Topical pharmaceutical compositions comprising 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4,4-dimethylpent-2-enenitrile

Abstract

Disclosed herein are, for example, topical pharmaceutical compositions comprising (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I)) for application to the skin of a subject, methods of making the topical pharmaceutical compositions, and methods of using the topical pharmaceutical compositions, for example, for treating a variety of skin disorders.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 958,616, filed January 8, 2020, and U.S. Provisional Application No. 63 / 003,536, filed April 1, 2020, the contents of each of which are incorporated by reference herein in their entirety.

[0002] The present disclosure relates to topical pharmaceutical compositions comprising 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I), also known as PRN473) or a pharmaceutically acceptable salt thereof, and methods of using the topical pharmaceutical compositions, e.g., to treat various skin disorders.

[0003] Compound (I) is an inhibitor of Bruton’s tyrosine kinase (BTK). The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B-cell related hematological cancers (e.g., non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, pemphigus, IBD, lupus, and asthma).

[0004] Compound (I), pharmaceutically acceptable salts thereof, and various solid forms of any of the foregoing can inhibit BTK and are useful in treating disorders and conditions mediated by BTK activity, including various skin disorders. Compound (I) is disclosed as, e.g., Compound 125A / 125B in Table 1 of WO2012 / 158764 and has the following structure:

[0005]

[0006] wherein *C is a center of stereochemistry.

[0007] Topical pharmaceutical compositions are useful in treating various skin disorders. These formulations enable the topical delivery of active pharmaceutical ingredients (APIs), potentially increasing efficacy and reducing side effects associated with systemic administration of the APIs. However, many active pharmaceutical ingredients are difficult to formulate as suspensions or solutions (e.g., gels, ointments, or creams) suitable for application to the skin of patients with skin disorders. Illustratively, some APIs exhibit insufficient chemical and physical stability in topical formulations, reducing their shelf life and safety.

[0008] Stable topical formulations can extend shelf life and provide better chemical and physical stability, and in some embodiments, provide better efficacy, particularly in the treatment of skin disorders using BTK inhibitors such as Compound (I). Thus, there is a need in the art for stable topical formulations comprising Compound (I), or a pharmaceutically acceptable salt thereof. Such formulations are useful in the treatment of skin disorders, including but not limited to, pemphigus vulgaris, pemphigus foliaceus, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, discoid lupus, atopic dermatitis, bullous pemphigoid, drug-related skin reactions, chronic idiopathic urticaria, chronic spontaneous urticaria, symptomatic dermographism, alopecia, alopecia areata, vitiligo, pyoderma gangrenosum, pemphigoid gestationis, epidermolysis bullosa acquisita, Steven Johnson Syndrome, TEN toxic epidermal necrolysis, drug eruptions, folliculitis decalvans, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rhinophyma, rhinophyma erythema, papulopustular rhinophyma, neutrophilic dermatosis, chronic kidney disease-related pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and sweet syndrome.

[0009] Disclosed herein are novel topical pharmaceutical compositions comprising Compound (I), or a pharmaceutically acceptable salt thereof, and methods of using and making the topical pharmaceutical compositions. In some embodiments, the topical pharmaceutical compositions are used to treat a subject having a skin disorder, for example, by applying the composition to at least a portion of the subject’s skin.

[0010] In some embodiments, the present disclosure provides a topical pharmaceutical composition for application to the skin of a subject, the topical pharmaceutical composition comprising:

[0011] a compound selected from the group consisting of the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4- dimethylpent-2-enonitrile (Compound (I)), or a pharmaceutically acceptable salt of any of the foregoing; and

[0012] at least one pharmaceutically acceptable excipient,

[0013] wherein the composition is in a form selected from the group consisting of a suspension, a solution, and combinations thereof.

[0014] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is micronized. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, has a particle size distribution D 90 .

[0015] In some embodiments, the compound is Compound (I).

[0016] In some embodiments, the compound is an amorphous form of Compound (I).

[0017] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0018] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile.

[0019] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0020] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0021] In some embodiments, the topical pharmaceutical composition is in the form of a suspension.

[0022] In some embodiments, the topical pharmaceutical composition is in the form selected from the group consisting of a gel, an ointment, and a cream.

[0023] In some embodiments, the present disclosure provides a topical pharmaceutical composition for application to the skin of a subject, wherein the topical pharmaceutical composition is in the form of a suspension comprising:

[0024] a compound selected from the group consisting of the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I)), or a pharmaceutically acceptable salt thereof; and

[0025] at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient comprises:

[0026] a vehicle;

[0027] a humectant and / or emollient;

[0028] a wetting agent; and

[0029] a thickening agent.

[0030] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is micronized. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, has a particle size distribution D 90 .

[0031] In some embodiments, the compound is Compound (I).

[0032] In some embodiments, the compound is an amorphous form of Compound (I).

[0033] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0034] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enenitrile.

[0035] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0036] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enenitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0037] In some embodiments, the vehicle, alone or in combination, does not substantially solubilize Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the vehicle is selected from the group consisting of water, mineral oil, and combinations thereof.

[0038] In some embodiments, the humectant and / or the emollient retain Compound (I), or a pharmaceutically acceptable salt thereof, on the skin, e.g., retain an amount of Compound (I), or a pharmaceutically acceptable salt thereof, on at least a portion of the skin of a subject. The humectant and / or emollient comprises at least one component selected from the group consisting of propylene glycol, glycerin, medium chain triglycerides, and combinations of any of the foregoing.

[0039] In some embodiments, the wetting agent keeps Compound (I), or a pharmaceutically acceptable salt thereof, from agglomerating, e.g., the wetting agent reduces the amount of agglomeration relative to a substantially similar formulation without the wetting agent. In some embodiments, the wetting agent comprises at least one component selected from the group consisting of polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof.

[0040] In some embodiments, the thickening agent comprises at least one component selected from the group consisting of cross-linked polyacrylic acid polymer (Carbopol®), hydrogenated castor oil, microcrystalline wax, and combinations of any of the foregoing.

[0041] In some embodiments, the at least one pharmaceutically acceptable excipient comprises:

[0042] a vehicle selected from the group consisting of water, mineral oil, and combinations thereof;

[0043] a humectant and / or emollient comprising at least one component selected from the group consisting of propylene glycol, glycerin, medium chain triglycerides, and combinations of any of the foregoing;

[0044] a wetting agent comprising at least one component selected from the group consisting of polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof; and

[0045] a thickening agent comprising at least one component selected from the group consisting of cross-linked polyacrylic acid polymer (Carbopol®), hydrogenated castor oil, microcrystalline wax, and combinations of any of the foregoing.

[0046] In some embodiments, the topical pharmaceutical composition comprises:

[0047] about 0.1% to about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0048] about 0.1% to about 20% by weight of medium chain triglycerides;

[0049] about 0.1% to about 20% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); ​​

[0050] From about 0.1% to about 20% by weight of natural glycerin;

[0051] Propylene glycol, by weight, approximately 0.1% to approximately 45%;

[0052] Methylparaben, by weight, about 0.01% to about 0.5%;

[0053] Propylparaben by weight: about 0.01% to about 0.2%;

[0054] Crosslinked polyacrylic acid polymer, by weight, from about 0.1% to about 4%;

[0055] A certain amount of approximately 10% (w / w) sodium hydroxide solution; and

[0056] Add enough water to a volume of 100.

[0057] In some embodiments, the crosslinked polyacrylic acid polymer is 980 polymer.

[0058] In some embodiments, the amount of 10% (w / w) sodium hydroxide solution is sufficient to adjust the pH of the topical pharmaceutical composition to a value in the range of about 3.5 to about 8.5.

[0059] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of the composition.

[0060] In some embodiments, the compound is compound (I).

[0061] In some embodiments, the compound is an amorphous form of compound (I).

[0062] In some embodiments, the compound is a crystal form of compound (I). In some embodiments, the compound is a crystal form (I) of compound (I). In some embodiments, the compound is a crystal form (II) of compound (I).

[0063] In some embodiments, at least about 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile.

[0064] In some embodiments, at least about 95% of compound (I) by weight is the (E) isomer.

[0065] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enonitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0066] In some embodiments, the topical pharmaceutical composition comprises:

[0067] about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof;

[0068] about 2% by weight of a medium chain triglyceride;

[0069] about 2% by weight of a polyethoxylated sorbitan and oleic acid (Polysorbate 80);

[0070] about 5% by weight of a natural glycerin;

[0071] about 10% by weight of propylene glycol;

[0072] about 0.20% by weight of methyl paraben;

[0073] about 0.05% by weight of propyl paraben;

[0074] about 0.75% by weight of a cross-linked polyacrylic acid polymer;

[0075] an amount of a 10% (w / w) sodium hydroxide solution; and

[0076] water q.s. to 100.

[0077] In some embodiments, the cross-linked polyacrylic acid polymer is 980 polymer.

[0078] In some embodiments, the amount of the 10% (w / w) sodium hydroxide solution is sufficient to adjust the pH of the topical pharmaceutical composition to a value in the range of about 4.5 to about 5.5.

[0079] In some embodiments, the topical pharmaceutical composition is in the form of a gel.

[0080] In some embodiments, the compound is Compound (I).

[0081] In some embodiments, the compound is an amorphous form of Compound (I).

[0082] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0083] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0084] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0085] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0086] In some embodiments, the topical pharmaceutical composition comprises:

[0087] about 0.1% to about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0088] about 0.1% to about 20% by weight of a medium chain triglyceride;

[0089] about 0.1% to about 20% by weight of a microcrystalline wax;

[0090] about 0.1% to about 10% by weight of hydrogenated castor oil;

[0091] about 0.01% to about 10% by weight of dimethicone; and

[0092] a sufficient amount to 100 of white mineral oil.

[0093] In some embodiments, the dimethicone has a viscosity of 12500 centistokes (cSt).

[0094] In some embodiments, the white mineral oil is Kaydol white mineral oil.

[0095] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of the composition.

[0096] In some embodiments, the compound is Compound (I).

[0097] In some embodiments, the compound is an amorphous form of Compound (I).

[0098] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0099] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enenitrile.

[0100] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0101] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enenitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0102] In some embodiments, the topical pharmaceutical composition comprises:

[0103] about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0104] about 2% by weight of a medium chain triglyceride;

[0105] about 2% to about 20% by weight of a polyethoxylated sorbitan and oleic acid (Polysorbate 80);

[0106] about 5% by weight of a natural glycerin;

[0107] about 10% by weight of propylene glycol;

[0108] about 0.20% by weight of methyl paraben;

[0109] about 0.05% by weight of propyl paraben;

[0110] about 0.75% by weight of a cross-linked polyacrylic acid polymer;

[0111] an amount of a 10% (w / w) sodium hydroxide solution; and

[0112] water q.s. 100.

[0113] In some embodiments, the cross-linked polyacrylic acid polymer is 980 polymer.

[0114] In some embodiments, the amount of the 10% (w / w) sodium hydroxide solution is sufficient to adjust the pH of the topical pharmaceutical composition to a value in the range of about 4.5 to about 5.5.

[0115] In some embodiments, the topical pharmaceutical composition is in the form of a gel.

[0116] In some embodiments, the compound is Compound (I).

[0117] In some embodiments, the compound is an amorphous form of Compound (I).

[0118] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0119] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enonitrile.

[0120] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0121] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enonitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0122] In some embodiments, the topical pharmaceutical composition comprises:

[0123] about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof;

[0124] about 0.1% to about 20% by weight of a medium chain triglyceride;

[0125] about 0.1% to about 20% by weight of a microcrystalline wax;

[0126] about 0.1% to about 10% by weight of hydrogenated castor oil;

[0127] about 0.01% to about 10% by weight of dimethicone; and

[0128] a sufficient amount to 100 of mineral oil.

[0129] In some embodiments, the dimethicone has a viscosity of 12500 centistokes (cSt).

[0130] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is present in the topical pharmaceutical composition in an amount of about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of the composition.

[0131] In some embodiments, the compound is Compound (I).

[0132] In some embodiments, the compound is an amorphous form of Compound (I).

[0133] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0134] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile.

[0135] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0136] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0137] In some embodiments, the topical pharmaceutical composition comprises:

[0138] about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0139] Approximately 10% by weight of medium-chain triglycerides;

[0140] Approximately 5% microcrystalline wax by weight;

[0141] Approximately 2% hydrogenated castor oil by weight;

[0142] Approximately 3% by weight of dimethylpolysiloxane; and

[0143] Mineral oil in sufficient quantity up to 100.

[0144] In some embodiments, the topical pharmaceutical composition is in the form of an ointment.

[0145] In some embodiments, the compound is compound (I).

[0146] In some embodiments, the compound is an amorphous form of compound (I).

[0147] In some embodiments, the compound is a crystal form of compound (I). In some embodiments, the compound is a crystal form (I) of compound (I). In some embodiments, the compound is a crystal form (II) of compound (I).

[0148] In some embodiments, at least about 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile.

[0149] In some embodiments, at least about 95% of compound (I) by weight is the (E) isomer.

[0150] In some embodiments, at least about 95% by weight of compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile and at least about 95% by weight of compound (I) is (E) isomer.

[0151] In some embodiments, this disclosure provides a topical pharmaceutical composition in cream form for application to the skin of a subject, the composition comprising:

[0152] About 0.01% to about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof;

[0153] Oleic acid, by weight, is approximately 1% to approximately 45%.

[0154] about 0.1% to about 20% by weight of glycerin;

[0155] about 0.1% to about 45% by weight of propylene glycol;

[0156] about 0.1% to about 5% by weight of benzyl alcohol;

[0157] about 0.1% to about 5% by weight of acrylic acid and acrylic acid C 10 -C 30 alkyl ester crosslinked with allyl pentaerythritol (Pemulen TM polymer);

[0158] a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to about 3.5 to about 8.5; and

[0159] water q.s. 100.

[0160] In some embodiments, the acrylic acid and acrylic acid C 10 -C 30 alkyl ester crosslinked with allyl pentaerythritol (Pemulen TM polymer) is Permulen TM TR-1.

[0161] In some embodiments, the compound is Compound (I).

[0162] In some embodiments, the compound is an amorphous form of Compound (I).

[0163] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0164] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enonitrile.

[0165] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0166] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enonitrile and at least about 95% by weight of Compound (I) is the (E) isomer.

[0167] In some embodiments, the topical pharmaceutical composition in the form of a cream comprises:

[0168] about 0.2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0169] about 25% by weight of oleic acid;

[0170] about 5% by weight of glycerin;

[0171] about 5% by weight of propylene glycol;

[0172] about 1% by weight of benzyl alcohol;

[0173] about 0.75% by weight of Pemulen TM TR-1 polymer;

[0174] an amount of a 10% (w / w) sodium hydroxide solution; and

[0175] water q.s. 100.

[0176] In some embodiments, the amount of the 10% (w / w) sodium hydroxide solution is sufficient to adjust the pH of the topical pharmaceutical composition to a value in the range of about 4.5 to about 5.5.

[0177] In some embodiments, the compound is Compound (I).

[0178] In some embodiments, the compound is an amorphous form of Compound (I).

[0179] In some embodiments, the compound is a crystalline form of Compound (I). In some embodiments, the compound is crystalline Form (I) of Compound (I). In some embodiments, the compound is crystalline Form (II) of Compound (I).

[0180] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enonitrile.

[0181] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0182] In some embodiments, at least about 95% by weight of Compound (I) is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l- carbonyl)-4,4-dimethylpent-2-enonitrile and at least about 95% by weight of Compound (I) is the (E) isomer. BRIEF DESCRIPTION OF DRAWINGS

[0183] FIG. 1 shows an X-ray powder diffraction pattern of crystalline Form (I) of Compound (I) (referred to herein as Form (I)), showing degrees 2 theta (2-Theta) on the X-axis and relative intensity on the Y-axis.

[0184] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermogram of crystalline Form (I) of Compound (I).

[0185] FIG. 3 shows an X-ray powder diffraction pattern of crystalline Form (II) of Compound (I) (referred to herein as Form (II)), showing degrees 2 theta (2-Theta) on the X-axis and relative intensity on the Y-axis.

[0186] FIG. 4 shows a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermogram of crystalline Form (II) of Compound (I).

[0187] FIG. 5A and FIG. 5B depict IgG (FcgR) inhibition results in a rat Arthus (macrophage / neutrophil) model employing a three-day administration of a gel formulation comprising Compound (I).

[0188] FIG. 6A and FIG. 6B depict IgG (FcgR) inhibition results in a rat Arthus (macrophage / neutrophil) model employing a one-day administration of a soft paste formulation comprising Compound (I).

[0189] FIG. 7A and FIG. 7B depict IgG (FcgR) inhibition results in a rat Arthus (macrophage / neutrophil) model employing a three-day administration of a soft paste formulation comprising Compound (I).

[0190] Figure 8 graphically depicts the average amount (ng) of Compound (I) delivered to the epidermis and dermis 24 h after application of three 2% formulation variants using crystalline Form (I) of Compound (I), amorphous Compound (I), and crystalline Form (II) of Compound (I). Data points represent the cumulative amount of Compound (I) from 5 replicates and 1 donor (n = 4-5). Error bars represent one standard deviation. Statistical outliers were removed.

[0191] Definitions:

[0192] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.

[0193] As used herein, the term “about” or “approximately” means approximately, around, roughly, or in the ballpark of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values by a margin of 5%. Generally, the term “about” is used herein to modify a value to be within 5% above and below the stated value.

[0194] As used herein, “Compound (I)” refers to the (E) isomer, the (Z) isomer, or a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile, or a mixture of the (R) and (S) enantiomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2-enenitrile, which has the structure:

[0195]

[0196] wherein *C is a center of stereochemistry.

[0197] When Compound (I) is represented as (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, it can contain less than 1% by weight of the corresponding (S) enantiomer as an impurity or less than 5% by weight of the corresponding (S) enantiomer as an impurity. Thus, when Compound (I) is represented as a mixture of (R) and (S) enantiomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, the amount of (R) or (S) enantiomer in the mixture is greater than 1% by weight. Similarly, when Compound (I) is represented as the (E) isomer, it can contain less than 1% by weight of the corresponding (Z) isomer as an impurity. Thus, when Compound (I) is represented as a mixture of (E) and (Z) isomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, the amount of (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0198] In some embodiments, Compound (I) is a mixture of (R) and (S) enantiomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0199] In some embodiments, Compound (I) is substantially (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4- dimethylpent-2-enenitrile. In some embodiments, Compound (I) is at least about 75% by weight, e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, Compound (I) is at least about 95% by weight (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0200] In this document, Compound (I) can be referred to as a "drug," "active agent," "therapeutically active agent," or "API."

[0201] As used herein, the term "solution" in reference to the form of a topical pharmaceutical composition includes such emulsions in which the API is dissolved in the vehicle.

[0202] As used herein, the term "suspension" in reference to the form of a topical pharmaceutical composition includes such formulations in which the API is dispersed / suspended in the vehicle.

[0203] As used herein, "substantially pure" in connection with geometric isomeric forms refers to a compound, such as Compound (I), in which greater than 70% by weight or mole of the compound exists in a given isomeric form. For example, the phrase "Compound (I) is substantially pure (E) isomer" refers to Compound (I) having at least 70% by weight or mole of the (E) isomeric form, and the phrase "Compound (I) is substantially pure (Z) isomer" refers to Compound (I) having at least 70% by weight or mole of the (Z) isomeric form. In some embodiments, at least 80% by weight or mole of Compound (I) is in the (E) form, or at least 80% by weight or mole of Compound (I) is in the (Z) form. In some embodiments, at least 85% by weight or mole of Compound (I) is in the (E) form, or at least 85% by weight or mole of Compound (I) is in the (Z) form. In some embodiments, at least 90% by weight or mole of Compound (I) is in the (E) form, or at least 90% by weight or mole of Compound (I) is in the (Z) form. In some embodiments, at least 95% by weight or mole of Compound (I) is in the (E) form, or at least 95% by weight or mole of Compound (I) is in the (Z) form. In some embodiments, at least 97% by weight or mole or 98% by weight or mole of Compound (I) is in the (E) form, or at least 97% by weight or mole or 98% by weight or mole of Compound (I) is in the (Z) form. In some embodiments, at least 99% by weight or mole of Compound (I) is in the (E) form, or at least 99% by weight or mole of Compound (I) is in the (Z) form. The relative amounts of (E) and (Z) isomers in a solid mixture can be determined according to standard methods and techniques known in the art.

[0204] In some embodiments, Compound (I) is a mixture of (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carbonyl)-4,4-dimethylpent-2- enenitrile.

[0205] In some embodiments, Compound (I) is the substantially pure (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, Compound (I) is at least about 75% by weight, e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, of the (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile. In some embodiments, Compound (I) is at least about 95% by weight of the (E) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0206] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic salt forms of the compounds of the disclosure. Pharmaceutically acceptable salts of Compound (I) of the disclosure include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are those disclosed in, for example, Berge, S.M. et al. J. Pharma. Sci. 66: 1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in this article include: acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isothionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methylnitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate / diphosphate; polygalacturonate; salicylate; stearate; subacetate; succinate; sulfate; tannate; tartrate; teociate; triethiodide; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum; calcium; lithium; magnesium; potassium; sodium; and zinc.

[0207] Non-limiting examples of pharmaceutically acceptable salts derived from suitable acids include: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable, non-limiting examples of salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate-heptanoate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Non-limiting examples of pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0208] As used herein, “pharmaceuticalally acceptable excipient” means a carrier or excipient that can be used to prepare a pharmaceutical composition. For example, pharmaceutically acceptable excipients are generally safe and include carriers and excipients that are generally considered pharmaceutically acceptable for mammals.

[0209] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given condition, symptom, or disorder or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0210] As used herein, the term "treat," "treating," or "treatment" when used in connection with a disorder or condition includes any effect that results in an improvement in the disorder or condition, e.g., reduction, lessening, modulation, alleviation, or elimination. Improvements in any symptoms of the disorder or condition or reduction in severity thereof can be readily assessed according to standard methods and techniques known in the art.

[0211] As used herein, "mammal" refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0212] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0213] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also known as thermogravimetric) analysis.

[0214] As used herein, particle size is expressed in terms of particle size distribution (PSD) (e.g., D 10 , D 50 , and D 90 values). Particle size distribution can be affected by the hydration state of the particles. Illustratively, a wet particle size distribution can be different from a dry particle size distribution, and accordingly have different characteristic D 10 , D 50 , and D 90 values.

[0215] As will be appreciated by one of ordinary skill in the art, particle size and particle size distribution of a powder can be measured using various techniques known in the art, such as laser diffraction. In some embodiments, the particle size distribution of a solid form of Compound (I) is expressed using values (e.g., D 10 , D 50 , and D 90 values) measured by laser diffraction.

[0216] As used herein, "D 50 " refers to the median diameter of a particle size distribution.

[0217] As used herein, "D 10 " refers to the particle size at which 10% of the population of particles have a particle size of D 10 or less.

[0218] As used herein, "D 90 " refers to the particle size at which 90% of the population of particles have a particle size of D 90 or less.

[0219] Example Embodiment 1:

[0220] Non-limiting embodiments of the present disclosure include:

[0221] 1. A topical pharmaceutical composition for application to the skin of a subject, the pharmaceutical composition comprising:

[0222] a compound selected from the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enonitrile (Compound (I)), or a pharmaceutically acceptable salt thereof; and

[0223] at least one pharmaceutically acceptable excipient,

[0224] wherein the composition is in a form selected from the group consisting of a suspension, a solution, and combinations thereof.

[0225] 2. The topical pharmaceutical composition according to embodiment 1, wherein the composition is in the form of a suspension.

[0226] 3. The topical pharmaceutical composition according to embodiment 1, wherein the composition is a formulation selected from the group consisting of a gel, an ointment, and a cream.

[0227] 4. The topical pharmaceutical composition according to embodiment 2, wherein the composition comprises:

[0228] a compound selected from the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enonitrile (Compound (I)), or a pharmaceutically acceptable salt thereof; and

[0229] the at least one pharmaceutically acceptable excipient comprises:

[0230] a vehicle that individually or in combination does not substantially solubilize Compound (I) or a pharmaceutically acceptable salt thereof;

[0231] a humectant and / or an emollient to retain Compound (I) or a pharmaceutically acceptable salt thereof on the skin;

[0232] a wetting agent to keep Compound (I) or a pharmaceutically acceptable salt thereof from deagglomeration; and

[0233] a thickening agent.

[0234] 5. The topical pharmaceutical composition according to embodiment 4, wherein Compound (I) or a pharmaceutically acceptable salt of Compound (I) is micronized.

[0235] 6. The topical pharmaceutical composition according to embodiment 4, wherein Compound (I) or a pharmaceutically acceptable salt of Compound (I) has a particle size distribution D 90 .

[0236] 7. The topical pharmaceutical composition according to any one of embodiments 4-6, wherein:

[0237] the vehicle is selected from the group consisting of water, mineral oil, and combinations thereof;

[0238] the humectant and / or emollient comprises at least one of propylene glycol, glycerin, medium chain triglycerides, and combinations thereof;

[0239] the wetting agent comprises at least one of polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof; and

[0240] the thickening agent comprises at least one of cross-linked polyacrylic acid polymer ( Carbopol®), hydrogenated castor oil, microcrystalline wax, and combinations thereof.

[0241] 8. The topical pharmaceutical composition according to any one of embodiments 4-7, wherein the composition comprises:

[0242] about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof;

[0243] about 0.1% to about 20% by weight of medium chain triglycerides;

[0244] about 0.1% to about 20% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80);

[0245] about 0.1% to about 20% by weight of natural glycerin;

[0246] about 0.1% to about 45% by weight of propylene glycol;

[0247] about 0.01% to about 0.5% by weight of methyl paraben;

[0248] about 0.01% to about 0.2% by weight of propyl paraben;

[0249] about 0.1% to about 4% by weight of cross-linked polyacrylic acid polymer ( Carbopol® 980 polymer);

[0250] a 10% (w / w) sodium hydroxide solution in an amount to adjust the pH to about 3.5 to about 8.5; and

[0251] water q.s. to 100.

[0252] 9. The topical pharmaceutical composition according to embodiment 8, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of 0.1%, 0.5%, 2%, or 5% or 10% by weight of the composition.

[0253] 10. The topical pharmaceutical composition according to embodiment 8 or 9, wherein the composition comprises:

[0254] about 0.1%, 0.5%, 2%, 5%, or 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0255] about 2% by weight of a medium chain triglyceride;

[0256] about 2% by weight of a polyethoxylated sorbitan and oleic acid (Polysorbate 80);

[0257] about 5% by weight of a natural glycerin;

[0258] about 10% by weight of propylene glycol;

[0259] about 0.20% by weight of methyl paraben;

[0260] about 0.05% by weight of propyl paraben;

[0261] about 0.75% by weight of a cross-linked polyacrylic acid polymer (Carbopol Ultrez 10®); 980);

[0262] a 10% (w / w) sodium hydroxide solution in an amount to adjust the pH to about 5.0 ± 0.5; and

[0263] water q.s. to 100.

[0264] 11. The topical pharmaceutical composition according to any one of embodiments 8-10, wherein the composition is a gel formulation.

[0265] 12. The topical pharmaceutical composition according to any one of embodiments 4-6, wherein the composition comprises:

[0266] about 0.1% to about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof;

[0267] about 0.1% to about 20% by weight of a medium chain triglyceride;

[0268] about 0.1% to about 20% by weight of a microcrystalline wax;

[0269] about 0.1% to about 10% by weight of hydrogenated castor oil;

[0270] Dimethyl polysiloxane, by weight, from about 0.01% to about 10%; and

[0271] Mineral oil in sufficient quantity up to 100.

[0272] 13. The topical pharmaceutical composition according to embodiment 12, wherein the compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of 0.1%, 0.5%, 2%, 5% or 10% by weight of the composition.

[0273] 14. The topical pharmaceutical composition according to embodiment 12 or 13, wherein the composition comprises:

[0274] About 0.1%, 0.5%, 2%, 5% or 10% by weight of compound (I) or a pharmaceutically acceptable salt thereof;

[0275] Approximately 10% medium-chain triglycerides by weight;

[0276] Approximately 5% microcrystalline wax by weight;

[0277] Approximately 2% hydrogenated castor oil by weight;

[0278] Approximately 3% by weight of dimethylpolysiloxane; and

[0279] Mineral oil in sufficient quantity up to 100.

[0280] 15. The topical pharmaceutical composition according to embodiment 14, wherein the dimethicone has a viscosity of 12,500 centitrate (cSt).

[0281] 16. A topical pharmaceutical composition according to any one of embodiments 12-14, wherein the composition is an ointment formulation.

[0282] 17. A topical pharmaceutical composition in the form of an ointment for application to the skin of a subject, said composition comprising:

[0283] About 0.01% to about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof;

[0284] Oleic acid, by weight, is approximately 1% to approximately 45%.

[0285] Glycerin, approximately 0.1% to approximately 20% by weight;

[0286] Propylene glycol, by weight, approximately 0.1% to approximately 45%;

[0287] benzyl alcohol, by weight, is approximately 0.1% to approximately 5%.

[0288] about 0.1% to about 5% by weight of a high molecular weight copolymer of alkyl ester of acrylic acid and C 10 -C 30 about 0.1% to about 5% by weight of a high molecular weight copolymer of alkyl ester of acrylic acid and C TM polymer);

[0289] an amount of a 10% (w / w) sodium hydroxide solution to adjust the pH to about 3.5 to about 8.5; and

[0290] water q.s. to 100.

[0291] 18. The topical pharmaceutical composition according to embodiment 18, wherein the Permulen TM polymer is Permulen TM TR-1.

[0292] 19. The topical pharmaceutical composition according to embodiment 17 or 18, wherein the composition comprises:

[0293] about 0.2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof;

[0294] about 25% by weight of oleic acid;

[0295] about 5% by weight of glycerin;

[0296] about 5% by weight of propylene glycol;

[0297] about 1% by weight of benzyl alcohol;

[0298] about 0.75% by weight of Permulen TM TR-1 polymer;

[0299] an amount of a 10% (w / w) sodium hydroxide solution to adjust the pH to about 4.5 to about 5.5; and

[0300] water q.s. to 100.

[0301] 20. The topical pharmaceutical composition according to any one of embodiments 1-19, wherein the compound is in free base form (R)-2-(3-(4-amino-3-(2-fluoro-4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4- dimethylpent-2-enoic acid (Compound (I)).

[0302] 21. The topical pharmaceutical composition according to any one of embodiments 1-20, wherein the compound is an amorphous or crystalline form of (R)-2-(3-(4-amino-3-(2-fluoro-4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4- dimethylpent-2-enoic acid (Compound (I)) or a pharmaceutically acceptable salt thereof.

[0303] 22. The topical pharmaceutical composition according to embodiment 21, wherein the crystalline form is crystalline Form I or Form II of the free base (R)-2-(3-(4-amino-3-(2-fluoro-4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4- dimethylpent-2-enoic acid (Compound (I)).

[0304] 23. The topical pharmaceutical composition according to embodiment 21 or 22, wherein at least 95% of the (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enoic acid (Compound (I)) is the (E) isomer.

[0305] 24. A method of treating a skin disorder mediated by Bruton's tyrosine kinase (BTK) in a mammal in need thereof, the method comprising:

[0306] topically administering to the skin of the mammal a topical pharmaceutical composition according to any one of embodiments 1-23.

[0307] 25. A method of treating a skin disorder selected from the group consisting of: pemphigus vulgaris, pemphigus foliaceus, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, discoid lupus, atopic dermatitis, bullous pemphigoid, drug-related skin reactions, chronic idiopathic urticaria, chronic spontaneous urticaria, symptomatic dermographism, alopecia, alopecia areata, vitiligo, pyoderma gangrenosum, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, drug eruptions, folliculitis decalvans, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rhinophyma, rhinophyma erythema, papulopustular rhinophyma, neutrophilic dermatosis, chronic kidney disease-related pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet's syndrome, in a mammal in need thereof, the method comprising:

[0308] topically administering to the skin of the mammal a topical pharmaceutical composition according to any one of embodiments 1-23.

[0309] 26. The method of embodiments 24 or 25, wherein the mammal is a human.

[0310] Example Embodiment 2:

[0311] Non-limiting embodiments of the present disclosure include:

[0312] 1. A pharmaceutical composition comprising:

[0313] at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2- enenitrile and pharmaceutically acceptable salts thereof; and

[0314] at least one pH dependent gelling agent,

[0315] wherein the pharmaceutical composition is in the form of a gel.

[0316] 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises about 0.1% to about 4% by weight of the at least one pH dependent gelling agent.

[0317] 3. The pharmaceutical composition of embodiments 1 or 2, wherein the at least one pH dependent gelling agent is selected from a polymer.

[0318] 4. The pharmaceutical composition of any one of embodiments 1-3, wherein the at least one pH dependent gelling agent is 980 a polymer.

[0319] 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the at least one compound is at least partially suspended in the gel.

[0320] 6. The pharmaceutical composition of any one of embodiments 1-5, wherein the at least one compound is substantially suspended in the gel.

[0321] 7. The pharmaceutical composition of any one of embodiments 1-6, wherein the at least one compound is suspended in the gel.

[0322] 8. The pharmaceutical composition of any one of embodiments 1-7, further comprising at least one emollient or humectant.

[0323] 9. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition comprises about 0.1% to about 65% by weight of the at least one emollient or humectant.

[0324] 10. The pharmaceutical composition according to embodiment 8 or 9, wherein the at least one emollient or humectant is selected from the group consisting of glycerin, propylene glycol, and combinations thereof.

[0325] 11. The pharmaceutical composition according to any one of embodiments 8-10, wherein the at least one emollient or humectant is glycerin and propylene glycol.

[0326] 12. The pharmaceutical composition according to any one of embodiments 1-11, further comprising at least one preservative.

[0327] 13. The pharmaceutical composition according to embodiment 12, wherein the pharmaceutical composition comprises about 0.01% to about 0.7% by weight of the at least one preservative.

[0328] 14. The pharmaceutical composition according to embodiment 12 or 13, wherein the at least one preservative is selected from the group consisting of methyl paraben, propyl paraben, and combinations thereof.

[0329] 15. The pharmaceutical composition according to any one of embodiments 12-14, wherein the at least one preservative is methyl paraben and propyl paraben.

[0330] 16. The pharmaceutical composition according to any one of embodiments 1-15, further comprising at least one lubricant.

[0331] 17. The pharmaceutical composition according to embodiment 16, wherein the pharmaceutical composition comprises about 0.1% to about 20% by weight of the at least one lubricant.

[0332] 18. The pharmaceutical composition according to embodiment 16 or 17, wherein the at least one lubricant is selected from the group consisting of medium chain triglycerides.

[0333] 19. The pharmaceutical composition according to any one of embodiments 1-18, further comprising at least one wetting agent.

[0334] 20. The pharmaceutical composition according to embodiment 19, wherein the pharmaceutical composition comprises about 0.1% to about 20% by weight of the at least one wetting agent.

[0335] 21. The pharmaceutical composition according to embodiment 19 or 20, wherein the at least one wetting agent is polysorbate 80.

[0336] 22. The pharmaceutical composition according to any one of embodiments 1-21, further comprising at least one vehicle.

[0337] 23. The pharmaceutical composition according to embodiment 22, wherein the at least one vehicle is selected from an aqueous solution.

[0338] 24. The pharmaceutical composition according to embodiment 22 or 23, wherein the at least one vehicle is purified water.

[0339] 25. The pharmaceutical composition according to any one of embodiments 1-24, further comprising a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH of the pharmaceutical composition to a value in the range of about 3.5 to about 8.5.

[0340] 26. The pharmaceutical composition according to embodiment 25, wherein the value is in the range of about 4 to about 6.

[0341] 27. The pharmaceutical composition according to embodiment 25 or 26, wherein the value is in the range of about 4.5 to about 5.5.

[0342] 28. The pharmaceutical composition according to any one of embodiments 25-27, wherein the value is about 5.

[0343] 29. The pharmaceutical composition according to embodiment 4, wherein the pharmaceutical composition comprises:

[0344] about 0.1% to about 20% by weight of medium chain triglycerides;

[0345] about 0.1% to about 20% by weight of polysorbate 80;

[0346] about 0.1% to about 20% by weight of glycerin;

[0347] about 0.1% to about 45% by weight of propylene glycol;

[0348] about 0.01% to about 0.5% by weight of methyl paraben;

[0349] about 0.01% to about 0.2% by weight of propyl paraben;

[0350] about 0.1% to about 4% by weight of 980 polymer;

[0351] a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH of the pharmaceutical composition to a value in the range of about 4 to about 6; and

[0352] a sufficient amount of purified water to 100.

[0353] 30. The pharmaceutical composition according to embodiment 29, wherein the pharmaceutical composition comprises:

[0354] about 2% by weight of medium chain triglycerides;

[0355] about 2% by weight of polysorbate 80;

[0356] about 5% by weight of glycerin;

[0357] about 10% by weight of propylene glycol;

[0358] about 0.2% by weight of methyl paraben;

[0359] about 0.05% by weight of propyl paraben;

[0360] about 0.75% by weight of 980 polymer;

[0361] an amount of 10% (w / w) sodium hydroxide solution sufficient to adjust the pH of the pharmaceutical composition to a value in the range of about 4 to about 6; and

[0362] a sufficient amount of purified water to 100.

[0363] 31. A pharmaceutical composition comprising:

[0364] at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl)piperidine- 1 -carbonyl)-4,4-dimethylpent-2- enenitrile and pharmaceutically acceptable salts thereof; and

[0365] at least one saturated hydrocarbon,

[0366] wherein the pharmaceutical composition is in the form of an ointment.

[0367] 32. The pharmaceutical composition according to embodiment 31, wherein the at least one saturated hydrocarbon is selected from mineral oil, hydrogenated castor oil, and combinations thereof.

[0368] 33. The pharmaceutical composition according to embodiment 31 or 32, wherein the at least one saturated hydrocarbon is mineral oil and hydrogenated castor oil.

[0369] 34. The pharmaceutical composition according to embodiment 32 or 33, wherein the mineral oil is selected from white mineral oil.

[0370] 35. The pharmaceutical composition according to any one of embodiments 32-34, wherein the mineral oil is Kaydol white mineral oil.

[0371] 36. The pharmaceutical composition of any one of embodiments 31-35, wherein the at least one compound is at least partially suspended in the ointment.

[0372] 37. The pharmaceutical composition of any one of embodiments 31-36, wherein the at least one compound is substantially suspended in the ointment.

[0373] 38. The pharmaceutical composition of any one of embodiments 31-37, wherein the at least one compound is suspended in the ointment.

[0374] 39. The pharmaceutical composition of any one of embodiments 31-38, further comprising at least one viscosity modifier.

[0375] 40. The pharmaceutical composition of embodiment 39, wherein the pharmaceutical composition comprises about 0.1% to about 20% by weight of the at least one viscosity modifier.

[0376] 41. The pharmaceutical composition of embodiment 39 or 40, wherein the at least one viscosity modifier is microcrystalline wax.

[0377] 42. The pharmaceutical composition of any one of embodiments 31-41, further comprising at least one dispersing agent.

[0378] 43. The pharmaceutical composition of embodiment 42, wherein the pharmaceutical composition comprises about 0.01% to about 30% by weight of the at least one dispersing agent.

[0379] 44. The pharmaceutical composition of embodiment 42 or 43, wherein the at least one dispersing agent is selected from the group consisting of dimethicone, medium-chain triglyceride, and combinations thereof.

[0380] 45. The pharmaceutical composition of any one of embodiments 42-44, wherein the at least one dispersing agent is dimethicone and medium-chain triglyceride.

[0381] 46. The pharmaceutical composition of embodiment 44 or 45, wherein the dimethicone has a viscosity of 12500 centistokes (cSt).

[0382] 47. The pharmaceutical composition of embodiment 32, wherein the pharmaceutical composition comprises:

[0383] about 0.1% to about 20% by weight of medium-chain triglyceride;

[0384] about 0.1% to about 20% by weight of microcrystalline wax;

[0385] about 0.1% to about 10% by weight of hydrogenated castor oil;

[0386] about 0.01% to about 10% by weight of dimethicone; and

[0387] a sufficient amount to 100 of white mineral oil.

[0388] 48. The pharmaceutical composition of embodiment 47, wherein the pharmaceutical composition comprises:

[0389] about 10% by weight of medium chain triglycerides;

[0390] about 5% by weight of microcrystalline wax;

[0391] about 2% by weight of hydrogenated castor oil;

[0392] about 3% by weight of dimethicone; and

[0393] a sufficient amount to 100 of white mineral oil.

[0394] 49. A pharmaceutical composition comprising:

[0395] at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl)piperidine- 1 -carbonyl)-4,4-dimethylpent-2- enenitrile and pharmaceutically acceptable salts thereof; and

[0396] at least one solubilizing agent,

[0397] wherein the pharmaceutical composition is in the form of a cream.

[0398] 50. The pharmaceutical composition of embodiment 49, wherein the pharmaceutical composition comprises about 1% to about 45% by weight of the at least one solubilizing agent.

[0399] 51. The pharmaceutical composition of embodiment 49 or 50, wherein the at least one solubilizing agent is oleic acid.

[0400] 52. The pharmaceutical composition of any one of embodiments 49-51, wherein the at least one compound is at least partially solubilized in the cream.

[0401] 53. The pharmaceutical composition of any one of embodiments 49-52, wherein the at least one compound is substantially solubilized in the cream.

[0402] 54. The pharmaceutical composition of any one of embodiments 49-53, wherein the at least one compound is solubilized in the cream.

[0403] 55. The pharmaceutical composition according to any one of embodiments 49-54, further comprising at least one gelling emulsifier.

[0404] 56. The pharmaceutical composition according to embodiment 55, wherein the pharmaceutical composition comprises about 0.1% to about 5% by weight of the at least one gelling emulsifier.

[0405] 57. The pharmaceutical composition according to embodiment 55 or 56, wherein the at least one gelling emulsifier is selected from Pemulen TM TR-1.

[0406] 58. The pharmaceutical composition according to any one of embodiments 55-57, wherein the at least one gelling emulsifier is Pemulen TM TR-1.

[0407] 59. The pharmaceutical composition according to any one of embodiments 49-58, further comprising at least one alcohol.

[0408] 60. The pharmaceutical composition according to embodiment 59, wherein the pharmaceutical composition comprises about 0.1% to about 5% by weight of the at least one alcohol.

[0409] 61. The pharmaceutical composition according to embodiment 59 or 60, wherein the at least one alcohol is benzyl alcohol.

[0410] 62. The pharmaceutical composition according to any one of embodiments 49-61, further comprising at least one emollient or humectant.

[0411] 63. The pharmaceutical composition according to embodiment 62, wherein the pharmaceutical composition comprises about 0.1% to about 65% by weight of the at least one emollient or humectant.

[0412] 64. The pharmaceutical composition according to embodiment 62 or 63, wherein the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof.

[0413] 65. The pharmaceutical composition according to any one of embodiments 62-64, wherein the at least one emollient or humectant is glycerin and propylene glycol.

[0414] 66. The pharmaceutical composition according to any one of embodiments 49-65, further comprising at least one vehicle.

[0415] 67. The pharmaceutical composition of embodiment 66, wherein the at least one vehicle is selected from an aqueous solution.

[0416] 68. The pharmaceutical composition of embodiment 66 or 67, wherein the at least one vehicle is purified water.

[0417] 69. The pharmaceutical composition of any one of embodiments 49-68, further comprising a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH of the pharmaceutical composition to a value in the range of about 3.5 to about 8.5.

[0418] 70. The pharmaceutical composition of embodiment 69, wherein the value is in the range of about 4 to about 6.

[0419] 71. The pharmaceutical composition of embodiment 69 or 70, wherein the value is in the range of about 4.5 to about 5.5.

[0420] 72. The pharmaceutical composition of any one of embodiments 69-71, wherein the value is about 5.

[0421] 73. The pharmaceutical composition of embodiment 49, wherein the pharmaceutical composition comprises:

[0422] about 1% to about 45% by weight oleic acid;

[0423] about 0.1% to about 20% by weight glycerin;

[0424] about 0.1% to about 45% by weight propylene glycol;

[0425] about 0.1% to about 5% by weight benzyl alcohol;

[0426] about 0.1% to about 5% by weight Pemulen TM polymer;

[0427] a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to a value in the range of about 4 to about 6; and

[0428] a sufficient amount of purified water to 100.

[0429] 74. The pharmaceutical composition of embodiment 73, wherein the pharmaceutical composition comprises:

[0430] about 10% by weight oleic acid;

[0431] about 5% by weight glycerin;

[0432] about 5% by weight propylene glycol;

[0433] about 1% by weight of benzyl alcohol;

[0434] about 0.75% by weight of Pemulen TM polymer;

[0435] an amount of 10% (w / w) sodium hydroxide solution sufficient to adjust the pH to a value in the range of about 4 to about 6; and

[0436] a sufficient quantity of purified water to 100.

[0437] 75. The pharmaceutical composition of any one of embodiments 49-74, wherein the pharmaceutical composition comprises about 0.01% to about 2% by weight of the at least one compound.

[0438] 76. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 0.1% to about 10% by weight of the at least one compound.

[0439] 77. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 0.5% by weight of the at least one compound.

[0440] 78. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises at least about 0.5% by weight of the at least one compound.

[0441] 79. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 1% by weight of the at least one compound.

[0442] 80. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 2% by weight of the at least one compound.

[0443] 81. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 5% by weight of the at least one compound.

[0444] 82. The pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition comprises about 10% by weight of the at least one compound.

[0445] 83. The pharmaceutical composition of any one of embodiments 1-82, wherein at least about 95% by weight of the at least one compound is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile.

[0446] 84. The pharmaceutical composition of any one of embodiments 1-83, wherein at least about 95% by weight of the at least one compound is the (E) isomer.

[0447] 85. The pharmaceutical composition of embodiments 83 or 84, wherein the at least one compound is substantially amorphous.

[0448] 86. The pharmaceutical composition of any one of embodiments 83-85, wherein the at least one compound is micronized.

[0449] 87. The pharmaceutical composition of embodiment 86, wherein the at least one compound has a particle size distribution Dv90 in the range of about 5 to about 10 microns. 90 .

[0450] 88. The pharmaceutical composition of any one of embodiments 1-84, wherein the at least one compound is crystalline.

[0451] 89. The pharmaceutical composition of any one of embodiments 1-88, wherein the at least one compound is in crystalline Form (I).

[0452] 90. The pharmaceutical composition of embodiment 89, wherein crystalline Form (I) is characterized by an X-ray powder diffraction pattern having a signal at at least three 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2.

[0453] 91. The pharmaceutical composition of embodiment 89, wherein crystalline Form (I) is characterized by an X-ray powder diffraction pattern substantially similar to that in FIG. 1.

[0454] 92. The pharmaceutical composition of any one of embodiments 89-91, wherein crystalline Form (I) is characterized by a DSC thermogram having a peak endotherm (melting temperature) at about 177 °C to about 178 °C.

[0455] 93. The pharmaceutical composition of any one of embodiments 89-92, wherein crystalline Form (I) is characterized by a DSC thermogram showing onset of melting at about 174.8 °C to about 175.2 °C.

[0456] 94. The pharmaceutical composition of embodiment 89, wherein crystalline Form (I) is prepared by a process comprising:

[0457] methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4- dimethylpent-2-enenitrile to form a solution;

[0458] stirring the solution to form a precipitate; and

[0459] isolating Form (I) by filtration.

[0460] 95. The pharmaceutical composition of any one of embodiments 1-88, wherein the at least one compound is Form (II).

[0461] 96. The pharmaceutical composition of embodiment 95, wherein Form (II) is characterized by an X-ray powder diffraction pattern having a signal at at least three 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2.

[0462] 97. The pharmaceutical composition of embodiment 95, wherein Form (II) is characterized by an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in FIG. 3.

[0463] 98. The pharmaceutical composition of any one of embodiments 95-97, wherein Form (II) is characterized by a DSC thermogram having a peak endotherm (melting temperature) at about 170.0 °C to about 170.2 °C.

[0464] 99. The pharmaceutical composition of any one of embodiments 95-98, wherein Form (II) is characterized by a DSC thermogram showing onset of melting at about 167.2 °C to about 167.6 °C.

[0465] 100. The pharmaceutical composition of any one of embodiments 95-99, wherein Form (II) is characterized by less than 1.5 wt.% mass loss between 35 °C and 220 °C by thermogravimetric analysis.

[0466] 101. The pharmaceutical composition of embodiment 95, wherein Form (II) is prepared by a method comprising:

[0467] dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2- enenitrile in methyl tert-butyl ether to form a solution;

[0468] stirring the solution to form a precipitate; and

[0469] Form II is isolated by filtration.

[0470] 102. A method of treating a skin disorder in a mammal in need thereof, the method comprising topically administering to at least a portion of the skin of a subject mammal at least one topical pharmaceutical composition according to any one of embodiments 1-101.

[0471] 103. The method according to embodiment 102, wherein the skin disorder is mediated by BTK.

[0472] 104. The method according to embodiments 102 or 103, wherein the skin disorder is selected from pemphigus vulgaris, pemphigus foliaceus, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, discoid lupus, atopic dermatitis, bullous pemphigoid, drug-related skin reactions, chronic idiopathic urticaria, chronic spontaneous urticaria, symptomatic dermographism, alopecia, alopecia areata, vitiligo, pyoderma gangrenosum, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, drug eruptions, hair follicle inflammation in alopecia, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rhinophyma, rhinophyma erythema, papulopustular rhinophyma, neutrophilic dermatosis, chronic kidney disease-related pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet syndrome in a mammal in need thereof.

[0473] 105. The method according to any one of embodiments 102-104, wherein the skin disorder is pemphigus vulgaris.

[0474] 106. The method according to any one of embodiments 102-104, wherein the skin disorder is pemphigus foliaceus.

[0475] 107. The method according to any one of embodiments 102-104, wherein the skin disorder is atopic dermatitis.

[0476] 108. The method according to any one of embodiments 102-107, wherein the mammal is a human.

[0477] 109. The method according to any one of embodiments 102-107, wherein the mammal is a canine.

[0478] 110. The method according to any one of embodiments 102-107, wherein the mammal is a feline.

[0479] 111. The method of any one of embodiments 102-107, wherein the mammal is not a human.

[0480] Crystalline Form (I) of Compound (I)

[0481] In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising crystalline Form (I) of Compound (I):

[0482]

[0483] FIG. 1 shows an X-ray powder diffraction pattern of crystalline Form (I) of Compound (I).

[0484] FIG. 2 shows a DSC thermogram of crystalline Form (I) of Compound (I). In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram having a peak endotherm (melting temperature) at about 177 °C to about 178 °C. In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram showing onset of melting / decomposition at about 174.8 °C to about 175.2 °C. In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram showing onset of melting at about 174.8 °C to about 175.2 °C. In some embodiments, the enthalpy of the associated is about 85 J / g (ΔΗ = 85 J / g).

[0485] In some embodiments, crystalline Form (I) of Compound (I) is characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG. 2.

[0486] FIG. 2 also shows a TGA thermogram of crystalline Form (I) of Compound (I).

[0487] In some embodiments, crystalline Form (I) of Compound (I) is a white solid.

[0488] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis with an incident beam of Cu Ka radiation, wherein the signals are substantially similar to those set out in Table 1.

[0489] Table 1.

[0490]

[0491]

[0492] In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X- ray powder diffraction pattern having a signal at 6.3 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 12.6 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.2 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.6 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.2 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.4 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.1 ± 0.2° 2-Theta.

[0493] In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X- ray powder diffraction pattern having a signal at 2-theta values of 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least six 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least five 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least four 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least three 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2. In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 6.3 ± 0.2, 12.6 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, and 22.1 ± 0.2.

[0494] In some embodiments, the crystalline Form (I) of Compound (I) is characterized by an X- ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern in FIG. 1.

[0495] In some embodiments, the topical pharmaceutical composition comprises crystalline Form (I) of Compound (I) prepared by a process comprising adding methyl isobutyl ketone to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enonitrile to form a solution. In some embodiments, the process further comprises agitating the solution to form a precipitate. In some embodiments, the process further comprises isolating crystalline Form (I) by filtration.

[0496] A process for preparing crystalline Form (I) of Compound (I) is disclosed in Example 1.

[0497] Crystalline Form II of Compound (I)

[0498] In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising crystalline Form (II) of Compound (I):

[0499]

[0500] FIG. 3 shows an X-ray powder diffraction pattern of crystalline Form (II) of Compound (I).

[0501] FIG. 4 shows a DSC thermogram of crystalline Form (II) of Compound (I). In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram having a peak endotherm (melting temperature) at about 170.0 °C to about 170.2 °C. In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram showing onset of melting / decomposition at about 167.2 °C to about 167.6 °C. In some embodiments, the associated enthalpy is about 68 J / g (AH = 68 J / g).

[0502] In some embodiments, crystalline Form (II) of Compound (I) is characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG. 4.

[0503] FIG. 4 also shows a TGA thermogram of crystalline Form (II) of Compound (I). In some embodiments, crystalline Form (II) of Compound (I) is characterized by a mass loss of less than 1.5 wt.% between 35 °C and 220 °C by thermogravimetric analysis.

[0504] Crystalline Form (II) cannot be converted to crystalline Form (I) by heating and cooling.

[0505] In some embodiments, crystalline Form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis with an incident beam of Cu Ka radiation, wherein the signals are substantially similar to those described in Table 2.

[0506] Table 2.

[0507]

[0508]

[0509] In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X- ray powder diffraction pattern having a signal at 6.3 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 15.2 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.0 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.6 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.7 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.0 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.8 ± 0.2° 2-Theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 27.5 ± 0.2° 2-Theta.

[0510] In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X- ray powder diffraction pattern having a signal at 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2 of 2-theta. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least seven 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least six 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least five 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least four 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least three 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least two 2-theta values selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2. In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 6.3 ± 0.2, 15.2 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 20.0 ± 0.2, 24.8 ± 0.2, and 27.5 ± 0.2.

[0511] In some embodiments, the crystalline Form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG. 3.

[0512] In some embodiments, the topical pharmaceutical composition comprises the crystalline Form (II) of Compound (I) prepared by a process comprising dissolving amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile in methyl tert-butyl ether to form a solution. In some embodiments, the process further comprises stirring the solution to form a precipitate. In some embodiments, the process further comprises isolating the crystalline Form (II) by filtration.

[0513] A process for preparing the crystalline Form (II) of Compound (I) is disclosed in Example 2.

[0514] Topical pharmaceutical compositions

[0515] The compounds (I), pharmaceutically acceptable salts thereof, and solid forms of Compound (I) (e.g., crystalline forms of Compound (I)) described herein can be used as active pharmaceutical ingredients (APIs), as well as materials for preparing topical pharmaceutical compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration (e.g., topical administration to the skin) to a mammal, such as a human subject. In some embodiments, these topical pharmaceutical compositions will be drug products, such as, for example, suspensions, solutions, or combinations thereof.

[0516] In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising at least one crystalline form of Compound (I). In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising at least one crystalline form of Compound (I) selected from Form (I) and Form (II). In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of Compound (I) and at least one pharmaceutically acceptable excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of Compound (I) selected from Form (I) and Form (II) and at least one pharmaceutically acceptable excipient. Each excipient must be “pharmaceutically acceptable” in the sense of being compatible for use with the subject composition and not deleterious to the patient. The use of otherwise conventional pharmaceutically acceptable excipients is contemplated within the scope of this disclosure unless there is a contraindication for use of such excipient with Compound (I), such as by creating any undesirable biological effect or otherwise interacting in a deleterious manner with any one or more of the other components of the pharmaceutically acceptable composition.

[0517] In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising at least one substantially amorphous form of Compound (I). In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising at least one amorphous form of Compound (I). In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one substantially amorphous form of Compound (I) and at least one pharmaceutically acceptable excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one amorphous form of Compound (I) and at least one pharmaceutically acceptable excipient.

[0518] In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising at least one micronized form of Compound (I). In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one micronized form of Compound (I) and at least one pharmaceutically acceptable excipient.

[0519] In some embodiments, the topical pharmaceutical composition comprises at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include, but are not limited to, components of different classes, such as vehicles, humectants, emollients, wetting agents, thickening agents, fillers, surfactants, diluents, binders, glidants, lubricants, and any combination thereof. Some non-limiting examples of materials that can be used as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and derivatives thereof, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0520] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by D. B. Troy, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using them.

[0521] The pharmaceutical compositions disclosed herein can be administered topically, especially when the treatment target comprises a region or an organ that is easily accessible by local application, including diseases of the eye, skin, or lower intestinal tract.

[0522] The topical pharmaceutical composition can be in the form of a suitable gel, ointment, or cream.

[0523] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, can be suspended or dissolved in at least one excipient to form an ointment. Excipients for topical administration include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.

[0524] In some embodiments, the topical pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, is in the form of a gel. In some embodiments, the gel further comprises at least one pH-dependent gelling agent. In some embodiments, the at least one pH-dependent gelling agent is selected from a polymer. In some embodiments, the polymer is 980 polymer. In some embodiments, the gel further comprises at least one preservative. In some embodiments, the at least one preservative is selected from the group consisting of methylparaben, propylparaben, and combinations thereof. In some embodiments, the gel further comprises at least one humectant. In some embodiments, the at least one humectant is polysorbate 80. In some embodiments, the gel further comprises at least one emollient or moisturizer. In some embodiments, the at least one emollient or moisturizer is selected from the group consisting of glycerin, propylene glycol, and combinations thereof. In some embodiments, the gel further comprises at least one lubricant. In some embodiments, the at least one lubricant is selected from the group consisting of medium chain triglycerides. In some embodiments, the gel further comprises at least one vehicle. In some embodiments, the at least one vehicle is selected from the group consisting of aqueous solutions. In some embodiments, the aqueous solution is purified water. In some embodiments, the at least one vehicle is substantially free of solubilized Compound (I) or a pharmaceutically acceptable salt thereof.

[0525] In some embodiments, the gel comprises about 0.5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 1% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0526] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is at least partially suspended in the gel. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is substantially suspended in the gel. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is suspended in the gel.

[0527] In some embodiments, the gel comprising Compound (I) or a pharmaceutically acceptable salt thereof further comprises at least one (e.g., 1, 2, 3, 4, 5, 6, at least 2, at least 3, at least 4, or at least 5) component selected from the group consisting of:

[0528] at least one pH-dependent gelling agent;

[0529] at least one emollient or moisturizer;

[0530] at least one preservative;

[0531] at least one lubricant;

[0532] at least one humectant; and

[0533] at least one vehicle.

[0534] In some embodiments, the at least one pH dependent gelling agent is selected from a polymer. In some embodiments, the polymer is 980 a polymer. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof. In some embodiments, the at least one lubricant is selected from medium chain triglycerides. In some embodiments, the at least one humectant is polysorbate 80. In some embodiments, the gel further comprises at least one vehicle. In some embodiments, the at least one vehicle is selected from an aqueous solution. In some embodiments, the aqueous solution is purified water.

[0535] In some embodiments, the gel comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0536] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the gel.

[0537] In some embodiments, a gel comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises:

[0538] at least one pH dependent gelling agent;

[0539] at least one emollient or humectant;

[0540] at least one preservative;

[0541] at least one lubricant;

[0542] at least one humectant; and

[0543] at least one vehicle.

[0544] In some embodiments, the at least one pH dependent gelling agent is selected from a polymer. In some embodiments, the polymer is 980 a polymer. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof. In some embodiments, the at least one lubricant is selected from medium chain triglycerides. In some embodiments, the at least one humectant is polysorbate 80. In some embodiments, the gel further comprises at least one vehicle. In some embodiments, the at least one vehicle is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0545] In some embodiments, the gel comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0546] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the gel.

[0547] In some embodiments, the gel comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises:

[0548] about 0.1% to about 4% by weight of at least one pH dependent gelling agent;

[0549] about 0.1% to about 65% by weight of at least one emollient or humectant;

[0550] about 0.01% to about 0.7% by weight of at least one preservative;

[0551] about 20% by weight of at least one lubricant;

[0552] about 20% by weight of at least one wetting agent; and

[0553] at least one vehicle,

[0554] wherein the gel comprises about 0.1% to about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the at least one pH-dependent gelling agent is selected from a polymer. In some embodiments, the polymer is 980 a polymer. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof. In some embodiments, the at least one lubricant is selected from medium chain triglycerides. In some embodiments, the at least one wetting agent is polysorbate 80. In some embodiments, the gel further comprises at least one vehicle. In some embodiments, the at least one vehicle is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0556] In some embodiments, the gel comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gel comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the gel. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the gel.

[0558] In some embodiments, the topical pharmaceutical compositions disclosed herein can be formulated into a suitable lotion or cream comprising Compound (I), or a pharmaceutically acceptable salt thereof, suspended or dissolved in at least one pharmaceutically acceptable excipient. Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, polysorbate 80, cetyl esters wax, cetylstearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0559] In some embodiments, the topical pharmaceutical compositions comprising Compound (I), or a pharmaceutically acceptable salt thereof, are in the form of an ointment. In some embodiments, the ointment further comprises at least one saturated hydrocarbon. In some embodiments, the at least one saturated hydrocarbon is selected from the group consisting of mineral oil, hydrogenated castor oil, and combinations thereof. In some embodiments, the ointment further comprises at least one viscosity modifier. In some embodiments, the at least one viscosity modifier is microcrystalline wax. In some embodiments, the ointment further comprises at least one dispersing agent. In some embodiments, the at least one dispersing agent is selected from the group consisting of dimethicone, medium-chain triglycerides, and combinations thereof.

[0560] In some embodiments, the ointment comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the ointment.

[0562] In some embodiments, the ointment comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises at least one (e.g., 1, 2, 3, or at least 2) component selected from the group consisting of:

[0563] at least one saturated hydrocarbon;

[0564] at least one viscosity modifier; and

[0565] at least one dispersing agent.

[0566] In some embodiments, the at least one saturated hydrocarbon is selected from the group consisting of mineral oil, hydrogenated castor oil, and combinations thereof. In some embodiments, the at least one viscosity modifier is microcrystalline wax. In some embodiments, the at least one dispersing agent is selected from the group consisting of dimethicone, medium-chain triglycerides, and combinations thereof.

[0567] In some embodiments, the ointment comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0568] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the ointment.

[0569] In some embodiments, the ointment comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises:

[0570] at least one saturated hydrocarbon;

[0571] at least one viscosity modifier; and

[0572] at least one dispersing agent.

[0573] In some embodiments, the at least one saturated hydrocarbon is selected from the group consisting of mineral oil, hydrogenated castor oil, and combinations thereof. In some embodiments, the at least one viscosity modifier is microcrystalline wax. In some embodiments, the at least one dispersing agent is selected from the group consisting of dimethicone, medium-chain triglycerides, and combinations thereof.

[0574] In some embodiments, the ointment comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the ointment.

[0576] In some embodiments, the ointment comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises:

[0577] at least one saturated hydrocarbon;

[0578] about 0.1% to about 20% by weight of at least one viscosity modifier; and

[0579] about 0.01% to about 30% by weight of at least one dispersing agent,

[0580] wherein the ointment comprises about 0.1% to about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0581] In some embodiments, the at least one saturated hydrocarbon is selected from the group consisting of mineral oil, hydrogenated castor oil, and combinations thereof. In some embodiments, the at least one viscosity modifier is microcrystalline wax. In some embodiments, the at least one dispersing agent is selected from the group consisting of dimethicone, medium-chain triglycerides, and combinations thereof.

[0582] In some embodiments, the ointment comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof

[0583] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially suspended in the ointment. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is suspended in the ointment.

[0584] In some embodiments, the topical pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, is in the form of a cream. In some embodiments, the cream further comprises at least one solubilizing agent. In some embodiments, the at least one solubilizing agent is oleic acid. In some embodiments, the cream further comprises at least one gelling emulsifier. In some embodiments, the at least one gelling emulsifier is selected from Pemulen TM Aqueous Polymer. In some embodiments, the Pemulen TM Aqueous Polymer is Pemulen TM TR-1. In some embodiments, the cream further comprises at least one alcohol. In some embodiments, the at least one alcohol is benzyl alcohol. In some embodiments, the cream further comprises at least one emollient or humectant. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the cream further comprises at least one vehicle. In some embodiments, the at least one vehicle is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0585] In some embodiments, the cream comprises about 0.01% to about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0586] In some embodiments, the cream comprises about 0.5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cream comprises about 1% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cream comprises about 2% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cream comprises about 5% by weight of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cream comprises about 10% by weight of Compound (I), or a pharmaceutically acceptable salt thereof.

[0587] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is at least partially dissolved in the cream. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is substantially dissolved in the cream. In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is dissolved in the cream.

[0588] In some embodiments, the cream comprising Compound (I), or a pharmaceutically acceptable salt thereof, further comprises at least one (e.g., 1, 2, 3, 4, 5, at least 2, at least 3, or at least 4) component selected from:

[0589] at least one solubilizing agent;

[0590] At least one gelling emulsifier;

[0591] At least one alcohol;

[0592] At least one emollient or moisturizer; and

[0593] At least one medium.

[0594] In some embodiments, the at least one solvent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen. TM Polymer. In some embodiments, the Pemulen TM The polymer is Pemulen TM TR-1. In some embodiments, the at least one alcohol is benzyl alcohol. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one mediator is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0595] In some embodiments, the cream contains about 0.01% to about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0596] In some embodiments, the cream contains about 0.5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 1% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 10% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0597] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is at least partially soluble in the cream. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is substantially soluble in the cream. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is soluble in the cream.

[0598] In some embodiments, the cream comprising compound (I) or a pharmaceutically acceptable salt thereof further comprises:

[0599] At least one solvent;

[0600] At least one gelling emulsifier;

[0601] At least one alcohol;

[0602] At least one emollient or moisturizer; and

[0603] At least one medium.

[0604] In some embodiments, the at least one solvent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen. TM Polymer. In some embodiments, the Pemulen TM The polymer is Pemulen TM TR-1. In some embodiments, the at least one alcohol is benzyl alcohol. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one mediator is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0605] In some embodiments, the cream contains about 0.01% to about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0606] In some embodiments, the cream contains about 0.5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 1% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 10% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0607] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is at least partially soluble in the cream. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is substantially soluble in the cream. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is soluble in the cream.

[0608] In some embodiments, the cream comprising compound (I) or a pharmaceutically acceptable salt thereof further comprises:

[0609] At least one solvent, comprising about 1% to about 45% by weight;

[0610] At least one gelling emulsifier, comprising about 0.1% to about 5% by weight;

[0611] At least one alcohol, comprising about 0.1% to about 5% by weight;

[0612] At least one emollient or moisturizing agent, by weight, comprising about 0.1% to about 65%; and

[0613] At least one medium,

[0614] The cream contains about 0.01% to about 10% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0615] In some embodiments, the at least one solvent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen. TM Polymer. In some embodiments, the Pemulen TM The polymer is Pemulen TM TR-1. In some embodiments, the at least one alcohol is benzyl alcohol. In some embodiments, the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. In some embodiments, the at least one mediator is selected from aqueous solutions. In some embodiments, the aqueous solution is purified water.

[0616] In some embodiments, the cream contains about 0.01% to about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the cream contains about 0.5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 1% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 2% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 5% by weight of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cream contains about 10% by weight of compound (I) or a pharmaceutically acceptable salt thereof.

[0618] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is at least partially soluble in the cream. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is substantially soluble in the cream.

[0619] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is dissolved in the cream.

[0620] Indications

[0621] The topical pharmaceutical compositions described herein can be used to treat a skin disorder mediated by BTK activity in a mammal, such as a skin disorder. In some embodiments, the topical pharmaceutical compositions can be used to treat a human or a non-human. In some embodiments, the topical pharmaceutical compositions can be used to treat a human. In some embodiments, the topical pharmaceutical compositions can be used to treat a non-human. In some embodiments, the topical pharmaceutical compositions can be used to treat a canine. In some embodiments, the topical pharmaceutical compositions can be used to treat a feline.

[0622] In some embodiments, the skin disorder is selected from pemphigus vulgaris, pemphigus foliaceus, cutaneous lupus, cutaneous lupus erythematosus, dermatitis, discoid lupus, atopic dermatitis, bullous pemphigoid, drug-related skin reactions, chronic idiopathic urticaria, alopecia, alopecia areata, vitiligo, pyoderma gangrenosum, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, drug eruptions, folliculitis decalvans, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rhinophyma, rhinophyma erythema, papulopustular rhinophyma, neutrophilic dermatosis, chronic kidney disease-related pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet syndrome.

[0623] In some embodiments, the skin disorder is selected from pemphigus vulgaris and pemphigus foliaceus. In some embodiments, the skin disorder is pemphigus vulgaris. In some embodiments, the skin disorder is pemphigus foliaceus.

[0624] In some embodiments, the skin disorder is atopic dermatitis.

[0625] Dosing

[0626] In general, an effective dose for any particular mammal (e.g., any particular human) in the topical pharmaceutical compositions of the present disclosure will depend on a variety of factors, including: the disorder being treated and the severity of the disorder; the particular pharmaceutical composition employed; the age, body weight, general health, gender, and diet of the mammal; the time of administration, the duration of the treatment; and like factors well known in the medical arts. A therapeutically-effective amount of Compound (I) can range, e.g., from 0.01 to 500 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Suitable dosage levels can be, e.g., 0.01 to 250 mg / kg per day, 0.05 to 100 mg / kg per day, or 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day in some embodiments.

[0627] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference in its entirety.

[0628] Unless the context indicates otherwise or other explicit meaning is apparent, a claim or description including "or," "and / or" between at least one member of a group of one, more than one or all members of a group is satisfied if one, more than one or all members of the group are present in, used in or otherwise associated with a given product or process. The disclosure includes embodiments in which exactly one member of the group is present in, used in or otherwise associated with a given product or process. The disclosure includes embodiments in which more than one or all members of the group are present in, used in or otherwise associated with a given product or process.

[0629] Further, the disclosure encompasses all variations, combinations and permutations of the following: introducing at least one limitation, element, clause and descriptive term from at least one listed claim into another claim. For example, any claim dependent on another claim can be modified to include at least one limitation found in any other claim dependent from the same base claim. Where elements are presented in a list, such as in Markush group format, each subgroup of elements is also disclosed, and any one or more elements from the group can be removed. It should be understood that, generally speaking, where the disclosure or aspects of the disclosure are referred to as comprising particular elements and / or features, embodiments of the disclosure or aspects of the disclosure consist of, or consist essentially of, such elements and / or features. These embodiments are not expressly recited in haec verba for simplicity purposes. Where ranges are given, the endpoints are included. Further, unless otherwise indicated by context or understanding by one of ordinary skill in the art, values expressed as a range can assume any specific value or sub-range within the stated range, to the tenth of the unit of the lower limit of the range (unless otherwise indicated by context or understanding by one of ordinary skill in the art). Examples

[0630] The following examples are intended to be illustrative and are not intended to limit the scope of the disclosure in any way.

[0631] General Methods:

[0632] The crystal form screening of compound (I) was conducted using various solvents and three different crystallization techniques to produce multiple crystal forms of compound (I), such as crystal form (I) and crystal form (II). In short, the three different crystallization techniques were thermal cycling (TC), rapid cooling (RC), and slow evaporation (EV). To prepare the crystal form of compound (I) by thermal cycling, the slurry containing compound (I) was cycled at temperatures between 5°C and 40°C for 36 hours, followed by equilibration at 25°C for 8 hours. To prepare the crystal form of compound (I) by rapid cooling, a clear saturated solution of compound (I) was rapidly cooled from 25°C to 4°C and held at 4°C for 48 hours. To prepare the crystal form of compound (I) by slow evaporation, the solution containing compound (I) was slowly evaporated for up to 10 days. The solvents and solvent systems used to produce crystal forms (I) and (II) are shown in Table 3 below.

[0633] Table 3.

[0634]

[0635]

[0636] Example 1: Preparation of crystal form I of compound (I)

[0637] Methyl isobutyl ketone (MIBK; 6 mL) was added to amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile (1.0 g) and stirred to form a solution. After stirring for about 5 minutes, a precipitate began to form. Additional MIBK (10 mL) was added, and the slurry was stirred. After about 10 days, the solid was filtered and washed with MIBK (10 mL). The solid was dried under vacuum by heating to provide approximately 0.5 g of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile in crystal form (I), as a white solid. XRPD (2-θ): 12.6, 15.7, 16.2, 18.3, 18.4, 22.1; DSC: starting at 175°C, melting at 177.6°C.

[0638] Example 2: Preparation of crystal form II of compound (I)

[0639] Amorphous (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile (1.0 g) was dissolved in methyl tert-butyl ether (MTBE, 4 mL). The solution was stirred at room temperature. After about 5 minutes, a precipitate started to form. Additional MTBE (about 10 mL) was added to the slurry. The solids were filtered and dried under vacuum to give about 0.7 g of crystalline Form II of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carbonyl)-4,4-dimethylpent-2-enenitrile. XRPD (2-theta): 15.2, 16.6, 17.6, 20.0, 24.8; DSC: onset 167 °C, melt 170 °C.

[0640] Example 3: Rat Arthus Study

[0641] An IgG-mediated acute Arthus rat model was used as an in vivo pharmacology screen, with commercially available betamethasone used as a control. Two endpoints were evaluated: (1) dye diameter measurement post-dose; and (2) density measurement post-dose.

[0642] Thirty SD female rats (120-130 g) were received, housed individually and quarantined. For identification purposes, the rats were notched on the ear. Upon quarantine, the rats selected for the study were assigned to 6 groups of 5 rats each; the groups had approximately the same average body weight.

[0643] On Day -1, the rats were shaved on the back, and on Day 0, the rats were weighed. Prior to anesthesia and intradermal injection of rabbit anti-ovalbumin IgG 3 hours (T = -3 hours), the rats were fitted with an Elizabethan collar and topically dosed with Carbopol gel suspension containing Compound (I), as shown in Table 4 below. At T = -20 minutes, the rats were intravenously injected with 10 mg / kg ovalbumin in phosphate buffered saline (PBS) and 2% Evans Blue dye (EBD) [2 mL / kg].

[0644] Table 4. Treatment Groups

[0645]

[0646] At T=0, rats in the study were anesthetized, and rabbit anti-ovalbumin IgG (50 μg in 25 μL) was injected intradermally at three different sites on one side of the back, and the same type of rabbit IgG was injected intradermally at three different sites on the opposite side of the back. Four hours later, the rats were euthanized, and the skin was removed from the back and turned inside out. The diameter of the EBD leak was measured for area calculation, and a biopsy perforation (approximately 8 mm) centered at the injection site was incubated overnight at 80°C in 2 mL of formamide, and the OD was measured. 610nm EBD was measured. Suspension gel topical drug formulations showed promising results in this study.

[0647] Promising results were also observed at the extended time point of 16 hours prior to the antibody challenge study (multi-day dosing study). In the one-day dosing study, the topical formulation showed steroid-like efficacy at 3 hours and 16 hours with 1% compound (I) in the gel formulation. Steroid-like efficacy was also observed at 3 hours and 16 hours in the three-day dosing study, and the application of the 0.5% compound (I) gel formulation after 3 days was advantageous compared to betamethasone.

[0648] Figures 5A and 5B show the inhibition results of IgG (FcgR) in a rat Arthus (macrophage / neutrophil) model at 3 hours in a 3-day dosing study. The data show that, after multiple days of dosing at the final dose 3 hours before IgG challenge, the suspension gel topical pharmaceutical formulation of this disclosure provides steroid-like efficacy with ≥0.5% of compound (I) in the gel formulation.

[0649] An IgG-mediated acute Arthus rat model was also used to screen certain ointment suspensions of compound (I). Figures 6A and 6B show the results of the ointment suspension studies in a 1-day dosing study, while Figures 7A and 7B show the results of the ointment suspension studies in a 3-day dosing study.

[0650] Example 4: Penetration of compound (I) into the dermis and epidermis

[0651] Compound (I) was able to penetrate the abdominal skin (500 ± 50 μm) of a person undergoing selective surgery, entering the dermis and epidermis. Using skin from one donor (n = 4–5 replicates per condition) and a recipient solution containing phosphate / citrate buffer at pH 5.6 with 0.01% Brij 98, 10 mg / cm³ of compound (I) was applied in one of three 2% compound (I) gel formulations containing one of crystalline (I), amorphous compound (I), or crystalline (II). 2Dose of Compound (I). Samples were collected every 3 hours for 24 hours. Prior to isolating epidermis and dermis, residual formulation was removed from the skin surface, then the skin surface was tape-stripped up to 5 times to remove residual formulation and the top layer of the skin surface (stratum corneum). The dermis and epidermis were isolated by heating to 60 °C for 2 minutes followed by manual separation using tweezers. The extraction fluid used was 90:10 acetonitrile:water (with 0.1% BHT). Epidermis and dermis samples were homogenized then shaken overnight at 130 RPM and transferred to a lo-bind DW96 plate.

[0652] Table 5 and Figure 8 show the average amount of Compound (I) (ng) delivered to the epidermis and dermis 24 hours after application of three 2% formulation variants containing one of Formulation (I) of Compound (I), amorphous Compound (I), or Formulation (II) of Compound (I). No significant difference in skin penetration ability was observed between the different formulations containing different forms of Compound (I) (two crystalline forms and one amorphous form), even though Compound (I) was in the form of a suspension.

[0653] Table 5. Average amount of Compound (I) 24 hours after application

[0654]

[0655]

[0656] Example 5: Example Carbopol gel suspension

[0657] An example of a formulation containing Compound (I) and Carbopol in the form of a gel suspension was prepared as shown in Table 6 below. Carbopol is a synthetic, high molecular weight acrylic acid polymer that acts as a pH dependent gelling agent.

[0658] Table 6.

[0659] Ingredient % w / w Compound (I) Propylene glycol 0.2-2 Methyl paraben 10.0 Propyl paraben 0.2 Medium chain triglycerides 0.05 Glycerin 2.0 Polysorbate 80 5.0 Carbopol 2.0 10% Sodium hydroxide 0.75 Adjust pH to 4.5-5.5 Purified water q.s. to 100 Ingredient % w / w

[0660] Methyl and propyl parabens were added as preservatives. Propylene glycol acts as a good solvent to dissolve the preservatives. Polysorbate 80 acts as a wetting agent to help Compound (I) deagglomerate, which is typical in suspensions. Medium chain triglycerides were added as a lubricant, along with glycerin and propylene glycol as skin moisturizers.

[0661] Example 6: Example ointment suspension

[0662] An example of a formulation containing Compound (I) in the form of an ointment suspension is shown in Table 7 below.

[0663] Table 7.

[0664] Compound (I) Medium chain triglycerides Microcrystalline wax 0.2-2 Hydrogenated castor oil 10.0 Dimethicone 5 Mineral oil 2.0 q.s. to 100 3.0 Ingredient % w / w Compound (I)

[0665] Mineral oil / hydrogenated castor oil suspensions of Compound (I) exhibit excellent high temperature suspendability characteristics. Dimethicone and medium chain triglyceride are added for Compound (I) dispersion, with microcrystalline wax added as a viscosity modifier.

[0666] Example 7: Example Cream Formulations

[0667] Examples of formulations comprising Compound (I) in dissolved cream form are shown in Table 8 below. Pemulen TM TR-1 was selected as the gelling emulsifier for the cream formulations, thus the product can be manufactured at room temperature to avoid possible heat-induced degradation during the manufacturing process.

[0668] Table 8.

[0669] Oleic acid Glycerin Propylene glycol 0.2-2 Benzyl alcohol 10.0 1 N Sodium hydroxide 5.0 Adjust pH to 5.5 5.0 Purified water 1.0 Pemulen TM TR-1 0.75 q.s. to 100 ​ ​ ​

[0670] Example 8: Stability Testing

[0671] The formulations of Tables 6-8 were manufactured and placed in flint bottles for monitoring of stability at 25 °C and 40 °C. Non-micronized Compound (I) was used for the stability testing. The total impurities of the suspended Carbopol gel and the suspended ointment formulations comprising Compound (I) never exceeded 1% over the 2.5 month stability testing at 25 °C and 40 °C.

[0672] Table 9.

[0673]

[0674] Another stability study was performed with ointment suspensions and gel suspensions comprising micronized Compound (I). Stability data for the example formulations are summarized in Table 10.

[0675] Table 10

[0676]

[0677] The formulations were stable at 25 °C for 3 months, and both 5% formulations were stable at 40 °C for 3 months, with some phase separation observed between the vehicle and drug particles of the ointment suspension at 40 °C.

[0678] One of ordinary skill in the art would recognize or be able to determine many equivalents of the specific embodiments of the disclosure described herein using no more than routine experimentation. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A topical pharmaceutical composition comprising: At least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpentan-2-enonitrile and pharmaceutically acceptable salts thereof; and At least one pH-dependent gelling agent, comprising about 0.1% to about 4% by weight, wherein said at least one pH-dependent gelling agent is 980 polymer; At least one emollient or moisturizer, comprising about 0.1% to about 65% by weight, wherein the at least one emollient or moisturizer is selected from glycerin, propylene glycol, and combinations thereof; The presence of at least one preservative, in a weight ratio of about 0.01% to about 0.7%, wherein the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof. At least one lubricant, comprising about 0.1% to about 20% by weight, wherein the at least one lubricant is selected from medium-chain triglycerides; At least one wetting agent, comprising about 0.1% to about 20% by weight, wherein said at least one wetting agent is polysorbate 80; and The pharmaceutical composition is in the form of a gel.

2. The topical pharmaceutical composition according to claim 1, wherein the at least one compound is suspended in the gel.

3. The topical pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: Medium-chain triglycerides, by weight, amounting to approximately 0.1% to approximately 20%; Polysorbate 80, by weight, is approximately 0.1% to approximately 20%; Glycerin, approximately 0.1% to approximately 20% by weight; Propylene glycol, by weight, approximately 0.1% to approximately 45%; Methylparaben, by weight, about 0.01% to about 0.5%; Propylparaben by weight: about 0.01% to about 0.2%; From about 0.1% to about 4% by weight 980 polymer; A sufficient amount of 10% w / w sodium hydroxide solution to adjust the pH of the pharmaceutical composition to a value in the range of about 4 to about 6; as well as Sufficient amount of purified water up to 100%.

4. A topical pharmaceutical composition, said pharmaceutical composition comprising: At least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpentan-2-enonitrile and pharmaceutically acceptable salts thereof; and At least one saturated hydrocarbon, wherein the at least one saturated hydrocarbon is selected from mineral oil, hydrogenated castor oil, and combinations thereof; At least one viscosity modifier, comprising about 0.1% to about 20% by weight, wherein the at least one viscosity modifier is a microcrystalline wax; At least one dispersant, comprising about 0.01% to about 30% by weight, wherein the at least one dispersant is selected from dimethicone, medium-chain triglycerides, and combinations thereof; The pharmaceutical composition is in the form of an ointment.

5. The topical pharmaceutical composition according to claim 4, wherein the at least one compound is suspended in the ointment.

6. The topical pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises: Medium-chain triglycerides, by weight, amounting to approximately 0.1% to approximately 20%; Microcrystalline wax, by weight, approximately 0.1% to approximately 20%; Hydrogenated castor oil, by weight, from about 0.1% to about 10%; Dimethyl polysiloxane, by weight, from about 0.01% to about 10%; and Sufficient amount of 100% white mineral oil.

7. A topical pharmaceutical composition, said pharmaceutical composition comprising: At least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpentan-2-enonitrile and pharmaceutically acceptable salts thereof; and At least one solvent, comprising about 1% to about 45% by weight, wherein the at least one solvent is oleic acid; At least one gelling emulsifier, comprising about 0.1% to about 5% by weight, wherein said at least one gelling emulsifier is Pemulen. TM TR-1; At least one alcohol, comprising about 0.1% to about 5% by weight. At least one emollient or moisturizer, comprising about 0.1% to about 65% by weight, wherein said at least one emollient or moisturizer is selected from glycerin, propylene glycol, and combinations thereof; and The pharmaceutical composition is in the form of a cream.

8. The topical pharmaceutical composition according to claim 7, wherein the at least one compound is dissolved in the cream.

9. The topical pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises: Oleic acid, by weight, is approximately 1% to approximately 45%. Glycerin, approximately 0.1% to approximately 20% by weight; Propylene glycol, by weight, approximately 0.1% to approximately 45%; benzyl alcohol, by weight, is approximately 0.1% to approximately 5%. Pemulen, approximately 0.1% to approximately 5% by weight TM polymer; A sufficient amount of 10% w / w sodium hydroxide solution to adjust the pH to a value in the range of approximately 4 to approximately 6; and Sufficient amount of purified water up to 100%.

10. The topical pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition comprises about 0.1% to about 10% by weight of the at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile and pharmaceutically acceptable salts thereof.

11. The topical pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition comprises at least about 0.5% by weight of the at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile and pharmaceutically acceptable salts thereof.

12. The topical pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition comprises about 1% by weight of the at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile and pharmaceutically acceptable salts thereof.

13. The topical pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition comprises about 2% by weight of the at least one compound selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-carbonyl)-4,4-dimethylpent-2-enonitrile and pharmaceutically acceptable salts thereof.

14. The topical pharmaceutical composition according to any one of claims 1-9, wherein at least about 95% by weight of the at least one compound is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile, wherein the at least one compound is selected from 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile and pharmaceutically acceptable salts thereof.

15. The topical pharmaceutical composition according to any one of claims 1-9, wherein at least about 95% by weight of the at least one compound is an (E) isomer.

16. The topical pharmaceutical composition of claim 14, wherein the at least one compound is amorphous.

17. The topical pharmaceutical composition of claim 14, wherein the at least one compound is micronized.

18. The topical composition of claim 17, wherein the at least one compound has a particle size distribution D in the range of about 5 to about 10 micrometers. 90 .

19. The topical pharmaceutical composition according to any one of claims 1-9, wherein the at least one compound is crystalline.

20. The topical pharmaceutical composition of claim 19, wherein the at least one compound is crystal form (I), and wherein crystal form (I) is characterized in that the X-ray powder diffraction pattern has a signal at at least three 2θ values ​​selected from 6.3±0.2, 12.6±0.2, 16.2±0.2, 17.6±0.2, 18.2±0.2, 18.4±0.2 and 22.1±0.

2.

21. The topical pharmaceutical composition according to claim 19, wherein the at least one compound is crystal form (II), and wherein crystal form (II) is characterized in that the X-ray powder diffraction pattern has a signal at at least three 2θ values ​​selected from 6.3±0.2, 15.2±0.2, 16.0±0.2, 16.6±0.2, 17.7±0.2, 20.0±0.2, 24.8±0.2, and 27.5±0.

2.

22. Use of the topical pharmaceutical composition according to any one of claims 1-21 in the preparation of a medicament for treating pemphigus vulgaris or pemphigus foliaceus in mammals in need.

23. The use according to claim 22, wherein the mammal is a human.

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