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CN117157080A - JAK inhibitors containing vitamin D analogues for the treatment of skin disorders - Google Patents

JAK inhibitors containing vitamin D analogues for the treatment of skin disorders Download PDF

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CN117157080A
CN117157080A CN202180091979.6A CN202180091979A CN117157080A CN 117157080 A CN117157080 A CN 117157080A CN 202180091979 A CN202180091979 A CN 202180091979A CN 117157080 A CN117157080 A CN 117157080A
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pharmaceutically acceptable
acceptable salt
vitamin
formulation
emulsion
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P·史密斯
张铮
M·帕克
J·菲奇
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Incyte Corp
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Incyte Corp
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Priority claimed from PCT/US2021/061744 external-priority patent/WO2022120131A1/en
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Abstract

The present disclosure relates to the topical treatment of dermatological disorders such as psoriasis, atopic dermatitis, alopecia, vitiligo, listlessness syndrome, pityriasis pilaris, epidermolysis simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and keratinization disorders using (a) JAK inhibitors or pharmaceutically acceptable salts thereof and (b) vitamin D3, vitamin D3 analogs or pharmaceutically acceptable salts thereof.

Description

JAK inhibitors containing vitamin D analogues for the treatment of skin disorders
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application number 63/121,531, filed on day 4 of 12 in 2020, and U.S. provisional application number 63/199,876, filed on day 29 of 1 in 2021, each of which is hereby incorporated by reference in its entirety.
Technical Field
The present disclosure relates to the topical treatment of dermatological disorders using (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
Background
Inflammation mediated by Janus kinase (JAK) -signal transduction factors is one of the important features 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, JAK inhibitors may not be equally effective on all subjects with inflammatory skin diseases for any treatment. There is a need to develop more effective formulations comprising JAK inhibitors to treat a wider number of subjects with various inflammatory skin diseases.
In view of these limitations, new treatment options are medically needed. The present disclosure addresses this need and other needs.
Disclosure of Invention
The present disclosure provides a method of treating a dermatological disorder 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.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxolitinib (ruxolitinib) 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 method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) calcipotriol (calcipotriol) or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a JAK inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for the topical treatment of a dermatological disorder described herein.
The present disclosure also provides for the topical treatment of a dermatological disorder described herein in combination with vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
The present disclosure also provides for the topical treatment of a dermatological disorder described herein in combination with calcipotriol or a pharmaceutically acceptable salt thereof.
The present disclosure also provides the use of a JAK inhibitor or a pharmaceutically acceptable salt thereof in combination with vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the topical treatment of a dermatological disorder described herein.
The present disclosure also provides the use of ruxotinib, or a pharmaceutically acceptable salt thereof, in combination with vitamin D3, a vitamin D3 analogue, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the topical treatment of a dermatological disorder described herein.
The present disclosure also provides the use of ruxotinib, or a pharmaceutically acceptable salt thereof, in combination with calcipotriol, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the topical treatment of a dermatological disorder described herein.
In some embodiments of each of the foregoing, the patient is a human patient.
The present disclosure further provides a topical formulation for topical treatment of a skin disorder described herein comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
The present disclosure further provides a topical formulation for the topical treatment of a skin disorder described herein comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
The present disclosure further provides topical formulations for the topical treatment of skin disorders described herein comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) calcipotriol or a pharmaceutically acceptable salt thereof.
The present disclosure also provides the use of a topical formulation comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the topical treatment of a skin disorder described herein.
The present disclosure also provides the use of a topical formulation comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the topical treatment of a skin disorder described herein.
The present disclosure also provides the use of a topical formulation comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) calcipotriol or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the topical treatment of a skin condition described herein.
The present disclosure further provides a pharmaceutical formulation for topical treatment of a skin disorder comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
The present disclosure further provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib phosphate, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.
Drawings
Figure 1 depicts fold-change and p-values of IL-22 levels of skin treated basolaterally with different concentrations of Lu Suoti ni, calcipotriol, and combinations thereof 24 hours after stimulation relative to normal (healthy) unstimulated and stimulated human skin.
Figure 2 depicts fold-change and p-values of CXCL10 levels of skin treated basolaterally with different concentrations of Lu Suoti ni, calcipotriol, and combinations thereof 24 hours after stimulation relative to normal (healthy) unstimulated and stimulated human skin.
Figure 3 depicts fold-change and p-values of MMP12 levels in skin treated basolaterally with different concentrations of Lu Suoti ni, calcipotriol, and combinations thereof 24 hours after stimulation relative to normal (healthy) unstimulated and stimulated human skin.
FIG. 4 depictsSchematic of the insert.
Fig. 5 depicts photographs of cream formulations #1 to # 6.
Fig. 6A-6B depict absolute fold changes in certain gene expression after treatment with a combination of calcipotriol and ruxotinib (white for <2 absolute fold change, grey for >2 absolute fold change, and black for >4 absolute fold change) after Th1 or Th17 stimulation, respectively, compared to untreated controls.
Figures 7A-7B depict fold changes (mean + SEM) in IL-22 levels and CXCL10 of skin treated basolaterally with different concentrations of Lu Suoti ni, maxacalcitol, and combinations thereof, respectively, 24 hours post-stimulation, relative to normal (healthy) unstimulated and stimulated human skin (JAKi is ruxotinib; vit D is maxacalcitol, and Combo is a combination of Lu Suoti ni and maxacalcitol).
Figures 8A-8C depict fold changes (mean + SEM) of S100a12, defb4 and serpin 4 of skin treated topically with different concentrations of Lu Suoti ni, calcipotriol and combinations thereof 24 hours after stimulation relative to normal (healthy) unstimulated and stimulated human skin, respectively (JAKi is ruxotinib; vit D is calcipotriol; and Combo is a combination of Lu Suoti ni and calcipotriol).
Figures 9A-9C depict fold changes (mean + SEM) of MMP12, IL-22 and CXCL10 (JAKi is ruxotinib; vit D is calcipotriol, and Combo is a combination of Lu Suoti and calcipotriol) of skin treated topically with different concentrations of Lu Suoti, calcipotriol, and combinations thereof, respectively, 24 hours after stimulation, relative to normal (healthy) unstimulated and stimulated human skin.
Fig. 10 depicts changes in ear thickness in IL-23 induced psoriasis-like in vivo mouse models treated with vehicle or a combination cream of ruxotinib and calcipotriol (JAKi is ruxotinib; vit D is calcipotriol, and Combo is Lu Suoti ni and calcipotriol in combination).
Detailed Description
The present disclosure provides a method of treating a dermatological disorder 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.
The present disclosure provides a method of treating a dermatological disorder 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.
The present disclosure also provides a method of treating a dermatological disorder 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.
The present disclosure also provides a method of treating a dermatological disorder 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.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib 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 method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3 or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) Lu Suoti n phosphate and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) Lu Suoti ni phosphate and (b) vitamin D3 or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) Lu Suoti ni phosphate and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) phosphoric acid Lu Suoti and (b) calcipotriol or a pharmaceutically acceptable salt thereof. In some embodiments, the skin disorder is an autoimmune skin disorder.
The present disclosure also provides a method of treating a dermatological disorder 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 disorder is an autoimmune skin disorder.
In some embodiments, the skin disorder is an inflammatory skin disorder.
In some embodiments, the dermatological disorder is associated with Th1 or Th 2. T helper (Th) 1 cells and/or T helper (Th) 17 cells are involved in many inflammatory and autoimmune skin diseases. For example, the following diseases are predominantly Th17 bias: (i) Psoriasis (Fletcher et al, clin Exp Immunol,201 (2): 121-134 (2020), PMID:32379344; liu et al, front Immunol, 11:594535 (2020), PMID: 33281823); (ii) Ichthyosis (Czarnonowicki et al J Invest Dermatol,138 (10): 2157-2167 (2018), PMID:29660300; paller et al J Allergy Clin Immunol,139 (1): 152-165 (2017), PMID: 27554821); and (iii) pityriasis rubra pilaris (Liu, supra, PMID: 33281823). Furthermore, the following diseases are mainly Th 1-biased: (i) Alopecia areataEt al, cent Eur J Immunol,45 (3): 325-333 (2020), PMID:33437185; and (ii) vitiligo (Boniface et al, clin Rev Allergy Immunol,54 (1): 52-67 (2018), PMID: 28685247). Some diseases are associated with both Th1 and Th17, including: (i) Hidradenitis suppurativa (Fletcher, supra, PMID:32379344; liu, supra, PMID:33281823; banerjee et al, immunol Invest,46 (2): 149-158 (2017), PMID:27819528; moran et al, J Invest Dermatol,137 (11): 2389-2395 (2017), PMID: 28652108); and (ii) lichen planus (Aghamajidi et al, scand J Immunol, e13000 (2020), PMID: 33190330). In addition, inflammatory cytokines, such as IL-22 and CXCL10, that are involved in the proliferation, survival and function of Th1 or Th17 lymphocytes are useful in the treatment of Th1 or Th17 related diseases. For example, T helper (Th) 17 cells are unique effector cd4+ T cell lineages characterized by IL-17 production. See Liang et al, J Exp Med,203 (10): 2271-9 (2006), PMID:16982811. Th17 cells have been shown to express IL-22 in much higher amounts than Th1 or Th2 cells. In addition, IL-22 producing cells are dependent on IL-23 for expansion. In turn, blocking IL-17 and IL-23 is a clinically proven method of psoriasis treatment. Examples of such methods for treating psoriasis, a Th 17-associated disease, include secukinumab (seukinumab) and gulkumab (guselkum) ab), which block IL-17 and IL-23, respectively. T helper (Th) 1 cells are unique effector CD4+ T cell lineages characterized by their production of IFN-gamma and T-bet transcriptional markers. See Szabo et al, cell,100 (6): 655-69 (2000), PMID:10761931.CXCL10, also known as Interferon gamma-inducible protein 10 (IP-10), attracts lymphocytes to the skin. Furthermore, CXCR3 is a receptor for CXCL10 ligands. Conversely, diseases such as vitiligo appear to be associated with Th1, as infiltration of lymphocytes into vitiligo skin is thought to be driven by CXCR3 positive Th1 cells in response to CXCL10 ligands.
In some embodiments, the skin disorder is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metalloproteinase 12 (MMP 12), or a combination thereof. In some embodiments, the skin disorder is mediated by IL-22. In some embodiments, the skin disorder is mediated by MMP 12. In some embodiments, the skin disorder is mediated by CXCL 10.
In some embodiments, the dermatological disorder is mediated by Defb4, S100a12, or serpin 4. S100a12 is an important marker of psoriasis disease activity (Wilsmann-Theis, D et al, J Eur Acad Dermatol Venereol,30 (7): 1165-70 (2016); doi:10.1111/jdv.13269, incorporated herein by reference in its entirety). Defb4 encodes human beta-defensin 2 (hBD 2), an antimicrobial peptide, which plays an important role in the inflammatory process of the skin and in the pathogenesis of psoriasis (Johansen C et al, J Invest Derm,136 (8): 1608-1616 (2016); doi:10.1016/j.jid.2016.04.012, which is incorporated herein by reference in its entirety). Serpinb4 causes inflammation in patients with chronic skin disorders, including atopic dermatitis (Sivaprasad, U.S. et al, J Invest Derm 135 (1): 160-169 (2015); DOI:10.1038/jid.2014.353, which is incorporated herein by reference in its entirety).
In some embodiments, the dermatological disorder is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and keratinization disorders.
In some embodiments, the dermatological disorder is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, sjogren's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.
In some embodiments, the skin disorder is psoriasis. In some embodiments, psoriasis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metalloproteinase 12 (MMP 12), or a combination thereof. The relationship between psoriasis and IL-22, CXCL10 and/or MMP12 can be found, for example, at IL-22, CXCL10 and/or MMP12, see He et al, "Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis" J Allergy Clin immunol.2020, 7, 9; s0091-6749 (20) 30824-1, PMID:32709423, which is incorporated herein by reference in its entirety. In some embodiments, psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, psoriasis is mediated by C-X-C motif chemokine 10 (CXCL 10). In some embodiments, psoriasis is mediated by matrix metallopeptidase 12 (MMP 12). In some embodiments, the psoriasis is selected from plaque psoriasis, nail psoriasis, scrubing psoriasis, palmoplantar psoriasis, and pustular psoriasis. In some embodiments, the psoriasis is plaque psoriasis. In some embodiments, plaque psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, plaque psoriasis is mediated by C-X-C motif chemokine 10 (CXCL 10). In some embodiments, plaque psoriasis is mediated by matrix metallopeptidase 12 (MMP 12).
In some embodiments, the dermatological disorder is atopic dermatitis. In some embodiments, atopic dermatitis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metallopeptidase 12 (MMP 12), or a combination thereof. The relationship between atopic dermatitis and IL-22 and/or MMP12 may be found, for example, in He et al, "Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis" J Allergy Clin Immunol.2020, 7/9; s0091-6749 (20) 30824-1, PMID:32709423. The relationship between atopic dermatitis and CXCL10 can be found, for example, in Brunner et al, "Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues" allergy.2017, month 12; 72 (12) found at 2017-2025, PMID: 28599078. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, atopic dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, atopic dermatitis is mediated by the C-X-C motif chemokine 10 (CXCL 10). In some embodiments, the atopic dermatitis is mediated by matrix metal peptidase 12 (MMP 12).
In some embodiments, the skin disorder is alopecia. In some embodiments, the skin condition is alopecia areata. The relationship between alopecia areata and IL-22 can be found, for example, in Loh et al, "rotor of T helper17cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients," J Eur Acad Dermatol Venereol.2018, month 6; 32 (6) 1028-1033. PMID, 29283462. The relationship between alopecia areata and CXCL10 can be found, for example, at PMID 32215911, duca et al, "Frontal fibrosing alopecia shows robust T helper 1and Janus kinase 3skewing"Br J Dermatol.2020, 3-month 25. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, alopecia is mediated by interleukin 22 (IL-22). In some embodiments, baldness is mediated by the C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the skin disorder is vitiligo. The relationship between vitiligo and IL-22 can be found, for example, in Czarnonowicki et al, "Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases" J Allergy Clin immunol.2019, month 6; 143 (6) 2095-2107.PMID: 3057756. The relationship between vitiligo and CXCL10 can be found, for example, in Abdallah et al, "CXCL-10and Interlukin-6are reliable serum markers for vitiligo activity:A multicenter cross-section study" Pigment Cell Melanoma Res.2018, month 3; 31 (2) found at 330-336. PMID:29094481. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, vitiligo is mediated by interleukin 22 (IL-22). In some embodiments, vitiligo is mediated by C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the dermatological disorder is rett syndrome. The relationship between Litty syndrome and IL-22 may be found, for example, in Zhao et al, "IL-22+CD4+T cells in patients with rheumatoid arthritis"Int J Rheum Dis.2013, month 10; 16 (5) 518-26, PMID: 24164838. The relationship between Litty syndrome and CXCL10 can be found, for example, in Pandya et al, "Blood chemokine profile in untreated early rheumatoid Arthritis," CXCL10 as a disease activity marker "Arthritis Res Ther.2017, 2 months and 2 days; 19 (1) 20, PMID:28148302. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, the Leider syndrome is mediated by interleukin 22 (IL-22). In some embodiments, the Leider syndrome is mediated by the C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the skin disorder is pityriasis rubra. The relationship between pityriasis rubra pilaris and IL-22 may be found, for example, in Feldmeyer et al, "Interlukin 23-Helper T Cell 17Axis as a Treatment Target for Pityriasis Rubra Pilaris"JAMA Dermatol.2017, month 4 and 1; 153 (4) found at 304-308, PMID:28122069. The relationship between pityriasis rubra pilaris and CXCL10 may be found, for example, in Adnot-Desanlis et al, "Effectiveness of infliximab in pityriasis rubra pilaris is associated with pro-inflammatory cytokine inhibition" Dermatolog 2013;226 (1) found at 41-6, PMID: 23548788. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, pityriasis rubra pilaris is mediated by interleukin 22 (IL-22). In some embodiments, pityriasis rubra pilaris is mediated by C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the skin disorder is simple epidermolysis bullosa. The relationship between epidermolysis bullosa simplex and IL-22 and/or CXCL10 may be found, for example, in Castela et al, "Epidermolysis bullosa simplex generalized severe induces a T helper 17response and is improved by apremilast treatment"Br J Dermatol.2019, month 2; 180 (2) 357-364, PMID:29932457, which is incorporated herein by reference in its entirety. In some embodiments, simple epidermolysis bullosa is mediated by interleukin 22 (IL-22). In some embodiments, simple epidermolysis bullosa is mediated by the C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the skin disorder is palmoplantar keratosis. The relationship between palmoplantar keratosis and IL-22 can be found, for example, in dreetz et al, "Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid" JAMA dermotol.2019, month 2, 1; 155 (2) found at 216-220, PMID:3048821, which is incorporated herein by reference in its entirety. In some embodiments, palmoplantar keratosis is mediated by interleukin 22 (IL-22).
In some embodiments, the skin disorder is congenital nail thickness. The relationship between congenital nail and IL-22 may be found, for example, in Yang et al, "Keratin 17in disease pathogenesis:from cancer to dermatoses"J Pathol.2019, month 2; 247 (2) found at 158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, the congenital nail is mediated by interleukin 22 (IL-22).
In some embodiments, the skin disorder is multiple sebaceous cysts. The relationship between sebaceous cysts and IL-22 may be found, for example, in Yang et al, "Keratin 17in disease pathogenesis:from cancer to dermatoses"J Pathol.2019, month 2; 247 (2) found at 158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, the sebaceous cyst is mediated by interleukin 22 (IL-22).
In some embodiments, the skin disorder is lichen planus. The relationship between lichen planus and IL-22 can be found, for example, in Chen et al, "Immunoexpression of interleukin-22and interlukin-23in oral and cutaneous lichen planus lesions:a preliminary study"Mediators Inflamm.2013; 2013:80974, PMID:24376306. The relationship between lichen planus and CXCL10 may be found, for example, in dominages 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, 1 month; 172 48-55 PMID:24976336 and Wenzel et al, "CXCR3< - > bond-mediated skin inflammation in cutaneous lichenoid graft-versus-host treatment" J Am Acad Dermatol.2008, month 3; 58 (3) 437-42, PMID:18280341, each of which is incorporated herein by reference in its entirety. In some embodiments, the lichen planus is mediated by interleukin 22 (IL-22). In some embodiments, the lichen planus is mediated by the C-X-C motif chemokine 10 (CXCL 10).
In some embodiments, the skin disorder is cutaneous T cell lymphoma. In some embodiments, cutaneous T cell lymphoma is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metalloproteinase 12 (MMP 12), or a combination thereof. The relationship between cutaneous T cell Lymphoma and IL-22 and/or MMP12 can be found, for example, in Litvinov et al, "The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL)" Clin Cancer Res.2015, 6-15; 21 (12) 2820-9, PMID: 25779945. The relationship between cutaneous T cell lymphoma and CXCL10 can be found, for example, in Mehul et al, "Proteomic analysis of stratum corneumin Cutaneous T-Cell Lymphomas and psoriasis" Exp dermotol.2019, month 3; 28 (3) found at 317-321, PMID:30637808. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, cutaneous T cell lymphoma is mediated by interleukin 22 (IL-22). In some embodiments, cutaneous T cell lymphoma is mediated by C-X-C motif chemokine 10 (CXCL 10). In some embodiments, cutaneous T cell lymphoma is mediated by matrix metallopeptidase 12 (MMP 12).
In some embodiments, the skin disorder is hidradenitis suppurativa. The relationship between hidradenitis suppurativa and IL-22 can be found, for example, in samberger et al, "Transcriptomic analysis of hidradenitis suppurativa skin suggests roles for multiple inflammatory pathways in disease pathogenesis" Inflamm res.2020, month 10; 69 (10) 967-973, PMID:326611800, which is incorporated herein by reference in its entirety. In some embodiments, hidradenitis suppurativa is mediated by interleukin 22 (IL-22).
In some embodiments, the dermatological disorder is contact dermatitis. In some embodiments, contact dermatitis is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metalloproteinase 12 (MMP 12), or a combination thereof. The relationship between contact dermatitis and IL-22 can be found, for example, in Robb et al, "Prostaglandin E2 stimulates adaptive IL-22production and promotes allergic contact dermatitis"J Allergy Clin Immunol.2018, month 1; 141 (1) 152-162, PMID: 28583370. The relationship between Contact dermatitis and CXCL10 can be found, for example, at 21 months 11 in Brans et al, "Stratum corneum levels of inflammatory mediators and natural moisturizing factor in patch test reactions to thiurams and fragrances and their possible role in discrimination between irritant and allergic reactions to hapten mixtures" Contact Dermatis 2020, PMID: 33222241. The relationship between contact dermatitis and MMP12 can be found, for example, in Meguro et al, "SOCS3Expressed in M2 Macrophages Attenuates Contact Hypersensitivity by Suppressing MMP-12Production"J Invest Dermatol.2016, month 3; 136 (3) 649-657, PMID: 27015453. Each reference cited herein is incorporated by reference in its entirety. In some embodiments, contact dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, contact dermatitis is mediated by C-X-C motif chemokine 10 (CXCL 10). In some embodiments, the contact dermatitis is mediated by matrix metal peptidase 12 (MMP 12).
In some embodiments, the dermatological disorder is ichthyosis. The relationship between ichthyosis and IL-22 can be found, for example, in Czarnow 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, month 10; 138 (10) 2157-2167, PMID:29660300, which is incorporated herein by reference in its entirety. In some embodiments, ichthyosis is mediated by interleukin 22 (IL-22). In some embodiments, ichthyosis is ichthyosis vulgaris, X-linked ichthyosis, bullous Congenital Ichthyoid Erythroderma (BCIE), non-bullous congenital ichthyoid erythroderma (NBCIE), lamellar ichthyosis, ugly horn ichthyosis, ichthyosis syndrome, or acquired ichthyosis.
Typically, the keratinization disorder is a group of keratosis disorders. The relationship between keratinization disorders and IL-22 may be found, for example, in Yang et al, "Keratin 17in disease pathogenesis:from cancer to dermatoses"J Pathol.2019, month 2; 247 (2) found at 158-165, PMID:30306595, which is incorporated herein by reference in its entirety. In some embodiments, the keratinization disorder is mediated by IL-22. In some embodiments, the keratinization disorder is selected from ichthyosis, palmoplantar keratosis, follicular keratosis, and acanthosis pinnatifida.
In some embodiments, the skin disorder is rosacea, psoriatic arthritis, dermal fibrosis, scleroderma, stutznevi, dermatomycosis, or acne vulgaris. In some embodiments, the skin disorder is rosacea. In some embodiments, rosacea is mediated by interleukin 22 (IL-22) or C-X-C motif chemokine 10 (CXCL 10) or a combination thereof. The relationship between rosacea and IL-22 and CXCL10 can be found, for example, see Buhl et al, j. Invest. Derm, 135 (9), P2198-2208 (2015), PMID:25848978, which is incorporated herein by reference in its entirety. In some embodiments, rosacea is mediated by interleukin 22 (IL-22). In some embodiments, psoriasis is mediated by C-X-C motif chemokine 10 (CXCL 10). In some embodiments, the skin disorder is psoriasis mediated by S100a 12. In some embodiments, the skin disorder is psoriatic arthritis mediated by S100a 12. In some embodiments, the dermatological disorder is dermal fibrosis mediated by S100a 12. In some embodiments, the skin disorder is a hard spot disorder mediated by S100a 12. In some embodiments, the dermatological disorder is atopic dermatitis mediated by S100a 12. In some embodiments, the skin disorder is a schpiz nevus mediated by S100a 12.
In some embodiments, the skin disorder is psoriasis mediated by Defb 4. In some embodiments, the skin disorder is psoriatic arthritis mediated by Defb 4. In some embodiments, the dermatological disorder is a dermatomycosis mediated by Defb 4. In some embodiments, the skin disorder is acne vulgaris mediated by Defb 4. In some embodiments, the skin disorder is hidradenitis suppurativa mediated by Defb 4.
In some embodiments, the skin disorder is psoriasis mediated by serpin 4. In some embodiments, the skin disorder is psoriatic arthritis mediated by serpin 4.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered sequentially.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered sequentially.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered at least once daily.
In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily.
In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered once daily.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered twice daily.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as separate formulations.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered as a single formulation.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered once daily.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof are administered twice daily.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in a synergistic amount.
In some embodiments, there is a synergy between the JAK inhibitor or a pharmaceutically acceptable salt thereof and vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
The present disclosure provides methods of treating a dermatological disorder 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.
In some embodiments, (b) is vitamin D3 or a pharmaceutically acceptable salt thereof.
In some embodiments, there is provided a method as described herein, wherein (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.
In some embodiments, there is provided a method as described herein, wherein (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
In some embodiments of each of the foregoing, the patient is a human patient.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered once daily.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least twice daily.
In some embodiments, (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof are administered at least twice daily.
In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are each administered in a topical formulation. In some embodiments, each topical formulation is an ointment, cream, or lotion. In some embodiments, the JAK inhibitor or a pharmaceutically acceptable salt thereof and the vitamin D3 analog or a pharmaceutically acceptable salt thereof are in a single formulation. In some embodiments, the single formulation is a cream or lotion. In some embodiments, the formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.
Vitamin D3 and vitamin D3 analogues for use in methods and topical formulations
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (I):
In some embodiments, R 1 Is H or OH. In some embodiments, R 1 Is H. In some embodiments, R 1 Is OH.
In some embodiments, R 2 And R is 3 Each is H. In some embodiments, R 2 Is H. In some embodiments, R 3 Is H. In some embodiments, R 2 And R is 3 Are all H.
In some embodiments, R 2 Is O-R 2A And R is 3 Is H.
In some embodiments, R 2 And R is 3 Together form =ch 2 A group.
In some embodiments, R 2A is-C 1-4 alkylene-OH.
In some embodiments, R 4 And R is 5 Each is H. In some embodiments, R 4 Is H. In some embodiments, R 5 Is H. In some embodiments, R 4 And R is 5 Are all H.
In some embodiments, R 4 And R is 5 Together form =ch 2 A group.
In some embodiments, R 6 And R is 7 Each is H. In some embodiments, R 6 And R is 7 Are all H. In some embodiments, R 6 Is H. In some embodiments, R 7 Is H.
In some embodiments, R 6 And R is 7 Together form =ch 2 A group.
In some embodiments, 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 -. In some embodiments, L is-CH 2 -CH 2 -CH(R 12 ) -. In some embodiments, L is-CH 2 -CH 2 -CH 2 -CH(R 12 ) -. In some embodiments, L is-ch=ch-CH (R 12 ) -. In some embodiments, L is-ch=ch-. In some embodiments, L is-CH 2 -C≡C-. In some embodiments, L is-O-CH 2 -CH 2 -. In some embodiments, L is-O-CH 2 -CH 2 -CH 2 -. In some embodiments, R 12 Is H or OH. In some embodiments, R 12 Is OH. In some embodiments, R 12 Is H.
In some embodiments, R 9 Is C 1-3 Alkyl orC 1-4 A haloalkyl group. In some embodiments, R 9 Is C 1-3 An alkyl group. In some embodiments, R 9 Is C 1-4 A haloalkyl group.
In some embodiments, R 10 Is C 1-3 Alkyl or C 1-4 A haloalkyl group. In some embodiments, R 10 Is C 1-3 An alkyl group. In some embodiments, R 10 Is C 1-4 A haloalkyl group.
In some embodiments, R 11 Is H or OH. In some embodiments, R 11 Is OH. In some embodiments, R 11 Is H.
In some embodiments, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 Cycloalkyl rings. In some embodiments, R 11 Is H.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (II):
in some embodiments, R 1 Is H or OH. In some embodiments, R 1 Is H. In some embodiments, R 1 Is OH.
In some embodiments, R 2 And R is 3 Each is H. In some embodiments, R 2 Is H. In some embodiments, R 3 Is H. In some embodiments, R 2 And R is 3 Are all H.
In some embodiments, R 2 Is O-R 2A And R is 3 Is H.
In some embodiments, R 2 And R is 3 Together form =ch 2 A group.
In some embodiments, R 2A is-C 1-4 alkylene-OH.
In some casesIn embodiments, R 4 And R is 5 Each is H. In some embodiments, R 4 Is H. In some embodiments, R 5 Is H. In some embodiments, R 4 And R is 5 Are all H.
In some embodiments, R 4 And R is 5 Together form =ch 2 A group.
In some embodiments, R 6 And R is 7 Each is H. In some embodiments, R 6 And R is 7 Are all H. In some embodiments, R 6 Is H. In some embodiments, R 7 Is H.
In some embodiments, R 6 And R is 7 Together form =ch 2 A group.
In some embodiments, 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 -. In some embodiments, L is-CH 2 -CH 2 -CH(R 12 ) -. In some embodiments, L is-CH 2 -CH 2 -CH 2 -CH(R 12 ) -. In some embodiments, L is-ch=ch-CH (R 12 ) -. In some embodiments, L is-ch=ch-. In some embodiments, L is-CH 2 -C≡C-. In some embodiments, L is-O-CH 2 -CH 2 -. In some embodiments, L is-O-CH 2 -CH 2 -CH 2 -. In some embodiments, R 12 Is H or OH. In some embodiments, R 12 Is OH. In some embodiments, R 12 Is H.
In some embodiments, R 9 Is C 1-3 Alkyl or C 1-4 A haloalkyl group. In some embodiments, R 9 Is C 1-3 An alkyl group. In some embodiments, R 9 Is C 1-4 A haloalkyl group.
In some embodiments, R 10 Is C 1-3 Alkyl or C 1-4 A haloalkyl group. In some embodiments, R 10 Is C 1-3 An alkyl group. In some embodiments, R 10 Is C 1-4 A haloalkyl group.
In some embodiments, R 11 Is H or OH. In some embodiments, R 11 Is OH. In some embodiments, R 11 Is H.
In some embodiments, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 Cycloalkyl rings. In some embodiments, R 11 Is H.
In some embodiments, (b) is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin 1 a- (OH) D3 analog or a pharmaceutically acceptable salt thereof.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is vitamin 1 a, 25 (OH) 2 D3 analog, vitamin 1 alpha, 24 (OH) 2 D3 analog or vitamin 1 alpha, 26 (OH) 2 D3 analog or a pharmaceutically acceptable salt thereof.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is vitamin 1 a, 25 (OH) 2 D3 analog or a pharmaceutically acceptable salt thereof.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is vitamin 1 a, 24 (OH) 2 D3 analog or a pharmaceutically acceptable salt thereof.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is vitamin 1 a, 26 (OH) 2 D3 analog or a pharmaceutically acceptable salt thereof.
As used herein, "vitamin D3" (calcitol) has the formula of formula (i), numbered as follows. As used herein, "vitamin D derivative" refers to vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol) and structural analogues of formula (i), sharing a scaffold formed of carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20 and 21, wherein the stereochemistry at carbon 20 may be (R) or (S).
In some embodiments, the phrase "vitamin D3 analog" refers to structural analogs of formula (i) sharing a scaffold formed of carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, and 21, wherein the stereochemistry at carbon 20 may be (R) or (S), wherein the compound does not contain a methyl substituent at carbon 24, and wherein the substitution and linkage at carbons 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 20, and 21 remain unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, a double bond at carbon 19 is present. In some embodiments, carbon 1 may have a hydroxyl group alpha to the hydroxyl group at carbon 3.
As used herein, the phrase "vitamin 1 a- (OH) D3 analog" refers to structural analogs of formula (ii) sharing a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, and 21, wherein each dotted line can be a single, double, or triple bond within the appropriate valence limits, 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 unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, a double bond at carbon 19 is present.
As used herein, the phrase "vitamin 1 a, 25- (OH) 2 D3 analog "refers to structural analogs of formula (iii), shared byA 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 bond, double bond, or triple bond within the appropriate valence limit, 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 unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, a double bond at carbon 19 is present.
As used herein, the phrase "vitamin 1 a, 24- (OH) 2 D3 analog "refers to structural analogs of structure (iv) sharing a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, and 24, wherein each dotted line can be a single, double, or triple bond within the appropriate valence limit, 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 unchanged. In some embodiments, the double bond at carbon 19 is absent. In some embodiments, a double bond at carbon 19 is present.
As used herein, the phrase "vitamin 1 a, 26- (OH) 2 D3 analog "refers to structural analogs of structure (v) sharing a scaffold formed by carbons 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, and 26, wherein each dotted line can be a single, double, or triple bond within the appropriate valence limits, 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 unchanged. In some embodiments, the double bond at carbon 19 is not Exists. In some embodiments, a double bond at carbon 19 is present.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a compound having formula (III):
in some embodiments, R 2 And R is 3 Each is H. In some embodiments, R 2 Is H. In some embodiments, R 3 Is H. In some embodiments, R 2 And R is 3 Are all H.
In some embodiments, R 2 Is O-R 2A And R is 3 Is H.
In some embodiments, R 2A is-C 1-4 alkylene-OH.
In some embodiments, R 6 And R is 7 Each is H. In some embodiments, R 6 And R is 7 Are all H. In some embodiments, R 6 Is H. In some embodiments, R 7 Is H.
In some embodiments, R 6 And R is 7 Together form =ch 2 A group.
In some embodiments, L is-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 -. In some embodiments, L is-CH 2 -CH 2 -CH(R 12 ) -. In some embodiments, L is-ch=ch-CH (R 12 ) -. In some embodiments, L is-ch=ch-. In some embodiments, L is-CH 2 -C≡C-. In some embodimentsIn the case, L is-O-CH 2 -CH 2 -. In some embodiments, L is-O-CH 2 -CH 2 -CH 2 -. In some embodiments, R 12 Is H or OH. In some embodiments, R 12 Is OH. In some embodiments, R 12 Is H.
In some embodiments, R 9 Is CH 3 Or CF (CF) 3 . In some embodiments, R 9 Is CH 3 . In some embodiments, R 9 Is CF (CF) 3 。
In some embodiments, R 10 Is CH 3 Or CF (CF) 3 . In some embodiments, R 10 Is CF (CF) 3 . In some embodiments, R 10 Is CH 3 。
In some embodiments, R 11 Is H or OH. In some embodiments, R 11 Is H. In some embodiments, R 11 Is OH.
In some embodiments, R 9 And R is 10 Together with the carbon atoms to which they are attached form a cyclopropyl ring. In some embodiments, R 11 Is H.
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is selected from the group consisting of calcitol, calcitriol, calcipotriol, alfacalcidol, tacalcitol (tacalcitol), maxacalcitol (maxacalcitol), floc-triol (farelectalcitol), idecalcitol (eldecitol), anecalcitol (inecalitol), seocalcitol (seecalitol), leccalcitol (lexicalcitol), 20-table-1 alpha, 25 (OH) 2 D 3 CD578 (17-methyl-19-nor-21-nor-23-alkyne-26, 27-F6-1α,25 (OH) 2 D 3 ) TX527 (19-nor-14, 20-double Table-23-alkyne-1. Alpha., 25 (OH) 2 D 3 ) 2MD (2-methylene-19-nor- (20S) -1α,25 (OH) 2 D 3 ) PRI-2205 ((5E, 7E) -22-en-26, 27-dehydro-1α,25 (OH) 2 D 3 ) ILX23-7553 (16-ene-23-yne-1. Alpha., 25 (OH) 2 D 3 ) And MART-10 (19-nor-2α - (3-hydroxypropyl) -1α,25 (OH) 2 D 3 )。
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is selected from calcitriol, calcipotriol, alfacalcidol, tacalcidol, marshacalcitol, fluocalcitriol, idecalcitol, inecalcitol, seocalcitol, and leccalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is selected from calcipotriol, tacalcitol, maxacalcitol, and seocalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is calcipotriol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is maxacalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is tacalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is pezicalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is calcitonin.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is calcitriol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is alfacalcidol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is fluoxetine.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is idecalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is inecalcitol.
In some embodiments, the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is calcitol.
Formulations of vitamin D3 or vitamin D3 analogues for use in the methods
In some embodiments, vitamin D3 analogs, or pharmaceutically acceptable salts thereof are administered in a topical formulation. In some embodiments, the topical formulation is a foam, ointment, lotion, or cream.
In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0001% to about 0.1% by weight of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0001% to about 0.02% by weight of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0001% to about 0.005% by weight of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0004% to about 0.005% by weight of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on the free base formulation.
In some embodiments, the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is calcipotriol, which is administered as a topical formulation comprising about 50 μg calcipotriol per gram of formulation.
In some embodiments, the topical formulation is a foam, ointment, lotion, or cream. In some embodiments, the topical formulation further comprises betamethasone dipropionate. In some embodiments, betamethasone dipropionate is present in an amount of about 0.5 mg/gram of formulation.
In some embodiments, the vitamin D3 analog is tacalcitol that is administered as a topical formulation comprising about 4 μg tacalcitol per gram of formulation. In some embodiments, the topical formulation is an ointment, cream, or lotion.
In 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/g formulation. In some embodiments, the topical formulation is an ointment.
JAK inhibitors for use in methods and topical formulations
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a compound that inhibits JAK1, JAK2, JAK3, and/or TYK 2. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from the group consisting of a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor, a JAK1/JAK2 inhibitor, a ubiquity JAK inhibitor, a JAK1/TYK2 inhibitor, and a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from Lu Suoti, baratinib (baratinib), olanatinib (oclacetinib), mollotinib (momellotinib), CTP-543, AH057, gan Duo tinib (ganlotinib), phenanthridine Zhuo Tini (feldatinib), letatinib (lesatinib), paxitinib (pacritinib), CHZ868, wu Pati ni (upadacitinib), tofacitinib (tofacitinib), fingolitinib (filocitinib), abatinib (abrocitib), itatinib (itacitinib), cloth Lei Xiti ni (brepatinib), ATI-501, ATI-1777, ATI-502, high-tidtinib (delgolitinib), afatinib (petatinib), sartinib (tofacitinib), BMS (38-38, or pharmaceutically acceptable salts thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, the JAK1 inhibitor is selectiveA JAK1 inhibitor or a pharmaceutically acceptable salt thereof. JAK1 plays a central role in many cytokine and growth factor signaling pathways that when deregulated cause or lead to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, in which it has been shown to have deleterious effects (see, e.g., fonesca et al, autoimmunity Reviews,8:538-42,2009). Because IL-6 signals at least in part through JAK1, IL-6 may indirectly generate potential clinical benefits through JAK1 inhibition (see, e.g., guschin et al Embo J14:1421, 1995; and Smolen et al Lancet 371:987, 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also lead to disease and/or related symptoms. Thus, patients suffering from such diseases may benefit from JAK1 inhibition. Selective inhibitors of JAK1 may be effective while avoiding unnecessary and potentially adverse effects of inhibiting other JAK kinases, as described herein. In some embodiments, JAK1 inhibitors have a selectivity for JAK1 over JAK2 (e.g., have >1 JAK2/JAK1 IC 50 Ratio). In some embodiments, a compound or salt as provided and described herein is about 10-fold selective for JAK1 over JAK 2. In some embodiments, such as by measuring IC at 1mM ATP 50 As calculated, the compounds or salts provided herein are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK1 over JAK2 (see example 1).
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK2 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, the JAK2 inhibitor is a selective JAK2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, such as by measuring IC at 1mM ATP 50 The JAK2 inhibitors were calculated to be about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK2 over JAK1, JAK3, and TYK 2.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK3 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, the JAK3 inhibitor is a selective JAK3 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, such as by measuring IC at 1mM ATP 50 The JAK3 inhibitors were calculated to be about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK3 over JAK1, JAK2, and TYK 2.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a TYK2 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, the TYK2 inhibitor is a selective TYK2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, such as by measuring IC at 1mM ATP 50 The TYK2 inhibitors were calculated to be about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for TYK2 over JAK1, JAK2, and JAK 3.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/JAK2 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, a JAK1/JAK2 inhibitor or pharmaceutically acceptable salt thereof is selective for JAK1 and JAK2 over JAK3 and TYK 2. In some embodiments, a JAK1/JAK2 inhibitor or pharmaceutically acceptable salt thereof is selective for JAK1 and JAK2 over JAK 3. In some embodiments, the compound or salt is about 10-fold selective for JAK1 and JAK2 over JAK 3. In some embodiments, such as by measuring IC at 1mM ATP 50 The compound or salt is calculated to be about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK1 and JAK2 over JAK 3.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a pan JAK inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/TYK2 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, such as by measuring IC at 1mM ATP 50 The calculated value of the sum of the values,JAK1/TYK2 inhibitors are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK1 and TYK2 over JAK2 and JAK 3.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/JAK3 inhibitor or pharmaceutically acceptable salt thereof.
In some embodiments, such as by measuring IC at 1mM ATP 50 The JAK1/JAK3 inhibitors were calculated to be about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK1 and JAK3 over JAK2 and TYK 2.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof. Lu Suoti is a JAK1/JAK2 inhibitor. Lu Suoti Nile IC for JAK1 and JAK2 at 1mM ATP 50 Less than 10nM. Ruxotinib can be prepared by the procedure described in US 7,598,257 (example 67) filed 12/2006, which is incorporated herein by reference in its entirety.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is 1:1 ruxotinib phosphate. Phosphates may be prepared as described in U.S. patent 8,722,693, which is incorporated herein by reference in its entirety.
In some embodiments, the ruxotinib or salt thereof is administered as a topical formulation. In some embodiments, the topical formulation comprises from about 0.05 wt% to about 3.0 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.1 wt% to about 3.0 wt%, from about 0.1 wt% to about 2.0 wt%, from about 0.1 wt% to about 1.5 wt%, from about 0.1 wt% to about 1.0 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.5 wt% to about 2.0 wt%, from about 0.5 wt% to about 1.5 wt% or from about 0.5 wt% to about 1.0 wt% of ruxotinib, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, the topical formulation comprises from about 0.5% to about 1.5% by weight of the formulation based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof. In some embodiments of the present invention, in some embodiments, the topical formulation comprises about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt% >, about 0. about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.65 wt%, about 1.7 wt%, about 1.75 wt%, about 1.8 wt%, about 1.85 wt%, about 1.9 wt%, about 1.95 wt%, about 2.0 wt%, about 2.5 wt% or about 3.0 wt% of ruxotinib, or a pharmaceutically acceptable salt thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced with deuterium atoms. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is any compound of us patent 9,249,149, which is incorporated herein by reference in its entirety, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is CTP-543 (having the structure) or a pharmaceutically acceptable salt thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 13 selected from H and D;
each R 14 Independently selected from H and D, provided that each R attached to a common carbon 14 Are identical;
each R 15 Independently selected from H and D, provided that each R attached to a common carbon 15 Are identical;
R 16 selected from H and D;
each R 17 Identical and selected from H and D; and is also provided with
R 18 、R 19 And R is 20 Each independently selected from H and D; provided that when R 13 Is H, each R 14 And each R 15 Is H, R 16 Is H, and R 18 、R 19 And R is 20 Each H, then each R 17 Is D.
CTP-543 is a compound of formula IV which is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a compound of formula IV selected from the following compounds 100-130 in the following table (wherein R 18 、R 19 And R is 20 Each is H) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is a compound of formula IV selected from the following compounds 200-231 in the table below (wherein R 18 、R 19 And R is 20 Each is D) or a pharmaceutically acceptable salt thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is baratinib or a pharmaceutically acceptable salt thereof. Baritinib is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is baratinib or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced with deuterium atoms. In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is any compound of us patent 9,540,367 (which is incorporated herein by reference in its entirety) or a pharmaceutically acceptable salt thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is olatinib or a pharmaceutically acceptable salt thereof. Olatinib is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is molatinib or a pharmaceutically acceptable salt thereof. Molotinib is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is AH057 or a pharmaceutically acceptable salt thereof. AH057 is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is glytinib or a pharmaceutically acceptable salt thereof. Gan Duo tinib is a JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is trepontinib or a pharmaceutically acceptable salt thereof. Phenanthrene Zhuo Tini is a JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is letatinib or a pharmaceutically acceptable salt thereof. Letatinib is a JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is pecetinib or a pharmaceutically acceptable salt thereof. Parcritinib is a JAK2 inhibitor that also inhibits fms-like tyrosine kinase 3 (FLT 3).
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is CHZ868 or a pharmaceutically acceptable salt thereof. CHZ868 is a JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is lapatinib or a pharmaceutically acceptable salt thereof. Wu Pati is a JAK1 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is regorafenib or a pharmaceutically acceptable salt thereof. Non-golitinib is a JAK1 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is albuxinib or a pharmaceutically acceptable salt thereof. Albumitinib is a JAK1 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is itratinib or a pharmaceutically acceptable salt thereof. Itatinib is a JAK1 inhibitor.
In some embodiments, the JAK inhibitor or 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 TYK 2). The IC obtained by the method of example 1 at 1mM ATP is shown in Table 1 50 Values.
Table 1.
+ means <10nM (assay conditions see example 1)
++ means +.ltoreq.100 nM (assay conditions see example 1)
++ meaning the finger is less than or equal to 300nM (assay) conditions see example 1)
a Data for enantiomer 1
b Data for enantiomer 2
In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is {1- {1- [ 3-fluoro-2- (trifluoromethyl) isonicotinyl ] 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 pharmaceutically acceptable salt thereof is a JAK1 inhibitor that 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 adipate. 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 its adipate salts can be found, for example, in U.S. patent publication Nos. 2011/0224190, 2013/0060026, and 2014/0256941, each of which is incorporated herein by reference in its entirety.
In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is a JAK1 inhibitor that is 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is a JAK1 inhibitor that is 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide phosphate. In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide hydrochloride. In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide hydrobromide. In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide sulfate. The synthesis and preparation of 4- [3- (cyanomethyl) -3- (3 ',5' -dimethyl-1 h,1'h-4,4' -bipyrazol-1-yl) azetidin-1-yl ] -2, 5-difluoro-N- [ (1S) -2, 2-trifluoro-1-methylethyl ] benzamide and its phosphate salts can be found in, for example, U.S. patent publication No. US2014/0343030 filed on 5/16 of 2014, which is incorporated herein by reference in its entirety.
In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is ((2R, 5 s) -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.
In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is ((2R, 5 s) -5- {2- [ (1R) -1-hydroxyethyl ] -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-1-yl } tetrahydro-2H-pyran-2-yl) acetonitrile monohydrate or a pharmaceutically acceptable salt thereof. The synthesis of (((2R, 5S) -5- {2- [ (1R) -1-hydroxyethyl ] -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-1-yl } tetrahydro-2H-pyran-2-yl) acetonitrile and characterization of its anhydrous and monohydrate forms are described in U.S. patent publication Nos. 2014/012398 and 2015/0344497, filed on 10/31 and 29, 2015, each of which is incorporated herein by reference in its entirety.
In some embodiments, the compounds of table 1 are prepared by synthetic procedures described in the following patents: U.S. patent publication No. 2011/0224190 submitted at 3/9 in 2011, U.S. patent publication No. 2014/0343030 submitted at 5/16 in 2014, U.S. patent publication No. 2014/01231198 submitted at 31 in 10 in 2013, U.S. patent publication No. 2010/0298334 submitted at 21 in 2010, U.S. patent publication No. 2011/0059951 submitted at 31 in 8 in 2010, U.S. patent publication No. 2012/0149681 submitted at 18 in 2011, U.S. patent publication No. 2012/0149682 submitted at 18 in 2011, U.S. patent publication No. 2013/0018034 submitted at 19 in 2012, U.S. patent publication No. 2013/0045963 submitted at 17 in 8 in 2012, and U.S. patent No. 2014/0005166 submitted at 17 in 5 in 2013, each of which are incorporated herein by reference in their entirety.
In some embodiments, the JAK1 inhibitor or pharmaceutically acceptable salt thereof is selected from the compounds of the following patents or pharmaceutically acceptable salts thereof: U.S. patent publication No. 2011/0224190 submitted at 3/9 in 2011, U.S. patent publication No. 2014/0343030 submitted at 5/16 in 2014, U.S. patent publication No. 2014/01231198 submitted at 31 in 10 in 2013, U.S. patent publication No. 2010/0298334 submitted at 21 in 2010, U.S. patent publication No. 2011/0059951 submitted at 31 in 8 in 2010, U.S. patent publication No. 2012/0149681 submitted at 18 in 2011, U.S. patent publication No. 2012/0149682 submitted at 18 in 2011, U.S. patent publication No. 2013/0018034 submitted at 19 in 2012, U.S. patent publication No. 2013/0045963 submitted at 17 in 8 in 2012, and U.S. patent No. 2014/0005166 submitted at 17 in 5 in 2013, each of which are incorporated herein by reference in their entirety.
In some embodiments, the JAK inhibitor is bunt Lei Xiti or a pharmaceutically acceptable salt thereof. Cloth Lei Xiti is a JAK1/JAK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ATI-501 or a pharmaceutically acceptable salt thereof. ATI-501 (Aclaris) is a JAK1/JAK3 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ATI-1777 or a pharmaceutically acceptable salt thereof. ATI-1777 (Aclaris) is a JAK1/JAK3 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ATI-502 or a pharmaceutically acceptable salt thereof. ATI-502 (Aclaris) is a JAK1/JAK3 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is tofacitinib or a pharmaceutically acceptable salt thereof. Tofacitinib inhibits JAK1 and JAK3.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is diltiazem or a pharmaceutically acceptable salt thereof. Dipitinib is a floodjak inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is pefetinib or a pharmaceutically acceptable salt thereof. Pefetinib is a pan JAK inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is dasatinib or a pharmaceutically acceptable salt thereof. Gusatinib is a floodjak inhibitor and also inhibits SYK.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is cucurbitacin I or a pharmaceutically acceptable salt thereof. Cucurbitacin I is a JAK inhibitor that also inhibits STAT3.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is ceritinib or a pharmaceutically acceptable salt thereof. Ceritinib is a floodjak inhibitor, also inhibiting spleen tyrosine kinase (SYK).
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is dixetine or a pharmaceutically acceptable salt thereof. Decetinib is a JAK3 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is BMS-986165 having the structure:
or a pharmaceutically acceptable salt thereof. BMS-986165 is a TYK2 inhibitor.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is Li Texi tinib or a pharmaceutically acceptable salt thereof. Li Texi Tinib (Pfizer) is a JAK3 inhibitor that also inhibits TEC.
In some embodiments, there is provided a method as described herein, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from the group consisting of Lu Suoti ni, olatinib, baritinib, molatinib, and CTP-543 or pharmaceutically acceptable salts thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from Lu Suoti, olatinib, baritinib, molotinib, CTP-543, gan Duo, phenanthrene Zhuo Tini, letatinib, panatinib, wu Pati, tofacitinib, fingolitinib, abxitinib, itatinib, bu Lei Xiti, ATI-501, ATI-1777, ATI-502, digatinib, pefacitinib, archarotitinib, cucurbitacin I, and ceritinib, or pharmaceutically acceptable salts thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from Lu Suoti, olatinib, baritinib, molotinib, CTP-543, gan Duo, phenanthrene Zhuo Tini, letatinib, panatinib, wu Pati, tofacitinib, fingolitinib, abxitinib, itatinib, bu Lei Xiti, dygatitinib, pefetinib, gulatinib, cucurbitacin I, and ceritinib or pharmaceutically acceptable salts thereof.
In some embodiments, the JAK inhibitor or pharmaceutically acceptable salt thereof may be an isotopically labeled compound or pharmaceutically acceptable salt thereof. An "isotopically-labeled" or "radiolabeled" compound is a compound in which 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 usually found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present disclosure include, but are not limited to 2 H (D for deuterium), 3 H (also written as T for tritium), 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 18 F、 35 S、 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I、 124 I、 125 I and 131 I. for example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced with deuterium atoms, such as-CD 3 substituted-CH 3 。
Thus, in some embodiments, a JAK inhibitor or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the compound are replaced with deuterium atoms.
In some embodiments, there is provided a method as described herein, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is combined with any of the JAK inhibitors or pharmaceutically acceptable salts thereof as described herein.
In some embodiments, there is provided a method as described herein, wherein (a) a JAK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.
In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, is administered as a topical formulation. In some embodiments, the topical formulation comprises from about 0.1 wt% to about 3.0 wt%, from about 0.1 wt% to about 2.0 wt%, from about 0.1 wt% to about 1.5 wt%, from about 0.1 wt% to about 1.0 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.5 wt% to about 2.0 wt%, from about 0.5 wt% to about 1.5 wt% or from about 0.5 wt% to about 1.0 wt% of a JAK inhibitor, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, the topical formulation comprises from about 0.5% to about 1.5% by weight of the JAK inhibitor, or a pharmaceutically acceptable salt thereof, based on the free base formulation. In some embodiments, the topical formulation comprises about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.7 wt%, about 1.95 wt%, about 1.5 wt%, or about 1.5 wt%, or about 2.95 wt%, of a pharmaceutically acceptable salt of the free base formulation.
Ruxotinib cream formula
In some embodiments, the ruxotinib, or a pharmaceutically acceptable salt thereof, is administered as a cream formulation comprising ruxotinib, or a pharmaceutically acceptable salt thereof.
In some embodiments, the ruxotinib, or pharmaceutically acceptable salt thereof, is administered as a cream formulation comprising ruxotinib phosphate.
In some embodiments, the ruxotinib, or pharmaceutically acceptable salt thereof, is in the form of a cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion. In some embodiments, the cream formulation is described in U.S. patent 10,758,543, which is incorporated by reference in its entirety. In particular, examples 3-6 of U.S. patent 10,758,543 (and tables 3-5 and accompanying text in particular) are incorporated herein by reference. In some embodiments of the present invention, in some embodiments, the cream comprises from about 0.1 wt% to about 3.0 wt%, from about 0.1 wt% to about 3.2 wt%, from about 0.1 wt% to about 1.5 wt%, from about 0.1 wt% to about 1.0 wt%, from about 0.1 wt% to about 1.5 wt%, from about 0.5 wt% to about 2.0 wt%, from about 0.5 wt% to about 1.5 wt%, from about 0.5 wt% to about 1.4 wt%, from about 0.5 wt% to about 1.3 wt%, from about 0.5 wt% to about 1.2 wt% to about 1.1 wt%, from about 0.5 wt% to about 1.1 wt%, from about 0.6 wt% to about 1.2 wt% from about 0.1.1.1.1 wt% to about 1.1 wt% from about 0.1.1 wt% to about 1.1 wt% of the free-base emulsion, from about 0.0.5 wt% to about 1.1 wt% to about 1.0 wt% to about 1.1 wt%, from about 0.0.0.5 wt% to about 1 wt% to about 1.4 wt% from about 1.0 wt% to about 1.0 wt% from about 0.0 wt% to about 1.0 wt% from about 1.0 wt% to about 1.0 wt% from about 0.0 wt% to about 1 wt% to about 1.3 wt% from about 0.0 wt% to about 0.3 wt% to about 0 wt% from about 0.3 wt% to about 0.3 wt, from about 1.0% to about 1.1% by weight or from about 0.5% to about 1.0% by weight of ruxotinib or a 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 ruxotinib, or pharmaceutically acceptable salt thereof, based on the free base emulsion. In some embodiments, the oil-in-water emulsion comprises about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.7 wt%, about 1.75 wt%, or about 1.85 wt%, or about 1.95 wt%, of the pharmaceutically acceptable salt based on the free base emulsion. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
In some embodiments, the cream formulation has a pH of about 6.5 to about 7.0.
In some embodiments, the cream formulation has a pH of about 2.8 to about 3.9.
In some embodiments, the cream formulation has a pH of about 2.8 to about 3.6.
In some embodiments, the cream comprises an oil-in-water emulsion comprising ruxotinib.
In some embodiments, the cream comprises an oil-in-water emulsion comprising ruxotinib phosphate. In some embodiments, the cream is an oil-in-water emulsion as described in US2015/0250790, which is incorporated herein by reference in its entirety. In particular, examples 3-6 of US2015/0250790 (and in particular tables 3-5 and accompanying text) are incorporated herein by reference.
In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.
In some embodiments, the oil component is present in an amount of about 10% to about 24% by weight of the emulsion.
In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the emulsion.
In some embodiments, the oil component is present in an amount of about 18% to about 24% by weight of the emulsion.
In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of: petrolatum, fatty alcohols, mineral oil, triglycerides and silicone oil.
In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of: white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and polydimethylsiloxane.
In some embodiments, the oil component comprises a sealant component.
In some embodiments, the blocking agent component is present in an amount of about 2% to about 15% by weight of the emulsion.
In some embodiments, the sealer component is present in an amount of about 5% to about 10% by weight of the emulsion.
In some embodiments, the sealant component comprises one or more materials selected from the group consisting of: fatty acids (e.g., lanolin acids), fatty alcohols (e.g., lanolin alcohols), hydrocarbon oils and waxes (e.g., petrolatum), polyols (e.g., propylene glycol), polysiloxanes (e.g., polydimethylsiloxane), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).
In some embodiments, the sealant component comprises one or more materials selected from the group consisting of: lanolin fatty alcohol, lanolin alcohol, vaseline, propylene glycol, polydimethylsiloxane, cholesterol, cocoa butter, carnauba wax and beeswax.
In some embodiments, the sealant component comprises petrolatum.
In some embodiments, the sealant component comprises white petrolatum.
In some embodiments, white petrolatum is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the white petrolatum is present in an amount of about 7% by weight of the emulsion.
In some embodiments, the oil component comprises a hardener component.
In some embodiments, the hardener component is present in an amount of about 2 to about 8 weight percent of the emulsion.
In some embodiments, the hardener component is present in an amount of about 3 to about 6 weight percent of the emulsion.
In some embodiments, the hardener component is present in an amount of about 4 to about 7 weight percent of the emulsion.
In some embodiments, the hardener component comprises one or more substances independently selected from fatty alcohols.
In some embodiments, the hardener component comprises one or more components independently selected from C 12-20 Fatty alcohol.
In some embodiments, the hardener component comprises one or more components independently selected from C 16-18 Fatty alcohol.
In some embodiments, the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
In some embodiments, cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the amount of cetyl alcohol is about 3% by weight of the emulsion.
In some embodiments, stearyl alcohol is present in an amount from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, stearyl alcohol is present in an amount of about 1.75 weight percent of the emulsion.
In some embodiments, the hardener component comprises one or more of the following independently selected from: cetyl alcohol, stearyl alcohol, oleyl alcohol, and cetostearyl alcohol.
In some embodiments, cetostearyl alcohol is present in an amount from about 0.1% to about 30% by weight of the emulsion.
In some embodiments, cetostearyl alcohol is present in an amount from about 1% to about 20% by weight of the emulsion.
In some embodiments, the oil component comprises an emollient component.
In some embodiments, the emollient component is present in an amount of about 5% to about 15% by weight of the emulsion.
In some embodiments, the emollient component is present in an amount of about 7% to about 13% by weight of the emulsion.
In some embodiments, the emollient component comprises one or more materials independently selected from mineral oil and triglycerides.
In some embodiments, the emollient component comprises one or more materials independently selected from light mineral oil and medium chain triglycerides.
In some embodiments, the light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the light mineral oil is present in an amount of about 4% by weight of the emulsion.
In some embodiments, the emollient component comprises one or more materials independently selected from the group consisting of light mineral oil, medium chain triglycerides, and dimethicone.
In some embodiments, the polydimethylsiloxane is present in an amount from about 0.1 wt% to about 15 wt% of the emulsion.
In some embodiments, the polydimethylsiloxane is present in an amount of about 1% by weight of the emulsion.
In some embodiments, the amount of medium chain triglycerides is from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the amount of medium chain triglycerides is about 7.0% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 35% to about 65% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 40% to about 60% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 45% to about 55% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the emulsion.
In some embodiments, the emulsion comprises an emulsifier component and a hardener component, wherein the combined amount of the emulsifier component and the hardener component is at least about 8 weight percent of the emulsion.
In some embodiments, the emulsifier component comprises one or more materials independently selected from glycerol fatty acid esters and sorbitan fatty acid esters.
In 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 from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the glyceryl stearate is present in an amount of about 3% by weight of the emulsion.
In some embodiments, polysorbate 20 is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.
In some embodiments, the emulsifier component comprises a nonionic surfactant.
In some embodiments, the nonionic surfactant is docetaxel 1000 or poloxamer 407.
In some embodiments, the docetaxel 1000 is present in an amount of about 0.01% to about 15% by weight of the emulsion.
In some embodiments, the docetaxel 1000 is present in an amount of about 0.1% to about 10% by weight of the emulsion.
In some embodiments, the poloxamer is poloxamer 407.
In some embodiments, poloxamer 407 is present in an amount of about 0.01% to about 15% by weight of the emulsion.
In some embodiments, the emulsifier component further comprises glyceryl stearate and PEG-100 stearate, such as Arlacel TM 165。
In some embodiments, the glyceryl stearate and PEG-100 stearate are present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the emulsion further comprises a stabilizer component.
In some embodiments, the stabilizer component is present in an amount of about 0.05 wt% to about 5 wt% of the emulsion.
In some embodiments, the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the emulsion.
In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.
In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.
In some embodiments, the stabilizer component comprises xanthan gum.
In some embodiments, the xanthan gum is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, the xanthan gum is present in an amount of about 0.2% to about 0.6% by weight of the emulsion.
In some embodiments, the xanthan gum is present in an amount of about 0.4% by weight of the emulsion.
In some embodiments, the emulsion further comprises a solvent component.
In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the emulsion.
In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the emulsion.
In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the emulsion.
In some embodiments, the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols.
In some embodiments, the solvent component comprises one or more materials independently selected from propylene glycol and polyethylene glycol.
In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, propylene glycol.
In some embodiments, the solvent component comprises PEG300 and propylene glycol.
In some embodiments, PEG300 is present in an amount of about 7 wt% w/w of the emulsion.
In some embodiments, the solvent is a combination of PEG400 and propylene glycol.
In some embodiments, PEG400 is present in an amount of about 7% by weight of the emulsion.
In some embodiments, propylene glycol is present in an amount of about 6.5% by weight of the emulsion. In some embodiments, the solvent component comprises diethylene glycol monoethyl ether, such asP. In some embodiments, diethylene glycol monoethyl ether is present in an amount of from about 0.1% to about 30% w/w of the emulsion. In some embodiments, diethylene glycol monoethyl ether is present in an amount of from about 0.1% to about 20% w/w of the emulsion.
In some embodiments, the emulsion further comprises:
about 35% to about 65% by weight of the emulsion of water;
about 10% to about 40% by weight of the emulsion of an oil component;
About 1% to about 9% by weight of the emulsion of an emulsifier component;
about 10% to about 35% by weight of the emulsion of a solvent component; and
from about 0.05% to about 5% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 35% to about 65% by weight of the emulsion of water;
about 10% to about 40% by weight of the emulsion of an oil component;
about 1% to about 9% by weight of the emulsion of an emulsifier component;
about 10% to about 35% by weight of the emulsion of a solvent component;
about 0.05% to about 5% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 35% to about 65% by weight of the emulsion of water;
about 10% to about 24% by weight of the emulsion of an oil component;
about 1% to about 9% by weight of the emulsion of an emulsifier component;
about 10% to about 35% by weight of the emulsion of a solvent component; and
from about 0.05% to about 5% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 35% to about 65% by weight of the emulsion of water;
About 10% to about 24% by weight of the emulsion of an oil component;
about 1% to about 9% by weight of the emulsion of an emulsifier component;
about 10% to about 35% by weight of the emulsion of a solvent component;
about 0.05% to about 5% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 40% to about 60% by weight of the emulsion of water;
about 15% to about 30% by weight of the emulsion of an oil component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 15% to about 30% by weight of the emulsion of a solvent component; and
about 0.1% to about 2% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 40% to about 60% by weight of the emulsion of water;
about 15% to about 30% by weight of the emulsion of an oil component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 15% to about 30% by weight of the emulsion of a solvent component;
about 0.1% to about 2% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 40% to about 60% by weight of the emulsion of water;
about 15% to about 30% by weight of the emulsion of an oil component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 15% to about 24% by weight of the emulsion of a solvent component; and
about 0.1% to about 2% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 40% to about 60% by weight of the emulsion of water;
about 15% to about 30% by weight of the emulsion of an oil component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 15% to about 24% by weight of the emulsion of a solvent component;
about 0.1% to about 2% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 45% to about 55% by weight of the emulsion of water;
about 15% to about 24% by weight of the emulsion of an oil component;
about 3% to about 5% by weight of the emulsion of an emulsifier component; about 20% to about 25% by weight of the emulsion of a solvent component; and
From about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 45% to about 55% by weight of the emulsion of water;
about 15% to about 24% by weight of the emulsion of an oil component;
about 3% to about 5% by weight of the emulsion of an emulsifier component; about 20% to about 25% by weight of the emulsion of a solvent component;
about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 45% to about 55% by weight of the emulsion of water;
about 15% to about 24% by weight of the emulsion of an oil component;
about 4% to about 7% by weight of the emulsion of an emulsifier component; about 20% to about 25% by weight of the emulsion of a solvent component; and
from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component.
In some embodiments, the emulsion comprises:
about 45% to about 55% by weight of the emulsion of water;
about 15% to about 24% by weight of the emulsion of an oil component;
about 4% to about 7% by weight of the emulsion of an emulsifier component; about 20% to about 25% by weight of the emulsion of a solvent component;
About 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments:
the oil component comprises one or more substances independently selected from the group consisting of: petrolatum, fatty alcohols, mineral oil, triglycerides and dimethicone;
the emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and sorbitan fatty acid esters;
the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols; and is also provided with
The stabilizer component comprises one or more substances independently selected from polysaccharides.
In some embodiments:
the oil component comprises one or more substances independently selected from the group consisting of: white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and polydimethylsiloxane;
the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
the solvent component comprises one or more materials independently selected from propylene glycol and polyethylene glycol; and is also provided with
The stabilizer component comprises xanthan gum.
In some embodiments, the emulsion further comprises:
about 35% to about 65% by weight of the emulsion of water;
from about 2% to about 15% by weight of the emulsion of a blocking agent component;
about 2% to about 8% by weight of the emulsion of a hardener component;
about 5% to about 15% by weight of the emulsion of an emollient component;
about 1% to about 9% by weight of the emulsion of an emulsifier component; and
from about 0.05% to about 5% by weight of the emulsion of a stabilizer component.
About 10% to about 35% by weight of the emulsion of a solvent component; in some embodiments, the emulsion comprises:
about 35% to about 65% by weight of the emulsion of water;
from about 2% to about 15% by weight of the emulsion of a blocking agent component;
about 2% to about 8% by weight of the emulsion of a hardener component;
about 5% to about 15% by weight of the emulsion of an emollient component;
about 1% to about 9% by weight of the emulsion of an emulsifier component;
about 0.05% to about 5% by weight of the emulsion of a stabilizer component;
about 10% to about 35% by weight of the emulsion of a solvent component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
about 40% to about 60% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 2% to about 8% by weight of the emulsion of a hardener component;
about 7% to about 12% by weight of the emulsion of an emollient component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 0.1% to about 2% by weight of the emulsion of a stabilizer; and
about 15% to about 30% by weight of the emulsion.
In some embodiments, the emulsion comprises:
about 40% to about 60% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 2% to about 8% by weight of the emulsion of a hardener component;
about 7% to about 12% by weight of the emulsion of an emollient component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 0.1% to about 2% by weight of the emulsion of a stabilizer;
about 15% to about 30% by weight of the emulsion of a solvent component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
About 45% to about 55% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 3% to about 6% by weight of the emulsion of a hardener component;
about 7% to about 13% by weight of the emulsion of an emollient component;
about 3% to about 5% by weight of the emulsion of an emulsifier component;
about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and
about 20% to about 25% by weight of the emulsion of a solvent component.
In some embodiments, the emulsion comprises:
about 45% to about 55% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 3% to about 6% by weight of the emulsion of a hardener component;
about 7% to about 13% by weight of the emulsion of an emollient component;
about 3% to about 5% by weight of the emulsion of an emulsifier component;
about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component;
about 20% to about 25% by weight of the emulsion of a solvent component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
About 45% to about 55% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 4% to about 7% by weight of the emulsion of a hardener component;
about 7% to about 13% by weight of the emulsion of an emollient component;
about 4% to about 7% by weight of the emulsion of an emulsifier component;
about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and
about 20% to about 25% by weight of the emulsion of a solvent component.
In some embodiments, the emulsion comprises:
about 45% to about 55% by weight of the emulsion of water;
from about 5% to about 10% by weight of the emulsion of a blocking agent component;
about 4% to about 7% by weight of the emulsion of a hardener component;
about 7% to about 13% by weight of the emulsion of an emollient component;
about 4% to about 7% by weight of the emulsion of an emulsifier component;
about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component;
about 20% to about 25% by weight of the emulsion of a solvent component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion further comprises:
About 45% to about 55% by weight of the emulsion of water;
about 7% by weight of the emulsion of a sealer component;
about 4.5% to about 5% by weight of the emulsion of a hardener component;
about 10% by weight of the emulsion of an emollient component;
about 4% to about 4.5% by weight of the emulsion of an emulsifier component;
about 0.4% by weight of the emulsion of a stabilizer component; and
about 22% by weight of the emulsion of solvent component.
In some embodiments, the emulsion comprises:
about 45% to about 55% by weight of the emulsion of water;
about 7% by weight of the emulsion of a sealer component;
about 4.5% to about 5% by weight of the emulsion of a hardener component;
about 10% by weight of the emulsion of an emollient component;
about 4% to about 4.5% by weight of the emulsion of an emulsifier component;
about 0.4% by weight of the emulsion of a stabilizer component;
about 22% by weight of the emulsion of a solvent component; and
from 0.5% to 1.5% by weight of the emulsion based on the free base of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the ruxotinib, or pharmaceutically acceptable salt thereof, is present as phosphoric acid Lu Suoti ni.
In some embodiments, the emulsion comprises 1.5% by weight of the emulsion of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion comprises 1.5% ruxotinib phosphate by weight of the emulsion.
In some embodiments, the emulsion comprises 1.1% by weight of the emulsion of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion comprises 1.1% by weight of the emulsion of ruxotinib phosphate.
In some embodiments, the emulsion comprises 0.75% by weight of the emulsion of ruxotinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the emulsion comprises 0.75% ruxotinib phosphate by weight of the emulsion.
In some embodiments, the combined amount of hardener component and emulsifier component is at least about 8 weight percent of the emulsion.
In some embodiments:
the sealant component comprises petrolatum;
the hardener component comprises one or more substances independently selected from one or more fatty alcohols;
the emollient component comprises one or more materials independently selected from mineral oil and triglycerides;
the emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and sorbitan fatty acid esters;
the stabilizer component comprises one or more substances independently selected from polysaccharides; and is also provided with
The solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols.
In some embodiments:
the sealant component comprises white petrolatum;
the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;
the emollient component comprises one or more materials independently selected from the group consisting of light mineral oil, medium chain triglycerides, and polydimethylsiloxane;
the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
the stabilizer component comprises xanthan gum; and is also provided with
The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
In some embodiments, the emulsion further comprises an antimicrobial preservative component.
In some embodiments, the antimicrobial preservative component is present in an amount from about 0.05% to about 3% by weight of the emulsion.
In some embodiments, the antimicrobial preservative component is present in an amount from about 0.1% to about 1% by weight of the emulsion.
In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.
In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.
In some embodiments, the antimicrobial preservative component comprises methylparaben and propylparaben.
In some embodiments, the methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, the methylparaben is present in an amount of about 0.1% by weight of the emulsion.
In some embodiments, propyl parahydroxybenzoate is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, propyl parahydroxybenzoate is present in an amount of about 0.05% by weight of the emulsion.
In some embodiments, phenoxyethanol is present in an amount from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.
In some embodiments, phenoxyethanol is present in an amount from about 0.1% to about 10% by weight of the emulsion.
In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, or about 7.0.
In some embodiments, the pH of the cream is adjusted to about 4.0, about 5.5, about 6.5, or about 7.0.
In some embodiments, the pH of the cream is adjusted to a range of about 6.5 to about 7.0.
In some embodiments, the pH of the cream is adjusted with triethanolamine and/or phosphoric acid. In some embodiments, the pH of the cream is adjusted with triethanolamine. In some embodiments, the pH of the cream is adjusted with phosphoric acid. In some embodiments, the pH of the cream is adjusted with triethanolamine and phosphoric acid.
In some embodiments, the emulsion further comprises an antioxidant.
In some embodiments, the antioxidant is Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), or tocopherol, or a combination thereof.
In some embodiments, the emulsion further comprises a chelating agent component.
In some embodiments, the chelator component comprises disodium ethylenediamine tetraacetate.
In some embodiments, disodium edetate is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, disodium edetate is present in an amount of about 0.001% to about 1% by weight of the emulsion.
In some embodiments, the emulsion further comprises a calcipotriol stabilizer.
In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, or citric acid, or a combination thereof.
In some embodiments, the emulsion further comprises a humectant.
In some embodiments, the humectant is glycerin.
In some embodiments, the glycerol is present in an amount of about 0.01% to about 20% by weight of the emulsion.
In some embodiments, the glycerol is present in an amount of about 0.1% to about 20% by weight of the emulsion.
In some embodiments, the emulsion further comprises a surfactant.
In some embodiments, the surfactant is polysorbate 80. In some embodiments, polysorbate 80 is present in an amount of about 0.01% to about 15% by weight of the emulsion. In some embodiments, polysorbate 80 is present in an amount of about 0.1% to about 15% by weight of the emulsion.
Ruxotinib can be prepared as described in U.S. patent 7,598,257 and U.S. patent publication No. 2009/0181959, each of which is incorporated herein by reference in its entirety. The 1:1 phosphate salt of ruxotinib can be prepared as described in U.S. patent No. 2008/0312259, which is incorporated herein by reference in its entirety.
It is understood that some components of the creams (emulsions) described herein may have a variety of functions. For example, a given substance may act as both an emulsifier component and a stabilizer. In some such cases, the function of a given component may be considered singular, even though its characteristics may allow for multiple functions. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.
Pharmaceutical preparation (fixed dose combination)
The pharmaceutical formulations provided and described herein may be used in the methods described in the present disclosure.
The concentrations of JAK inhibitors, vitamin D3 or vitamin D3 analogs, or pharmaceutically acceptable salts of any of the foregoing described above may also be used in fixed dose combination formulations as described below. As used herein, "pharmaceutical formulation for topical treatment of skin disorders" and "topical formulation" are used interchangeably.
The present disclosure further provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.
The present disclosure further provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib phosphate or a pharmaceutically acceptable salt thereof and (b) a vitamin D derivative or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a pharmaceutical formulation for topical treatment of a dermatological disorder comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof.
The present disclosure further provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof. In some embodiments of the present invention, in some embodiments, ruxotinib, or a pharmaceutically acceptable salt thereof, is formulated in an amount of about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.65 wt%, about 1.7 wt%, about 1.75 wt%, about 1.8 wt%, about 1.85 wt%, about 1.9 wt%, about 1.95 wt%, about 2.0 wt%, about 2.5 wt%, or about 3.0 wt% is present.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) ruxotinib 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 skin disorders comprising (a) from about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) from about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base 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, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL to about 50 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL to about 50 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL to about 50 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 10 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 50 μg/mL of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate. The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.0001% w/w to about 0.01% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) from about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base 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, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of vitamin D3, vitamin D3 analog or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of vitamin D3, vitamin D3 analog or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of vitamin D3, vitamin D3 analog or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The formulation described in the preceding paragraph, wherein the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof is a vitamin D3 analog or pharmaceutically acceptable salt thereof. In some embodiments, the vitamin D3 analog or pharmaceutically acceptable salt thereof is selected from the group consisting of calcitol, calcitriol, calcipotriol, alfacalcidol, tacalcidol, maxacalcitol, floc-triol, idecalcitol, inecalcitol, seocalcitol, leccalcitol, 20-epi-1 a, 25 (OH) 2 D 3 CD578 (17-methyl-19-nor-21-nor-23-alkyne-26, 27-F6-1α,25 (OH) 2D3 ) TX527 (19-nor-14, 20-double Table-23-alkyne-1. Alpha., 25 (OH) 2 D 3 ) 2MD (2-methylene-19-nor- (20S) -1α,25 (OH) 2 D 3 ) PRI-2205 ((5E, 7E) -22-en-26, 27-dehydro-1α,25 (OH) 2 D 3 ) ILX23-7553 (16-ene-23-yne-1. Alpha., 25 (OH) 2 D 3 ) And MART-10 (19-nor-2α - (3-hydroxypropyl) -1α,25 (OH) 2 D 3 ). In some embodiments, the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol. In some embodiments, the vitamin D3 analog or pharmaceutically acceptable salt thereof is tacalcitol. In some embodiments, the vitamin D3 analogue or pharmaceutically acceptable salt thereof is maxacalcitol.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, and (b) about 0.005% w/w of calcipotriol, based on free base. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 0.75% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
The present disclosure also provides a pharmaceutical formulation for topical treatment of skin disorders comprising (a) about 1.1% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol. In some embodiments, the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
In some embodiments, the pharmaceutical formulation described herein is a cream. In some embodiments, the cream formulations of ruxotinib described above may also be used in fixed dose combination formulations as described below.
In some embodiments, the pharmaceutical formulations described herein are lotions.
In some embodiments, the pharmaceutical formulations described herein further comprise water. In some embodiments, water comprises from about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 80% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 50% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 5 wt% to about 90 wt%, from about 10 wt% to about 80 wt%, from about 10 wt% to about 70 wt%, from about 10 wt% to about 60 wt%, from about 20 wt% to about 70 wt%, from about 20 wt% to about 60 wt%, or from about 20 wt% to about 50 wt% of the pharmaceutical formulation.
In some embodiments, the pharmaceutical formulations described herein have a pH of no more than about 3.6. In some embodiments, the pharmaceutical formulations described herein have a pH of about 2.7 to about 3.9. In some embodiments, the pharmaceutical formulations described herein have a pH of about 2.7 to about 3.6. In some embodiments, the pharmaceutical formulations described herein have a pH of about 4 to about 8. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.0 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.5 to about 7.0. In some embodiments, the pharmaceutical formulations described herein have a pH of about 6.5 to about 7.5.
In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions.
In 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.
In some embodiments, water comprises from about 5% to about 90% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 80% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 10% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 70% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 60% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 20% to about 50% by weight of the pharmaceutical formulation. In some embodiments, water comprises from about 5 wt% to about 90 wt%, from about 10 wt% to about 80 wt%, from about 10 wt% to about 70 wt%, from about 10 wt% to about 60 wt%, from about 20 wt% to about 70 wt%, from about 20 wt% to about 60 wt%, or from about 20 wt% to about 50 wt% of the pharmaceutical formulation.
In 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 wt% to about 90 wt%, from about 5 wt% to about 80 wt%, from about 5 wt% to about 70 wt%, from about 5 wt% to about 60 wt%, from about 5 wt% to 50 wt%, or from about 5 wt% to about 40 wt% of the pharmaceutical formulation. In some embodiments, the oil component comprises fatty alcohols, nut oils, and/or mineral oils. In some embodiments, the oil component comprises one of the oil components described herein, including an emollient, a sclerosant, or other oil component.
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 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 nonionic surfactant. In some embodiments, the emulsifier or stabilizer component comprises a polysorbate, a poloxamer, a fatty alcohol, a polyethylene glycol fatty ether, a glycerol fatty acid ester, and/or a polyethylene glycol fatty acid ester. In some embodiments, the emulsifier or stabilizer component comprises one of the emulsifiers, stabilizers, or surfactants described herein.
In some embodiments, the emulsifier or stabilizer component comprises a nonionic surfactant. In some embodiments, the nonionic surfactant is docetaxel 1000 or poloxamer 407.
In some embodiments, the pharmaceutical formulation further comprises a solvent component for dissolving the ruxotinib or pharmaceutically acceptable salt thereof. In some embodiments, the solvent component comprises from about 1% to about 40% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 2% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 5% to about 30% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 5% to about 25% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 5% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation. In some embodiments, the solvent component comprises from about 5% to about 20%, from about 2% 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 P. In some embodiments, the solvent component comprises one of the solvent components described herein. In some embodiments, propylene glycol is present in an amount of about 6.5% by weight of the emulsion. In some embodiments, the solvent component comprises diethylene glycol monoethyl ether, such as + ->P. In some embodiments, diethylene glycol monoethyl ether is present in an amount of from about 0.1% to about 30% w/w of the emulsion. In some embodiments, diethylene glycol monoethyl ether is present as milkThe liquid is present in an amount of about 0.1% to about 20% w/w by weight.
In some embodiments, the pharmaceutical formulation further comprises an antioxidant. In some embodiments, the antioxidant is Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), or tocopherol, or a combination thereof. In some embodiments, the antioxidant 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.
In 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 triethanolamine.
In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.
In some embodiments, the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.
In some embodiments, the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.
In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of: petrolatum, fatty alcohols, mineral oil, triglycerides and silicone oil.
In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of: white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and polydimethylsiloxane.
In some embodiments, the oil component comprises a sealant component.
In some embodiments, the blocking agent is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the blocking agent component is present in an amount of about 2% to about 15% by weight of the emulsion.
In some embodiments, the sealer component is present in an amount of about 5% to about 10% by weight of the emulsion.
In some embodiments, the sealant component comprises one or more materials selected from the group consisting of: fatty acids (e.g., lanolin acids), fatty alcohols (e.g., lanolin alcohols), hydrocarbon oils and waxes (e.g., petrolatum), polyols (e.g., propylene glycol), polysiloxanes (e.g., polydimethylsiloxane), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).
In some embodiments, the sealant component comprises one or more materials selected from the group consisting of: lanolin fatty alcohol, lanolin alcohol, vaseline, propylene glycol, polydimethylsiloxane, cholesterol, cocoa butter, carnauba wax and beeswax.
In some embodiments, the sealant component comprises petrolatum.
In some embodiments, the sealant component comprises white petrolatum.
In some embodiments, the white petrolatum is present in an amount of about 7% by weight of the emulsion.
In some embodiments, the oil component comprises a hardener component.
In some embodiments, the hardener component is present in an amount of about 0.1 weight percent to about 15 weight percent of the emulsion.
In some embodiments, the hardener component is present in an amount of about 2 to about 8 weight percent of the emulsion.
In some embodiments, the hardener component is present in an amount of about 3 to about 6 weight percent of the emulsion.
In some embodiments, the hardener component comprises one or more substances independently selected from fatty alcohols.
In some embodiments, the hardener component includes one or more materials independently selected from C12-20 fatty alcohols.
In some embodiments, the hardener component includes one or more materials independently selected from C16-18 fatty alcohols.
In some embodiments, the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
In some embodiments, cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the amount of cetyl alcohol is about 3% by weight of the emulsion.
In some embodiments, stearyl alcohol is present in an amount from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, stearyl alcohol is present in an amount of about 1.75 weight percent of the emulsion.
In some embodiments, the oil component comprises an emollient component.
In some embodiments, the emollient component is present in an amount of about 0.1% to about 20% by weight of the emulsion.
In some embodiments, the emollient component is present in an amount of about 5% to about 20% by weight of the emulsion.
In some embodiments, the emollient component is present in an amount of about 10% to about 15% by weight of the emulsion.
In some embodiments, the emollient component comprises one or more materials independently selected from mineral oil, triglycerides, and silicone oil.
In some embodiments, the emollient component comprises one or more materials independently selected from the group consisting of light mineral oil, medium chain triglycerides, and dimethicone.
In some embodiments, the light mineral oil is present in an amount of about 0.1% to about 15% by weight of the emulsion.
In some embodiments, the light mineral oil is present in an amount of about 4% by weight of the emulsion.
In some embodiments, the polydimethylsiloxane is present in an amount of about 1% by weight of the emulsion.
In some embodiments, the amount of medium chain triglycerides is about 7% by weight of the emulsion.
In some embodiments, the amount of medium chain triglycerides is about 10% by weight of the emulsion.
In some embodiments, the emollient component comprises one or more materials independently selected from mineral oil, triglycerides, silicone oil, and nut oil.
In some embodiments, the nut oil is almond oil. In some embodiments, the almond oil is sweet almond oil. In some embodiments, the sweet almond oil is present in an amount of about 0.1% to about 15% by weight of the emulsion. In some embodiments, the sweet almond oil is present in an amount of about 0.1% to about 10% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 20% to about 80% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 35% to about 65% by weight of the emulsion.
In some embodiments, the water is present in an amount of about 45% to about 65% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 0.5% to about 15% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 1% to about 10% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.
In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.
In some embodiments, the emulsion comprises an emulsifier component and a hardener component, wherein the combined amount of the emulsifier component and the hardener component is at least about 8 weight percent of the emulsion.
In some embodiments, the emulsifier component comprises one or more nonionic emulsifiers.
In some embodiments, the emulsifier component comprises one or more materials independently selected from glycerol fatty acid esters and sorbitan fatty acid esters.
In 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.
In some embodiments, polysorbate 20 is present in an amount of about 1.25% by weight of the emulsion.
In some embodiments, the emulsion further comprises a stabilizer component.
In some embodiments, the stabilizer component is present in an amount of about 0.05 wt% to about 5 wt% of the emulsion.
In some embodiments, the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the emulsion.
In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.
In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.
In some embodiments, the stabilizer component comprises xanthan gum.
In some embodiments, the emulsion further comprises a solvent component. In some embodiments, the solvent component is a solvent for a JAK inhibitor (e.g., ruxotinib) or a pharmaceutically acceptable salt thereof.
In some embodiments, the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.
In some embodiments, the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.
In some embodiments, the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.
In some embodiments, the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols.
In some embodiments, the solvent component comprises one or more materials independently selected from propylene glycol and polyethylene glycol.
In some embodiments, the solvent component comprises one or more substances independently selected from PEG200, PEG300, PEG400, and propylene glycol.
In some embodiments, the solvent component comprises PEG300 and propylene glycol.
In some embodiments, PEG300 is present in an amount of about 7% by weight of the emulsion.
In some embodiments, the solvent is a combination of PEG400 and propylene glycol.
In some embodiments, PEG400 is present in an amount of about 7% by weight of the emulsion.
In some embodiments, propylene glycol is present in an amount of about 6.5% by weight of the emulsion.
In some embodiments, the oil-in-water emulsion further comprises:
about 20% to about 80% by weight of the emulsion of water;
about 10% to about 40% by weight of the emulsion of an oil component;
about 1% to about 10% by weight of the emulsion of an emulsifier component;
about 1% to about 35% by weight of the emulsion of a solvent component; and
from about 0.05% to about 5% by weight of the emulsion of a stabilizer component.
In some embodiments, the oil-in-water emulsion further comprises:
about 35% to about 65% by weight of the emulsion of water;
about 15% to about 35% by weight of the emulsion of an oil component;
about 2% to about 6% by weight of the emulsion of an emulsifier component;
about 5% to about 25% by weight of the emulsion of a solvent component; and
from about 0.05% to about 5% by weight of the emulsion of a stabilizer component.
In some embodiments, the oil-in-water emulsion further comprises:
about 40% to about 65% by weight of the emulsion of water;
about 20% to about 28% by weight of the emulsion of an oil component;
about 3% to about 5% by weight of the emulsion of an emulsifier component;
about 10% to about 20% by weight of the emulsion of a solvent component; and
about 0.1% to about 2% by weight of the emulsion of a stabilizer component.
In some embodiments, the oil-in-water emulsion further comprises:
about 40% to about 65% by weight of the emulsion of water;
about 20% to about 28% by weight of the emulsion of an oil component;
about 3% to about 5% by weight of the emulsion of an emulsifier component;
about 10% to about 20% by weight of the emulsion of a solvent component; and
from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component.
In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising an oil-in-water emulsion comprising water, an oil component, and an emulsifier component, wherein:
the oil component comprises one or more substances independently selected from the group consisting of: petrolatum, fatty alcohols, mineral oil, triglycerides and dimethicone;
the emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and sorbitan fatty acid esters;
the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols; and is also provided with
The stabilizer component comprises one or more substances independently selected from polysaccharides.
In some embodiments, the pharmaceutical formulations described herein are oil-in-water emulsions comprising an oil-in-water emulsion comprising water, an oil component, and an emulsifier component, wherein:
the oil component comprises one or more substances independently selected from the group consisting of: white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and polydimethylsiloxane;
the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
the solvent component comprises one or more materials independently selected from propylene glycol and polyethylene glycol; and is also provided with
The stabilizer component comprises xanthan gum.
In some embodiments, the emulsion further comprises an antimicrobial preservative component.
In some embodiments, the antimicrobial preservative component is present in an amount from about 0.05% to about 3% by weight of the emulsion.
In some embodiments, the antimicrobial preservative component is present in an amount from about 0.1% to about 1% by weight of the emulsion.
In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.
In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.
In some embodiments, the antimicrobial preservative component comprises methylparaben and propylparaben.
In some embodiments, the methylparaben is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, the methylparaben is present in an amount of about 0.1% by weight of the emulsion.
In some embodiments, propyl parahydroxybenzoate is present in an amount of about 0.001% to about 5% by weight of the emulsion.
In some embodiments, propyl parahydroxybenzoate is present in an amount of about 0.05% by weight of the emulsion.
In some embodiments, phenoxyethanol is present in an amount from about 0.1% to about 15% by weight of the emulsion.
In some embodiments, phenoxyethanol is present in an amount of about 0.5% by weight of the emulsion.
In some embodiments, the pH of the cream is from about 4 to about 8.
In some embodiments, the pH of the cream is about 6.5 to about 7.0.
In some embodiments, the emulsion further comprises an antioxidant.
In some embodiments, the antioxidant is Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), or tocopherol, or a combination thereof.
In some embodiments, the butylated hydroxytoluene is present in an amount of about 0.01% to about 15% w/w 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.
In some embodiments, the butyl hydroxy anisole is present in an amount of about 0.001 weight% to about 5 weight% w/w of the emulsion. In some embodiments, the butyl hydroxy anisole is present in an amount of about 0.01% to about 1% w/w by weight of the emulsion.
In some embodiments, the emulsion further comprises a calcipotriol stabilizer.
In some embodiments, the calcipotriol stabilizer is ascorbyl palmitate, ascorbic acid, fumaric acid, or citric acid, or a combination thereof.
In some embodiments, the present disclosure also provides a pharmaceutical formulation (or alternatively, a method as in any of embodiments 1-75) for topical treatment of skin disorders, wherein the formulation is an oil-in-water emulsion comprising about 1.5% w/w phosphoric acid Lu Suoti ni, 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 glyceryl stearate SE, about 3% w/w wax alcohol, about 1.75% w/w stearyl alcohol, about 1% w/w polydimethylsiloxane, about 7% w/w triglyceride, about 1.05% w/w polyoxyethylene triglyceride, about 25% w/w, and about 20.5% ethanol.
In some embodiments, the present disclosure also provides a pharmaceutical formulation (or alternatively, a method as in any of embodiments 1-75) for topical treatment of skin disorders, wherein the formulation is an oil-in-water emulsion comprising about 1.5% w/w phosphate Lu Suoti ni, 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 glyceryl stearate SE, about 3% w/w wax alcohol, about 1.75% w/w stearyl alcohol, about 1% w/w polydimethylsiloxane, about 7% w/w triglyceride, about 1.25% w/w polyoxyethylene triglyceride and about 20.5% w ethanol.
In some embodiments, the pH of the pharmaceutical formulations described herein is adjusted with triethanolamine (trolamine/trienolamine). In some embodiments, the pH of the pharmaceutical formulations described herein is adjusted with phosphoric acid.
In some embodiments, the emulsion formulations of ruxotinib described above may also be used in fixed dose combination formulations as described below. The topical formulations described above may use any of the vitamin D derivatives, vitamin D3 analogs, and JAK inhibitors described above in any suitable combination.
As used in the context of "treating skin disorders locally," locally "means application to the skin.
Pharmaceutical formulations for topical application to the skin may include solutions, suspensions, foams, ointments, lotions, creams, gels, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powdered or oily matrices, thickeners and the like may be necessary or desirable. In some embodiments, the compositions are formulated for topical administration by solutions, suspensions, gels, creams, ointments, lotions, sprays, foams, liquids, and powders.
For the treatment of skin disorders described herein, topical drugs that are able to penetrate the skin barrier and provide limited systemic effects are particularly important.
Topical (dermal/intradermal) formulations are typically solutions, suspensions, gels, creams, ointments, lotions, sprays and foams. The preferred topical formulation should be physically and chemically stable, not cause skin irritation, and deliver the active agent at a concentration that will cause a therapeutic response at the appropriate skin layer with limited systemic exposure.
In some embodiments, administration is topical and includes formulations with one or more pharmaceutically (e.g., dermatologically) acceptable excipients. Examples of dermatologically acceptable excipients include, but are not limited to, pH adjusters, chelating agents, preservatives, co-solvents, permeation promoters, humectants, thickeners, gelling agents, viscosity enhancers, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof. In some embodiments, the topical formulation is topically applied to the patient (e.g., at the site of injury).
In some embodiments, the pH adjuster is selected from an acid, an acid salt, 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.
In some embodiments, the chelating agent is a single excipient. In some embodiments, the chelating agent is a mixture of two or more chelating agents. Exemplary chelating agents include, but are not limited to, ethylenediamine tetraacetic acid (EDTA) or salts thereof. In some embodiments, the chelating agent comprises a mixture of a chelating agent and an antioxidant, wherein the chelating agent and the antioxidant prevent, minimize, or reduce oxidative degradation reactions in the composition. Exemplary antioxidants include, but are not limited to, butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), tocopherols, and propyl gallate.
In some embodiments, the composition comprises one or more preservatives. In some embodiments, the composition comprises a mixture of two or more preservatives. In some embodiments, the composition comprises one to five preservatives. Exemplary preservatives include, but are not limited to, benzyl alcohol, phenoxyethanol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, and imidazolidinyl urea.
In 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 (propylene glycol), diethylene glycol monoethyl ether, isosorbide dimethyl ether, ethanol, isopropanol, benzyl alcohol, propylene glycol (propylene glycol), polyethylene glycol (e.g., polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, etc.). In some embodiments, the solvent is a non-water soluble agent. Exemplary water insoluble agents include, but are not limited to, diethyl sebacate, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, and medium chain triglycerides.
In 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 permeation enhancer may act as both a solvent and a permeation enhancer. Exemplary permeation enhancers include, but are not limited to, fatty acids, fatty acid esters, fatty alcohols, pyrrolidones, sulfoxides, alcohols, glycols and polyols or any mixtures thereof. In some embodiments, the co-solvents provided herein are permeation enhancers.
In some embodiments, the composition comprises one or more thickening, gelling or viscosifying agents. In some embodiments, the composition comprises a mixture of two or more thickening, gelling or viscosifying agents. In some embodiments, the composition comprises one to five thickening, gelling or viscosifying agents. Exemplary thickening, gelling or viscosifying agents include, but are not limited to, cellulose derivatives (e.g., hydroxyethyl cellulose (HEC), carboxymethyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP).
Surfactants are compounds that reduce the surface tension between two liquids or between a liquid and a solid. The surfactant may be a mixture of two or more surfactants. Exemplary surfactants include, but are not limited to, ethoxylated fatty alcohol ethers (e.g., steareth-2, steareth-10, steareth-20, cetostearyl polyether-2, cetostearyl polyether-10, etc.), PEG esters (e.g., PEG-4 dilaurate, PEG-20 stearate, etc.), glycerol esters or derivatives thereof (e.g., glycerol dioleate, glycerol stearate, etc.), polymeric ethers (e.g., poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 407, etc.), sorbitan derivatives (e.g., polysorbate 80, sorbitan monostearate, etc.), fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol, etc.), and emulsifying waxes (e.g., emulsifying wax NF, mixtures of cetostearyl alcohol and polysorbate 60, etc.).
Local (e.g., intradermal) administration provides the advantage of locally treating dermatological and/or dermatological conditions as described herein, minimizing potential adverse events associated with systemic exposure, and allowing easier interruption of treatment when needed. In addition, some topical dosage forms (such as creams, ointments and gels) have the advantage of excipients that can act as emollients or blocking agents, which can improve the patient's health and compliance during treatment. Other dose routes (such as oral, parenteral and inhalation) may lead to systemic drug levels exceeding the therapeutic range, increased likelihood of adverse events occurring, drug-drug interactions and the production of active/toxic metabolites, which may lead to discontinuation of therapy and insufficient patient compliance.
Topical formulations intended for dermal delivery are typically solutions, suspensions, gels, creams, ointments, lotions, sprays and foams, and may contain one or more conventional carriers as described herein. The preparation of the formulation composition should be aimed at delivering the active ingredient to the appropriate skin layers, minimizing systemic exposure and preventing skin irritation. In addition, the pharmaceutical composition should be physically and chemically stable. Depending on the dosage form selected, one or more additional excipients as described herein may be required, such as pH modifiers, chelating agents, preservatives, co-solvents, permeation promoters, humectants, thickeners, gelling agents, viscosity enhancers, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof.
In some embodiments, the topical formulation may contain one or more conventional carriers as described herein. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of the cream may be based on a combination of water with glycerin and one or more other components such as glycerin monostearate, PEG-glycerin monostearate, and cetostearyl alcohol. The gel may be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.
The composition to be administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packaged for use as such or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration.
The compositions of the presently claimed subject matter may further comprise one or more additional agents, examples of which are set forth above.
Combination therapy
The methods described herein may further comprise administering one or more additional therapeutic agents. One or more additional therapeutic agents may be administered to the patient simultaneously or sequentially.
In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, erythromycin, metronidazole, rifampin, moxifloxacin, dapsone, or a combination thereof. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, or a combination of erythromycin and 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 rifampicin.
In some embodiments, the additional therapeutic agent is a retinoid. In some embodiments, the retinoid is adapalene, itrate, abamectin, or isotretinoin.
In some embodiments, the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the steroid is, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or fluorometholone.
In 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 or mycophenolate sodium.
In some embodiments, the additional therapeutic agent is azelaic acid.
In some embodiments, the additional therapeutic agent is used for topical treatment. In some embodiments, the additional therapeutic agent is used to treat psoriasis, atopic dermatitis, alopecia, vitiligo, listlessness syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis. In some embodiments, the additional therapeutic agent is used to treat atopic dermatitis. In some embodiments, the additional therapeutic agent is pimecrolimus. In some embodiments, the additional therapeutic agent is used to treat psoriasis. In some embodiments, the additional therapeutic agent is used to treat alopecia. In some embodiments, the additional therapeutic agent is used to treat vitiligo. In some embodiments, the additional therapeutic agent is used to treat rett syndrome. In some embodiments, the additional therapeutic agent is used to treat pityriasis rubra pilaris. In some embodiments, the additional therapeutic agent is used to treat simple epidermolysis bullosa. In some embodiments, the additional therapeutic agent is used to treat palmoplantar keratosis. In some embodiments, the additional therapeutic agent is used to treat congenital thick nails. In some embodiments, the additional therapeutic agent is used to treat multiple sebaceous cysts. In some embodiments, the additional therapeutic agent is used to treat lichen planus. In some embodiments, the additional therapeutic agent is used to treat cutaneous T cell lymphoma. In some embodiments, the additional therapeutic agent is used to treat hidradenitis suppurativa. In some embodiments, the additional therapeutic agent is used to treat contact dermatitis. In some embodiments, the additional therapeutic agent is used to treat ichthyosis.
In some embodiments, the additional therapeutic agent is clenbuterol.
In some embodiments, the additional therapeutic agent is tacrolimus.
In some embodiments, the additional therapeutic agent is pimecrolimus.
Medicine box
The present disclosure also includes a pharmaceutical kit useful, for example, in the treatment and/or prevention of skin disorders such as psoriasis, alopecia, and vitiligo as described herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of ruxotinib, or a pharmaceutically acceptable salt thereof, as described herein. Such kits may also include one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as desired, as would be apparent to one of skill in the art. Instructions (in the form of inserts or in the form of labels) indicating the amount of the components to be administered, the instructions for administration and/or instructions for mixing the components may also be included in the kit.
It is also to be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Definition of the definition
As used herein, "affected skin area" refers to an area of skin of a patient suffering from a skin disorder as described herein.
As used herein, "ruxotinib phosphate" means a phosphate salt of ruxotinib, wherein the ratio of Lu Suoti ni to phosphoric acid is 1:1.
As used herein, "cream" means an emulsion-like semisolid dosage form that is applied to the skin.
As used herein, the term "C", alone or in combination with other terms 3-4 Cycloalkyl "refers to a non-aromatic monocyclic hydrocarbon moiety having 3 to 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 the cycloalkyl group may be oxidized to form a carbonyl linkage. Exemplary C 3-4 Cycloalkyl includes cyclopropyl, cyclobutyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl.
As used herein, the term "synergistic effect" or "synergistic effect" when used in connection with a description of the efficacy of an agent or compound combination means any measured effect of the combination that is greater than the effect predicted from the sum of the effects of the individual agents or compounds. For example, as described herein, the synergistic effect of (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, respectively, inhibiting IL-22, MMP12, and CXCL10 exists, meaning that the combined inhibition of (a) and (b) is greater than the sum of the inhibition of (a) and (b) alone.
As used herein, "statistically significant" means a p-value <0.05 (preferably <0.001, and most preferably < 0.0001).
As 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 the tissues of humans and animals. In some embodiments, "pharmaceutically acceptable" means approved by a federal regulatory agency 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.
The 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 into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; acidic residues such as alkali metal or organic salts of carboxylic acids; etc. Pharmaceutically acceptable salts of the presently claimed subject matter include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the presently claimed subject matter can be synthesized from the parent compound containing a base or acid moiety by conventional chemical methods. Typically, 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 a mixture of both; nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile (MeCN) are generally preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th edition, mack Publishing Company, easton, pa.,1985, pages 1418 and Journal of Pharmaceutical Science,66,2 (1977), each of which is incorporated herein by reference in its entirety. In some embodiments, the pharmaceutically acceptable salt is a phosphate, sulfate, or maleate salt.
As used herein, the term "emulsifier component" refers in one aspect to a substance or mixture of substances that keeps elements or particles suspended in a fluid medium. In some embodiments, the emulsifier component allows the oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component refers to one or more nonionic surfactants.
As used herein, the term "sealer component" refers to a hydrophobic agent or mixture of hydrophobic agents that forms a sealing film on the skin to reduce transepidermal water loss (TEWL) by preventing evaporation of water from the stratum corneum.
As used herein, the term "hardener 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.
As used herein, the term "emollient component" refers to an agent that softens or soothes the skin or soothes the irritated interior surface.
As used herein, the term "stabilizer 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 cream. In some embodiments, the stabilizer component prevents the emulsion from agglomerating and stabilizes droplets in the oil-in-water emulsion.
As used herein, the term "solvent component" is a liquid substance or mixture of liquid substances that is capable of dissolving a JAK inhibitor as described herein, such as ruxotinib or a pharmaceutically acceptable salt or cream thereof, among others. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which the ruxotinib or pharmaceutically acceptable salt thereof has reasonable solubility. For example, the solubility of ruxotinib (free base) or its phosphate (1:1 salt) is reported in table 1. In some embodiments, the solvent is a substance or mixture thereof in which the ruxotinib or pharmaceutically acceptable salt thereof (whichever is used) has a solubility of at least about 10mg/mL or greater, at least about 15mg/mL or greater, or at least about 20mg/mL or greater.
As used herein, the phrase "antimicrobial preservative component" is a substance or mixture of substances that inhibits microbial growth in a cream.
As used herein, the phrase "chelator component" refers to a compound or mixture of compounds that has the ability to bind strongly to metal ions.
As used herein, "wt% of the emulsion" means the percent concentration of the components in the emulsion on a w/w basis. For example, 1% w/w of component a= [ (mass of component a)/(total mass of emulsion) ] x 100.
As used herein, "wt% of emulsion based on free base" of a JAK inhibitor such as ruxotinib or a pharmaceutically acceptable salt thereof as described herein means that the% w/w is calculated based on the weight of ruxotinib in the total emulsion. For example, "1.5% w/w based on free base" of ruxotinib phosphate means that 1.98 grams of ruxotinib phosphate (equivalent to 1.5 grams of free base ruxotinib) is present in the emulsion for 100 grams of the total formulation.
As used herein, "wt% of a free base-based formulation" of a JAK inhibitor such as ruxotinib or a pharmaceutically acceptable salt thereof as described herein means that the% w/w is calculated based on the weight of ruxotinib in the total formulation. For example, "1.5% w/w based on free base" of ruxotinib phosphate means that 1.98 grams of ruxotinib phosphate (equivalent to 1.5 grams of free base ruxotinib) is present in the formulation for 100 grams of the total formulation.
As used herein, the term "component" may mean a substance or mixture of substances.
As used herein, the term "fatty acid" refers to saturated or unsaturated fatty acids. In some embodiments, the fatty acid is a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about eight to about thirty carbons. In some embodiments, the fatty acids have an average of about 12 to 20, 14-20, or 16-18 carbons. 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, sesquiisostearic acid, behenic acid, isosbestic acid and arachidonic acid or mixtures thereof.
As used herein, the term "fatty alcohol" refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of from about 12 to about 20, from about 14 to about 20, or from about 16 to about 18 carbons. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, octanoyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isosbestic alcohol, squalol, squalene alcohol, and linoleyl alcohol or mixtures thereof.
As used herein, the term "polyalkylene glycol" alone or in combination with other terms refers to a polymer containing alkylene oxide monomer units or a copolymer of different alkylene oxide monomer units, wherein the alkylene has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "alkylene oxide" alone or in combination with other terms refers to a group of the formula-O-alkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.
As used herein, the term "sorbitan fatty acid 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 acid ester is a polyethoxylated sorbitan ester.
As used herein, the term "sorbitan ester" refers to a compound or mixture of compounds derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for deriving sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to Span TM Series (available from Uniqema) including Span20 (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 r.c. rowe and p.j. Shesky, handbook of pharmaceutical excipients, (2006), 5 th edition, which are incorporated herein by reference in their entirety.
As used herein, the term "polyethoxylated sorbitan esters" refers to ethoxylated compounds derived from sorbitan esters or mixtures thereof. The polyoxyethylene portion of the compound may be between the fatty acid ester and the sorbitan portion. 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 polyethoxylated raw sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene of the compound or mixture The moiety has from about 4 to about 80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to Tween TM Series (available from Uniqema) including 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 numbers following the POE abbreviation refer to the number of oxyethylene repeat units in the compound. Other suitable polyethoxylated sorbitan esters include the polyoxyethylene sorbitan fatty acid esters listed in r.c. rowe and p.j. Shesky, handbook of pharmaceutical excipients, (2006), 5 th edition, 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.
As used herein, the term "glycerol fatty acid ester" refers to a monoglyceride, diglyceride, or triglyceride of a fatty acid. The glycerol fatty acid ester may be optionally substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids for deriving the fatty acid glycerides include, but are not limited to, those described herein. In some embodiments, the glycerol fatty acid ester is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glycerol fatty acid ester is glycerol stearate.
As used herein, the term "triglyceride" refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium chain triglyceride.
As used herein, the term "alkylene glycol" refers to a group of the formula-O-alkylene-wherein the alkylene has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1, 2-propylene glycol).
The term "polyethylene glycol" as used herein means a polymer containing the formula-O-CH 2 -CH 2 -a polymer of ethylene glycol monomer units. Suitable polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with lower alkyl groups (e.g., methyl). Derivatives of polyethylene glycol having an esterifiable carboxyl group are also suitable. Polyethylene glycols useful in the present disclosure may be any polymer of chain length or molecular weight, and may include branching. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 to about 9000. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 to about 5000. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 to about 900. In some embodiments, the polyethylene glycol has an average molecular weight of 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 numbers following the dashes in the designations refer to the average molecular weight of the polymer.
As used herein, "comprising" is equivalent to "including.
As used herein, the terms "subject," "individual," or "patient" are used interchangeably to refer to a human. In some embodiments, a "subject," "individual," or "patient" is in need of such treatment.
In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical formulation thereof, a topical formulation thereof, is administered in a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or agent that causes a biological or medical response that a researcher, veterinarian, medical doctor or other clinician seeks in a tissue, system, animal, individual or human.
As used herein, the term "treatment" refers to one or more of the following: (1) inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., preventing further development of the pathology and/or symptoms); (2) alleviation of disease; for example, alleviating a disease, condition, or disorder (i.e., reversing pathology and/or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, such as reducing the severity of the disease; or (3) preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptomatology of the disease. In some embodiments, treating refers to inhibiting or alleviating a disease. In some embodiments, the treatment is prophylaxis of the disease.
In some embodiments, the components are present precisely within the specified range (e.g., without the term "about"). In some embodiments, "about" means the value ± 10%.
The present disclosure also provides the following non-limiting embodiments:
in order that the embodiments disclosed herein may be understood more efficiently, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the embodiments in any way.
In some embodiments, the following embodiments are provided:
1. a method of treating a dermatological disorder 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.
2. The method of embodiment 1, wherein the skin disorder is an autoimmune skin disorder.
3. The method of embodiment 1 or 2, wherein the skin disorder is an inflammatory skin disorder.
4. The method of any one of embodiments 1-3, wherein the dermatological disorder is a Th1 or Th 17-related dermatological disorder.
5. The method of any one of embodiments 1-4, wherein the skin disorder is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metallopeptidase 12 (MMP 12), or a combination thereof.
6. The method of any one of embodiments 1-5, wherein the dermatological disorder is mediated by IL-22.
7. The method of any of embodiments 1-5, wherein the dermatological disorder is mediated by MMP 12.
8. The method of any one of embodiments 1-5, wherein the dermatological disorder is mediated by CXCL 10.
9. The method of any one of embodiments 1-8, wherein the skin disorder is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, lisi syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.
10. The method of embodiment 9, wherein the skin disorder is psoriasis.
11. The method of embodiment 9, wherein the dermatological disorder is alopecia.
12. The method of embodiment 11, wherein the alopecia is alopecia areata.
13. The method of embodiment 9, wherein the skin disorder is vitiligo.
14. The method of any one of embodiments 1-13, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof are administered simultaneously.
15. The method of any one of embodiments 1-13, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof are administered sequentially.
16. The method of any one of embodiments 1-15, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof are administered at least once daily.
17. The method of any one of embodiments 1-15, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is administered once daily.
18. The method of any one of embodiments 1-15, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is administered twice daily.
19. The method of any one of embodiments 1-18, wherein the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered once daily.
20. The method of any one of embodiments 1-18, wherein the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered twice daily.
21. The method of any one of embodiments 1-20, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof are administered as separate formulations.
22. The method of any one of embodiments 1-14, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof are administered as a single formulation.
23. The method of embodiment 22, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof are administered once daily.
24. The method of embodiment 22, wherein (a) the JAK inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3, vitamin D3 analog or pharmaceutically acceptable salt thereof are administered twice daily.
25. The method of any one of embodiments 1-24, wherein the vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is administered in synergistic amounts.
26. The method of any one of embodiments 1-24, wherein there is a synergy between the JAK inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof.
27. The method of any one of embodiments 1-26, further comprising administering an additional therapeutic agent.
28. The method of embodiment 27, wherein the additional therapeutic agent is a corticosteroid.
29. The method of any one of embodiments 1-28, wherein the patient is a human patient.
30. The method of any one of embodiments 1-29, wherein the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is a compound having formula (I):
wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
31. The method of any one of embodiments 1-29, wherein the vitamin D3, vitamin D3 analog, or pharmaceutically acceptable salt thereof is a compound having formula (II):
wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
32. The method of any one of embodiments 1-29, wherein (b) is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
33. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is a vitamin 1 a- (OH) D3 analog or pharmaceutically acceptable salt thereof.
34. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is vitamin 1 a, 25 (OH) 2 D3 analog, vitamin 1 alpha, 24 (OH) 2 D3 analog or vitamin 1 alpha, 26 (OH) 2 D3 analog or a pharmaceutically acceptable salt thereof.
35. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is a compound having the formula (III):
Wherein:
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H;
R 2A is-C 1-4 An alkylene-OH;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A group;
l is-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 is 12 Is H or OH;
R 9 is CH 3 Or CF (CF) 3 ；
R 10 Is CH 3 Or CF (CF) 3 ；
R 11 Is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form a cyclopropyl ring; and R is 11 Is H.
36. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is selected from the group consisting of calcitonin, calcitriol, calcipotriol, alfacalcidol, tacalcidol, maxacalcitol, floc-ritol, idecalcitol, inecalcitol, seocalcitol, leccalcitol, 20-epi-1 a, 25 (OH) 2 D 3 CD578 (17-methyl-19-nor-21-nor-23-alkyne-26, 27-F6-1α,25 (OH) 2D3 ) TX527 (19-nor-14, 20-double Table-23-alkyne-1. Alpha., 25 (OH) 2 D 3 ) 2MD (2-methylene-19-nor- (20S) -1α,25 (OH) 2 D 3 ) PRI-2205 ((5E, 7E) -22-en-26, 27-dehydro-1α,25 (OH) 2 D 3 ) ILX23-7553 (16-ene-23-yne-1. Alpha., 25 (OH) 2 D 3 ) And MART-10 (19-nor-2α - (3-hydroxypropyl) -1α,25 (OH) 2 D 3 )。
37. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol.
38. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is maxacalcitol.
39. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is tacalcitol.
40. The method of any one of embodiments 32-39, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is administered in a topical formulation.
41. The method of embodiment 40, wherein the topical formulation is a foam, ointment, lotion, or cream.
42. The method of embodiment 40 or 41, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0001% to about 0.1% by weight of the formulation of the vitamin D3 analog.
43. The method of embodiment 40 or 41, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is administered as a topical formulation comprising from about 0.0004% to about 0.005% by weight of the formulation of the vitamin D3 analog.
44. The method of embodiment 32, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol or pharmaceutically acceptable salt thereof, which is administered as a topical formulation comprising about 50 μg calcipotriol per gram of the formulation.
45. The method of embodiment 44, wherein the topical formulation is a foam, ointment, lotion, or cream.
46. The method of embodiment 44 or 45, wherein said topical formulation further comprises betamethasone dipropionate.
47. The method of embodiment 46, wherein the betamethasone dipropionate is present in an amount of about 0.5 mg/gram of the formulation.
48. The method of embodiment 33, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is tacalcitol that is administered as a topical formulation comprising about 4 μg tacalcitol per gram of the formulation.
49. The method of embodiment 48, wherein the topical formulation is an ointment, cream, or lotion.
50. The method of embodiment 33, wherein the vitamin D3 analog or 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.
51. The method of embodiment 50, wherein the topical formulation is an ointment.
52. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from the group consisting of a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor, a JAK1/JAK3 inhibitor, a ubijak inhibitor, and a JAK1/TYK2 inhibitor, or a pharmaceutically acceptable salt.
53. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1 inhibitor or pharmaceutically acceptable salt thereof.
54. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK2 inhibitor or pharmaceutically acceptable salt thereof.
55. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/JAK2 inhibitor or pharmaceutically acceptable salt thereof.
56. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/JAK3 inhibitor or pharmaceutically acceptable salt thereof.
57. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK inhibitor or pharmaceutically acceptable salt thereof.
58. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/TYK2 inhibitor or a pharmaceutically acceptable salt.
59. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from Lu Suoti, baritinib, olatinib, molotinib, CTP-543, AH057, gan Duo tinib, phenanthrene Zhuo Tini, letatinib, panatinib, CHZ868, wu Pati ni, tofacitinib, afatinib, albutitinib, itatinib, bu Lei Xiti ni, ATI-501, ATI-1777, ATI-502, digatinib, pefeitinib, vanatinib, cucurbitacin I, ceritinib, dicetitinib, BMS-986165, and Li Texi tinib, or a pharmaceutically acceptable salt thereof.
60. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is selected from Lu Suoti, olatinib, baritinib, molotinib, CTP-543, gan Duo, phenanthrene Zhuo Tini, letatinib, panatinib, wu Pati, tofacitinib, fingolitinib, abxitinib, itatinib, bu Lei Xiti, dygatitinib, pefacitinib, vanatinib, gesatinib, cucurbitacin I, and ceritinib, or a pharmaceutically acceptable salt thereof.
61. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof.
62. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
63. The method of embodiment 61 or 62, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is administered as a cream formulation.
64. The method of embodiment 63, wherein the cream formulation is an oil-in-water emulsion.
65. The method of embodiment 63 or 64, wherein the cream formulation has a pH of about 2.8 to about 3.9.
66. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is diltiatinib or a pharmaceutically acceptable salt thereof.
67. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is tofacitinib or a pharmaceutically acceptable salt thereof.
68. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is ATI-1777 or a pharmaceutically acceptable salt thereof.
69. The method of any one of embodiments 1-51, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is bunt Lei Xiti or pharmaceutically acceptable salt thereof.
70. The method of any one of embodiments 1-69, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
71. The method of any one of embodiments 1-70, wherein (b) vitamin D3, a vitamin D3 analog or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
72. A method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
73. A method of treating a dermatological disorder in a patient in need thereof, comprising topically administering to an affected area of the patient (a) ruxotinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
74. The method of embodiment 73, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol or a pharmaceutically acceptable salt thereof.
75. The method of any one of embodiments 72-74, wherein the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
76. A pharmaceutical formulation for the topical treatment of a dermatological disorder comprising (or alternatively, the 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.
77. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) ruxotinib or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
78. The formulation of embodiment 77 (or alternatively, the method) wherein the ruxotinib or pharmaceutically acceptable salt thereof is present in an amount of about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.65 wt%, about 1.7 wt%, about 1.9 wt%, about 1.95 wt%, or about 2.3 wt%, about 1.3 wt%, about 1.5 wt%, about 1.3 wt%, or about 2 wt%, about 1.3 wt%, or about 1.3 wt%.
79. A pharmaceutical formulation for topical treatment of a dermatological disorder (or alternatively, a method according to any one of embodiments 1-75, wherein the formulation comprises) comprising (a) about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
80. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
81. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof.
82. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 1 μg/mL to about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
83. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 1 μg/mL to about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
84. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
85. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
86. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
87. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
88. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
89. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 1 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
90. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 10 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
91. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 50 μg/mL of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
92. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.0001% w/w to about 0.01% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
93. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
94. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
95. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.0001% w/w to about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
96. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of vitamin D3, a vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
97. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
98. A pharmaceutical formulation for topical treatment of a dermatological disorder comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib, or a pharmaceutically acceptable salt thereof, based on free base and (b) about 0.005% w/w of vitamin D3, vitamin D3 analog, or a pharmaceutically acceptable salt thereof, based on free base.
99. The formulation of any one of embodiments 77-98 (or alternatively, the method of any one of embodiments 77-98), wherein the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
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, vitamin D3 analog, or a pharmaceutically acceptable salt thereof is a vitamin D3 analog or a pharmaceutically acceptable salt thereof.
101. The formulation (or alternatively, the method) of embodiment 100, wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is selected from the group consisting of calcitonin, calcitriol, calcipotriol, alfacalcidol, tacalcidol, maxacalcitol, flo-glycerol, idecalcitol, inecalcitol, seocalcitol, leccalcitol, 20-epi-1 a, 25 (OH) 2 D 3 CD578 (17-methyl-19-nor-21-nor-23-alkyne-26, 27-F6-1α,25 (OH) 2D3 ) TX527 (19-nor-14, 20-double Table-23-alkyne-1. Alpha., 25 (OH) 2 D 3 ) 2MD (2-methylene-19-nor- (20S) -1α,25 (OH) 2 D 3 ) PRI-2205 ((5E, 7E) -22-en-26, 27-dehydro-1α,25 (OH) 2 D 3 ) ILX23-7553 (16-ene-23-yne-1. Alpha., 25 (OH) 2 D 3 ) And MART-10 (19-nor-2α - (3-hydroxypropyl) -1α,25 (OH) 2 D 3 )。
102. The formulation of embodiment 100 (or alternatively, the method), wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is calcipotriol.
103. The formulation of embodiment 100 (or alternatively, the method), wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is tacalcitol.
104. The formulation of embodiment 100 (or alternatively, the method), wherein the vitamin D3 analog or a pharmaceutically acceptable salt thereof is maxacalcitol.
105. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w to about 1.5% w/w of ruxotinib or a pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol.
106. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 0.75% w/w of ruxotinib or pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol.
107. A pharmaceutical formulation for topical treatment of skin disorders comprising (or alternatively, the method of any one of embodiments 1-75, wherein the formulation comprises) (a) about 1.5% w/w of ruxotinib or pharmaceutically acceptable salt thereof, based on free base, and (b) about 0.005% w/w of calcipotriol.
108. The formulation (or alternatively, the method) of any one of embodiments 105-107, wherein the ruxotinib or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
109. The formulation (or alternatively, the method) of any one of embodiments 76-108, wherein the formulation is a cream.
110. The formulation (or alternatively, the method) of any one of embodiments 76-108, wherein the formulation is a lotion.
111. The formulation (or alternatively, the method) of any one of embodiments 76-110, wherein the formulation further comprises water.
112. The formulation (or alternatively, the method) of any one of embodiments 76-111, wherein the formulation has a pH of no more than about 3.6.
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.
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.
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.
116. The formulation (or alternatively, the method) of any one of embodiments 76-115, wherein the formulation is an oil-in-water emulsion.
117. The formulation of embodiment 116 (or alternatively, the method), wherein the oil-in-water emulsion comprises water, an oil component, and an emulsifier component.
118. The formulation of embodiment 117 (or alternatively, the method), wherein the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.
119. The formulation of embodiment 117 (or alternatively, the method), wherein the oil component is present in an amount of about 15% to about 30% by weight of the emulsion.
120. The formulation of embodiment 117 (or alternatively, the method), wherein the oil component is present in an amount of about 20% to about 28% by weight of the emulsion.
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 the group consisting of: petrolatum, fatty alcohols, mineral oil, triglycerides and silicone oil.
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 the group consisting of: white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and polydimethylsiloxane.
123. The formulation (or alternatively, the method) of any one of embodiments 117-120, wherein the oil component comprises a sealant component.
124. The formulation of embodiment 123 (or alternatively, the method), wherein the sealer component is present in an amount of about 2% to about 15% by weight of the emulsion.
125. The formulation of embodiment 123 (or alternatively, the method), wherein the sealer component is present in an amount of about 5% to about 10% by weight of the emulsion.
126. The formulation (or alternatively, the method) of any one of embodiments 123-125, wherein the sealant component comprises white petrolatum.
127. The formulation (or alternatively, the method) of any one of embodiments 117-126, wherein the oil component comprises a hardener component.
128. The formulation of embodiment 127 (or alternatively, the method), wherein the hardener component is present in an amount of about 2 weight percent to about 8 weight percent of the emulsion.
129. The formulation of embodiment 127 (or alternatively, the method), wherein the hardener component is present in an amount of about 3 weight percent to about 6 weight percent of the emulsion.
130. The formulation of embodiment 127 (or alternatively, the method), wherein the hardener component is present in an amount of about 4 weight percent to about 7 weight percent of the emulsion.
131. The formulation (or alternatively, the method) of any one of embodiments 127-130, wherein the hardener component comprises one or more substances independently selected from fatty alcohols.
132. As in embodiment 131The formulation (or alternatively, the method) wherein the hardener component comprises one or more components independently selected from C 12-20 Fatty alcohol.
133. The formulation of embodiment 131 (or alternatively, the method), wherein the hardener component comprises one or more agents independently selected from C 16-18 Fatty alcohol.
134. The formulation (or alternatively, the method) of any one of embodiments 127-130, wherein the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
135. The formulation (or alternatively, the method) of any one of embodiments 117-134, wherein the oil component comprises an emollient component.
136. The formulation of embodiment 135 (or alternatively, the method), wherein the emollient component is present in an amount of about 0.1% to about 20% by weight of the emulsion.
137. The formulation of embodiment 135 (or alternatively, the method), wherein the emollient component is present in an amount of about 5% to about 20% by weight of the emulsion.
138. The formulation of embodiment 135 (or alternatively, the method), wherein the emollient component is present in an amount of about 10% to about 15% by weight of the emulsion.
139. The formulation (or alternatively, the method) of any of embodiments 135-138, wherein the emollient component comprises one or more substances independently selected from mineral oil, triglycerides, and silicone oil.
140. The formulation (or alternatively, the method) of any of embodiments 135-138, wherein the emollient component comprises one or more substances independently selected from the group consisting of light mineral oil, medium chain triglycerides, and dimethicone.
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.
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.
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.
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 wt% to about 15 wt% of the emulsion.
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 wt% to about 10 wt% of the emulsion.
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 wt% to about 6 wt% of the emulsion.
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 wt% to about 5 wt% of the emulsion.
148. The formulation (or alternatively, the method) of any of embodiments 117-147, wherein the emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and sorbitan fatty acid esters.
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.
150. The formulation (or alternatively, the method) of any one of embodiments 117-149, wherein the emulsion further comprises a stabilizer component.
151. The formulation of embodiment 150 (or alternatively, the method), wherein the stabilizer component is present in an amount of about 0.05% to about 5% by weight of the emulsion.
152. The formulation of embodiment 150 (or alternatively, the method), wherein the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the emulsion.
153. The formulation of embodiment 150 (or alternatively, the method), wherein the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.
154. The formulation (or alternatively, the method) of any one of embodiments 150-153, wherein the stabilizer component comprises one or more substances independently selected from polysaccharides.
155. The formulation (or alternatively, the method) of any one of embodiments 150-153, wherein the stabilizer component comprises xanthan gum.
156. The formulation (or alternatively, the method) of any one of embodiments 117-155, wherein the emulsion further comprises a solvent component.
157. The formulation of embodiment 156 (or alternatively, the method), wherein the solvent component is present in an amount of about 1% to about 35% by weight of the emulsion.
158. The formulation of embodiment 156 (or alternatively, the method), wherein the solvent component is present in an amount of about 5% to about 25% by weight of the emulsion.
159. The formulation of embodiment 156 (or alternatively, the method), wherein the solvent component is present in an amount of about 10% to about 20% by weight of the emulsion.
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.
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.
162. A pharmaceutical formulation for the topical treatment of skin disorders comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof.
163. The pharmaceutical formulation of embodiment 162, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/2 inhibitor or pharmaceutically acceptable salt thereof; and the vitamin D3, vitamin D3 analogue or pharmaceutically acceptable salt thereof is a vitamin D3 analogue or pharmaceutically acceptable salt thereof.
164. The pharmaceutical formulation of embodiment 163, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof.
165. The pharmaceutical formulation of embodiment 165, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
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):
wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
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.
168. The pharmaceutical formulation of embodiment 163, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.
169. The pharmaceutical formulation of embodiment 163, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.
170. The pharmaceutical formulation of any one of embodiments 164-169, wherein the formulation comprises about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxotinib, or pharmaceutically acceptable salt thereof, on a free base basis.
171. The pharmaceutical formulation of any one of embodiments 164-169, wherein the formulation comprises about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.7 wt%, about 1.95 wt%, or about 1.95 wt%, or about 1.2 wt%, of the pharmaceutically acceptable salts thereof, based on the free base.
172. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises 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.
173. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises 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.
174. The pharmaceutical formulation of any one of embodiments 163-171, wherein the formulation comprises about 0.0001% w/w to about 0.01% w/w or about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analog or pharmaceutically acceptable salt thereof, based on free base.
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 pharmaceutically acceptable salt thereof on a free base basis.
176. The pharmaceutical formulation of any one of embodiments 162-175, wherein the formulation is a cream or lotion.
177. The pharmaceutical formulation of any one of embodiments 162-176, wherein the formulation is an oil-in-water emulsion.
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.
179. The pharmaceutical formulation of embodiment 178, wherein the water comprises about 5% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 20% to about 70%, about 20% to about 60%, or about 20% to about 50% by weight of the pharmaceutical formulation.
180. The pharmaceutical formulation of any one of embodiments 178-179, wherein the oil component comprises about 5 wt% to about 90 wt%, about 5 wt% to about 80 wt%, about 5 wt% to about 70 wt%, about 5 wt% to about 60 wt%, about 5 wt% to about 50 wt%, or about 5 wt% to about 40 wt% of the pharmaceutical formulation.
181. The pharmaceutical formulation of any one of embodiments 178-180, wherein the emulsifier or stabilizer component comprises about 1% to about 30% or about 5% to about 25% by weight of the pharmaceutical formulation.
182. The pharmaceutical formulation of any one of embodiments 178-180, further comprising a solvent component for dissolving ruxotinib or a pharmaceutically acceptable salt thereof.
183. The pharmaceutical formulation of embodiment 182, wherein the solvent component comprises about 5% to about 20%, about 2% to about 30%, about 5% to about 25%, about 5% to about 20%, or about 10% to about 20% by weight of the pharmaceutical formulation.
184. The pharmaceutical formulation of any one of embodiments 163-183, wherein the formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.
185. The pharmaceutical formulation of embodiment 184, wherein the pH of the formulation is adjusted with triethanolamine.
186. A method of treating a dermatological disorder 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.
187. The method of embodiment 186, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/2 inhibitor or pharmaceutically acceptable salt thereof; and the vitamin D3, vitamin D3 analogue or pharmaceutically acceptable salt thereof is a vitamin D3 analogue or pharmaceutically acceptable salt thereof.
188. The method of embodiment 187, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof.
189. The method of embodiment 187, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
190. The method of any one of embodiments 187-189, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is a compound having the formula (II):
Wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
191. The method of any one of embodiments 187-189, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol or pharmaceutically acceptable salt thereof.
192. The method of embodiment 187, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof and the vitamin D3 analog is calcipotriol.
193. The method of embodiment 187, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof and the vitamin D3 analog is maxacalcitol.
194. The method of any one of embodiments 187-193, wherein the skin disorder is an autoimmune or inflammatory skin disorder.
195. The method of any one of embodiments 187-193, wherein the skin disorder is a Th1 or Th 17-related skin disorder.
196. The method of any one of embodiments 187-193, wherein the skin disorder is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metallopeptidase 12 (MMP 12), or a combination thereof.
197. The method of any one of embodiments 187-193 wherein the skin disorder is mediated by Defb4, S100a12, or serpin 4.
198. The method of any one of embodiments 187-193 wherein the skin disorder is mediated by filaggrin/FLG, lorecin/LOR, IL-31, TSLP, CAMP, CCL17, CCL22, defB4a, interferon- γ, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF 18.
199. The method of any one of embodiments 187-193 wherein the skin disorder is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, lisieri syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.
200. The method of any of embodiments 187-193 wherein the skin disorder is rosacea, psoriatic arthritis, dermal fibrosis, scleroderma, schneits' nevi, dermatomycosis, or acne vulgaris.
201. The method of any one of embodiments 187-200 wherein there is a synergy between the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof.
202. The method of any one of embodiments 187-201 wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered at least once daily.
203. The method of any one of embodiments 187-201, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered at least twice daily.
204. The method of any one of embodiments 187-203 wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered simultaneously.
205. The method of any one of embodiments 187-203, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered sequentially.
206. The method of any one of embodiments 187-205 wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered as separate formulations.
207. The method of any one of embodiments 187-204 wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered in a single formulation.
208. The method of embodiment 206, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof are each administered in a topical formulation.
209. The method of embodiment 207, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered in a single topical formulation.
210. The method of embodiment 208, wherein each topical formulation is an ointment, cream, or lotion.
211. The method of embodiment 209, wherein the single topical formulation is an ointment, cream, or lotion.
212. The method of embodiment 211, wherein said single topical formulation is a cream or lotion.
213. The method of embodiment 211, wherein said single topical formulation is a cream formulation.
214. The method of any of embodiments 211-213, wherein said single topical formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.
215. The method of any one of embodiments 187-214 further comprising administering an additional therapeutic agent.
216. The method of embodiment 215, wherein the additional therapeutic agent is a corticosteroid.
217. The method of embodiment 216, wherein the corticosteroid is betamethasone dipropionate.
Examples
The presently claimed subject matter will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the claimed subject matter in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that may be changed or modified to produce substantially the same result.
All statistical analyses of in vitro experiments were performed using GraphPad prism software (7 th edition) using Kruskal-Wallis-Test and Mann-Whitney U assays. Gene expression was analyzed using the Partek Flow genome analysis software and the Subio Platform software v1.22.5266 using the Welch's t assay. The confidence interval was determined to be 95%. P <0.05 is considered "significant" (x) and P <0.01 is considered "highly significant" (x). KEGG pathways were mapped to differentially expressed genes using DAVID v6.8 (annotation, visualization, and integrated discovery database).
Example 1 in vitro JAK kinase assay
The JAK1 inhibitors useful in the treatment of cytokine-related diseases or disorders were tested for their inhibitory activity against JAK targets according to the following in vitro assay described in Park et al, analytical Biochemistry 1999,269,94-104. The catalytic domains of human JAK1 (a.a.837-1142), JAK2 (a.a.828-1132) and JAK3 (a.a.781-1124) with an N-terminal His tag were expressed in insect cells using baculovirus and purified. The catalytic activity of JAK1, JAK2 or JAK3 is determined by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by Homogeneous Time Resolved Fluorescence (HTRF). IC for measuring compounds for each kinase in a 40. Mu.L reaction 50 The reaction contained enzyme, ATP and 500nM peptide in 50mM Tris (pH 7.8) buffer with 100mM NaCl, 5mM DTT and 0.1mg/mL (0.01%) BSA. For 1mM IC 50 The ATP concentration in the reaction was measured to be 1mM. The reaction was carried out at room temperature for 1 hour and then incubated with 20. Mu.L of 45mM EDTA, 300nM SA-APC, in assay buffer (Perkin Elmer, boston, mass.),6nM Eu-Py20 termination. Binding of μ to europium-labeled antibodies occurred for 40 minutes and HTRF signals were measured on a fusion plate reader (Perkin Elmer, boston, MA). The compounds of Table 1 were tested in this assay and IC is shown in Table 1 50 Values.
Example 2: ex vivo skin pharmacodynamic experiments on combinations of JAK inhibitors and vitamin D3 analogs
Materials and methods
The pharmacodynamic assays described in this disclosure relate to examples of eliciting TH1, TH2 and TH17 responses similar to those published by Susan h.smith et al (Development of a Topical Treatment for Psoriasis Targeting ROR γ: from Bench to skin. Ploson. Publication time: month 2016, 2, which is incorporated by reference in its entirety). This paradigm was used to evaluate the therapeutic potential of active compounds in topical formulations against skin diseases (i.e. psoriasis, vitiligo and alopecia).
Can be usedThe dermatome removes the healthy human skin just removed from the cosmetic surgery to a thickness of about 750±100 μm. The removed skin was then further divided into 7mm biopsies for basal lateral or topical administration, taking care to avoid areas of varying thickness or streaks. The biopsies were placed in 6.5mm permeable membrane +.>In the insert for basal lateral or topical administration. Placing human skin in->In the insert, the stratum corneum side is on top, with a small amount of collagen between the basal dermis tissue and the permeable membrane.A schematic of the insert is shown in fig. 4. Overall experiments were performed on 8 individual skin donors, n=4 for basolateral administration; or 2 individual skin donors For topical administration. According to method a for basolateral administration or method B for topical administration, one donor may be used according to the combination of JAK inhibitor and vitamin D3 analogue at the desired concentration.
Method A (basolateral administration)
(i) Using an average surface area of about 0.33cm 2 And has a volume of 0.5mLPermeable insert (n=4 per treatment).
(ii) Placing skin prepared as described hereinIn the insert, the stratum corneum side is on top, with a small amount of collagen between the basal dermis tissue and the permeable membrane.
(iii) The basal chamber was filled with 0.5mL of medium and the drugs (JAK inhibitors and/or vitamin D3 analogues) were added to the medium at the indicated final concentrations, pre-treated overnight (about 16 hours) in a humidified incubator at 37 ℃.
(iv) The next day, the basal chamber contents of each insert were aspirated in vacuo and replaced with 0.5mL of pre-heated (about 37 ℃) keratinization medium containing test compound and fresh stimulation mixture.
(v) The culture may be stored in a humidified incubator at 37 ℃.
(vi) Tissue explants can be harvested 24 hours after stimulation. Half of the tissue was placed in RNALater to determine cytokine production by RT-qPCR.
(vii) Tissue homogenization: the tissue tube was placed in an Omni homogenizer and run at 5m/s for 3 cycles for 30 seconds with a residence time set to 10 seconds. Homogenization was repeated 4 times for a total of 12 cycles, with 1 minute and 30 seconds on ice between each run to cool the sample. After the last run, the tissue tube was cooled on ice for the same duration.
(viii) Samples were subjected to RT-PCR in duplicate with 40 cycle thresholds on a Applied Biosystems Quant standard RT-qPCR program, using GAPDH as a housekeeping gene.
IC based on compound 50 Appropriate concentrations of JAK inhibitors and vitamin D3 analogs were determined. For example, JAK inhibitor Lu Suoti Ni inhibits IL-23 stimulated IL-22 production in human T cells 50 50nM and IC50 of 281nM in human whole blood TPO-induced STAT3 phosphorylation assay (Fridman et al, J Invest Dermatol,2011, 9; 131 (9): 1838-44 (PMID: 21677670), and Fridman et al, J Immunol,2010, 5, 184 (9): 5298-307 (PMID: 20363976). Likewise, tacalcitol, calcipotriol and maxacalcitol reduce keratinocyte line proliferation in a concentration-dependent manner, IC thereof 50 About 10-100nM (Takahasi et al, J Dermatol Sci, month 2 2003; 31 (1): 21-8 (PMID: 12615360)). Below (down to 0) and above IC 50 Concentrations can be used for JAK inhibitors (e.g., lu Suoti ni, diltiazem, etc.) and vitamin D3 analogs (e.g., tacalcitol, calcipotriol, and maxacalcitol).
Method B (topical administration)
(i) Using an average surface area of about 0.33cm 2 And has a volume of 0.5mLPermeable insert (n=4 per treatment).
(ii) Placing skin prepared as described hereinIn the insert, the stratum corneum side is located on the basolateral side with a small amount of collagen between the basal dermis tissue and the permeable membrane.
(iii) The basal chamber was filled with 0.5mL of medium. Topical application of drugs (JAK inhibitors and/or vitamin D3 analogues) to the apical side of removed skin (about 18ul/cm 2 ) Pretreatment was carried out overnight (16 or 24 hours) at 37℃in a humidified incubator.
(iv) The next day, the contents of the basal chamber of each insert were aspirated under vacuum. The medium was replaced with 0.5mL of pre-warmed (about 37 ℃) keratinization medium containing fresh stimulation mixture.
(v) The culture may be stored in a humidified incubator at 37 ℃.
(vi) Tissue explants can be harvested 24 hours after stimulation. Half of the tissue was placed in RNALater to determine cytokine production by RT-qPCR.
(vii) Tissue homogenization: the tissue tube was placed in an Omni homogenizer and run at 5m/s for 3 cycles for 30 seconds with a residence time set to 10 seconds. Homogenization was repeated 4 times for a total of 12 cycles, with 1 minute and 30 seconds on ice between each run to cool the sample. After the last run, the tissue tube was cooled on ice for the same duration.
(viii) Samples were subjected to RT-PCR in duplicate with 40 cycle thresholds on a Applied Biosystems Quant standard RT-qPCR program, using GAPDH as a housekeeping gene.
Lu Suoti Niand calcipotriol-administered basolaterally (method A)
Experiments were performed as described above in the materials and methods of example 2 (method a) section, with respect to phosphoric acid Lu Suoti ni and calcipotriol. The list of treatment conditions for donors 2 and 3 with the addition of ruxotinib phosphate (calculated on the basis of the free base) and/or calcipotriol to stimulate Th1 or Th17 is shown in tables 2 and 3, respectively.
TABLE 2
TABLE 3 Table 3
Note that: after 1000-fold dissolution of each test compound in 100% DMSO, the stock solution was stored at-20 ℃.
Biomarkers such as IL-22, CXCL10, and MMP12 levels for test compounds and combinations thereof were quantified and fold changes in gene expression relative to untreated controls were calculated. Unexpectedly and surprisingly, the combination of calcipotriol and ruxotinib showed a synergistic effect in reducing IL-22, CXCL10 and MMP12 levels, as shown in figures 1-3. For example, the combination of tests significantly reduced IL-22 levels, and this reduction was statistically significant. The combination tested also effectively reduced CXCL10 levels, and this reduction was statistically significant. The combination tested effectively reduced MMP12 levels and this reduction was statistically significant. These results are unexpected and surprising for several reasons. One reason generally known in the art is that the major source of vitamin D in humans is skin synthesized in sunlight, and to date, the anti-inflammatory efficacy of JAK inhibitors against skin diseases has not been correlated with geographic location or sunlight exposure. Another reason is that the clinical efficacy of vitamin D3 analogs is thought to be driven primarily by their ability to normalize keratinocyte hyperproliferation and regulate epidermal differentiation, and these mechanisms are independent of inflammatory cytokines that utilize the JAK pathway. See Hu et al, "Reciprocal role of vitamin D receptor on beta-catenin regulated keratinocyte proliferation and differentiation" J Steroid Biochem Mol biol.2014, month 10; 144Pt A:237-41, PMID:24239508, which is incorporated herein by reference in its entirety. Furthermore, a recent study on psoriasis showed that skin biopsies of psoriatic patients treated with topical calcipotriol showed a significant decrease in CD8 (+) IL-17 (+) T cells in psoriasis lesions, but no change in the frequency of IL-22 (+) or IFN- γ (+) cells. See Dyring-Andersen et al, "The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+IL-17+T Cells in Psoriasis Lesions.Scand J Immunol"2015, 7 months; 82 (1) 84-91, PMID:25904071, which is incorporated by reference in its entirety. Thus, it was unexpectedly and surprisingly found that there was a synergy between calcipotriol and ruxotinib in reducing IL-22, CXCL10 and MMP12 levels.
In addition, the levels of the test compounds (Lu Suoti ny and calcipotriol) and other gene markers of the combination thereof were also quantified. Absolute fold changes in gene expression relative to untreated controls were calculated. Fig. 6A-6B show that the combination of calcipotriol and ruxotinib caused >2 or >4 absolute fold changes in certain genes compared to untreated controls (white indicates <2 absolute fold changes, grey indicates >2 absolute fold changes, and black indicates >4 absolute fold changes). Among the genes with the highest absolute fold change, the barrier function genes (filaggrin/FLG and lorecin/LOR) are associated with many dermatological diseases; IL-31 and TSLP are associated with itch and are common in many dermatological diseases; and CAMP and DefB4 are antimicrobial peptides, associated with skin disorders where the barrier is disrupted (which can increase infection).
Lu Suoti Niand Maxacalcitol-basolateral administration (method A)
Experiments were performed as described above in the materials and methods of example 2 (method a) section, with respect to Lu Suoti ni phosphate and maxacalcitol. The list of treatment conditions for donor 2 and 3 with the addition of ruxotinib phosphate (calculated on the basis of the free base) and/or maxacalcitol to stimulate Th1 or Th17 is shown in tables 4 and 5, respectively.
TABLE 4 Table 4
TABLE 5
Note that: after 1000-fold dissolution of each test compound in 100% DMSO, the stock solution was stored at-20 ℃.
The levels of the test compounds and their combined biomarkers, such as IL-22 and CXCL10, were quantified and fold changes in gene expression relative to untreated controls were calculated. Unexpectedly and surprisingly, the combination of maxacalcitol and ruxotinib showed a synergistic effect in reducing IL-22 and CXCL10 levels, as shown in fig. 7A-7B.
Lu Suoti Niand calcipotriol-topical administration (method B)
Aqueous based solutions of phosphoric acid Lu Suoti ni and calcipotriol, alone and in combination, were prepared using phosphoric acid Lu Suoti ni and calcipotriol according to the following procedure (see table 6):
(i) BHT was initially added to Transcutol P in amber Duran and stirred at 500RPM until visually homogeneous.
(ii) The solution of step (i) was added to the remaining polar phase excipients in amber Duran and stirred by a magnetic stirrer bar at 500RPM until visually homogeneous.
(iii) Ruxotinib phosphate was added to the polar phase of step (ii) and stirred at 500RPM for 5min, at which step Lu Suoti of the phosphate was not completely dissolved.
(iv) The pH of the suspension of step (iii) was adjusted to pH 6.5-7.0 with triethanolamine and phosphoric acid Lu Suoti ni dissolved during this step.
(v) Calcipotriol monohydrate was added to the polar phase of step (iv) and stirred at 500RPM for 1 hour at 65 ℃ and then at ambient laboratory temperature overnight to dissolve.
(vi) Proper amount of water is added to 100 percent.
TABLE 6
The aqueous solutions shown in table 6 were tested against phosphoric acid Lu Suoti ni and calcipotriol as described above in the materials and methods section of example 2 (method B). The list of treatment conditions for donor 1 and 2 with the addition of ruxotinib phosphate (calculated on the basis of the free base) and/or calcipotriol to stimulate Th1 or Th17 is shown in tables 7 and 8, respectively.
TABLE 7
TABLE 8
The levels of the test compounds and their combined biomarkers, such as S100a12, defb4, serpin 4, MMP12, IL-22, and CXCL10, were quantified and fold changes in gene expression relative to untreated controls were calculated (fig. 8A-8C and fig. 9A-9C). Unexpectedly and surprisingly, calcipotriol and Lu Suoti ni combined in a topically applied aqueous based solution showed synergy in reducing the levels of S100a12, defb4, serpin 4 and MMP12, as shown in fig. 8A-8C and fig. 9A. S100a12 is an important marker for psoriasis disease activity (Wilsmann-Theis, D et al, J Eur Acad Dermatol Venereol,30 (7): 1165-70 (2016); doi: 10.1111/jdv.13269). Defb4 encodes the antimicrobial peptide human beta-defensin 2 (hBD 2), which plays a vital role in the inflammatory process of the skin and in the pathogenesis of psoriasis (Johansen C et al, J Invest Derm,136 (8): 1608-1616 (2016); doi: 10.1016/j.jid.2016.04.012). Serpinb4 causes inflammation in patients with chronic skin disorders, including atopic dermatitis (Sivaprasad, U.S. et al, J Invest Derm 135 (1): 160-169 (2015); DOI: 10.1038/jid.2014.353). These results are unexpected and surprising for several reasons. One reason generally known in the art is that the major source of vitamin D in humans is skin synthesized in sunlight, and to date, the anti-inflammatory efficacy of JAK inhibitors against skin diseases has not been correlated with geographic location or sunlight exposure. Another reason is that the clinical efficacy of vitamin D3 analogs is thought to be driven primarily by their ability to normalize keratinocyte hyperproliferation and regulate epidermal differentiation, and these mechanisms are independent of inflammatory cytokines that utilize the JAK pathway. Thus, it was unexpectedly and surprisingly found that there was a synergy between calcipotriol and ruxotinib in reducing the levels of S100a12, defb4, serpin b4 and MMP 12. The combination of calcipotriol and Lu Suoti ni in the topically applied aqueous solution also reduced gene expression of IL-22 and CXCL10 (fig. 9B-9C); however, high levels of ruxotinib (0.75% and 1.5%) in aqueous solutions also have a strong effect on gene expression, and thus it is difficult to assess the synergistic effect of topical application, although this synergistic effect is observed at lower concentrations in basolateral applications (method a).
Example 3: a process for preparing a ruxotinib cream and a process for preparing a Lu Suoti ni and calcipotriol combined cream.
Described herein are methods for preparing ruxotinib creams (formulations #1, #2, #4 and # 5) containing 1.5% w/w ruxotinib based on free base and methods for preparing Lu Suoti and calcipotriol combination creams (formulations #3 and # 6) containing 1.5% w/w Lu Suoti ni and 50 micrograms/g calcipotriol based on free base.
For the preparation of Lu Suoti-ni and calcipotriol combined cream, ruxotinib was incorporated in the aqueous phase and calcipotriol was first dissolved in medium chain triglycerides and then added to the oil-in-water emulsion. The preparation steps are as follows:
1. preparation of 1mg/g calcipotriol solution in medium chain triglycerides. Calcipotriol was dissolved in medium chain triglycerides at 1mg/g via heating at about 60 ℃. When the calcipotriol is completely dissolved, the heating is stopped. The resulting stock solution was covered with aluminum foil to protect from light.
2. And (3) preparation of an aqueous phase. Purified water, disodium EDTA, low molecular weight PEG, and phosphoric acid Lu Suoti ni were mixed together according to their respective weight percentages as set forth in table 10, and the resulting mixture was heated at about 55 ℃ to about 60 ℃ while stirring to dissolve the disodium EDTA and Lu Suoti ni to form an aqueous phase.
3. Preparation of the paraben phase. Methyl parahydroxybenzoate and propyl parahydroxybenzoate were added to propylene glycol according to their respective weight percentages as described in table 10 to form a mixture. The resulting mixture is heated at about 55 ℃ to about 60 ℃ while stirring to dissolve the methyl and propyl parabens to form a paraben phase.
4. And (3) preparation of a xanthan gum phase. Xanthan gum is mixed with propylene glycol according to the corresponding weight percentages described in table 10, and the resulting mixture is heated at about 55 ℃ to about 60 ℃ to form a xanthan gum phase in dispersion.
5. And (3) preparing an oil phase. White petrolatum, light mineral oil, glyceryl stearate SE, cetyl alcohol, stearyl alcohol, dimethicone, medium chain triglycerides and polysorbate 20 were mixed according to the corresponding weight percentages described in table 10, and the resulting mixture was heated to about 65 ℃ to about 68 ℃ while stirring until all excipients melted to form an oil phase.
6. The aqueous phase is heated to about 65 ℃ to about 68 ℃ while stirring at about 600-800 rpm.
7. The paraben phase was transferred to the heated aqueous phase according to the percentages described in table 10 and the resulting mixture was thoroughly stirred and maintained at about 65 ℃ to about 68 ℃ with the stirring speed maintained at about 600-800 rpm.
8. The xanthan gum was transferred to the mixture of the aqueous phase and the paraben phase according to the percentages described in table 10 and the resulting mixture was thoroughly stirred and maintained at about 65 ℃ to about 68 ℃ with the stirring speed maintained at about 600-800 rpm.
9. Preparation of oil-in-water emulsion. The oil phase was transferred to a mixture of the aqueous phase, the paraben phase and the xanthan phase according to the percentages described in table 10. The resulting mixture was thoroughly stirred and maintained at about 65 ℃ to about 68 ℃ and the stirring speed was maintained at about 600-800rpm to form an oil-in-water emulsion.
10. The oil-in-water emulsion is cooled to about 38 ℃ to about 40 ℃.
11. Phenoxyethanol was added to the cooled oil-in-water emulsion according to the percentages described in table 10. The temperature of the resulting mixture was maintained at about 38 ℃ to about 40 ℃ and the stirring speed was maintained at about 600-800 rpm.
For the Lu Suoti-ni and calcipotriol combined cream (formulations #3 and # 6), the solution of calcipotriol in medium chain triglycerides and light mineral oil were added to the oil-in-water emulsion according to the respective percentages described in table 10. The resulting mixture was maintained at about 38 ℃ to about 40 ℃ and the stirring speed was maintained at about 600-800 rpm. For the ruxotinib cream alone (formulations #1, #2, #4 and # 5), medium chain triglycerides and light mineral oil were added to the oil-in-water emulsion according to the corresponding percentages described in table 10. The resulting mixture was maintained at about 38 ℃ to about 40 ℃ while maintaining the stirring speed at about 600-800 rpm. After the resulting mixture was cooled and stirring was stopped, creams (formulations #1 to # 6) were formed and collected.
Table 9 lists the weight percentages of the different phases of cream formulations #1 to # 6. Table 10 lists the weight percentages of phosphoric acid Lu Suoti, calcipotriol and excipients in cream formulations #1 to # 6.
Table 9 weight percent of different phases of the ruxotinib cream (formulations #1, #2, #4, and # 5) and the ruxotinib and calcipotriol combined cream (formulations #3 and # 6). It should be noted that the amount of ruxotinib phosphate for formulations #1 to #6 is 1.98%, which corresponds to 1.5% w/w ruxotinib based on free base. For formulations #3 and #6, the amount of calcipotriol was 0.005% w/w or 50 micrograms/g. Formulations #1, #2, #4, and #5 contained no calcipotriol.
Table 10 weight percent of phosphoric acid Lu Suoti, calcipotriol and excipients for formulations #1 to # 6.
The cream forms of formulations #1 to #6 are shown in fig. 5. Cream formulations #1 to #3 contained 7.0% w/w PEG 300; whereas cream formulations #4 to #6 contained 7.0% w/w PEG400. Propylene glycol content in cream formulations #1, #3, #4 and #6 was 6.5% w/w, while propylene glycol content in cream formulations #2 and #5 was 8.5% w/w. In all cream formulations #1 to #6, the content of ruxotinib was 1.5% w/w based on free base. Formulations #3 and #6 are Lu Suoti-Ni and calcipotriol combination creams containing ruxotinib (1.5% w/w based on free base) and calcipotriol (0.005% w/w).
Additional formulations (formulation # 7) containing 1.1% w/w Lu Suoti Ni and 0.0005% w/w calcipotriol based on free base were prepared.
For the preparation of Lu Suoti-ni and calcipotriol combined cream, ruxotinib was incorporated into the aqueous phase and calcipotriol was heated to dissolve in the liquid oil phase, the solid oil phase vehicle was heated to melt and then the aqueous phase, liquid oil phase and melted solid oil phase vehicle were combined and homogenized to produce a formulation, which was then cooled. Antimicrobial preservatives are added to the cooled formulation and the resulting formulation is stirred until visually homogeneous, its pH is adjusted if necessary and water is added thereto as needed to make up the volume. The preparation steps are as follows:
(i) EDTA was initially added to the water in amber Duran and stirred at 500RPM until visually homogeneous.
(ii) BHA was initially added to Transcutol P in amber Duran and stirred at 500RPM until visually homogeneous.
(iii) The solutions of steps (i) and (ii) were added to the remaining aqueous phase vehicle (glycerin) in amber Duran and stirred by a magnetic stirrer bar at 500RPM until visually homogeneous.
(iv) Ruxotinib phosphate was added to the aqueous phase of step (iii) and stirred at 500RPM for 5min, at which step Lu Suoti of the phosphate was not completely dissolved.
(v) The pH of the suspension of step (iv) was adjusted to pH 6.0-7.0 with triethanolamine and phosphoric acid Lu Suoti ni dissolved during this step.
(vi) In amber Duran alone, BHT was added to the oleyl alcohol and sweet almond oil and stirred at 250RPM until visually homogeneous.
(vii) The solution of step (vi) was added to the remaining liquid oil phase excipients (polysorbate 80 and light mineral oil) and stirred at 500RPM for 3-5min until visually homogeneous.
(viii) Calcipotriol is added to the liquid oil phase of step (vii) and stirred at 500RPM for 1 hour at 65 ℃ and then stirred overnight at ambient laboratory temperature to dissolve.
(ix) After dissolution of the calcipotriol in step (viii), poloxamer 407 is dispersed into the solution of step (viii) by stirring at 500 RPM.
(x) The solid oil phase vehicle was weighed into an amber Duran alone and placed in a 70 ℃ water bath until melted. The aqueous phase of step (v), the liquid oil phase of step (ix) and the homogenizer head (silverson, square-hole, high shear screen) were also placed in a water bath for 3min.
(xi) The phases were combined and homogenized at 10,000RPM for 2min.
(xii) The formulation of step (xi) was stirred using an IKA anchor at 100RPM until the formulation cooled to ambient laboratory temperature.
(xiii) Phenoxyethanol was added to the formulation of step (xii) and stirred manually until visually homogeneous.
(xiv) The pH of the formulation was checked, adjusted if necessary, fixed volume with water and further manually stirred until visually homogeneous.
Table 11 lists the weight percentages of formulation # 7.
Table 11 composition of cream formulation # 7. It should be noted that the amount of ruxotinib phosphate is 1.464%, which corresponds to 1.1% w/w ruxotinib based on free base. The amount of calcipotriol was 0.005% w/w.
1 Triethanolamine and phosphoric acid can be used to adjust the pH, and additional water can be added to make up 100w/w% of formulation # 7.
Example 4. Lu Suoti Niand calcipotriol combination cream with other excipient concentrations.
A cream formulation was prepared as described in example 3, wherein phosphoric acid Lu Suoti ni was present in an amount of about 0.75% w/w based on free base, the water percentage in example 3 being adjusted as needed.
The cream formulation is prepared as described in example 3, wherein propylene glycol is 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), the water percentage in example 3 being adjusted as desired.
Cream formulations were prepared as described in example 3, using various low molecular weight polyethylene glycols (PEG), including PEG200, PEG300, PEG400, or combinations thereof as co-solvents.
A cream formulation was prepared as described in example 3, wherein the methyl parahydroxybenzoate content ranged between 0 and about 0.1% w/w, and wherein the propyl parahydroxybenzoate content was 0 to about 0.05% w/w (the water percentage in example 3 was adjusted as needed).
A cream formulation was prepared as described in example 3, and a cream formulation having a xanthan gum content of about 0.2 to about 0.6% w/w (the water percentage in example 3 was adjusted as needed) was prepared.
A cream formulation was prepared as described in example 3, wherein Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA) and tocopherol were used alone or in combination, added to the oil phase (adjusting the water percentage in example 3 if needed).
A cream formulation was prepared as described in example 3, wherein ascorbyl palmitate, ascorbic acid or citric acid or a combination thereof was added to enhance the stability of calcipotriol.
Example 5A combination cream of Lu Suoti Ni and calcipotriol in a mouse model of IL-23 induced psoriasis-like disease
The combination cream formulation (formulation #7 of example 3) was tested in an established mouse model of IL-23-induced psoriasis-like disease (Rizzo HL et al, "IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A," J Immunol186:1495-1502 (2011); 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), which diseases include acanthosis and inflammatory cell accumulation in the epidermis and dermis, resulting in localized skin thickening. IL-23 was injected intradermally into one ear on day 0, day 2, day 4 and day 7. Topical cream vehicle or formulation #7 (example 3) was topically applied to one ear of an IL-23 induced psoriasis-like mouse. The cream was applied twice daily (b.i.d.), 20ug each, for 8 days. The extent of swelling of the ear was measured with an engineer caliper. A statistically significant reduction in ear thickening (p < 0.001) was measured in mice treated with formulation #7 compared to vehicle treated mice (fig. 10).
Various modifications of the 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 this disclosure, including all patents, patent applications, and publications, is incorporated by reference in its entirety.

Claims (56)

1. A pharmaceutical formulation for the topical treatment of skin disorders comprising (a) a JAK inhibitor or a pharmaceutically acceptable salt thereof and (b) vitamin D3, a vitamin D3 analogue or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical formulation of claim 1, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/2 inhibitor or 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.
3. The pharmaceutical formulation of claim 2, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof.
4. The pharmaceutical formulation of claim 2, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
5. The pharmaceutical formulation of any one of claims 1-4, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is a compound having formula (II):
wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
6. The pharmaceutical formulation of any one of claims 1-5, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol or pharmaceutically acceptable salt thereof.
7. The pharmaceutical formulation of claim 2, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.
8. The pharmaceutical formulation of claim 2, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.
9. The pharmaceutical formulation of any one of claims 3-8, wherein the formulation comprises about 0.05% to about 3.0% or about 0.05% to about 1.5% w/w of the ruxotinib, or pharmaceutically acceptable salt thereof, on a free base basis.
10. The pharmaceutical formulation of any one of claims 3-8, wherein the formulation comprises about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1.0 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.25 wt%, about 1.3 wt%, about 1.35 wt%, about 1.4 wt%, about 1.45 wt%, about 1.5 wt%, about 1.55 wt%, about 1.6 wt%, about 1.5 wt%, about 1.95 wt%, or about 1.95 wt%, or about 1.2 wt%, or about 1.95 wt%, of the pharmaceutically acceptable salts thereof, based on the free base.
11. The pharmaceutical formulation of any one of claims 2-10, wherein the formulation comprises about 0.0001% w/w to about 0.01% w/w of the vitamin D3 analogue or a pharmaceutically acceptable salt thereof, based on free base.
12. The pharmaceutical formulation of any one of claims 2-10, wherein the formulation comprises about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analogue or a pharmaceutically acceptable salt thereof, based on free base.
13. The pharmaceutical formulation of any one of claims 2-10, wherein the formulation comprises about 0.0001% w/w to about 0.01% w/w or about 0.0001% w/w to about 0.005% w/w of the vitamin D3 analogue or pharmaceutically acceptable salt thereof, based on free base.
14. The pharmaceutical formulation of any one of claims 2-10, wherein the formulation comprises about 0.005% w/w of the vitamin D3 analogue or pharmaceutically acceptable salt thereof, on a free base basis.
15. The pharmaceutical formulation of any one of claims 1-14, wherein the formulation is a cream or lotion.
16. The pharmaceutical formulation of any one of claims 1-15, wherein the formulation is an oil-in-water emulsion.
17. The pharmaceutical formulation of any one of claims 1-16, wherein the formulation comprises water, an oil component, and an emulsifier or stabilizer component.
18. The pharmaceutical formulation of claim 17, wherein the water comprises about 5 wt% to about 90 wt%, about 10 wt% to about 80 wt%, about 10 wt% to about 70 wt%, about 10 wt% to about 60 wt%, about 20 wt% to about 70 wt%, about 20 wt% to about 60 wt%, or about 20 wt% to about 50 wt% of the pharmaceutical formulation.
19. The pharmaceutical formulation of any one of claims 17-18, wherein the oil component comprises about 5 wt% to about 90 wt%, about 5 wt% to about 80 wt%, about 5 wt% to about 70 wt%, about 5 wt% to about 60 wt%, about 5 wt% to about 50 wt%, or about 5 wt% to about 40 wt% of the pharmaceutical formulation.
20. The pharmaceutical formulation of any one of claims 17-19, wherein the emulsifier or stabilizer component comprises about 1% to about 30% or about 5% to about 25% by weight of the pharmaceutical formulation.
21. The pharmaceutical formulation of any one of claims 17-20, further comprising a solvent component for dissolving ruxotinib or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical formulation of claim 21, wherein the solvent component comprises from about 5% to about 20%, from about 2% 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.
23. The pharmaceutical formulation of any one of claims 2-22, wherein the formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.
24. The pharmaceutical formulation of claim 23, wherein the pH of the formulation is adjusted with triethanolamine.
25. A method of treating a dermatological disorder 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.
26. The method of claim 25, wherein the JAK inhibitor or pharmaceutically acceptable salt thereof is a JAK1/2 inhibitor or 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.
27. The method of claim 26, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib or a pharmaceutically acceptable salt thereof.
28. The method of claim 26, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof is ruxotinib phosphate.
29. The method of any one of claims 26-28, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is a compound having formula (II):
Wherein:
R 1 is H or OH;
R 2 and R is 3 Each is H; or alternatively
R 2 Is O-R 2A The method comprises the steps of carrying out a first treatment on the surface of the And R is 3 Is H; or alternatively
R 2 And R is 3 Together form =ch 2 A group;
R 2A is-C 1-4 An alkylene-OH;
R 4 and R is 5 Each is H; or alternatively
R 4 And R is 5 Together form =ch 2 A group;
R 6 and R is 7 Each is H; or alternatively
R 6 And R is 7 Together form =ch 2 A 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 is 12 Is H or OH;
R 9 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 10 is C 1-3 Alkyl or C 1-4 A haloalkyl group;
R 11 is H or OH;
or alternatively, R 9 And R is 10 Together with the carbon atoms to which they are attached form C 3-4 A cycloalkyl ring; and R is 11 Is H.
30. The method of any one of claims 26-28, wherein the vitamin D3 analog or pharmaceutically acceptable salt thereof is calcipotriol or maxacalcitol or pharmaceutically acceptable salt thereof.
31. The method of claim 26, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is calcipotriol.
32. The method of claim 26, wherein the JAK1/2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analog is maxacalcitol.
33. The method of any one of claims 26-32, wherein the skin disorder is autoimmune or inflammatory skin disorder.
34. The method of any one of claims 26-32, wherein the dermatological disorder is a Th1 or Th17 related dermatological disorder.
35. The method of any one of claims 26-32, wherein the skin disorder is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL 10), matrix metallopeptidase 12 (MMP 12), or a combination thereof.
36. The method of any one of claims 26-32, wherein the dermatological disorder is mediated by Defb4, S100a12, or serpin 4.
37. The method of any one of claims 26-32, wherein the skin disorder is mediated by filaggrin/FLG, lorecin/LOR, IL-31, TSLP, CAMP, CCL17, CCL22, defB4a, interferon- γ, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF 18.
38. The method of any one of claims 26-32, wherein the skin disorder is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, rette's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, congenital pachyrhizus, multiple sebaceous cysts, lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.
39. The method of any one of claims 26-32, wherein the skin disorder is rosacea, psoriatic arthritis, dermal fibrosis, scleroderma, schneider's nevi, dermatomycosis, or acne vulgaris.
40. The method of any one of claims 26-39, wherein there is a synergy between the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof.
41. The method of any one of claims 26-40, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered at least once daily.
42. The method of any one of claims 26-40, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered at least twice daily.
43. The method of any one of claims 26-42, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered simultaneously.
44. The method of any one of claims 26-42, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered sequentially.
45. The method of any one of claims 26-44, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered as separate formulations.
46. The method of any one of claims 26-43, wherein (a) the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and (b) the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered in a single formulation.
47. The method of claim 45, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof are each administered in a topical formulation.
48. The method of claim 46, wherein the JAK1/2 inhibitor or pharmaceutically acceptable salt thereof and the vitamin D3 analog or pharmaceutically acceptable salt thereof are administered in a single topical formulation.
49. The method of claim 47, wherein each topical formulation is an ointment, cream, or lotion.
50. The method of claim 48, wherein the single topical formulation is an ointment, cream, or lotion.
51. The method of claim 50, wherein the single topical formulation is a cream or lotion.
52. The method of claim 50, wherein the single topical formulation is a cream formulation.
53. The method of any one of claims 50-52, wherein the single topical formulation has a pH of about 6.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0.
54. The method of any one of claims 26-53, further comprising administering an additional therapeutic agent.
55. The method of claim 54, wherein the additional therapeutic agent is a corticosteroid.
56. The method of claim 55, wherein the corticosteroid is betamethasone dipropionate.
CN202180091979.6A 2020-12-04 2021-12-03 JAK inhibitors containing vitamin D analogues for the treatment of skin disorders Pending CN117157080A (en)

Applications Claiming Priority (4)

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US63/121,531 2020-12-04
US202163199876P 2021-01-29 2021-01-29
US63/199,876 2021-01-29
PCT/US2021/061744 WO2022120131A1 (en) 2020-12-04 2021-12-03 Jak inhibitor with a vitamin d analog for treatment of skin diseases

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