Topical formulations of ruxolitinib and organic amine pH modifiers for the treatment of skin diseases

Abstract

The present disclosure relates to a topical formulation comprising a JAK1 / 2 inhibitor, ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjuster, and a method of using the topical formulation to treat skin diseases, including, but not limited to, psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, and keratinization disorders. The organic amine pH adjuster is a tertiary amine or an alkanolamine.

Description

[Technical field]

[0001] This application claims priority to U.S. Patent Application No. 17 / 541,601, filed December 3, 2021, and U.S. Provisional Patent Application No. 63 / 365,973, filed June 7, 2022, the contents of each of which are incorporated by reference in their entirety herein.

[0002] The present disclosure relates to topical formulations and methods of treating skin disorders administering a JAK1 / 2 inhibitor that is ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjusting agent. [Background technology]

[0003] Inflammation mediated by Janus kinase (JAK) signal transducer is one of the key features of autoimmune skin diseases.Janus kinase (JAK) inhibitors have been developed as drugs for treating inflammatory skin diseases, including atopic dermatitis, alopecia areata, psoriasis, and vitiligo.For example, JAK1 / 2 inhibitor ruxolitinib has been approved as a topical product for the treatment of atopic dermatitis, and has been investigated in clinical trials for the treatment of vitiligo and psoriasis.

[0004] Current topical formulations of ruxolitinib utilize the phosphate salt of ruxolitinib, which is described and patented in U.S. Patent No. 8,722,693, which is incorporated herein by reference in its entirety. Because phosphate salts are acidic, topical cream products generally have a low pH. Furthermore, formulations with higher pH have not been clinically studied, in part because the solubility of ruxolitinib is pH-dependent, and currently approved formulations are limited to a strength of 1.5% w / w ruxolitinib on a free base basis.

[0005] Unexpectedly, topical formulations of ruxolitinib with higher pH have been discovered and are disclosed herein. Summary of the Invention

[0006] As mentioned above, ruxolitinib phosphate is approved as a topical cream formulation of 1.5% w / w for the treatment of atopic dermatitis, and is being investigated in clinical trials for the treatment of vitiligo and psoriasis. Because phosphates are acidic, cream products generally have a low pH (e.g., pH 3.6 or less). Cream products are approved at a strength of ruxolitinib phosphate 1.5% w / w on a free base basis, in part because the solubility of acidic ruxolitinib phosphate is pH-dependent. In fact, the solubility of ruxolitinib phosphate has been shown to be dramatically higher in deionized water (about 1.8% w / w) than in pH 7 buffer (0.03% w / w) (see Example 1).

[0007] Unexpectedly, topical formulations of ruxolitinib with higher pH have been discovered, which are disclosed herein. This discovery utilizes organic amine pH modifiers that allow good solubility of ruxolitinib in solution and in the formulation and at a pH greater than 4 (e.g., pH 5.5). In some of the solvent systems of the formulations, the use of organic pH modifiers surprisingly resulted in higher saturated solubility of ruxolitinib in the formulations.

[0008] Moreover, it was surprisingly discovered that formulations utilizing organic pH modifiers were able to deliver greater amounts of ruxolitinib to the dermis of the skin compared to formulations without an organic pH modifier, even though the strength of ruxolitinib in the formulations utilizing the organic pH modifiers was substantially lower.

[0009] In addition, it was found that the solubility of ruxolitinib salt was synergistically increased using the solvent combinations of Transcutol P and glycerol, and water and ethanol. These solvent combinations are useful for preparing novel formulations of ruxolitinib.

[0010] Thus, the present disclosure provides a topical formulation for treating skin disease, comprising a JAK1 / 2 inhibitor that is ruxolitinib or its pharma- ceutically acceptable salt, and an organic amine pH adjuster.The present disclosure further provides an organic amine pH adjuster that is a tertiary amine or an alkanolamine.In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine.In some embodiments, the alkanolamine is a trialkanolamine.

[0011] The present disclosure also provides a formulation in which the JAK1 / 2 inhibitor is a pharma- ceutically acceptable salt of ruxolitinib. The present disclosure also provides a formulation in which the JAK1 / 2 inhibitor or a pharma-ceutically acceptable salt thereof is ruxolitinib phosphate. The present disclosure also provides a formulation in which the JAK1 / 2 inhibitor or a pharma-ceutically acceptable salt thereof is ruxolitinib sulfate. The present disclosure also provides a formulation in which the JAK1 / 2 inhibitor or a pharma-ceutically acceptable salt thereof is ruxolitinib maleate. It is recognized that organic pH adjusters may interact with acid salts of ruxolitinib, such as ruxolitinib phosphate, and may result in the formation of ruxolitinib free base or other complex mixtures. Thus, the embodiments and claims that describe ruxolitinib salts, including ruxolitinib phosphate, are intended to encompass such species or mixtures.

[0012] The present disclosure provides formulations comprising about 0.05% to about 3.0% or about 0.05% to about 1.5% w / w of ruxolitinib or a pharma- ceutically acceptable salt thereof on a free base basis. Further for example, the disclosure provides for about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 2.5% by weight of the formulation on a free base basis. %, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof.

[0013] The present disclosure provides for the formulation to be in a form selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel. The present disclosure provides for the formulation to be a cream or a lotion.

[0014] The present disclosure also provides formulations further comprising one or more of water, an oil component, an emulsifier or stabilizer component, and a solvent component. The present disclosure provides formulations in which water is present in an amount of about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the formulation. The present disclosure provides formulations in which an oil component is present in an amount of about 5% to about 90% by weight, about 5% to about 80% by weight, about 5% to about 70% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, or about 5% to about 40% by weight of the formulation. The disclosure provides formulations in which the emulsifier or stabilizer component is present in an amount of about 1% to about 30% by weight or about 5% to about 25% by weight of the formulation. The disclosure provides formulations in which the solvent component constitutes about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the pharmaceutical formulation.

[0015] The present disclosure provides formulations further comprising one or more of a stabilizer and an antioxidant.

[0016] The present disclosure provides formulations having a pH of 4 or greater. The present disclosure provides formulations having a pH of about 4.0 to about 8.0, about 4.0 to about 7.0, about 4.0 to about 6.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.0 to about 6.0, and about 5.5. The present disclosure provides amine pH adjusters independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. The present disclosure provides formulations in which the amine pH adjuster is trolamine. The present disclosure provides formulations in which the drug loading is increased to greater than 8% w / w by pH adjustment to greater than 5.5% with trolamine.

[0017] The present disclosure provides formulations further comprising one or more pH adjusters, chelating agents, preservatives, co-solvents, penetration enhancers, humectants, thickening agents, gelling agents, viscosity building agents, surfactants, propellants, fragrances, colorants, and any combination thereof.

[0018] The disclosure provides a formulation in which the organic amine pH adjuster is trolamine and further comprises Transcutol P and glycerol.The disclosure provides a formulation in which the organic amine pH adjuster is trolamine and further comprises ethanol and water.

[0019] The present disclosure further provides a method of treating a skin disease in a patient in need of treatment, comprising topically administering to the affected area of ​​the patient a topical formulation comprising a JAK1 / 2 inhibitor that is ruxolitinib or a pharma- ceutically acceptable salt thereof and an organic amine pH adjusting agent. The present disclosure provides a JAK1 / 2 inhibitor that is ruxolitinib phosphate or a pharma- ceutically acceptable salt thereof. In some embodiments, the skin disease is an autoimmune or inflammatory skin disease. In some embodiments, the skin disease is a Th1 or Th17-associated skin disease. The present disclosure provides that the skin disease is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. In some embodiments, the skin disease is mediated by Defb4, S100a12, or Serpinb4. In some embodiments, the skin disease is mediated by filaggrin / FLG, loricin / LOR, IL-31, TSLP, CAMP, CCL17, CCL22, DefB4a, interferon-gamma, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF18. In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis. In some embodiments, the skin disease is rosacea, psoriatic arthritis, dermatofibrosis, morphea, Spitz nevus, dermatophytosis, or acne vulgaris. The present disclosure provides methods in which a synergistic effect occurs between a JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof, and an amine pH adjuster.

[0020] The disclosure also provides methods wherein the formulation is administered at least once daily.The disclosure also provides methods wherein the formulation is administered at least twice daily.

[0021] The disclosure provides methods in which the topical formulation is selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel. The disclosure provides formulations that are creams or lotions. The disclosure provides formulations having a pH of about 4.0 to about 8.0, about 4.0 to about 7.0, about 4.0 to about 6.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.0 to about 6.0, and about 5.5.

[0022] The present disclosure provides a method in which the organic amine pH adjuster is a tertiary amine or an alkanolamine. In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine. The present disclosure provides a method in which the amine pH adjuster is independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. The present disclosure provides an amine pH adjuster that is trolamine. The present disclosure provides a method in which drug loading is increased to greater than 8% w / w by pH adjustment to greater than 5.5% with trolamine.

[0023] The present disclosure provides a formulation comprising one or more of water, an oil component, an emulsifier or stabilizer component, and a solvent component. The present disclosure provides a formulation in which water constitutes about 5% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, or about 20% to about 50% by weight of the pharmaceutical formulation. The present disclosure provides a formulation in which an oil component constitutes about 5% to about 90% by weight, about 5% to about 80% by weight, about 5% to about 70% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, or about 5% to about 40% by weight of the pharmaceutical formulation. The present disclosure provides a formulation in which an emulsifier or stabilizer component constitutes about 1% to about 30% by weight or about 5% to about 25% by weight of the formulation. The present disclosure provides formulations in which the solvent component constitutes about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the formulation.

[0024] The present disclosure provides a formulation further comprising one or more of a stabilizer and an antioxidant. The present disclosure provides a formulation further comprising one or more of a pH adjuster, a chelating agent, a preservative, a co-solvent, a penetration enhancer, a humectant, a thickener, a gelling agent, a viscosity builder, a surfactant, a propellant, a fragrance, a colorant, and any combination thereof. The present disclosure provides a formulation where the organic amine pH adjuster is trolamine and further comprises Transcutol P and glycerol. The present disclosure provides a formulation where the organic amine pH adjuster is trolamine and further comprises ethanol and water. [Brief description of the drawings]

[0025] [Figure 1] The amount of ruxolitinib that permeated the epidermis and dermis after 24 hours is shown. [Diagram 2] The amount of ruxolitinib that permeated the skin into the receiver solution over a 24 hour period is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present disclosure provides a topical formulation for treating a skin disease comprising a JAK1 / 2 inhibitor, ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjusting agent.

[0027] JAK1 / 2 inhibitors In some embodiments, the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib. Ruxolitinib is a JAK1 / JAK2 inhibitor. Ruxolitinib has an IC50 activity of less than 10 nM at 1 mM ATP for JAK1 and JAK2. 50 Ruxolitinib can be made by the procedures described in US Pat. No. 7,598,257, filed Dec. 12, 2006 (Example 67), which is incorporated by reference herein in its entirety. [ka]

[0028] In some embodiments, the JAK1 / 2 inhibitor or its pharmaceutically acceptable salt is a pharmaceutically acceptable salt of ruxolitinib.In some embodiments, the JAK1 / 2 inhibitor or its pharmaceutically acceptable salt is ruxolitinib sulfate.In some embodiments, the JAK1 / 2 inhibitor or its pharmaceutically acceptable salt is ruxolitinib maleate.

[0029] In some embodiments, the JAK inhibitor or its pharmaceutically acceptable salt is ruxolitinib phosphate. In some embodiments, the JAK inhibitor or its pharmaceutically acceptable salt is 1:1 ruxolitinib phosphate. Ruxolitinib can be prepared as described in U.S. Patent No. 7,598,257 and U.S. Patent Publication No. 8,415,362, each of which is incorporated herein by reference in its entirety. Phosphate can be made as described in U.S. Patent No. 8,722,693, which is incorporated herein by reference in its entirety.

[0030] In some embodiments, the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib, or a pharma- ceutically acceptable salt thereof, in which one or more hydrogen atoms have been replaced by deuterium atoms.

[0031] In some embodiments, ruxolitinib or a salt thereof is administered as a topical formulation, hi some embodiments, the topical formulation comprises about 0.05% to about 3.0% or about 0.05% to about 1.5% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof on a free base basis. In some embodiments, the topical formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 0.97% by weight of the formulation on a free base basis. In some embodiments, the topical formulation comprises about 0.5% to about 1.5% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof, in an amount of about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof, on a free base basis.

[0032] Organic amine pH adjuster The present disclosure provides a topical formulation for treating a skin disease comprising a JAK1 / 2 inhibitor, ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjusting agent.

[0033] In some embodiments, the organic amine pH adjuster is a tertiary amine. In some embodiments, the organic amine pH adjuster is an alkanolamine. In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine. In some embodiments, the organic amine pH adjuster is independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine.

[0034] In some embodiments, the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diisopropanolamine, 2-amino-2-methyl-1-propanol, imidazole, and pyridine.

[0035] In some embodiments, the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the topical formulation is non-aqueous and the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the organic amine pH adjuster is trolamine.

[0036] In some embodiments, the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diisopropanolamine, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the topical formulation comprises water and a solvent component, and the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diisopropanolamine, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the solvent component comprises polyethylene glycol or propylene glycol, Transcutol P, or mixtures thereof. In some embodiments, the water comprises 30% to 70% by weight of the topical formulation. In some embodiments, the water comprises 40% to 60% by weight of the topical formulation. In some embodiments, the solvent component comprises 40% to 80% by weight of the topical formulation. In some embodiments, the organic amine pH adjuster is trolamine.

[0037] In some embodiments, the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, imidazole, and pyridine. In some embodiments, the topical formulation comprises water and a solvent component, and the organic amine pH adjuster is independently selected from trolamine, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, imidazole, and pyridine. In some embodiments, the solvent component comprises polyethylene glycol or propylene glycol, or a mixture thereof. In some embodiments, the solvent component comprises glycerol or Transcutol P, or a mixture thereof. In some embodiments, the water comprises 10% to 40% by weight of the topical formulation. In some embodiments, the solvent comprises 10% to 40% by weight of the topical formulation. In some embodiments, the organic amine pH adjuster is trolamine.

[0038] In some embodiments, the amine pH adjuster is trolamine.

[0039] In some embodiments, adjusting the pH of the formulation with trolamine to greater than 5.5% increased the drug loading to greater than 8% w / w.

[0040] In some embodiments, the amine pH adjuster is present in an amount to adjust the pH of the formulation, and the formulation has a pH of about 4.0 to about 8.0, about 4.0 to about 7.0, about 4.0 to about 6.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.0 to about 6.0, and about 5.5. In some embodiments, the formulation has a pH of about 4.0 to about 8.0. In some embodiments, the formulation has a pH of about 4.0 to about 7.0. In some embodiments, the formulation has a pH of about 4.0 to about 6.0. In some embodiments, the formulation has a pH of about 5.0 to about 8.0. In some embodiments, the formulation has a pH of about 5.5 to about 7.5. In some embodiments, the formulation has a pH of about 5.5 to about 7.0. In some embodiments, the formulation has a pH of about 5.5 to about 6.5. In some embodiments, the formulation has a pH of about 5.0 to about 6.0, hi some embodiments, the formulation has a pH of about 5.5.

[0041] In some embodiments, the amine pH adjuster is present in an amount of up to 11% w / w or up to 2.6% w / w by weight of the formulation. Further for example, in some embodiments, the amine pH adjuster is present in an amount of about 0.25% to about 0.5%, about 0.5% to about 0.75%, about 0.75% to about 1%, about 1% to about 1.25%, about 1.25% to about 1.5%, about 1.5% to about 1.75%, about 1.75% to about 2%, about 2% to about 2.25%, about 2.25% to about 2.5%, about 2.5% to about 2.6%, about 2.6% to about 2.75%, about 2.75% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, or about 10% to about 11% (w / w) by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of up to 5% (w / w) by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of up to 4% (w / w) by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of up to 3% (w / w) by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of up to 2% (w / w) by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of about 0.25% to about 5% w / w by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of about 0.5% to about 5% w / w by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of about 1% to about 5% w / w by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of about 2% to about 5% w / w by weight of the formulation. In some embodiments, the amine pH adjuster is present in an amount of about 1 ...3% w / w by weight of the formulation. In some embodiments, the amine pH adjuster is trolamine.

[0042] In some embodiments, the organic amine pH adjuster is utilized without the need for a separate buffer (e.g., a citric acid / sodium citrate buffer). In some embodiments, the organic amine pH adjuster is the only basic pH adjuster utilized. In some embodiments, there is no separate pH buffer.

[0043] In some embodiments, there is a synergistic effect between the JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the organic amine pH adjuster.

[0044] The present disclosure also provides pharmaceutical formulations, the formulations having a pH of about 4.0 to about 8.0, about 4.0 to about 7.0, about 4.0 to about 6.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.0 to about 6.0, and about 5.5. In some embodiments, the formulation has a pH of about 4.0 to about 8.0. In some embodiments, the formulation has a pH of about 4.0 to about 7.0. In some embodiments, the formulation has a pH of about 4.0 to about 6.0. In some embodiments, the formulation has a pH of about 5.0 to about 8.0. In some embodiments, the formulation has a pH of about 5.5 to about 7.5. In some embodiments, the formulation has a pH of about 5.5 to about 7.0. In some embodiments, the formulation has a pH of about 5.5 to about 6.5. In some embodiments, the formulation has a pH of about 5.0 to about 6.0, hi some embodiments, the formulation has a pH of about 5.5.

[0045] Topical preparations The present disclosure provides a topical formulation for treating a skin disease comprising a JAK1 / 2 inhibitor, ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjusting agent.

[0046] Topical (e.g., intradermal) administration offers the advantage of treating skin diseases and / or disorders as described herein locally, minimizing potential adverse events associated with systemic exposure, and allowing easier discontinuation of treatment if necessary. Additionally, some topical dosage forms, such as creams, ointments, and gels, have the advantage of excipients that can act as emollients or occlusive agents, which can improve patient well-being and compliance during treatment. Other routes of administration, such as oral, parenteral, and inhalation, can lead to systemic drug levels above therapeutic doses, increased likelihood of adverse events, drug interactions, and generation of active / toxic metabolites, which can lead to treatment discontinuation and poor patient compliance.

[0047] Topical formulations intended for dermal delivery are typically solutions, suspensions, gels, creams, ointments, lotions, sprays, and foam or effervescent formulations, and may include one or more conventional carriers as described herein. The formulation composition should be prepared with the aim of delivering the active ingredient to the appropriate layer(s) of the skin, minimizing systemic exposure, and preventing skin irritation. In addition, the pharmaceutical composition must 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 adjusters, chelating agents, preservatives, cosolvents, penetration enhancers, humectants, thickeners, gelling agents, viscosity builders, surfactants, propellants, fragrances, colorants, or any combination or mixture thereof.

[0048] In some embodiments, the topical formulation is an aqueous formulation. In some embodiments, the topical formulation is independently selected from a cream, a lotion, a foam or effervescent formulation, a spray, an aqueous gel, a non-aqueous gel, and an emulsified gel. The present disclosure also provides a topical formulation that is a cream or a lotion.

[0049] The present disclosure provides a topical formulation for treating a skin disease comprising a JAK1 / 2 inhibitor, ruxolitinib, or a pharma- ceutically acceptable salt thereof, and an organic amine pH adjusting agent.

[0050] In some embodiments, the topical formulation further comprises one or more of water, an oil component, and a solvent component. In some embodiments, the oil component further comprises an emulsifier or stabilizing component (or alternatively, an emulsifier or humectant component). The present disclosure also provides topical formulations further comprising one or more of a stabilizer and an antioxidant. In some embodiments, the topical formulation comprises one or more of a pH adjuster, a chelating agent, a preservative, a co-solvent, a penetration enhancer, a moisturizer, a thickener, a gelling agent, a viscosity builder, a surfactant, a propellant, a fragrance, a colorant, or any combination or mixture thereof.

[0051] In some embodiments, the topical formulation comprises water. In some embodiments, the topical formulation comprises water and an oil component. In some embodiments, the topical formulation comprises water, an oil component, and an emulsifier or stabilizer component. In some embodiments, the topical formulation comprises water, an oil component, an emulsifier or stabilizer component, and a solvent component.

[0052] In some embodiments, the topical formulation comprises an oil component. In some embodiments, the topical formulation comprises an oil component and an emulsifier or stabilizer component. In some embodiments, the topical formulation comprises an oil component, an emulsifier or stabilizer component, and a solvent component.

[0053] In some embodiments, the topical formulation comprises an emulsifier or stabilizer component. In some embodiments, the topical formulation comprises water, and an emulsifier or stabilizer component. In some embodiments, the topical formulation comprises an oil component and an emulsifier or stabilizer component. In some embodiments, the topical formulation comprises an emulsifier or stabilizer component, and a solvent component.

[0054] In some embodiments, the topical formulation comprises a solvent component. In some embodiments, the topical formulation comprises a water and solvent component. In some embodiments, the topical formulation comprises an oil component and a solvent component.

[0055] In some embodiments, the topical formulation comprises: About 20% to 60% water by weight of the formulation; A solvent component of about 10% by weight to about 50% by weight of the formulation; An oil component in an amount of about 10% to about 40% by weight of the formulation, and Contains an organic amine modifier, The pH of the formulation ranges from 5.5 to about 7.5.

[0056] In some embodiments, the topical formulation comprises: About 30% to 60% water by weight of the formulation; A solvent component of about 10% to about 40% by weight of the formulation; An oil component of about 10% by weight to about 30% by weight of the formulation; about 0.1% to about 20% glycerol, Contains an organic amine modifier, The pH of the formulation ranges from 5.5 to about 7.5.

[0057] In some embodiments, the topical formulation comprises: About 30% to 60% water by weight of the formulation; A solvent component of about 10% to about 40% by weight of the formulation; An oil component of about 10% by weight to about 30% by weight of the formulation; About 5% to about 20% glycerol, Contains an organic amine modifier, The pH of the formulation ranges from 5.5 to about 7.5, and the topical formulation is a cream or lotion.

[0058] In some embodiments, the topical formulation comprises: About 30% to 60% water by weight of the formulation; A solvent component of about 10% to about 40% by weight of the formulation; An oil component of about 10% by weight to about 30% by weight of the formulation; About 10% to about 20% glycerol, Contains an organic amine modifier, The pH of the formulation ranges from 5.5 to about 7.5, and the topical formulation is a cream or lotion.

[0059] In some embodiments, the topical formulation comprises water, glycerol, Transcutol P, polysorbate 80, cetyl alcohol, stearyl alcohol, light mineral oil, white soft paraffin, GTCC, and trolamine, and the topical formulation is a cream.

[0060] In some embodiments, the topical formulation comprises water, glycerol, Transcutol P, polysorbate 80, cetyl alcohol, mineral oil, white soft paraffin, GTCC, and trolamine, and the topical formulation is a lotion.

[0061] The water, oil component, emulsifier or stabilizer / emulsifier or wetting agent component, solvent component, stabilizer, antioxidant, and additional components may be combined in any suitable combination from the embodiments described below.

[0062] In some embodiments, the formulation does not include a vitamin D3 analog.

[0063] water In some embodiments, the formulation comprises water, in an amount of about 5% to about 90%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 20% to about 70%, about 20% to about 60%, about 30% to about 60%, or about 20% to about 50% by weight of the formulation.

[0064] In some embodiments, water is present in an amount of about 35% to about 65% by weight of the formulation.

[0065] In some embodiments, water is present in an amount of about 40% to about 60% by weight of the emulsion.

[0066] In some embodiments, water is present in an amount of about 45% to about 55% by weight of the emulsion.

[0067] oil component In some embodiments, the formulation includes an oil component, hi some embodiments, the oil component is present in an amount of about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, about 5% to about 60%, about 5% to about 50%, or about 5% to about 40% by weight of the formulation.

[0068] In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation.

[0069] In some embodiments, the oil component is present in an amount of about 10% to about 24% by weight of the formulation.

[0070] In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the formulation.

[0071] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), fatty acid esters (cocoyl caprylocaprate (Kollicream 3C)), and triglycerides (caprylic / capric triglyceride (Crodamol 1000)). In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0072] In some embodiments, the oil component comprises one or more materials independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

[0073] In some embodiments, the oil component comprises one or more materials independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone.

[0074] In some embodiments, the oil component comprises an emulsifier or stabilizer component, which are described below.

[0075] In some embodiments, the oil component further comprises one or more materials independently selected from emollients, occlusive agents, and sclerosing agents, and combinations thereof.

[0076] In some embodiments, the emollient component is present in an amount of about 5% to about 15% by weight of the formulation.

[0077] In some embodiments, the emollient component comprises one or more materials independently selected from mineral oils and triglycerides.

[0078] In some embodiments, the emollient component comprises one or more materials independently selected from light mineral oils and medium chain triglycerides.

[0079] In some embodiments, the light mineral oil is present in an amount of about 0.1% to about 15% by weight of the formulation.

[0080] In some embodiments, the emollient component comprises one or more materials independently selected from light mineral oil, medium chain triglycerides, and dimethicone.

[0081] In some embodiments, the occlusive agent component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).

[0082] In some embodiments, the occlusive agent component comprises one or more materials selected from lanolinic acid fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

[0083] In some embodiments, the occlusive agent component comprises petrolatum.

[0084] In some embodiments, the occlusive agent component comprises white petrolatum.

[0085] In some embodiments, white petrolatum is present in an amount of about 0.1% to about 15% by weight of the formulation.

[0086] In some embodiments, the oil component comprises a stiffening agent component.

[0087] In some embodiments, the stiffening agent component is present in an amount of about 2% to about 8% by weight of the formulation.

[0088] In some embodiments, the stiffening agent component comprises one or more materials independently selected from fatty alcohols.

[0089] In some embodiments, the curing agent component is 12-20 The composition comprises one or more materials independently selected from fatty alcohols.

[0090] In some embodiments, the curing agent component is 16-18 The composition comprises one or more materials independently selected from fatty alcohols.

[0091] In some embodiments, the stiffening agent component comprises one or more materials independently selected from cetyl alcohol and stearyl alcohol.

[0092] In some embodiments, cetyl alcohol is present in an amount of about 0.1% to about 15% by weight of the formulation.

[0093] In some embodiments, stearyl alcohol is present in an amount of about 0.1% to about 15% by weight of the formulation.

[0094] In some embodiments, the stiffening agent component comprises one or more materials independently selected from cetyl alcohol, stearyl alcohol, oleyl alcohol, and cetostearyl alcohol.

[0095] Emulsifier or Stabilizer Ingredient / Emulsifier or Wetting Ingredient In some embodiments, the formulation includes an emulsifier or stabilizer (or emulsifier or wetting agent) component. In some embodiments, the oil component includes an emulsifier or stabilizer component. In some embodiments, the emulsifier or stabilizer component is present in an amount of about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 5% to about 40%, or about 5% to about 25% by weight of the formulation. In some embodiments, the emulsifier component is added to the oil component, and the weight percentages of the individual components may be adjusted accordingly. In some embodiments, the emulsifier component when added to the oil component may be a separate component of the formulation.

[0096] In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the formulation.

[0097] In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the formulation.

[0098] In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the formulation.

[0099] In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the formulation.

[0100] In some embodiments, the emulsion comprises an emulsifier component and a hardener component, and the combined amount of the emulsifier component and the hardener component is at least about 8% by weight of the formulation.

[0101] In some embodiments, the emulsifier or wetting agent component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)), and emulsifying wax (Polawax). In some embodiments, the emulsifier or wetting agent component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (such as Kolliphor CSA50)), fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), and polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)).

[0102] In some embodiments, the emulsifier component comprises one or more materials independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0103] In some embodiments, the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20.

[0104] In some embodiments, the emulsifier component comprises a non-ionic surfactant.

[0105] In some embodiments, the non-ionic surfactant is cetomacrogol 1000 or poloxamer 407.

[0106] In some embodiments, the poloxamer is poloxamer 407.

[0107] In some embodiments, the emulsifier component further includes glyceryl stearate and PEG-100 stearate, for example, Arlacel™ 165.

[0108] Solvent composition In some embodiments, the emulsion further comprises a solvent component. In some embodiments, the solvent component is present in an amount of about 1% to about 70% by weight, about 1% to about 60% by weight, about 1% to about 50% by weight, about 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 1% to about 20% by weight, about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the pharmaceutical formulation.

[0109] In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the formulation.

[0110] In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the formulation.

[0111] In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the formulation.

[0112] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from diethylene glycol diethers (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycols (e.g., propylene glycol), or polyethylene glycols (e.g., PEG400).

[0113] In some embodiments, the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols.

[0114] In some embodiments, the solvent component comprises one or more materials independently selected from propylene glycol and polyethylene glycol.

[0115] In some embodiments, the solvent component comprises one or more materials independently selected from PEG200, PEG300, PEG400, and propylene glycol.

[0116] In some embodiments, the solvent component comprises PEG300 and propylene glycol.

[0117] In some embodiments, the PEG300 is present in an amount of about 7% w / w by weight of the formulation.

[0118] In some embodiments, the solvent is a combination of PEG400 and propylene glycol.

[0119] In some embodiments, propylene glycol is present at about 6.5% by weight of the formulation. In some embodiments, the solvent component includes diethylene glycol monoethyl ether, such as Transcutol® P. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 30% w / w by weight of the emulsion. In some embodiments, diethylene glycol monoethyl ether is present in an amount of about 0.1% to about 20% w / w by weight of the formulation.

[0120] Stabilizers In some embodiments, the formulation further comprises a stabilizer component.

[0121] In some embodiments, the stabilizer component is present in an amount of about 0.05% to about 5% by weight of the formulation.

[0122] In some embodiments, the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the formulation.

[0123] In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.

[0124] In some embodiments, the stabilizer component comprises one or more materials independently selected from polysaccharides.

[0125] In some embodiments, the stabilizer component comprises xanthan gum.

[0126] Antioxidants In some embodiments, the formulation further comprises an antioxidant.

[0127] In some embodiments, the antioxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopherol, or a combination thereof.

[0128] Additional Ingredients In some embodiments, the formulation further comprises a chelating agent component.

[0129] In some embodiments, the chelating agent component comprises edetate disodium.

[0130] In some embodiments, edetate disodium is present in an amount of about 0.001% to about 5% by weight of the formulation.

[0131] In some embodiments, the formulation further comprises a moisturizer.

[0132] In some embodiments, the humectant is glycerol.

[0133] In some embodiments, glycerol is present in an amount of about 0.01% to about 20% by weight of the formulation.

[0134] In some embodiments, glycerol is present in an amount of about 0.1% to about 20% by weight of the formulation.

[0135] In some embodiments, the formulation further comprises a surfactant.

[0136] In some embodiments, the surfactant is polysorbate 80. In some embodiments, the surfactant is polysorbate 80 and is present in an amount of about 0.01% to about 15% by weight of the formulation. In some embodiments, the surfactant is polysorbate 80 and is present in an amount of about 0.1% to about 15% by weight of the formulation.

[0137] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0138] In some embodiments, the formulation comprises one or more propellants. In some embodiments, the propellant comprises one or more hydrofluorocarbons (HFCs) or hydrofluoroolefins (HFOs). In some embodiments, the propellant comprises one or more hydrofluorocarbons (HFCs). In some embodiments, the propellant comprises one or more hydrofluoroolefins (HFOs). In some embodiments, the propellant comprises HFA-134. In some embodiments, the propellant comprises HFO-1234ze.

[0139] In some embodiments, the formulation includes a penetration enhancer. In some embodiments, the penetration enhancer facilitates delivery of the formulation throughout the affected area of ​​the patient. In some embodiments, the penetration enhancer is a polyol, such as polyethylene glycol (PEG), glycerol (glycerin), maltitol, sorbitol, diethylene glycol monoethyl ether, azone, benzalkonium chloride (ADBAC), cetylperidium chloride, cetylmethylammonium bromide, dextran sulfate, lauric acid, menthol, methoxysalicylate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium glycolate, sodium glycer ... glycholate), sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxide, sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate, and surfactants such as sodium lauryl sulfate, laureth-9, cetylpyridinium chloride, and polyoxyethylene monoalkyl ethers; benzoic acids such as sodium salicylate and methoxysalicylate; fatty acids such as lauric acid, oleic acid, undecanoic acid, and methyl oleate; fatty alcohols such as octanol and nonanol; laurocapram, cyclodextrin, thymol, limonene, urea, chitosan, and other natural and synthetic polymers.

[0140] In some embodiments, the formulation comprises a thickening agent, which in some embodiments comprises beeswax, hard paraffin or cetyl alcohol, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, or povidone (e.g., Kollidon 90F).

[0141] In some embodiments, the formulation comprises a gelling agent. In some embodiments, the gelling agent is a material that can swell or expand when in contact with water. In some embodiments, the gelling agent comprises a swellable polymer, such as an osmopolymer or a hydrogel. In some embodiments, the gelling agent is non-crosslinked or lightly crosslinked. In some embodiments, the gelling agent is an oligohydroxyalkylcellulose having a molecular weight of greater than 50,000, such as hydroxypropylmethylcellulose (METHOCEL K 100M available from Dow Chemical); poly(hydroxyalkylmethacrylates) having a molecular weight of 5,000 to 5,000,000; poly(vinylpyrrolidones) having a molecular weight of 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohols) having low acetate residuals; swellable mixtures of agar and carboxymethylcellulose; swellable compositions comprising methylcellulose mixed with sparsely crosslinked agar; polyethers having a molecular weight of 10,000 to 6,000,000; water-swellable copolymers produced by dispersion of finely divided copolymers of maleic anhydride with styrene, ethylene, propylene, or isobutylene; water-swellable polymers of N-vinyl lactams, and the like.

[0142] In some embodiments, the formulation includes a viscosity building agent. In some embodiments, the viscosity building agent is a natural or synthetic wax such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin, ceresin, esparto wax, olicury wax, and rezowax, hard fats (e.g., hydrogenated vegetable glycerides), hydrogenated vegetable oils, C 12 ~C60 Alcohol, C. 12 ~C 60 These include, but are not limited to, fatty acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and combinations thereof.

[0143] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, butylated hydroxytoluene (BHT), phenoxyethanol, and combinations thereof.

[0144] In some embodiments, the formulation further comprises one or more co-solvents. In some embodiments, the one or more co-solvents comprise one or more additional hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0145] In some embodiments, topical formulations may contain one or more conventional carriers as described herein. In some embodiments, ointments may contain water and one or more hydrophobic carriers, such as selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of creams may be based on water combined with glycerol and one or more other ingredients, such as glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other ingredients, such as glycerol, hydroxyethylcellulose, etc.

[0146] The preparation administered to patient can be in the form of the above-mentioned pharmaceutical composition.These preparations or compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solutions can be packaged for immediate use or lyophilized, and lyophilized preparations are combined with sterile aqueous carriers before administration.

[0147] As will be understood, some components of the formulations described herein can have multiple functions. For example, a given substance can act as both an emulsifier component and a stabilizer. In some such cases, the function of a given component can be considered singular, even though its properties may allow for multiple functions. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.

[0148] As noted above, in some embodiments, the present disclosure provides a topical formulation that is in a form selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel.

[0149] cream In some embodiments, the formulation is a cream formulation. In some embodiments, the formulation is an aqueous cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion. In some embodiments, the cream formulation comprises a water and an oil component. In some embodiments, the cream formulation comprises a water, a solvent component, and an oil component. In some embodiments, the oil component comprises an emulsifier or humectant component. In some embodiments, the oil component comprises one or more stabilizers.

[0150] In some embodiments, water is present in an amount of about 10% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 30% to about 50% by weight of the formulation.

[0151] In some embodiments, the oil component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 30% by weight of the formulation.

[0152] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters (isopropyl myristate), glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethylene glycol hexadecyl ether (cetomacrogol 1000), diethylene glycol monoethyl ether (Transcutol P), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S3), polyoxyethylene tetradecyl ether (Brij S4), polyoxyethylene tetradecyl ether (Brij S5), polyoxyethylene tetradecyl ether (Brij S6), polyoxyethylene tetradecyl ether (Brij S7), polyoxyethylene tetradecyl ether (Brij S8), polyoxyethylene tetradecyl ether (Brij S9), polyoxyethylene tetradecyl ether (Brij S10), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl ether (Brij S12), polyoxyethylene tetradecyl ether (Brij S13), polyoxyethylene tetradecyl ether (Brij S14), polyoxyethylene tetradecyl ether (Brij S15), polyoxyethylene tetradecyl ether (Brij S16), polyoxyethylene tetradecyl ether (Brij S17), polyoxyethylene tetradecyl ether (Brij S18), polyoxyethylene tetradecyl ether (Brij S19), polyoxyethylene tetradecyl ether (Brij S19), polyoxyethylene tetradecyl ether (Brij S11), poly S721), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), and triglycerides (caprylic / capric triglyceride (Crodamol S721)). In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), xanthan gum, vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0153] In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 2% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 5% to about 20% by weight of the formulation.

[0154] In some embodiments, the emulsifier or wetting agent component comprises one or more nonionic emulsifiers and emulsifying waxes, or combinations thereof. In some embodiments, the emulsifier or wetting agent component comprises one or more substances selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721)), and emulsifying waxes (Polawax)), or combinations thereof.

[0155] In some embodiments, the oil phase comprises one or more stabilizers. In some embodiments, the one or more stabilizers comprise one or more substances independently selected from polysaccharides. In some embodiments, the one or more stabilizers are xanthan gum.

[0156] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation.

[0157] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from dimethyl glycol, diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0158] In some embodiments, the solvent component comprises about 0.1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 5% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 10% to about 20% glycerol by weight of the formulation.

[0159] In some embodiments, the formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0160] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0161] lotion In some embodiments, the formulation is a lotion formulation. In some embodiments, the formulation is an aqueous lotion formulation. In some embodiments, the lotion formulation is an oil-in-water emulsion. In some embodiments, the lotion formulation comprises a water and an oil component. In some embodiments, the lotion formulation comprises a water, a solvent component, and an oil component. In some embodiments, the oil component comprises an emulsifier or humectant component. In some embodiments, the oil component comprises one or more stabilizers.

[0162] In some embodiments, water is present in an amount of about 10% to about 90% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 90% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 25% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 30% to about 60% by weight of the formulation.

[0163] In some embodiments, the oil component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 30% by weight of the formulation.

[0164] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters (isopropyl myristate), glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S3), polyoxyethylene tetradecyl ether (Brij S4), polyoxyethylene tetradecyl ether (Brij S5), polyoxyethylene tetradecyl ether (Brij S6), polyoxyethylene tetradecyl ether (Brij S7), polyoxyethylene tetradecyl ether (Brij S8), polyoxyethylene tetradecyl ether (Brij S9), polyoxyethylene tetradecyl ether (Brij S10), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl ether (Brij S12), polyoxyethylene tetradecyl ether (Brij S13), polyoxyethylene tetradecyl ether (Brij S14), polyoxyethylene tetradecyl ether (Brij S15), polyoxyethylene tetradecyl ether (Brij S16), polyoxyethylene tetradecyl ether (Brij S17), polyoxyethylene tetradecyl ether (Brij S18), polyoxyethylene tetradecyl ether (Brij S19), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl S721), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), and triglycerides (caprylic / capric triglyceride (Crodamol S721)). In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), xanthan gum, vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0165] In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 2% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 5% to about 20% by weight of the formulation.

[0166] In some embodiments, the emulsifier or wetting agent component comprises one or more nonionic emulsifiers and emulsifying waxes, or combinations thereof. In some embodiments, the emulsifier or wetting agent component comprises one or more substances selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721)), and emulsifying waxes (Polawax)), or combinations thereof.

[0167] In some embodiments, the oil phase comprises one or more stabilizers. In some embodiments, the one or more stabilizers comprise one or more substances independently selected from polysaccharides. In some embodiments, the one or more stabilizers are xanthan gum.

[0168] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 70% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation.

[0169] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from dimethyl glycol, diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0170] In some embodiments, the solvent component comprises about 0.1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 5% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 10% to about 20% glycerol by weight of the formulation.

[0171] In some embodiments, the formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0172] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0173] Foams and effervescent preparations In some embodiments, the formulation is an effervescent formulation. In some embodiments, the formulation is an aqueous foam or effervescent formulation. In some embodiments, the foam or effervescent formulation comprises a base component and a propellant component. In some embodiments, the base component is an oil-in-water emulsion. In some embodiments, the propellant phase comprises one or more hydrofluorocarbons (HFCs) or hydrofluoroolefins (HFOs). In some embodiments, the propellant phase comprises one or more hydrofluorocarbons (HFCs). In some embodiments, the propellant phase comprises one or more hydrofluoroolefins (HFOs). In some embodiments, the propellant phase comprises HFA-134. In some embodiments, the propellant phase comprises HFO-1234ze.

[0174] In some embodiments, the base component is present in an amount of about 50% to about 98% of the formulation. In some embodiments, the base component is present in an amount of about 50% to about 95% of the formulation. In some embodiments, the base component is present in an amount of about 60% to about 95% of the formulation. In some embodiments, the base component is present in an amount of about 70% to about 95% of the formulation. In some embodiments, the base component is present in an amount of about 75% to about 98% of the formulation. In some embodiments, the base component is present in an amount of about 75% to about 95% of the formulation. In some embodiments, the base component is present in an amount of about 80% to about 90% of the formulation.

[0175] In some embodiments, the propellant phase is present in an amount of about 2% to about 50% of the formulation. In some embodiments, the propellant phase is present in an amount of about 5% to about 50% of the formulation. In some embodiments, the propellant phase is present in an amount of about 5% to about 40% of the formulation. In some embodiments, the propellant phase is present in an amount of about 5% to about 30% of the formulation. In some embodiments, the propellant phase is present in an amount of about 2% to about 25% of the formulation. In some embodiments, the propellant phase is present in an amount of about 5% to about 25% of the formulation. In some embodiments, the propellant phase is present in an amount of about 10% to about 20% of the formulation.

[0176] In some embodiments, the base component comprises a water and an oil component. In some embodiments, the base component comprises a water, a solvent component, and an oil component. In some embodiments, the oil component comprises an emulsifier or humectant component. In some embodiments, the oil component comprises one or more stabilizers.

[0177] In some embodiments, water is present in an amount of about 10% to about 90% by weight of the base component. In some embodiments, water is present in an amount of about 10% to about 80% by weight of the base component. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the base component. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the base component. In some embodiments, water is present in an amount of about 10% to about 50% by weight of the base component. In some embodiments, water is present in an amount of about 20% to about 80% by weight of the base component. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the base component. In some embodiments, water is present in an amount of about 20% to about 60% by weight of the base component. In some embodiments, water is present in an amount of about 25% to about 50% by weight of the base component.

[0178] In some embodiments, the oil component is present in an amount of about 3% to about 60% by weight of the base component. In some embodiments, the oil component is present in an amount of about 5% to about 60% by weight of the base component. In some embodiments, the oil component is present in an amount of about 5% to about 50% by weight of the base component. In some embodiments, the oil component is present in an amount of about 5% to about 40% by weight of the base component. In some embodiments, the oil component is present in an amount of about 5% to about 30% by weight of the base component. In some embodiments, the oil component is present in an amount of about 10% to about 60% by weight of the base component. In some embodiments, the oil component is present in an amount of about 10% to about 50% by weight of the base component. In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the base component. In some embodiments, the oil component is present in an amount of about 10% to about 30% by weight of the base component.

[0179] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters (isopropyl myristate), glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), fatty acid esters (cocoyl caprylocaprate (Kollicream 3C)), and triglycerides (caprylic / capric triglyceride (Crodamol 1000)). In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), xanthan gum, vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0180] In some embodiments, the oil component comprises an emulsifier or stabilizer component, or an emulsifier or wetting agent component.

[0181] In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 40% by weight of the base component. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 30% by weight of the base component. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 20% by weight of the base component. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 2% to about 20% by weight of the base component. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 5% to about 20% by weight of the base component. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 10% to about 20% by weight of the base component.

[0182] In some embodiments, the emulsifier or wetting agent component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)), and emulsifying wax (Polawax). In some embodiments, the emulsifier or wetting agent component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (such as Kolliphor CSA50)), fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), and polyoxyethylene stearyl ether (Brij S721), ethoxylated stearic acid and cetyl alcohol (Kolliphor CS20)).

[0183] In some embodiments, the oil phase comprises one or more stabilizers. In some embodiments, the one or more stabilizers comprise one or more substances independently selected from polysaccharides. In some embodiments, the one or more stabilizers are xanthan gum.

[0184] In some embodiments, the base component includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 70% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 5% to about 60% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 5% to about 50% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 10% to about 70% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 10% to about 60% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 10% to about 50% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 20% to about 70% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 20% to about 60% by weight of the base component. In some embodiments, the solvent component is present in an amount of about 20% to about 50% by weight of the base component.

[0185] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from dimethyl glycol, diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0186] In some embodiments, the solvent component comprises from about 0.1% to about 20% glycerol by weight of the base component. In some embodiments, the solvent component comprises from about 1% to about 20% glycerol by weight of the base component. In some embodiments, the solvent component comprises from about 5% to about 20% glycerol by weight of the base component. In some embodiments, the solvent component comprises from about 10% to about 20% glycerol by weight of the base component.

[0187] In some embodiments, the base component comprises one or more chelating agents, hi some embodiments, the chelating agent is EDTA.

[0188] In some embodiments, the base component comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0189] spray In some embodiments, the formulation is a spray (e.g., a pump spray). In some embodiments, the formulation is an aqueous spray formulation. In some embodiments, the spray formulation comprises water, a solvent component, and a volatile excipient. In some embodiments, the spray formulation comprises water, a solvent component, a volatile excipient, and a film-forming component.

[0190] In some embodiments, the spray formulation comprises water, a solvent component, a volatile excipient, a film-forming agent, and a preservative component. In some embodiments, the spray formulation comprises water, a solvent component, a volatile excipient, a film-forming agent, a preservative component, and a chelating agent.

[0191] In some embodiments, water is present in an amount of about 5% to about 65% by weight of the spray formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 5% to about 60% by weight of the base component. In some embodiments, water is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 65% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 65% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 60% by weight of the formulation.

[0192] In some embodiments, the solvent component is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 25% by weight of the formulation.

[0193] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from sorbitol, dimethyl glycol, diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0194] In some embodiments, the volatile excipient is present in an amount of about 20% to about 90% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 30% to about 90% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 35% to about 85% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 40% to about 80% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 45% to about 75% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 45% to about 75% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 50% to about 70% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 30% to about 85% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 30% to about 80% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 30% to about 75% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 30% to about 70% by weight of the formulation.

[0195] In some embodiments, the volatile excipient comprises one or more alcohols. In some embodiments, the volatile excipient comprises one or more small alkyl chain alcohols. In some embodiments, the volatile excipient comprises ethanol.

[0196] In some embodiments, the spray formulation includes a film-forming component. In some embodiments, the film-forming component includes one or more film formers. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 30% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 20% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.5% to about 20% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 15% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 5% by weight of the formulation.

[0197] In some embodiments, the film-forming component comprises one or more film-forming polymers. In some embodiments, the film-forming component comprises one or more film-forming cationic copolymers. In some embodiments, the film-forming component comprises one or more film-forming nonionic polymers. In some embodiments, the film-forming component comprises one or more film-forming anionic copolymers. In some embodiments, the film-forming component comprises one or more film-forming agents selected from polyvinylpyrrolidone, cationic methacrylate polymers (e.g., Eudragit 100), hydrophilic nonionic surfactants (e.g., Poloxamer 407, a triblock copolymer consisting of polypropylene glycol sandwiched between two hydrophilic blocks of polyethylene glycol), and copolymers of monoalkyl esters of poly(methyl vinyl ether / maleic acid) (e.g., Gantres™ ES-435). In some embodiments, the film-forming component comprises a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a 2:1:1 ratio (Eudragit E 100), a polyethylene glycol-copolypropylene glycol-co-polyethylene glycol triblock copolymer (e.g., a poloxamer such as Poloxamer 407), or a copolymer of a monoalkyl ester of poly(methyl vinyl ether / maleic acid) (e.g., Gantrez ES-435), or a combination thereof.

[0198] In some embodiments, the spray formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, butylated hydroxytoluene (BHT), and combinations thereof.

[0199] In some embodiments, the spray formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0200] In some embodiments, the spray formulation is a propellant spray formulation.In some embodiments, the propellant spray formulation comprises one or more of a solvent, a volatile excipient, a film-forming polymer, and a propellant.In some embodiments, the propellant spray formulation does not comprise water.The solvent, the volatile excipient, and the film-forming polymer are as described above for pump spray.

[0201] In some embodiments, the propellant spray formulation includes one or more solvent components. In some embodiments, the solvent component is present in an amount of about 0.5% to about 10% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 0.5% to about 5% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 0.5% to about 1% by weight of the formulation.

[0202] In some embodiments, the propellant spray formulation comprises one or more film-forming polymers. In some embodiments, the film-forming polymer is present in an amount of about 0.5% to about 10% by weight of the formulation. In some embodiments, the film-forming polymer is present in an amount of about 0.5% to about 5% by weight of the formulation. In some embodiments, the film-forming polymer is present in an amount of about 0.5% to about 1% by weight of the formulation.

[0203] In some embodiments, the propellant spray formulation includes one or more volatile excipients. In some embodiments, the volatile excipients are present in an amount of about 5% to about 35% by weight of the formulation. In some embodiments, the volatile excipients are present in an amount of about 10% to about 30% by weight of the formulation. In some embodiments, the volatile excipients are present in an amount of about 15% to about 30% by weight of the formulation.

[0204] In some embodiments, the propellant spray formulation comprises one or more propellants. In some embodiments, the propellant comprises one or more hydrofluorocarbons (HFCs) or hydrofluoroolefins (HFOs). In some embodiments, the propellant comprises one or more hydrofluorocarbons (HFCs). In some embodiments, the propellant comprises one or more hydrofluoroolefins (HFOs). In some embodiments, the propellant comprises HFA-134. In some embodiments, the propellant comprises HFO-1234ze. In some embodiments, the propellant is present in an amount of about 10% to about 90% of the formulation. In some embodiments, the propellant is present in an amount of about 10% to about 95% of the formulation. In some embodiments, the propellant is present in an amount of about 20% to about 80% of the formulation. In some embodiments, the propellant phase is present in an amount of about 30% to about 80% of the formulation.

[0205] Water-based gel In some embodiments, the formulation is an aqueous gel. In some embodiments, the aqueous gel comprises water, a solvent component, a stabilizing component, and a gelling agent component. In some embodiments, the aqueous gel formulation comprises water, a solvent component, a stabilizing component, a gelling agent component, and a preservative. In some embodiments, the aqueous gel formulation comprises water, a solvent component, a stabilizing component, a gelling agent component, a preservative, and a chelating agent.

[0206] In some embodiments, water is present in an amount of about 10% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 30% to about 50% by weight of the formulation.

[0207] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 95% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 95% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 20% to about 95% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 25% to about 90% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 30% to about 85% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 35% to about 85% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 20% to about 90% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 20% to about 85% by weight of the formulation.

[0208] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from diethylene glycol diethers (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycols (e.g., propylene glycol), or polyethylene glycols (e.g., PEG400).

[0209] In some embodiments, the stabilizing component is present in an amount of about 0.05% to about 10% by weight of the formulation. In some embodiments, the stabilizing component is present in an amount of about 0.05% to about 8% by weight of the formulation. In some embodiments, the stabilizing component is present in an amount of about 0.5% to about 8% by weight of the formulation. In some embodiments, the stabilizing component is present in an amount of about 1% to about 6% by weight of the formulation.

[0210] In some embodiments, the stabilizing component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), or polyethylene glycol fatty acid ethers (e.g., polyoxyl castor oil, polyethylene glycol hexadecyl ether (cetomacrogol 1000), diethylene glycol monoethyl ether (Transcutol P), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721)), or combinations thereof.

[0211] In some embodiments, the aqueous gel formulation comprises a gelling agent component, hi some embodiments, the gelling agent component comprises hydroxyethyl cellulose, hypermellose, hydroxypropyl cellulose, and combinations thereof.

[0212] In some embodiments, the aqueous gel formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, butylated hydroxytoluene (BHT), phenoxyethanol, and combinations thereof.

[0213] In some embodiments, the aqueous gel formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0214] Non-aqueous gel In some embodiments, the formulation is a non-aqueous gel formulation. In some embodiments, the non-aqueous gel formulation comprises a solvent component. In some embodiments, the non-aqueous gel formulation comprises a solvent component and a gelling agent component. In some embodiments, the non-aqueous gel formulation comprises a solvent component and a volatile excipient. In some embodiments, the non-aqueous gel formulation comprises a solvent component, a volatile excipient, and a preservative. In some embodiments, the non-aqueous gel formulation comprises a solvent component, a volatile excipient, a preservative, and a gelling agent component.

[0215] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 60% to about 99% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 65% to about 99% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 70% to about 99% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 75% to about 99% by weight of the formulation. In some embodiments, the solvent component includes one or more hydroxylated solvents. In some embodiments, the solvent component includes one or more materials selected from diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol, hexylene glycol), or polyethylene glycol (e.g., PEG 400), and glycerol.

[0216] In some embodiments, the formulation includes a volatile excipient. In some embodiments, the volatile excipient is a solvent for ruxolitinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the volatile excipient is present in an amount of about 1% to about 60% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 1% to about 50% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 10% to about 35% by weight of the base component. In some embodiments, the volatile excipient is present in an amount of about 10% to about 30% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 15% to about 30% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 15% to about 40% by weight of the formulation. In some embodiments, the volatile excipient is present in an amount of about 15% to about 35% by weight of the formulation. In some embodiments, the volatile excipient comprises one or more alcohols. In some embodiments, the volatile excipient comprises ethanol.

[0217] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0218] In some embodiments, the non-aqueous gel formulation comprises a gel-forming component, hi some embodiments, the gel-forming component comprises hydroxyethyl cellulose, hypermellose, hydroxypropyl cellulose, and combinations thereof.

[0219] Emulsion Gel In some embodiments, the formulation is an emulsion gel formulation. In some embodiments, the emulsion gel formulation comprises water, a solvent component, and an oil component. In some embodiments, the oil component comprises an emulsifier component. In some embodiments, the emulsion gel formulation comprises water, a solvent component, an oil component, an emulsifier component, and a chelating agent. In some embodiments, the emulsion gel formulation comprises water, a solvent component, an oil component, an emulsifier component, a chelating agent, and a preservative component.

[0220] In some embodiments, water is present in an amount of about 10% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 30% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 40%.

[0221] In some embodiments, the oil component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 30% by weight of the formulation.

[0222] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters (isopropyl myristate), glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethoxyl castor oil, polyethylene glycol hexadecyl ether (cetomacrogol 1000), diethylene glycol monoethyl ether (Transcutol P), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S3), polyoxyethylene tetradecyl ether (Brij S4), polyoxyethylene tetradecyl ether (Brij S5), polyoxyethylene tetradecyl ether (Brij S6), polyoxyethylene tetradecyl ether (Brij S7), polyoxyethylene tetradecyl ether (Brij S8), polyoxyethylene tetradecyl ether (Brij S9), polyoxyethylene tetradecyl ether (Brij S10), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl ether (Brij S12), polyoxyethylene tetradecyl ether (Brij S13), polyoxyethylene tetradecyl ether (Brij S14), polyoxyethylene tetradecyl ether (Brij S15), polyoxyethylene tetradecyl ether (Brij S16), polyoxyethylene tetradecyl ether (Brij S17), polyoxyethylene tetradecyl ether (Brij S18), polyoxyethylene tetradecyl ether (Brij S19), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl ether S721), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), acrylamide / sodium acryloyldimethyltaurate copolymer (e.g., Sepino P600), and triglycerides (caprylic / capric triglyceride (Crodamol P600), In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), xanthan gum, vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0223] In some embodiments, the emulsifier component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the emulsifier component is present in an amount of about 2% to about 30% by weight of the formulation. In some embodiments, the emulsifier component is present in an amount of about 1% to about 20% by weight of the formulation. In some embodiments, the emulsifier component is present in an amount of about 5% to about 30% by weight of the formulation. In some embodiments, the emulsifier component is present in an amount of about 5% to about 20% by weight of the formulation. In some embodiments, the emulsifier component is present in an amount of about 0.5% to about 10% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 0.5% to about 8% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 0.5% to about 5% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 5% by weight of the formulation.

[0224] In some embodiments, the emulsifier component includes one or more nonionic emulsifiers and emulsifying waxes, or a combination thereof. In some embodiments, the emulsifier or wetting agent component comprises one or more materials selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721)), and emulsifying wax (Polawax)), polyoxyl castor oil and polyoxyl hydrogenated castor oil (polyoxyl 35 castor oil), or combinations thereof.

[0225] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation.

[0226] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from diethylene glycol diethers (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycols (e.g., propylene glycol), or polyethylene glycols (e.g., PEG400).

[0227] In some embodiments, the formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0228] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0229] Treatment The present disclosure is further directed to a method of treating a skin disease in a patient in need of treatment, comprising topically administering to the affected area of ​​the patient a topical formulation comprising a JAK1 / 2 inhibitor that is ruxolitinib or a pharma- ceutically acceptable salt thereof and an organic amine pH adjuster. The present disclosure also provides a method in which the organic amine pH adjuster is a tertiary amine. The present disclosure also provides a method in which the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib phosphate. The present disclosure also provides a method in which the skin disease is an autoimmune or inflammatory skin disease.

[0230] The present disclosure also provides a method in which a synergistic effect occurs between a JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof, and an amine pH adjuster.

[0231] The present disclosure also provides methods, wherein the pharmaceutical formulation is administered at least once daily.The present disclosure also provides methods, wherein the pharmaceutical formulation is administered at least twice daily.

[0232] The present disclosure also provides a method, wherein the topical formulation is in a form selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel. The present disclosure also provides a method, wherein the topical formulation is a cream or a lotion.

[0233] skin diseases The present disclosure also provides a method of treating a skin disease in a patient in need thereof, comprising topically administering to the patient an affected area a topical formulation comprising a JAK1 / 2 inhibitor that is ruxolitinib or a pharma- ceutically acceptable salt thereof and an organic amine pH adjusting agent. In some embodiments, the skin disease is an autoimmune skin disease.

[0234] In some embodiments, the skin disease is an inflammatory skin disease.

[0235] In some embodiments, the skin disease is Th1 or Th2 associated. T helper (Th)1 and / or T helper (Th)17 cells are involved in many inflammatory and autoimmune skin diseases. For example, the following diseases are predominantly Th17 biased: (i) psoriasis (Fletcher, et al., Clin Exp Immunol, 201(2):121-134(2020), PMID:32379344; Liu, et al., Front Immunol, 11:594735(2020), PMID:33281823); (ii) ichthyosis (Czarnowicki, et al., J Invest Dermatol, 138(10):2157-2167(2018), PMID:29660300; Paller, et al., J Allergy Clin Immunol, 139(1):152-165(2017), PMID:27554821); and (iii) pityriasis pilaris (Liu (cited above), PMID:33281823). In addition, the following diseases are predominantly Th1 biased: (i) alopecia areata (Zeberkiewicz, et al., Cent Eur J Immunol, 45(3):325-333(2020), PMID:33437185; and (ii) vitiligo (Boniface, et al., Clin Rev Allergy Immunol, 54(1):52-67(2018), PMID:28685247). Several diseases are associated with both Th1 and Th17, including: (i) hidradenitis suppurativa (Fletcher, supra, PMID:32379344; Liu, supra, PMID:33281823; Banerjee, et al., Immunol Invest, 46(2):149-158(2017), PMID:27819528; Moran, et al. al., J Invest Dermatol, 137(11):2389-2395(2017), PMID: 28652108); and (ii) cutaneous lichen planus (Aghamajidi, et al., Scand J Immunol, e13000(2020), PMID: 33190330).Furthermore, blocking inflammatory cytokines such as IL-22 and CXCL10, which are involved in the proliferation, survival and function of Th1 or Th17 lymphocytes, can be useful for treating Th1 or Th17-related diseases. For example, T helper (Th) 17 cells are a unique lineage of effector CD4+ T cells characterized by the production of IL-17. See Liang, et al., J Exp Med, 203(10):2271-9 (2006), PMID:16982811. Th17 cells have been shown to express IL-22 in substantially higher amounts than Th1 or Th2 cells. Furthermore, the expansion of IL-22-producing cells is dependent on IL-23. Therefore, blocking IL-17 and IL-23 is a clinically proven approach in psoriasis. Examples of this approach in the treatment of psoriasis, a Th17-related disease, include secukinumab and guselkumab, which block IL-17 and IL-23, respectively. T helper (Th) 1 cells are a distinct lineage of effector CD4+ T cells characterized by the production of IFN-gamma and T-bet 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 the CXCL10 ligand. Thus, diseases such as vitiligo are believed to be Th1-related, since lymphocyte infiltration into vitiligo-prone skin is believed to be driven by CXCR3-positive Th1 cells that respond to the CXCL10 ligand.

[0236] In some embodiments, the skin disease is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. In some embodiments, the skin disease is mediated by IL-22. In some embodiments, the skin disease is mediated by MMP12. In some embodiments, the skin disease is mediated by CXCL10.

[0237] In some embodiments, the skin disease is mediated by Defb4, S100a12, or Serpinb4. 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, which is incorporated herein by reference in its entirety). Defb4 encodes human beta-defensin 2 (hBD2), an antimicrobial peptide that plays an essential role in inflammatory processes in the skin and is important in the development of psoriasis (Johansen C, et al., J Invest Derm, 136(8):1608-1616(2016); doi:10.1016 / j.jid.2016.04.012, which is incorporated herein by reference in its entirety). Serpinb4 contributes to inflammation in patients with chronic skin diseases, including atopic dermatitis (Sivaprasad, U, et al., J Invest Derm 135(1):160-169 (2015); DOI:10.1038 / jid.2014.353, which is incorporated by reference in its entirety).

[0238] In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, ichthyosis, prurigo nodularis, lichen planus, and keratinization disorders.

[0239] In some embodiments, the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, prurigo nodularis, lichen planus, and ichthyosis.

[0240] In some embodiments, the skin disease is psoriasis. In some embodiments, the psoriasis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The relationship between psoriasis and IL-22, CXCL10, and / or MMP12 can be found, for example, in IL-22, CXCL10, and / or MMP12. See He et al. "Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis" J Allergy Clin Immunol. 2020 Jul 9; S0091-6749 (20) 30824-1, PMID: 32709423, which is incorporated herein by reference in its entirety. In some embodiments, the psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, the psoriasis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the psoriasis is mediated by matrix metallopeptidase 12 (MMP12). In some embodiments, the psoriasis is selected from plaque psoriasis, nail psoriasis, trigeminal psoriasis, palmoplantar psoriasis, and pustular psoriasis. In some embodiments, the psoriasis is plaque psoriasis. In some embodiments, the plaque psoriasis is mediated by interleukin 22 (IL-22). In some embodiments, the plaque psoriasis is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the plaque psoriasis is mediated by matrix metallopeptidase 12 (MMP12).

[0241] In some embodiments, the skin disease is atopic dermatitis. In some embodiments, the atopic dermatitis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The relationship between atopic dermatitis and IL-22 and / or MMP12 can be found, for example, in He et al. "Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis" J Allergy Clin Immunol. 2020 Jul 9; S0091-6749 (20) 30824-1, PMID: 32709423. The 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 Dec; 72(12): 2017-2025, PMID: 28599078. Each document cited herein is incorporated by reference in its entirety. In some embodiments, the atopic dermatitis is mediated by interleukin 22 (IL-22). In some embodiments, the atopic dermatitis is mediated by CXC motif chemokine 10 (CXCL10). In some embodiments, the atopic dermatitis is mediated by matrix metallopeptidase 12 (MMP12).

[0242] In some embodiments, the skin disease is alopecia. In some embodiments, the skin disease is alopecia areata. The relationship between alopecia areata and IL-22 can be found, for example, in Loh et al. "Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients" J Eur Acad Dermatol Venereol. 2018 Jun; 32 (6): 1028-1033., PMID: 29283462. The relationship between alopecia areata and CXCL10 can be found, for example, in Duca et al. "Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing" Br J Dermatol. 2020 Mar 25, PMID: 32215911. Each document cited herein is incorporated by reference in its entirety. In some embodiments, the alopecia is mediated by interleukin 22 (IL-22). In some embodiments, the alopecia is mediated by C-X-C motif chemokine 10 (CXCL10).

[0243] In some embodiments, the skin disease is vitiligo. The relationship between vitiligo and IL-22 can be found, for example, in Czarnowicki et al. "Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases" J Allergy Clin Immunol. 2019 Jun; 143(6): 2095-2107. PMID: 30576756. The relationship between vitiligo and CXCL10 can be found, for example, in Abdallah et al. "CXCL-10 and Interleukin-6 are reliable serum markers for vitiligo activity: A multicenter cross-sectional study" Pigment Cell Melanoma Res. 2018 Mar; 31(2): 330-336. PMID: 29094481. Each document 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 (CXCL10).

[0244] In some embodiments, the skin disease is Reiter's syndrome. The relationship between Reiter's syndrome and IL-22 can be found, for example, in Zhao et al. "IL-22+CD4+T cells in patients with rheumatoid arthritis" Int J Rheum Dis. 2013 Oct; 16(5): 518-26, PMID: 24164838. The relationship between Reiter's syndrome and CXCL10 can be found, for example, in Pandya et al. "Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker" Arthritis Res Ther. 2017 Feb 2; 19(1): 20, PMID: 28148302. Each document cited herein is incorporated by reference in its entirety. In some embodiments, Reiter's syndrome is mediated by interleukin 22 (IL-22). In some embodiments, Reiter's syndrome is mediated by C-X-C motif chemokine 10 (CXCL10).

[0245] In some embodiments, the skin disease is pityriasis rubra pilaris. The relationship between pityriasis rubra pilaris and IL-22 can be found, for example, in Feldmeyer et al. "Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris" JAMA Dermatol. 2017 Apr 1; ​​153(4): 304-308, PMID: 28122069. The relationship between pityriasis rubra pilaris and CXCL10 can be found, for example, in Adnot-Desanlis et al. "Effectiveness of infliximab in pityriasis rubra pilaris is associated with pro-inflammatory cytokine inhibition" Dermatology 2013; 226(1): 41-6, PMID: 23548788. Each document 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 (CXCL10).

[0246] In some embodiments, the skin disease is epidermolysis bullosa simplex. The relationship between epidermolysis bullosa simplex and IL-22 and / or CXCL10 can be found, for example, in Castela et al. "Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment" Br J Dermatol. 2019 Feb; 180(2): 357-364, PMID: 29932457, which is incorporated by reference in its entirety. In some embodiments, epidermolysis bullosa simplex is mediated by interleukin 22 (IL-22). In some embodiments, epidermolysis bullosa simplex is mediated by C-X-C motif chemokine 10 (CXCL10).

[0247] In some embodiments, the skin disease is palmoplantar keratosis. The relationship between palmoplantar keratosis and IL-22 can be found, for example, in Druetz et al. "Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid" JAMA Dermatol. 2019 Feb 1; 155 (2): 216-220, PMID: 30484821, which is incorporated herein by reference in its entirety. In some embodiments, palmoplantar keratosis is mediated by interleukin 22 (IL-22).

[0248] In some embodiments, the skin disease is pachyonychia congenita. The relationship between pachyonychia congenita and IL-22 can be found, for example, in Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb; 247(2): 158-165, PMID: 30306595, which is incorporated herein by reference in its entirety. In some embodiments, pachyonychia congenita is mediated by interleukin 22 (IL-22).

[0249] In some embodiments, the skin disease is multiple sebaceous cysts. The relationship between multiple sebaceous cysts and IL-22 can be found, for example, in Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb; 247 (2): 158-165, PMID: 30306595, which is incorporated herein by reference in its entirety. In some embodiments, multiple sebaceous cysts are mediated by interleukin 22 (IL-22).

[0250] In some embodiments, the skin disease is cutaneous lichen planus. The relationship between cutaneous lichen planus and IL-22 can be found, for example, in Chen et al. "Immunoexpression of interleukin-22 and interleukin-23 in oral and cutaneous lichen planus lesions: a preliminary study" Mediators Inflamm. 2013; 2013: 801974, PMID: 24376306. The relationship between cutaneous lichen planus and CXCL10 can be found, for example, in Domingues et al. "The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7 / TLR8 and TLR9 ligands in cutaneous lichen planus" Br J Dermatol. 2015 Jan;172(1):48-55, PMID:24976336 and Wenzel et al. "CXCR3<->ligand-mediated skin inflammation in cutaneous lichenoid graft-versus-host disease" J Am Acad Dermatol. 2008 Mar;58(3):437-42, PMID:18280341, each of which is incorporated by reference herein in its entirety. In some embodiments, cutaneous lichen planus is mediated by interleukin 22 (IL-22). In some embodiments, cutaneous lichen planus is mediated by C-X-C motif chemokine 10 (CXCL10).

[0251] In some embodiments, the skin disease is cutaneous T-cell lymphoma. In some embodiments, the cutaneous T-cell lymphoma is mediated by interleukin 22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The 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 Jun 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 corneum in Cutaneous T-Cell Lymphomas and psoriasis” Exp Dermatol. 2019 Mar;28(3):317-321, PMID:30637808. Each document cited herein is incorporated by reference in its entirety. In some embodiments, the cutaneous T-cell lymphoma is mediated by interleukin 22 (IL-22). In some embodiments, the cutaneous T-cell lymphoma is mediated by C-X-C motif chemokine 10 (CXCL10). In some embodiments, the cutaneous T-cell lymphoma is mediated by matrix metallopeptidase 12 (MMP12).

[0252] In some embodiments, the skin disease is hidradenitis suppurativa. The relationship between hidradenitis suppurativa and IL-22 can be found, for example, in Rumberger et al. "Transcriptomic analysis of hidradenitis suppurativa skin suggests roles for multiple inflammatory pathways in disease pathogenesis" Inflamm Res. 2020 Oct; 69(10): 967-973, PMID: 32661800, which is incorporated herein by reference in its entirety. In some embodiments, hidradenitis suppurativa is mediated by interleukin 22 (IL-22).

[0253] In some embodiments, the skin disease is contact dermatitis. In some embodiments, the contact dermatitis is mediated by interleukin 22 (IL-22), CXC motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof. The relationship between contact dermatitis and IL-22 can be found, for example, in Robb et al. "Prostaglandin E 2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis" J Allergy Clin Immunol. 2018 Jan; 141 (1): 152-162, PMID: 28583370. The relationship between contact dermatitis and CXCL10 can be found, for example, in Brans et al. "Stratum corneum levels of inflammatory mediators and natural moisturizing factor in patch test reactions to thiurams and fragrances and their possible role in discrimination between irritant and allergic reactions to hapten mixtures" Contact Dermatitis. 2020 Nov 21, PMID: 33222241. The relationship between contact dermatitis and MMP12 can be found, for example, in Meguro et al. "SOCS3 Expressed in M2 Macrophages Attenuates Contact Hypersensitivity by Suppressing MMP-12 Production" J Invest Dermatol. 2016 Mar; 136 (3): 649-657, PMID: 27015453. Each of the documents cited herein is incorporated herein by reference in its entirety. In some embodiments, the contact dermatitis is mediated by interleukin 22 (IL-22).In some embodiments, the contact dermatitis is mediated by C-X-C motif chemokine 10 (CXCL10).In some embodiments, the contact dermatitis is mediated by matrix metallopeptidase 12 (MMP12).

[0254] In some embodiments, the skin disease is ichthyosis. The relationship between ichthyosis and IL-22 can be found, for example, in Czarnowicki et al. "The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17 / Tc-17 / Th-22 / Tc-22 Polarization in Blood" J Invest Dermatol. 2018 Oct; 138(10): 2157-2167, PMID: 29660300, which is incorporated herein by reference in its entirety. In some embodiments, ichthyosis is mediated by interleukin 22 (IL-22). In some embodiments, the ichthyosis is ichthyosis vulgaris, X-linked recessive ichthyosis, bullous congenital ichthyosis-like erythroderma (BCIE), non-bullous congenital ichthyosis-like erythroderma (NBCIE), lamellar ichthyosis, harlequin ichthyosis, ichthyosis syndrome, or acquired ichthyosis.

[0255] Generally, keratinization disorders are a group of disorders of keratinization. The relationship between keratinization disorders and IL-22 can be found, for example, in Yang et al. "Keratin 17 in disease pathogenesis: from cancer to dermatoses" J Pathol. 2019 Feb; 247(2): 158-165, PMID: 30306595, which is incorporated herein by reference in its entirety. In some embodiments, the keratinization disorder is mediated by IL-22. In some embodiments, the keratinization disorder is selected from ichthyosis, palmoplantar keratosis, keratosis pilaris, and acantholytic dermatosis.

[0256] In some embodiments, the skin disease is rosacea, psoriatic arthritis, skin fibrosis, morphea, Spitz nevus, dermatophytosis, or acne vulgaris. In some embodiments, the skin disease is rosacea. In some embodiments, the rosacea is mediated by interleukin 22 (IL-22) or CXC motif chemokine 10 (CXCL10), or a combination thereof. The relationship between rosacea and IL-22 and CXCL10 can be found, for example, in 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, the rosacea is mediated by interleukin 22 (IL-22). In some embodiments, the psoriasis is rosacea by CXC motif chemokine 10 (CXCL10). In some embodiments, the skin disease is psoriasis mediated by S100a12. In some embodiments, the skin disease is psoriatic arthritis mediated by S100a12. In some embodiments, the skin disease is dermal fibrosis mediated by S100a12. In some embodiments, the skin disease is morphea mediated by S100a12. In some embodiments, the skin disease is atopic dermatitis mediated by S100a12. In some embodiments, the skin disease is Spitz nevus mediated by S100a12.

[0257] In some embodiments, the skin disease is psoriasis mediated by Defb4. In some embodiments, the skin disease is psoriatic arthritis mediated by Defb4. In some embodiments, the skin disease is dermatophytosis mediated by Defb4. In some embodiments, the skin disease is acne vulgaris mediated by Defb4. In some embodiments, the skin disease is hidradenitis suppurativa mediated by Defb4.

[0258] In some embodiments, the skin disease is psoriasis, which is mediated by Serpinb4. In some embodiments, the skin disease is psoriatic arthritis, which is mediated by Serpinb4.

[0259] In some embodiments, ruxolitinib or a salt thereof is administered as a topical formulation, hi some embodiments, the topical formulation comprises about 0.05% to about 3.0% or about 0.05% to about 1.5% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof on a free base basis. In some embodiments, the topical formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 0.97% by weight of the formulation on a free base basis. In some embodiments, the topical formulation comprises about 0.5% to about 1.5% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof, in an amount of about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight of ruxolitinib or a pharma- ceutically acceptable salt thereof, on a free base basis. In some embodiments, the ruxolitinib is ruxolitinib phosphate.

[0260] In some embodiments, as disclosed above, the amine pH adjuster is a tertiary amine. In some embodiments, the organic amine pH adjuster is an alkanolamine. In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine. In some embodiments, as disclosed above, the amine pH adjuster is independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine.

[0261] In some embodiments, the amine pH adjuster is trolamine.

[0262] In some embodiments, adjusting the pH of the formulation with trolamine to greater than 5.5% increased the drug loading to greater than 8% w / w.

[0263] In some embodiments, the amine pH adjuster is present in an amount to adjust the pH of the formulation, such that the formulation has a pH of about 5.0 to about 8.0, about 5.5 to about 7.5, or about 5.5 to about 7.0. In some embodiments, the amine pH adjuster is present in an amount up to 11% w / w or up to 2.6% w / w. Further for example, in some embodiments, the amine pH adjuster is present in an amount of about 0.25% to about 0.5%, about 0.5% to about 0.75%, about 0.75% to about 1%, about 1% to about 1.25%, about 1.25% to about 1.5%, about 1.5% to about 1.75%, about 1.75% to about 2%, about 2% to about 2.25%, about 2.25% to about 2.5%, about 2.5% to about 2.6%, about 2.6% to about 2.75%, about 2.75% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, or about 10% to about 11% (w / w) by weight of the formulation.

[0264] In some embodiments, there is a synergistic effect between the JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the organic amine pH adjuster.

[0265] The disclosure also provides pharmaceutical formulations, the formulations having a pH of about 5.0 to about 8.0, about 5.5 to about 7.5, or about 5.5 to about 7.0.

[0266] In some embodiments, methods provided herein wherein a JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0267] In some embodiments of each of the foregoing, the patient is a human patient.

[0268] Formulations with water and ethanol The present disclosure further provides a topical formulation for treating skin disease, comprising a JAK1 / 2 inhibitor that is ruxolitinib or a pharmaceutically acceptable salt thereof, water, and ethanol. In some embodiments, the JAK1 / 2 inhibitor is a pharmaceutically acceptable salt of ruxolitinib. In some embodiments, the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib phosphate. In some embodiments, the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib sulfate. In some embodiments, the JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof is ruxolitinib maleate.

[0269] In some embodiments, ruxolitinib or a pharma- ceutically acceptable salt thereof is present in an amount of about 0.05% to about 3.0% or about 0.05% to about 1.5% w / w of ruxolitinib or a pharma- ceutically acceptable salt thereof on a free base basis. Further for example, the disclosure provides for about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about Formulations comprising 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight are provided.

[0270] The present disclosure provides a formulation that is in a form selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel. The present disclosure provides a formulation that is a cream or a lotion. In some embodiments, the formulation is a spray formulation (e.g., a pump spray formulation).

[0271] In some embodiments, ethanol comprises about 20% to about 90% by weight of the formulation. In some embodiments, ethanol comprises about 30% to about 90% by weight of the formulation. In some embodiments, ethanol comprises about 30% to about 80% by weight of the formulation. In some embodiments, ethanol comprises about 40% to about 80% by weight of the formulation. In some embodiments, ethanol comprises about 30% to about 90% by weight of the formulation. In some embodiments, ethanol comprises about 40% to about 90% by weight of the formulation.

[0272] In some embodiments, the formulation further comprises an organic pH adjuster. In some embodiments, the organic amine pH adjuster is a tertiary amine. In some embodiments, the organic amine pH adjuster is an alkanolamine. In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine. In some embodiments, the organic amine pH adjuster is independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the amine pH adjuster is trolamine.

[0273] In some embodiments, the formulation is a spray formulation. In some embodiments, the formulation comprises water, a solvent component, and ethanol. In some embodiments, the spray formulation comprises water, a solvent component, ethanol, and a film-forming component.

[0274] In some embodiments, water is present in an amount of about 5% to about 65% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 65% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 65% by weight of the formulation. In some embodiments, water is present in an amount of about 15% to about 60% by weight of the formulation.

[0275] In some embodiments, the solvent component is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 40% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 35% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 15% to about 25% by weight of the formulation.

[0276] In some embodiments, the solvent component comprises one or more hydroxylated solvents. In some embodiments, the solvent component comprises one or more substances selected from sorbitol, diethylene glycol diether (e.g., diethylene glycol monoethyl ether (Transcutol P)), glycerol, alkylene glycol (e.g., propylene glycol), or polyethylene glycol (e.g., PEG400).

[0277] In some embodiments, ethanol is present in an amount of about 20% to about 90% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 30% to about 90% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 35% to about 85% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 40% to about 80% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 45% to about 75% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 45% to about 75% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 50% to about 70% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 30% to about 85% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 30% to about 80% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 30% to about 75% by weight of the formulation. In some embodiments, ethanol is present in an amount of about 30% to about 70% by weight of the formulation.

[0278] In some embodiments, the formulation includes a film-forming component. In some embodiments, the film-forming component includes one or more film formers. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 30% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 20% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.5% to about 20% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 15% by weight of the formulation. In some embodiments, the film-forming component is present in an amount of about 0.1% to about 5% by weight of the formulation.

[0279] In some embodiments, the film-forming component comprises one or more film-forming polymers. In some embodiments, the film-forming component comprises one or more film-forming cationic copolymers. In some embodiments, the film-forming component comprises one or more film-forming nonionic polymers. In some embodiments, the film-forming component comprises one or more film-forming anionic copolymers. In some embodiments, the film-forming component comprises one or more film-forming agents selected from polyvinylpyrrolidone, cationic methacrylate polymers (e.g., Eudragit 100), hydrophilic nonionic surfactants (e.g., Poloxamer 407, a triblock copolymer consisting of polypropylene glycol sandwiched between two hydrophilic blocks of polyethylene glycol), and copolymers of monoalkyl esters of poly(methyl vinyl ether / maleic acid) (e.g., Gantres™ ES-435). In some embodiments, the film-forming component comprises a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a 2:1:1 ratio (Eudragit E 100), a polyethylene glycol-copolypropylene glycol-co-polyethylene glycol triblock copolymer (e.g., a poloxamer such as Poloxamer 407), or a copolymer of a monoalkyl ester of poly(methyl vinyl ether / maleic acid) (e.g., Gantrez ES-435), or a combination thereof.

[0280] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, butylated hydroxytoluene (BHT), and combinations thereof.

[0281] In some embodiments, the formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0282] Formulation with glycerol and Transcutol P The present disclosure further provides a topical formulation for treating a skin disease, comprising a JAK1 / 2 inhibitor that is ruxolitinib, or a pharma- ceutically acceptable salt thereof, and a solvent component, the solvent component comprising glycerol and Transcutol P. The present disclosure further provides a topical formulation for treating a skin disease, comprising a JAK1 / 2 inhibitor that is ruxolitinib, or a pharma- ceutically acceptable salt thereof, water, and a solvent component, the solvent component comprising glycerol and Transcutol P. In some embodiments, the JAK1 / 2 inhibitor is a pharma- ceutically acceptable salt of ruxolitinib. In some embodiments, the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib phosphate. In some embodiments, the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib sulfate. In some embodiments, the JAK1 / 2 inhibitor or a pharma- ceutically acceptable salt thereof is ruxolitinib maleate.

[0283] In some embodiments, ruxolitinib or a pharma- ceutically acceptable salt thereof is present in an amount of about 0.05% to about 3.0% or about 0.05% to about 1.5% w / w of ruxolitinib or a pharma- ceutically acceptable salt thereof on a free base basis. Further for example, the disclosure provides for about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about Formulations comprising 0.95%, about 1.0%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2.0%, about 2.5%, or about 3.0% by weight are provided.

[0284] The present disclosure provides a formulation that is in a form selected from a cream, a lotion, a foam or effervescent formulation, a spray (e.g., a pump spray), an aqueous gel, a non-aqueous gel, and an emulsified gel. The present disclosure provides a formulation that is a cream or a lotion. In some embodiments, the formulation is a spray formulation (e.g., a pump spray formulation).

[0285] In some embodiments, the solvent component comprises glycerol in an amount of about 10% to about 90% by weight of the component, and Transcutol P in an amount of about 10% to about 90% by weight of the component. In some embodiments, the solvent component comprises glycerol in an amount of about 20% to about 80% by weight of the component, and Transcutol P in an amount of about 20% to about 80% by weight of the component. In some embodiments, the solvent component comprises glycerol in an amount of about 30% to about 70% by weight of the component, and Transcutol P in an amount of about 30% to about 70% by weight of the component. In some embodiments, the solvent component comprises glycerol in an amount of about 40% to about 60% by weight of the component, and Transcutol P in an amount of about 40% to about 60% by weight of the component. In some embodiments, the ratio of glycerol:Transcutol is about 1:1.

[0286] In some embodiments, the formulation further comprises an organic pH adjuster. In some embodiments, the organic amine pH adjuster is a tertiary amine. In some embodiments, the organic amine pH adjuster is an alkanolamine. In some embodiments, the alkanolamine is a dialkanolamine or a trialkanolamine. In some embodiments, the organic amine pH adjuster is independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine. In some embodiments, the amine pH adjuster is trolamine.

[0287] In some embodiments, the formulation is a lotion formulation. In some embodiments, the formulation is an aqueous lotion formulation. In some embodiments, the lotion formulation is an oil-in-water emulsion. In some embodiments, the lotion formulation comprises a water and an oil component. In some embodiments, the lotion formulation comprises a water, a solvent component, and an oil component. In some embodiments, the oil component comprises an emulsifier or humectant component. In some embodiments, the oil component comprises one or more stabilizers.

[0288] In some embodiments, water is present in an amount of about 10% to about 90% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 90% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 80% by weight of the formulation. In some embodiments, water is present in an amount of about 20% to about 70% by weight of the formulation. In some embodiments, water is present in an amount of about 25% to about 60% by weight of the formulation. In some embodiments, water is present in an amount of about 30% to about 60% by weight of the formulation.

[0289] In some embodiments, the oil component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation. In some embodiments, the oil component is present in an amount of about 10% to about 30% by weight of the formulation.

[0290] In some embodiments, the oil component is selected from the group consisting of fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., PEG 100 stearate (a component of Arlacel 165), polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S4), polyoxyethylene tetradecyl ether (Brij S5), polyoxyethylene tetradecyl ether (Brij S6), polyoxyethylene tetradecyl ether (Brij S7), polyoxyethylene tetradecyl ether (Brij S8), polyoxyethylene tetradecyl ether (Brij S9), polyoxyethylene tetradecyl ether (Brij S10), polyoxyethylene tetradecyl ether (Brij S11), polyoxyethylene tetradecyl ether (Brij S12), polyoxyethylene tetradecyl ether (Brij S13), polyoxyethylene tetradecyl ether (Brij S14), polyoxyethylene tetradecyl ether (Brij S15), polyoxyethylene tetradecyl ether (Brij S16), polyoxyethylene tetradecyl ether (Brij S17), polyoxyethylene tetradecyl ether (Brij S18), polyoxyethylene tetradecyl ether (Brij S19), polyoxyethylene tetradecyl ether (Brij S15), polyoxyethylene tetradecyl ether (Brij S16), polyoxyethylene tetradecyl ether (Brij S S721), waxes (e.g., paraffin (soft white paraffin), emulsifying wax (Polawax)), mineral oils, natural oils, hydrogenated oils, and silicone oils (e.g., light mineral oil, castor oil, silicone oils (e.g., cyclomethicone, dimethicone), hydrogenated castor oil (Kolliphor HCO), and triglycerides (caprylic / capric triglyceride (Crodamol S721)). In some embodiments, the oil component comprises one or more materials selected from fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax), or combinations thereof.

[0291] In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 40% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 30% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 1% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 2% to about 20% by weight of the formulation. In some embodiments, the emulsifier or wetting agent component is present in an amount of about 5% to about 20% by weight of the formulation.

[0292] In some embodiments, the emulsifier or wetting agent component comprises one or more nonionic emulsifiers and emulsifying waxes, or combinations thereof. In some embodiments, the emulsifier or wetting agent component comprises one or more substances selected from fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol (such as Kolliphor CSA50), and octodecanol (Kolliphor OD)), fatty acids, fatty acid esters, glyceryl fatty acid esters (e.g., glyceryl monostearate (Kolliwax GMS II)), sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80 (Span 80)), polyethylene glycol fatty acid ethers (e.g., polyethylene glycol hexadecyl ether (cetomacrogol 1000), polyethylene glycol octadecyl ether (Brij S2), polyoxyethylene stearyl ether (Brij S721)), and emulsifying waxes (Polawax)), or combinations thereof.

[0293] In some embodiments, the oil phase comprises one or more stabilizers. In some embodiments, the one or more stabilizers comprise one or more substances independently selected from polysaccharides. In some embodiments, the one or more stabilizers are xanthan gum.

[0294] In some embodiments, the formulation includes a solvent component. In some embodiments, the solvent component is present in an amount of about 5% to about 70% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 5% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 70% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 60% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 50% by weight of the formulation. In some embodiments, the solvent component is present in an amount of about 10% to about 40% by weight of the formulation.

[0295] In some embodiments, the solvent component further comprises one or more additional hydroxylated solvents. In some embodiments, the solvent component comprises one or more materials selected from diethylene glycol diethers (e.g., diethylene glycol monoethyl ether (Transcutol P)), alkylene glycols (e.g., propylene glycol), or polyethylene glycols (e.g., PEG400).

[0296] In some embodiments, the solvent component comprises about 0.1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 1% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 5% to about 20% glycerol by weight of the formulation. In some embodiments, the solvent component comprises about 10% to about 20% glycerol by weight of the formulation.

[0297] In some embodiments, the formulation comprises one or more chelating agents. In some embodiments, the chelating agent is EDTA.

[0298] In some embodiments, the formulation comprises one or more preservatives, hi some embodiments, the one or more preservatives are benzyl alcohol, methylparaben, propylparaben, phenoxyethanol, and combinations thereof.

[0299] definition As used herein, "affected skin area" refers to an area of ​​the skin of a patient who has a skin disorder as described herein.

[0300] As used herein, "ruxolitinib phosphate" means a phosphate salt of ruxolitinib in a 1:1 ratio of ruxolitinib to phosphate.

[0301] As used herein, an "alkanolamine" is an amine selected from the group consisting of HO-(C 2-6 Alkyl) n amine, where n is 1, 2, or 3; 2-6 The alkyl groups are independently selected and can be branched or straight chain alkyl groups.

[0302] As used herein, "cream" means an emulsion, semi-solid dosage form for application to the skin.

[0303] As used herein, "topical formulation," "pharmaceutical composition," or "pharmaceutical formulation" are used interchangeably and refer to compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissue of human and animals.

[0304] As used herein, the term "C" used alone or in combination with other terms means 3-4 The term "cycloalkyl" refers to a non-aromatic monocyclic hydrocarbon moiety having 3 to 4 carbon atoms and which may optionally contain one or more alkenylene groups as part of the ring structure. One or more ring-forming carbon atoms of a cycloalkyl group may be oxidized to form a carbonyl bond. Exemplary C 3-4 Cycloalkyl groups include cyclopropyl, cyclobutyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl. In some embodiments, the cycloalkyl group is cyclobutyl.

[0305] As used herein, the term "synergy" or "synergistic effect," when used in connection with describing the effectiveness of a combination of agents or compounds, means any measured effect of the combination that is greater than that expected from the sum of the effects of the individual agents or compounds.

[0306] As used herein, "statistically significant" means a p-value of <0.05 (preferably <0.001, most preferably <0.0001).

[0307] As used herein, "apparent pH" refers to the pH value measured in the presence of an organic solvent.

[0308] As used herein, the phrase "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals, within the scope of sound medical judgment. In some embodiments, "pharmaceutical acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias, for use in animals, and more specifically, in humans.

[0309] The subject matter claimed in this application also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the subject matter claimed in this application include conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the subject matter claimed in this application can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. In some embodiments, the pharma- ceutically acceptable salt is a phosphate, sulfate, or maleate salt.

[0310] As used herein, the term "emulsifier component" refers, in one aspect, to a substance or mixture of substances that maintain elements or particles in suspension 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 non-ionic surfactants.

[0311] As used herein, the term "occlusive agent component" refers to a hydrophobic agent or mixture of hydrophobic agents that form an occlusive film on the skin that reduces transepidermal water loss (TEWL) by preventing evaporation of water from the stratum corneum.

[0312] As used herein, the term "sclerosing agent component" refers to a substance or mixture of substances that increases the viscosity and / or consistency of a cream or improves the rheology of the cream.

[0313] As used herein, the term "emollient ingredient" refers to an agent that softens or soothes the skin or soothes irritated internal surfaces.

[0314] As used herein, the term "stabilizer ingredient" refers to a substance or mixture of substances that improves the stability of the cream and / or the compatibility of ingredients in the cream.

[0315] As used herein, the term "solvent component" refers to a liquid substance or mixture of liquid substances that can dissolve ruxolitinib or its pharma- ceutically acceptable salt or other substances in the cream. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which ruxolitinib or its pharma- ceutically acceptable salt has suitable solubility. For example, the solvent is a substance or mixture of liquid substances in which ruxolitinib or its pharma- ceutically acceptable salt (whichever is used) has a solubility of at least about .5% or more, 1% or more, 10 mg / mL or more, at least about 15 mg / mL or more, or at least about 20 mg / mL or more.

[0316] As used herein, the phrase "antimicrobial preservative component" is a substance or mixture of substances that inhibits the growth of microorganisms in the cream.

[0317] As used herein, the phrase "chelator component" refers to a compound or mixture of compounds that has the ability to strongly bind metal ions.

[0318] As used herein, "wt % of the formulation" means the percent concentration of a component in the formulation on a weight / weight basis. For example, 1% w / w of component A = [(mass of component A) / (total mass of the formulation)] x 100.

[0319] As used herein, "weight % of emulsion on a free base basis" of the JAK inhibitor described herein, such as ruxolitinib or its pharma- ceutically acceptable salt, means that the % w / w is calculated based on the weight of ruxolitinib in the total emulsion.For example, "1.5% w / w on a free base basis" of ruxolitinib phosphate means that for 100 grams of total formulation, there is 1.98 grams of ruxolitinib phosphate in the emulsion (which corresponds to 1.5 grams of free base, ruxolitinib).

[0320] As used herein, "% by weight of formulation on a free base basis" of the JAK inhibitor described herein, such as ruxolitinib or its pharma- ceutically acceptable salt, means that % w / w is calculated based on the weight of ruxolitinib in the total formulation.For example, "1.5% w / w on a free base basis" of ruxolitinib phosphate means that for 100 grams of total formulation, there is 1.98 grams of ruxolitinib phosphate in the formulation (which corresponds to 1.5 grams of free base, ruxolitinib).If not already indicated in the examples, the percentage of ruxolitinib phosphate can be converted to free base basis by multiplying by a conversion factor of 0.7575.

[0321] As used herein, the term "ingredient" may mean a substance or a mixture of substances.

[0322] As used herein, the term "fatty acid" refers to a saturated or unsaturated fatty acid. In some embodiments, the fatty acid is in a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about 8 to about 30 carbons. In some embodiments, the fatty acid has an average of about 12 to 20, 14 to 20, or 16 to 18 carbons. Suitable fatty acids include, but are not limited to, cetylic acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof.

[0323] As used herein, the term "fatty alcohol" refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, serratyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.

[0324] As used herein, the term "polyalkylene glycol", used alone or in combination with other terms, refers to a polymer comprising oxyalkylene monomer units or a copolymer of different oxyalkylene monomer units, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene", used alone or in combination with other terms, refers to a group of formula -O-oxyalkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.

[0325] As used herein, the term "sorbitan fatty acid esters" 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 esters are polyethoxylated sorbitan esters.

[0326] 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, the Span™ series (available from Uniqema), including Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). Other suitable sorbitan esters include those listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0327] As used herein, the term "polyethoxylated sorbitan ester" refers to a compound or mixture of compounds derived from the ethoxylation of a sorbitan ester. 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 sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to, the Tween™ 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 number following the abbreviation POE refers to the number of oxyethylene repeat units in the compound.Other suitable polyethoxylated sorbitan esters include the polyoxyethylene sorbitan fatty acid esters listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety. In some embodiments, the polyethoxylated sorbitan ester is polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

[0328] As used herein, the term "glyceryl fatty acid ester" refers to a mono-, di-, or triglyceride of a fatty acid. The glyceryl fatty acid ester may be optionally substituted with a sulfonic acid group or a pharma- ceutically acceptable salt thereof. Suitable fatty acids for deriving the glyceride of a fatty acid include, but are not limited to, those described herein. In some embodiments, the glyceryl fatty acid ester is a monoglyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceryl fatty acid ester is glyceryl stearate.

[0329] As used herein, the term "triglyceride" refers to a triglyceride of a fatty acid. In some embodiments, the triglyceride is a medium chain triglyceride.

[0330] As used herein, the term "alkylene glycol" refers to a group of formula -O-alkylene-, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).

[0331] As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., methyl, group. Also suitable are derivatives of polyethylene glycol having esterifiable carboxy groups. Polyethylene glycols useful in the present disclosure may be polymers of any chain length or molecular weight and may include branching. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number after the dash in the name refers to the average molecular weight of the polymer.

[0332] As used herein, "contains" is equivalent to "comprises."

[0333] As used herein, the terms "subject," "individual," or "patient," which are used interchangeably, refer to a human. In some embodiments, a "subject," "individual," or "patient" is in need of the treatment.

[0334] In some embodiments, the compound described herein or its pharma- ceutically acceptable salt, or its pharmaceutical formulation, its topical formulation is administered in a therapeutically effective amount.As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that induces the biological or medicinal response that a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human.

[0335] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting symptoms or symptomology of the disease, condition, or disorder (i.e., preventing further development of symptoms and / or symptomology); (2) ameliorating a disease, e.g., reducing the severity of a disease, in an individual experiencing or exhibiting symptoms or symptomology of the disease, condition, or disorder (i.e., reversing symptoms and / or symptomology); or (3) preventing a disease, condition, or disorder in an individual who may be predisposed to a disease, condition, or disorder but has not yet experienced or exhibited symptoms or symptomology of the disease. In some embodiments, treating refers to inhibiting or ameliorating a disease. In some embodiments, treating is preventing a disease.

[0336] In some embodiments, an ingredient is present only within a specified range (e.g., the term "about" is not present). In some embodiments, the term "about" refers to ±10% of a value. EXAMPLES

[0337] The subject matter claimed herein will be described in more detail by specific examples.The following examples are presented for illustrative purposes and are not intended to limit the subject matter claimed herein in any manner.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.

[0338] Example 1: Solubility of Ruxolitinib phosphate The solubility of ruxolitinib phosphate in aqueous media is shown in Table 1. The solubility of ruxolitinib phosphate was substantially higher (about 1.8% w / w) in unbuffered water compared to water at pH 5 or 7. [Table 1]

[0339] Example 2: Solubility of Ruxolitinib phosphate using trolamine as a pH adjuster Unexpectedly, it was found that the use of trolamine to adjust the pH of the solvent system improved the solubility of ruxolitinib phosphate. Various iterations of the solvent system were evaluated using trolamine (FDA IID approved for topical use up to 2.6% w / w) as the pH adjusting solution instead of NaOH, and bringing the solvent system to the target volume with either water or PEG 200. The composition of the solvent systems, their apparent pH, and the solubility of ruxolitinib phosphate in the systems are detailed in Tables 2 and 3.

[0340] SSCR27-29 were pH adjusted to different levels, SSCR30 was a control with no pH adjustment, SSCR31-32 were pH adjusted to 4.0 and 5.0, SSAG05 was based on SSAG01 with no pH adjustment, SSAG06 and SSAG07 were pH adjusted to 4.0 and 5.5 respectively, and SSNA03 was pH adjusted to 5.5.

[0341] These experiments showed that the more trolamine included in the solvent system to adjust the pH of the solvent system to above 5.0, the more the solubility of ruxolitinib phosphate increases. For example, the more trolamine included in the solvent system to adjust the pH of the solvent system to above 5.0, the more the solubility of ruxolitinib phosphate increases in a system with low water content (≦25% w / w) (4.82% w / w drug in SSCR27 at pH 4.11 compared to about 11.29% w / w drug in SSCR29 at pH 7.27) (see FIG. 1). Here, the apparent pH of the system is maintained and an increase (or no change) in drug solubility is observed. These would be surprising to a person skilled in the art (POSA) based on preformulation data, e.g., Example 1. Without being bound by a particular theory, it is hypothesized that trolamine shifts the drug polymorph to one with a higher solubility profile, allowing a higher drug loading over about 24 hours of stirring at 20° C. than without trolamine. Furthermore, at low water levels (<25% w / w), it was unexpectedly found that pH adjustment with trolamine to above 5.5% increased drug loading to above 8% w / w in some systems. [Table 2] [Table 3]

[0342] Example 3: Solvent Systems for Creams, Lotions, and Foams Solvent systems for ruxolitinib phosphate suitable for inclusion in creams, lotions, and foams were investigated and are shown in Table 4. Saturation solubility data is presented as ruxolitinib free base, and potential drug loading in the formulation represents solubility values ​​after adjustment for the amount of solvent system in the final formulation (assuming no solubility in the oil phase) and adjustment to ensure that the drug is at approximately 80% saturation. All systems were loaded with approximately 5% w / w of the ruxolitinib phosphate form (approximately 3.79% w / w of free base). [Table 4]

[0343] Example 4: Cream formulation development A series of cream formulations of ruxolitinib phosphate were prepared using trolamine to adjust the pH. The formulations selected for short-term stability testing using these compositions are presented in Tables 5 and 6, and the characterization of these formulations is presented in Table 7.

[0344] All formulations had similarly low instability indices (0.024 for CR03 and 0.011 for CR07) and were described as thick creams that applied smoothly. Given their apparent pH (approximately 5.5), these formulations should pose a low risk of causing potential irritation.

[0345] These cream formulations were prepared according to the following general manufacturing method for the preparation of cream and lotion formulations. (i) The aqueous phase of the formulation was prepared in an amber Duran bottle and stirred at 400 RPM with a magnetic stir bar until visually homogenous. (ii) For formulations containing EDTA and / or propyl gallate, these were first dissolved in a portion of the water, stirred at 400 RPM and then added to the vessel in step (i). (iii) Ruxolitinib phosphate was added to the aqueous phase and stirred at 400 RPM for approximately 5 minutes, followed by pH adjustment. The apparent pH of the phase was monitored until visual dissolution of the API was observed. (iv) The oil phase of the formulation was prepared in a separate amber Duran bottle. (v) For formulations containing gelling agents, these are dispersed in a suitable liquid oil and stirred at 500 RPM until visually homogenous, then added to the vessel of step (iv). (vi) The oil phase was placed in a 70° C. water bath until melted (approximately 1 hour) or, in the case of the solid oil phase containing Kolliphor HCO, in a 90° C. water bath. Additionally, the aqueous phase, the liquid oil phase and the homogenizer head were heated. (vii) The three phases (aqueous phase, liquid oil phase, and molten solid oil phase) were combined and homogenized using an IKA T25 Ultra Turrax at 10,000 RPM for 2 minutes. (viii) After homogenization, the formulation was allowed to cool to room temperature while stirring using an IKA stirrer at 200 RPM. (ix) Once the formulation had reached room temperature, phenoxyethanol was added and the formulation was manually stirred to incorporate. (x) Check the apparent pH of the formulation and complete any final pH adjustments or addition of water as appropriate. [Table 5-1] [Table 5-2] [Table 6] [Table 7]

[0346] Example 5: Development of a Lotion Formulation A series of lotion formulations of ruxolitinib phosphate were prepared and are presented in Table 8, with characterization of these formulations presented in Table 9: they incorporate various oil phases that provide different organoleptic properties.

[0347] These lotion formulations were prepared according to the following general manufacturing method for the preparation of cream and lotion formulations. (i) The aqueous phase of the formulation was prepared in an amber Duran bottle and stirred at 400 RPM with a magnetic stir bar until visually homogenous. (ii) For formulations containing EDTA and / or propyl gallate, these were first dissolved in a portion of the water, stirred at 400 RPM and then added to the vessel in step (i). (iii) Ruxolitinib phosphate was added to the aqueous phase and stirred at 400 RPM for approximately 5 minutes, followed by pH adjustment. The apparent pH of the phase was monitored until visual dissolution of the API was observed. (iv) The oil phase of the formulation was prepared in a separate amber Duran bottle. (v) For formulations containing gelling agents, these are dispersed in a suitable liquid oil and stirred at 500 RPM until visually homogenous, then added to the vessel of step (iv). (vi) The oil phase was placed in a 70° C. water bath until melted (approximately 1 hour) or, in the case of the solid oil phase containing Kolliphor HCO, in a 90° C. water bath. Additionally, the aqueous phase, the liquid oil phase and the homogenizer head were heated. (vii) The three phases (aqueous phase, liquid oil phase, and molten solid oil phase) were combined and homogenized using an IKA T25 Ultra Turrax at 10,000 RPM for 2 minutes. (viii) After homogenization, the formulation was allowed to cool to room temperature while stirring using an IKA stirrer at 200 RPM. (ix) Once the formulation had reached room temperature, phenoxyethanol was added and the formulation was manually stirred to incorporate. (x) Check the apparent pH of the formulation and complete any final pH adjustments or addition of water as appropriate. [Table 8] [Table 9]

[0348] Example 6: Foam formulation development Foam formulations (i.e., effervescent formulations) of ruxolitinib phosphate using trolamine to increase the pH were also investigated. The foam formulations were prepared similarly to the cream and lotion formulations, and then propellant was added using Pamasol Aerosol Filler. Their compositions are presented in Table 10, and the characterization of these formulations is presented in Table 11.

[0349] The foam formulations were prepared using the following general manufacturing process: (i) Foam premixes were prepared according to the method used to prepare the creams and lotions. (ii) The foam premix was added to the canister. The valve was crimped. (iii) Pamasol was used to add propellant to the canister of step (ii). (iv) The finished foam was allowed to mix overnight on a roller mixer. [Table 10-1] [Table 10-2] [Table 11]

[0350] Example 7: Development of a spray (pump spray) formulation A set of pump spray formulations of ruxolitinib phosphate was investigated. Pump spray formulations are simple solutions, typically containing high levels of volatile excipients (such as ethanol) that evaporate when applied to the skin. Since no propellant is included, the formulations are actuated by a manual pump rather than opening a valve as propellant sprays do. The compositions are presented in Table 12.

[0351] To prepare the pump spray, the following general manufacturing method is used: (i) BHT was added to ethanol and stirred with a magnetic stir bar at 500 RPM for approximately 15 minutes until visibly dissolved. (ii) The poloxamer or Gantrez is added to the vessel from step (i). This is stirred at 500 RPM for approximately 30 minutes until visually dissolved. (iii) The remaining excipients were added to the vessel from step (iii) and the solution was stirred at 500 RPM for approximately 10 minutes until visually homogenous. (iv) Ruxolitinib phosphate was added to the vessel from step (iii) and stirred at 500 RPM for approximately 1 hour until visibly dissolved, and the pH of the solution was adjusted. [Table 12]

[0352] Example 8: Synergy between glycerol and Transcutol P The effect of Transcutol P on the solubility of ruxolitinib phosphate in the solvent system was observed to be much greater than expected based on its solubility in the excipient alone (11.3 mg / mL). First, SSCR23 was developed as a system containing 20% ​​w / w glycerol and 15% Transcutol P. Ruxolitinib phosphate could be dissolved in this system at about 1% w / w. As shown in Table 13, increasing the level of Transcutol P by 3% w / w (to 18% w / w in SSCR30) resulted in an increase in solubility to about 1.7% w / w, and further increasing Transcutol P by 2% w / w (to 20% w / w in SSCR26) increased the drug solubility to 3.62% w / w, much more than expected. This is presumably caused by the synergistic solvent effect between glycerol and Transcutol P. [Table 13]

[0353] Example 9: Synergism of Ethanol-Water Formulations As shown in Table 14, unexpectedly high solubility of ruxolitinib phosphate (≧3.79% w / w) was observed in the pump spray formulation, considering the high level of ethanol in the system (>50% w / w) and the relatively low solubility of ruxolitinib phosphate in this excipient alone (about 0.76% w / w). The solubility of the API in this system was greater than 3.79% w / w. This suggests that there may be a synergistic solvent effect between water and ethanol that causes high solubility of ruxolitinib phosphate. [Table 14]

[0354] Example 10: Short-term stability studies The formulations selected for short-term stability studies are detailed in Tables 15-20. These formulations were manufactured at 250 g scale and characterized at each time point as follows: - Ruxolitinib phosphate assay and purity - Appearance to the naked eye - Microscopic appearance and droplet size, if applicable - Apparent pH - Texture analysis, t=0, 1 month, and 3 months only, 25°C - Rheology, t=0, 1 month, and 3 months only, 25°C - Acceleration physical stability, t=0 only

[0355] Considering the nature of the formulation for topical administration, the apparent pH of the formulation for short-term stability is presented in Table 20. Other characterization data (e.g., ruxolitinib phosphate assay and purity, macroscopic appearance, microscopic appearance and droplet size where applicable, texture analysis, rheology, and accelerated physical stability) are not presented herein. [Table 15-1] [Table 15-2] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20]

[0356] Example 11: Characterization of formulations Tables 21 and 22 show the properties of the cream and lotion formulations based on the results of short-term stability studies, in vitro permeation and penetration studies, and RHE irritation studies.

[0357] In Tables 21 and 22, the rankings are on a scale of 1 to 3, with 1 (dark grey) being best, 2 (medium grey) being average, and 3 (light grey) being worst. In Table 22, the rankings from the performance tests are in order of relative performance, with the lowest number being the best. [Table 21] [Table 22-1] [Table 22-2]

[0358] Example 12: Additional Comparative Examples In Table 23, the following comparative examples are compared to exemplary cream formulations (CR01a, CR10 ACT, CR13 ACT, CR15 ACT, and CR16 ACT) and lotion formulations (LO07 ACT, LO10 ACT, LO11 ACT, LO14 ACT, and LO15 ACT) in in vitro permeation and penetration (IVPT) studies at 10 mg / cm in a low flow cell (6 μL / min). 2 Human abdominal skin from elective surgery was used at a thickness of 400 micrometers, using a receptor solution of PBS (pH 7.4) with 0.01% Brij at a dosage of 100 mg / mL. Extraction of the dermis and epidermis was performed.

[0359] The amount of ruxolitinib that penetrated the epidermis and dermis 24 hours after application of the test formulation, with data normalized to the average performance of the bridge formulation CR01a, is shown in Figure 1. The amount of ruxolitinib that penetrated the skin into the receptor solution over 24 hours after application of the test formulation, with data normalized to the average performance of the bridge formulation CR01a, is shown in Figure 2.

[0360] Surprisingly, it was found that formulations pH adjusted with trolamine were able to deliver greater amounts of ruxolitinib to the dermis (e.g., CR16) even though the formulations pH adjusted with trolamine had substantially lower ruxolitinib strength compared to formulations without trolamine (COM1). [Table 23]

[0361] Example 13: Product Conversion: Apparent pH A. Product Conversion Product transformation of lead formulations from formulation development was also investigated. Product transformation, or vehicle degradation, describes the changes that occur to a formulation between storage in the primary packaging and dose delivery. This typically includes formulation vitrification caused by dispensing and applying the product; evaporation of volatile excipients; and excipient and API penetration into tissues. Each of these can affect the formulation's Q3 microstructure, efficacy, organoleptic properties, and safety profile, and therefore represent critical quality attributes (CQAs) in topical product development. Therefore, understanding product transformation of topical products is used early in development and is recognized by regulatory agencies.

[0362] Method development was performed based on previous studies to identify conversion parameters and test methodology. PermeaPad membrane was used as the conversion medium in this study because it is a biomimetic and offers the opportunity to absorb excipients into a lipid layer, like the stratum corneum of skin, without the challenging practical considerations of using ex vivo skin (e.g., vaccination, which requires sourcing the necessary amounts of tissue and handling it). The investigations performed in this study evaluated the absorption of API and excipients into the skin (using PermeaPad membrane as a model) as well as the effect of heat (32°C), which causes evaporation of volatile excipients, on the following parameters, using formulations selected for short-term stability testing: - Adhesion by texture analysis - Appearance to the naked eye - Microscopic appearance - Apparent pH

[0363] The results of adhesion, macroscopic appearance, and microscopic appearance by texture analysis are not provided here.

[0364] B. Apparent pH Considering topical administration of the formulation to the dermis, the apparent pH results are included herein. The apparent pH of the formulation after product conversion was evaluated using t=0 of the short-term stability study as pre-conversion data for comparison. The data are presented in Table 24. The apparent pH of the spray formulation after conversion was not evaluated because only a solid film remained.

[0365] There was no significant change in apparent pH for any of the converted formulations, although slight variations were observed as expected given the low levels of water remaining in the converted formulations and the highly viscous nature of the residual phase. [Table 24]

[0366] Example 14. Ruxolitinib phosphate and alternative bases Part 1: Identification of Alternative Bases: Several alternative bases (i.e., alternative organic amine pH modifiers) with structures similar to trolamine were also identified and additional testing was performed to determine whether the alternative bases have a comparable effect as trolamine on the solubility of ruxolitinib phosphate and the apparent pH of the system. The alternative bases (including trolamine) are presented in Table 25. [Table 25]

[0367] The saturated solubility of ruxolitinib phosphate was evaluated using each of the bases detailed in Table 25 in the solvent systems detailed in Table 26 according to the following procedure: (i) Ruxolitinib phosphate (approximately 25 mg) was weighed out and placed into individual appropriately sized glass vials. (ii) Each of the solvent systems (approximately 475 mg) was added to an individual glass vial from step (i). (iii) Once saturation was achieved in a pre-calibrated water bath at 20° C., the drug and solvent system was stirred for approximately 24 hours. During the 24 hours of stirring, the solution was visually inspected as needed to observe whether the drug had dissolved in the solvent system. (iv) If the drug was observed to dissolve (ie, the system was unsaturated), additional drug was added and the 24 hour stirring / observation period was resumed after each drug addition. (v) For saturated systems, undissolved drug was removed from the saturated solution by centrifugation: as much of the saturated solution as possible was transferred to a suitable centrifuge tube and centrifuged at approximately 16,000 g for 10 minutes at 20°C. (vi) If the solution was still visually saturated after the first 10 minutes, the solution was transferred to a new centrifuge tube (taking care not to disturb any API pellet present) and the centrifugation was repeated. If a visually clear solution cannot be obtained, it may be necessary to repeat the centrifugation using a centrifugal filter. (vii) Once a visually clear supernatant was obtained, the pH was measured and recorded. (viii) Samples of the saturated supernatant were examined using light microscopy at magnifications of 200–1000×. If drug particles were present, the samples were centrifuged further until the supernatant was free of drug crystals. (ix) Prior to analysis, appropriate dilution / extraction of the supernatant was performed to achieve a drug concentration in the sample diluent above the LOQ of the HPLC method. (x) The saturation solubility was calculated based on the drug concentration observed in the analytical method and the dilution procedure performed in step (x). [Table 26]

[0368] Table 27 provides a summary of the solvent systems listed above (i.e., SSNA01, SSAG01, and SSCR01) for the surrogate bases investigated, including trolamine. [Table 27]

[0369] Bases listed in the FDA IID: For the SSNA01 solvent system in Table 27, Tris was found to be incompatible due to the absence of water in this solvent system. All other bases resulted in higher (>2% w / w) solubility of ruxolitinib phosphate than trolamine (6.84% w / w), with ethanolamine resulting in particularly high drug solubility (15.18% w / w) that was more than double. Furthermore, these bases were not compatible with the measurement of apparent pH in non-aqueous systems (USP <791> Considering the variability associated with SSNA01, the apparent pH of SSNA01 after addition of the API was maintained similar to that of trolamine (approximately 9-11).

[0370] For the SSAG01 solvent system, similar to SSNA01, tris was not compatible with this solvent system due to its low water content (about 34% w / w), as shown in Table 27. Diethanolamine and ammonia (25%) were also incompatible with SSAG01, resulting in precipitation of BHT. Diisopropylamine resulted in a ruxolitinib phosphate solubility similar to trolamine (about 8% w / w), but similar to SSNA01, ethanolamine resulted in a much higher API solubility (16.39% w / w). Although a higher amount of ruxolitinib phosphate was dissolved in the ethanolamine system, the ethanolamine system had a higher apparent pH (6.55) than the trolamine (4.27) and diisopropanolamine (4.29) systems.

[0371] For the SSCR01 solvent system, all bases were found to be compatible with SSCR01, as shown in Table 27. Contrary to the observations in SSNA01 and SSAG01, ethanolamine resulted in the lowest API solubility in SSCR01 (0.9% w / w), and the remaining bases resulted in ruxolitinib phosphate solubility equivalent to trolamine (about 1.6% w / w). However, similar to SSAG01, ethanolamine in SSCR01 resulted in an apparent pH (5.33) after drug addition that was about 2 units higher than the remaining bases. This may be due to the lower level of ruxolitinib phosphate dissolved in the solution.

[0372] Overall, the solubility of ruxolitinib phosphate and the final system pH were generally consistent when different bases were evaluated in each solvent system, with the exception of ethanolamine. However, these trends were not consistent across different solvent systems (e.g., SSCR01). Because ruxolitinib phosphate is acidic, it was expected that if the API had a higher solubility, the apparent pH of the final solution would be lowered by the drug, rendering the base ineffective, as previously observed. However, this was not the case for SSNA01 and SSAG01, as the apparent pH of the final solution was also higher when the API was more soluble. This was particularly evident when ethanolamine was included, where very high ruxolitinib phosphate solubility (about 16% w / w) was observed in SSNA01 and SSAG01 along with a higher apparent pH (about 6.6), but the increase in apparent pH was not proportional to the increase in API solubility. Thus, in SSNA01 and SSAG01, ethanolamine provided a system with a more skin-tolerated apparent pH than the other bases and with a much higher drug loading. Interestingly, this was not the case for SSCR01, where a decrease in API solubility was observed in the presence of ethanolamine, even though this solvent system is a substantially different combination of SSAG01 and SSNA01 from each other.

[0373] Bases not listed in the FDA IID: For SSNA01, all compounds evaluated except pyridine resulted in higher ruxolitinib phosphate solubility in SSNA01 compared to trolamine (6.84% w / w), with the highest solubility observed when imidazole was used (15.56% w / w), as shown in Table 27. Pyridine resulted in the lowest API solubility in SSNA01 (4.30% w / w) and imidazole the highest (15.65% w / w), but these systems had similar apparent pH (pH 4-5) to the other bases evaluated.

[0374] For SSAG01, 2-amino-2-ethyl-1,3-propanediol was found to be incompatible with this solvent system, resulting in precipitation of BHT, as shown in Table 27. All other bases resulted in higher (1.5-4.5% w / w) ruxolitinib phosphate solubility than when trolamine was included (8.22% w / w), and similar to SSNA01, imidazole resulted in the highest ruxolitinib phosphate solubility (12.88% w / w). As with SSNA01, the apparent pH of the solvent systems containing each base after addition of the API was comparable (approximately 4.2-4.5), despite differences in drug solubility.

[0375] For SSCR01, as shown in Table 27, diisopropylamine was found to be incompatible with SSCR01. This is likely due to the high level of water (42.45% w / w) in this system. Contrary to the observations with SSNA01, pyridine resulted in the highest ruxolitinib phosphate solubility in SSCR01 (2.14% w / w) and imidazole resulted in the lowest API solubility (1.31% w / w). The remaining bases resulted in API solubility equivalent to trolamine (approximately 1.3-1.8% w / w). Imidazole resulted in the highest apparent pH after API addition (4.81) and the remaining bases (including pyridine) resulted in an apparent pH after API addition equivalent to trolamine (approximately 3.4-3.7).

[0376] Similar to the bases listed in the FDA IID, generally consistent ruxolitinib phosphate solubility and apparent pH were observed among the bases in each solvent system evaluated, with some interesting findings when imidazole and pyridine were evaluated. However, these trends were again not consistent across different solvent systems (e.g., SSCR01). In SSNA01 (anhydrous solvent system), imidazole resulted in very high API solubility (~16% w / w) and pyridine resulted in low API solubility (~4% w / w) compared to trolamine (~7% w / w), with little change in the apparent pH of the system (~4-5). Increasing the level of water in the solvent system to 34.95% w / w in SSAG01 reduced this solubility difference (~13% w / w for imidazole and ~10% w / w for pyridine), but still resulted in virtually no difference in the apparent pH (~4). Surprisingly, the system with the highest amount of water (SSCR01, 42.45% w / w) resulted in the lowest API solubility with imidazole (1.31% w / w) and the highest with pyridine (2.14% w / w), with only slight differences in apparent pH in this system (4.81 for imidazole and 3.69 for pyridine). Compared to the bases listed in the FDA IID, an inverse trend between API solubility and apparent pH was observed for ethanolamine.

[0377] Part 2: Identification of upper limit of trolamine: The current FDA IID limit for topical application of trolamine is 11% w / w. This was investigated in a mixture design (DoE) to determine the point at which the level of trolamine no longer favorably affects ruxolitinib phosphate solubility or the apparent pH of the system becomes too high to be tolerated by the skin. This was done for up to three solvent systems and the identified upper limit of trolamine was set in the mixture design (DoE).

[0378] The saturation solubility of ruxolitinib phosphate was evaluated in the solvent systems detailed in Table 28. This data and the apparent pH of the supernatant were used to provide the basis for the upper limit of trolamine for investigation in the mix design (DoE). [Table 28]

[0379] As shown in Table 29 below, for SSNA, variable ruxolitinib phosphate solubility was observed between 11% w / w and 20% w / w trolamine, so the experiment was repeated. Very subtle immiscibility was observed at levels of trolamine ≧7.5% w / w, which may also have been present in the first setup. Where no immiscibility was observed, good reproducibility in the solubility of ruxolitinib phosphate was observed. [Table 29]

[0380] As shown in Table 30 below, for SSAG, incompatibility was observed at levels of trolamine ≧11% w / w, therefore this experiment was not repeated. [Table 30]

[0381] As shown in Table 31 below, for SSCR, variable ruxolitinib phosphate solubility was observed between 3.5% w / w and 20% w / w trolamine, so the experiment was repeated. Very subtle immiscibility was observed at levels of trolamine ≧14% w / w, which may also have been present in the first setup. Even when immiscibility was not observed, variability between setups was still observed, which may have been due to within-batch variability in ruxolitinib phosphate solubility. [Table 31]

[0382] In general, immiscibility of the solvent system was observed at the following trolamine levels: ≥ 7.5% w / w for SSNA; ≥ 11% w / w for SSAG; ≥ 15% w / w for SSCR. Therefore, it is not feasible to include trolamine at these levels or above without concern for the long-term physical stability of the formulation. The apparent pH of the solvent system was observed to be above pH 8 (pH 8 is the upper limit recommended for topical application) at the following trolamine levels: ≥ 5.5% w / w for SSNA; not determined due to immiscibility for SSAG; and ≥ 5.5% w / w for SSCR. Considering these findings, the upper limit for trolamine in the mix design DoE is set at 5.0% w / w to ensure validity for topical application and to minimize the risk of observing immiscibility that may reduce the reliability of the results generated.

[0383] Part 3: Mixture Design (DoE): Additional studies were performed as Mixture Design (DoE) to understand the relationship between trolamine and ruxolitinib phosphate solubility and the apparent pH of the system. For example, a solvent system that may be included in any of the major topical dosage forms may be utilized, with the levels of excipients other than trolamine varying from 0% to the FDA IID limits for topical application, as shown in Table 33.

[0384] The saturation solubility of ruxolitinib phosphate was evaluated in the runs detailed in Table 32, and the apparent pH of each run was measured before and after the addition of ruxolitinib phosphate. Following statistical analysis of the results, a set of saturation solubility experiments was performed to confirm the accuracy of the predictions made by the model. [Table 32] [Table 33]

[0385] Table 34 shows the mix design DOE data. From Table 34, there was a lack of fit observed when analyzing ruxolitinib phosphate solubility (p-value <0.0001) and apparent pH (p-value <0.0458) from the mix design DoE. Nevertheless, low variability was observed between replicate runs (1 and 5, 4 and 10, 17 and 18, 19 and 22, and 21 and 27): (1) for ruxolitinib phosphate solubility, the maximum %CV between replicates was 3.25; (2) for apparent pH, the %CV between runs with more than 30% water was <2.5, and for runs with less than 30% water, the variability was within ±1 pH unit, which is consistent with the USP <791> and (3) this suggests that the lack of fit observed in the model was not a result of variability in the solubility of ruxolitinib phosphate as previously observed. [Table 34-1] [Table 34-2]

[0386] Example 15: Ruxolitinib Formulations / Compositions The topical formulations (or pharmaceutical compositions) in Tables 35-41 below disclose topical formulations according to the present disclosure. These topical formulations are in a form selected from creams, lotions, foams, pump sprays, aqueous gels, non-aqueous gels, and emulsified gels. The topical formulations in Tables 35-41 are hypothetical.

[0387] Creams and lotions For the preparation of cream and lotion formulations, the following general manufacturing method is used: (i) Prepare the aqueous phase of the formulation in an amber Duran bottle and stir with a magnetic stir bar at 400 RPM until visually homogenous. (ii) For formulations containing EDTA and / or propyl gallate, these are first dissolved in a portion of the water, stirred at 400 RPM, and then added to the vessel of step (i). (iii) Add ruxolitinib phosphate to the aqueous phase and stir at 400 RPM for approximately 5 minutes, then adjust the pH. Monitor the apparent pH of the phase until visual dissolution of the API is observed. (iv) The oil phase of the formulation is prepared in a separate amber Duran bottle. (v) For formulations containing gelling agents, disperse these in a suitable liquid oil and stir at 500 RPM until visually homogenous, then add them to the vessel of step (iv). (vi) Place the oil phase in a 70° C. water bath until melted (approximately 1 hour) or, in the case of a solid oil phase containing Kolliphor HCO, place in a 90° C. water bath. Additionally, the aqueous phase, liquid oil phase and homogenizer head are also heated. (vii) Combine the three phases (aqueous phase, liquid oil phase, and molten solid oil phase) and homogenize using an IKA T25 Ultra Turrax at 10,000 RPM for 2 minutes. (viii) After homogenization, the formulation is allowed to cool to room temperature while stirring using an IKA stirrer at 200 RPM. (ix) Once the formulation has reached room temperature, add the phenoxyethanol and manually stir the formulation to incorporate. (x) Check the apparent pH of the formulation and complete any final pH adjustments or addition of water as appropriate.

[0388] Forms The foam formulations are prepared using the following general manufacturing process: (i) Prepare the foam premix according to the method used to prepare the creams and lotions. (ii) The foam premix is ​​added to the canister and the valve is crimped. (iii) Adding propellant to the canister of step (ii) using Pamasol. (iv) The finished foam is mixed overnight on a roller mixer.

[0389] Pump spray To prepare the pump spray, the following general manufacturing method is used: (i) Add BHT to ethanol and stir with a magnetic stir bar at 500 RPM for approximately 15 minutes until visibly dissolved. (ii) Add the poloxamer or Gantrez to the vessel from step (i) and stir this at 500 RPM for approximately 30 minutes until visually dissolved. (iii) Add the remaining excipients to the vessel from step (iii) and stir the solution at 500 RPM for approximately 10 minutes until visually homogenous. (iv) Add ruxolitinib phosphate to the vessel from step (iii) and stir at 500 RPM for approximately 1 hour until visibly dissolved, and adjust the pH of the solution.

[0390] Water-based gel To prepare the aqueous gel, the following general manufacturing method is used: (i) Prepare the solvent system in an amber Duran bottle and stir with a magnetic stir bar at 400 RPM until visually homogenous. (ii) For formulations containing EDTA, this is first dissolved in a portion of the water, stirred at 400 RPM, and then added to the vessel of step (i). (ii) For formulations containing BHT, this is first dissolved in Transcutol P, stirred at 400 RPM and then added to the vessel of step (i). (iii) The ruxolitinib phosphate is added to the solvent system and stirred at 400 RPM for approximately 5 minutes, followed by pH adjustment. The apparent pH of the solvent system is monitored until complete dissolution of the API is observed and the target apparent pH is reached. (iv) After the API has completely dissolved, the gelling agent is added to the solvent system of step (iv) and stirred at 400 RPM until visually homogenous.

[0391] Non-aqueous gel For the preparation of the non-aqueous gel, the following general manufacturing method is used: (i) Prepare the solvent system in an amber Duran bottle and stir with a magnetic stir bar at 400 RPM until visually homogenous. (ii) For formulations containing BHT, this is first dissolved in Transcutol P, stirred at 400 RPM and then added to the vessel of step (i). (iii) The ruxolitinib phosphate is added to the solvent system and stirred at 400 RPM for approximately 5 minutes, followed by pH adjustment. The apparent pH of the solvent system is monitored until complete dissolution of the API is observed and the target apparent pH is reached. (iv) After the API has completely dissolved, the gelling agent is added to the solvent system of step (iv) and stirred at 400 RPM until visually homogenous.

[0392] Emulsion Gel The emulsion gel is prepared using the following general manufacturing method: (i) Prepare the aqueous phase of the formulation in an amber Duran bottle and stir with a magnetic stir bar at 400 RPM until visually homogenous. (ii) For formulations containing EDTA, this is first dissolved in a portion of the water, stirred at 400 RPM, and then added to the vessel of step (i). (iii) Add ruxolitinib phosphate to the aqueous phase and stir at 400 RPM for approximately 5 minutes, then adjust the pH. Monitor the apparent pH of the phase until visual dissolution of the API is observed and the target apparent pH is reached. (iv) The oil phase of the formulation is prepared in a separate amber Duran bottle. Disperse the Sepineo P600 into the oil phase and stir at 500 RPM until visually homogenous. (v) Combine the aqueous phase (from step (iii)) and the oil phase (from step (v)) and homogenize using an IKA T25 Ultra Turrax at 10,000 RPM for 2 minutes. (vi) After homogenization, the formulation is allowed to cool to room temperature while stirring using an IKA stirrer at 200 RPM. (vii) Check the apparent pH of the formulation and complete any final pH adjustments or addition of water as appropriate. [Table 35-1] [Table 35-2] [Table 35-3] [Table 35-4] [Table 36-1] [Table 36-2] [Table 36-3] [Table 37-1] [Table 37-2] [Table 38-1] [Table 38-2] [Table 39] [Table 40] [Table 41]

[0393] Example 16. Additional Short-Term Stability Studies Additional formulations were selected for short-term stability studies. These formulations are detailed in Tables 42 and 43. Formulations were evaluated at t=0 and subsequent time points at storage conditions of 25° C. and 40° C. Formulations were evaluated in 7 mL borosilicate vials. The following studies were performed: Ruxolitinib phosphate content; Ruxolitinib phosphate related substances; • Macroscopic appearance; • Appearance under a microscope; • Apparent pH; ●Instability index by LUMiSizer.

[0394] Considering the nature of the formulation for topical administration, the apparent pH of the formulation for short-term stability is presented in Table 44. Other characterization data (e.g., ruxolitinib phosphate content, macroscopic appearance of ruxolitinib phosphate-related substances, microscopic appearance, and instability index by LUMiSizer) are not presented here. [Table 42] [Table 43]

[0395] Apparent pH The apparent pH of the prepared formulations was evaluated at t=0 and at subsequent time points after storage at 25° C. and 40° C. The results are presented in Table 44.

[0396] At t=0, the apparent pH of the formulations ranged from 3.95 to 10.75, with the corresponding placebo formulations being 0.67 to 5.39 apparent pH units higher than the active drug, which was expected given the addition of trolamine to the placebo formulation in the absence of ruxolitinib phosphate. Notably, the apparent pH of the active formulation, SUOO02, was difficult to measure as a result of the formulation being a suspension, and measurements were only achieved at t=4 weeks at 40°C.

[0397] The lowest apparent pH was observed in solutions 1, EG09 and CR10 2.93%, which were active formulations containing no or low levels (1% w / w) of trolamine (apparent pH 3.95, 4.51 and 4.54, respectively) and, as expected, increasing the level of trolamine in the solutions (2.47% w / w and 5% w / w trolamine in solutions 2 and 3, respectively) resulted in a corresponding increase in apparent pH.

[0398] After storage at 25°C and 40°C for t=2 and 4 weeks, there was no appreciable change in apparent pH for any of the formulations evaluated (formulations were within 0.48 apparent pH units of t=0). [Table 44]

[0399] In addition to those described herein, various modifications of the subject matter claimed herein will become 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 is incorporated herein by reference in its entirety, including all patents, patent applications, and publications.

Claims

1. A topical formulation for treating a skin disease comprising a JAK1 / 2 inhibitor that is ruxolitinib or a pharmaceutically acceptable salt thereof, and an organic amine pH adjusting agent.

2. 10. The formulation of claim 1, wherein the organic amine pH adjuster is a tertiary amine or an alkanolamine.

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

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

5. 10. The formulation of claim 1, wherein the formulation is in a form selected from a cream, a lotion, a foam or effervescent formulation, a pump spray, an aqueous gel, a non-aqueous gel, and an emulsified gel.

6. 10. The formulation of claim 1, further comprising one or more of water, an oil component, an emulsifier or stabilizer component, and a solvent component. (i) the water is present in an amount of about 5% to about 90%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 20% to about 70%, about 20% to about 60%, about 30% to about 60%, or about 20% to about 50% by weight of the formulation; (ii) the oil component is present in an amount of about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, about 5% to about 60%, about 5% to about 50%, or about 5% to about 40% by weight of the formulation; (iii) the emulsifier or stabilizer is present in an amount of from about 1% to about 40%, from about 1% to about 30%, from about 1% to about 20%, from about 5% to about 40%, or from about 5% to about 25% by weight of the formulation; and / or (iv) the solvent component comprises about 1% to about 70% by weight, about 1% to about 60% by weight, about 1% to about 50% by weight, about 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 1% to about 20% by weight, about 5% to about 20% by weight, about 2% to about 30% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, or about 10% to about 20% by weight of the formulation; The formulation of claim 6.

8. 10. The formulation of claim 1, further comprising one or more of a stabilizer and an antioxidant.

9. 10. The formulation of claim 1, wherein the formulation has a pH of about 4.0 to about 8.0, about 4.0 to about 7.0, about 4.0 to about 6.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.0 to about 6.0, and about 5.5, and the amine pH adjusters are independently selected from trolamine, tris, ethanolamine, diethanolamine, ammonia, diisopropanolamine, 1-amino-2-propanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, diisopropylamine, imidazole, and pyridine.

10. 10. The formulation of claim 1, wherein the amine pH adjuster is trolamine.

11. 10. The formulation of claim 1, further comprising one or more pH adjusters, chelating agents, preservatives, cosolvents, penetration enhancers, humectants, thickeners, gelling agents, viscosity builders, surfactants, propellants, fragrances, colorants, and any combination thereof.

12. (i) the organic amine pH adjuster is trolamine and further comprises transcutol P and glycerol; or 2. The formulation of claim 1, wherein (ii) the organic amine pH adjuster is trolamine and further comprises ethanol and water.

13. The form is (i) is a cream or lotion; (ii) is a foam or effervescent preparation; (iii) Is it a spray? (iv) Is it an aqueous gel? (v) a non-aqueous gel formulation; or (vi) an emulsified gel formulation; The formulation of claim 1.

14. The skin disease is (i) autoimmune or inflammatory skin disease, (ii) a Th1- or Th17-related skin disease; (iii) mediated by interleukin-22 (IL-22), C-X-C motif chemokine 10 (CXCL10), matrix metallopeptidase 12 (MMP12), or a combination thereof; (iv) mediated by Defb4, S100a12, or Serpinb4; and / or (v) mediated by filaggrin / FLG, loricin / LOR, IL-31, TSLP, CAMP, CCL17, CCL22, DefB4a, interferon-gamma, IL-17A, IL-17F, IL-22, IL-33, IL-4, or TNFSF18; The formulation according to any one of claims 1 to 13.

15. The formulation according to any one of claims 1 to 13, wherein the skin disease is selected from psoriasis, atopic dermatitis, alopecia, vitiligo, Reiter's syndrome, pityriasis rubra pilaris, epidermolysis bullosa simplex, palmoplantar keratosis, pachyonychia congenita, multiple sebaceous cysts, cutaneous lichen planus, cutaneous T-cell lymphoma, hidradenitis suppurativa, contact dermatitis, and ichthyosis.

16. The formulation of any one of claims 1 to 13, wherein the skin disease is rosacea, psoriatic arthritis, skin fibrosis, morphea, Spitz nevus, dermatophytosis, or acne vulgaris.

17. The formulation of any one of claims 1 to 13, wherein a synergistic effect occurs between the JAK1 / 2 inhibitor or the pharmaceutically acceptable salt thereof and the amine pH adjuster.

18. The formulation of any one of claims 1 to 13, wherein the formulation is administered at least once daily.

19. The formulation of any one of claims 1 to 13, wherein the formulation is administered at least twice daily.

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