Jak inhibitor with a vitamin d analog for treatment of skin diseases
Abstract
The present disclosure relates to topical treatment of skin diseases, such as psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and a disorder of keratinization, using (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
Term
Projected expiry 3 December 2041.
- Priority and filed
- Published
- Today
- Projected expiry
15 claims: 12 independent, 3 dependent
- 1A pharmaceutical formulation for topical treatment of a skin disease, 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.
- 3The pharmaceutical formulation of any one of claims 1-2, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having Formula (II):wherein: R 1 is H or OH;R 2 and R 3 are each H;or R 2 is O-R 2A ;and R 3 is H;or R 2 and R 3 are taken together to form a =CH 2 group;R 2A is -C 1-4 alkylene-OH;R 4 and R 5 are each H;or R 4 and R 5 are taken together to form a =CH 2 group;R 6 and R 7 are each H;or R 6 and R 7 are taken together to form a =CH 2 group;L is -CH 2 -CH 2 -CH(R 12 )-, -CH 2 -CH 2 -CH 2 -CH(R 12 )-, -CH=CH-CH(R 12 )-, -CH=CH-CH=CH-, -CH 2 -C≡C-, -O-CH 2 -CH 2 -, or -O-CH 2 -CH 2 -CH 2 -, wherein R 12 is H or OH;R 9 is C 1-3 alkyl or C 1-4 haloalkyl;R 10 is C 1-3 alkyl or C 1-4 haloalkyl;R 11 is H or OH;or, alternatively, R 9 and R 10 together with the carbon atom to which they are attached form a C 3-4 cycloalkyl ring;and R 11 is H, for example wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.
- 4The pharmaceutical formulation according to any one of claims 2-3, wherein:(a)(i) the formulation comprises from about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis;or (a)(ii) the formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof;and/or (b)(i) the formulation comprises from about 0.0001% w/w to about 0.01% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis;(b)(ii) the formulation comprises from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis;(b)(iii) the formulation comprises from about 0.0001% w/w to about 0.01% w/w or from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis;or (b)(iv) the formulation comprises about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.
- 5The pharmaceutical formulation of any one of claims 1-4, wherein:(a) the formulation is a cream or a lotion;(b) the formulation is an oil-in-water emulsion;and/or (c) the formulation comprises water, an oil component, and an emulsifier or stabilizer component, optionally wherein: (i) the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation;(ii) the oil component comprises from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 50%, or from about 5% to about 40% by weight of the pharmaceutical formulation;(iii) the emulsifier or stabilizer component comprises from about 1% to about 30% or from about 5% to about 25% by weight of the pharmaceutical formulation;and/or (iv) further comprising a solvent component for dissolving ruxolitinib, or a pharmaceutically acceptable salt thereof, optionally wherein the solvent component comprises from about 5% to about 20%, from about 2% to about 30%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, or from about 10% to about 20% by weight of the pharmaceutical formulation.
- 7A JAK inhibitor, or a pharmaceutically acceptable salt thereof, and vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use in a method of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (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.
- 10The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-9, wherein:(a) the skin disease is an autoimmune or an inflammatory skin disease;(b) the skin disease is a Th1 or Th17 associated skin disease;(c) 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;(d) the skin disease is mediated by Defb4, S100a12, or Serpinb4;(e) 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;(f) the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis;or (g) the skin disease is rosacea, psoriatic arthritis, dermal fibrosis, morphea, spitz nevi, dermatophytosis, or acne vulgaris.
- 11The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-10, wherein there is a synergistic effect between the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof.
- 12The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-11, wherein:(a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least one time per day;or (b) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least two times per day.
- 13The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-12, wherein:(a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered simultaneously;or (b) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered sequentially.
- 14The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-12, wherein:(a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as separate formulations, optionally wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are each administered in a topical formulation, further optionally wherein each topical formulation is an ointment, a cream, or a lotion;or (b) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single formulation, optionally wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single topical formulation, further optionally wherein the single topical formulation is an ointment, a cream, or a lotion.
- 15The JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 8-14, further comprising administering an additional therapeutic agent, optionally wherein the additional therapeutic agent is a corticosteroid, further optionally wherein the corticosteroid is betamethasone dipropionate.
Independent claims12
652 paragraphs in 7 sections, as filed
CROSS REFERENCE TO RELATED APPLICATIONS
0001This application claims priority to <patcit id="pcit0001" dnum="US63121531"><text>U.S. Provisional Application No. 63/121,531, filed December 4, 2020</text></patcit>, and <patcit id="pcit0002" dnum="US63199876"><text>U.S. Provisional Application No. 63/199,876, filed January 29, 2021</text></patcit>, each of which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
0002The present disclosure relates to 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
0003Inflammation mediated by the Janus kinase (JAK)-signal transducer is one of the important characteristics of autoimmune skin diseases. Janus kinase (JAK) inhibitors have been developed as agents for the treatment of inflammatory skin diseases including atopic dermatitis, alopecia areata, psoriasis, and vitiligo. However, as for any therapeutic, JAK inhibitors may not be equally effective in all subjects that have an inflammatory skin disease. There is a need for developing more effective formulations comprising JAK inhibitors to treat a broader number of subjects with various inflammatory skin disease.
0004Considering these limitations, there is a medical need for new therapeutic options. The present disclosure is directed to that need and others.
SUMMARY
0005The present disclosure provides methods of treating skin disease in a patient in need thereof, comprising topically administering to an 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.
0006The present disclosure also provides methods of treating skin disease a patient in need thereof, comprising topically administering to an 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.
0007The present disclosure also provides methods of treating skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) calcipotriol, or a pharmaceutically acceptable salt thereof to patients.
0008The present disclosure also provides a JAK inhibitor, or a pharmaceutically acceptable salt thereof, for use in topical treatment of a skin disease described herein in combination with a vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0009The present disclosure also provides ruxolitinib, or a pharmaceutically acceptable salt thereof, for use in topical treatment of a skin disease described herein in combination with a vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0010The present disclosure also provides ruxolitinib, or a pharmaceutically acceptable salt thereof, for use in topical treatment of a skin disease described herein in combination with calcipotriol, or a pharmaceutically acceptable salt thereof.
0011The present disclosure also provides use of a JAK inhibitor, or a pharmaceutically acceptable salt thereof, for manufacture of a medicament for topical treatment of a skin disease described herein in combination with a vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0012The present disclosure also provides use of ruxolitinib, or a pharmaceutically acceptable salt thereof, for manufacture of a medicament for topical treatment of a skin disease described herein in combination with a vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0013The present disclosure also provides use of ruxolitinib, or a pharmaceutically acceptable salt thereof, for manufacture of a medicament for topical treatment of a skin disease described herein in combination with calcipotriol, or a pharmaceutically acceptable salt thereof.
0014In some embodiments of each of the aforementioned, the patient is a human patient.
0015The present disclosure further provides a topical formulation 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, for use in topical treatment of a skin disorder described herein.
0016The present disclosure further provides a topical formulation comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof for use in topical treatment of a skin disorder described herein.
0017The present disclosure further provides ruxolitinib topical formulation comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) calcipotriol, or a pharmaceutically acceptable salt thereof for use in topical treatment of a skin disorder described herein.
0018The present disclosure also provides use of a topical formulation 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 for manufacture of a medicament for use in topical treatment of a skin disorder described herein.
0019The present disclosure also provides use of a topical formulation comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof for manufacture of a medicament for use in topical treatment of a skin disorder described herein.
0020The present disclosure also provides use of a topical formulation comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) calcipotriol, or a pharmaceutically acceptable salt thereof for manufacture of a medicament for use in topical treatment of a skin disorder described herein.
0021The present disclosure further provides pharmaceutical formulations for topical treatment of a skin disease 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.
0022The present disclosure also provides pharmaceutical formulations for topical treatment of a skin disease, comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0023The present disclosure further provides pharmaceutical formulations for topical treatment of a skin disease, comprising (a) ruxolitinib phosphate, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0024The details of one or more embodiments of the present disclosure are set forth in the description below. Other features, objects, and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
0025<ul id="ul0001" list-style="none" compact="compact"><li><figref idref="f0001">FIG. 1</figref> depicts fold changes and p-values of IL-22 levels of the skins treated basolaterally with various concentrations of ruxolitinib, calcipotriol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins.</li><li><figref idref="f0002">FIG. 2</figref> depicts fold changes and p-values of CXCL10 levels of the skins treated basolaterally with various concentrations of ruxolitinib, calcipotriol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins.</li><li><figref idref="f0003">FIG. 3</figref> depicts fold changes and p-values of MMP12 levels of the skins treated basolaterally with various concentrations of ruxolitinib, calcipotriol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins.</li><li><figref idref="f0004">FIG. 4</figref> depicts a schematic representation of a Transwell<sup>®</sup> insert.</li><li><figref idref="f0005">FIG. 5</figref> depicts photograph of cream formulations #1 to #6.</li><li><figref idref="f0006">FIG. 6A-6B</figref> depict the absolute fold changes in certain gene expression after treatment with combinations of calcipotriol and ruxolitinib as compared to untreated control after Th1 or Th17 stimulation, respectively (white indicates <2 absolute fold change, grey indicates >2 absolute fold change, and black indicates >4 absolute fold change).</li><li><figref idref="f0007">FIG. 7A-7B</figref> depict fold changes (with mean + SEM) of IL-22 levels and CXCL10, respectively of the skins treated basolaterally with various concentrations of ruxolitinib, maxacalcitol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins (JAKi is ruxolitinib; Vit D is maxacalcitol; and Combo is a combination of ruxolitinib and maxacalcitol).</li><li><figref idref="f0008">FIG. 8A-8C</figref> depict fold changes (with mean + SEM) of S 100a12, Defb4, and Serpinb4, respectively of the skins treated topically with various concentrations of ruxolitinib, calcipotriol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins (JAKi is ruxolitinib; Vit D is calcipotriol; and Combo is a combination of ruxolitinib and calcipotriol).</li><li><figref idref="f0009">FIG. 9A-9C</figref> depict fold changes (with mean + SEM) of MMP12, IL-22, and CXCL10, respectively of the skins treated topically with various concentrations of ruxolitinib, calcipotriol, and a combination of thereof at 24 hours following stimulation over normal (healthy) unstimulated and stimulated human skins (JAKi is ruxolitinib; Vit D is calcipotriol; and Combo is a combination of ruxolitinib and calcipotriol).</li><li><figref idref="f0010">FIG. 10</figref> depicts the change in ear thickness in an IL-23 induced psoriasis-like <i>in vivo</i> mouse model with treatment with vehicle or a combination cream of ruxolitinib and calcipotriol (*** indicates a p<0.001) (JAKi is ruxolitinib; Vit D is calcipotriol; and Combo is a combination of ruxolitinib and calcipotriol).</li></ul>
DETAILED DESCRIPTION
0026The present disclosure provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0027The present disclosure provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0028The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0029The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0030The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0031The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, or a pharmaceutically acceptable salt thereof.
0032The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0033The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib phosphate, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0034The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib phosphate, and (b) vitamin D3, or a pharmaceutically acceptable salt thereof.
0035The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib phosphate, and (b) a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0036The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib phosphate, and (b) calcipotriol, or a pharmaceutically acceptable salt thereof. In some embodiments, the skin disease is an autoimmune skin disease.
0037The present disclosure also provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.
0038In some embodiments, the skin disease is an inflammatory skin disease.
0039In some embodiments, the skin disease is associated with Th1 or Th2. T helper (Th)1 and/or T helper (Th)17 cells are involved in many inflammatory and autoimmune skin diseases. For example, the following diseases are primarily Th17 biased: (i) psoriasis (<nplcit id="ncit0001" npl-type="s"><text>Fletcher, et al., Clin Exp Immunol, 201(2):121-134 (2020) at PMID: 32379344</text></nplcit>; <nplcit id="ncit0002" npl-type="s"><text>Liu, et al., Front Immunol, 11:594735 (2020) at PMID: 33281823</text></nplcit>); (ii) ichthyosis (<nplcit id="ncit0003" npl-type="s"><text>Czarnowicki, et al., J Invest Dermatol, 138(10):2157-2167 (2018) at PMID: 29660300</text></nplcit>; <nplcit id="ncit0004" npl-type="s"><text>Paller, et al, J Allergy Clin Immunol, 139(1):152-165 (2017) at PMID: 27554821</text></nplcit>); and (iii) pityriasis rubra pilaris (Liu, <i>supra,</i> at PMID: 33281823). Further, the following diseases are primarily Th1 biased: (i) alopecia areata (Żeberkiewicz, et al., <i>Cent Eur J Immunol,</i> 45(3):325-333 (2020) at PMID: 33437185; and (ii) vitiligo (<nplcit id="ncit0005" npl-type="s"><text>Boniface, et al., Clin Rev Allergy Immunol, 54(1):52-67 (2018) at PMID: 28685247</text></nplcit>). Some diseases are associated with both Th1 and Th17, including: (i) hidradenitis suppurativa (Fletcher, <i>supra,</i> at PMID: 32379344; Liu, <i>supra,</i> at PMID: 33281823; <nplcit id="ncit0006" npl-type="s"><text>Banerjee, et al., Immunol Invest, 46(2):149-158 (2017) at PMID: 27819528</text></nplcit>; <nplcit id="ncit0007" npl-type="s"><text>Moran, et al., J Invest Dermatol, 137(11):2389-2395 (2017) at PMID: 28652108</text></nplcit>); and (ii) cutaneous lichen planus (<nplcit id="ncit0008" npl-type="s"><text>Aghamajidi, et al., Scand J Immunol, e13000 (2020) at PMID: 33190330</text></nplcit>). Further, blocking of inflammatory cytokines, such as IL-22 and CXCL10 which are involved in Th1 or Th17 lymphocyte proliferation, survival and function, can be useful for treating Th1 or Th17 associated diseases. For example, T helper (Th)17 cells are a distinct lineage of effector CD4+ T cells characterized by their production of IL-17. <i>See</i><nplcit id="ncit0009" npl-type="s"><text>Liang, et al., J Exp Med, 203(10):2271-9 (2006) at PMID: 16982811</text></nplcit>. Th17 cells have been shown to express IL-22 at substantially higher amounts than Th1 or Th2 cells. Further, expansion of IL-22-producing cells is dependent on IL-23. In turn, blocking IL-17 and IL-23 are clinically validated approaches in psoriasis. Examples of this approach in treating psoriasis, a Th17 associated disease, include secukinumab and guselkumab, which block blocking IL-17 and IL-23, respectively. T helper (Th)1 cells are a distinct lineage of effector CD4+ T cells characterized by their production of IFN-gamma and T-bet transcriptional marker. <i>See</i><nplcit id="ncit0010" npl-type="s"><text>Szabo, et al., Cell, 100(6):655-69 (2000) at PMID: 10761931. CXCL10</text></nplcit>, also known as interferon gamma-induced protein 10 (IP-10), attracts lymphocytes to the skin. Further, CXCR3 is the receptor for the CXCL10 ligand. In turn, diseases such as vitiligo appear to be Th1 associated, as lymphocyte infiltration into vitiliginous skin is thought to be driven by CXCR3-positive Th1 cells responding to the CXCL10 ligand.
0040In some embodiments, 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. In some embodiments, the skin disease is mediated by IL-22. In some embodiments, the skin disease is mediated by MMP12. In some embodiments, the skin disease is mediated by CXCL10.
0041In some embodiments, the skin disease is mediated by Defb4, S 100a12, or Serpinb4. S 100a12 is a significant marker for psoriasis disease activity (<nplcit id="ncit0011" npl-type="s"><text>Wilsmann-Theis, D, et al., J Eur Acad Dermatol Venereol, 30(7):1165-70 (2016); doi: 10.1111/jdv.13269</text></nplcit>, which is incorporated herein by reference in its entirety). Defb4 encodes human beta-defensin 2(hBD2), an antimicrobial peptide that plays an essentially role in inflammatory processes in the skin and is important in the pathogenesis of psoriasis (<nplcit id="ncit0012" npl-type="s"><text>Johansen C, et al., J Invest Derm, 136(8):1608-1616 (2016); doi: 10.1016/j.jid.2016.04.012</text></nplcit>, which is incorporated herein by reference in its entirety). Serpinb4 contributes to inflammation in patients with chronic skin diseases, including atopic dermatitis (<nplcit id="ncit0013" npl-type="s"><text>Sivaprasad, U, et al., J Invest Derm 135(1):160-169 (2015); DOI:10.1038/jid.2014.353</text></nplcit>, which is incorporated herein by reference in its entirety).
0042In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and a disorder of keratinization.
0043In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.
0044In some embodiments, the skin disease is psoriasis. In some embodiments, the psoriasis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The nexus between psoriasis and IL-22, CXCL10, and/or MMP12 can be found, for example, at IL-22, CXCL10, and/or MMP12, see <nplcit id="ncit0014" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, the psoriasis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the psoriasis is mediated by matrix metallopeptidase 12 (MMP12). In some embodiments, the psoriasis is selected from plaque psoriasis, nail psoriasis, intertriginous psoriasis, palmoplantar psoriasis, and pustular psoriasis. In some embodiments, the psoriasis is plaque psoriasis. In some embodiments, the plaque psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, the plaque psoriasis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the plaque psoriasis is mediated by matrix metallopeptidase 12 (MMP12).
0045In some embodiments, the skin disease is atopic dermatitis. In some embodiments, the atopic dermatitis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The nexus between atopic dermatitis and IL-22 and/or MMP12 can be found, for example, at <nplcit id="ncit0015" npl-type="s"><text>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</text></nplcit>. The nexus between atopic dermatitis and CXCL10 can be found, for example, at <nplcit id="ncit0016" npl-type="s"><text>Brunner et al. "Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues" Allergy. 2017 Dec;72(12):2017-2025, PMID: 28599078</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the atopic dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, the atopic dermatitis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the atopic dermatitis is mediated by matrix metallopeptidase 12 (MMP12).
0046In some embodiments, the skin disease is alopecia. In some embodiments, the skin disease is alopecia areata. The nexus between alopecia areata and IL-22 can be found, for example, at <nplcit id="ncit0017" npl-type="s"><text>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</text></nplcit>. The nexus between alopecia areata and CXCL10 can be found, for example, at <nplcit id="ncit0018" npl-type="s"><text>Duca et al. "Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing" Br J Dermatol. 2020 Mar 25, PMID: 32215911</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the alopecia is mediated by interleukin 22 (IL-22). In some embodiments, the alopecia is mediated by C-X-C motif chemokine 10 (CXCL10).
0047In some embodiments, the skin disease is vitiligo. The nexus between vitiligo and IL-22 can be found, for example, at <nplcit id="ncit0019" npl-type="s"><text>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</text></nplcit>. The nexus between vitiligo and CXCL10 can be found, for example, at <nplcit id="ncit0020" npl-type="s"><text>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</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the vitiligo is mediated by interleukin 22 (IL-22). In some embodiments, the vitiligo is mediated by C-X-C motif chemokine 10 (CXCL10).
0048In some embodiments, the skin disease is Reiter's syndrome. The nexus between Reiter's syndrome and IL-22 can be found, for example, at <nplcit id="ncit0021" npl-type="s"><text>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</text></nplcit>. The nexus betweenReiter's syndrome and CXCL10 can be found, for example, at <nplcit id="ncit0022" npl-type="s"><text>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</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the Reiter's syndrome is mediated by interleukin 22 (IL-22). In some embodiments, the Reiter's syndrome is mediated by C-X-C motif chemokine 10 (CXCL10).
0049In some embodiments, the skin disease is pityriasis rubra pilaris. The nexus between pityriasis rubra pilaris and IL-22 can be found, for example, at <nplcit id="ncit0023" npl-type="s"><text>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</text></nplcit>. The nexus between pityriasis rubra pilaris and CXCL10 can be found, for example, at <nplcit id="ncit0024" npl-type="s"><text>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</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the pityriasis rubra pilaris is mediated by interleukin 22 (IL-22). In some embodiments, the pityriasis rubra pilaris is mediated by C-X-C motif chemokine 10 (CXCL10).
0050In some embodiments, the skin disease is epidermolysis bullosa simplex. The nexus between epidermolysis bullosa simplex and IL-22 and/or CXCL10 can be found, for example, at <nplcit id="ncit0025" npl-type="s"><text>Castela et al. "Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment" Br J Dermatol. 2019 Feb;180(2):357-364, PMID: 29932457</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the epidermolysis bullosa simplex is mediated by interleukin 22 (IL-22). In some embodiments, the epidermolysis bullosa simplex is mediated by C-X-C motif chemokine 10 (CXCL10).
0051In some embodiments, the skin disease is palmoplantar keratoderma. The nexus between almoplantar keratoderma and IL-22 can be found, for example, at <nplcit id="ncit0026" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the palmoplantar keratoderma is mediated by interleukin 22 (IL-22).
0052In some embodiments, the skin disease is pachyonychia congenita. The nexus between pachyonychia congenita and IL-22 can be found, for example, at <nplcit id="ncit0027" npl-type="s"><text>Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb;247(2):158-165, PMID: 30306595</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the pachyonychia congenita is mediated by interleukin 22 (IL-22).
0053In some embodiments, the skin disease is steatocystoma multiplex. The nexus between steatocystoma multiplex and IL-22 can be found, for example, at <nplcit id="ncit0028" npl-type="s"><text>Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb;247(2):158-165, PMID: 30306595</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the steatocystoma multiplex is mediated by interleukin 22 (IL-22).
0054In some embodiments, the skin disease is cutaneous lichen planus. The nexus between cutaneous lichen planus and IL-22 can be found, for example, at <nplcit id="ncit0029" npl-type="s"><text>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</text></nplcit>. The nexus between cutaneous lichen planus and CXCL10 can be found, for example, at <nplcit id="ncit0030" npl-type="s"><text>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</text></nplcit> and <nplcit id="ncit0031" npl-type="s"><text>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</text></nplcit>, each of which is incorporated by reference in its entirety herein. In some embodiments, the cutaneous lichen planus is mediated by interleukin 22 (IL-22). In some embodiments, the cutaneous lichen planus is mediated by C-X-C motif chemokine 10 (CXCL10).
0055In some embodiments, the skin disease is cutaneous T-cell lymphoma. In some embodiments, the cutaneous T-cell lymphoma is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The nexus between cutaneous T-cell lymphoma and IL-22 and/or MMP12 can be found, for example, at <nplcit id="ncit0032" npl-type="s"><text>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</text></nplcit>. The nexus between cutaneous T-cell lymphoma and CXCL10 can be found, for example, at <nplcit id="ncit0033" npl-type="s"><text>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</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the cutaneous T-cell lymphoma is mediated by interleukin 22 (IL-22). In some embodiments, the cutaneous T-cell lymphoma is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the cutaneous T-cell lymphoma is mediated by matrix metallopeptidase 12 (MMP12).
0056In some embodiments, the skin disease is hidradenitis suppurativa. The nexus between hidradenitis suppurativa and IL-22 can be found, for example, at <nplcit id="ncit0034" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the hidradenitis suppurativa is mediated by interleukin 22 (IL-22).
0057In some embodiments, the skin disease is contact dermatitis. In some embodiments, the contact dermatitis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The nexus between contact dermatitis and IL-22 can be found, for example, at <nplcit id="ncit0035" npl-type="s"><text>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</text></nplcit>. The nexus between contact dermatitis and CXCL10 can be found, for example, at <nplcit id="ncit0036" npl-type="s"><text>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</text></nplcit>. The nexus between contact dermatitis and MMP12 can be found, for example, at <nplcit id="ncit0037" npl-type="s"><text>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</text></nplcit>. Each of the references cited herein is incorporated by reference in its entirety herein. In some embodiments, the contact dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, the contact dermatitis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the contact dermatitis is mediated by matrix metallopeptidase 12 (MMP12).
0058In some embodiments, the skin disease is ichthyosis. The nexus between ichthyosis and IL-22 can be found, for example, at <nplcit id="ncit0038" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the ichthyosis is mediated by interleukin 22 (IL-22). In some embodiments, the ichthyosis is ichthyosis vulgaris, x-linked ichthyosis, bullous congenital ichthyosiform erythroderma (BCIE), nonbullous congential ichthyosiform erythroderma (NBCIE), lamellar ichthyosis, harlequin ichthyosis, ichthyosis syndrome, or acquired ichthyosis.
0059Generally, disorders of keratinization are a group of disorders of cornification. The nexus between a disorder of keratinization and IL-22 can be found, for example, at <nplcit id="ncit0039" npl-type="s"><text>Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb;247(2):158-165, PMID: 30306595</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the disorder of keratinization is mediated by IL-22. In some embodiments, the disorder of keratinization is selected from ichthyosis, palmoplantar keratoderma, keratosis pilari, and acantholytic dermatosis.
0060In some embodiments, the skin disease is rosacea, psoriatic arthritis, dermal fibrosis, morphea, spitz nevi, dermatophytosis, or acne vulgaris. In some embodiments, the skin disease is rosacea. In some embodiments, the rosacea is mediated by interleukin 22 (IL-22) or C-X-C motif chemokine 10 (CXCL10), or a combination thereof. The nexus between rosacea and IL-22 and CXCL10 can be found, for example, see <nplcit id="ncit0040" npl-type="s"><text>Buhl, et al., J. Invest. Derm., 135(9), P2198-2208 (2015), PMID: 25848978</text></nplcit>, which is incorporated by reference in its entirety herein. In some embodiments, the rosacea is mediated by interleukin 22 (IL-22). In some embodiments, the psoriasis is rosacea by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the skin disease is psoriasis mediated by S 100a12. In some embodiments, the skin disease is psoriatic arthritis mediated by S100a12. In some embodiments, the skin disease is dermal fibrosis mediated by S 100a12. In some embodiments, the skin disease is morphea mediated by S 100a12. In some embodiments, the skin disease is atopic dermatitis mediated by S100a12. In some embodiments, the skin disease is spitz nevi mediated by S100a12.
0061In some embodiments, the skin disease is psoriasis mediated by Defb4. In some embodiments, the skin disease is psoriatic arthritis mediated by Defb4. In some embodiments, the skin disease is dermatophytosis mediated by Defb4. In some embodiments, the skin disease is acne vulgaris mediated by Defb4. In some embodiments, the skin disease is hidradenitis suppurativa mediated by Defb4.
0062In some embodiments, the skin disease is psoriasis mediated by Serpinb4. In some embodiments, the skin disease is psoriatic arthritis mediated by Serpinb4.
0063In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered sequentially.
0064In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered sequentially.
0065In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered at least one time per day.
0066In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered once per day.
0067In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered twice per day.
0068In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered once per day.
0069In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered twice per day.
0070In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as separate formulations.
0071In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as a single formulation.
0072In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered once per day.
0073In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered twice per day.
0074In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a synergistic amount.
0075In some embodiments, there is a synergistic effect between the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof.
0076The present disclosure provides methods of treating a skin disease in a patient in need thereof, comprising topically administering to an 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, further comprising administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a corticosteroid.
0077In some embodiments, (b) is vitamin D3, or a pharmaceutically acceptable salt thereof.
0078In some embodiments, provided are the methods as described herein, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.
0079In some embodiments, provided are the methods as described herein, wherein (b) vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.
0080In some embodiments of each of the aforementioned, the patient is a human patient.
0081In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered one time per day.
0082In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least two times per day.
0083In some embodiments, (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least two times per day.
0084In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are each administered in a topical formulation. In some embodiments, each topical formulation is an ointment, a cream, or a lotion. In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are in a single formulation. In some embodiments, the single formulation is a cream or a lotion. In some embodiments, the formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.
Vitamin D3 and Vitamin D3 Analogs for Use in Methods and Topical Formulations
0085In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (I): <chemistry id="chem0001" num="0001"><img file="EP4570321A2_D0001.tif" /></chemistry>
0086In some embodiments, R<sup>1</sup> is H or OH. In some embodiments, R<sup>1</sup> is H. In some embodiments, R<sup>1</sup> is OH.
0087In some embodiments, R<sup>2</sup> and R<sup>3</sup> are each H. In some embodiments, R<sup>2</sup> is H. In some embodiments, R<sup>3</sup> is H. In some embodiments, R<sup>2</sup> and R<sup>3</sup> are both H.
0088In some embodiments, R<sup>2</sup> is O-R<sup>2A</sup> and R<sup>3</sup> is H.
0089In some embodiments, R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group.
0090In some embodiments, R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH.
0091In some embodiments, R<sup>4</sup> and R<sup>5</sup> are each H. In some embodiments, R<sup>4</sup> is H. In some embodiments, R<sup>5</sup> is H. In some embodiments, R<sup>4</sup> and R<sup>5</sup> are both H.
0092In some embodiments, R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group.
0093In some embodiments, R<sup>6</sup> and R<sup>7</sup> are each H. In some embodiments, R<sup>6</sup> and R<sup>7</sup> are both H. In some embodiments, R<sup>6</sup> is H. In some embodiments, R<sup>7</sup> is H.
0094In some embodiments, R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group.
0095In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-. In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-. In some embodiments, L is -CH=CH-CH(R<sup>12</sup>)-. In some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH<sub>2</sub>-C≡C-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, R<sup>12</sup> is H or OH. In some embodiments, R<sup>12</sup> is OH. In some embodiments, R<sup>12</sup> is H.
0096In some embodiments, R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl. In some embodiments, R<sup>9</sup> is C<sub>1-3</sub> alkyl. In some embodiments, R<sup>9</sup> is C<sub>1-4</sub> haloalkyl.
0097In some embodiments, R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl. In some embodiments, R<sup>10</sup> is C<sub>1-3</sub> alkyl. In some embodiments, R<sup>10</sup> is C<sub>1-4</sub> haloalkyl.
0098In some embodiments, R<sup>11</sup> is H or OH. In some embodiments, R<sup>11</sup> is OH. In some embodiments, R<sup>11</sup> is H.
0099In some embodiments, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring. In some embodiments, R<sup>11</sup> is H.
0100In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (II): <chemistry id="chem0002" num="0002"><img file="EP4570321A2_D0002.tif" /></chemistry>
0101In some embodiments, R<sup>1</sup> is H or OH. In some embodiments, R<sup>1</sup> is H. In some embodiments, R<sup>1</sup> is OH.
0102In some embodiments, R<sup>2</sup> and R<sup>3</sup> are each H. In some embodiments, R<sup>2</sup> is H. In some embodiments, R<sup>3</sup> is H. In some embodiments, R<sup>2</sup> and R<sup>3</sup> are both H.
0103In some embodiments, R<sup>2</sup> is O-R<sup>2A</sup> and R<sup>3</sup> is H.
0104In some embodiments, R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group.
0105In some embodiments, R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH.
0106In some embodiments, R<sup>4</sup> and R<sup>5</sup> are each H. In some embodiments, R<sup>4</sup> is H. In some embodiments, R<sup>5</sup> is H. In some embodiments, R<sup>4</sup> and R<sup>5</sup> are both H.
0107In some embodiments, R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group.
0108In some embodiments, R<sup>6</sup> and R<sup>7</sup> are each H. In some embodiments, R<sup>6</sup> and R<sup>7</sup> are both H. In some embodiments, R<sup>6</sup> is H. In some embodiments, R<sup>7</sup> is H.
0109In some embodiments, R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group.
0110In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-. In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-. In some embodiments, L is -CH=CH-CH(R<sup>12</sup>)-. In some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH<sub>2</sub>-C≡C-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, R<sup>12</sup> is H or OH. In some embodiments, R<sup>12</sup> is OH. In some embodiments, R<sup>12</sup> is H.
0111In some embodiments, R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl. In some embodiments, R<sup>9</sup> is C<sub>1-3</sub> alkyl. In some embodiments, R<sup>9</sup> is C<sub>1-4</sub> haloalkyl.
0112In some embodiments, R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl. In some embodiments, R<sup>10</sup> is C<sub>1-3</sub> alkyl. In some embodiments, R<sup>10</sup> is C<sub>1-4</sub> haloalkyl.
0113In some embodiments, R<sup>11</sup> is H or OH. In some embodiments, R<sup>11</sup> is OH. In some embodiments, R<sup>11</sup> is H.
0114In some embodiments, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring. In some embodiments, R<sup>11</sup> is H.
0115In some embodiments, (b) is a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
0116In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α-(OH) D3 analog, or a pharmaceutically acceptable salt thereof.
0117In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α,25(OH)<sub>2</sub> D3 analog, a vitamin 1α,24(OH)<sub>2</sub> D3 analog or a vitamin 1α,26(OH)<sub>2</sub> D3 analog, or a pharmaceutically acceptable salt thereof.
0118In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α,25(OH)<sub>2</sub> D3 analog, or a pharmaceutically acceptable salt thereof.
0119In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α,24(OH)<sub>2</sub> D3 analog, or a pharmaceutically acceptable salt thereof.
0120In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α,26(OH)<sub>2</sub> D3 analog, or a pharmaceutically acceptable salt thereof.
0121As used herein, "vitamin D3" (calcitol; cholecalciferol) has a formula of Formula (i) with numbering as shown below. As used herein, "vitamin D derivatives" refers to vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), and structural analogs of Formula (i), sharing the scaffold the 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 can be (R) or (S). <chemistry id="chem0003" num="0003"><img file="EP4570321A2_D0003.tif" /></chemistry>
0122In some embodiments, the phrase "vitamin D3 analog" refers a structural analog of Formula (i), sharing the 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 can be (R) or (S), wherein the compound does not contain a methyl substituent at carbon 24, and wherein the substitution and bonding at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remains unaltered. 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 hydroxy group α to the hydroxy group at carbon 3.
0123As used herein, the phrase "vitamin 1α-(OH) D3 analog" refers a structural analog of Formula (ii), sharing 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 each dotted line can be a single, double or triple bond within the constraints of proper valency, wherein the compound does not contain a methyl substituent at carbon 24 and wherein the substitution at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remains unaltered. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. <chemistry id="chem0004" num="0004"><img file="EP4570321A2_D0004.tif" /></chemistry>
0124As used herein, the phrase "vitamin 1α,25-(OH)<sub>2</sub> D3 analog" refers a structural analog of Formula (iii), sharing 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, wherein each dotted line can be a single, double or triple bond within the constraints of proper valency, wherein the compound does not contain a methyl substituent at carbon 24, and wherein the substitution at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remains unaltered. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. <chemistry id="chem0005" num="0005"><img file="EP4570321A2_D0005.tif" /></chemistry>
0125As used herein, the phrase "vitamin 1α,24-(OH)<sub>2</sub> D3 analog" refers a structural analog of structure (iv), sharing 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, wherein each dotted line can be a single, double or triple bond within the constraints of proper valency, wherein the compound does not contain a methyl substituent at carbon 24, and wherein the substitution at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remains unaltered. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. <chemistry id="chem0006" num="0006"><img file="EP4570321A2_D0006.tif" /></chemistry>
0126As used herein, the phrase "vitamin 1α,26-(OH)<sub>2</sub> D3 analog" refers a structural analog of structure (v), sharing 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 wherein each dotted line can be a single, double or triple bond within the constraints of proper valency, wherein the compound does not contain a methyl substituent at carbon 24, and wherein the substitution at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remains unaltered. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, the double bond at carbon 19 is present. <chemistry id="chem0007" num="0007"><img file="EP4570321A2_D0007.tif" /></chemistry>
0127In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (III): <chemistry id="chem0008" num="0008"><img file="EP4570321A2_D0008.tif" /></chemistry>
0128In some embodiments, R<sup>2</sup> and R<sup>3</sup> are each H. In some embodiments, R<sup>2</sup> is H. In some embodiments, R<sup>3</sup> is H. In some embodiments, R<sup>2</sup> and R<sup>3</sup> are both H.
0129In some embodiments, R<sup>2</sup> is O-R<sup>2A</sup> and R<sup>3</sup> is H.
0130In some embodiments, R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH.
0131In some embodiments, R<sup>6</sup> and R<sup>7</sup> are each H. In some embodiments, R<sup>6</sup> and R<sup>7</sup> are both H. In some embodiments, R<sup>6</sup> is H. In some embodiments, R<sup>7</sup> is H.
0132In some embodiments, R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group.
0133In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-. In some embodiments, L is -CH=CH-CH(R<sup>12</sup>)- In some embodiments, L is -CH=CH-CH=CH-. In some embodiments, L is -CH<sub>2</sub>-C≡C-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, L is -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-. In some embodiments, R<sup>12</sup> is H or OH. In some embodiments, R<sup>12</sup> is OH. In some embodiments, R<sup>12</sup> is H.
0134In some embodiments, R<sup>9</sup> is CH<sub>3</sub> or CF<sub>3</sub>. In some embodiments, R<sup>9</sup> is CH<sub>3</sub>. In some embodiments, R<sup>9</sup> is CF<sub>3</sub>.
0135In some embodiments, R<sup>10</sup> is CH<sub>3</sub> or CF<sub>3</sub>. In some embodiments, R<sup>10</sup> is CF<sub>3</sub>. In some embodiments, R<sup>10</sup> is CH<sub>3</sub>.
0136In some embodiments, R<sup>11</sup> is H or OH. In some embodiments, R<sup>11</sup> is H. In some embodiments, R<sup>11</sup> is OH.
0137In some embodiments, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a cyclopropyl ring. In some embodiments, R<sup>11</sup> is H.
0138In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, falecalcitriol, eldecalcitol, inecalcitol, seocalcitol, lexicalcitol, 20-epi-1α,25(OH)<sub>2</sub>D<sub>3</sub>, CD578 (17-methyl-19-nor-21-nor-23-yne-26,27-F6-1α,25(OH)<sub>2</sub>D<sub>3</sub>), TX527 (19-nor-14,20-bisepi-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)<sub>2</sub>D<sub>3</sub>), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)<sub>2</sub>D<sub>3</sub>), ILX23-7553 (16-ene-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), and MART-10(19-nor-2α-(3-hydroxypropyl)-1α,25(OH)<sub>2</sub>D<sub>3</sub>).
0139In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, falecalcitriol, eldecalcitol, inecalcitol, seocalcitol, and lexicalcitol.
0140In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is selected from calcipotriol, tacalcitol, maxacalcitol, and seocalcitol.
0141In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcipotriol.
0142In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is maxacalcitol.
0143In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is tacalcitol.
0144In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is seocalcitol.
0145In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcidiol.
0146In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcitriol.
0147In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is alfacalcidol.
0148In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is falecalcitriol.
0149In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is eldecalcitol.
0150In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is inecalcitol,
0151In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is lexicalcitol.
Formulations of Vitamin D3 or Vitamin D3 Analogs for Use in Methods
0152In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a topical formulation. In some embodiments, the topical formulation is a foam, an ointment, a lotion, or a cream.
0153In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0001% to about 0.1% of the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, on a free base basis by weight of the formulation. In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0001% to about 0.02% of the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, on a free base basis by weight of the formulation. In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0001% to about 0.005% of the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, on a free base basis by weight of the formulation. In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0004% to about 0.005% of the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, on a free base basis by weight of the formulation.
0154In some embodiments, the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcipotriol, which is administered as a topical formulation comprising about 50 µg calcipotriol per gram of the formulation.
0155In some embodiments, the topical formulation is a foam, an ointment, a lotion, or a cream. In some embodiments, the topical formulation further comprises betamethasone dipropionate. In some embodiments, the betamethasone dipropionate is present in an amount of about 0.5 mg per gram of the formulation.
0156In some embodiments, the vitamin D3 analog is tacalcitol, which is administered as a topical formulation comprising about 4 µg tacalcitol per gram of the formulation. In some embodiments, the topical formulation is an ointment, a cream, or a lotion.
0157In some embodiments, the vitamin D3 analog is maxacalcitol, which is administered as a topical formulation comprising about 6 µg, about 12.5 µg/g, about 25 µg, or about 50 µg per gram of the formulation. In some embodiments, the topical formulation is an ointment.
JAK inhibitors for Use in Methods and Topical Formulations
0158In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a compound that inhibits JAK1, JAK2, JAK3, and/or TYK2. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor, a JAK1/JAK2 inhibitor, a pan-JAK inhibitor, a JAK1/TYK2 inhibitor, and a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt of any of the aforementioned.
0159In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, baricitinib, oclacitinib, momelotinib, CTP-543, AH057, gandotinib, fedratinib, lestaurtinib, pacritinib, CHZ868, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, cerdulatinib, decernotinib, BMS-986165, and ritlecitinib, or a pharmaceutically acceptable salt thereof.
0160In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, or a pharmaceutically acceptable salt thereof.
0161In some embodiments, the JAK1 inhibitor is a selective JAK1 inhibitor, or a pharmaceutically acceptable salt thereof. JAK1 plays a central role in a number of cytokine and growth factor signaling pathways that, when dysregulated, can result in or contribute to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease in which it has been suggested to have detrimental effects (see <i>e.g.,</i><nplcit id="ncit0041" npl-type="s"><text>Fonesca, et al., Autoimmunity Reviews, 8:538-42, 2009</text></nplcit>). Because IL-6 signals, at least in part, through JAK1, IL-6 can be indirectly through JAK1 inhibition, resulting in potential clinical benefit (see e.g., <nplcit id="ncit0042" npl-type="s"><text>Guschin, et al. Embo J 14:1421, 1995</text></nplcit>; and <nplcit id="ncit0043" npl-type="s"><text>Smolen, et al. Lancet 371:987, 2008</text></nplcit>). 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 efficacious while avoiding unnecessary and potentially undesirable effects of inhibiting other JAK kinases, as described herein. In some embodiments, the JAK1 inhibitor is selective for JAK1 preferentially over JAK2 (e.g., having a JAK2/JAK1 IC<sub>50</sub> ratio >1). In some embodiments, the compounds or salts as provided and described herein are about 10-fold more selective for JAK1 over JAK2. In some embodiments, the compounds or salts provided herein are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 over JAK2 as calculated by measuring IC<sub>50</sub> at 1 mM ATP (see Example 1).
0162In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK2 inhibitor, or a pharmaceutically acceptable salt thereof.
0163In some embodiments, the JAK2 inhibitor is a selective JAK2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK2 over JAK1, JAK3 and TYK2 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0164In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK3 inhibitor, or a pharmaceutically acceptable salt thereof.
0165In some embodiments, the JAK3 inhibitor is a selective JAK3 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK3inhibitor is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK2 over JAK1, JAK2 and TYK2 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0166In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a TYK2 inhibitor, or a pharmaceutically acceptable salt thereof.
0167In some embodiments, the TYK2 inhibitor is a selective TYK2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the TYK2 inhibitor is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for TYK2 over JAK1, JAK2 and JAK3 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0168In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof.
0169In some embodiments, the JAK1/JAK2 inhibitor, or the pharmaceutically acceptable salt thereof, is selective for JAK1 and JAK2 over JAK3 and TYK2. In some embodiments, the JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof, is selective for JAK1 and JAK2 over JAK3. In some embodiments, the compounds or salts are about 10-fold more selective for JAK1 and JAK2 over JAK3. In some embodiments, the compounds or salts are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 and JAK2 over JAK3 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0170In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a pan-JAK inhibitor, or a pharmaceutically acceptable salt thereof.
0171In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/TYK2 inhibitor, or a pharmaceutically acceptable salt thereof.
0172In some embodiments, the JAK1/TYK2 inhibitor is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 and TYK2 over JAK2 and JAK3 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0173In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt thereof.
0174In some embodiments, the JAK1/JAK3 inhibitor is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 and JAK3 over JAK2 and TYK2 as calculated by measuring IC<sub>50</sub> at 1 mM ATP.
0175In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt thereof. Ruxolitinib is a JAK1/JAK2 inhibitor. Ruxolitinib has an IC<sub>50</sub> of less than 10 nM at 1 mM ATP at JAK1 and JAK2. ruxolitinib can be made by the procedure described in <patcit id="pcit0003" dnum="US7598257B"><text>US 7,598,257 (Example 67), filed December 12, 2006</text></patcit>, which is incorporated herein by reference in its entirety. <chemistry id="chem0009" num="0009"><img file="EP4570321A2_D0009.tif" /></chemistry>
0176In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is the 1:1 ruxolitinib phosphoric acid salt. The phosphoric acid salt can be made as described in <patcit id="pcit0004" dnum="US8722693B"><text>U.S. Patent 8,722,693</text></patcit>, which is incorporated herein by reference in its entirety.
0177In some embodiments, the ruxolitinib or the salt thereof is administered as a topical formulation. In some embodiments, the topical formulation comprises from about 0.05% to about 3.0%, about 0.05% to about 1.5%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.1% to about 3.0%, about 0.1% to about 2.0%, from about 0.1% to about 1.5%, from about 0.1% to about 1.0%, from about 0.1% to about 0.5%, from about 0.5% to about 2.0%%, from about 0.5% to about 1.5%, or from about 0.5% to about 1.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises from about 0.5% to about 1.5% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof.
0178In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ruxolitinib, wherein one or more hydrogen atoms are replaced by deuterium atoms, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is any of the compounds in <patcit id="pcit0005" dnum="US9249149B"><text>US Patent 9,249,149</text></patcit>, which is incorporated herein by reference in its entirety, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is CTP-543 (having the structure below), or a pharmaceutically acceptable salt thereof. <chemistry id="chem0010" num="0010"><img file="EP4570321A2_D0010.tif" /></chemistry>
0179In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a compound of Formula IV: <chemistry id="chem0011" num="0011"><img file="EP4570321A2_D0011.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein: <ul id="ul0002" list-style="none" compact="compact"><li>R<sup>13</sup> is selected from H and D;</li><li>each R<sup>14</sup> is independently selected from H and D, provided that each R<sup>14</sup> attached to a common carbon is the same;</li><li>each R<sup>15</sup> is independently selected from H and D, provided that each R<sup>15</sup> attached to a common carbon is the same;</li><li>R<sup>16</sup> is selected from H and D;</li><li>each R<sup>17</sup> is the same and is selected from H and D; and</li><li>R<sup>18</sup>, R<sup>19</sup>, and R<sup>20</sup> are each independently selected from H and D; provided that when R<sup>13</sup> is H, each R<sup>14</sup> and each R<sup>15</sup> are H, R<sup>16</sup> is H, and each of R<sup>18</sup>, R<sup>19</sup>, and R<sup>20</sup> is H, then each R<sup>17</sup> is D.</li><li>CTP-543 is a compound of Formula IV, which is a JAK1/JAK2 inhibitor.</li></ul>
0180In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a compound of Formula IV selected from the following compounds 100-130 in the table below (wherein R<sup>18</sup>, R<sup>19</sup>, and R<sup>20</sup> are each H), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a compound of Formula IV selected from the following compounds 200-231 in the table below (wherein R<sup>18</sup>, R<sup>19</sup>, and R<sup>20</sup> are each D), or a pharmaceutically acceptable salt thereof. <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="6"><colspec colnum="1" colname="col1" colwidth="22mm" /><colspec colnum="2" colname="col2" colwidth="11mm" /><colspec colnum="3" colname="col3" colwidth="19mm" /><colspec colnum="4" colname="col4" colwidth="19mm" /><colspec colnum="5" colname="col5" colwidth="11mm" /><colspec colnum="6" colname="col6" colwidth="19mm" /><thead valign="middle"><row><entry>Compound</entry><entry>R<sup>13</sup></entry><entry>Each R<sup>14</sup></entry><entry>Each R<sup>15</sup></entry><entry>R<sup>16</sup></entry><entry>Each R<sup>17</sup></entry></row></thead><tbody valign="middle"><row><entry>100</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>101</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>102</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>103</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>104</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>105</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>106</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>107</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>108</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>109</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>110</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>111</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>112</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>113</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>114</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>115</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>116</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>117</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>118</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>119</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>120</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>121</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>122</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>123</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>124</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>125</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>126</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>127</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>128</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>129</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>130</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>200</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>201</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>202</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>203</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>204</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>205</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>206</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>207</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>208</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>209</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>210</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>211</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>212</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>213</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>214</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>215</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>216</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>217</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>218</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>219</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>220</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>221</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>222</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>223</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>H</entry></row><row><entry>224</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>H</entry></row><row><entry>225</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry><entry>D</entry></row><row><entry>226</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry><entry>D</entry></row><row><entry>227</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>H</entry></row><row><entry>228</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry></row><row><entry>229</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>H</entry><entry>D</entry></row><row><entry>230</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry><entry>D</entry></row><row><entry>231</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry><entry>H</entry></row></tbody></tgroup></table></tables>
0181In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is baricitinib, or a pharmaceutically acceptable salt thereof. Baricitinib is a JAK1/JAK2 inhibitor.
0182In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is baricitinib, wherein one or more hydrogen atoms are replaced by deuterium atoms, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is any of the compounds in <patcit id="pcit0006" dnum="US9540367B"><text>US Patent 9,540,367</text></patcit> (which is incorporated herein by reference in its entirety), or a pharmaceutically acceptable salt thereof.
0183In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is oclacitinib, or a pharmaceutically acceptable salt thereof. Oclacitinib is a JAK1/JAK2 inhibitor.
0184In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is momelotinib, or a pharmaceutically acceptable salt thereof. Momelotinib is a JAK1/JAK2 inhibitor.
0185In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is AH057, or a pharmaceutically acceptable salt thereof. AH057 is a JAK1/JAK2 inhibitor.
0186In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is gandotinib, or a pharmaceutically acceptable salt thereof. Gandotinib is a JAK2 inhibitor.
0187In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is fedratinib, or a pharmaceutically acceptable salt thereof. Fedratinib is a JAK2 inhibitor.
0188In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is lestaurtinib, or a pharmaceutically acceptable salt thereof. Lestaurtinib is a JAK2 inhibitor.
0189In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is pacritinib, or a pharmaceutically acceptable salt thereof. Pacritinib is a JAK2 inhibitor, which also inhibits fms-like tyrosine kinase 3 (FLT3).
0190In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is CHZ868, or a pharmaceutically acceptable salt thereof. CHZ868 is a JAK2 inhibitor.
0191In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is upadacitinib, or a pharmaceutically acceptable salt thereof. Upadacitinib is a JAK1 inhibitor.
0192In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is filgotinib, or a pharmaceutically acceptable salt thereof. Filgotinib is a JAK1 inhibitor.
0193In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is abrocitinib, or a pharmaceutically acceptable salt thereof. Abrocitinib is a JAK1 inhibitor.
0194In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is itacitinib, or a pharmaceutically acceptable salt thereof. Itacitinib is a JAK1 inhibitor.
0195In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, which is a compound of Table 1, or a pharmaceutically acceptable salt thereof. The compounds in Table 1 are JAK1 selective inhibitors (e.g., selective over JAK2, JAK3, and TYK2). The IC<sub>50</sub> values obtained by the method of Example 1 at 1 mM ATP are shown in Table 1. <tables id="tabl0002" num="0002"><table frame="all"><title><b>Table 1.</b></title><tgroup cols="6"><colspec colnum="1" colname="col1" colwidth="14mm" /><colspec colnum="2" colname="col2" colwidth="26mm" /><colspec colnum="3" colname="col3" colwidth="44mm" /><colspec colnum="4" colname="col4" colwidth="54mm" /><colspec colnum="5" colname="col5" colwidth="12mm" /><colspec colnum="6" colname="col6" colwidth="12mm" /><thead valign="top"><row><entry>Comp. No.</entry><entry>Prep.</entry><entry>Name</entry><entry>Structure</entry><entry>JAK1 IC<sub>50</sub> (nM)</entry><entry>JAK2 / JAK1</entry></row></thead><tbody><row><entry>1</entry><entry>Itacitinib; <patcit id="pcit0007" dnum="us20110224190a"><text>US 2011/ 0224190</text></patcit> (Example 1)</entry><entry>{ 1-{ 1-[3-Fluoro-2-(trifluoromethyl)isonico tinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0012" num="0012"><img file="EP4570321A2_D0012.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>2</entry><entry><patcit id="pcit0008" dnum="us20110224190a"><text>US 2011/ 0224190</text></patcit> (Example 154)</entry><entry>4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl] piperidine-1-carboxamide</entry><entry><chemistry id="chem0013" num="0013"><img file="EP4570321A2_D0013.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>3</entry><entry><patcit id="pcit0009" dnum="us20110224190a"><text>US 2011/ 0224190</text></patcit> (Example 85)</entry><entry>[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimi din-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile</entry><entry><chemistry id="chem0014" num="0014"><img file="EP4570321A2_D0014.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>4</entry><entry><patcit id="pcit0010" dnum="us20140343030a"><text>US 2014/03430 30</text></patcit> (Example 7)</entry><entry>4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide</entry><entry><chemistry id="chem0015" num="0015"><img file="EP4570321A2_D0015.tif" /></chemistry></entry><entry>+++</entry><entry>>10</entry></row><row><entry>5</entry><entry><patcit id="pcit0011" dnum="us20140121198a"><text>US 2014/01211 98</text></patcit> (Example 20)</entry><entry>((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile</entry><entry><chemistry id="chem0016" num="0016"><img file="EP4570321A2_D0016.tif" /></chemistry></entry><entry>++</entry><entry>>10</entry></row><row><entry>6</entry><entry><patcit id="pcit0012" dnum="us20100298334a"><text>US 2010/ 0298334</text></patcit> (Example 2)<sup>a</sup></entry><entry>3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile</entry><entry><chemistry id="chem0017" num="0017"><img file="EP4570321A2_D0017.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>7</entry><entry><patcit id="pcit0013" dnum="us20100298334a"><text>US 2010/ 0298334</text></patcit> (Example 13c)</entry><entry>3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile</entry><entry><chemistry id="chem0018" num="0018"><img file="EP4570321A2_D0018.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>8</entry><entry><patcit id="pcit0014" dnum="us20110059951a"><text>US 2011/ 0059951</text></patcit> (Example 12)</entry><entry>4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile</entry><entry><chemistry id="chem0019" num="0019"><img file="EP4570321A2_D0019.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>9</entry><entry><patcit id="pcit0015" dnum="us20110059951a"><text>US 2011/ 0059951</text></patcit> (Example 13)</entry><entry>4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile</entry><entry><chemistry id="chem0020" num="0020"><img file="EP4570321A2_D0020.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>10</entry><entry><patcit id="pcit0016" dnum="us20120149681a"><text>US 2012/ 0149681</text></patcit> (Example 7b)</entry><entry>[<i>trans</i>-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimi din-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitril e</entry><entry><chemistry id="chem0021" num="0021"><img file="EP4570321A2_D0021.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>11</entry><entry><patcit id="pcit0017" dnum="us20120149681a"><text>US 2012/ 0149681</text></patcit> (Example 157)</entry><entry>{<i>trans</i>-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0022" num="0022"><img file="EP4570321A2_D0022.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>12</entry><entry><patcit id="pcit0018" dnum="us20120149681a"><text>US 2012/ 0149681</text></patcit> (Example 161)</entry><entry>{<i>trans</i>-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrroli din-1-yl]methyl}-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0023" num="0023"><img file="EP4570321A2_D0023.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>13</entry><entry><patcit id="pcit0019" dnum="us20120149681a"><text>US 2012/ 0149681</text></patcit> (Example 162)</entry><entry>{<i>trans</i>-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrroli din-1-yl]methyl}-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0024" num="0024"><img file="EP4570321A2_D0024.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>14</entry><entry><patcit id="pcit0020" dnum="us20120149682a"><text>US 2012/ 0149682</text></patcit> (Example 20)<sup>b</sup></entry><entry>4-(4-{3-[(dimethylamino)methyl ]-5-fluorophenoxy}piperidi n-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile</entry><entry><chemistry id="chem0025" num="0025"><img file="EP4570321A2_D0025.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>15</entry><entry><patcit id="pcit0021" dnum="us20130018034a"><text>US 2013/ 0018034</text></patcit> (Example 18)</entry><entry>5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide</entry><entry><chemistry id="chem0026" num="0026"><img file="EP4570321A2_D0026.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>16</entry><entry><patcit id="pcit0022" dnum="us20130018034a"><text>US 2013/ 0018034</text></patcit> (Example 28)</entry><entry>4- { 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide</entry><entry><chemistry id="chem0027" num="0027"><img file="EP4570321A2_D0027.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>17</entry><entry><patcit id="pcit0023" dnum="us20130018034a"><text>US 2013/ 0018034</text></patcit> (Example 34)</entry><entry>5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl] azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide</entry><entry><chemistry id="chem0028" num="0028"><img file="EP4570321A2_D0028.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>18</entry><entry><patcit id="pcit0024" dnum="us20130045963a"><text>US 2013/ 0045963</text></patcit> (Example 45)</entry><entry>{1-(<i>cis</i>-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimi din-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0029" num="0029"><img file="EP4570321A2_D0029.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>19</entry><entry><patcit id="pcit0025" dnum="us20130045963a"><text>US 2013/ 0045963</text></patcit> (Example 65)</entry><entry>{1-(<i>cis</i>-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin -2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0030" num="0030"><img file="EP4570321A2_D0030.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>20</entry><entry><patcit id="pcit0026" dnum="us20130045963a"><text>US 2013/ 0045963</text></patcit> (Example 69)</entry><entry>{1-(<i>cis</i>-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin -2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0031" num="0031"><img file="EP4570321A2_D0031.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>21</entry><entry><patcit id="pcit0027" dnum="us20130045963a"><text>US 2013/ 0045963</text></patcit> (Example 95)</entry><entry>{1-(<i>cis</i>-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin -2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0032" num="0032"><img file="EP4570321A2_D0032.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>22</entry><entry><patcit id="pcit0028" dnum="us20130045963a"><text>US 2013/ 0045963</text></patcit> (Example 95)</entry><entry>{1-(<i>cis</i>-4-{[4-{1(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin -2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile</entry><entry><chemistry id="chem0033" num="0033"><img file="EP4570321A2_D0033.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>23</entry><entry><patcit id="pcit0029" dnum="us20140005166a"><text>US 2014/ 0005166</text></patcit> (Example 1)</entry><entry>{<i>trans</i>-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}met hyl)-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0034" num="0034"><img file="EP4570321A2_D0034.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>24</entry><entry><patcit id="pcit0030" dnum="us20140005166a"><text>US 2014/ 0005166</text></patcit> (Example 14)</entry><entry>{<i>trans</i>-3-(4-{[4-({[(2R)-2-hydroxypropyl] amino } methyl)-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0035" num="0035"><img file="EP4570321A2_D0035.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>25</entry><entry><patcit id="pcit0031" dnum="us20140005166a"><text>US 2014/ 0005166</text></patcit> (Example 15)</entry><entry>{<i>trans</i>-3-(4-{[4-({[(2S)-2-hydroxypropyl] amino } methyl)-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0036" num="0036"><img file="EP4570321A2_D0036.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row><row><entry>26</entry><entry><patcit id="pcit0032" dnum="us20140005166a"><text>US 2014/ 0005166</text></patcit> (Example 20)</entry><entry>{<i>trans</i>-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin -2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitril e</entry><entry><chemistry id="chem0037" num="0037"><img file="EP4570321A2_D0037.tif" /></chemistry></entry><entry>+</entry><entry>>10</entry></row></tbody></tgroup><tgroup cols="6" rowsep="0"><colspec colnum="1" colname="col1" colwidth="14mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="26mm" /><colspec colnum="3" colname="col3" colwidth="44mm" /><colspec colnum="4" colname="col4" colwidth="54mm" /><colspec colnum="5" colname="col5" colwidth="12mm" /><colspec colnum="6" colname="col6" colwidth="12mm" /><tbody><row><entry namest="col1" nameend="col6">+ means <10 nM (see Example 1 for assay conditions) ++ means ≤ 100 nM (see Example 1 for assay conditions) +++ means ≤ 300 nM (see Example 1 for assay conditions) <sup>a</sup>Data for enantiomer 1 <sup>b</sup>Data for enantiomer 2</entry></row></tbody></tgroup></table></tables>
0196In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt. The synthesis and preparation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and the adipic acid salt of the same can be found, e.g., in <patcit id="pcit0033" dnum="US20110224190A"><text>US Patent Publ. No. 2011/0224190, filed March 9, 2011</text></patcit>, <patcit id="pcit0034" dnum="US20130060026A"><text>US Patent Publ. No. 2013/0060026, filed September 6, 2012</text></patcit>, and <patcit id="pcit0035" dnum="US20140256941A"><text>US Patent Publ. No. 2014/0256941, filed March 5, 2014</text></patcit>, each of which is incorporated herein by reference in its entirety.
0197In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, which is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-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 the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, which is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt. In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrochloric acid salt. In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrobromic acid salt. In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is s 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide sulfuric acid salt. The synthesis and preparation of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and the phosphoric acid salt of the same can be found, e.g., in US Patent Publ. No. <patcit id="pcit0036" dnum="US20140343030A"><text>US 2014/0343030, filed May 16, 2014</text></patcit>, which is incorporated herein by reference in its entirety.
0198In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.
0199In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrilemonohydrate, or a pharmaceutically acceptable salt thereof. Synthesis of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile and characterization of the anhydrous and monohydrate forms of the same are described in <patcit id="pcit0037" dnum="US20140121198A"><text>US Patent Publ. No. 2014/0121198, filed October 31, 2013</text></patcit> and <patcit id="pcit0038" dnum="US20150344497A"><text>US Patent Publ. No. 2015/0344497, filed April 29, 2015</text></patcit>, each of which is incorporated herein by reference in its entirety.
0200In some embodiments, the compounds of Table 1 are prepared by the synthetic procedures described in <patcit id="pcit0039" dnum="US20110224190A"><text>US Patent Publ. No. 2011/0224190, filed March 9, 2011</text></patcit>, <patcit id="pcit0040" dnum="US20140343030A"><text>US Patent Publ. No. 2014/0343030, filed May 16, 2014</text></patcit>, <patcit id="pcit0041" dnum="US20140121198A"><text>US Patent Publ. No. 2014/0121198, filed October 31, 2013</text></patcit>, <patcit id="pcit0042" dnum="US20100298334A"><text>US Patent Publ. No. 2010/0298334, filed May 21, 2010</text></patcit>, <patcit id="pcit0043" dnum="US20110059951A"><text>US Patent Publ. No. 2011/0059951, filed August 31, 2010</text></patcit>, <patcit id="pcit0044" dnum="US20120149681A"><text>US Patent Publ. No. 2012/0149681, filed November 18, 2011</text></patcit>, <patcit id="pcit0045" dnum="US20120149682A"><text>US Patent Publ. No. 2012/0149682, filed November 18, 2011</text></patcit>, <patcit id="pcit0046" dnum="US20130018034A"><text>US Patent Publ. 2013/0018034, filed June 19, 2012</text></patcit>, <patcit id="pcit0047" dnum="US20130045963A"><text>US Patent Publ. No. 2013/0045963, filed August 17, 2012</text></patcit>, and <patcit id="pcit0048" dnum="US20140005166A"><text>US Patent Publ. No. 2014/0005166, filed May 17, 2013</text></patcit>, each of which is incorporated herein by reference in its entirety.
0201In some embodiments, the JAK1 inhibitor, or the pharmaceutically acceptable salt thereof, is selected from the compounds, or pharmaceutically acceptable salts thereof, of US
0202Patent Publ. No. <patcit id="pcit0049" dnum="US20110224190A"><text>2011/0224190, filed March 9, 2011</text></patcit>, <patcit id="pcit0050" dnum="US20140343030A"><text>US Patent Publ. No. 2014/0343030, filed May 16, 2014</text></patcit>, <patcit id="pcit0051" dnum="US20140121198A"><text>US Patent Publ. No. 2014/0121198, filed October 31, 2013</text></patcit>, <patcit id="pcit0052" dnum="US20100298334A"><text>US Patent Publ. No. 2010/0298334, filed May 21, 2010</text></patcit>, <patcit id="pcit0053" dnum="US20110059951A"><text>US Patent Publ. No. 2011/0059951, filed August 31, 2010</text></patcit>, <patcit id="pcit0054" dnum="US20120149681A"><text>US Patent Publ. No. 2012/0149681, filed November 18, 2011</text></patcit>, <patcit id="pcit0055" dnum="US20120149682A"><text>US Patent Publ. No. 2012/0149682, filed November 18, 2011</text></patcit>, <patcit id="pcit0056" dnum="US20130018034A"><text>US Patent Publ. 2013/0018034, filed June 19, 2012</text></patcit>, <patcit id="pcit0057" dnum="US20130045963A"><text>US Patent Publ. No. 2013/0045963, filed August 17, 2012</text></patcit>, and <patcit id="pcit0058" dnum="US20140005166A"><text>US Patent Publ. No. 2014/0005166, filed May 17, 2013</text></patcit>, each of which is incorporated herein by reference in its entirety.
0203In some embodiments, the JAK inhibitor, is brepocitinib, or a pharmaceutically acceptable salt thereof. Brepocitinib is a JAK1/JAK2 inhibitor.
0204In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ATI-501, or a pharmaceutically acceptable salt thereof. ATI-501 (Aclaris) is a JAK1/JAK3 inhibitor.
0205In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ATI-1777, or a pharmaceutically acceptable salt thereof. ATI-1777 (Aclaris) is a JAK1/JAK3 inhibitor.
0206In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ATI-502, or a pharmaceutically acceptable salt thereof. ATI-502 (Aclaris) is a JAK1/JAK3 inhibitor.
0207In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is tofacitinib, or a pharmaceutically acceptable salt thereof. Tofacinitib inhibits JAK1 and JAK3.
0208In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is delgocitinib, or a pharmaceutically acceptable salt thereof. Delgocitinib is a pan-JAK inhibitor.
0209In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is peficitinib, or a pharmaceutically acceptable salt thereof. Peficitinib is a pan-JAK inhibitor.
0210In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is gusacitinib, or a pharmaceutically acceptable salt thereof. Gusacitinib is a pan-JAK inhibitor that also inhibits SYK.
0211In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is cucurbitacin I, or a pharmaceutically acceptable salt thereof. Cucurbitacin I is a pan-JAK inhibitor which also inhibits STAT3.
0212In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is cerdulatinib, or a pharmaceutically acceptable salt thereof. Cerdulatinib is a pan-JAK inhibitor, which also inhibits spleen tyrosine kinase (SYK).
0213In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is decernotinib, or a pharmaceutically acceptable salt thereof. Decernotinib is a JAK3 inhibitor.
0214In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is BMS-986165 having the structure below: <chemistry id="chem0038" num="0038"><img file="EP4570321A2_D0038.tif" /></chemistry> or a pharmaceutically acceptable salt thereof. BMS-986165 is a TYK2 inhibitor.
0215In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ritlecitinib, or a pharmaceutically acceptable salt thereof. Ritlecitinib (Pfizer) is a JAK3 inhibitor, which also inhibits TEC.
0216In some embodiments, provided are the methods as described herein, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, oclacitinib, baricitinib, momelotinib, and CTP-543, or a pharmaceutically acceptable salt thereof.
0217In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, oclacitinib, baricitinib, momelotinib, CTP-543, gandotinib, fedratinib, lestaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and cerdulatinib, or a pharmaceutically acceptable salt thereof.
0218In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, oclacitinib, baricitinib, momelotinib, CTP-543, gandotinib, fedratinib, lestaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and cerdulatinib, or a pharmaceutically acceptable salt thereof.
0219In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, can be an isotopically-labeled compound, or a pharmaceutically acceptable salt thereof. An "isotopically" or "radio-labeled" compound is a compound wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (<i>i.e.,</i> naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present disclosure include but are not limited to <sup>2</sup>H (also written as D for deuterium), <sup>3</sup>H (also written as T for tritium), <sup>11</sup>C, <sup>13</sup>C, <sup>14</sup>C, <sup>13</sup>N, <sup>15</sup>N, <sup>15</sup>O, <sup>17</sup>O, <sup>18</sup>O, <sup>18</sup>F, <sup>35</sup>S, <sup>36</sup>Cl, <sup>82</sup>Br, <sup>75</sup>Br, <sup>76</sup>Br, <sup>77</sup>Br, <sup>123</sup>I, <sup>124</sup>I, <sup>125</sup>I and <sup>131</sup>I. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms, such as -CD<sub>3</sub> being substituted for -CH<sub>3</sub>).
0220Accordingly, in some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a compound, wherein one or more hydrogen atoms in the compound are replaced by deuterium atoms, or a pharmaceutically acceptable salt thereof.
0221In some embodiments, provided are the methods as described herein, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is combined with any of the JAK inhibitors, or a pharmaceutically acceptable salt thereof, as described herein.
0222In some embodiments, provided are the methods as described herein, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.
0223In some embodiments, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation. In some embodiments, the topical formulation comprises from about 0.1% to about 3.0%, about 0.1% to about 2.0%, from about 0.1% to about 1.5%, from about 0.1% to about 1.0%, from about 0.1% to about 0.5%, from about 0.5% to about 2.0%%, from about 0.5% to about 1.5%, or from about 0.5% to about 1.0% by weight of the formulation on a free base basis of the JAK inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises from about 0.5% to about 1.5% by weight of the formulation on a free base basis of the JAK inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the topical formulation comprises 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%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the JAK inhibitor, or the pharmaceutically acceptable salt thereof.
Cream Formulations of Ruxolitinib
0224In some embodiments, the ruxolitinib, or pharmaceutically acceptable salt thereof, is administered as a cream formulation comprising the ruxolitinib, or the pharmaceutically acceptable salt thereof.
0225In some embodiments, the ruxolitinib, or pharmaceutically acceptable salt thereof, is administered as a cream formulation comprising ruxolitinib phosphate.
0226In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is in a 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 <patcit id="pcit0059" dnum="US10758543B"><text>U.S. Patent 10,758,543</text></patcit>, which is incorporated by reference in its entirety. In particular, Examples 3-6 of <patcit id="pcit0060" dnum="US10758543B"><text>U.S. Patent 10,758,543</text></patcit> (and particularly Tables 3-5 and accompanying text) are incorporated herein by reference. In some embodiments, the cream comprises from about 0.1% to about 3.0%, from about 0.1% to about 3.0%, from about 0.1% to about 1.5%, from about 0.1% to about 1.0%, from about 0.1% to about 0.5%, from about 0.5% to about 2.0%%, from about 0.5% to about 1.5%, from about 0.5% to about 1.4%, from about 0.5% to about 1.3%, from about 0.5% to about 1.2%, from about 0.5% to about 1.1%, from about 0.6% to about 2.0%%, from about 0.6% to about 1.5%, from about 0.6% to about 1.4%, from about 0.6% to about 1.3%, from about 0.6% to about 1.2%, from about 0.6% to about 1.1%, from about 0.7% to about 2.0%%, from about 0.7% to about 1.5%, from about 0.7% to about 1.4%, from about 0.7% to about 1.3%, from about 0.7% to about 1.2%, from about 0.7% to about 1.1%, from about 0.8% to about 2.0%%, from about 0.8% to about 1.5%, from about 0.8% to about 1.4%, from about 0.8% to about 1.3%, from about 0.8% to about 1.2%, from about 0.8% to about 1.1%, from about 0.9% to about 2.0%%, from about 0.9% to about 1.5%, from about 0.9% to about 1.4%, from about 0.9% to about 1.3%, from about 0.9% to about 1.2%, from about 0.9% to about 1.1%, from about 1.0% to about 2.0%%, from about 1.0% to about 1.5%, from about 1.0% to about 1.4%, from about 1.0% to about 1.3%, from about 1.0% to about 1.2%, from about 1.0% to about 1.1%, or from about 0.5% to about 1.0% by weight of the emulsion on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof. In some embodiments, the oil-in-water emulsion comprises from about 0.5% to about 1.5% by weight of the emulsion on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof. In some embodiments, the oil-in-water emulsion comprises 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%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, or 2.0% by weight of the emulsion on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0227In some embodiments, the cream formulation has a pH from about 6.5 to about 7.0.
0228In some embodiments, the cream formulation has a pH from about 2.8 to about 3.9.
0229In some embodiments, the cream formulation has a pH from about 2.8 to about 3.6.
0230In some embodiments, the cream comprises an oil-in-water emulsion, comprising ruxolitinib.
0231In some embodiments, the cream comprises an oil-in-water emulsion, comprising ruxolitinib phosphate. In some embodiments, the cream is an oil-in-water emulsion as described in <patcit id="pcit0061" dnum="US20150250790A"><text>US 2015/0250790</text></patcit>, which is incorporated herein by reference in its entirety. In particular, Examples 3-6 of <patcit id="pcit0062" dnum="US20150250790A"><text>US 2015/0250790</text></patcit> (and particularly Tables 3-5 and accompanying text) are incorporated herein by reference.
0232In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.
0233In some embodiments, the oil component is present in an amount of about 10% to about 24% by weight of the emulsion.
0234In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the emulsion.
0235In some embodiments, the oil component is present in an amount of about 18% to about 24% by weight of the emulsion.
0236In some embodiments, the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and silicone oils.
0237In 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.
0238In some embodiments, the oil component comprises an occlusive agent component.
0239In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.
0240In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.
0241In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils & waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fat (e.g., cocoa butter), vegetable wax (e.g., Carnauba wax), and wax ester (e.g., bees wax).
0242In some embodiments, the occlusive agent component comprises one or more substances selected from lanolin acid fatty alcohols, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, Carnauba wax, and bees wax.
0243In some embodiments, the occlusive agent component comprises petrolatum.
0244In some embodiments, the occlusive agent component comprises white petrolatum.
0245In some embodiments, the white petrolatum is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0246In some embodiments, the white petrolatum is present in an amount of about 7% by weight of the emulsion.
0247In some embodiments, the oil component comprises a stiffening agent component.
0248In some embodiments, the stiffening agent component is present in an amount of about 2% to about 8% by weight of the emulsion.
0249In some embodiments, the stiffening agent component is present in an amount of about 3% to about 6% by weight of the emulsion.
0250In some embodiments, the stiffening agent component is present in an amount of about 4% to about 7% by weight of the emulsion.
0251In some embodiments, the stiffening agent component comprises one or more substances independently selected from fatty alcohols.
0252In some embodiments, the stiffening agent component comprises one or more substances independently selected from C<sub>12-20</sub> fatty alcohols.
0253In some embodiments, the stiffening agent component comprises one or more substances independently selected from C<sub>16-18</sub> fatty alcohols.
0254In some embodiments, the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
0255In some embodiments, the cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0256In some embodiments, the cetyl alcohol in an amount of about 3% by weight of the emulsion.
0257In some embodiments, the stearyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0258In some embodiments, the stearyl alcohol is present in an amount of about 1.75% by weight of the emulsion.
0259In some embodiments, the stiffening agent component comprises one or more substances independently selected from cetyl alcohol, stearyl alcohol, oleyl alcohol, and cetosteryl alcohol.
0260In some embodiments, the cetosteryl alcohol is present in an amount of about 0.1% to about 30% by weight of the emulsion.
0261In some embodiments, the cetosteryl alcohol is present in an amount of about 1% to about 20% by weight of the emulsion.
0262In some embodiments, the oil component comprises an emollient component.
0263In some embodiments, the emollient component is present in an amount of about 5% to about 15% by weight of the emulsion.
0264In some embodiments, the emollient component is present in an amount of about 7% to about 13% by weight of the emulsion.
0265In some embodiments, the emollient component comprises one or more substances independently selected from mineral oils and triglycerides.
0266In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oil and medium chain triglycerides.
0267In some embodiments, the light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0268In some embodiments, the light mineral oil is present in an amount of about 4% by weight of the emulsion.
0269In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone.
0270In some embodiments, the dimethicone is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0271In some embodiments, the dimethicone is present in an amount of about 1% by weight of the emulsion.
0272In some embodiments, the medium chain triglycerides are in an amount of about 0.1% to about 15% by weight of the emulsion.
0273In some embodiments, the medium chain triglycerides are in an amount of about 7.0% by weight of the emulsion.
0274In some embodiments, the water is present in an amount of about 35% to about 65% by weight of the emulsion.
0275In some embodiments, the water is present in an amount of about 40% to about 60% by weight of the emulsion.
0276In some embodiments, the water is present in an amount of about 45% to about 55% by weight of the emulsion.
0277In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the emulsion.
0278In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.
0279In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.
0280In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the emulsion.
0281In some embodiments, the emulsion comprises an emulsifier component and a stiffening agent component, wherein the combined amount of emulsifier component and stiffening agent component is at least about 8% by weight of the emulsion.
0282In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.
0283In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate, and polysorbate 20.
0284In some embodiments, the glyceryl stearate is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0285In some embodiments, the glyceryl stearate is present in an amount of about 3% by weight of the emulsion.
0286In some embodiments, the polysorbate 20 is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0287In some embodiments, the polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.
0288In some embodiments, the emulsifier component comprises a non-ionic surfactant.
0289In some embodiments, the non-ionic surfactant is cetomacrogol 1000 or poloxamer 407.
0290In some embodiments, the cetomacrogol 1000 is present in an amount of about 0.01% to about 15% by weight of the emulsion.
0291In some embodiments, the cetomacrogol 1000 is present in an amount of about 0.1% to about 10% by weight of the emulsion.
0292In some embodiments, the poloxamer is poloxamer 407.
0293In some embodiments, the poloxamer 407 is present in an amount of about 0.01% to about 15% by weight of the emulsion.
0294In some embodiments, the emulsifier component further comprises glyceryl stearate and PEG-100 stearate, such as Arlacel<sup>™</sup> 165
0295In some embodiments, the glyceryl stearate andPEG-100 stearate is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0296In some embodiments, the emulsion further comprises a stabilizing agent component.
0297In some embodiments, the stabilizing agent component is present in an amount of about 0.05% to about 5% by weight of the emulsion.
0298In some embodiments, the stabilizing agent component is present in an amount of about 0.1% to about 2% by weight of the emulsion.
0299In some embodiments, the stabilizing agent component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.
0300In some embodiments, the stabilizing agent component comprises one or more substances independently selected from polysaccharides.
0301In some embodiments, the stabilizing agent component comprises xanthan gum.
0302In some embodiments, the xanthan gum is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0303In some embodiments, the xanthan gum is present in an amount of about 0.2% to about 0.6% by weight of the emulsion.
0304In some embodiments, the xanthan gum is present in an amount of about 0.4%.by weight of the emulsion.
0305In some embodiments, the emulsion further comprises a solvent component.
0306In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the emulsion.
0307In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the emulsion.
0308In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the emulsion.
0309In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
0310In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
0311In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, propylene glycol.
0312In some embodiments, the solvent component comprises PEG300 and propylene glycol.
0313In some embodiments, the PEG300 is present in an amount of about 7% w/w by weight of the emulsion.
0314In some embodiments, the solvent is a combination of PEG400 and propylene glycol.
0315In some embodiments, the PEG400 is present in an amount of about 7% by weight of the emulsion.
0316In some embodiments, the propylene glycol is present of about 6.5% by weight of the emulsion. In some embodiments, the solvent component comprises diethylene glycol monoethyl ether, such as Transcutol<sup>®</sup> P. In some embodiments, the diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 30% w/w by weight of the emulsion. In some embodiments, the diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 20% w/w by weight of the emulsion.
0317In some embodiments, the emulsion further comprises: <ul id="ul0003" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 10% to about 40% of an oil component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion; and</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0318In some embodiments, the emulsion comprises: <ul id="ul0004" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 10% to about 40% of an oil component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion;</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0319In some embodiments, the emulsion further comprises: <ul id="ul0005" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 10% to about 24% of an oil component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion; and</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0320In some embodiments, the emulsion comprises: <ul id="ul0006" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 10% to about 24% of an oil component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion;</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0321In some embodiments, the emulsion further comprises: <ul id="ul0007" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 15% to about 30% of an oil component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 15% to about 30% of a solvent component by weight of the emulsion; and</li><li>from about 0.1% to about 2% of a stabilizing agent component by weight of the emulsion.</li></ul>
0322In some embodiments, the emulsion comprises: <ul id="ul0008" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 15% to about 30% of an oil component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 15% to about 30% of a solvent component by weight of the emulsion;</li><li>from about 0.1% to about 2% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0323In some embodiments, the emulsion further comprises: <ul id="ul0009" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 15% to about 30% of an oil component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 15% to about 24% of a solvent component by weight of the emulsion; and</li><li>from about 0.1% to about 2% of a stabilizing agent component by weight of the emulsion.</li></ul>
0324In some embodiments, the emulsion comprises: <ul id="ul0010" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 15% to about 30% of an oil component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 15% to about 24% of a solvent component by weight of the emulsion;</li><li>from about 0.1% to about 2% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0325In some embodiments, the emulsion further comprises: <ul id="ul0011" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 15% to about 24% of an oil component by weight of the emulsion;</li><li>from about 3% to about 5% of an emulsifier component by weight of the emulsion;</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion; and</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0326In some embodiments, the emulsion comprises: <ul id="ul0012" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 15% to about 24% of an oil component by weight of the emulsion;</li><li>from about 3% to about 5% of an emulsifier component by weight of the emulsion; from about 20% to about 25% of a solvent component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0327In some embodiments, the emulsion further comprises: <ul id="ul0013" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 15% to about 24% of an oil component by weight of the emulsion;</li><li>from about 4% to about 7% of an emulsifier component by weight of the emulsion;</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion; and</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0328In some embodiments, the emulsion comprises: <ul id="ul0014" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 15% to about 24% of an oil component by weight of the emulsion;</li><li>from about 4% to about 7% of an emulsifier component by weight of the emulsion;</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0329In some embodiments: <ul id="ul0015" list-style="none" compact="compact"><li>the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and dimethicones;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;</li><li>the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; and</li><li>the stabilizing agent component comprises one or more substances independently selected from polysaccharides.</li></ul>
0330In some embodiments: <ul id="ul0016" list-style="none" compact="compact"><li>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;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;</li><li>the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and</li><li>the stabilizing agent component comprises xanthan gum.</li></ul>
0331In some embodiments, the emulsion further comprises: <ul id="ul0017" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 2% to about 15% of an occlusive agent component by weight of the emulsion;</li><li>from about 2% to about 8% of a stiffening agent component by weight of the emulsion;</li><li>from about 5% to about 15% of an emollient component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion; and</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion.</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion; In some embodiments, the emulsion comprises: <ul id="ul0018" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 2% to about 15% of an occlusive agent component by weight of the emulsion;</li><li>from about 2% to about 8% of a stiffening agent component by weight of the emulsion;</li><li>from about 5% to about 15% of an emollient component by weight of the emulsion;</li><li>from about 1% to about 9% of an emulsifier component by weight of the emulsion;</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion;</li><li>from about 10% to about 35% of a solvent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul></li></ul>
0332In some embodiments, the emulsion further comprises: <ul id="ul0019" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 2% to about 8% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 12% of an emollient component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 0.1% to about 2% of a stabilizing agent by weight of the emulsion; and</li><li>from about 15% to about 30% of a solvent component by weight of the emulsion.</li></ul>
0333In some embodiments, the emulsion comprises: <ul id="ul0020" list-style="none" compact="compact"><li>from about 40% to about 60% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 2% to about 8% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 12% of an emollient component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 0.1% to about 2% of a stabilizing agent by weight of the emulsion;</li><li>from about 15% to about 30% of a solvent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0334In some embodiments, the emulsion further comprises: <ul id="ul0021" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 3% to about 6% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 13% of an emollient component by weight of the emulsion;</li><li>from about 3% to about 5% of an emulsifier component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion; and</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion.</li></ul>
0335In some embodiments, the emulsion comprises: <ul id="ul0022" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 3% to about 6% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 13% of an emollient component by weight of the emulsion;</li><li>from about 3% to about 5% of an emulsifier component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion;</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0336In some embodiments, the emulsion further comprises: <ul id="ul0023" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 4% to about 7% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 13% of an emollient component by weight of the emulsion;</li><li>from about 4% to about 7% of an emulsifier component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion; and</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion.</li></ul>
0337In some embodiments, the emulsion comprises: <ul id="ul0024" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>from about 5% to about 10% of an occlusive agent component by weight of the emulsion;</li><li>from about 4% to about 7% of a stiffening agent component by weight of the emulsion;</li><li>from about 7% to about 13% of an emollient component by weight of the emulsion;</li><li>from about 4% to about 7% of an emulsifier component by weight of the emulsion;</li><li>from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion;</li><li>from about 20% to about 25% of a solvent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0338In some embodiments, the emulsion further comprises: <ul id="ul0025" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>about 7% of an occlusive agent component by weight of the emulsion;</li><li>from about 4.5% to about 5% of a stiffening agent component by weight of the emulsion;</li><li>about 10% of an emollient component by weight of the emulsion;</li><li>from about 4% to about 4.5% of an emulsifier component by weight of the emulsion;</li><li>about 0.4% of a stabilizing agent component by weight of the emulsion; and</li><li>about 22% of a solvent component by weight of the emulsion.</li></ul>
0339In some embodiments, the emulsion comprises: <ul id="ul0026" list-style="none" compact="compact"><li>from about 45% to about 55% of water by weight of the emulsion;</li><li>about 7% of an occlusive agent component by weight of the emulsion;</li><li>from about 4.5% to about 5% of a stiffening agent component by weight of the emulsion;</li><li>about 10% of an emollient component by weight of the emulsion;</li><li>from about 4% to about 4.5% of an emulsifier component by weight of the emulsion;</li><li>about 0.4% of a stabilizing agent component by weight of the emulsion;</li><li>about 22% of a solvent component by weight of the emulsion; and</li><li>from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion on a free base basis.</li></ul>
0340In some embodiments, the ruxolitinib, or pharmaceutically acceptable salt thereof, is present as ruxolitinib phosphate.
0341In some embodiments, the emulsion comprises 1.5% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion.
0342In some embodiments, the emulsion comprises 1.5% of ruxolitinib phosphate by weight of the emulsion.
0343In some embodiments, the emulsion comprises 1.1% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion.
0344In some embodiments, the emulsion comprises 1.1% of ruxolitinib phosphate by weight of the emulsion.
0345In some embodiments, the emulsion comprises 0.75% of ruxolitinib, or a pharmaceutically acceptable salt thereof, by weight of the emulsion.
0346In some embodiments, the emulsion comprises 0.75% of ruxolitinib phosphate by weight of the emulsion.
0347In some embodiments, the combined amount of the stiffening agent component and the emulsifier component is at least about 8% by weight of the emulsion.
0348In some embodiments: <ul id="ul0027" list-style="none" compact="compact"><li>the occlusive agent component comprises a petrolatum;</li><li>the stiffening agent component comprises one or more substances independently selected from one or more fatty alcohols;</li><li>the emollient component comprises one or more substances independently selected from mineral oils and triglycerides;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;</li><li>the stabilizing agent component comprises one or more substances independently selected from polysaccharides; and</li><li>the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.</li></ul>
0349In some embodiments: <ul id="ul0028" list-style="none" compact="compact"><li>the occlusive agent component comprises white petrolatum;</li><li>the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;</li><li>the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;</li><li>the stabilizing agent component comprises xanthan gum; and</li><li>the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.</li></ul>
0350In some embodiments, the emulsion further comprises an antimicrobial preservative component.
0351In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the emulsion.
0352In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the emulsion.
0353In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.
0354In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methyl paraben, propyl paraben, and phenoxyethanol.
0355In some embodiments, the antimicrobial preservative component comprises methyl paraben and propyl paraben.
0356In some embodiments, the methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0357In some embodiments, the methylparaben is present in an amount of about 0.1% by weight of the emulsion.
0358In some embodiments, the propylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0359In some embodiments, the propylparaben is present in an amount of about 0.05% by weight of the emulsion.
0360In some embodiments, the phenoxyethanol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0361In some embodiments, the phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.
0362In some embodiments, the phenoxyethanol is present in an amount of about 0.1% to about 10% by weight of the emulsion.
0363In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, or about 7.0.
0364In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, about 6.5, or about 7.0.
0365In some embodiments, the pH of the cream is adjusted to a range of about 6.5 to about 7.0.
0366In 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.
0367In some embodiments, the emulsion further comprises an anti-oxidant.
0368In some embodiments, the anti-oxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof.
0369In some embodiments, the emulsion further comprises a chelating agent component.
0370In some embodiments, the chelating agent component comprises edetate disodium.
0371In some embodiments, the edetate disodium is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0372In some embodiments, the edetate disodium is present in an amount of about 0.001% to about 1% by weight of the emulsion.
0373In some embodiments, the emulsion further comprises a calcipotriol stabilizer.
0374In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, or citric acid, or a combination thereof.
0375In some embodiments, the emulsion further comprises a humectant.
0376In some embodiments, the humectant is glycerol.
0377In some embodiments, the glycerol is present in an amount of about 0.01% to about 20% by weight of the emulsion.
0378In some embodiments, the glycerol is present in an amount of about 0.1% to about 20% by weight of the emulsion.
0379In some embodiments, the emulsion further comprises a surfactant.
0380In some embodiments, the surfactant is polysorbate 80. In some embodiments, the surfactant is polysorbate 80 is present in an amount of about 0.01% to about 15% by weight of the emulsion. In some embodiments, the surfactant is polysorbate 80 is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0381Ruxolitinib can be prepared as described in <patcit id="pcit0063" dnum="US7598257B"><text>U.S. Patent 7,598,257</text></patcit> and <patcit id="pcit0064" dnum="US20090181959A"><text>U.S. Patent Publ. No. 2009/0181959</text></patcit>, each of which is incorporated herein by reference in its entirety. The 1:1 phosphate salt of ruxolitinib can be prepared as described in <patcit id="pcit0065" dnum="US20080312259A"><text>U.S. Patent Publ. No. 2008/0312259</text></patcit>, which is incorporated herein by reference in its entirety.
0382As will be appreciated, some components of the cream (emulsion) described herein can possess multiple functions. For example, a given substance may act as both an emulsifying agent component and a stabilizing agent. In some such cases, the function of a given component can be considered singular, even though its properties may allow multiple functionality. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.
Pharmaceutical Formulations (fixed-dose combinations)
0383Pharmaceutical formulations provided and described herein may be used in the methods described in the present disclosure.
0384The concentrations of JAK inhibitors, vitamin D3, or Vitamin D3 analogs, or the pharmaceutically acceptable salts of any of the aforementioned, described <i>supra,</i> may also be used in the fixed-dose combination formulations described as follows. As used herein, "pharmaceutical formulation for topical treatment of a skin disease" and "topical formulation" are used interchangeably.
0385The present disclosure further provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative, or a pharmaceutically acceptable salt thereof.
0386The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative, or a pharmaceutically acceptable salt thereof.
0387The present disclosure further provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) ruxolitinib phosphate, or a pharmaceutically acceptable salt thereof, and (b) a vitamin D derivative, or a pharmaceutically acceptable salt thereof.
0388The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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.
0389The present disclosure further provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is present in an amount of about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis.
0390The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) ruxolitinib phosphate, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0391The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0392The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0393The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0394The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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) from about 1 µg/mL to 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0395The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from about 1 µg/mL to 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0396The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.5% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from about 1 µg/mL to 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0397The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from about 1 µg/mL to 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0398The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0399The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0400The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0401The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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 of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0402The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% w/w of 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0403The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0404The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0405The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) about 1 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0406The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0407The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% w/w of 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0408The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate. The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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) from 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.
0409The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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) from 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0410The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.5% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0411The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0412The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) from 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0413The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.
0414The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0415The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0416The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% 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, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0417The formulations described in the preceding paragraphs, 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. In some embodiments, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, falecalcitriol, eldecalcitol, inecalcitol, seocalcitol, lexicalcitol, 20-epi-1α,25(OH)<sub>2</sub>D<sub>3</sub>, CD578 (17-methyl-19-nor-21-nor-23-yne-26,27-F6-1α,25(OH)<sub>2D3</sub>), TX527 (19-nor-14,20-bisepi-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)<sub>2</sub>D<sub>3</sub>), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)<sub>2</sub>D<sub>3</sub>), ILX23-7553 (16-ene-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), and MART-10(19-nor-2α-(3-hydroxypropyl)-1α,25(OH)<sub>2</sub>D<sub>3</sub>). 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.
0418The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) from 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. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0419The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 0.75% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) about 0.005% w/w of calcipotriol. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0420The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, 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 calcipotriol. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0421The present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease, comprising (a) about 1.1% w/w of ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis, and (b) about 0.005% w/w of calcipotriol. In some embodiments, the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.
0422In some embodiments, the pharmaceutical formulations described herein are creams. In some embodiments, the cream formulations of ruxolitinib described <i>supra,</i> may also be used in the fixed-dose combination formulations described as follows.
0423In some embodiments, the pharmaceutical formulations described herein are lotions.
0424In some embodiments, the pharmaceutical formulations described herein further comprise water. In some embodiments, the water comprises from about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 80% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 50% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation.
0425In some embodiments, the pharmaceutical formulations described herein have a pH of not more than about 3.6. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 2.7 to about 3.9. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 2.7 to about 3.6. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 4 to about 8. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 6.0 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 6.5 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of from about 6.5 to about 7.5.
0426In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions.
0427In some embodiments, the oil-in-water emulsion comprises water, an oil component, and an emulsifier or stabilizer component. In some embodiments, the oil-in-water emulsion comprises water, an oil component, and an emulsifier component.
0428In some embodiments, the water comprises from about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 80% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 10% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 20% to about 50% by weight of the pharmaceutical formulation. In some embodiments, the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation.
0429In some embodiments, the oil component comprises from about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 80% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 70% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 60% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 50% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 50%, or from about 5% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the oil component comprises a fatty alcohol, a nut oil and/or a mineral oil. In some embodiments, the oil component comprises one of the oil components described herein, including emollients, stiffening agents or other oil components.
0430In some embodiments, the emulsifier or stabilizer component comprises from about 1% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component comprises from about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component comprises from about 1% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier or stabilizer component comprises from about 1% to about 30% or from about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the emulsifier component comprises a non-ionic surfactant. In some embodiments, the emulsifier or stabilizer component comprises a polysorbate, a poloxamer, a fatty alcohol, a polyethylene glycol fatty ether, glyceryl fatty esters, and/or a polyethylene glycol fatty ester. In some embodiments, the emulsifier or stabilizer component comprises one of the emulsifier, stabilizer, or surfactants described herein.
0431In some embodiments, the emulsifier or stabilizer component comprises a non-ionic surfactant. In some embodiments, the non-ionic surfactant is cetomacrogol 1000 or poloxamer 407.
0432In some embodiment, the pharmaceutical formulation further comprises a solvent component for dissolving ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiment, the solvent component comprises from about 1% to about 40% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 2% to about 30% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 5% to about 30% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 5% to about 20% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation. In some embodiment, the solvent component comprises from about 5% to about 20%, from about 2% to about 30%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, or from about 10% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises diethylene glycol monoethyl ether, such as Transcutol<sup>®</sup> P. In some embodiments, the solvent component comprises one of the solvent components described herein. In some embodiments, the propylene glycol is present of about 6.5% by weight of the emulsion. In some embodiments, the solvent component comprises diethylene glycol monoethyl ether, such as Transcutol<sup>®</sup> P. In some embodiments, the diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 30% w/w by weight of the emulsion. In some embodiments, the diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 20% w/w by weight of the emulsion.
0433In some embodiments, the pharmaceutical formulations further comprise an antioxidant. <b>In</b> some embodiments, the anti-oxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof. In some embodiments, the antioxidant comprises from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 2%, from about 0.01% to about 1%, or from about 0.1% to about 10% by weight of the pharmaceutical formulation.
0434In some embodiments, the pH is adjusted to about 6.0 to about 7.0, about 6.5 to about 7.0. In some embodiments, the pH is adjusted with trolamine.
0435In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.
0436In some embodiments, the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.
0437In some embodiments, the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.
0438In some embodiments, the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and silicone oils.
0439In 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.
0440In some embodiments, the oil component comprises an occlusive agent component.
0441In some embodiments, the occlusive agent is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0442In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.
0443In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.
0444In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils & waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fat (e.g., cocoa butter), vegetable wax (e.g., Carnauba wax), and wax ester (e.g., bees wax).
0445In some embodiments, the occlusive agent component comprises one or more substances selected from lanolin acid fatty alcohols, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, Carnauba wax, and bees wax.
0446In some embodiments, the occlusive agent component comprises petrolatum.
0447In some embodiments, the occlusive agent component comprises white petrolatum.
0448In some embodiments, the white petrolatum is present in an amount of about 7% by weight of the emulsion.
0449In some embodiments, the oil component comprises a stiffening agent component.
0450In some embodiments, the stiffening agent component is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0451In some embodiments, the stiffening agent component is present in an amount of about 2% to about 8% by weight of the emulsion.
0452In some embodiments, the stiffening agent component is present in an amount of about 3% to about 6% by weight of the emulsion.
0453In some embodiments, the stiffening agent component comprises one or more substances independently selected from fatty alcohols.
0454In some embodiments, the stiffening agent component comprises one or more substances independently selected from C12-20 fatty alcohols.
0455In some embodiments, the stiffening agent component comprises one or more substances independently selected from C16-18 fatty alcohols.
0456In some embodiments, the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
0457In some embodiments, the cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0458In some embodiments, the cetyl alcohol in an amount of about 3% by weight of the emulsion.
0459In some embodiments, the stearyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0460In some embodiments, the stearyl alcohol is present in an amount of about 1.75% by weight of the emulsion.
0461In some embodiments, the oil component comprises an emollient component.
0462In some embodiments, the emollient component is present in an amount of about 0.1% to about 20% by weight of the emulsion.
0463In some embodiments, the emollient component is present in an amount of about 5% to about 20% by weight of the emulsion.
0464In some embodiments, the emollient component is present in an amount of about 10% to about 15% by weight of the emulsion.
0465In some embodiments, the emollient component comprises one or more substances independently selected from mineral oils, triglycerides, and silicone oils.
0466In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone.
0467In some embodiments, the light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0468In some embodiments, the light mineral oil is present in an amount of about 4% by weight of the emulsion.
0469In some embodiments, the dimethicone is present in an amount of about 1% by weight of the emulsion.
0470In some embodiments, the medium chain triglycerides are in an amount of about 7% by weight of the emulsion.
0471In some embodiments, the medium chain triglycerides are in an amount of about 10% by weight of the emulsion.
0472In some embodiments, the emollient component comprises one or more substances independently selected from mineral oils, triglycerides, silicone oils, and nut oils.
0473In some embodiments, the nut oil is an almond oil. In some embodiments, the almond oil is a 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.
0474In some embodiments, the water is present in an amount of about 20% to about 80% by weight of the emulsion.
0475In some embodiments, the water is present in an amount of about 35% to about 65% by weight of the emulsion.
0476In some embodiments, the water is present in an amount of about 45% to about 65% by weight of the emulsion.
0477In some embodiments, the emulsifier component is present in an amount of about 0.5% to about 15% by weight of the emulsion.
0478In some embodiments, the emulsifier component is present in an amount of about 1% to about 10% by weight of the emulsion.
0479In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.
0480In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.
0481In some embodiments, the emulsion comprises an emulsifier component and a stiffening agent component, wherein the combined amount of emulsifier component and stiffening agent component is at least about 8% by weight of the emulsion.
0482In some embodiments, the emulsifier component comprises one or more non-ionic emulsifiers.
0483In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.
0484In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate, and polysorbate 20. In some embodiments, the glyceryl stearate is present in an amount of about 3% by weight of the emulsion.
0485In some embodiments, the polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.
0486In some embodiments, the emulsion further comprises a stabilizing agent component.
0487In some embodiments, the stabilizing agent component is present in an amount of about 0.05% to about 5% by weight of the emulsion.
0488In some embodiments, the stabilizing agent component is present in an amount of about 0.1% to about 2% by weight of the emulsion.
0489In some embodiments, the stabilizing agent component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.
0490In some embodiments, the stabilizing agent component comprises one or more substances independently selected from polysaccharides.
0491In some embodiments, the stabilizing agent component comprises xanthan gum.
0492In some embodiments, the emulsion further comprises a solvent component. In some embodiments, the solvent component is a solvent for the JAK inhibitor (e.g., ruxolitinib), or the pharmaceutically acceptable salt thereof.
0493In some embodiments, the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.
0494In some embodiments, the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.
0495In some embodiments, the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.
0496In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
0497In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
0498In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, and propylene glycol
0499In some embodiments, the solvent component comprises PEG300 and propylene glycol.
0500In some embodiments, the PEG300 is present in an amount of about 7% by weight of the emulsion.
0501In some embodiments, the solvent is a combination of PEG400 and propylene glycol.
0502<b>In</b> some embodiments, the PEG400 is present in an amount of about 7% by weight of the emulsion.
0503In some embodiments, the propylene glycol is present of about 6.5% by weight of the emulsion.
0504In some embodiments, the oil-in-water emulsion further comprises: <ul id="ul0029" list-style="none" compact="compact"><li>from about 20% to about 80% of water by weight of the emulsion;</li><li>from about 10% to about 40% of an oil component by weight of the emulsion;</li><li>from about 1% to about 10% of an emulsifier component by weight of the emulsion;</li><li>from about 1% to about 35% of a solvent component by weight of the emulsion; and</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0505In some embodiments, the oil-in-water emulsion further comprises: <ul id="ul0030" list-style="none" compact="compact"><li>from about 35% to about 65% of water by weight of the emulsion;</li><li>from about 15% to about 35% of an oil component by weight of the emulsion;</li><li>from about 2% to about 6% of an emulsifier component by weight of the emulsion;</li><li>from about 5% to about 25% of a solvent component by weight of the emulsion; and</li><li>from about 0.05% to about 5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0506In some embodiments, the oil-in-water emulsion further comprises: from about 40% to about 65% of water by weight of the emulsion; <ul id="ul0031" list-style="none" compact="compact"><li>from about 20% to about 28% of an oil component by weight of the emulsion; from about 3% to about 5% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 20% of a solvent component by weight of the emulsion; and</li><li>from about 0.1% to about 2% of a stabilizing agent component by weight of the emulsion.</li></ul>
0507In some embodiments, the oil-in-water emulsion further comprises: <ul id="ul0032" list-style="none" compact="compact"><li>from about 40% to about 65% of water by weight of the emulsion;</li><li>from about 20% to about 28% of an oil component by weight of the emulsion;</li><li>from about 3% to about 5% of an emulsifier component by weight of the emulsion;</li><li>from about 10% to about 20% of a solvent component by weight of the emulsion; and from about 0.3% to about 0.5% of a stabilizing agent component by weight of the emulsion.</li></ul>
0508In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising the oil-in-water emulsion comprises water, an oil component, and an emulsifier component, wherein: <ul id="ul0033" list-style="none" compact="compact"><li>the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and dimethicones;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;</li><li>the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; and</li><li>the stabilizing agent component comprises one or more substances independently selected from polysaccharides.</li></ul>
0509In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising the oil-in-water emulsion comprises water, an oil component, and an emulsifier component, wherein: <ul id="ul0034" list-style="none" compact="compact"><li>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;</li><li>the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;</li><li>the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and</li><li>the stabilizing agent component comprises xanthan gum.</li></ul>
0510In some embodiments, the emulsion further comprises an antimicrobial preservative component.
0511In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the emulsion.
0512In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the emulsion.
0513In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.
0514In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methyl paraben, propyl paraben, and phenoxyethanol.
0515In some embodiments, the antimicrobial preservative component comprises methyl paraben and propyl paraben.
0516In some embodiments, the methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0517In some embodiments, the methylparaben is present in an amount of about 0.1% by weight of the emulsion.
0518In some embodiments, the propylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
0519In some embodiments, the propylparaben is present in an amount of about 0.05% by weight of the emulsion.
0520In some embodiments, the phenoxyethanol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
0521In some embodiments, the phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.
0522In some embodiments, the pH of the cream is from about 4 to about 8.
0523In some embodiments, the pH of the cream is from about 6.5 to about 7.0.
0524In some embodiments, the emulsion further comprises an antioxidant. In some embodiments, the anti-oxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof.
0525In some embodiments, butylated hydroxytoluene is present in an amount of about 0.01% to about 15% w/w by weight of the emulsion. In some embodiments, the butylated hydroxytoluene is present in an amount of about 0.1% to about 10% by weight of the emulsion. In some embodiments, the butylated hydroxytoluene is present in an amount of about 0.1% to about 5% by weight of the emulsion.
0526In some embodiments, butylhydroxyanisole is present in an amount of about 0.001% to about 5% w/w by weight of the emulsion. In some embodiments, the butylhydroxyanisole is present in an amount of about 0.01% to about 1% by weight of the emulsion.
0527In some embodiments, the emulsion further comprises a calcipotriol stabilizer.
0528In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, fumaric acid, or citric acid, or a combination thereof.
0529In some embodiments, the present disclosure also provides a pharmaceutical formulation for topical treatment of a skin disease (or, alternatively, a method of any one of embodiments 1-75), wherein the formulation is an oil-in-water emulsion comprising about 1.5% w/w ruxolitinib phosphate on a free base basis, 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, about 0.1% w/w methylparaben, about 0.05% w/w propylparaben, about 0.4% w/w xanthan gum, about 7% w/w white petrolatum, about 4% w/w light mineral oil, about 3% w/w glycerol stearate SE, about 3% w/w cetyl alcohol, about 1.75% w/w stearyl alcohol, about 1% w/w dimethicone, about 7% w/w medium chain triglycerides, about 1.25% w/w polysorbate 20, and about 0.5% w/w phenoxyethanol.
0530In some embodiments, the present disclosure also provides pharmaceutical formulations for topical treatment of a skin disease (or, alternatively, a method of any one of embodiments 1-75), wherein the formulation is an oil-in-water emulsion comprising about 1.5% w/w ruxolitinib phosphate on a free base basis, 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, about 0.1% w/w methylparaben, about 0.05% w/w propylparaben, about 0.4% w/w xanthan gum, about 7% w/w white petrolatum, about 4% w/w light mineral oil, about 3% w/w glycerol stearate SE, about 3% w/w cetyl alcohol, about 1.75% w/w stearyl alcohol, about 1% w/w dimethicone, about 7% w/w medium chain triglycerides, about 1.25% w/w polysorbate 20, and about 0.5% w/w phenoxyethanol.
0531In some embodiments, the pH of pharmaceutical formulation described herein is adjusted with trolamine (triethanolamine). In some embodiments, the pH of pharmaceutical formulation described herein is adjusted with phosphoric acid.
0532In some embodiments, the emulsion formulations of ruxolitinib described supra, may also be used in the fixed-dose combination formulations described as follows. The topical formulation described above can utilize any of the vitamin D derivatives, vitamin D3 analogs, and JAK inhibitors described supra in any suitable combination.
0533As used in the context of "topical treatment of a skin disease", "topical" means administration to the skin.
0534Pharmaceutical formulations for topical administration for administration to skin may include solutions, suspensions, foams, ointments, lotions, creams, gels, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. In some embodiments, the composition is formulated for topical administration by solution, suspension, gel, cream, ointment, lotion, spray, foam, liquid, and powder.
0535For the treatment of skin diseases as described herein, topical drugs, which are able to penetrate the skin barrier and provide limited systemic effects, are of particular importance.
0536Topical (dermal/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 agent at the appropriate layer of the skin in concentrations that would result in therapeutic response, with limited systemic exposure.
0537In some embodiments, the administration is topical and comprised of formulations with one or more pharmaceutically (<i>e.g.,</i> dermatologically) acceptable excipients. Examples of dermatologically acceptable excipients include, but are not limited to, a pH adjusting agents, chelating agents, preservatives, co-solvents, penetration enhancers, humectants, thickening, gelling, viscosity building agents, surfactants, propellants, fragrance, colorants, or any combination or mixture thereof. In some embodiments, the topical formulation is administered locally to the patient (<i>e.g.,</i> administered at the site of a lesion).
0538In some embodiments, the pH-adjusting agent is selected from an acid, an acid salt, a base, a base salt, and a buffer, or any mixture thereof. Exemplary acids include, but are not limited to, lactic acid, acetic acid, citric acid, and benzoic acid, and salts thereof. Exemplary buffers include, but are not limited to, citrate/citric acid, acetate/acetic acid, edetate/edetic acid, lactate/lactic acid, and the like.
0539In 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 a salt thereof. In some embodiments, the chelating agent comprises a mixture of a chelating agent and an antioxidant, wherein the chelating agent and antioxidant prevent, minimize, or reduce oxidative degradation reactions in the composition. Exemplary anti-oxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, and propyl gallate.
0540In 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, phenonyexthanol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, and imidazolidinyl urea.
0541In some embodiments, the composition comprises one or more co-solvents. In some embodiments, the composition comprises a mixture of two or more co-solvents. In some embodiments, the composition comprises one to five co-solvents. 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, polyethylene glycols (<i>e.g.,</i> polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like). In some embodiments, the solvent is a non-water soluble agent. Exemplary non-water soluble agents include, but are not limited to, diethyl sebacate, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, and medium chain triglycerides.
0542In some embodiments, the composition comprises one or more penetration enhancers. In some embodiments, the composition comprises a mixture of two or more penetration enhancers. In some embodiments, the composition comprises one to five penetration enhancers. The penetration enhancers can act as both a solvent and a penetration enhancer. Exemplary penetration enhancers 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, a co-solvent provided herein is a penetration enhancer.
0543In some embodiments, the composition comprises one or more thickening, gelling, or viscosity building agents. In some embodiments, the composition comprises a mixture of two or more thickening, gelling, or viscosity building agents. In some embodiments, the composition comprises one to five thickening, gelling, or viscosity building agents. Exemplary thickening, gelling, or viscosity building agents include, but are not limited to, cellulosic derivatives (<i>e.g.,</i> hydroxyethylcellulose (HEC), carboxymethylcellulose, hydroxypropylcellulose (HPC), and hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP).
0544The surfactant is a compound that lowers the surface tension between two liquids or between a liquid and a solid. Surfactant may be a mixture of two or more surfactants. Exemplary surfactants include, but are not limited to, ethoxylated fatty alcohol ether (<i>e.g.,</i> steareth-2, steareth-10, steareth-20, ceteareth-2, ceteareth-10, and the like), PEG esters (e.g., PEG-4 dilaurate, PEG-20 stearate, and the like), Glyceryl esters or derivatives thereof (<i>e.g.,</i> glyceryl dioleate, glyceryl stearate, and the like), polymeric ethers (<i>e.g.,</i> poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 407, and the like), sorbitan derivatives (<i>e.g.,</i> polysorbate 80, sorbitan monostearate, and the like), fatty alcohols (<i>e.g.,</i> cetyl alcohol, stearyl alcohol, cetearyl alcohol, and the like), and emulsifying wax (<i>e.g.,</i> emulsifying wax NF, mixtures of mixture of cetearyl alcohol and polysorbate 60, and the like).
0545Topical (<i>e.g.,</i> intradermal) administration provides the advantage of treating the skin diseases and/or disorder as described herein locally, minimizing potential adverse events associated with systemic exposure, and allowing an easier discontinuation of the therapy, if necessary. Additionally, some topical dosage forms such as creams, ointments, and gels have the benefit of excipients that may act as emollients or occlusive agents, which can increase patient well-being and compliance during the treatment period. Other dosage routes such as oral, parenteral, and inhalation may lead to supratherapeutic systemic drug levels, increased likelihood of adverse events, drug-drug interactions, and generation of active/toxic metabolites, which may result in treatment discontinuation and inadequate patient compliance.
0546Topical formulations intended for dermal delivery are typically solutions, suspensions, gels, creams, ointments, lotions, sprays, and foams and can contain one or more conventional carriers as described herein. The formulation composition should be prepared with the goal of delivering the active ingredient to the appropriate layer(s) of the skin, minimizing systemic exposure, and preventing skin irritation. Additionally, the pharmaceutical composition should be physically and chemically stable. Depending on the selected dosage form, one or more additional excipients as described herein may be necessary, <i>e.g.,</i> pH adjusting agents, chelating agents, preservatives, co-solvents, penetration enhancers, humectants, thickening, gelling, viscosity building agents, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof.
0547In some embodiments, topical formulations can contain one or more conventional carriers as described herein. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, <i>e.g.,</i> glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.
0548The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
0549The compositions of the presently claimed subject matter can further include one or more additional pharmaceutical agents, examples of which are listed hereinabove.
Combination Therapies
0550The methods described herein can further comprise administering one or more additional therapeutic agents. The one or more additional therapeutic agents can be administered to a patient simultaneously or sequentially.
0551In 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.
0552In some embodiments, the additional therapeutic agent is a retinoid. In some embodiments, the retinoid is adapalene, etretinate, acitretin, or isotretinoin.
0553In 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 such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or flumetholone.
0554In some embodiments, the additional therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate or cyclosporin A. In some embodiments, the immunosuppressant is mycophenolate mofetil or mycophenolate sodium.
0555In some embodiments, the additional therapeutic agent is azelaic acid.
0556In 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 keratoderma, pachyonychia congenita, steatocystoma multiplex, 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 keratoderma. In some embodiments, the additional therapeutic agent is for treating pachyonychia congenita. In some embodiments, the additional therapeutic agent is for treating steatocystoma multiplex. 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.
0557In some embodiments, the additional therapeutic agent is crisaborole.
0558In some embodiments, the additional therapeutic agent is tacrolimus.
0559In some embodiments, the additional therapeutic agent is pimecrolimus.
Kits
0560The present disclosure also includes pharmaceutical kits useful, for example, in the treatment and/or prevention of skin diseases as described herein such as psoriasis, alopecia, and vitiligo, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof, as described herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
0561It is further appreciated that certain features of the presently claimed subject matter, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the presently claimed subject matter, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
Definitions
0562As used herein, "an affected skin area" refers to an area of the patient's skin having a skin disease as described herein.
0563As used herein, "ruxolitinib phosphate" means the phosphoric acid salt of ruxolitinib, wherein the ruxolitinib and phosphoric acid are in a 1:1 ratio.
0564As used herein, "cream" means an emulsion, semisolid dosage form for application to the skin.
0565As used herein, the term "C<sub>3-4</sub> cycloalkyl", employed alone or in combination with other terms, refers to a non-aromatic monocyclic hydrocarbon moiety, having 3-4 carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. Exemplary C<sub>3-4</sub> cycloalkyl groups include cyclopropyl, cyclobutyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl. In some embodiments, the cycloalkyl group is cyclobutyl.
0566As used herein, the term "synergy" or "synergistic effect" when used in connection with a description of the efficacy of a combination of agents or compounds, means any measured effect of the combination which is greater that the effect predicted from a sum of the effects of the individual agents or compounds. For example, as described herein, there are synergistic effects of inhibiting IL-22, MMP12, and CXCL10 respectively between (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, which means that total inhibiting effects from the combination of (a) and (b) is greater than the sum of the inhibition effects of (a) and (b) alone.
0567As used herein, "statistically significant" means a p-value of < 0.05 (preferably < 0.001, and most preferably < 0.0001).
0568As used herein, the phrase "pharmaceutically acceptable" means those compounds, materials, compositions, and/or dosage forms, which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
0569The presently claimed subject matter also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the presently claimed subject matter include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the presently claimed subject matter can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in <nplcit id="ncit0044" npl-type="b"><text>Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 </text></nplcit>and <nplcit id="ncit0045" npl-type="s"><text>Journal of Pharmaceutical Science, 66, 2 (1977</text></nplcit>), each of which is incorporated herein by reference in its entirety. In some embodiments, the pharmaceutically acceptable salt is a phosphoric acid salt, a sulfuric acid salt, or a maleic acid salt.
0570As used herein, the term "emulsifier component" refers, in one aspect, to a substance, or mixtures of substances that maintains an element or particle in suspension within a fluid medium. In some embodiments, the emulsifier component allows an oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component refers to one or more non-ionic surfactants.
0571As used herein, the term "occlusive agent component" refers to a hydrophobic agent or mixtures of hydrophobic agents that form an occlusive film on skin that reduces transepidermal water loss (TEWL) by preventing evaporation of water from the stratum corneum.
0572As used herein, the term "stiffening agent component" refers to a substance or mixture of substances that increases the viscosity and/or consistency of the cream or improves the rheology of the cream.
0573As used herein, the term "emollient component" refers to an agent that softens or soothes the skin or soothes an irritated internal surface.
0574As used herein, the term "stabilizing agent component" refers to a substance or mixture of substances that improves the stability of the cream and/or the compatibility of the components in the cram. In some embodiments, the stabilizing agent component prevents agglomeration of the emulsion and stabilizes the droplets in the oil-in-water emulsion.
0575As used herein, the term "solvent component" is a liquid substance or mixture of liquid substances capable of dissolving a JAK inhibitor as 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 its pharmaceutically acceptable salt, has reasonable solubility. For example, solubilities of ruxolitinib (free base) or its phosphate salt (1:1 salt) are reported in Table 1. In some embodiments, a solvent is a substance or mixture thereof, in which ruxolitinib, or its pharmaceutically acceptable salt (whichever is used), has a solubility of at least about 10 mg/mL or greater, at least about 15 mg/mL or greater, or at least about 20 mg/mL or greater.
0576As used herein, the phrase "antimicrobial preservative component" is a substance or mixtures of substances, which inhibits microbial growth in the cream.
0577As used herein, the phrase "chelating agent component" refers to a compound or mixtures of compounds that has the ability to bind strongly with metal ions.
0578As used herein, "% by weight of the emulsion" means the percent concentration of the component in the emulsion is on weight/weight basis. For example, 1% w/w of component A = [(mass of component A) / (total mass of the emulsion)] x 100.
0579As used herein, "% by weight of the emulsion on a free base basis" of a JAK inhibitor as described herein such as ruxolitinib, or a 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 on a free base basis" of ruxolitinib phosphate means that for 100 grams of total formulation, there are 1.98 grams of ruxolitinib phosphate in the emulsion (which equates to 1.5 grams of the free base, ruxolitinib).
0580As used herein, "% by weight of the formulation on a free base basis" of a JAK inhibitor as described herein such as ruxolitinib, or pharmaceutically acceptable salt thereof" means that the% w/w is calculated based on the weight of ruxolitinib in the total formulation. For example, "1.5% w/w on a free base basis" of ruxolitinib phosphate means that for 100 grams of total formulation, there are 1.98 grams of ruxolitinib phosphate in the formulation (which equates to 1.5 grams of the free base, ruxolitinib).
0581As used herein, the term "component" can mean one substance or a mixture of substances.
0582As used herein, the term "fatty acid" refers to an aliphatic acid that is saturated or unsaturated. In some embodiments, the fatty acid is in a mixture of different fatty acids. In some embodiments, the fatty acid has between about eight to about thirty carbons on average. In some embodiments, the fatty acid has about 12 to 20, 14-20, or 16-18 carbons on average. 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.
0583As used herein, the term "fatty alcohol" refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has between about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons on average. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.
0584As used herein, the term "polyalkylene glycol", employed alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units, or copolymer of different oxyalkylene monomer units, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene", employed alone or in combination with other terms, refers to a group of formula -O-alkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.
0585As used herein, the term, "sorbitan fatty ester" includes products derived from sorbitan or sorbitol and fatty acids and, optionally, poly (ethylene glycol) units, including sorbitan esters and polyethoxylated sorbitan esters. In some embodiments, the sorbitan fatty ester is a polyethoxylated sorbitan ester.
0586As 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 the sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span<sup>™</sup> 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 suitable sorbitan esters include those listed in<nplcit id="ncit0046" npl-type="b"><text> R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed</text></nplcit>., which is incorporated herein by reference in its entirety.
0587As used herein, the term "polyethoxylated sorbitan ester" refers to a compound, or mixture thereof, derived from the ethoxylation of a sorbitan ester. The polyoxethylene portion of the compound can be between the fatty ester and the sorbitan moiety. 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 the polyethoyxlated sorbitan esters include, 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<sup>™</sup> 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 refers to the number of oxyethylene repeat units in the compound. Other suitable polyethoxylated sorbitan esters include the polyoxyethylene sorbitan fatty acid esters listed in <nplcit id="ncit0047" npl-type="b"><text>R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed</text></nplcit>., which is incorporated herein by reference in its entirety. In some embodiments, the polyethoxylated sorbitan ester is a polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.
0588As used herein, the term "glyceryl fatty esters" refers to mono-, di- or triglycerides of fatty acids. The glyceryl fatty esters may be optionally substituted with sulfonic acid groups, or pharmaceutically acceptable salts thereof. Suitable fatty acids for deriving glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceryl fatty ester is a mono-glyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceryl fatty ester is glyceryl stearate.
0589As used herein, the term "triglycerides" refers to a triglyceride of a fatty acid. In some embodiments, the triglyceride is medium chain triglycerides.
0590As used herein, the term "alkylene glycol" refers to a group of formula -O-alkylene-, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).
0591As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units of formula -O-CH<sub>2</sub>-CH<sub>2</sub>-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having esterifiable carboxy groups. Polyethylene glycols useful in the present disclosure can be polymers of any chain length or molecular weight, and can include branching. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the 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 following the dash in the name refers to the average molecular weight of the polymer.
0592As used herein, "contains" is equivalent to "comprises".
0593As used herein, the term "subject," "individual," or "patient," used interchangeably, refers to humans. In some embodiments, the "subject," "individual," or "patient" is in need of said treatment.
0594In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical formulations thereof, topical formulations thereof, as described herein are administered in a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
0595As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease; or (3) preventing the disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, treating refers to inhibiting or ameliorating the disease. In some embodiments, treating is preventing the disease.
0596In some embodiments, the components are present in exactly the ranges specified (e.g., the term "about" is not present). In some embodiments, "about" means plus or minus 10% of the value.
0597The present disclosure also provides the following non-limiting embodiments: In order that the embodiments disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the embodiments in any manner.
0598In some embodiments, the following embodiments are provided: <ol id="ol0001" compact="compact"><li>1. A method of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.</li><li>2. The method of embodiment 1, the skin disease is an autoimmune skin disease.</li><li>3. The method of embodiment 1 or 2, the skin disease is an inflammatory skin disease.</li><li>4. The method of any one of embodiments 1-3, wherein the skin disease is a Th1 or Th17 associated skin disease.</li><li>5. The method of any one of embodiments 1-4, 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.</li><li>6. The method of any one of embodiments 1-5, wherein the skin disease is mediated by IL-22.</li><li>7. The method of any one of embodiments 1-5, wherein the skin disease is mediated by MMP12.</li><li>8. The method of any one of embodiments 1-5, wherein the skin disease is mediated by CXCL10.</li><li>9. The method of any one of embodiments 1-8, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.</li><li>10. The method of embodiment 9, wherein the skin disease is psoriasis.</li><li>11. The method of embodiment 9, wherein the skin disease is alopecia.</li><li>12. The method of embodiment 11, wherein the alopecia is alopecia areata.</li><li>13. The method of embodiment 9, wherein the skin disease is vitiligo.</li><li>14. The method of any one embodiments 1-13, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered simultaneously.</li><li>15. The method of any one embodiments 1-13, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered sequentially.</li><li>16. The method of any one embodiments 1-15, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least one time per day.</li><li>17. The method of any one embodiments 1-15, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered once per day.</li><li>18. The method of any one embodiments 1-15, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered twice per day.</li><li>19. The method of any one embodiment 1-18, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered once per day.</li><li>20. The method of any one embodiment 1-18, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered twice per day.</li><li>21. The method of any one embodiment 1-20, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as separate formulations.</li><li>22. The method of any one embodiment 1-14, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as a single formulation.</li><li>23. The method of embodiment 22, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered once per day.</li><li>24. The method of embodiment 22, wherein (a) the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered twice per day.</li><li>25. The method of any one of embodiments 1-24, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a synergistic amount.</li><li>26. The method of any one embodiment 1-24, wherein there is a synergistic effect between the JAK inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof.</li><li>27. The method of any one of embodiments 1-26, further comprising administering an additional therapeutic agent.</li><li>28. The method of embodiment 27, wherein the additional therapeutic agent is a corticosteroid.</li><li>29. The method of any one of embodiments 1-28, wherein the patient is a human patient.</li><li>30. The method of any one of embodiments 1-29, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (I): <chemistry id="chem0039" num="0039"><img file="EP4570321A2_D0039.tif" /></chemistry> wherein: <ul id="ul0035" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>31. The method of any one of embodiments 1-29, wherein the vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (II): <chemistry id="chem0040" num="0040"><img file="EP4570321A2_D0040.tif" /></chemistry> wherein: <ul id="ul0036" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>32. The method of any one of embodiments 1-29, wherein (b) is a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>33. The method of 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.</li><li>34. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a vitamin 1α,25(OH)<sub>2</sub> D3 analog, a vitamin 1α,24(OH)<sub>2</sub> D3 analog, or a vitamin 1α,26(OH)<sub>2</sub> D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>35. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is a compound having Formula (III): <chemistry id="chem0041" num="0041"><img file="EP4570321A2_D0041.tif" /></chemistry> wherein: <ul id="ul0037" list-style="none" compact="compact"><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is CH<sub>3</sub> or CF<sub>3</sub>;</li><li>R<sup>10</sup> is CH<sub>3</sub> or CF<sub>3</sub>;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a cyclopropyl ring; and R<sup>11</sup> is H.</li></ul></li><li>36. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, falecalcitriol, eldecalcitol, inecalcitol, seocalcitol, lexicalcitol, 20-epi-1α,25(OH)<sub>2</sub>D<sub>3</sub>, CD578 (17-methyl-19-nor-21-nor-23-yne-26,27-F6-1α,25(OH)<sub>2D3</sub>), TX527 (19-nor-14,20-bisepi-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)<sub>2</sub>D<sub>3</sub>), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)<sub>2</sub>D<sub>3</sub>), ILX23-7553 (16-ene-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), and MART-10(19-nor-2α-(3-hydroxypropyl)-1α,25(OH)<sub>2</sub>D<sub>3</sub>).</li><li>37. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcipotriol.</li><li>38. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is maxacalcitol.</li><li>39. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is tacalcitol.</li><li>40. The method of any one of embodiments 32-39, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a topical formulation.</li><li>41. The method of embodiment 40, wherein the topical formulation is a foam, an ointment, a lotion, or a cream.</li><li>42. The method of embodiment 40 or 41, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0001% to about 0.1% of the vitamin D3 analog by weight of the formulation.</li><li>43. The method of embodiment 40 or 41, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered as a topical formulation comprising from about 0.0004% to about 0.005% of the vitamin D3 analog by weight of the formulation.</li><li>44. The method of embodiment 32, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcipotriol, or a pharmaceutically acceptable salt thereof which is administered as a topical formulation comprising about 50 µg calcipotriol per gram of the formulation.</li><li>45. The method of embodiment 44, wherein the topical formulation is a foam, an ointment, a lotion, or a cream.</li><li>46. The method of embodiment 44 or 45, wherein the topical formulation further comprises betamethasone dipropionate.</li><li>47. The method of embodiment 46, wherein the betamethasone dipropionate is present in an amount of about 0.5 mg per gram of the formulation.</li><li>48. The method of embodiment 33, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is tacalcitol, which is administered as a topical formulation comprising about 4 µg tacalcitol per gram of the formulation.</li><li>49. The method of embodiment 48, wherein the topical formulation is an ointment, a cream, or a lotion.</li><li>50. The method of embodiment 33, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is maxacalcitol, which is administered as a topical formulation comprising about 6 µg, about 12.5 µg, about 25 µg, or about 50 µg per gram of the formulation.</li><li>51. The method of embodiment 50, wherein the topical formulation is an ointment.</li><li>52. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor, a JAK1/JAK2 inhibitor, a JAK1/JAK3 inhibitor, a pan-JAK inhibitor, and a JAK1/TYK2 inhibitor, or a pharmaceutically acceptable salt.</li><li>53. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1 inhibitor, or a pharmaceutically acceptable salt thereof.</li><li>54. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK2 inhibitor, or a pharmaceutically acceptable salt thereof.</li><li>55. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof.</li><li>56. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt thereof.</li><li>57. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a pan-JAK inhibitor, or a pharmaceutically acceptable salt thereof.</li><li>58. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is a JAK1/TYK2 inhibitor, or a pharmaceutically acceptable salt.</li><li>59. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, baricitinib, oclacitinib, momelotinib, CTP-543, AH057, gandotinib, fedratinib, lestaurtinib, pacritinib, CHZ868, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, ATI-501, ATI-1777, ATI-502, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, cerdulatinib, decernotinib, BMS-986165, and ritlecitinib, or a pharmaceutically acceptable salt thereof.</li><li>60. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is selected from ruxolitinib, oclacitinib, baricitinib, momelotinib, CTP-543, gandotinib, fedratinib, lestaurtinib, pacritinib, upadacitinib, tofacitinib, filgocitinib, abrocitinib, itacitinib, brepocitinib, delgocitinib, peficitinib, gusacitinib, cucurbitacin I, and cerdulatinib, or a pharmaceutically acceptable salt thereof</li><li>61. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt.</li><li>62. The method of any one of embodiments 1-51, the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>63. The method of embodiment 61 or 62, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered as a cream formulation.</li><li>64. The method of embodiment 63, wherein the cream formulation is an oil-in-water emulsion.</li><li>65. The method of embodiment 63 or 64, wherein the cream formulation has a pH from about 2.8 to about 3.9.</li><li>66. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is delgocitinib, or a pharmaceutically acceptable salt thereof.</li><li>67. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is tofacitinib, or a pharmaceutically acceptable salt thereof.</li><li>68. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is ATI-1777, or a pharmaceutically acceptable salt thereof.</li><li>69. The method of any one of embodiments 1-51, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is brepocitinib, or a pharmaceutically acceptable salt thereof.</li><li>70. The method of any one of embodiments 1-69, wherein the JAK inhibitor, or the pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.</li><li>71. The method of any one of embodiments 1-70, wherein (b) vitamin D3, the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.</li><li>72. A method of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.</li><li>73. A method of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.</li><li>74. The method of embodiment 73, wherein the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, is calcipotriol, or a pharmaceutically acceptable salt thereof.</li><li>75. The method of any one of embodiments 72-74, wherein the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>76. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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.</li><li>77. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises), comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>78. The formulation (or, alternatively, the method) of embodiment 77, wherein the ruxolitinib, or the pharmaceutically acceptable salt thereof, is present in an amount of about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis.</li><li>79. A pharmaceutical formulation for topical treatment of a skin disease (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises), comprising (a) from 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) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>80. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>81. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.</li><li>82. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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) from about 1 µg/mL to about 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>83. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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) from about 1 µg/mL to about 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>84. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>85. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>86. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 1 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>87. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 10 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>88. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>89. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 1 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>90. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 10 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>91. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 50 µg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>92. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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) from 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.</li><li>93. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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) from 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.</li><li>94. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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) from 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.</li><li>95. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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) from 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.</li><li>96. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>97. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 0.005% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>98. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 0.005% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>99. The formulation of any one of embodiments 77-98 (or, alternatively, the method of any one of embodiments 77-98), wherein the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>100. The formulation of any one of embodiments 76-99 (or, alternatively, the method of any one of embodiments 76-99), 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.</li><li>101. The formulation (or, alternatively, the method) of embodiment 100, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is selected from calcidiol, calcitriol, calcipotriol, alfacalcidol, tacalcitol, maxacalcitol, falecalcitriol, eldecalcitol, inecalcitol, seocalcitol, lexicalcitol, 20-epi-1α,25(OH)<sub>2</sub>D<sub>3</sub>, CD578 (17-methyl-19-nor-21-nor-23-yne-26,27-F6-1α,25(OH)<sub>2D3</sub>), TX527 (19-nor-14,20-bisepi-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), 2MD (2-methylene-19-nor-(20S)-1α,25(OH)<sub>2</sub>D<sub>3</sub>), PRI-2205 ((5E,7E)-22-ene-26,27-dehydro-1α,25(OH)<sub>2</sub>D<sub>3</sub>), ILX23-7553 (16-ene-23-yne-1α,25(OH)<sub>2</sub>D<sub>3</sub>), and MART-10(19-nor-2α-(3-hydroxypropyl)-1α,25(OH)<sub>2</sub>D<sub>3</sub>).</li><li>102. The formulation (or, alternatively, the method) of embodiment 100, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is calcipotriol.</li><li>103. The formulation (or, alternatively, the method) of embodiment 100, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is tacalcitol.</li><li>104. The formulation (or, alternatively, the method) of embodiment 100, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is maxacalcitol.</li><li>105. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, wherein the formulation comprises) (a) from 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.</li><li>106. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 0.005% w/w of calcipotriol.</li><li>107. A pharmaceutical formulation for topical treatment of a skin disease, comprising (or, alternatively, a method of any one of embodiments 1-75, 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 0.005% w/w of calcipotriol.</li><li>108. The formulation (or, alternatively, the method) of any one of embodiments 105-107, wherein the ruxolitinib, or the pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>109. The formulation (or, alternatively, the method) of any one of embodiments 76-108, wherein the formulation is a cream.</li><li>110. The formulation (or, alternatively, the method) of any one of embodiments 76-108, wherein the formulation is a lotion.</li><li>111. The formulation (or, alternatively, the method) of any one of embodiments 76-110, wherein the formulation further comprises water.</li><li>112. The formulation (or, alternatively, the method) of any one of embodiments 76-111, wherein the formulation has a pH of not more than about 3.6.</li><li>113. The formulation (or, alternatively, the method) of any one of embodiments 76-111, wherein the formulation has a pH of about 2.7 to about 3.9.</li><li>114. The formulation (or, alternatively, the method) of any one of embodiments 76-111, wherein the formulation has a pH of about 2.7 to about 3.6.</li><li>115. The formulation (or, alternatively, the method) of any one of embodiments 76-111, wherein the formulation has a pH of about 4 to about 8.</li><li>116. The formulation (or, alternatively, the method) of any one of embodiments 76-115, wherein the formulation is an oil-in-water emulsion.</li><li>117. The formulation (or, alternatively, the method) of embodiment 116, wherein the oil-in-water emulsion comprises water, an oil component, and an emulsifier component.</li><li>118. The formulation (or, alternatively, the method) of embodiment 117, wherein the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.</li><li>119. The formulation (or, alternatively, the method) of embodiment 117, wherein the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.</li><li>120. The formulation (or, alternatively, the method) of embodiment 117, wherein the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.</li><li>121. The formulation (or, alternatively, the method) of any one of embodiments 117-120, wherein the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and silicone oils.</li><li>122. The formulation (or, alternatively, the method) of any one of embodiments 117-120, 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.</li><li>123. The formulation (or, alternatively, the method) of any one of embodiments 117-120, wherein the oil component comprises an occlusive agent component.</li><li>124. The formulation (or, alternatively, the method) of embodiment 123, wherein the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.</li><li>125. The formulation (or, alternatively, the method) of embodiment 123, wherein the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.</li><li>126. The formulation (or, alternatively, the method) of any one of embodiments 123-125, wherein the occlusive agent component comprises white petrolatum.</li><li>127. The formulation (or, alternatively, the method) of any one of embodiments 117-126, wherein the oil component comprises a stiffening agent component.</li><li>128. The formulation (or, alternatively, the method) of embodiment 127, wherein the stiffening agent component is present in an amount of about 2% to about 8% by weight of the emulsion.</li><li>129. The formulation (or, alternatively, the method) of embodiment 127, wherein the stiffening agent component is present in an amount of about 3% to about 6% by weight of the emulsion.</li><li>130. The formulation (or, alternatively, the method) of embodiment 127, wherein the stiffening agent component is present in an amount of about 4% to about 7% by weight of the emulsion.</li><li>131. The formulation (or, alternatively, the method) of any one of embodiments 127-130, wherein the stiffening agent component comprises one or more substances independently selected from fatty alcohols.</li><li>132. The formulation (or, alternatively, the method) of embodiment 131, wherein the stiffening agent component comprises one or more substances independently selected from C<sub>12-20</sub> fatty alcohols.</li><li>133. The formulation (or, alternatively, the method) of embodiment 131, wherein the stiffening agent component comprises one or more substances independently selected from C<sub>16-18</sub> fatty alcohols.</li><li>134. The formulation (or, alternatively, the method) of any one of embodiments 127-130, wherein the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.</li><li>135. The formulation (or, alternatively, the method) of any one of embodiments 117-134, wherein the oil component comprises an emollient component.</li><li>136. The formulation (or, alternatively, the method) of embodiment 135, wherein the emollient component is present in an amount of about 0.1% to about 20% by weight of the emulsion.</li><li>137. The formulation (or, alternatively, the method) of embodiment 135, wherein the emollient component is present in an amount of about 5% to about 20% by weight of the emulsion.</li><li>138. The formulation (or, alternatively, the method) of embodiment 135, wherein the emollient component is present in an amount of about 10% to about 15% by weight of the emulsion.</li><li>139. The formulation (or, alternatively, the method) of any one of embodiments 135-138, wherein the emollient component comprises one or more substances independently selected from mineral oils, triglycerides, and silicone oils.</li><li>140. The formulation (or, alternatively, the method) of any one of embodiments 135-138, wherein the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone.</li><li>141. The formulation (or, alternatively, the method) of any one of embodiments 117-140, wherein the water is present in an amount of about 20% to about 80% by weight of the emulsion.</li><li>142. The formulation (or, alternatively, the method) of any one of embodiments 117-140, wherein the water is present in an amount of about 35% to about 65% by weight of the emulsion.</li><li>143. The formulation (or, alternatively, the method) of any one of embodiments 117-140, wherein the water is present in an amount of about 40% to about 65% by weight of the emulsion.</li><li>144. The formulation (or, alternatively, the method) of any one of embodiments 117-143, wherein the emulsifier component is present in an amount of about 0.5% to about 15% by weight of the emulsion.</li><li>145. The formulation (or, alternatively, the method) of any one of embodiments 117-143, wherein the emulsifier component is present in an amount of about 1% to about 10% by weight of the emulsion.</li><li>146. The formulation (or, alternatively, the method) of any one of embodiments 117-143, wherein the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.</li><li>147. The formulation (or, alternatively, the method) of any one of embodiments 117-143, wherein the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.</li><li>148. The formulation (or, alternatively, the method) of any one of embodiments 117-147, wherein the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.</li><li>149. The formulation (or, alternatively, the method) of any one of embodiments 117-147, wherein the emulsifier component comprises one or more substances independently selected from glyceryl stearate, and polysorbate 20.</li><li>150. The formulation (or, alternatively, the method) of any one of embodiments 117-149, wherein the emulsion further comprises a stabilizing agent component.</li><li>151. The formulation (or, alternatively, the method) of embodiment 150, wherein the stabilizing agent component is present in an amount of about 0.05% to about 5% by weight of the emulsion.</li><li>152. The formulation (or, alternatively, the method) of embodiment 150, wherein the stabilizing agent component is present in an amount of about 0.1% to about 2% by weight of the emulsion.</li><li>153. The formulation (or, alternatively, the method) of embodiment 150, wherein the stabilizing agent component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.</li><li>154. The formulation (or, alternatively, the method) of any one of embodiments 150-153, wherein the stabilizing agent component comprises one or more substances independently selected from polysaccharides.</li><li>155. The formulation (or, alternatively, the method) of any one of embodiments 150-153, wherein the stabilizing agent component comprises xanthan gum.</li><li>156. The formulation (or, alternatively, the method) of any one of embodiments 117-155, wherein the emulsion further comprises a solvent component.</li><li>157. The formulation (or, alternatively, the method) of embodiment 156, wherein the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.</li><li>158. The formulation (or, alternatively, the method) of embodiment 156, wherein the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.</li><li>159. The formulation (or, alternatively, the method) of embodiment 156, wherein the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.</li><li>160. The formulation (or, alternatively, the method) of any one of embodiments 156-159, wherein the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.</li><li>161. The formulation (or, alternatively, the method) of any one of embodiments 156-159, wherein the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.</li><li>162. A pharmaceutical formulation for topical treatment of a skin disease, 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.</li><li>163. The pharmaceutical formulation of 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.</li><li>164. The pharmaceutical formulation of embodiment163, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt thereof.</li><li>165. The pharmaceutical formulation of embodiment 165, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>166. The pharmaceutical formulation of any one of embodiments 162-165, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having Formula (II): <chemistry id="chem0042" num="0042"><img file="EP4570321A2_D0042.tif" /></chemistry> wherein: <ul id="ul0038" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>167. The pharmaceutical formulation of any one of embodiments 162-166, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.</li><li>168. The pharmaceutical formulation of embodiment 163, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.</li><li>169. The pharmaceutical formulation of embodiment 163, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.</li><li>170. The pharmaceutical formulation according to any one of embodiments 164-169, wherein the formulation comprises from about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>171. The pharmaceutical formulation according to any one of embodiments 164-169, wherein the formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof.</li><li>172. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>173. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>174. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w or from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>175. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>176. The pharmaceutical formulation of any one of embodiments 162-175, wherein the formulation is a cream or a lotion.</li><li>177. The pharmaceutical formulation of any one of embodiments 162-176, wherein the formulation is an oil-in-water emulsion.</li><li>178. The pharmaceutical formulation of any one of embodiments 162-177, wherein the formulation comprises water, an oil component, and an emulsifier or stabilizer component.</li><li>179. The pharmaceutical formulation of embodiment 178, wherein the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation.</li><li>180. The pharmaceutical formulation of any one of embodiments 178-179, wherein the oil component comprises from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 50%, or from about 5% to about 40% by weight of the pharmaceutical formulation.</li><li>181. The pharmaceutical formulation of any one of embodiments 178-180 wherein the emulsifier or stabilizer component comprises from about 1% to about 30% or from about 5% to about 25% by weight of the pharmaceutical formulation.</li><li>182. The pharmaceutical formulation of any one of embodiments 178-180, further comprising a solvent component for dissolving ruxolitinib, or a pharmaceutically acceptable salt thereof.</li><li>183. The pharmaceutical formulation of embodiment 182, wherein the solvent component comprises from about 5% to about 20%, from about 2% to about 30%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, or from about 10% to about 20% by weight of the pharmaceutical formulation.</li><li>184. The pharmaceutical formulation of any one of embodiments 163-183, wherein the formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.</li><li>185. The pharmaceutical formulation of embodiment 184, wherein pH of the formulation is adjusted with trolamine.</li><li>186. A method of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.</li><li>187. The method of 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.</li><li>188. The method of embodiment 187, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt thereof..</li><li>189. The method of embodiment 187, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>190. The method of any one of embodiments 187-189, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having Formula (II): <chemistry id="chem0043" num="0043"><img file="EP4570321A2_D0043.tif" /></chemistry> wherein: <ul id="ul0039" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub>haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>191. The method of any one of embodiments 187-189, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.</li><li>192. The method of embodiment 187, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.</li><li>193. The method of embodiment 187, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.</li><li>194. The method of any one of embodiments 187-193, the skin disease is an autoimmune or an inflammatory skin disease.</li><li>195. The method of any one of embodiments 187-193, wherein the skin disease is a Th1 or Th17 associated skin disease.</li><li>196. The method of any one of embodiments 187-193, 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.</li><li>197. The method of any one of embodiments 187-193, wherein the skin disease is mediated by Defb4, S100a12, or Serpinb4.</li><li>198. The method of any one of embodiments 187-193, 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.</li><li>199. The method of any one of embodiments 187-193, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.</li><li>200. The method of any one of embodiments 187-193, wherein the skin disease is rosacea, psoriatic arthritis, dermal fibrosis, morphea, spitz nevi, dermatophytosis, or acne vulgaris.</li><li>201. The method of any one of embodiments 187-200, wherein there is a synergistic effect between the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof.</li><li>202. The method of any one of embodiments 187-201, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least one time per day.</li><li>203. The method of any one of embodiments 187-201, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least two times per day.</li><li>204. The method of any one of embodiments 187-203, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered simultaneously.</li><li>205. The method of any one of embodiments 187-203, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered sequentially.</li><li>206. The method of any one of embodiments 187-205, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as separate formulations.</li><li>207. The method of any one of embodiments 187-204, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single formulation.</li><li>208. The method of embodiment 206, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are each administered in a topical formulation.</li><li>209. The method of embodiment 207, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single topical formulation.</li><li>210. The method of embodiment 208, wherein each topical formulation is an ointment, a cream, or a lotion.</li><li>211. The method of embodiment 209, wherein the single topical formulation is an ointment, a cream, or a lotion.</li><li>212. The method of embodiment 211, wherein the single topical formulation is a cream or a lotion.</li><li>213. The method of embodiment 211, wherein the single topical formulation is a cream formulation.</li><li>214. The method of any one of embodiments 211-213, wherein the single topical formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.</li><li>215. The method of any one of embodiments 187-214, further comprising administering an additional therapeutic agent.</li><li>216. The method of embodiment 215, wherein the additional therapeutic agent is a corticosteroid.</li><li>217. The method of embodiment 216, wherein the corticosteroid is betamethasone dipropionate.</li></ol>
EXAMPLES
0599The presently claimed subject matter will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the presently claimed subject matter in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters, which can be changed or modified to yield essentially the same results.
0600All statistical analysis of <i>in vitro</i> experiments were performed with GraphPad prism software (version 7) using Kruskal-Wallis-Test and Mann-Whitney <i>U</i> test. Gene expression was analyzed with Partek Flow genomic analysis software and Subio Platform software v1.22.5266 using Welch's <i>t</i>-test. Confidence intervals were determined at 95%. <i>P</i><0.05 was considered to be "significant" (*), <i>p<0.01</i> to be "highly significant" (**). KEGG pathways were mapped to differentially expressed genes using DAVID v6.8 (Database for Annotation, Visualization and Integrated Discovery).
Example 1. <i>In vitro</i> JAK Kinase Assay
0601JAK1 inhibitors that can be used for the treatment of cytokine-related diseases or disorders are tested for inhibitory activity of JAK targets according to the following <i>in vitro</i> assay described in <nplcit id="ncit0048" npl-type="s"><text>Park et al., Analytical Biochemistry 1999, 269, 94-104</text></nplcit>. The catalytic domains of human JAK1 (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a. 781-1124) with an N-terminal His tag are expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC<sub>50</sub>s of compounds are measured for each kinase in the 40 µL reactions that contain 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. For the 1 mM IC<sub>50</sub> measurements, ATP concentration in the reactions is 1 mM. Reactions are carried out at room temperature for 1 hour and then stopped with 20 µL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the Europium labeled antibody takes place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). The compounds in Table 1 were tested in this assay and shown to have the IC<sub>50</sub> values in Table 1.
Example 2: <i>Ex vivo</i> skin pharmacodynamics experiment on the combination of a JAK inhibitor and a vitamin D3 analog
Materials and Methods
0602The pharmacodynamics assay described in the present disclosure involves a similar paradigm to elicit a Th1, Th2 and Th17 responses as the one to elicit a TH17 response published by Susan H. Smith, et al., Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PlosOne. Published: February 2016, which is incorporated by reference in its entirety. This paradigm was used to evaluate the therapeutic potential of the active compounds in topical formulations for dermatological diseases (i.e. psoriasis, vitiligo, and alopecia).
0603Freshly excised healthy human skin from cosmetic reduction surgery can be dermatomed to an approximate thickness of 750 ± 100µm using an Integra<sup>®</sup> dermatome. The dermatomed skin is then be further sectioned into 7mm biopsies for basolateral or topical dosing, careful to avoid areas of variable thickness or striation. The biopsies are placed into 6.5mm permeable membrane Transwell<sup>®</sup> inserts for basolateral or topical dosing. Human skin are placed into Transwell<sup>®</sup> inserts, <i>Stratum corneum</i> side apical, with a small volume of collagen between the basal dermal tissue and the permeable membrane. A schematic representation of a Transwell<sup>®</sup> insert is shown in <figref idref="f0004"><b>FIG. 4</b></figref><b>.</b> A full-scale experiment was performed with 8 individual skin donors, n= 4 for basolateral dosing; or 2 individual skin donors for topical dosing. One donor can be utilized per combination of the JAK inhibitor and the vitamin D3 analog at desired concentrations according to Method A for basolateral dosing or Method B for topical dosing.
<i>Method A (basolateral dosing)</i>
0604<ol id="ol0002"><li>(i) Transwell<sup>®</sup> permeable inserts (n=4 per treatment), with an average surface area of approximately 0.33 cm<sup>2</sup> and a volume of 0.5 mL are employed.</li><li>(ii) Skin prepared as described herein are placed into the Transwell<sup>®</sup> inserts, <i>Stratum corneum</i> side apical, with a small volume of collagen between the basal dermal tissue and the permeable membrane.</li><li>(iii) The basal chambers are filled with 0.5 mL of culture media and drug (the JAK inhibitor and/or the vitamin D3 analog) added to the media at the designated final concentration to pre-treat in a humidified incubator overnight at 37°C (ca. 16 hours).</li><li>(iv) The next day, the contents of the basal chambers from each insert were vacuum aspirated and replaced with 0.5 mL of pre-warmed (ca. 37 °C) Cornification media containing test compound and fresh stimulation cocktail.</li><li>(v) Cultures can be stored in a humidified incubator with a temperature of 37 °C.</li><li>(vi) Tissue explants can be harvested at 24 hours post stimulation. Half of tissue are placed in RNALater to assay cytokine production by RT-qPCR.</li><li>(vii) Tissue homogenization: tissue tubes were placed in Omni homogenizer and run at 3 cycles for 30sec at 5m/s with a 10sec dwell setting. The homogenization was repeated 4 times for a total of 12 cycles with 1 min and 30 seconds on ice between each run to cool sample. After final run, the tissue tubes cooled on ice for the same duration of time.</li><li>(viii) RT-PCR was ran on the samples in duplicate on the Applied Biosystems Quant 6 standard RT-qPCR program with a 40 cycle threshold, utilizing GAPDH as a housekeeping gene.</li></ol>
0605Appropriate concentrations for the JAK inhibitor and the vitamin D3 analog can be determined based on the IC<sub>50</sub> of the compounds. For example, the JAK inhibitor, ruxolitinib, has an IC<sub>50</sub> of 50 nM for inhibiting IL-23 stimulated IL-22 production in human T-cells and an IC50 of 281 nM in a human whole blood TPO induced STAT3 phosphorylation assay (<nplcit id="ncit0049" npl-type="s"><text>Fridman, et al., J Invest Dermatol, 2011 Sep;131(9):1838-44 (PMID: 21677670</text></nplcit>); and <nplcit id="ncit0050" npl-type="s"><text>Fridman, et al., J Immunol, 2010 May 1;184(9):5298-307 (PMID: 20363976</text></nplcit>). Similarly, tacalcitol, calcipotriol, and maxacalcitol decreased keratinocyte cell line proliferation in a concentration-dependent manner with IC<sub>50</sub>s of about 10-100nM (<nplcit id="ncit0051" npl-type="s"><text>Takahasi, et al., J Dermatol Sci, 2003 Feb;31(1):21-8 (PMID: 12615360</text></nplcit>)). Concentrations below (down to 0) and above the IC<sub>50</sub> concentrations can be used for the JAK inhibitor (e.g., ruxolitinib, delgocitinib, etc.) and the vitamin D3 analog (e.g., tacalcitol, calcipotriol, and maxacalcitol).
<i>Method B (topical dosing)</i>
0606<ol id="ol0003"><li>(i) Transwell<sup>®</sup> permeable inserts (n=4 per treatment), with an average surface area of approximately 0.33 cm<sup>2</sup> and a volume of 0.5 mL are employed.</li><li>(ii) Skin prepared as described herein are placed into the Transwell<sup>®</sup> inserts, <i>Stratum corneum</i> side basolateral, with a small volume of collagen between the basal dermal tissue and the permeable membrane.</li><li>(iii) The basal chambers are filled with 0.5 mL of culture media. Drug (the JAK inhibitor and/or the vitamin D3 analog) applied topically to the apical side of dermatomed skin (~18 ul/cm<sup>2</sup>) to pre-treat for 16 or 24 hr, in a humidified incubator overnight at 37°C.</li><li>(iv) The next day, the contents of the basal chambers from each insert were vacuum aspirated. Media replaced with 0.5 mL of pre-warmed (ca. 37 °C) cornification media containing fresh stimulation cocktail.</li><li>(v) Cultures can be stored in a humidified incubator with a temperature of 37 °C.</li><li>(vi) Tissue explants can be harvested at 24 hours post stimulation. Half of tissue are placed in RNALater to assay cytokine production by RT-qPCR.</li><li>(vii) Tissue homogenization: tissue tubes were placed in Omni homogenizer and run at 3 cycles for 30sec at 5m/s with a 10sec dwell setting. The homogenization was repeated 4 times for a total of 12 cycles with 1 min and 30 seconds on ice between each run to cool sample. After final run, the tissue tubes cooled on ice for the same duration of time.</li><li>(viii) RT-PCR was ran on the samples in duplicate on the Applied Biosystems Quant 6 standard RT-qPCR program with a 40 cycle threshold, utilizing GAPDH as a housekeeping gene.</li></ol>
<i>Ruxolitinib and calcipotriol - basolateral dosing (Method A)</i>
0607Experiments were carried out as described above in the Materials and Methods <b>(Method A)</b> section of Example 2 for ruxolitinib phosphate and calcipotriol. A list of the treatment conditions for donors 2 and 3 with stimulation for Th1 or Th17 with addition of ruxolitinib phosphate (calculated on a free base basis) and/or calcipotriol are as shown in Table 2 and 3, respectively. <tables id="tabl0003" num="0003"><table frame="all"><title><b>Table 2</b></title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="9mm" align="center" /><colspec colnum="2" colname="col2" colwidth="30mm" align="center" /><colspec colnum="3" colname="col3" colwidth="29mm" align="center" /><colspec colnum="4" colname="col4" colwidth="22mm" align="center" /><thead valign="middle"><row><entry namest="col1" nameend="col4" align="center">Donor 2</entry></row><row><entry /><entry>Calcipotriol (nM)</entry><entry>Ruxolitinib (nM)</entry><entry>Stimulation</entry></row></thead><tbody valign="middle"><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th1</entry></row><row><entry>c</entry><entry>2250</entry><entry>0</entry><entry>Th1</entry></row><row><entry>d</entry><entry>750</entry><entry>0</entry><entry>Th1</entry></row><row><entry>e</entry><entry>250</entry><entry>0</entry><entry>Th1</entry></row><row><entry>f</entry><entry>83.3</entry><entry>0</entry><entry>Th1</entry></row><row><entry>g</entry><entry>27.8</entry><entry>0</entry><entry>Th1</entry></row><row><entry>h</entry><entry>0</entry><entry>500</entry><entry>Th1</entry></row><row><entry>i</entry><entry>0</entry><entry>166.7</entry><entry>Th1</entry></row><row><entry>j</entry><entry>0</entry><entry>55.6</entry><entry>Th1</entry></row><row><entry>k</entry><entry>0</entry><entry>18.5</entry><entry>Th1</entry></row><row><entry>l</entry><entry>2250</entry><entry>500</entry><entry>Th1</entry></row><row><entry>m</entry><entry>2250</entry><entry>18.5</entry><entry>Th1</entry></row><row><entry>n</entry><entry>750</entry><entry>166.7</entry><entry>Th1</entry></row><row><entry>o</entry><entry>750</entry><entry>55.6</entry><entry>Th1</entry></row><row><entry>p</entry><entry>250</entry><entry>166.7</entry><entry>Th1</entry></row><row><entry>q</entry><entry>250</entry><entry>55.6</entry><entry>Th1</entry></row><row><entry>r</entry><entry>83.3</entry><entry>166.7</entry><entry>Th1</entry></row><row><entry>s</entry><entry>83.3</entry><entry>55.6</entry><entry>Th1</entry></row><row><entry>t</entry><entry>27.8</entry><entry>500</entry><entry>Th1</entry></row></tbody></tgroup></table></tables><tables id="tabl0004" num="0004"><table frame="all"><title><b><u>Table 3</u></b></title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="27mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><colspec colnum="3" colname="col3" colwidth="45mm" align="center" /><colspec colnum="4" colname="col4" colwidth="39mm" align="center" /><thead valign="middle"><row><entry namest="col1" nameend="col4" align="center">Donor 3</entry></row><row><entry /><entry>Calcipotriol (nM)</entry><entry>Ruxolitinib (nM)</entry><entry>Stimulation</entry></row></thead><tbody valign="middle"><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th17</entry></row><row><entry>c</entry><entry>2250</entry><entry>0</entry><entry>Th17</entry></row><row><entry>d</entry><entry>750</entry><entry>0</entry><entry>Th17</entry></row><row><entry>e</entry><entry>250</entry><entry>0</entry><entry>Th17</entry></row><row><entry>f</entry><entry>83.3</entry><entry>0</entry><entry>Th17</entry></row><row><entry>g</entry><entry>27.8</entry><entry>0</entry><entry>Th17</entry></row><row><entry>h</entry><entry>0</entry><entry>500</entry><entry>Th17</entry></row><row><entry>i</entry><entry>0</entry><entry>166.7</entry><entry>Th17</entry></row><row><entry>j</entry><entry>0</entry><entry>55.6</entry><entry>Th17</entry></row><row><entry>k</entry><entry>0</entry><entry>18.5</entry><entry>Th17</entry></row><row><entry>l</entry><entry>2250</entry><entry>500</entry><entry>Th17</entry></row><row><entry>m</entry><entry>2250</entry><entry>18.5</entry><entry>Th17</entry></row><row><entry>n</entry><entry>750</entry><entry>166.7</entry><entry>Th17</entry></row><row><entry>o</entry><entry>750</entry><entry>55.6</entry><entry>Th17</entry></row><row><entry>p</entry><entry>250</entry><entry>166.7</entry><entry>Th17</entry></row><row><entry>q</entry><entry>250</entry><entry>55.6</entry><entry>Th17</entry></row><row><entry>r</entry><entry>83.3</entry><entry>166.7</entry><entry>Th17</entry></row><row><entry>s</entry><entry>83.3</entry><entry>55.6</entry><entry>Th17</entry></row><row><entry>t</entry><entry>27.8</entry><entry>500</entry><entry>Th17</entry></row></tbody></tgroup><tgroup cols="4" rowsep="0"><colspec colnum="1" colname="col1" colwidth="27mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="46mm" /><colspec colnum="3" colname="col3" colwidth="45mm" /><colspec colnum="4" colname="col4" colwidth="39mm" /><tbody><row><entry namest="col1" nameend="col4">Note: After solubilizing each of the test compounds in 100% DMSO at 1000X, the stocks were stored at -20 °C.</entry></row></tbody></tgroup></table></tables>
0608The levels of biomarkers such as IL-22, CXCL10, and MMP12 with regard to the test compounds and combinations thereof were quantified and fold changes in gene expression were calculated against untreated control. Unexpectedly and surprisingly, combinations of calcipotriol and ruxolitinib showed synergistic effects in decreasing the levels of IL-22, CXCL10, and MMP12, as shown in <figref idref="f0001 f0002 f0003"><b>FIG. 1-3</b></figref><b>.</b> For example, the tested combinations significantly decreased the IL-22 level and such decreasing effect is statistically significant. The tested combinations also effectively decreased the CXCL10 level and such decreasing effect is statistically significant. The tested combinations effectively decreased the MMP12 level and such decreasing effect is statistically significant. These results are unexpected and surprising for several reasons. One reason is that it is commonly known in the art that the major source of vitamin D in humans is the cutaneous synthesis in the presence of sunlight and, to date, the antiinflammatory efficacy of JAK inhibitors on skin diseases has not been associated to geographic location or sunlight exposure. Another reason is that the clinical efficacy of vitamin D3 analogues is thought to be primarily driven by their ability to normalize keratinocyte hyperproliferation and modulation of epidermal differentiation and these mechanisms are independent of inflammatory cytokines utilizing the JAK pathway. See, <nplcit id="ncit0052" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. Moreover, a recent study on psoriasis shows that the skin biopsies from psoriasis patients treated with topical calcipotriol demonstrate a significant decrease in CD8(+) IL-17(+) T cells but there was no changes in the frequency of IL-22(+) or IFN-γ(+) cells in psoriasis lesions. See, <nplcit id="ncit0053" npl-type="s"><text>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</text></nplcit>, which is incorporated by reference in its entirety herein. Therefore, it is unexpected and surprising to find the synergistic effect between calcipotriol and ruxolitinib in decreasing the levels of IL-22, CXCL10, and MMP12.
0609Additionally, the levels of other gene markers were also quantified with respect to the test compounds (ruxolitinib and calcipotriol) and combinations thereof. Absolute fold changes in gene expression were calculated against untreated control. <figref idref="f0006"><b>FIG. 6A-6B</b></figref> shows that combinations of calcipotriol and ruxolitinib caused >2 or >4 absolute fold changes in certain genes as compared to untreated control (white indicates <2 absolute fold change, grey indicates >2 absolute fold change, and black indicates >4 absolute fold change). Of the genes having the highest absolute fold change, barrier function genes (filaggrin/FLG and Loricin/LOR) are involved in many dermatology diseases; IL-31 and TSLP are involved in itch, prevalent in many dermatology diseases, and CAMP and DefB4 are antimicrobial peptides with involvement of skin diseases with barrier disruptions (that can increase infection).
<i>Ruxolitinib and maxacalcitol - basolateral dosing (Method A)</i>
0610Experiments were carried out as described above in the Materials and Methods <b>(Method</b> A) section of Example 2 for ruxolitinib phosphate and maxacalcitol. A list of the treatment conditions for donors 2 and 3 with stimulation for Th1 or Th17 with addition of ruxolitinib phosphate (calculated on a free base basis) and/or <b><i>maxacalcitol</i></b> are as shown in Tables 4 and 5, respectively. <tables id="tabl0005" num="0005"><table frame="all"><title><b>Table 4</b></title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="9mm" align="center" /><colspec colnum="2" colname="col2" colwidth="29mm" align="center" /><colspec colnum="3" colname="col3" colwidth="31mm" align="center" /><colspec colnum="4" colname="col4" colwidth="22mm" align="center" /><thead valign="top"><row><entry /><entry>Ruxolitinib (nM)</entry><entry>Maxacalcitol (nM)</entry><entry>Stimulation</entry></row></thead><tbody><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th1</entry></row><row><entry>c</entry><entry>18.519</entry><entry>0</entry><entry>Th1</entry></row><row><entry>d</entry><entry>6.173</entry><entry>0</entry><entry>Th1</entry></row><row><entry>e</entry><entry>0</entry><entry>0</entry><entry>Th1</entry></row><row><entry>f</entry><entry>0</entry><entry>0</entry><entry>Th1</entry></row><row><entry>g</entry><entry>0</entry><entry>540</entry><entry>Th1</entry></row><row><entry>h</entry><entry>0</entry><entry>0</entry><entry>Th1</entry></row><row><entry>i</entry><entry>18.519</entry><entry>0</entry><entry>Th1</entry></row><row><entry>j</entry><entry>18.519</entry><entry>0</entry><entry>Th1</entry></row><row><entry>k</entry><entry>18.519</entry><entry>240</entry><entry>Th1</entry></row><row><entry>l</entry><entry>18.519</entry><entry>0</entry><entry>Th1</entry></row><row><entry>m</entry><entry>6.173</entry><entry>0</entry><entry>Th1</entry></row><row><entry>n</entry><entry>6.173</entry><entry>0</entry><entry>Th1</entry></row><row><entry>o</entry><entry>6.173</entry><entry>240</entry><entry>Th1</entry></row><row><entry>p</entry><entry>6.173</entry><entry>0</entry><entry>Th1</entry></row></tbody></tgroup></table></tables><tables id="tabl0006" num="0006"><table frame="all"><title><b>Table 5</b></title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="26mm" align="center" /><colspec colnum="2" colname="col2" colwidth="45mm" align="center" /><colspec colnum="3" colname="col3" colwidth="48mm" align="center" /><colspec colnum="4" colname="col4" colwidth="39mm" align="center" /><thead valign="top"><row><entry /><entry>Ruxolitinib (nM)</entry><entry>Maxacalcitol (nM)</entry><entry>Stimulation</entry></row></thead><tbody><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th17</entry></row><row><entry>c</entry><entry>18.519</entry><entry>0</entry><entry>Th17</entry></row><row><entry>d</entry><entry>6.173</entry><entry>0</entry><entry>Th17</entry></row><row><entry>e</entry><entry>0</entry><entry>0</entry><entry>Th17</entry></row><row><entry>f</entry><entry>0</entry><entry>0</entry><entry>Th17</entry></row><row><entry>g</entry><entry>0</entry><entry>540</entry><entry>Th17</entry></row><row><entry>h</entry><entry>0</entry><entry>0</entry><entry>Th17</entry></row><row><entry>i</entry><entry>18.519</entry><entry>0</entry><entry>Th17</entry></row><row><entry>j</entry><entry>18.519</entry><entry>0</entry><entry>Th17</entry></row><row><entry>k</entry><entry>18.519</entry><entry>240</entry><entry>Th17</entry></row><row><entry>l</entry><entry>18.519</entry><entry>0</entry><entry>Th17</entry></row><row><entry>m</entry><entry>6.173</entry><entry>0</entry><entry>Th17</entry></row><row><entry>n</entry><entry>6.173</entry><entry>0</entry><entry>Th17</entry></row><row><entry>o</entry><entry>6.173</entry><entry>240</entry><entry>Th17</entry></row><row><entry>p</entry><entry>6.173</entry><entry><u>0</u></entry><entry>Th17</entry></row></tbody></tgroup><tgroup cols="4" rowsep="0"><colspec colnum="1" colname="col1" colwidth="26mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="45mm" /><colspec colnum="3" colname="col3" colwidth="48mm" /><colspec colnum="4" colname="col4" colwidth="39mm" /><tbody><row><entry namest="col1" nameend="col4">Note: After solubilizing each of the test compounds in 100% DMSO at 1000X, the stocks were stored at - 20°C.</entry></row></tbody></tgroup></table></tables>
0611The levels of biomarkers such as IL-22 and CXCL10 with regard to the test compounds and combinations thereof were quantified and fold changes in gene expression were calculated against untreated control. Unexpectedly and surprisingly, combinations of maxacalcitol and ruxolitinib showed synergistic effects in decreasing the levels of IL-22 and CXCL10, as shown in <figref idref="f0007"><b>FIG. 7A-7B</b></figref><b>.</b>
<i>Ruxolitinib and calcipotriol - topical dosing (Method B)</i>
0612Aqueous based solutions of ruxolitinib phosphate and calcipotriol, alone and in combination (see Table 6), were prepared using ruxolitinib phosphate and calcipotriol according to the following procedure: <ol id="ol0004"><li>(i) BHT was initially added to the Transcutol P in an amber Duran and stirred at 500 RPM until visually homogenous.</li><li>(ii) The solution from Step (i) was added to the rest of the polar phase excipients in an amber Duran and stirred by magnetic stirrer bar at 500 RPM until visually homogenous.</li><li>(iii) Ruxolitinib phosphate was added to the polar phase from Step (ii) and stirred for 5 mins at 500 RPM, ruxolitinib phosphate does not fully dissolve in this step.</li><li>(iv) The suspension from Step (iii) was pH adjusted to pH 6.5 - 7.0 with Trolamine, and the ruxolitinib phosphate dissolved during this step.</li><li>(v) Calcipotriol monohydrate was added to the polar phase from Step (iv) and stirred at 500 RPM at 65 °C for 1 hour, then at ambient laboratory temperature overnight, to dissolve.</li><li>(vi) Quantity sufficient with water to 100%.</li></ol><tables id="tabl0007" num="0007"><table frame="all"><title><b>Table 6</b></title><tgroup cols="7"><colspec colnum="1" colname="col1" colwidth="27mm" /><colspec colnum="2" colname="col2" colwidth="15mm" /><colspec colnum="3" colname="col3" colwidth="30mm" /><colspec colnum="4" colname="col4" colwidth="31mm" /><colspec colnum="5" colname="col5" colwidth="20mm" /><colspec colnum="6" colname="col6" colwidth="19mm" /><colspec colnum="7" colname="col7" colwidth="19mm" /><thead valign="top"><row><entry>Component</entry><entry>Vehicle</entry><entry>Ruxolitinib 1.5% w/w + Calcipotriol 0.005% (w/w)</entry><entry>Ruxolitinib 0.75% w/w + Calcipotriol 0.005% (w/w)</entry><entry>Calcipotriol 0.005% (w/w)</entry><entry>Ruxolitinib 1.5% (w/w)</entry><entry>Ruxolitinib 0.75% (w/w)</entry></row></thead><tbody><row><entry>Ruxolitinib phosphate</entry><entry>-</entry><entry>1.982</entry><entry>0.99</entry><entry>-</entry><entry>1.982</entry><entry>0.99</entry></row><row><entry>Calcipotriol monohydrate</entry><entry>-</entry><entry>0.0052</entry><entry>0.0052</entry><entry>0.0052</entry><entry>-</entry><entry>-</entry></row><row><entry>Water</entry><entry>57.00</entry><entry>55.00</entry><entry>56.00</entry><entry>57.00</entry><entry>55.00</entry><entry>56.00</entry></row><row><entry>Transcutol P</entry><entry>27.50</entry><entry>27.50</entry><entry>27.50</entry><entry>27.50</entry><entry>27.50</entry><entry>27.50</entry></row><row><entry>PEG 400</entry><entry>6.50</entry><entry>6.50</entry><entry>6.50</entry><entry>6.50</entry><entry>6.50</entry><entry>6.50</entry></row><row><entry>Phenoxyethanol</entry><entry>1.00</entry><entry>1.00</entry><entry>1.00</entry><entry>1.00</entry><entry>1.00</entry><entry>1.00</entry></row><row><entry>BHA</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry></row><row><entry>Polyoxyl 35 castor oil</entry><entry>5.30</entry><entry>5.30</entry><entry>5.30</entry><entry>5.30</entry><entry>5.30</entry><entry>5.30</entry></row><row><entry>Phosphoric Acid Trolamine</entry><entry>To pH 6.5-7.0</entry><entry>To pH 6.5-7.0</entry><entry>To pH 6.5-7.0</entry><entry>To pH 6.5-7.0</entry><entry>To pH 6.5-7.0</entry><entry>To pH 6.5-7.0</entry></row><row><entry>2<sup>nd</sup> addition of water</entry><entry>Q.S.</entry><entry>Q.S.</entry><entry>Q.S.</entry><entry>Q.S.</entry><entry>Q.S.</entry><entry>Q.S.</entry></row><row><entry>Total</entry><entry>100.00</entry><entry>100.00</entry><entry>100.00</entry><entry>100.00</entry><entry>100.00</entry><entry>100.00</entry></row></tbody></tgroup></table></tables>
0613The aqueous solutions shown in Table 6 were tested as described above in the Materials and Methods <b>(Method B)</b> section of Example 2 for ruxolitinib phosphate and calcipotriol. A list of the treatment conditions for donors 1 and 2 with stimulation for Th1 or Th17 with addition of ruxolitinib phosphate (calculated on a free base basis) and/or calcipotriol are as shown in Tables 7 and 8, respectively. <tables id="tabl0008" num="0008"><table frame="all"><title><b>Table 7</b></title><tgroup cols="5"><colspec colnum="1" colname="col1" colwidth="9mm" align="center" /><colspec colnum="2" colname="col2" colwidth="30mm" align="center" /><colspec colnum="3" colname="col3" colwidth="32mm" align="center" /><colspec colnum="4" colname="col4" colwidth="22mm" align="center" /><colspec colnum="5" colname="col5" colwidth="33mm" align="center" /><thead><row valign="top"><entry namest="col1" nameend="col5" align="center">Donor 1</entry></row><row><entry valign="top" /><entry>Ruxolitinib (w/w/)</entry><entry>Calcipotriol (w/w/)</entry><entry valign="top">Stimulation</entry><entry valign="top">Pre-treatment time</entry></row></thead><tbody><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry><entry>16 hr</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>c</entry><entry>1.5 %</entry><entry>0</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>d</entry><entry>0.75%</entry><entry>0</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>e</entry><entry>0</entry><entry>0.005%</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>f</entry><entry>0</entry><entry>0.005%</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>g</entry><entry>1.5%</entry><entry>0.005%</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>h</entry><entry>0.75%</entry><entry>0.005%</entry><entry>Th1</entry><entry>16 hr</entry></row><row><entry>i</entry><entry>0</entry><entry>0</entry><entry>No</entry><entry>24 hr</entry></row><row><entry>j</entry><entry>0</entry><entry>0</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>k</entry><entry>1.5 %</entry><entry>0</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>l</entry><entry>0.75%</entry><entry>0</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>m</entry><entry>0</entry><entry>0.005%</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>n</entry><entry>0</entry><entry>0.005%</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>o</entry><entry>1.5%</entry><entry>0.005%</entry><entry>Th1</entry><entry>24 hr</entry></row><row><entry>p</entry><entry>0.75%</entry><entry>0.005%</entry><entry>Th1</entry><entry>24 hr</entry></row></tbody></tgroup></table></tables><tables id="tabl0009" num="0009"><table frame="all"><title><u>Table 8</u></title><tgroup cols="5"><colspec colnum="1" colname="col1" colwidth="9mm" align="center" /><colspec colnum="2" colname="col2" colwidth="30mm" align="center" /><colspec colnum="3" colname="col3" colwidth="32mm" align="center" /><colspec colnum="4" colname="col4" colwidth="22mm" align="center" /><colspec colnum="5" colname="col5" colwidth="33mm" align="center" /><thead><row valign="top"><entry namest="col1" nameend="col5" align="center">Donor 2</entry></row><row><entry valign="top" /><entry>Ruxolitinib (w/w/)</entry><entry>Calcipotriol (w/w/)</entry><entry valign="top">Stimulation</entry><entry valign="top">Pre-treatment time</entry></row></thead><tbody><row><entry>a</entry><entry>0</entry><entry>0</entry><entry>No</entry><entry>16 hr</entry></row><row><entry>b</entry><entry>0</entry><entry>0</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>c</entry><entry>1.5%</entry><entry>0</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>d</entry><entry>0.75%</entry><entry>0</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>e</entry><entry>0</entry><entry>0.005%</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>f</entry><entry>0</entry><entry>0.005%</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>g</entry><entry>1.5%</entry><entry>0.005%</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>h</entry><entry>0.75%</entry><entry>0.005%</entry><entry>Th17</entry><entry>16 hr</entry></row><row><entry>i</entry><entry>0</entry><entry>0</entry><entry>No</entry><entry>24 hr</entry></row><row><entry>j</entry><entry>0</entry><entry>0</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>k</entry><entry>1.5%</entry><entry>0</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>l</entry><entry>0.75%</entry><entry>0</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>m</entry><entry>0</entry><entry>0.005%</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>n</entry><entry>0</entry><entry>0.005%</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>o</entry><entry>1.5%</entry><entry>0.005%</entry><entry>Th17</entry><entry>24 hr</entry></row><row><entry>p</entry><entry>0.75%</entry><entry>0.005%</entry><entry>Th17</entry><entry>24 hr</entry></row></tbody></tgroup></table></tables>
0614The levels of biomarkers such as S100a12, Defb4, Serpinb4, MMP12, IL-22, and CXCL10 with regard to the test compounds and combinations thereof were quantified and fold changes in gene expression were calculated against untreated control <b>(</b><figref idref="f0008"><b>FIG. 8A-8C</b></figref><b>and</b><figref idref="f0009"><b>FIG.</b> 9A-9C</figref>). Unexpectedly and surprisingly, calcipotriol and ruxolitinib combined in a topically applied aqueous based solution showed synergistic effects in decreasing the levels of S100a12, Defb4, Serpinb4, and MMP12 as shown in <figref idref="f0008"><b>FIG. 8A-8C</b></figref> and <figref idref="f0009"><b>FIG. 9A</b></figref><b>.</b> S100a12 is a significant marker for psoriasis disease activity (<nplcit id="ncit0054" npl-type="s"><text>Wilsmann-Theis, D, et al., J Eur Acad Dermatol Venereol, 30(7):1165-70 (2016); doi: 10.1111/jdv.13269</text></nplcit>). Defb4 encodes human beta-defensin 2(hBD2), an antimicrobial peptide that plays an essential role in inflammatory processes in the skin and is important in the pathogenesis of psoriasis (<nplcit id="ncit0055" npl-type="s"><text>Johansen C, et al., J Invest Derm, 136(8):1608-1616 (2016); doi: 10.1016/j.jid.2016.04.012</text></nplcit>). Serpinb4 contributes to inflammation in patients with chronic skin diseases, including atopic dermatitis (<nplcit id="ncit0056" npl-type="s"><text>Sivaprasad, U, et al., J Invest Derm 135(1):160-169 (2015); DOI:10.1038/jid.2014.353</text></nplcit>). These results are unexpected and surprising for several reasons. One reason is that it is commonly known in the art that the major source of vitamin D in humans is the cutaneous synthesis in the presence of sunlight and, to date, the antiinflammatory efficacy of JAK inhibitors on skin diseases has not been associated to geographic location or sunlight exposure. Another reason is that the clinical efficacy of vitamin D3 analogues is thought to be primarily driven by their ability to normalize keratinocyte hyperproliferation and modulation of epidermal differentiation and these mechanisms are independent of inflammatory cytokines utilizing the JAK pathway. Therefore, it is unexpected and surprising to find the synergistic effect between calcipotriol and ruxolitinib in decreasing the levels of S100a12, Defb4, Serpinb4 and MMP12. The calcipotriol and ruxolitinib combined in a topically applied aqueous based solution also decreased the gene expression of IL-22 and CXCL10 (<figref idref="f0009">FIG. 9B-9C</figref>); however, the high level of ruxolitinib in the aqueous solutions (0.75% and 1.5%) also had a strong effect on gene expression, making it difficult to assess synergy in the topical application although such synergy is seen at lower concentrations in the basolateral application (Method A).
Example 3: Methods for preparations of Ruxolitinib creams and for preparations of ruxolitinib and calcipotriol combination creams.
0615Methods for preparations of ruxolitinib creams (Formulations #1, #2, #4, and #5) containing 1.5% w/w of ruxolitinib on a free base basis and preparations of ruxolitinib and calcipotriol combination creams (Formulations #3 and #6) containing 1.5% w/w of ruxolitinib on a free base basis and 50 microgram/g of calcipotriol are described herein.
0616For preparations of ruxolitinib and calcipotriol combination creams, ruxolitinib was incorporated in the water phase, and calcipotriol was first dissolved in medium chain triglycerides, and then added into the oil-in-water emulsion. Details of the preparation steps are as follows: <ol id="ol0005" compact="compact"><li>1. Preparation of a 1 mg/g calcipotriol solution in medium chain triglycerides. calcipotriol was dissolved in medium chain triglycerides at 1 mg/g via heating at about 60 °C. When calcipotriol was fully dissolved, the heating was stopped. The resulting stock solution was covered with aluminum foil to avoid light.</li><li>2. Preparation of an aqueous phase. Purified water, disodium EDTA, low molecular weight PEG, and ruxolitinib phosphate were mixed altogether according to their respective weight percentages as described in Table 10 and the resulting mixture was heated at about 55 °C to about 60 °C while stirring to dissolve disodium EDTA and ruxolitinib to form an aqueous phase.</li><li>3. Preparation of a paraben phase. Methylparaben and propylparaben were added into propylene glycol according to their respective weight percentages as described in Table 10 to form a mixture. The resulting mixture was heated at about 55 °C to about 60 °C while stirring to dissolve the methylparaben and propylparaben to form a paraben phase.</li><li>4. Preparation of the xanthan gum phase. Xanthan gum was mixed with propylene glycol according to the respective weight percentages described in Table 10 and the resulting mixture was heated at about 55 °C to about 60 °C to form a Xanthan gum phase in a form of dispersion.</li><li>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 described in Table 10 and the resulting mixture was heated to about 65 °C to about 68 °C while stirring till all of the excipients were melt to form an oil phase.</li><li>6. The aqueous phase was heated to about 65 °C to about 68 °C, while stirring at about 600 - 800 rpm.</li><li>7. Into the heated aqueous phase was transferred the paraben phase according to the percentage described in Table 10 and the resulting mixture was well stirred and maintained at about 65 °C to about 68 °C with the stirring speed maintained at about 600 - 800 rpm.</li><li>8. Into the mixture of the aqueous phase and the paraben phase was transferred the xanthan gum phase according to the percentage described in Table 10 and the resulting mixture was well stirred and maintained at about 65 °C to about 68 °C with the stirring speed maintained at about 600 - 800 rpm.</li><li>9. Preparation of the oil-in-water emulsion. Into the mixture of the aqueous phase, the paraben phase, and the xanthan Gum phase was transferred the oil phase according to the percentage described in Table 10. The resulting mixture was well stirred and maintained at about 65 °C to about 68 °C with the stirring speed maintained at about 600 - 800 rpm to form an oil-in-water emulsion.</li><li>10. The oil-in-water emulsion was cooled to about 38 °C to about 40 °C.</li><li>11. Into the cooled oil-in-water emulsion was added phenoxyethanol according to the percentage described in Table 10. The temperature of resulting mixture was maintained at about 38 °C to about 40 °C, and the stirring speed was maintained at about 600 - 800 rpm.</li></ol>
0617For the combination creams of ruxolitinib and calcipotriol (Formulations #3 and #6), calcipotriol solution in medium chain triglycerides, and light mineral oil were added into the oil-in-water emulsion according to the respective percentages described in Table 10. The resulting mixture was maintained at about 38 °C to about 40 °C with the stirring speed maintained at about 600 - 800 rpm. For ruxolitinib only creams (Formulation #1, #2, #4, and #5), medium chain triglycerides and light mineral oil were added into the oil-in-water emulsion according to the respective percentages described in Table 10. The resulting mixture was maintained at about 38 °C to about 40 °C with the stirring speed was maintained at about 600 - 800 rpm. After cooling down the resulting mixtures and stopping the stirring, the creams (Formulations #1 to #6) were formed and collected.
0618Table 9 lists weight percentages of different phases of the cream Formulations #1 to #6. Table 10 lists weight percentages of ruxolitinib phosphate, calcipotriol, and excipients in the cream Formulations #1 to #6. <tables id="tabl0010" num="0010"><table frame="all"><title><b>Table 9.</b> Weight percentages of different phases of the ruxolitinib creams (Formulations #1, #2, #4, and #5), and ruxolitinib and calcipotriol combination creams (Formulations #3 and #6). Note that ruxolitinib phosphate was in an amount of 1.98 wt% for Formulations #1 to# 6, which corresponds to 1.5% w/w of ruxolitinib on a free base basis. The calcipotriol was in an amount of 0.005% w/w or 50 microgram/g for Formulation #3 and #6. Formulations #1, #2, #4, and #5 do not contain calcipotriol.</title><tgroup cols="8"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><colspec colnum="7" colname="col7" colwidth="15mm" /><colspec colnum="8" colname="col8" colwidth="15mm" /><thead valign="top"><row><entry><b>Ingredient</b></entry><entry align="center"><b>Function</b></entry><entry align="center"><b>#1 (% w/w)</b></entry><entry align="center"><b>#2 (% w/w)</b></entry><entry align="center"><b>#3 (% w/w)</b></entry><entry align="center"><b>#4 (% w/w)</b></entry><entry align="center"><b>#5 (% w/w)</b></entry><entry align="center"><b>#6 (% w/w)</b></entry></row><row><entry namest="col1" nameend="col2" align="center" /><entry namest="col3" nameend="col8" align="center"><b><i><u>Aqueous Phase</u></i></b></entry></row></thead><tbody><row><entry><b>Purified water</b></entry><entry /><entry align="center">55.42</entry><entry align="center">53.42</entry><entry align="center">55.42</entry><entry align="center">55.42</entry><entry align="center">53.42</entry><entry align="center">55.42</entry></row><row><entry><b>Disodium EDTA</b></entry><entry align="center">Chelating agent</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry></row><row><entry><b>PEG300</b></entry><entry align="center">Solvent</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">0</entry><entry align="center">0</entry><entry align="center">0</entry></row><row><entry><b>PEG400</b></entry><entry align="center">Solvent</entry><entry align="center">0</entry><entry align="center">0</entry><entry align="center">0</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry></row><row><entry><b>Ruxolitinib phosphate</b></entry><entry align="center">Active</entry><entry align="center">1.98</entry><entry align="center">1.98</entry><entry align="center">1.98</entry><entry align="center">1.98</entry><entry align="center">1.98</entry><entry align="center">1.98</entry></row></tbody></tgroup><tgroup cols="8"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><colspec colnum="7" colname="col7" colwidth="15mm" /><colspec colnum="8" colname="col8" colwidth="15mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left" /><entry namest="col3" nameend="col8" align="center"><b><i><u>Paraben Phase</u></i></b></entry></row></thead><tbody><row><entry><b>Propylene glycol</b></entry><entry align="center">Solvent</entry><entry align="center">1.5</entry><entry align="center">3.5</entry><entry align="center">1.5</entry><entry align="center">1.5</entry><entry align="center">3.5</entry><entry align="center">1.5</entry></row><row><entry><b>Methylparaben</b></entry><entry align="center">Antimicrobial preservative</entry><entry align="center">0.1</entry><entry align="center">0.1</entry><entry align="center">0.1</entry><entry align="center">0.1</entry><entry align="center">0.1</entry><entry align="center">0.1</entry></row><row><entry><b>Propylparaben</b></entry><entry align="center">Antimicrobial preservative</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry><entry align="center">0.05</entry></row></tbody></tgroup><tgroup cols="8"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><colspec colnum="7" colname="col7" colwidth="15mm" /><colspec colnum="8" colname="col8" colwidth="15mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left" /><entry namest="col3" nameend="col8" align="center"><b><i><u>Xanthan Gum Phase</u></i></b></entry></row></thead><tbody><row><entry><b>Propylene glycol</b></entry><entry align="center">Solvent</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">5</entry></row><row><entry><b>Xanthan Gum</b></entry><entry align="center">Stabilizing agent</entry><entry align="center">0.4</entry><entry align="center">0.4</entry><entry align="center">0.4</entry><entry align="center">0.4</entry><entry align="center">0.4</entry><entry align="center">0.4</entry></row></tbody></tgroup><tgroup cols="8"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><colspec colnum="7" colname="col7" colwidth="15mm" /><colspec colnum="8" colname="col8" colwidth="15mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left" /><entry namest="col3" nameend="col8" align="center"><b><i><u>Oil Phase</u></i></b></entry></row></thead><tbody><row><entry><b>White petrolatum</b></entry><entry align="center">Occlusive agent</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry><entry align="center">7</entry></row><row><entry><b>Light mineral oil</b></entry><entry align="center">Emollient</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry></row><row><entry><b>Glycerol stearate SE</b></entry><entry align="center">Emulsifier</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry></row><row><entry><b>Cetyl alcohol</b></entry><entry align="center">Stiffening agent</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry><entry align="center">3</entry></row><row><entry><b>Stearyl alcohol</b></entry><entry align="center">Stiffening agent</entry><entry align="center">1.75</entry><entry align="center">1.75</entry><entry align="center">1.75</entry><entry align="center">1.75</entry><entry align="center">1.75</entry><entry align="center">1.75</entry></row><row><entry><b>Dimethicone</b></entry><entry align="center">Emollient; Skin protectant</entry><entry align="center">1</entry><entry align="center">1</entry><entry align="center">1</entry><entry align="center">1</entry><entry align="center">1</entry><entry align="center">1</entry></row><row><entry><b>Medium chain triglycerides</b></entry><entry align="center">Emollient</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry></row><row><entry><b>Polysorbate 20</b></entry><entry align="center">Emulsifier</entry><entry align="center">1.25</entry><entry align="center">1.25</entry><entry align="center">1.25</entry><entry align="center">1.25</entry><entry align="center">1.25</entry><entry align="center">1.25</entry></row></tbody></tgroup><tgroup cols="8"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><colspec colnum="7" colname="col7" colwidth="15mm" /><colspec colnum="8" colname="col8" colwidth="15mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left" /><entry namest="col3" nameend="col8" align="center"><b><i><u>Added into the oil-in-water emulsion at a lower temperature</u><u>(38- 40 °C)</u></i></b></entry></row></thead><tbody><row><entry><b>Phenoxyethanol</b></entry><entry align="center">Antimicrobial preservative</entry><entry align="center">0.5</entry><entry align="center">0.5</entry><entry align="center">0.5</entry><entry align="center">0.5</entry><entry align="center">0.5</entry><entry align="center">0.5</entry></row><row><entry><b>Calcipotriol in medium chain triglycerides (1 mg/g)</b></entry><entry align="center">Active</entry><entry align="center">0</entry><entry align="center">0</entry><entry align="center">5</entry><entry align="center">0</entry><entry align="center">0</entry><entry align="center">5</entry></row><row><entry><b>Medium chain triglycerides</b></entry><entry align="center">Emollient</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">0</entry><entry align="center">5</entry><entry align="center">5</entry><entry align="center">0</entry></row><row><entry><b>Light mineral oil</b></entry><entry align="center">Emollient</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry><entry align="center">2</entry></row></tbody></tgroup></table></tables><tables id="tabl0011" num="0011"><table frame="all"><title><b>Table 10.</b> Weight percentages of ruxolitinib phosphate, calcipotriol, and excipients for Formulations #1 to #6.</title><tgroup cols="7"><colspec colnum="1" colname="col1" colwidth="43mm" /><colspec colnum="2" colname="col2" colwidth="20mm" align="center" /><colspec colnum="3" colname="col3" colwidth="20mm" align="center" /><colspec colnum="4" colname="col4" colwidth="20mm" align="center" /><colspec colnum="5" colname="col5" colwidth="20mm" align="center" /><colspec colnum="6" colname="col6" colwidth="20mm" align="center" /><colspec colnum="7" colname="col7" colwidth="20mm" align="center" /><thead valign="top"><row><entry><b>Ingredient</b></entry><entry><b>#1 (% w/w)</b></entry><entry><b>#2 (% w/w)</b></entry><entry><b>#3 (% w/w)</b></entry><entry><b>#4 (% w/w)</b></entry><entry><b>#5 (% w/w)</b></entry><entry><b>#6 (% w/w)</b></entry></row></thead><tbody><row><entry><b>Ruxolitinib phosphate</b></entry><entry>1.98</entry><entry>1.98</entry><entry>1.98</entry><entry>1.98</entry><entry>1.98</entry><entry>1.98</entry></row><row><entry><b>Calcipotriol</b></entry><entry>0</entry><entry>0</entry><entry>0.005</entry><entry>0</entry><entry>0</entry><entry>0.005</entry></row><row><entry><b>Purified water</b></entry><entry>55.42</entry><entry>53.42</entry><entry>55.42</entry><entry>55.42</entry><entry>53.42</entry><entry>55.42</entry></row><row><entry><b>Disodium EDTA</b></entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry></row><row><entry><b>PEG300</b></entry><entry>7</entry><entry>7</entry><entry>7</entry><entry>0</entry><entry>0</entry><entry>0</entry></row><row><entry><b>PEG400</b></entry><entry>0</entry><entry>0</entry><entry>0</entry><entry>7</entry><entry>7</entry><entry>7</entry></row><row><entry><b>Propylene glycol</b></entry><entry>6.5</entry><entry>8.5</entry><entry>6.5</entry><entry>6.5</entry><entry>8.5</entry><entry>6.5</entry></row><row><entry><b>Methylparaben</b></entry><entry>0.1</entry><entry>0.1</entry><entry>0.1</entry><entry>0.1</entry><entry>0.1</entry><entry>0.1</entry></row><row><entry><b>Propylparaben</b></entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry><entry>0.05</entry></row><row><entry><b>Xanthan Gum</b></entry><entry>0.4</entry><entry>0.4</entry><entry>0.4</entry><entry>0.4</entry><entry>0.4</entry><entry>0.4</entry></row><row><entry><b>White petrolatum</b></entry><entry>7</entry><entry>7</entry><entry>7</entry><entry>7</entry><entry>7</entry><entry>7</entry></row><row><entry><b>Light mineral oil</b></entry><entry>4</entry><entry>4</entry><entry>4</entry><entry>4</entry><entry>4</entry><entry>4</entry></row><row><entry><b>Glycerol stearate SE</b></entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry></row><row><entry><b>Cetyl alcohol</b></entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry><entry>3</entry></row><row><entry><b>Stearyl alcohol</b></entry><entry>1.75</entry><entry>1.75</entry><entry>1.75</entry><entry>1.75</entry><entry>1.75</entry><entry>1.75</entry></row><row><entry><b>Dimethicone</b></entry><entry>1</entry><entry>1</entry><entry>1</entry><entry>1</entry><entry>1</entry><entry>1</entry></row><row><entry><b>Medium chain triglycerides</b></entry><entry>7.0</entry><entry>7.0</entry><entry>6.995</entry><entry>7.0</entry><entry>7.0</entry><entry>6.995</entry></row><row><entry><b>Polysorbate 20</b></entry><entry>1.25</entry><entry>1.25</entry><entry>1.25</entry><entry>1.25</entry><entry>1.25</entry><entry>1.25</entry></row><row><entry><b>Phenoxyethanol</b></entry><entry>0.5</entry><entry>0.5</entry><entry>0.5</entry><entry>0.5</entry><entry>0.5</entry><entry>0.5</entry></row></tbody></tgroup></table></tables>
0619The cream forms of Formulations #1 to #6 are as shown in <figref idref="f0005"><b>FIG. 5</b></figref><b>.</b> Cream Formulations #1 to #3 contained 7.0% w/w of PEG 300; while cream Formulations #4 to #6 contained 7.0% w/w of PEG400. The propylene glycol content in the cream Formulation #1, #3, #4, and #6 was 6.5% w/w, while the propylene glycol content in the cream Formulations #2 and #5 was 8.5% w/w. ruxolitinib content was 1.5% w/w on a free base basis in all the cream Formulations #1 to #6. Formulation #3 and #6 are ruxolitinib and calcipotriol combination creams containing both ruxolitinib (1.5% w/w on a free base basis) and calcipotriol (0.005% w/w).
0620An additional formulation (Formulation #7) containing 1.1% w/w of ruxolitinib on a free base basis and 0.0005 w/w of calcipotriol was prepared.
0621For preparations of ruxolitinib and calcipotriol combination creams, ruxolitinib was incorporated in the water phase, and calcipotriol was dissolved in the liquid oil phase upon heating, solid oil phase excipients were heated to melt, and then the water phase, the liquid oil phase and the melted solid oil phase excipients were combined and homogenized to produce a formulation, which was then cooled. To the cooled formulation, was added the antimicrobial preservative and the resulting formulation was stirred until visually homogeneous, of which the pH was adjusted if necessary and to which was added water to make up the volume as needed. Details of the preparation steps are as follows: <ol id="ol0006" compact="compact"><li>(i) EDTA was initially added to the water in an amber Duran and stirred at 500 RPM until visually homogenous.</li><li>(ii) BHA was initially added to the Transcutol P in an amber Duran and stirred at 500 RPM until visually homogeneous.</li><li>(iii) The solutions from Step (i) and (ii) were added to the rest of the aqueous phase excipients (glycerol) in an amber Duran and stirred by magnetic stirrer bar at 500 RPM until visually homogenous.</li><li>(iv) Ruxolitinib phosphate was added to the aqueous phase from Step (iii) and stirred for 5 mins at 500 RPM, ruxolitinib phosphate does not fully dissolve in this step.</li><li>(v) The suspension from Step (iv) was pH adjusted to pH 6.0 - 7.0 with trolamine, and ruxolitinib phosphate dissolved during this step.</li><li>(vi) In a separate amber Duran, BHT was added to oleyl alcohol and sweet almond oil and placed on stir at 250 RPM until visually homogenous.</li><li>(vii) The solution from Step (vi) was added to the remaining liquid oil phase excipients (polysorbate 80 and light mineral oil) and stirred for 3-5 mins at 500 RPM until visually homogenous.</li><li>(viii) Calcipotriol was added to the liquid oil phase from Step (vii) and stirred at 500 RPM at 65 °C for 1 hour, and then at ambient laboratory temperature overnight, to dissolve.</li><li>(ix) Following calcipotriol dissolution in Step (viii) poloxamer 407 was dispersed into the solution from Step (viii) by stirring at 500 RPM.</li><li>(x) The solid oil phase excipients were weighed into a separate amber Duran placed in a water bath at 70 °C until molten. The aqueous phase from Step (v), liquid oil phase from Step (ix) and the homogeniser head (silverson, square hole, high shear screen) were also placed in the water bath for 3 mins.</li><li>(xi) The phases were combined and homogenized for 2 mins at 10,000 RPM.</li><li>(xii) The formulation from Step (xi) was stirred using an IKA anchor paddle at 100 RPM until the formulation had cooled to ambient laboratory temperature.</li><li>(xiii) Phenoxyethanol was added to the formulation from Step (xii) and hand stirred until visually homogenous.</li><li>(xiv) The pH of the formulation was checked, adjusted if necessary, made to volume with water and further hand stirred until visually homogenous.</li></ol>
0622Table 11 lists weight percentages for Formulation #7. <tables id="tabl0012" num="0012"><table frame="all"><title><b>Table 11.</b> Composition of Cream Formulation #7. Note that ruxolitinib phosphate was in an amount of 1.464 wt%, which corresponds to 1.1% w/w of ruxolitinib on a free base basis. The calcipotriol was in an amount of 0.005% w/w.</title><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="61mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><colspec colnum="3" colname="col3" colwidth="57mm" align="center" /><thead><row><entry><b>Excipient</b></entry><entry valign="middle"><b>% w/w</b></entry><entry valign="top"><b>Functionality</b></entry></row><row valign="middle"><entry namest="col1" nameend="col3" align="center"><b>Aqueous Phase</b></entry></row></thead><tbody><row valign="middle"><entry>Purified Water</entry><entry>32.021</entry><entry>Solvent</entry></row><row valign="middle"><entry>Edetate disodium (EDTA)</entry><entry>0.050</entry><entry>Chelating agent</entry></row><row valign="middle"><entry>Butylhydroxyanisole (BHA)</entry><entry>0.020</entry><entry>Antioxidant</entry></row><row valign="middle"><entry>Transcutol P</entry><entry>16.090</entry><entry>Solvent/Solubilizer</entry></row><row valign="middle"><entry>Glycerol</entry><entry>8.045</entry><entry>Humectant</entry></row><row><entry valign="middle">Ruxolitinib Phosphate</entry><entry valign="middle">1.464 (1.1% on free base basis)</entry><entry>API</entry></row><row valign="middle"><entry>Trolamine<sup>1</sup></entry><entry>to pH 6.0 - 7.0</entry><entry>Buffering agent</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="61mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><colspec colnum="3" colname="col3" colwidth="57mm" align="center" /><thead valign="middle"><row><entry namest="col1" nameend="col3" align="center"><b>Oil Phase</b></entry></row></thead><tbody><row><entry valign="middle">Butylhydroxytoluene (BHT)</entry><entry valign="middle">0.500</entry><entry>Antioxidant</entry></row><row valign="middle"><entry>Oleyl Alcohol</entry><entry>5.000</entry><entry>Emulsifying agent</entry></row><row valign="middle"><entry>Sweet Almond Oil</entry><entry>2.000</entry><entry>Emollient</entry></row><row valign="middle"><entry>Polysorbate 80</entry><entry>2.011</entry><entry>Surfactant</entry></row><row valign="middle"><entry>Light Mineral Oil</entry><entry>10.000</entry><entry>Emollient, Solvent</entry></row><row valign="middle"><entry>Calcipotriol Monohydrate</entry><entry>0.0052</entry><entry>API</entry></row><row valign="middle"><entry>Poloxamer 407</entry><entry>1.000</entry><entry>Surfactant/Stabilizer</entry></row><row valign="middle"><entry>Cetosteryl Alcohol</entry><entry>12.000</entry><entry>Stiffening agent, consistency improver</entry></row><row valign="middle"><entry>Cetomacrogol 1000</entry><entry>1.962</entry><entry>Emulsifier/Surfactant</entry></row><row><entry valign="middle">Arlacel 165 (Glyceryl Stearate (and) PEG-100 Stearate)</entry><entry valign="middle">2.538</entry><entry>Emulsifier</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="61mm" /><colspec colnum="2" colname="col2" colwidth="46mm" /><colspec colnum="3" colname="col3" colwidth="57mm" /><thead valign="middle"><row><entry namest="col1" nameend="col3" align="center"><b>Added after cooling</b></entry></row></thead><tbody valign="middle"><row><entry align="center">Phenoxyethanol</entry><entry align="center">1.000</entry><entry>Preservative</entry></row><row><entry align="center">Trolamine</entry><entry morerows="1" align="center">to pH 6.5 - 7.0<sup>1</sup></entry><entry>Buffering agent</entry></row><row><entry align="center">Phosphoric acid</entry><entry>Buffering agent</entry></row><row><entry align="center">Purified Water</entry><entry align="center">Q.S to 100%</entry><entry>Solvent</entry></row><row><entry align="center">Total</entry><entry align="center">100.000</entry><entry align="center" /></row></tbody></tgroup><tgroup cols="3" rowsep="0"><colspec colnum="1" colname="col1" colwidth="61mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="46mm" /><colspec colnum="3" colname="col3" colwidth="57mm" /><tbody><row><entry namest="col1" nameend="col3"><sup>1</sup>Trolamine and phosphoric acid may be used to adjusted the pH and additional water may be added to make up 100 w/w% for Formulation #7.</entry></row></tbody></tgroup></table></tables>
Example 4. Ruxolitinib and calcipotriol combination creams with other excipient concentrations.
0623Cream formulations are prepared as described in Example 3 having ruxolitinib phosphate present in an amount of about 0.75% w/w on a free base basis with adjustments to the water percentage in Example 3 as necessary.
0624Cream formulations are prepared as described in Example 3 with propylene glycol of about 6.5% w/w to about 15% w/w (e.g., about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 10.5% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w or about 15% w/w) with adjustments to the water percentage in Example 3 as necessary.
0625Cream formulations are prepared as described in Example 3 with various low molecular weight polyethylene glycols (PEGs) as co-solvent, including PEG200, PEG300, PEG400, or a combination thereof.
0626Cream formulations are prepared as described in Example 3 with methylparaben content ranging between 0 and about 0.1% w/w, and with propylparaben content from 0 to about 0.05% w/w (with adjustments to the water percentage in Example 3 as necessary).
0627Cream formulations are prepared as described in Example 3 with the xanthan gum content from about 0.2 to about 0.6% w/w can be prepared (with adjustments to the water percentage in Example 3 as necessary).
0628Cream formulations are prepared as described in Example 3 with butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tocopherol, used either alone or in combination, added to the oil phase (with adjustments to the water percentage in Example 3 as necessary.
0629Cream formulations are prepared as described in Example 3 with ascorbyl palmitate, ascorbic acid, or citric acid, or a combination thereof, added to enhance the stability of calcipotriol.
Example 5. Ruxolitinib and calcipotriol combination creams in a murine model of IL-23 induced psoriasis-like disease
0630A combination cream formulation (Formulation #7 of Example 3) was tested in established murine model of IL-23 induced psoriasis-like disease (<nplcit id="ncit0057" npl-type="s"><text>Rizzo HL, et al., "IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A," J Immunol 186:1495-1502 (2011</text></nplcit>); <nplcit id="ncit0058" npl-type="s"><text>T.P. Singh, et al., "IL-23- and Imiquimod-induced models of experimental psoriasis in mice," Curr. Protoc. Immunol. e71, (2019); 10.1002/cpim.71</text></nplcit>), including acanthosis and accumulation of inflammatory cells in both the epidermis and dermis leading to local thickening of skin. IL-23 was intra-dermally injected to one ear on Day 0, 2, 4 and Day 7. Topical cream vehicle or Formulation #7 (Example 3) were topically applied to one ear of IL-23 -induced psoriasis like mice. Cream (20 ug per application) was applied twice per day (B.I.D) for 8 days. Ears were measured by engineer's calipers for swelling. A statistically significant decrease in ear thickening (p <0.001) was measured in mice treated with Formulation #7 compared to vehicle treated mice <b>(</b><figref idref="f0010"><b>FIG. 10</b></figref><b>).</b>
0631Various modifications of the presently claimed subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present disclosure, including all patent, patent applications, and publications, is incorporated herein by reference in its entirety.
Numbered clauses:
0632<ol id="ol0007"><li>1. A pharmaceutical formulation for topical treatment of a skin disease, 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.</li><li>2. The pharmaceutical formulation of clause 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.</li><li>3. The pharmaceutical formulation of clause 2, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt thereof.</li><li>4. The pharmaceutical formulation of clause 2, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>5. The pharmaceutical formulation of any one of clauses 1-4, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having Formula (II): <chemistry id="chem0044" num="0044"><img file="EP4570321A2_D0044.tif" /></chemistry> wherein: <ul id="ul0040" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>6. The pharmaceutical formulation of any one of clauses 1-5, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.</li><li>7. The pharmaceutical formulation of clause 2, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.</li><li>8. The pharmaceutical formulation of clause 2, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.</li><li>9. The pharmaceutical formulation according to any one of clauses 3-8, wherein the formulation comprises from about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxolitinib, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>10. The pharmaceutical formulation according to any one of clauses 3-8, wherein the formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of the formulation on a free base basis of the ruxolitinib, or the pharmaceutically acceptable salt thereof.</li><li>11. The pharmaceutical formulation of any one of clauses 2-10, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>12. The pharmaceutical formulation of any one of clauses 2-10, wherein the formulation comprises from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>13. The pharmaceutical formulation of any one of clauses 2-10, wherein the formulation comprises from about 0.0001% w/w to about 0.01% w/w or from about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>14. The pharmaceutical formulation of any one of clauses 2-10, wherein the formulation comprises about 0.005% w/w of the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, on a free base basis.</li><li>15. The pharmaceutical formulation of any one of clauses 1-14, wherein the formulation is a cream or a lotion.</li><li>16. The pharmaceutical formulation of any one of clauses 1-15, wherein the formulation is an oil-in-water emulsion.</li><li>17. The pharmaceutical formulation of any one of clauses 1-16, wherein the formulation comprises water, an oil component, and an emulsifier or stabilizer component.</li><li>18. The pharmaceutical formulation of clause 17, wherein the water comprises from about 5% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or from about 20% to about 50% by weight of the pharmaceutical formulation.</li><li>19. The pharmaceutical formulation of any one of clauses 17-18, wherein the oil component comprises from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 50%, or from about 5% to about 40% by weight of the pharmaceutical formulation.</li><li>20. The pharmaceutical formulation of any one of clauses 17-19, wherein the emulsifier or stabilizer component comprises from about 1% to about 30% or from about 5% to about 25% by weight of the pharmaceutical formulation.</li><li>21. The pharmaceutical formulation of any one of clauses 17-20, further comprising a solvent component for dissolving ruxolitinib, or a pharmaceutically acceptable salt thereof.</li><li>22. The pharmaceutical formulation of clause 21, wherein the solvent component comprises from about 5% to about 20%, from about 2% to about 30%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, or from about 10% to about 20% by weight of the pharmaceutical formulation.</li><li>23. The pharmaceutical formulation of any one of clauses 2-22, wherein the formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.</li><li>24. The pharmaceutical formulation of clause 23, wherein pH of the formulation is adjusted with trolamine.</li><li>25. A method of treating a skin disease in a patient in need thereof, comprising topically administering to an 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.</li><li>26. The method of clause 25, 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.</li><li>27. The method of clause 26, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib, or a pharmaceutically acceptable salt thereof.</li><li>28. The method of clause 26, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.</li><li>29. The method of any one of clauses 26-28, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having Formula (II): <chemistry id="chem0045" num="0045"><img file="EP4570321A2_D0045.tif" /></chemistry> wherein: <ul id="ul0041" list-style="none" compact="compact"><li>R<sup>1</sup> is H or OH;</li><li>R<sup>2</sup> and R<sup>3</sup> are each H; or</li><li>R<sup>2</sup> is O-R<sup>2A</sup>; and R<sup>3</sup> is H; or</li><li>R<sup>2</sup> and R<sup>3</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>2A</sup> is -C<sub>1-4</sub> alkylene-OH;</li><li>R<sup>4</sup> and R<sup>5</sup> are each H; or</li><li>R<sup>4</sup> and R<sup>5</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>R<sup>6</sup> and R<sup>7</sup> are each H; or</li><li>R<sup>6</sup> and R<sup>7</sup> are taken together to form a =CH<sub>2</sub> group;</li><li>L is -CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH(R<sup>12</sup>)-, -CH=CH-CH(R<sup>12</sup>)-, -CH=CH-CH=CH-, -CH<sub>2</sub>-C≡C-, -O-CH<sub>2</sub>-CH<sub>2</sub>-, or -O-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-, wherein R<sup>12</sup> is H or OH;</li><li>R<sup>9</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl;</li><li>R<sup>10</sup> is C<sub>1-3</sub> alkyl or C<sub>1-4</sub> haloalkyl;</li><li>R<sup>11</sup> is H or OH;</li><li>or, alternatively, R<sup>9</sup> and R<sup>10</sup> together with the carbon atom to which they are attached form a C<sub>3-4</sub> cycloalkyl ring; and R<sup>11</sup> is H.</li></ul></li><li>30. The method of any one of clauses 26-28, wherein the vitamin D3 analog, or a pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol, or a pharmaceutically acceptable salt thereof.</li><li>31. The method of clause 26, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.</li><li>32. The method of clause 26, wherein the JAK1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.</li><li>33. The method of any one of clauses 26-32, the skin disease is an autoimmune or an inflammatory skin disease.</li><li>34. The method of any one of clauses 26-32, wherein the skin disease is a Th1 or Th17 associated skin disease.</li><li>35. The method of any one of clauses 26-32, 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.</li><li>36. The method of any one of clauses 26-32, wherein the skin disease is mediated by Defb4, S100a12, or Serpinb4.</li><li>37. The method of any one of clauses 26-32, 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.</li><li>38. The method of any one of clauses 26-32, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratoderma, pachyonychia congenita, steatocystoma multiplex, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.</li><li>39. The method of any one of clauses 26-32, wherein the skin disease is rosacea, psoriatic arthritis, dermal fibrosis, morphea, spitz nevi, dermatophytosis, or acne vulgaris.</li><li>40. The method of any one of clauses 26-39, wherein there is a synergistic effect between the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof.</li><li>41. The method of any one of clauses 26-40, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least one time per day.</li><li>42. The method of any one of clauses 26-40, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered at least two times per day.</li><li>43. The method of any one of clauses 26-42, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered simultaneously.</li><li>44. The method of any one of clauses 26-42, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or a pharmaceutically acceptable salt thereof, are administered sequentially.</li><li>45. The method of any one of clauses 26-44, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered as separate formulations.</li><li>46. The method of any one of clauses 26-43, wherein (a) the JAK1/2 inhibitor, or the pharmaceutically acceptable salt thereof, and (b) the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single formulation.</li><li>47. The method of clause 45, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are each administered in a topical formulation.</li><li>48. The method of clause 46, wherein the JAK1/2 inhibitor, or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog, or the pharmaceutically acceptable salt thereof, are administered in a single topical formulation.</li><li>49. The method of clause 47, wherein each topical formulation is an ointment, a cream, or a lotion.</li><li>50. The method of clause 48, wherein the single topical formulation is an ointment, a cream, or a lotion.</li><li>51. The method of clause 50, wherein the single topical formulation is a cream or a lotion.</li><li>52. The method of clause 50, wherein the single topical formulation is a cream formulation.</li><li>53. The method of any one of clauses 50-52, wherein the single topical formulation has a pH of from about 6.0 to about 8.0, from about 6.5 to about 7.5, or from about 6.5 to about 7.0.</li><li>54. The method of any one of clauses 26-53, further comprising administering an additional therapeutic agent.</li><li>55. The method of clause 54, wherein the additional therapeutic agent is a corticosteroid.</li><li>56. The method of clause55, wherein the corticosteroid is betamethasone dipropionate.</li></ol>
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| US9540367B2 | Cites | United States of America | Applicant |
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45 members in 27 offices
Members45
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| CA3204186A1 | Canada | A1 | |
| WO2022120131A1 | World Intellectual Property Organization (WIPO) | A1 | |
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| WO2023102559A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU2021390533A1 | Australia | A1 | |
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| TW202329975A | Taiwan Province of China | A | |
| MX2023006638A | Mexico | A | |
| KR20230128472A | Republic of Korea | A | |
| EP4255442A1 | European Patent Office (EPO) | A1 | |
| CN117157080A | China | A | |
| JP2023552424A | Japan | A | |
| ZA202306521B | South Africa | B | |
| CL2023001603A1 | Chile | A1 | |
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| KR20240139048A | Republic of Korea | A | |
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| EP4440546A1 | European Patent Office (EPO) | A1 | |
| JP2024544686A | Japan | A | |
| US2025049817A1 | United States of America | A1 | |
| EP4255442B1 | European Patent Office (EPO) | B1 | |
| FI4255442T3 | Finland | T3 | |
| DK4255442T3 | Denmark | T3 | |
| PT4255442T | Portugal | T | |
| ES3025481T3 | Spain | T3 | |
| EP4570321A2This record | European Patent Office (EPO) | A2 | |
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| RS66785B1 | Serbia | B1 | |
| SI4255442T1 | Slovenia | T1 | |
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| LT4255442T | Lithuania | T | |
| US2025249009A1 | United States of America | A1 | |
| EP4570321A3 | European Patent Office (EPO) | A3 | |
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| Application deemed to be withdrawnWithdrawn18D | 18D | EP | |
| Information on the status of an ep patent application or granted ep patentGrantedSTATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWNSTAA | STAA | EP | |
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Numbers
- Publication
- 4570321
- Application
- 251593984
Titles3
- German
- JAK-HEMMER MIT EINEM VITAMIN-D-ANALOGON ZUR BEHANDLUNG VON HAUTERKRANKUNGEN
- English
- JAK INHIBITOR WITH A VITAMIN D ANALOG FOR TREATMENT OF SKIN DISEASES
- French
- INHIBITEUR DE JAK AVEC UN ANALOGUE DE VITAMINE D POUR LE TRAITEMENT DE MALADIES DE LA PEAU
Classification
- CPC, 14
- A61K45/06
- A61K31/593
- A61K31/519
- A61P37/06
- A61P17/06
- A61P17/14
- A61P17/00
- A61P35/00
- A61P17/10
- A61K9/107
- A61K9/0014
- A61K2300/00
- A61P37/00
- A61P29/00
- IPC, 1
- A61P37 06
Designated states44
- Contracting states, 38
- Albania
- Austria
- Belgium
- Bulgaria
- Switzerland
- Cyprus
- Czechia
- Germany
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- France
- United Kingdom
- Greece
- Croatia
- Hungary
- Ireland
- Iceland
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- Lithuania
- Luxembourg
- Latvia
and 14 moreShow fewer
- Monaco
- North Macedonia
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- Norway
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- Portugal
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- San Marino
- Türkiye
- Extension states, 2
- Bosnia and Herzegovina
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- Validation states, 4
- Cambodia
- Morocco
- Republic of Moldova
- Tunisia