S100a12, Defb4, Serpinb4, MMP12, IL-22, and CXCL10 for the test compounds and their combinations were quantified, and the multiplicative changes in gene expression were calculated relative to the untreated control (Figures 8A-8C and 9A-9C). Unexpectedly and surprisingly, calcipotriol and ruxolitinib, combined in topically applied aqueous solutions, showed a synergistic effect in reducing the levels of S100a12, Defb4, Serpinb4, and MMP12, as shown in Figures 8A-8C and 9A. S100a12 is an important marker of psoriatic disease activity (Wilsmann-Theis, D, et al., J Eur Acad Dermatol Venereol, 30(7):1165-70 (2016); doi:10.1111 / jdv.13269). Defb4 encodes human beta-defensin 2 (hBD2), an antimicrobial peptide that plays an essential role in the inflammatory process of the skin and is important in the development of psoriasis (Johansen C, et al., J Invest Derm, 136(8):1608-1616 (2016); doi:10.1016 / j.jid.2016.04.012). Serpinb4 contributes to inflammation in patients with chronic skin diseases, including atopic dermatitis (Sivaprasad, U, et al., J Invest Derm 135(1):160-169 (2015); DOI:10.1038 / jid.2014.353). These results are unexpected and surprising for several reasons. One reason is that the primary source of vitamin D in humans is cutaneous synthesis in the presence of sunlight, and it is generally known in the art that the anti-inflammatory effects of JAK inhibitors on skin diseases have not been associated with geographical location or sun exposure. Another reason is that the clinical efficacy of vitamin D3 analogs is thought to be primarily driven by their ability to normalize the regulation of keratinocyte hyperproliferation and epidermal differentiation, and these mechanisms are independent of inflammatory cytokines that utilize the JAK pathway.Therefore, the synergistic effect between calcipotriol and ruxolitinib that reduced the levels of S100a12, Defb4, Serpinb4, and MMP12 was unexpected and surprising. Calcipotriol and ruxolitinib combined in a topical aqueous solution also reduced the gene expression of IL-22 and CXCL10 (Figures 9B-9C); however, high levels of ruxolitinib in aqueous solutions (0.75% and 1.5%) also strongly affected gene expression, making it difficult to evaluate the synergistic effect in topical application, although such synergies are observed at low concentrations in basal application (Method A).

[0854] Example 3: Method for preparing ruxolitinib cream and a combination cream of ruxolitinib and calcipotriol. This specification describes methods for preparing ruxolitinib creams (formulations #1, #2, #4, and #5) containing 1.5% w / w ruxolitinib on a free base basis, and for preparing ruxolitinib and calcipotriol combination creams (formulations #3 and #6) containing 1.5% w / w ruxolitinib and 50 micrograms / g of calcipotriol on a free base basis.

[0855] To prepare the combination cream of ruxolitinib and calcipotriol, ruxolitinib was incorporated into the aqueous phase, and calcipotriol was first dissolved in a medium-chain triglyceride and then added to an oil-in-water emulsion. The details of the preparation process are as follows.

[0856] 1. Preparation of a 1 mg / g calcipotriol solution in medium-chain triglycerides. Calcipotriol was dissolved in 1 mg / g of medium-chain triglycerides by heating at approximately 60°C. Heating was stopped when the calcipotriol was completely dissolved. The resulting stock solution was covered with aluminum foil to protect it from light.

[0857] 2. Preparation of the aqueous phase. Purified water, disodium EDTA, low molecular weight PEG, and ruxolitinibrate were thoroughly mixed according to the respective weight percentages listed in Table 10. The resulting mixture was heated and stirred at approximately 55°C to 60°C to dissolve the disodium EDTA and ruxolitinib and form the aqueous phase.

[0858] 3. Preparation of the paraben phase. Methylparaben and propylparaben were added to propylene glycol according to the respective weight percentages listed in Table 10 to form a mixture. The resulting mixture was heated and stirred at approximately 55°C to 60°C to dissolve the methylparaben and propylparaben and form the paraben phase.

[0859] 4. Preparation of the xanthan gum phase. Xanthan gum was mixed with propylene glycol according to the respective weight percentages listed in Table 10, and the resulting mixture was heated at approximately 55°C to 60°C to form the xanthan gum phase in the form of a dispersion.

[0860] 5. Preparation of the oil phase. White petrolatum, light mineral oil, glycerol stearate SE, cetyl alcohol, stearyl alcohol, dimethicone, medium-chain triglycerides, and polysorbate 20 were mixed according to the respective weight percentages listed in Table 10. The resulting mixture was heated to approximately 65°C to 68°C while stirring until all excipients were melted to form the oil phase.

[0861] 6. The aqueous phase was heated to approximately 65°C to 68°C while being stirred at approximately 600-800 rpm.

[0862] 7. The paraben phase was transferred to the heated aqueous phase according to the percentages listed in Table 10. The resulting mixture was thoroughly stirred, maintained at approximately 65°C to 68°C, and the stirring speed was maintained at approximately 600 to 800 rpm.

[0863] 8. The xanthan gum phase was transferred to the mixture of the aqueous phase and the paraben phase according to the percentages listed in Table 10. The resulting mixture was thoroughly stirred and maintained at a stirring speed of approximately 600-800 rpm while being kept at approximately 65°C-68°C.

[0864] 9. Preparation of oil-in-water emulsion. The oil phase was transferred to a mixture of the aqueous phase, paraben phase, and xanthan gum phase according to the percentages shown in Table 10. The resulting mixture was thoroughly stirred, maintaining a stirring speed of approximately 600-800 rpm and a temperature of approximately 65°C-68°C to form an oil-in-water emulsion.

[0865] 10. The oil-in-water emulsion was cooled to approximately 38°C to 40°C.

[0866] 11. Phenoxyethanol was added to the cooled oil-in-water emulsion according to the percentages listed in Table 10. The temperature of the resulting mixture was maintained at approximately 38°C to 40°C, and the stirring speed was maintained at approximately 600 to 800 rpm.

[0867] For the ruxolitinib and calcipotriol combination creams (formulations #3 and #6), the calcipotriol solution in medium-chain triglycerides and light mineral oil were added to the oil-in-water emulsion according to the respective percentages listed in Table 10. The resulting mixture was maintained at approximately 38°C to 40°C while maintaining a stirring speed of approximately 600 to 800 rpm. For the ruxolitinib alone creams (formulations #1, #2, #4, and #5), medium-chain triglycerides and light mineral oil were added to the oil-in-water emulsion according to the respective percentages listed in Table 10. The resulting mixture was maintained at approximately 38°C to 40°C while maintaining a stirring speed of approximately 600 to 800 rpm. After the resulting mixture was cooled and stirring was stopped, the creams (formulations #1 to #6) were formed and collected.

[0868] Table 9 lists the weight percentages of the different phases of cream formulations #1 to #6. Table 10 lists the weight percentages of ruxolitinibrinate, calcipotriol, and excipients in cream formulations #1 to #6. [Table 10-1] [Table 10-2] [Table 11]

[0869] The cream formulations #1 to #6 are shown in Figure 5. Cream formulations #1 to #3 contained 7.0% w / w PEG300, while cream formulations #4 to #6 contained 7.0% w / w PEG400. The propylene glycol content in cream formulations #1, #3, #4, and #6 was 6.5% w / w, while the propylene glycol content in cream formulations #2 and #5 was 8.5% w / w. The ruxolitinib content in all cream formulations #1 to #6 was 1.5% w / w on a free base basis. Formulations #3 and #6 are combination creams of ruxolitinib and calcipotriol, containing both ruxolitinib (1.5% w / w on a free base basis) and calcipotriol (0.005% w / w).

[0870] An additional formulation (Formulation #7) was prepared containing 1.1% w / w ruxolitinib and 0.0005 w / w calcipotriol on a free base basis.

[0871] To prepare the combination cream of ruxolitinib and calcipotriol, ruxolitinib was incorporated into the aqueous phase, heated to dissolve calcipotriol in the liquid oil phase, and the solid oil phase excipient was heated to melt. The aqueous phase, liquid oil phase, and molten solid oil phase excipient were then combined and homogenized to prepare the formulation, which was then cooled. An antimicrobial preservative was added to the cooled formulation, and the resulting formulation was stirred until it was visually homogeneous. The pH was adjusted as needed, and water was added as needed to replenish the volume. The details of the preparation process are as follows.

[0872] (i) EDTA was first added to water in amber-colored Duran and stirred at 500 RPM until visually homogeneous.

[0873] (ii) BHA was first added to Transcutol P in amber-colored Duran and stirred at 500 RPM until visually homogeneous.

[0874] (iii) The solutions from steps (i) and (ii) were added to the remaining aqueous phase excipient (glycerol) in the amber-colored Duran and stirred at 500 RPM with a magnetic stirring rod until visually homogeneous.

[0875] (iv) Ruxolitinibulinate was added to the aqueous phase from step (iii) and stirred at 500 RPM for 5 minutes, but the ruxolitinibulinate did not completely dissolve in this step.

[0876] (v) The suspension from step (iv) was adjusted to pH 6.0-7.0 with trolamine, and ruxolitinibrinate was dissolved during this step.

[0877] (vi) In a separate amber Duarn, BHT was added to oleyl alcohol and sweet almond oil and stirred at 250 RPM until visually homogeneous.

[0878] (vii) The solution from step (vi) was added to the remaining liquid oil phase excipients (polysorbate 80 and light mineral oil) and stirred at 500 RPM for 3 to 5 minutes until visually homogeneous.

[0879] (viii) Calcipotriol was added to the liquid oil phase from step (vii), stirred at 500 RPM at 65°C for 1 hour, and then stirred overnight at ambient laboratory temperature to dissolve.

[0880] (ix) After dissolving calcipotriol in step (viii), poloxamer 407 was dispersed in the solution from step (viii) by stirring at 500 RPM.

[0881] (x) The solid oil phase excipient was weighed into a separate amber Duran container placed in a 70°C water bath until melted. The aqueous phase from step (v), the liquid oil phase from step (ix), and the homogenizer head (silverson, square hole, high shear screen) were also placed in the water bath for 3 minutes.

[0882] The (xi) phase was combined and homogenized at 10,000 RPM for 2 minutes.

[0883] (xii) The formulation from step (xi) was stirred using an IKA anchor paddle at 100 RPM until the formulation cooled to ambient laboratory temperature.

[0884] (xiii) Phenoxyethanol was added to the preparation from step (xii) and stirred by hand until it was visually homogeneous.

[0885] (xiv) Check the pH of the preparation, adjust it as needed, add water to the specified volume, and stir by hand until visually homogeneous.

[0886] Table 11 lists the weight percentages of formulation #7. [Table 12]

[0887] Example 4. Combination cream of ruxolitinib and calcipotriol, and concentrations of other excipients. A cream formulation is prepared as described in Example 3, having ruxolitinibrinate present in a free base amount of approximately 0.75% w / w, with adjustment to the water ratio of Example 3 as needed.

[0888] The cream formulation is prepared as described in Example 3, using propylene glycol in an amount of approximately 6.5% w / w to approximately 15% w / w (for example, approximately 6.5% w / w, approximately 7% w / w, approximately 7.5% w / w, approximately 8% w / w, approximately 8.5% w / w, approximately 9% w / w, approximately 9.5% w / w, approximately 10% w / w, approximately 10.5% w / w, approximately 11% w / w, approximately 11.5% w / w, approximately 12% w / w, approximately 12.5% ​​w / w, approximately 13% w / w, approximately 13.5% w / w, approximately 14% w / w, approximately 14.5% w / w, or approximately 15% w / w), with adjustment to the amount of water in Example 3 as necessary.

[0889] The cream formulation is prepared using various low molecular weight polyethylene glycols (PEGs) as cosolvents, including PEG200, PEG300, PEG400, or combinations thereof, as described in Example 3.

[0890] The cream formulation is prepared to have a methylparaben content in the range of 0 to about 0.1% w / w and a propylparaben content in the range of 0 to about 0.05% w / w (with adjustment to the water ratio of Example 3 as necessary), as described in Example 3.

[0891] The cream formulation is prepared to have a xanthan gum content of approximately 0.2 to approximately 0.6% by weight (with adjustment to the water ratio of Example 3 as necessary), as described in Example 3.

[0892] The cream formulation is prepared by adding butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tocopherol (used individually or in combination) to the oil phase, as described in Example 3 (with adjustment to the water ratio in Example 3, if necessary).

[0893] The cream formulation is prepared by adding ascorbyl palmitate, ascorbic acid, or citric acid, or a combination thereof, as described in Example 3, to enhance the stability of calcipotriol.

[0894] Example 5. Combination cream of ruxolitinib and calcipotriol in a mouse model of IL-23-induced psoriasis-like disease. The combination cream formulation (formulation #7 of Example 3) was tested in established mouse models of IL-23-induced psoriasis-like disease (Rizzo HL, et al., “IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A,” J Immunol 186:1495-1502 (2011), TPSingh, et al., “IL-23- and Imiquimod-induced models of experimental psoriasis in mice,” Curr. Protoc. Immunol. e71, (2019); 10.1002 / cpim.71), which include acanthosis and accumulation of inflammatory cells in both the epidermis and dermis, leading to localized thickening of the skin. IL-23 was intradermally injected into one ear on days 0, 2, 4, and 7. The topical cream vehicle or formulation #7 (Example 3) was topically applied to one ear of IL-23-induced psoriasis-like mice. The cream (20 ug per application) was applied twice daily (BID) for 8 days. Ear swelling was measured using an engineer's caliper. A statistically significant reduction in ear thickening (p<0.001) was measured in mice treated with formulation #7 compared to vehicles-treated mice (Figure 10).

[0895] In addition to those described herein, various modifications of the subject matter set forth in these claims will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All documents referenced in this disclosure, including all patents, patent applications, and publications, are incorporated herein by reference in their entirety. This application also includes the following aspects. [Aspect 1] A pharmaceutical preparation for topical treatment of skin diseases comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. [Aspect 2] The pharmaceutical preparation according to embodiment 1, wherein the JAK inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof. [Aspect 3] The pharmaceutical preparation according to embodiment 2, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib or a pharmaceutically acceptable salt thereof. [Aspect 4] The pharmaceutical preparation according to embodiment 2, wherein the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinibrinate. [Aspect 5] The vitamin D3 analog or a pharmaceutically acceptable salt thereof is a compound having formula (II),

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Claims

1. A pharmaceutical formulation for topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical preparation according to claim 1, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibrine salt.

3. The pharmaceutical formulation according to claim 1, comprising ruxolitinib or a pharmaceutically acceptable salt thereof, and calcipotriol.

4. The pharmaceutical formulation according to claim 1, comprising ruxolitinib or a pharmaceutically acceptable salt thereof, and maxacalcitol.

5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the formulation comprises, on a free base basis, about 0.05% w / w to about 3.0% w / w or about 0.05% w / w to about 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof.

6. The formulation, on a free base basis, is approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight, approximately 0.1% by weight, approximately 0.15% by weight, approximately 0.2% by weight, approximately 0.25% by weight, approximately 0.3% by weight, approximately 0.35% by weight, approximately 0.4% by weight, approximately 0.45% by weight, approximately 0.5% by weight, approximately 0.55% by weight, approximately 0.6% by weight, approximately 0.65% by weight, approximately 0.7% by weight, approximately 0.75% by weight, approximately 0.8% by weight, approximately 0.85% by weight, approximately 0.9% by weight, approximately 0.95% by weight, approximately 1.0% by weight, and approximately 1.05% by weight of the formulation. A pharmaceutical preparation according to any one of claims 1 to 5, comprising approximately 1.1% by weight, approximately 1.15% by weight, approximately 1.2% by weight, approximately 1.25% by weight, approximately 1.3% by weight, approximately 1.35% by weight, approximately 1.4% by weight, approximately 1.45% by weight, approximately 1.55% by weight, approximately 1.6% by weight, approximately 1.65% by weight, approximately 1.7% by weight, approximately 1.75% by weight, approximately 1.8% by weight, approximately 1.85% by weight, approximately 1.9% by weight, approximately 1.95% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight of the ruxolitinib or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the formulation comprises, on a free base basis, about 0.0001% w / w to about 0.01% w / w of calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the formulation comprises, on a free base basis, about 0.0001% w / w to about 0.005% w / w of calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the formulation comprises, on a free base basis, about 0.0001% w / w to about 0.01% w / w, or about 0.0001% w / w to about 0.005% w / w of calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein the formulation comprises, on a free base basis, about 0.005% w / w of calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the preparation is a cream or a lotion.

12. The pharmaceutical preparation according to any one of claims 1 to 11, wherein the preparation is an oil-in-water emulsion.

13. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the preparation comprises water, an oil component, and an emulsifier or stabilizer component.

14. The pharmaceutical preparation according to claim 13, wherein the water constitutes about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the pharmaceutical preparation.

15. The pharmaceutical preparation according to claim 13 or 14, wherein the oil component constitutes about 5% to about 90% by weight, about 5% to about 80% by weight, about 5% to about 70% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, or about 5% to about 40% by weight of the pharmaceutical preparation.

16. The pharmaceutical preparation according to any one of claims 13 to 15, wherein the emulsifier or the stabilizing component constitutes about 1% to about 30% by weight or about 5% to about 25% by weight of the pharmaceutical preparation.

17. A pharmaceutical preparation according to any one of claims 13 to 16, further comprising a solvent component for dissolving ruxolitinib or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical preparation according to claim 17, wherein the solvent component constitutes about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the pharmaceutical preparation.

19. The pharmaceutical preparation according to any one of claims 1 to 18, wherein the preparation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.

0.

20. The pharmaceutical preparation according to claim 19, wherein the pH of the preparation is adjusted with trolamine.

21. A combination pharmacopoeia for the topical treatment of skin diseases comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.

22. The combination drug according to claim 21, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

23. The combination pharmaceutical according to claim 21, comprising ruxolitinib or a pharmaceutically acceptable salt thereof, and calcipotriol.

24. The combination pharmacopoeia according to claim 21, comprising ruxolitinib or a pharmaceutically acceptable salt thereof, and maxacalcitol.

25. The combination pharmaceutical according to any one of claims 21 to 24, wherein there is a synergistic effect between ruxolitinib or a pharmaceutically acceptable salt thereof and calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof.

26. The combination pharmacopoeia according to any one of claims 21 to 25, wherein (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are administered at least once daily.

27. The combination pharmacopoeia according to any one of claims 21 to 26, wherein (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are administered at least twice a day.

28. (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof, administered simultaneously, according to any one of claims 21 to 27.

29. The combination pharmaceutical product according to any one of claims 21 to 27, wherein (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are administered in succession.

30. The combination pharmaceutical product according to any one of claims 21 to 29, wherein (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are administered as separate formulations.

31. (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof, administered in a single formulation, according to any one of claims 21 to 28.

32. The combination pharmaceutical product according to claim 30, wherein ruxolitinib or a pharmaceutically acceptable salt thereof, and calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are each administered as a topical formulation.

33. The combination pharmaceutical product according to claim 31, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof, and calcipotriol or maxacalcitol or a pharmaceutically acceptable salt thereof are administered in a single topical formulation.

34. The combination pharmaceutical according to claim 32, wherein each topical preparation is an ointment, cream, or lotion.

35. The combination pharmaceutical according to claim 33, wherein the single topical preparation is an ointment, cream, or lotion.

36. The combination pharmaceutical according to claim 35, wherein the single topical preparation is a cream or lotion.

37. The combination pharmaceutical according to claim 35, wherein the single topical formulation is a cream formulation.

38. The combination pharmaceutical according to any one of claims 35 to 37, wherein the single topical formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.

0.

39. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is an autoimmune disease or an inflammatory skin disease.

40. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is a Th1 or Th17-related skin disease.

41. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof.

42. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is mediated by Defb4, S100a12, or Serpinb4.

43. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is mediated by filaggrin / FLG, loricin / LOR, IL-31, TSLP, CAMP, CCL17, CCL22, DefB4a, interferon-gamma, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF18.

44. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital onychoplakia, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.

45. A pharmaceutical preparation according to any one of claims 1 to 20, or a combination pharmaceutical preparation according to any one of claims 21 to 38, wherein the skin disease is rosacea, psoriatic arthritis, dermatofibrosis, morphea, nevus spitz, dermatophytosis, or acne vulgaris.

46. A pharmaceutical preparation according to any one of claims 1 to 20, further comprising administering an additional therapeutic agent, or a combination pharmaceutical preparation according to any one of claims 21 to 38.

47. The pharmaceutical preparation or combination drug according to claim 46, wherein the additional therapeutic agent is a corticosteroid.

48. The pharmaceutical preparation or combination drug according to claim 47, wherein the corticosteroid is betamethasone dipropionate.

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