Stable formulation of SHR0302

Abstract

The present disclosure relates to stable topical pharmaceutical compositions of SHR0302 (also known as ARQ-250). In certain embodiments, pharmaceutical compositions of SHR0302 having a pH of less than about 4.6 have improved stability and do not exhibit crystal formation of the API. In certain embodiments, pharmaceutical compositions of SHR0302 comprising about 20% to about 30% dimethyl sulfoxide (DMSO) have improved stability and do not exhibit crystal formation of the API. Improved formulations of SHR0302 can exhibit acceptable commercial shelf life and do not exhibit loss of potency of the API after extended storage.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 289,780, filed December 15, 2021, and U.S. Provisional Application No. 63 / 370,740, filed August 8, 2022. The contents of these applications are incorporated herein by reference in their entireties.

[0002] FIELD OF THEINVENTION

[0002] The subject matter disclosed herein generally relates to stable topical formulations comprising SHR0302. In certain embodiments, the disclosure addresses the surprising discovery that formulations of SHR0302 having a pH of less than 4.6 have improved stability and do not exhibit crystal formation of the active ingredient. Additionally, in certain embodiments, the disclosure addresses the surprising discovery that formulations comprising a certain percentage of dimethyl sulfoxide have improved stability and do not exhibit crystal formation of the active ingredient. [Background technology]

[0003]

[0003] The present invention relates to a topical pharmaceutical composition of the JAK1 inhibitor (3aR,5S,6aS)-N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, also known as SHR0302 or ARQ-250. SHR0302 is a potent small molecule inhibitor of JAK1 that has been shown to have high selectivity for JAK1 over JAK2, and thus has the potential to treat inflammatory diseases without causing the hematopoietic adverse effects, such as anemia, thrombocytopenia, and neutropenia, associated with inhibition of JAK2. SHR0302 is disclosed in U.S. Pat. No. 9,527,851, which is incorporated herein by reference.

[0004]

[0004] Topical application of potent pharmacological agents to treat skin diseases can provide superior delivery, lower systemic exposure, and be significantly easier for patients to use. The molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the product is applied. For topical application to the skin, the choice of formulation components dictates the maximum skin penetration the formulator can achieve. Creams, lotions, gels, ointments, and foams are just a handful of the more familiar forms of topical products containing active pharmaceutical ingredients (APIs) for application to the skin. To ensure a consistent delivery of the API into or through the skin, it must either (1) remain dissolved throughout the shelf life of the topical product, or (2) remain suspended as particles with a consistent crystal habit and consistent particle size distribution throughout the shelf life of the topical product.

[0005]

[0005] In general, the most robust skin permeation of drugs from topical products occurs when the active ingredient is dissolved in the formulation. For this reason, formulators generally avoid developing topical products that are expected to precipitate particles or crystals of the active ingredient during storage according to the storage instructions indicated on the label. Precipitation of the active ingredient can occur for a variety of reasons. Certain active ingredients tend to form supersaturated solutions when formulated with certain pharmaceutical excipients. At the time of manufacture, all of the active ingredient is in solution. After a few days, weeks, or months, this metastable topical product equilibrates and particles of the active ingredient form. Regardless of the reason, irreversible precipitation of the active ingredient during storage of the topical product can seriously affect the bioavailability and efficacy of the topical product, since only dissolved active ingredients can penetrate into the intact stratum corneum (the outermost layer of the skin's epidermis). Summary of the Invention

[0006]

[0006] The present invention relates to improved topical formulations comprising SHR0302. The inventors of the present invention have produced stable pharmaceutical compositions of SHR0302 that exhibit reduced tendency of the active pharmaceutical ingredient ("API") to crystallize. The pharmaceutical compositions of the present invention may be stable for 6, 12, or 18 months at controlled room temperature. In certain embodiments, the inventors of the present invention have made the surprising discovery that a formulation of SHR0302 (also known as ARQ-250) having a pH of less than about 4.6 has improved stability and does not exhibit crystal formation of the API. Alternatively, in certain embodiments, the inventors of the present invention have made the surprising discovery that a formulation of SHR0302 having about 20% to about 30% dimethyl sulfoxide has improved stability and does not exhibit crystal formation of the API. The improved formulations of SHR0302 address the above problems and exhibit acceptable commercial shelf life and do not exhibit loss of potency of the API after extended storage.

[0007]

[0007] In certain embodiments of the present invention, a topical pharmaceutical composition is provided. The topical pharmaceutical composition comprises a pharma- ceutical effective amount of SHR0302, and the pharmaceutical composition has a pH of less than 4.6. In certain embodiments, the pharmaceutical composition has a pH of between about 3.8 and about 4.6. In certain embodiments, the pharmaceutical composition has a pH of between about 3.8 and about 4.2.

[0008]

[0008] In certain embodiments, the topical pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the topical pharmaceutical composition further comprises laureth-4. In certain embodiments, the topical pharmaceutical composition comprises laureth-4 in an amount of about 0.5 to about 5% w / w.

[0009]

[0009] In certain embodiments, the topical pharmaceutical composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment.

[0010]

[0010] In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0011] In another embodiment, a topical pharmaceutical composition is provided comprising a pharma- ceutical effective amount of SHR0302 and Laureth-4. The pharmaceutical composition has a pH of less than 4.6. In certain embodiments, the pharmaceutical composition has a pH of between about 3.8 and about 4.6. In certain embodiments, the pharmaceutical composition has a pH of between about 3.8 and about 4.2.

[0012]

[0012] In certain embodiments, the topical pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the topical pharmaceutical composition further comprises laureth-4. In certain embodiments, the topical pharmaceutical composition comprises laureth-4 in an amount of about 0.5 to about 5% w / w.

[0013]

[0013] In certain embodiments, the topical pharmaceutical composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment.

[0014]

[0014] In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0015] In another embodiment, a topical pharmaceutical composition is provided comprising a pharma- ceutically effective amount of SHR0302. The topical pharmaceutical composition further comprises one or more of dimethyl sulfoxide, laureth-4, butylated hydroxytoluene, benzyl alcohol, propylene glycol, polyethylene glycol 200, cyclomethicone, dimethicone, ST-Elastomer 10, Pemulen TR 1, Carbopol 974P, and a pH adjuster. The topical pharmaceutical composition has a pH of less than 4.6. In certain embodiments, the pharmaceutical composition has a pH between about 3.8 and about 4.6. In certain embodiments, the pharmaceutical composition has a pH between about 3.8 and about 4.2. In certain embodiments, the topical pharmaceutical composition is a cream.

[0016]

[0016] In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises dimethyl sulfoxide in an amount of about 20% to about 40% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises butylhydroxytoluene in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises benzyl alcohol in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises propylene glycol in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol 200 in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises cyclomethicone in an amount of about 5% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises dimethicone in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises ST-Elastomer 10 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises Pemulen TR 1 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises Carbopol 974P in an amount of about 0.1 to about 1.5% w / w.

[0017]

[0017] In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0018] In another embodiment, a topical pharmaceutical composition is provided comprising a pharma- ceutically effective amount of SHR0302. The topical pharmaceutical composition further comprises one or more of N-methyl-2 pyrrolidone, laureth-4, butyl hydroxytoluene, methylparaben, propylparaben, Crodafos CES, isopropyl palmitate, white petrolatum, propylene glycol, polyethylene glycol 200, a pH adjuster, and xanthan gum. The topical pharmaceutical composition has a pH of less than 4.6. In certain embodiments, the pharmaceutical composition has a pH between about 3.8 and about 4.6. In certain embodiments, the pharmaceutical composition has a pH between about 3.8 and about 4.2. In certain embodiments, the topical pharmaceutical composition is a cream.

[0019]

[0019] In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises N-methyl-2 pyrrolidone in an amount of about 15% to about 40% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises butylhydroxytoluene in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises methylparaben in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises propylparaben in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises Crodafos CES in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises isopropyl palmitate in an amount of about 1% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises white petrolatum in an amount of about 1% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises propylene glycol in an amount of about 5% to 20% w / w. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol 200 in an amount of about 5% to 20% w / w.

[0020]

[0020] In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0021] In certain embodiments, the topical pharmaceutical composition comprises a pharma- ceutically effective amount of SHR0302 and about 20% to about 30% dimethyl sulfoxide. In certain embodiments, the pharmaceutical composition may comprise about 25% dimethyl sulfoxide. In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1% to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4, which may be present in an amount of about 0.5 to about 5% w / w. In certain embodiments, the topical pharmaceutical composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment. In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0022]

[0022] In certain embodiments, the topical pharmaceutical composition comprises a pharma- ceutically effective amount of SHR0302, about 20% to about 27% dimethyl sulfoxide, and about 0.5% to about 5% laureth-4. In certain embodiments, the pharmaceutical composition may comprise about 25% dimethyl sulfoxide. In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1% to about 1.0% w / w. In certain embodiments, the topical pharmaceutical composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment. In certain embodiments, the topical pharmaceutical composition is stable at controlled room temperature for at least 6 months, 7 months, 8 months, 12 months, or 18 months.

[0023]

[0023] In certain embodiments, the topical pharmaceutical composition comprises a pharma- ceutical effective amount of SHR0302 stable for 12 months at controlled room temperature. In certain embodiments, the pharmaceutical composition comprises about 20% to about 27% dimethyl sulfoxide. In certain embodiments, the pharmaceutical composition further comprises laureth-4 in an amount of about 0.5% to about 5% laureth-4. In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1% to about 1.0% w / w. In certain embodiments, the topical pharmaceutical composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment.

[0024]

[0024] The accompanying drawings, which are incorporated in this specification and form a part of this disclosure, assist in illustrating various embodiments of the present invention and, together with the description, further serve to explain the invention so as to enable those skilled in the art to make and use the embodiments disclosed herein. [Brief description of the drawings]

[0025] [Figure 1]

[0025] Figure 1 shows the aqueous concentration (μg / mL) of SHR0302 (also known as ARQ-250) as a function of pH in a phosphate buffer system. The results show that the solubility of SHR0302 in water decreases as the pH level increases. [Diagram 2]

[0026] FIG. 1 shows the aqueous concentration (μg / mL) of SHR0302 (also known as ARQ-250) as a function of pH in phosphate and citrate buffer systems. The results show that the solubility of SHR0302 in water decreases as the pH level increases. [Diagram 3]

[0027] Figure 1 shows IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in receptor fluid. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302 and DMSO. [Figure 4]

[0028] Figure 1 shows IVPT results comparing three exemplary SHR0302 formulations with various concentrations of xanthan gum and laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in the receptor fluid. The results show that the addition of laureth-4 significantly enhances the skin penetration effect in formulations containing SHR0302 and NMP. [Diagram 5]

[0029] Figure 1 shows IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in the receptor fluid. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Figure 6]

[0030] Figure 1 shows IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in the receptor fluid. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Figure 7]

[0031] Figure 1 shows IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in the receptor fluid. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Figure 8]

[0032] Figure 1 shows IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The X-axis represents time (hours) and the Y-axis represents cumulative SHR0302 (ng / mL) in the receptor fluid. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026]

[0033] Before the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, as they may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0027]

[0034] All publications, patents, and patent applications cited herein are incorporated herein in their entirety by reference unless otherwise stated.When the same term is defined in the publication, patent, or patent application incorporated herein by reference and in this disclosure, the definition in this disclosure represents the controlling definition.In the case of publications, patents, and patent applications referenced to describe a particular type of compound, chemistry, etc., the portion relating to such compound, chemistry, etc. is the portion of the document incorporated herein by reference.

[0028]

[0035] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, "active ingredient" includes a single ingredient as well as two or more different ingredients, "solvent" refers to a single solvent as well as two or more different solvents or complex mixtures of solvents, and "sulfate" includes a single sulfate salt as well as two or more different sulfate salts.

[0029]

[0036] The term "about" when used in connection with a numerical value is meant to encompass numerical values ​​in a range having a lower limit of 5% less than the stated numerical value and an upper limit of 5% greater than the stated numerical value.

[0030]

[0037] The term "effective" refers to an amount of a compound, drug, substance, formulation, or composition sufficient to result in a decrease in the severity of symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of impaired function or disability due to a disease. The amount may be as a single dose or in a multiple dose regimen, alone or in combination with other compounds, drugs, or substances. One of ordinary skill in the art would be able to determine such amounts based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0031]

[0038] "Pharmaceutically acceptable" generally means safe for administration to humans or animals. Preferably, a pharmacopoeia is one that is approved by a federal or state regulatory agency or is listed in the United States Pharmacopeia published by the United States Pharmacopeial Convention, Inc. (Rockville Md.), or other pharmacopoeia generally accepted for use in animals, more particularly humans.

[0032]

[0039] A "pharmaceutical composition" according to the invention may be in the form of a composition in which the different active ingredients and diluents and / or carriers are mixed with one another, or it may take the form of a combined preparation in which the active ingredients are present in a partially or completely separate form. An example of such a combination or combined preparation is a kit-of-parts.

[0033]

[0040] A "pharmaceutical effective amount" or "therapeutically effective amount" is an amount of a pharmaceutical agent or therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size of the subject receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be empirically determined by those skilled in the art according to methods established in the art.

[0034]

[0041] The term "SHR0302" or "ARQ-250" refers to (3aR,5S,6aS)-N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide and salts thereof. For example, SHR0302 includes the hydrogen sulfate salt of SHR0302, which is disclosed in U.S. Pat. No. 9,422,300, which is incorporated herein by reference.

[0035]

[0042] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" may include any mammal that can benefit from the compounds described herein.

[0036]

[0043] The term "topical" with respect to administration of a drug or composition refers to application of such drug or composition to an external epithelial surface of the body, including the skin or cornea. In this regard, application inside a body orifice, such as the mouth, nose, or ear, is not considered to be a topical application.

[0037]

[0044] As used herein, "treating," "treating," or "treatment" of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder(s) being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing the recurrence of the disorder(s) in patients who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in patients who previously had symptoms related to the disorder(s).

[0038]

[0045] The abbreviation "w / w" expresses the relative concentrations of components in a composition on a "weight for weight" basis (i.e., percentages refer to percentages of the total mass) rather than on a volumetric or other quantity basis.

[0039]

[0046] The present invention relates to improved topical formulations comprising SHR0302. The inventors of the present invention have developed stable topical formulations comprising SHR0302 that can exhibit an acceptable commercial shelf life and do not exhibit loss of API potency after extended storage.

[0040]

[0047] In certain embodiments, the inventors of the present invention have discovered that topical pharmaceutical compositions of SHR0302 having a pH value of about 4.6 or greater may increase the tendency of the API to crystallize. In certain embodiments, the inventors of the present invention have made the surprising discovery that formulations of SHR0302 having a pH value of less than about 4.6 have improved stability and do not exhibit crystal formation of the API.

[0041]

[0048] In certain embodiments, the present inventors have discovered that topical pharmaceutical compositions of SHR0302 containing less than about 30% dimethyl sulfoxide have improved stability and do not exhibit crystal formation of the API. In certain embodiments, the topical pharmaceutical composition of SHR0302 can contain about 20% to about 27% dimethyl sulfoxide. In certain embodiments, the topical pharmaceutical composition of SHR0302 can contain about 25% dimethyl sulfoxide.

[0042]

[0049] Janus kinase inhibitors (JAK inhibitors) are a group of compounds that function by inhibiting the activity of one or more enzymes in the JAK family (e.g., JAK1, JAK2, JAK3, or Tyk2). These compounds are believed to act by interfering with the JAK-STAT signaling pathway, which plays a central role in immune system function. Many inflammatory cytokines and other signaling molecules depend on the JAK pathway, specifically JAK1. It has previously been shown that inhibiting JAK1 is shown to treat various inflammatory diseases, including rheumatoid arthritis, psoriasis, Crohn's disease, and eczema. There is particular interest in developing topical formulations of JAK inhibitors for the treatment of inflammatory skin conditions.

[0043]

[0050] In a preferred embodiment, the pharmaceutical composition of the present invention comprises the JAK1 inhibitor (3aR,5S,6aS)-N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, also known as SHR0302 or ARQ-250. The pharmaceutical composition may comprise SHR0302 as a free base or a pharma- ceutically acceptable salt. Suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company (1985), incorporated herein by reference. In certain embodiments, the pharmaceutical composition comprises the bisulfite salt of SHR0302. The structure of SHR0302 is as follows:

[0044] [ka]

[0045]

[0051] SHR0302 is a potent small molecule inhibitor of JAK1 that has been shown to have high selectivity for JAK1 over JAK2, and thus has the potential to treat inflammatory diseases without causing hematopoietic adverse effects associated with inhibition of JAK2, such as anemia, thrombocytopenia, and neutropenia. It is contemplated that topical formulations containing SHR0302 may be effective in treating inflammatory skin diseases, disorders, and conditions, including, but not limited to, atopic dermatitis, rosacea, psoriasis, seborrheic dermatitis, vitiligo, eczema, and alopecia areata.

[0046]

[0052] The pharmaceutical composition comprises a pharma- ceutical effective amount of SHR0302. In certain embodiments, SHR0302 is present in an amount of about 0.01% w / w to about 7.5% w / w, or about 0.01% w / w to about 5% w / w, or about 0.1% w / w to about 3% w / w, or about 0.01 to about 1.0% w / w, or about 0.05 to about 1.0% w / w, or about 0.1 to about 1.0% w / w, or about 0.1 to about 0.6% w / w, or about 0.1 to about 0.5% w / w. For example, the topical formulations may contain the following w / w percentages: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5 ...1%, 3. containing any of SHR0302, such as 5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, etc.

[0047]

[0053] The pharmaceutical composition of SHR0302 has a pH of less than about 4.6. In certain embodiments, the pharmaceutical composition of SHR0302 has a pH of less than about 4.6, less than about 4.5, less than about 4.4, less than about 4.3, less than about 4.2, less than about 4.1, or less than about 4.0. In certain embodiments, the pharmaceutical composition of SHR0302 has a pH of between about 3.5 and about 4.6, between about 3.8 and about 4.6, between about 4.0 and about 4.6, between about 3.8 and about 4.2, between about 4.0 and about 4.6, between about 4.2 and about 4.6, between about 4.3 and about 4.6, or between about 4.4 and about 4.6. In certain embodiments, the pharmaceutical composition is formulated to have a pH of 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, or 4.6. In certain embodiments, the pharmaceutical composition is formulated to have a pH of about 4.0.

[0048]

[0054] In certain embodiments, the inventors of the present application have discovered that SHR0302 unexpectedly crystallizes in pharmaceutical compositions formulated at a pH greater than 4.6. Furthermore, the inventors of the present application have discovered that compositions of SHR0302 formulated at a pH greater than 5.2 may exhibit loss of API potency and reduced biological activity. Pharmaceutical compositions of SHR0302 having a pH within the above ranges may exhibit improved stability and shelf life, as well as reduced susceptibility of API to crystal formation. Pharmaceutical formulations of SHR0302 may exhibit acceptable commercial shelf life and do not exhibit loss of API potency after extended storage.

[0049]

[0055] In certain embodiments, the pharmaceutical composition is stable at controlled room temperature (i.e., 20-25° C.) for at least 6 months. In certain embodiments, the pharmaceutical composition is stable at controlled room temperature for at least 12 months. In certain embodiments, the pharmaceutical composition is stable at controlled room temperature for at least 18 months. In certain embodiments, the pharmaceutical composition is stable at 30° C. for at least 6 months, at least 7 months, at least 8 months, at least 12 months, or at least 18 months. In certain embodiments, the pharmaceutical composition is stable at 40° C. for at least 6 months, at least 7 months, at least 8 months, at least 12 months, or at least 18 months.

[0050]

[0056] In certain embodiments, the pharmaceutical composition can exhibit no crystal formation of the API after storage at controlled room temperature for 6 months, 7 months, 8 months, 12 months, or 18 months. In certain embodiments, the pharmaceutical composition can exhibit no crystal formation of the API after storage at 30° C. for 6 months, 7 months, 8 months, 12 months, or 18 months. In certain embodiments, the pharmaceutical composition can exhibit no crystal formation of the API after storage at 40° C. for 6 months, 7 months, 8 months, 12 months, or 18 months.

[0051]

[0057] In certain embodiments, the pharmaceutical composition comprises laureth-4 (CAS number 5274-68-0), which is also known as tetraethylene glycol monododecyl ether, 3,6,9,12-tetraoxatetracosan-1-ol, lauryl alcohol tri(oxyethylene)ethanol, PEG-4 lauryl ether, polyethylene glycol 200 lauryl ether, polyoxyethylene(4) lauryl ether, and tetraethylene glycol dodecyl ether. The compound has the molecular formula C 20 H 42 O 5 and has a molecular weight of 362.5 g / mol. Laureth-4 is a synthetic polymer commonly used as a surfactant and emulsifier in several personal care products, including cosmetics, shampoos, soaps, deodorants, and moisturizing products. Laureth-4 may act as a skin penetration enhancer in the topical formulations of the present invention. In certain embodiments, laureth-4 is present in an amount of about 0.05 to about 8.0% w / w, about 0.1 to about 6.0% w / w, about 0.5 to about 5.0% w / w, about 1.0 to about 4.0% w / w, or about 2.0 to about 4.0% w / w. In certain embodiments, laureth-4 is about 0.05% w / w, 0.10% w / w, 0.15% w / w, 0.20% w / w, 0.25% w / w, 0.50% w / w, 0.75% w / w, 1.0% w / w, 1.25% w / w, 1.50% w / w, 1.75% w / w, 2.0% w / w, 2.25% w / w, 2. It is present in an amount of 50% w / w, 2.75% w / w, 3.0% w / w, 3.25% w / w, 3.50% w / w, 3.75% w / w, 4.0% w / w, 4.25% w / w, 4.50% w / w, 4.75% w / w, 5.0% w / w, 5.25% w / w, 5.50% w / w, 5.75% w / w, or 6.0% w / w.

[0052]

[0058] In certain embodiments, the inventors of the present application have also unexpectedly discovered that SHR0302 crystallizes in pharmaceutical compositions formulated with high concentrations of dimethyl sulfoxide (DMSO). Furthermore, the inventors of the present application have discovered that pharmaceutical compositions of SHR0302 containing less than about 30% dimethyl sulfoxide have improved stability and do not exhibit crystal formation of the API. In certain embodiments, the pharmaceutical composition comprises dimethyl sulfoxide (DMSO). In certain embodiments, DMSO is present in an amount of about 5% to about 30% w / w, about 10% to about 30% w / w, about 10% to about 27% w / w, about 10% to about 25%, about 15% to about 30% w / w, about 15% to about 27% w / w, about 15% to about 25% w / w, about 20% to about 30% w / w, about 20% to about 27% w / w, or about 20% to about 25% w / w. In certain embodiments, DMSO is present in an amount of about 5% w / w, 7.5% w / w, 10% w / w, 12.5% ​​w / w, 15% w / w, 17.5% w / w, 20% w / w, 21% w / w, 22% w / w, 22.5% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 27% w / w, 27.5% w / w, 28% w / w, 29% w / w, or 30% w / w. In certain embodiments, DMSO is present in an amount of about 20%, 25%, or 30% w / w.

[0053]

[0059] Preferably, the topical formulation of the present invention is in one of the following forms:

[0060] Oil-in-water emulsions: The product may be an emulsion that includes a discontinuous phase of hydrophobic components and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that help stabilize the emulsion.

[0054]

[0061] Water-in-oil emulsions: The compositions may be emulsions that include a continuous phase of hydrophobic components and an aqueous phase that includes water and, optionally, one or more polar hydrophilic carrier(s), as well as salts or other components. These emulsions may include an oil-soluble or oil-swellable polymer, as well as one or more emulsifier(s) that help stabilize the emulsion.

[0055]

[0062] Hydrophilic or hydrophobic ointments: The compositions are formulated with a hydrophobic base (e.g., petrolatum, water-insoluble thickened or gelled oils, etc.), optionally with a small amount of a water-soluble phase. Hydrophilic ointments generally contain one or more surfactants or humectants.

[0056]

[0063] Microemulsions: These are clear, thermodynamically stable, isotropic liquid systems that contain oil, water, and surfactants, often together with co-surfactants. Microemulsions may be water continuous, oil continuous, or bicontinuous mixtures. Formulations may also optionally contain up to 60% water by weight. Higher levels may be suitable for some compositions.

[0057]

[0064] Nanoemulsions: These are isotropic dispersion systems that contain water, oil, and emulsifiers. The systems may be oil-based systems dispersed in aqueous systems or aqueous systems dispersed in oil-based systems, forming nanometer-sized droplets or oily phases. Nanoemulsions often have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients can also be formulated in nanoemulsions. Nanoemulsions may be formed by any suitable method known in the art, including high pressure homogenization, microfluidization, and phase inversion temperature.

[0058]

[0065] Aerosol foams or sprays: The product may be an alcohol / solvent-based solution containing an emulsifying wax, or it may be an emulsion that includes a discontinuous phase of hydrophobic components and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, surfactants, emulsifiers, and other components. These solvent or emulsion foam concentrates may include water-soluble or water-swellable polymers that help stabilize the emulsion, and corrosion inhibitors to improve compatibility between the formulation and the package. Hydrocarbon, hydrochlorofluorocarbon (HCFC) or chlorofluorocarbon (CFC) aerosol propellants can be added to the solvent or emulsion foam concentrates in packaging designed to maintain pressure until the foam or spray product is dispensed and applied.

[0059]

[0066] In certain embodiments, the pharmaceutical composition may contain one or more of the following excipients:

[0060]

[0067] solvent

[0068] The composition according to the present invention may contain one or more solvents or co-solvents that modify the skin penetration or activity of other excipients contained in the formulation.Solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, isopropyl palmitate, N-methyl pyrrolidone, polyethylene glycol (e.g., PEG 200), glycerol, propylene glycol, and SD alcohol.

[0061]

[0069] Surfactants

[0070] The composition according to the invention may contain one or more surfactants or co-surfactants, including but not limited to short chain alcohols, alkane diols and triols, alkyl phosphate esters, polyethylene glycols and glycol ethers, polyethylene stearyl ethers (including those sold under the trade names Brij S2, Brij S20, Brij 721, Brij 38, Brij 52, Brij 56, and Brij W1), pyrrolidine derivatives, bile salts, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0062]

[0071] Polymer Emulsifier

[0072] The compositions for use in the present invention may contain one or more polymeric emulsifiers. The polymeric emulsifiers include acrylic acid crosslinked with allyl pentaerythritol and C 10~30 Included may be high molecular weight copolymers with alkyl acrylates. Polymeric emulsifiers particularly suitable for use in the method of the present invention include those commercially available under the trade name Pemulen™ and sold by Lubrizol, including Pemulen™ TR-1 and Pemulen™ TR-2 NF.

[0063]

[0073] Moisturizer

[0074] The compositions according to the present invention may include one or more moisturizing agents to increase the level of hydration. Moisturizing agents may be hydrophilic materials, including humectants, or hydrophobic materials, including emollients. Suitable moisturizing agents include, but are not limited to, 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, theobroma cacao butter, coconut oil, cyclomethicone, dimethicone, docosanol, elastomers, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl lau ... Ingredients include: glyceryl, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isopropyl palmitate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, ST-Elastomer 10 (a mixture of high molecular weight crosslinked silicone (12%) in decamethylcyclopentasiloxane (D5)), polypropylene glycol stearyl ether, and stearyl alcohol.

[0064]

[0075] Polymers and Thickeners

[0076] In certain applications, it may be desirable to formulate products thickened with soluble, swellable, or insoluble organic polymeric thickeners, such as natural and synthetic polymers, or inorganic thickeners, such as acrylates copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, acrylamide / sodium acryloyldimethyltaurate copolymer, carboxyvinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, xanthan gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax, and methylcellulose.In certain embodiments, the pharmaceutical formulation may include carbomers, such as Carbopol 974P or Carbomer Homopoylmer Type B USP.In certain embodiments, the pharmaceutical formulation may include Sepino P600 (acrylaminde / sodium acryloyldimethyltaurate copolymer / isohexadecane and polysorbate 80).

[0065]

[0077] Additional Components

[0078] The compositions according to the invention may be formulated with additional components conventionally found in topical cosmetic and pharmaceutical products, such as fillers, carriers, and excipients, including but not limited to antifoaming agents, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercuric salts, chlorocresol, methylparaben, propylparaben), antioxidants (e.g., BHT, BHA, ascorbic acid, tocopherol, citric acid, propyl gallate, sodium metabisulfite), sequestrants, stabilizers, buffers, pH adjusters (preferably agents that provide an acidic pH, including but not limited to gluconolactone, citric acid, lactic acid, and alpha hydroxy acids), skin penetration enhancers, skin protectants (including but not limited to petrolatum, paraffin wax, dimethicone, glyceryl monoisostearate, glyceryl ... Additional components may be added to the compositions, including isostearate (including isostearate, isopropyl isostearate, isostearyl isostearate, cetyl alcohol, potassium cetyl phosphate, cetyl behenate, and behenic acid), chelating agents, film-forming agents, suspending agents (e.g., xanthan gum), dyes, pigments, diluents, bulking agents, fragrances, aerosol forming agents, and other excipients to improve stability or aesthetics.

[0066]

[0079] The compositions according to the present invention may be formulated with additional active agents depending on the condition being treated.Exemplary additional active agents for combination topical drug products include corticosteroids (e.g., clobetasol, betamethasone, halobetasol, or triamcinolone), beta andrenergic antagonists (e.g., timolol), calcineurin inhibitors (e.g., tacrolimus, or pimecrolimus), methotrexate, or cyclosporine.

[0067]

[0080] Formulation examples

[0081] In certain embodiments, the topical pharmaceutical composition comprises pharma- ceutical effective amounts of SHR0302, laureth-4, and dimethyl sulfoxide. In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises dimethyl sulfoxide in an amount of about 20% to about 27% w / w.

[0068]

[0082] In certain embodiments, the topical pharmaceutical composition comprises a pharma- ceutical effective amount of SHR0302 and one or more of dimethyl sulfoxide, laureth-4, butylated hydroxytoluene, benzyl alcohol, propylene glycol, polyethylene glycol 200, cyclomethicone, dimethicone, ST-Elastomer 10, Pemulen TR 1, Carbopol 974P, and a pH adjuster. In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises dimethyl sulfoxide in an amount of about 20% to about 40% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises butylated hydroxytoluene in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises benzyl alcohol in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises propylene glycol in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol 200 in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises cyclomethicone in an amount of about 5% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises dimethicone in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises ST-Elastomer 10 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises Pemulen TR 1 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises Carbopol 974P in an amount of about 0.1 to about 1.5% w / w.

[0069]

[0083] In another exemplary embodiment, the topical pharmaceutical composition comprises a pharma- ceutical effective amount of SHR0302 and one or more of N-methyl-2 pyrrolidone, laureth-4, butylated hydroxytoluene, methylparaben, propylparaben, Crodafos CES, isopropyl palmitate, white petrolatum, propylene glycol, polyethylene glycol 200, pH adjusters, and xanthan gum. Crodafos CES is an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, manufactured by Croda. Crodafos™ CES PHARMA is manufactured using the same starting materials and processes, but has undergone enhanced quality control and release testing, and uses the names cetearyl alcohol, cetearyl phosphate, and ceteareth-10 phosphate, in line with standard practice for naming pharmaceutical excipients. This commercially available emulsifier blend contains cetearyl alcohol (cetyl alcohol (C)), a waxy material. 16 H 34 O) and stearyl alcohol (C 18 H 38O) in combination with 10-20% dicetyl phosphate (cetearyl phosphate) and 10-20% ceteth-10 phosphate (ceteareth-10 phosphate). In certain embodiments, the pharmaceutical composition comprises SHR0302 in an amount of about 0.1 to about 1.0% w / w. In certain embodiments, the pharmaceutical composition comprises N-methyl-2-pyrrolidone in an amount of about 15% to about 40% w / w. In certain embodiments, the pharmaceutical composition comprises laureth-4 in an amount of about 0.5% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises butylhydroxytoluene in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises methylparaben in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises propylparaben in an amount of about 0.01% to about 5% w / w. In certain embodiments, the pharmaceutical composition comprises Crodafos CES in an amount of about 5% to about 20% w / w. In certain embodiments, the pharmaceutical composition comprises isopropyl palmitate in an amount of about 1% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises white petrolatum in an amount of about 1% to about 10% w / w. In certain embodiments, the pharmaceutical composition comprises propylene glycol in an amount of about 5% to 20% w / w. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol 200 in an amount of about 5% to 20% w / w.

[0070]

[0084] Administration and Dosage

[0085] The composition according to the present invention can be administered by any suitable route of administration, including but not limited to dermal (topical), transdermal, and mucosal.In a preferred embodiment, the composition is administered topically.The composition can be administered once or more per month, once or more per week, or once or more per day.In a preferred embodiment, the composition is administered once, twice, or three times per day.

[0071]

[0086] In certain embodiments, topical formulations comprising laureth-4 disclosed herein can provide improved skin permeation. As disclosed in US Patent Application No. 17 / 443,699 (incorporated herein by reference), pharmaceutical compositions comprising laureth-4 can provide a 5-fold to 30-fold increase in skin permeation compared to the same topical formulation without laureth-4, as measured by in vitro permeation testing (IVPT). In preferred embodiments, topical formulations containing laureth-4 provide a greater than 5-fold, greater than 8-fold, greater than 10-fold, greater than 15-fold, or greater than 20-fold increase in skin permeation compared to the same topical formulation without laureth-4. EXAMPLES

[0072]

[0087] While various embodiments have been described herein, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or clearly contradicted by context.

[0073]

[0088] Example 1

[0089] A single batch of the pharmaceutical composition (Formulation A) described in Table 1 was prepared. The pH of the batch was increased incrementally from an initial pH of 4.31 to a final pH of 6.53. Samples were taken at each repetition with different pH.

[0074] [Table 1]

[0075]

[0091] Stability studies were performed using each of the samples of the formulations in Table 1 with different pH. The stability of each sample was observed at controlled room temperature, 30°C, and 40°C for up to 12 months. After the initial preparation and each month thereafter for up to 12 months (i.e., at 0 (initial), 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and 12 months), the samples were examined for the presence of crystals. Specifically, the samples were visually inspected using a magnifying glass with an integrated light to assess whether crystals were present. The same samples were used for the inspection because the inspection was non-destructive. A spatula was used to stir each sample during the inspection. The inspection was performed at all depths of the vial.

[0076]

[0092] The results of the stability studies are shown below in Table 2 (data from 0 to 6 months) and Table 3 (data from 7 to 12 months).

[0077] [Table 2]

[0078] [Table 3]

[0079]

[0095] As shown in Tables 2 and 3, the stability of the formulations decreased as the pH increased. The pharmaceutical compositions formulated at pHs of 4.31, 4.39, and 4.57 did not exhibit any crystal formation at controlled room temperature or at 30° C. for the duration of the study (i.e., 12 months). Additionally, these pharmaceutical compositions did not exhibit any crystal formation at 40° C. for 11 months.

[0080]

[0096] The inventors of the present application also observed a loss of potency due to loss of assay under intermediate and / or accelerated conditions in formulations having a pH of 4.6 or higher. None of the batches having a pH of 4.6 or lower were found to show a loss of potency due to loss of assay.

[0081]

[0097] Example 2

[0098] A single batch of a first pharmaceutical composition was prepared (Formulation B) similar to the composition described in Table 1, but containing 4% Laureth-4. The pH of the batch of Formulation B was incrementally increased from an initial pH of 4.57 to a final pH of 6.59. Samples were taken at each repetition with different pH.

[0082]

[0099] A single batch of a second pharmaceutical composition was prepared (Formulation C) similar to the composition described in Table 1 but containing 4% Laureth-4 and 25% dimethylsulfoxide (DMSO) instead of 30% DMSO. The batch pH of Formulation C was increased incrementally from an initial pH of 4.45 to a final pH of 6.61. Samples were taken at each repetition with different pH.

[0083] [000100] Stability studies were conducted using samples of Formulation B and Formulation C, each with different pH. The stability of each sample was observed at controlled room temperature, 30°C, and 40°C for up to 12 months. After initial preparation and each month thereafter for up to 8 months (i.e., at 0 (initial), 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and 12 months), the samples were examined for the presence of crystals. Specifically, the samples were visually inspected using a magnifying glass with an integrated light to assess whether crystals were present. The same samples were used for the inspection because the inspection was non-destructive. A spatula was used to stir each sample during the inspection. The inspection was performed at all depths of the vial.

[0084] [000101] The results of the stability studies are set forth below in Tables 4 (data from 0 to 6 months) and 5 (data from 7 to 12 months) for Formulation B and in Tables 6 (data from 0 to 6 months) and 7 (data from 7 to 12 months) for Formulation C.

[0085] [Table 4]

[0086] [Table 5]

[0087] [Table 6]

[0088] [Table 7]

[0089] [000106] As shown in Tables 4-7, the stability of the formulation containing 25% DMSO (Formulation C) was improved relative to the formulation containing 30% DMSO (Formulation B). Formulation C formulated at all pH values ​​except pH 6.61 did not show any crystal formation at controlled room temperature during the first 7 months of study. Furthermore, Formulation C formulated at all pH values ​​below 5.55 did not show any crystal formation at controlled room temperature during the first 8 months of study. Furthermore, Formulation C formulated at all pH values ​​did not show any crystal formation at 30°C or 40°C during the first 6 months of study.

[0090] [000107] Example 3 [000108] Five different batches of pharmaceutical compositions were prepared. A single batch of a first pharmaceutical composition was prepared similar to formulation B but without EDTA and containing Sepineo P600 (formulation D). A single batch of a second pharmaceutical composition was prepared similar to formulation D but with the free base of SHR0302 instead of the sulfate salt of SHR0302 (formulation E). A single batch of a third pharmaceutical composition was prepared similar to formulation B but without EDTA (formulation F). A single batch of a fourth pharmaceutical composition was prepared similar to formulation F but with the free base of SHR0302 instead of the sulfate salt of SHR0302 (formulation G). A single batch of a fifth pharmaceutical composition was prepared similar to formulation C but without EDTA and containing the free base of SHR0302 instead of the sulfate salt of SHR0302 (formulation H). The batch pH of formulations D, E, F, G, and H was incrementally increased as described in Tables 8-17 below. Samples were taken at each repetition with different pH.

[0091] [000109] Stability studies were conducted using samples of formulations D, E, F, G, and H, each with different pH. The stability of each sample was observed at controlled room temperature, 30°C, and 40°C for up to 9 months. After initial preparation and each month thereafter for up to 9 months (i.e., at 1, 2, 3, 4, 5, 6, 7, 8, and 9 months), the samples were examined for the presence of crystals. Specifically, the samples were visually inspected using a magnifying glass with an integrated light to assess whether crystals were present. The same samples were used for the inspection since the inspection was non-destructive. A spatula was used to stir each sample during the inspection. The inspection was performed at all depths of the vial.

[0092] [000110] The results of the stability studies are set forth below in Table 8 (1-4 month data for Formulation D), Table 9 (5-9 month data for Formulation D), Table 10 (1-4 month data for Formulation E), Table 11 (5-9 month data for Formulation E), Table 12 (1-4 month data for Formulation F), Table 13 (5-9 month data for Formulation F), Table 14 (1-4 month data for Formulation G), Table 15 (5-9 month data for Formulation G), Table 16 (1-4 month data for Formulation H), and Table 17 (5-9 month data for Formulation H).

[0093] [Table 8]

[0094] [Table 9]

[0095] [Table 10]

[0096] [Table 11]

[0097] [Table 12]

[0098] [Table 13]

[0099] [Table 14]

[0100] [Table 15]

[0101] [Table 16]

[0102] [Table 17]

[0103] [000121] As shown in Tables 8-17, formulations containing Sepineo appear to be less stable than formulations without Sepineo, regardless of formulation pH.

[0104] [000122] Example 4 [000123] The solubility of SHR0302 in water was determined at various pH values ​​in phosphate buffer. Figure 1 shows a plot of the aqueous concentration (μg / mL) of SHR0302 (also known as ARQ-250) as a function of pH in a phosphate buffer system. Figure 1 shows that the solubility of SHR0302 in water decreases as the pH level increases. Figure 1 further suggests that in samples with low pH, SHR0302 stays in solution, but samples with high pH may have solubility issues for SHR0302.

[0105] [000124] Example 5 [000125] The solubility of SHR0302 in water was determined at varying pH values ​​in various buffer systems. Figure 2 shows the concentration of SHR0302 in water (μg / mL) as a function of pH in two phosphate and citrate buffer systems. Figure 2 shows that the solubility of SHR0302 in water decreases as the pH level increases. Figure 2 further suggests that in samples with low pH, SHR0302 stays in solution, but samples with high pH may have solubility issues with SHR0302.

[0106] [000126] Example 6 [000127] The pharmaceutical compositions described in Table 18 were prepared:

[0107] [Table 18]

[0108] [000129] Example 7 [000130] IVPT results comparing prototype SHR0302 formulations with and without Laureth-4 used human cadaver skin excised by a dermatologist to a target thickness of 500 microns, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto a vertical Franz cell with a diffusion area of ​​0.503 cm2 (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of active substance in the receptor fluid (average of 4 replicates) was determined using LC / MS / MS.

[0109] [000131] The results of this experiment (reported as cumulative SHR0302 (ng / mL) in receptor fluid) are shown in Table 19 and depicted in Figure 3. The addition of laureth-4 to topical formulations containing DMSO demonstrated a surprising and significant increase in skin penetration compared to nearly identical formulations without laureth-4. These results demonstrate the efficacy of laureth-4 as a skin penetration enhancer in topical formulations. Formulations #1 and #2 from Example 4 formulated for IVPT testing were formulated at a pH of 5.5-5.9.

[0110] [Table 19]

[0111] [000133] Example 8 [000134] The pharmaceutical compositions described in Table 20 were prepared:

[0112] [Table 20]

[0113] [000136] Example 9 [000137] IVPT results comparing prototype SHR0302 formulations used human cadaver skin excised by a dermatophor to a target thickness of 500 microns, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto a vertical Franz cell with a diffusion area of ​​0.503 cm2 (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% BSA in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). Appearance of active substance in the receptor fluid (average of 4 replicates) was determined using LC / MS / MS.

[0114] [000138] The results of this experiment (reported as cumulative SHR0302 (ng / mL) in the receptor fluid) are shown in Table 21 and depicted in Figure 5. The addition of laureth-4 to topical formulations containing NMP demonstrated a surprising and significant increase in skin penetration compared to nearly identical formulations with minimal amounts of laureth-4. These results demonstrate the efficacy of laureth-4 as a skin penetration enhancer in topical formulations. Formulations #3, #4, and #5 from Example 6 formulated for IVPT testing were formulated at a pH of 5.5-5.9.

[0115] [Table 21]

[0116] [000140] Example 10 [000141] Pharmaceutical compositions were prepared having the following compositions as set forth in Table 22:

[0117] [Table 22]

[0118] [000143] Example 11 [000144] IVPT results comparing the prototype SHR0302 formulation used human cadaver skin excised by a dermatophor to a target thickness of 500 microns, which was received frozen from a US tissue bank and stored at -20°C until use. Skin was cut into 0.503 cm 2 The samples were loaded onto vertical Franz cells with a diffusion area of ​​1.5 mm (diameter 8 mm) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32° C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor fluid (average of 4 replicates) was determined using LC / MS / MS.

[0119] [000145] The results of this experiment (reported as cumulative SHR0302 (ng / mL) in the receptor fluid) are shown in Table 23 and depicted in Figure 5. The addition of laureth-4 to a topical formulation containing a 1:1:1 ratio of DMSO:DMI:DEGEE demonstrated a surprising and significant increase in skin penetration compared to an almost identical formulation without laureth-4. These results demonstrate the efficacy of laureth-4 as a skin penetration enhancer in topical formulations.

[0120] [Table 23]

[0121] [000147] Example 12 [000148] The pharmaceutical compositions described in Table 24 were prepared:

[0122] [Table 24]

[0123] [000150] Example 13 [000151] IVPT results comparing the prototype SHR0302 formulation used human cadaver skin excised by a dermatome to a target thickness of 500 microns, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto a vertical Franz cell with a diffusion area of ​​0.503 cm2 (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of active substance in the receptor fluid (average of 4 replicates) was determined using LC / MS / MS.

[0124] [000152] The results of this experiment (reported as cumulative SHR0302 (ng / mL) in the receptor fluid) are shown in Table 25 and depicted in Figure 6. The addition of laureth-4 to a topical formulation containing a 1:1:1 ratio of DMSO:DMI:DEGEE demonstrated a surprising and significant increase in skin penetration compared to an almost identical formulation without laureth-4. These results demonstrate the efficacy of laureth-4 as a skin penetration enhancer in topical formulations.

[0125] [Table 25]

[0126] [000154] Example 14 [000155] The pharmaceutical compositions described in Table 26 were prepared:

[0127] [Table 26]

[0128] [000157] Example 15 [000158] IVPT results comparing the prototype SHR0302 formulation used human cadaver skin excised by a dermatophor to a target thickness of 500 microns, which was received frozen from a US tissue bank and stored at -20°C until use. Skin was cut into 0.503 cm 2 The samples were loaded onto vertical Franz cells with a diffusion area of ​​1.5 mm (diameter 8 mm) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32° C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor fluid (average of 4 replicates) was determined using LC / MS / MS.

[0129] [000159] The results of this experiment (reported as cumulative SHR0302 (ng / mL) in the receptor fluid) are shown in Table 27 and depicted in Figure 7. The addition of laureth-4 to a topical formulation containing DMSO demonstrated a surprising and significant increase in skin penetration compared to an almost identical formulation without laureth-4. These results demonstrate the efficacy of laureth-4 as a skin penetration enhancer in topical formulations.

[0130] [Table 27]

[0131] [000161] Example 16 [000162] The pharmaceutical compositions described in Table 28 were prepared:

[0132] [Table 28]

[0133] [000164] Formulation #12 was prepared as follows: 38.93 grams of purified water was placed in the main manufacturing vessel. 0.50 grams of monosodium phosphate (anhydrous) was added to the water in the main manufacturing vessel and mixed until a clear solution was obtained. In a separate vessel labeled "Part B", 10.04 grams of dimethyl sulfoxide, 10.16 grams of diethylene glycol monoethyl ether (Transcutol P®), and 10.14 grams of dimethyl isosorbide were blended together. Two preservatives (0.10 grams of methylparaben and 0.021 grams of propylparaben) and 0.62 grams of the JAK inhibitor SHR0302 were added to "Part B" and stirred until completely dissolved. The entire contents of the vessel labeled "Part B" were added to the main manufacturing vessel and mixed until a clear solution was obtained. Polysorbate 60 (10.15 grams) was added to the main manufacturing vessel and mixed to form a cloudy, viscous liquid. Hydroxypropylcellulose (0.51 grams) was added to the main manufacturing vessel and mixed to form a cloudy viscous liquid. In a separate vessel labeled "Part E", 10.15 grams of white petrolatum, 10.16 grams of Crodafos™ CES, and 4.0 grams of Laureth-4 were combined and heated to 66°C. The main manufacturing vessel was heated to 68°C. Using a homogenizer (25 mm head, set at 10,230 rpm), the entire contents of "Part E" were added to the main manufacturing vessel and homogenized for 5 minutes. Dimethicone (1.01 grams) was added to the main manufacturing vessel and homogenized for an additional 2 minutes. Purified water (0.76 grams) was added in an amount sufficient to bring the batch to 100%.

[0134] [000165] Formulation #13 was prepared as follows: 38.63 grams of purified water was placed in the main manufacturing vessel. Glycerin (5.1 grams) and 0.50 grams of monosodium phosphate (anhydrous) were added to the water in the main manufacturing vessel and mixed until a clear solution was obtained. Xanthan gum (0.2 grams) was added to the main manufacturing vessel and mixed for 59 minutes. In a separate vessel labeled "Part D", 10.08 grams of dimethyl sulfoxide, 10.10 grams of diethylene glycol monoethyl ether (Transcutol P®), 10.06 grams of dimethyl isosorbide, 0.10 grams of methylparaben, 0.020 grams of propylparaben, 0.052 grams of butylhydroxytoluene, and 0.62 grams of the JAK inhibitor SHR0302 were combined and mixed until a clear solution was formed. In a third separate container labeled "Part C", 5.15 grams of polyethylene (2) stearyl ether, 5.06 grams of polyethylene (21) stearyl ether, 5.06 grams of PPG 15 stearyl ether, 6.10 grams of cetostearyl alcohol, and 4.06 grams of laureth-4 were combined and heated to 72°C. The main manufacturing vessel was heated to 74°C. Using a homogenizer (25 mm head, set at 9800 rpm), the entire contents of "Part C" were added to the main manufacturing vessel and homogenized for 3 minutes. While homogenization continued, the entire contents of "Part D" were slowly added to the main manufacturing vessel. The total homogenization time was 5 minutes. No additional purified water was used in sufficient quantity to bring the batch to 100% for this particular batch.

[0135] [000166] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will recognize that modifications and substitutions can be made to the basic invention description.

Claims

1. A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302 and having a pH of less than 4.

6.

2. 10. The topical pharmaceutical composition of claim 1 having a pH greater than 3.8 and less than 4.

6.

3. 10. The topical pharmaceutical composition of claim 1, having a pH between about 3.8 and about 4.

2.

4. 10. The topical pharmaceutical composition of claim 1, comprising SHR0302 in an amount of about 0.1 to about 1.0% w / w.

5. 10. The topical pharmaceutical composition of claim 1, further comprising laureth-4.

6. 6. The topical pharmaceutical composition of claim 5, wherein laureth-4 is present in an amount of about 0.5 to about 5% w / w.

7. 10. The topical pharmaceutical composition of claim 1, wherein the composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment.

8. 10. The topical pharmaceutical composition of claim 1, which inhibits crystal formation for 8 months at controlled room temperature.

9. A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302 and about 25% w / w dimethyl sulfoxide.

10. 10. The topical pharmaceutical composition of claim 9, comprising SHR0302 in an amount of about 0.1 to about 1.0% w / w.

11. 10. The topical pharmaceutical composition of claim 9, further comprising laureth-4.

12. 10. The topical pharmaceutical composition of claim 9, wherein laureth-4 is present in an amount of about 0.5 to about 5% w / w.

13. 10. The topical pharmaceutical composition of claim 9, wherein the composition is selected from the group consisting of a cream, a lotion, an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a gel, a hydrophilic ointment, or a hydrophobic ointment.

14. A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302 and about 20% to about 30% w / w dimethyl sulfoxide, which inhibits crystal formation for six months at controlled room temperature.

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