Topical formulation of deuclavacitinib

Abstract

Described herein are topical formulations of deuclavacitinib and methods of making such formulations. Also described are methods of treatment that involve topical administration of such formulations.

Description

[Technical field]

[0001] The present invention relates generally to topical formulations of deuclavacitinib, a tyrosine kinase 2 (TYK2) inhibitor, that are useful in the treatment and control of diseases such as psoriasis, psoriatic arthritis, lupus, and alopecia areata. [Background technology]

[0002] Deuclavacitinib is a selective TYK2 inhibitor that is effective in treating certain inflammatory and autoimmune diseases (e.g., psoriasis).Deuclavacitinib is formulated for oral administration, but there is a need for a topical administration form of deuclavacitinib.The present invention meets this need.

[0003] Summary of the Invention Described herein is a novel topical pharmaceutical composition comprising deuclavacitinib. Deuclavacitinib is also known as 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, which has the formula (I): [ka] It is a compound having the structure:

[0004] Deuclavacitinib is a selective TYK2 inhibitor useful for the treatment of certain inflammatory and autoimmune diseases (e.g., psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and alopecia areata). For such diseases, it may be desirable to administer one or more therapeutic agents locally during treatment. However, due to the low solubility of deuclavacitinib in water, it has been difficult to develop a local formulation of deuclavacitinib.

[0005] The present disclosure provides formulations of deuclavacitinib suitable for topical administration, in which deuclavacitinib is completely dissolved and stable during storage. By formulating deuclavacitinib as described herein, deuclavacitinib may be administered in a topical dosage form (e.g., cream, ointment, gel) that may be used to treat inflammatory and autoimmune diseases (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, and alopecia areata) in which topical administration of deuclavacitinib is desired.

[0006] In some embodiments, the topical formulation of deuclavacitinib includes an ether solvent in addition to deuclavacitinib. The ether solvent can be selected from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol. In some embodiments, the ether solvent is PEG 400. In further embodiments, the topical formulation of deuclavacitinib includes deuclavacitinib and two ether solvents. In some embodiments, the two ether solvents are selected from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol. In yet another embodiment, the topical formulation includes deuclavacitinib and three ether solvents. wherein the three ether solvents are selected from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol. In some embodiments, the formulation comprises at least PEG 400. For example, in embodiments in which two ether solvents are included in the formulation, the ether solvents are PEG 400 and DEGEE, or PEG 400 and DMI. In embodiments in which three ether solvents are included in the formulation, the ether solvents may be PEG 400, DEGEE, and DMI. In any of the above embodiments, the topical formulation of deuclavacitinib may be an aqueous formulation (e.g., an aqueous gel or cream), and may further comprise an acidic buffer.

[0007] The present invention also relates to a topical formulation of deuclavacitinib, comprising deuclavacitinib, an ether solvent, and an acidic buffer. In some embodiments, the ether solvent is selected from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol. In some embodiments, the ether solvent is PEG 400. Furthermore, the present invention relates to a topical formulation comprising deuclavacitinib, two ether solvents, and an acidic buffer. In such embodiments, the two ether solvents are selected from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol, e.g., PEG 400 and DEGEE, or PEG 400 and DMI. In further embodiments, the topical formulation comprises deuclavacitinib, three ether solvents, and an acidic buffer.

[0008] In any of the above-mentioned embodiments, the formulation may include one or more additional excipients (e.g., thickeners, preservatives, etc.) as described herein. Further, in any of the above-mentioned embodiments, deuclavacitinib may be included in the formulation in an amount ranging from about 0.075% w / w to about 1.1% w / w based on the total weight of the composition. In such an embodiment, deuclavacitinib may be included in the formulation in an amount ranging from about 0.3% w / w to about 1.1% w / w based on the total weight of the composition.

[0009] Methods for producing topical dosage forms of deuclavacitinib are also described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure relates to a topical pharmaceutical composition comprising deuclavacitinib. As used herein, the terms "topical pharmaceutical composition", "topical composition", "topical formulation" and "topical dosage form" generally refer to a composition that is pharma- ceutically acceptable and suitable for topically administering deuclavacitinib to a subject. Such compositions include, but are not limited to, creams, ointments, gels, foams, sprays, lotions, solutions, emulsions, suspensions, mists, aerosols, unguents, and pastes. Topical compositions generally include at least one ether solvent in addition to deuclavacitinib. The compositions may include one or more additional excipients as described herein. Such topical pharmaceutical compositions comprising deuclavacitinib may be used to treat diseases, such as psoriasis, psoriatic arthritis, systemic lupus erythematosus, and alopecia areata.

[0011] Deuclavacitinib and methods for making deuclavacitinib are disclosed in U.S. Patent RE47,929 E, the contents of which are incorporated herein by reference in their entirety. Deuclavacitinib is also known as 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, formula (I): [ka] It is a compound having the structure:

[0012] The deuclavacitinib used to manufacture any of the formulations described herein may include amorphous and / or crystalline deuclavacitinib. Crystalline forms of deuclavacitinib (and salts of deuclavacitinib) are described, for example, in International Application Nos. PCT / US2018 / 025114, PCT / US2019 / 034534, and PCT / US2020 / 036727 (International Publication Nos. WO 2018 / 183656, WO 2019 / 232138, and WO 2020 / 251911, respectively), the entire contents of each of which are incorporated herein by reference.

[0013] Deuclavacitinib is a selective TYK2 inhibitor currently in clinical trials for the treatment of inflammatory and autoimmune diseases (e.g., psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, ulcerative colitis, Crohn's disease, and ankylosing spondylitis). TYK2 is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be crucial in downstream regulation of IL-12, IL-23, and type I interferon receptor signaling cascades in both mice and humans (mouse: Ishizaki, M. et al., "Involvement of tyrosine kinase-2 in both the IL-12 / Th1 and IL-23 / Th17 axes in vivo," J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo," PLoS One, 7:e39141 (2012); human: Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity," Immunity, 25:745-755 (2006). TYK2 mediates essential signals that lead to receptor-induced phosphorylation of members of the STAT family of transcription factors, dimerization of STAT proteins, and STAT-dependent transcription of proinflammatory genes.TYK2-deficient mice were resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of TYK2-mediated signaling in autoimmune and related diseases (Ishizaki, M. et al., "Involvement of tyrosine kinase-2 in both the IL-12 / Th1 and IL-23 / Th17 axes in vivo," J. Immunol., 187:181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis," J. Immunol., 183:7539-7546 (2009)).

[0014] In humans, individuals expressing inactive mutants of TYK2 are free from multiple sclerosis and possibly other autoimmune diseases (Couturier, N. et al., "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility," Brain, 134:693-703 (2011)). Gene-wide association studies have shown that other variants in TYK2 are associated with autoimmune diseases (e.g., Crohn's disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis), further demonstrating the importance of TYK2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies 7Shared Susceptibility Loci," Am. J. Hum. Genet., 90:636-647 (2012); Graham, D. et al., "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families," Rheumatology (Oxford), 46:927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis," Nat. Genet., 44:1336-1340 (2012).

[0015] Deuclavacitinib is poorly soluble in water, with a solubility of about 0.009mg / mL or 0.00009%w / w.However, water is an essential component in many topical formulations (e.g., aqueous gels and creams).Described herein are various topical formulations that contain deuclavacitinib that is completely dissolved, despite its low solubility in water.Furthermore, the deuclavacitinib is stable during storage in the topical formulations.

[0016] In some embodiments, the topical formulation of deuclavacitinib comprises deuclavacitinib and at least one solvent belonging to ether group. Such solvents include, for example, polyethylene glycol (PEG) (e.g., PEG 200, PEG 300, PEG 400, and PEG 600), diethylene glycol monoethyl ether (DEGEE), isosorbide dimethyl ether (DMI), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), and propylene glycol. In some embodiments, the formulation comprises at least two ether solvents. In further embodiments, the solvents contained in the formulation include PEG (e.g., PEG 400) and at least one of DEGEE, DMI, TPGS, and propylene glycol. The formulation may further comprise an acidic buffer and / or water.

[0017] In some embodiments, the topical formulation comprises deuclavacitinib, PEG 400, and at least one DEGEE and DMI. For example, the formulation may comprise deuclavacitinib, PEG 400, and DEGEE (as well as DMI), or may comprise deuclavacitinib, PEG 400, and DMI (as well as DEGEE). In some embodiments, the topical formulation comprises deuclavacitinib, PEG 400, DMI, and DEGEE.

[0018] In some embodiments, the topical formulation of deuclavacitinib comprises an aqueous component (e.g., the topical formulation may be an aqueous gel or cream). In such embodiments, the topical formulation comprises deuclavacitinib, an ether solvent, and an acidic buffer. As provided herein, the use of an ether-based solvent (or two or more ether-based solvents) and / or adjustment of the pH with an acidic buffer is used to increase the solubility of deuclavacitinib. The ether solvent may be PEG (e.g., PEG 400), DEGEE, DMI, TPGS, or propylene glycol. In some embodiments, the ether solvent is PEG 400. In further embodiments, the topical formulation comprises deuclavacitinib, at least two ether solvents, and an acidic buffer. One of such ether solvents may be PEG (e.g., PEG 400), and the other ether solvent may be DEGEE, DMI, TPGS, or propylene glycol. For example, the topical formulation may include deuclavacitinib, PEG 400, DEGEE, and an acidic buffer, or may include deuclavacitinib, PEG 400, DMI, and an acidic buffer. In other embodiments, the topical formulation includes deuclavacitinib, PEG 400, DEGEE, DMI, and an acidic buffer. Suitable acidic buffers are known to those skilled in the art and include, for example, hydrochloric acid, citric acid, phosphoric acid, and other acidifying agents.

[0019] The total amount of ether solvent in the topical composition of deuclavacitinib described herein may range from about 30% w / w to about 98% w / w based on the total weight of the composition. For example, in non-aqueous formulations (e.g., non-aqueous gels and ointments), the one or more ether solvents may comprise about 60% w / w to about 98% w / w of the total weight % of the composition. In some embodiments, the amount of one or more ether solvents in a non-aqueous formulation ranges from about 70% w / w to about 98% w / w based on the total weight of the composition. In aqueous formulations (e.g., aqueous gels, emulsified gels, and creams), the one or more ether solvents may comprise about 40% w / w to about 90% w / w of the total weight % of the composition, and the aqueous components (e.g., water and / or buffer solution) may comprise about 5% w / w to about 30% w / w. In some embodiments, for example, the amount of one or more ethereal solvents may range from about 50% w / w to about 55% w / w, and the amount of aqueous components (e.g., water and / or buffer) may range from about 10% w / w to about 25% w / w, based on the total weight of the composition (other excipients making up the remaining total weight). In other embodiments, the one or more ethereal solvents make up about 85% w / w to about 90% w / w, and the aqueous components (e.g., water or acidic buffer) make up about 5% w / w to about 10% w / w (e.g., about 7% w / w) of the total weight of the composition.

[0020] Topical formulations containing deuclavacitinib and one or more ethereal solvents may also contain one or more additional pharma- ceutically acceptable excipients, including, for example, thickeners (e.g., carbomer or carbomer derivatives, cellulose and its derivatives, anionic polymers), emulsifiers and surfactants, wetting agents, viscosity enhancers, chelating agents, antioxidants and other preservatives, foaming agents, ointment bases, and propellants.

[0021] In certain embodiments, a topical formulation comprising deuclavacitinib and at least one of the above-mentioned ethereal solvents (e.g., a topical formulation comprising deuclavacitinib and two or three ethereal solvents) further comprises one or more of the following excipients: -Oily phase excipients: e.g. castor oil, medium chain triglycerides, mono / diglycerides, petrolatum, beeswax - Emulsifiers and surfactants: e.g. Polysorbate 80, emulsifying wax, Brij 20, glycerol monostearate, cationic and anionic surfactants -Solvents and solubilizers: e.g. cyclodextrins -Thickening agents: for example, cetostearyl alcohol, PEG 1500, cellulose and its derivatives, carbomer and its derivatives (for example, carbomer 910, 940, 941, 1342, 934P, and 974P). - Preservatives: e.g. phenoxyethanol, benzyl alcohol -Antioxidants: e.g., butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), and similar excipients (e.g., tert-butylhydroquinone (TBHQ)). - Chelating agents: e.g. ethylenediaminetetraacetic acid (EDTA) -Permeation enhancers: e.g. modified lipid / fatty acid solubilizers, salts of fatty acids

[0022] Table 3 below includes additional excipients suitable for topical formulations of deuclavacitinib described herein. The function of a particular excipient is not intended to be limiting, and an excipient may perform multiple functions or provide multiple benefits.

[0023] The topical formulations described herein may be characterized by varying amounts of deuclavacitinib. For example, the amount of deuclavacitinib included in any embodiment described herein may be about 0.075% w / w to about 1.1% w / w based on the total weight of the composition (e.g., in some embodiments, deuclavacitinib is included in the formulation at about 0.075% w / w, or about 1.1% w / w, or any amount therebetween (e.g., 0.3% w / w) based on the total weight of the composition). Generally, it is desirable for deuclavacitinib to be completely dissolved in the formulation. The solubility of deuclavacitinib can be determined, for example, by microscopic examination of a sample of the formulation. To avoid precipitation of deuclavacitinib in the formulation, the upper limit of drug loading can be set at 80% of the saturated solubility of deuclavacitinib in the particular solvent of the formulation. Since the saturated solubility of deuclavacitinib can be varied by varying the solvent combinations described herein, the amount of deuclavacitinib is generally not limited by the constraints of the dosage form, but rather can be based on the therapeutic window and the minimum effective amount required for treatment. To completely dissolve high concentrations of deuclavacitinib and increase the saturated solubility of deuclavacitinib, the formulation can be combined with an ether solvent and / or an acidic buffer (e.g., hydrochloric acid, citric acid, etc.).

[0024] The present invention also relates to a method of administering a topical composition comprising deuclavacitinib as described herein.For example, an embodiment of the present invention relates to a method of treating psoriasis, psoriatic arthritis, lupus or alopecia areata in a subject, characterized in that the topical composition comprising deuclavacitinib as described herein is administered to the subject.Compared to oral administration, topical administration of deuclavacitinib can provide multiple advantages, such as reduced dosage, reduced and / or alleviated serious side effects, and improved efficacy (e.g., by locally delivering therapeutic amounts of deuclavacitinib), and improved patient compliance.

[0025] Some embodiments of the invention relate to a method of treating or preventing psoriasis in a subject, comprising topically administering a topical composition comprising deuclavacitinib, as described herein, to the subject's skin, typically an area affected or susceptible to psoriasis (e.g., an area of ​​the skin exhibiting or susceptible to the appearance of symptoms associated with psoriasis, such as psoriatic plaques).

[0026] Furthermore, embodiments of the present invention relate to a method of treating psoriatic arthritis in a subject or preventing symptoms associated with psoriatic arthritis in a subject, comprising administering to the skin of the subject a topical composition comprising deuclavacitinib as described herein.

[0027] Another embodiment of the present invention relates to a method for treating alopecia areata in a subject or preventing alopecia areata-related hair loss in a subject, comprising administering a topical composition comprising deuclavacitinib as described herein to the skin of the subject.Topical administration of the composition to the relevant area of ​​the skin of a subject suffering from alopecia areata can promote hair growth in the relevant area.As a method for preventing recurrence of alopecia areata-related hair loss, a topical pharmaceutical composition comprising deuclavacitinib as described herein can be administered to a subject who has previously experienced alopecia areata-related hair loss, where the composition is administered to a specific area of ​​the scalp that may be susceptible to hair loss, for example.

[0028] Embodiments of the present invention further relate to a method of treating systemic lupus erythematosus in a subject, comprising administering to the skin of the subject a topical composition comprising deuclavacitinib as described herein.

[0029] In some embodiments, the topical composition comprising deuclavacitinib described herein is administered to a subject (e.g., a subject suffering from psoriasis, psoriatic arthritis, etc.) for 3 days, 7 days, 10 days, 14 days, or more. In some embodiments, administration may continue for weeks or months (e.g., 1 month, 3 months, etc.). Furthermore, administration of the topical composition comprising deuclavacitinib described herein may be characterized by consecutive administration of the topical composition once a day, twice a day, or three times a day. Alternatively, administration may be, for example, every other day (e.g., administration on days 1 and 3, but not on day 2), or every third day (e.g., administration on days 1 and 4, but not on days 2 and 3).

[0030] In the context of the present invention, a subject, in particular a human subject, may also be referred to as a patient.

[0031] Any definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or published patent application that is incorporated herein by reference. Any statements from any patent, patent application, and / or published patent application, or other document that are incorporated by reference are incorporated by reference to the extent that there is no conflict between such statements and this specification, in which case any conflicting statements will not be incorporated by reference.

[0032] Working Example The present invention is further illustrated by the following examples, which are used only to illustrate the present invention and its practice, and are not to be construed as limiting the scope and nature of the present invention.

[0033] All measurements are subject to experimental error but are within the scope of the invention.

[0034] Example 1: Solubility of Deuclavacitinib The solubility of deuclavacitinib was investigated in various solvents. In PEG 400, the solubility was 0.64% w / w. In two other ether solvents, DEGEE and DMI, the solubility was 0.62% w / w and 0.51% w / w, respectively. N-methyl-2-pyrrolidone (NMP) and dimethylsulfoxide (DMSO) showed high solubility of deuclavacitinib. In some cases, these solvents can cause skin irritation and therefore were not used in the development of the formulations described below in the Examples. [Table 1]

[0035] Example 2: Solubility of Duke Lavacitinib in different solvent systems Since water is an essential component in aqueous gels and creams, the solubility of duravacitinib in various solvent systems containing water was investigated. The example solvent systems in Table 2 are designed for creams. The total proportion of the solvent system is up to 80% of the total weight % of the composition, leaving the remaining 20% ​​for oily components. Water or an acidic buffer (aqueous solution) accounts for 25% w / w of the total composition.

[0036] A synergistic effect was observed in solvent systems containing PEG 400 and at least one of the other two solvents (DEGEE and DMI). The solubility of deuclavacitinib in the ternary solvent system (S3) containing PEG 400, DEGEE, and DMI was higher than that observed in the binary solvent systems (S1 and S2), and thus the ternary solvent system combining PEG 400, DEGEE, and DMI (S3) had the highest solubility of deuclavacitinib. Further solubility was observed in each solvent system tested when an acidic buffer was used instead of unbuffered distilled water (S4, S5, and S6). [Table 2]

[0037] Example 3: Topical Formulation of Deuclavacitinib All Deuclavacitinib formulations are manufactured by completely dissolving Deuclavacitinib in the solvent component. The maximum drug loading used in each formulation (Examples 4, 5, and 6) is limited to 80% of the saturated solubility of Deuclavacitinib in the particular solvent used in the formulation. Pharmaceutically acceptable excipients (e.g., oil phase of creams, and moisturizers and skin conditioners) were added as non-solvent components. Brij S2, Brij S721, and poloxamer were used as surfactants. Benzyl alcohol was used as a preservative in formulations with aqueous components. Citric acid, hydrochloric acid, and sodium hydroxide were used as pH adjusters. The final products were examined microscopically to confirm the absence of precipitation of Deuclavacitinib or excipients. [Table 3]

[0038] Example 4: Preparation of aqueous gel Aqueous gels (formulations F1, F2, F3, F4, and F5) were prepared by the following method. 1. The solvent and preservative (benzyl alcohol in these embodiments) were added to a container and mixed until uniform. 2. Deucrevacitinib was added and the mixture was stirred until the Deucrevacitinib was completely dissolved (visually). 3. Water was added dropwise while stirring. 4. For formulations containing carbomer as a thickener (formulations F1, F2, and F4), the carbomer was added slowly with stirring while maintaining a vortex. Stirring was continued until the carbomer was uniformly dispersed. The pH was then adjusted as necessary and sufficient water was added for the desired batch size. For formulations containing HPC as a thickener (formulations F3 and F5), the pH of the formulation was adjusted as necessary and water was added for the remainder, then the HPC was added with stirring. Stirring was continued until the HPC was uniformly dispersed. 5. For all formulations F1, F2, F3, F4 and F5, the resulting mixture was stirred overnight.

[0039] Samples from each final product were examined microscopically to determine whether there was any precipitation of deuclavacitinib or excipients. [Table 4]

[0040] Example 5: Preparation of non-aqueous gels and ointments The non-aqueous gels (Formulations F7, F8, and F9) were prepared by the following method. 1. PEG 400, DEGEE, and propylene glycol were added to the container according to the desired amounts in the formulation and mixed until uniform. For formulation F8, 0.5M citric acid was added to DEGEE and then mixed with the other solvents. 2. For formulation F8, TPGS was added and the mixture was stirred at 65° C. until the TPGS was melted. 3. Deucrevacitinib was added and the mixture was stirred until the Deucrevacitinib was completely dissolved (visually). 4. The thickener (in this embodiment, hydroxypropyl cellulose (HPC)) was slowly added with stirring, maintaining the vortex. 5. Stirring was continued overnight.

[0041] An ointment (Formulation F6) was prepared as follows. 1. PEG 400 and DEGEE were added to a container and mixed until uniform. 2. PEG 3350 was added to a separate container and heated at 70° C. until the PEG 3350 was melted. 3. Duke Lavacitinib was added to the first vessel and stirred until completely dissolved (visually). The mixture in the first vessel was then heated to 70° C. for 5 minutes. 4. The melted PEG 3350 was added to the first vessel while stirring. 5. The mixture in the first container was manually stirred with a spatula until cooled. [Table 5]

[0042] Example 6: Preparation of cream and emulsion gel The cream was prepared in the following manner. 1. The solvent and preservative (benzyl alcohol in this embodiment) were added to a vessel and mixed until uniform. 2. Oily excipients, surfactants, and emulsion stabilizers, if used, were added to a separate container. These ingredients, which include Brij S2, Brij S721, cetyl alcohol, stearic acid, mineral oil, lanolin, glycerol, and medium chain triglycerides, are listed in Table 6. 3. Deucrevacitinib was added to the first container and this mixture was stirred until the Deucrevacitinib was completely dissolved (visually). 4. Water or buffer was added dropwise to the first vessel while stirring. The oil phase in a separate vessel was heated at 70°C until melted. 5. The aqueous phase of the first vessel and the tip of the homogenizer were heated to 70°C. 6. The oil phase from the second vessel was added to the water phase from the first vessel. 7. The two phases were mixed to homogenize and stirred until cooled. 8. The pH was adjusted as necessary. 9. While stirring, water (enough for the desired batch size) was added dropwise. 10. Stirring was continued until the mixture was homogenous. [Table 6]

[0043] Example 7: Stability of Duke Lavacitinib Topical Formulations Table 7 shows the stability data for five formulations (F1, F6, F12, F13, and F14) upon storage for 2 or 4 weeks at 25° C. or 40° C. Formulations F1, F6, F12, and F14 are as described above. Purity of deuclavacitinib was maintained at >99% in all formulations. [Table 7]

[0044] Example 8: In vitro skin permeation and penetration studies Flow-through diffusion cell experiments were performed to assess the permeability and penetration of deuclavacitinib into excised human skin of 500±50 μm thickness. The formulation was applied at 10 mg / cm2. Table 8 shows the amount of drug extracted from the epidermis and dermis (mean±SD) and measured in the receptor compartment 24 hours after formulation application.

[0045] The concentration of deuclavacitinib (drug loading in Table 8) varies between formulations as each formulation is designed to deliver the appropriate amount of drug depending on the solubility capacity of the solvent system used. Although the concentrations of deuclavacitinib are similar in F1 and F13 (0.66% w / w and 0.69% w / w, respectively), the amount of deuclavacitinib extracted from the skin layers after 24 hours was significantly higher in F13 compared to F1. The amount of deuclavacitinib in the receptor compartment was also significantly higher in F13 compared to F1. F12 had the highest level of deuclavacitinib in the receptor compartment and was second only to F13 in the amount of deuclavacitinib measured in the epidermis and dermis. F14, which had a deuclavacitinib concentration of 0.55% w / w (slightly higher than the 0.50% w / w deuclavacitinib in F12), had lower amounts of deuclavacitinib in the skin tissue and receptor compartment compared to F12. Of these five formulations, F1 and F6 had lower amounts of deuclavacitinib in the skin layers and receptor compartment compared to F12, F13, and F14.

[0046] Formulations that can recover a higher amount of drug in the receptor compartment than in the skin layer may be suitable for transdermal administration. For topical formulations of drugs that exert their effect by acting locally in skin tissue, a low amount of drug in the receptor compartment (as in F1) may be desirable. Furthermore, topical formulations that deliver an effective amount of drug to skin tissue may be suitable for topical administration of the drug (even if the drug is absorbed through the skin). For example, as shown in F12 and F14, the formulations can deliver a higher amount of deuclavacitinib to the skin layer compared to the amount of deuclavacitinib recovered in the receptor compartment. Such formulations may be useful for delivering an effective amount of deuclavacitinib to the target skin tissue with minimal side effects. [Table 8]

[0047] Example 9: In vivo single dose formulation study in minipigs A single-dose study was performed in minipigs. Each formulation was applied at the maximum tolerated dose, with the corresponding dose calculated to provide a thin, uniform layer on the designated dorsal area of ​​the animal. At each time point (24 hours and 48 hours) after administration, the stratum corneum was removed by stripping with tape, and the administration site was then sampled as a skin sample for punch biopsy. Thermal biopsies were performed to separate the adipose tissue from the epidermis and dermis of the skin. Table 9 shows the amount of deuclavacitinib measured in the skin 24 hours and 48 hours after dermal administration for the five formulations.

[0048] F1 was administered at the highest dose of 7.18mg / kg, followed by F14 at 5.83mg / kg. After 24 hours, 195ng / g of deuclavacitinib was observed in the skin for F1 and 170ng / g for F14. After 48 hours, the amounts increased to 264ng / g and 416ng / g for F1 and F14, respectively. F13 administered at 3.28mg / kg had 206ng / g of deuclavacitinib in the skin at 24 hours and 436ng / g of deuclavacitinib in the skin at 48 hours, respectively, which is comparable to the levels of drug in F14. F12 had the most variability compared to the other formulations, and F6 had the least amount of deuclavacitinib in the skin at 48 hours. [Table 9]

[0049] Example 10: In vivo multi-dose formulation study in minipigs The minipigs were administered a formulation of deuclavacitinib topically on the designated dorsal area twice daily for 14 days. After 14 days of treatment, skin biopsies were taken from the treatment sites and analyzed to determine the concentration of deuclavacitinib in the treated skin. Table 10 shows the results for two formulations (F1 and F14). [Table 10]

[0050] While the present invention has been particularly described and illustrated with reference to preferred embodiments thereof, it will be understood by those skilled in the art in light of this disclosure that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

[Claim 1] A topical pharmaceutical composition comprising deuclavacitinib and two ether solvents.