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 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)), e.g., for application to the skin of a subject, methods of making same, and methods of using same, e.g., for the treatment of various skin disorders.

Description

[Technical Field]

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

[0002] The present disclosure is directed 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 same, for example, in the treatment of various skin disorders. [Background technology]

[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 B cell development and activation. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cell-related hematologic cancers (e.g., non-Hodgkin's lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjögren's syndrome, pemphigus, IBD, lupus, and asthma).

[0004] Compound (I), pharmaceutically acceptable salts thereof, and any of the foregoing in various solid forms can inhibit BTK and may be useful in treating disorders and conditions mediated by BTK activity, including various skin disorders. Compound (I) is disclosed, for example, in Table 1 of Patent Document 1 as Compounds 125A / 125B and has the following structure: [ka] (In the formula,* C is a stereochemical center)

[0005] Topical pharmaceutical compositions are useful for treating a variety of skin disorders. These formulations enable the local delivery of active pharmaceutical ingredients (APIs), potentially improving efficacy and reducing adverse effects associated with systemic administration of the API. However, many active pharmaceutical ingredients are difficult to formulate as suspensions or liquids (e.g., gels, ointments, or creams) suitable for application to the skin of patients suffering from skin disorders. For example, some APIs exhibit poor chemical and physical stability in topical formulations, reducing their shelf life and safety profile.

[0006] Stable topical formulations can improve shelf life, provide better chemical and physical stability, and in some embodiments, can provide better efficacy in treating skin disorders, particularly using BTK inhibitors such as Compound (I). Accordingly, there is a need in the art for stable topical formulations comprising Compound (I) or a pharmaceutically acceptable salt thereof. Such formulations may be used to treat a variety of skin conditions, 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 dermatosis, alopecia, alopecia areata, vitiligo, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, and others. It may be useful in treating skin disorders including Son's syndrome, TEN (toxic epidermal necrolysis), drug eruption, folliculitis barbae, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rosacea, erythema rosacea, papulopustular rosacea, neutrophilic dermatosis, chronic kidney disease-associated pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet's syndrome. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2012 / 158764 Summary of the Invention [Problem to be solved by the invention]

[0008] Disclosed herein are novel topical pharmaceutical compositions comprising Compound (I) or a pharmaceutically acceptable salt thereof, and methods of using and making the same. In some embodiments, the topical pharmaceutical compositions are used to treat a subject suffering from a skin disorder, for example, by applying the composition to at least a portion of the subject's skin. [Means for solving the problem]

[0009] In some embodiments, the present disclosure provides a topical pharmaceutical composition for application to the skin of a subject, the topical pharmaceutical composition comprising: 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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (I)), or a pharmaceutically acceptable salt of any of the foregoing; and at least one pharmaceutically acceptable excipient Including, The composition is in a form selected from a suspension, a solution, and combinations thereof.

[0010] 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 in the range of about 5 to about 10 microns. 90 It has.

[0011] In some embodiments, the compound is Compound (I).

[0012] In some embodiments, the compound is Compound (I) in amorphous form.

[0013] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0014] 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.

[0015] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0016] 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.

[0017] In some embodiments, the topical pharmaceutical composition is in the form of a suspension.

[0018] In some embodiments, the topical pharmaceutical composition is in a form selected from a gel, an ointment, and a cream.

[0019] In some embodiments, the present disclosure provides a topical pharmaceutical composition for application to the skin of a subject, the topical pharmaceutical composition comprising: 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)-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 The suspension is in the form of a suspension containing at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is Vehicle; Moisturizing and / or emollients; Wetting agents; and thickener Includes:

[0020] 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 in the range of 5 to 10 microns. 90 It has.

[0021] In some embodiments, the compound is Compound (I).

[0022] In some embodiments, the compound is Compound (I) in amorphous form.

[0023] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0024] 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.

[0025] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0026] 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.

[0027] In some embodiments, the vehicles, individually or combined, do not substantially dissolve Compound (I) or a pharmaceutically acceptable salt thereof, hi some embodiments, the vehicle is selected from water, mineral oil, and combinations thereof.

[0028] In some embodiments, the humectant and / or soothing agent retains Compound (I) or a pharmaceutically acceptable salt thereof on the skin, e.g., retains 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 soothing agent comprises at least one ingredient selected from propylene glycol, glycerin, medium chain triglycerides, and any combination of the foregoing.

[0029] In some embodiments, the wetting agent keeps Compound (I) or a pharmaceutically acceptable salt thereof deaggregated, e.g., the wetting agent reduces the amount of aggregates compared to a substantially similar formulation that does not contain the wetting agent. In some embodiments, the wetting agent comprises at least one component selected from polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof.

[0030] In some embodiments, the thickening agent comprises at least one component selected from crosslinked polyacrylic acid polymers (Carbopol® polymers), hydrogenated castor oil, microcrystalline wax, and any combination of the foregoing.

[0031] In some embodiments, the at least one pharmaceutically acceptable excipient is a vehicle selected from water, mineral oil, and combinations thereof; a moisturizing and / or emollient agent comprising at least one ingredient selected from propylene glycol, glycerin, medium chain triglycerides, and any combination of the foregoing; a wetting agent comprising at least one component selected from polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof; and A thickening agent comprising at least one component selected from crosslinked polyacrylic acid polymers (Carbopol® polymers), hydrogenated castor oil, microcrystalline wax, and any combination of the foregoing. Includes:

[0032] In some embodiments, the topical pharmaceutical composition comprises: about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); about 0.1% to about 20% by weight of natural glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.01% to about 0.5% by weight of methylparaben; about 0.01% to about 0.2% by weight of propylparaben; about 0.1% to about 4% by weight of a crosslinked polyacrylic acid polymer; a certain amount of approximately 10% (w / w) sodium hydroxide solution; and Add enough water to make up to 100ml Includes:

[0033] In some embodiments, the cross-linked polyacrylic acid polymer is a Carbopol® 980 polymer.

[0034] 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.

[0035] 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.

[0036] In some embodiments, the compound is Compound (I).

[0037] In some embodiments, the compound is Compound (I) in amorphous form.

[0038] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0039] 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.

[0040] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0041] 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.

[0042] In some embodiments, the topical pharmaceutical composition comprises: about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; approximately 2% by weight of medium-chain triglycerides; approximately 2% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); Approximately 5% by weight of natural glycerin; about 10% by weight propylene glycol; approximately 0.20% by weight of methylparaben; approximately 0.05% by weight of propylparaben; about 0.75% by weight of a cross-linked polyacrylic acid polymer; a certain amount of 10% (w / w) sodium hydroxide solution; and Add enough water to make up to 100ml Includes:

[0043] In some embodiments, the cross-linked polyacrylic acid polymer is a Carbopol® 980 polymer.

[0044] 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 4.5 to about 5.5.

[0045] In some embodiments, the topical pharmaceutical composition is in the form of a gel.

[0046] In some embodiments, the compound is Compound (I).

[0047] In some embodiments, the compound is Compound (I) in amorphous form.

[0048] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0049] 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.

[0050] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0051] 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.

[0052] In some embodiments, the topical pharmaceutical composition comprises: about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of a microcrystalline wax; about 0.1% to about 10% by weight of hydrogenated castor oil; about 0.01% to about 10% by weight of dimethicone; and 100g of white mineral oil Includes:

[0053] In some embodiments, the dimethicone has a viscosity of 12,500 centistokes (cSt).

[0054] In some embodiments, the white mineral oil is Kaydol white mineral oil.

[0055] 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.

[0056] In some embodiments, the compound is Compound (I).

[0057] In some embodiments, the compound is Compound (I) in amorphous form.

[0058] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0059] 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.

[0060] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0061] 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.

[0062] In some embodiments, the topical pharmaceutical composition comprises: about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; approximately 2% by weight of medium-chain triglycerides; about 2% to about 20% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); Approximately 5% by weight of natural glycerin; about 10% by weight propylene glycol; approximately 0.20% by weight of methylparaben; approximately 0.05% by weight propylparaben; about 0.75% by weight of a cross-linked polyacrylic acid polymer; a certain amount of 10% (w / w) sodium hydroxide solution; and Add enough water to make up to 100ml Includes.

[0063] In some embodiments, the cross-linked polyacrylic acid polymer is a Carbopol® 980 polymer.

[0064] 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 4.5 to about 5.5.

[0065] In some embodiments, the topical pharmaceutical composition is in the form of a gel.

[0066] In some embodiments, the compound is Compound (I).

[0067] In some embodiments, the compound is Compound (I) in amorphous form.

[0068] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0069] 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.

[0070] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0071] 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.

[0072] In some embodiments, the topical pharmaceutical composition comprises: about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of a microcrystalline wax; about 0.1% to about 10% by weight of hydrogenated castor oil; about 0.01% to about 10% by weight of dimethicone; and Mineral oil (up to 100%) Includes.

[0073] In some embodiments, the dimethicone has a viscosity of 12,500 centistokes (cSt).

[0074] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof in the topical pharmaceutical composition is present in an amount of about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of the composition.

[0075] In some embodiments, the compound is Compound (I).

[0076] In some embodiments, the compound is Compound (I) in amorphous form.

[0077] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0078] 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.

[0079] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0080] 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.

[0081] In some embodiments, the topical pharmaceutical composition comprises: about 0.1%, about 0.5%, about 2%, about 5%, or about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; approximately 10% by weight of medium-chain triglycerides; about 5% by weight of microcrystalline wax; approximately 2% by weight of hydrogenated castor oil; about 3% by weight of dimethicone; and Mineral oil (up to 100%) Includes.

[0082] In some embodiments, the topical pharmaceutical composition is in the form of an ointment.

[0083] In some embodiments, the compound is Compound (I).

[0084] In some embodiments, the compound is Compound (I) in amorphous form.

[0085] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0086] 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.

[0087] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0088] 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.

[0089] In some embodiments, the present disclosure provides a topical pharmaceutical composition in the form of a cream for application to the skin of a subject, the composition comprising: about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 1% to about 45% by weight of oleic acid; about 0.1% to about 20% by weight of glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.1% to about 5% by weight of benzyl alcohol; Acrylic acid and C crosslinked with allylpentaerythritol (Pemulen™ polymer) 10 ~C 30 about 0.1% to about 5% by weight of a high molecular weight copolymer of an alkyl acrylate; a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to about 3.5 to about 8.5; and Add enough water to make up to 100ml Includes:

[0090] In some embodiments, acrylic acid and C crosslinked with allylpentaerythritol (Pemulen™ polymer) 10 ~C 30 A high molecular weight copolymer of alkyl acrylate is Pemulen™ TR-1.

[0091] In some embodiments, the compound is Compound (I).

[0092] In some embodiments, the compound is Compound (I) in amorphous form.

[0093] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0094] 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.

[0095] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0096] 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.

[0097] In some embodiments, the topical pharmaceutical composition in the form of a cream comprises: about 0.2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 25% by weight of oleic acid; about 5% by weight glycerin; about 5% by weight propylene glycol; about 1% by weight of benzyl alcohol; about 0.75% by weight of Pemulen™ TR-1 polymer; a certain amount of 10% (w / w) sodium hydroxide solution; and Add enough water to make up to 100ml Includes.

[0098] 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 4.5 to about 5.5.

[0099] In some embodiments, the compound is Compound (I).

[0100] In some embodiments, the compound is Compound (I) in amorphous form.

[0101] In some embodiments, the compound is Compound (I) in crystalline form. In some embodiments, the compound is Compound (I) in crystalline form (I). In some embodiments, the compound is Compound (I) in crystalline form (II).

[0102] 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.

[0103] In some embodiments, at least about 95% by weight of Compound (I) is the (E) isomer.

[0104] 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. [Brief explanation of the drawings]

[0105] [Figure 1] 1 shows the X-ray powder diffraction diagram for Compound (I) in crystalline form (I), also referred to herein as crystalline form (I), with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 2] 1 shows a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for Compound (I) in crystalline form (I). [Figure 3] 1 shows the X-ray powder diffraction diagram for Compound (I) in crystalline form (II), also referred to herein as crystalline form (II), with angle 2θ (2 theta) on the X-axis and relative intensity on the Y-axis. [Figure 4] 1 shows a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) heat curve for crystalline form (II) of Compound (I). [Figure 5] Figures 5A and 5B show the results of IgG (FcgR) inhibition in a rat Arthus (macrophage / neutrophil) model utilizing a 3-day dosing of a gel formulation containing Compound (I). [Figure 6] Figures 6A and 6B show the results of IgG (FcgR) inhibition in a rat Arthus (macrophage / neutrophil) model utilizing daily dosing of an ointment formulation containing Compound (I). [Figure 7] Figures 7A and 7B show the results of IgG (FcgR) inhibition in a rat Arthus (macrophage / neutrophil) model utilizing a 3-day dosing of an ointment formulation containing Compound (I). [Figure 8] This figure illustrates the average amount (ng) of Compound (I) delivered to the epidermis and dermis 24 hours after application of three 2% formulation variants using Compound (I) in crystalline form (I), amorphous Compound (I), and Compound (I) in crystalline form (II). Data points represent the cumulative amount of Compound (I) from five replicates per donor (n=4-5). Error bars represent one standard deviation. Statistical outliers were excluded. DETAILED DESCRIPTION OF THE INVENTION

[0106] Definition: As used herein, "a" or "an" attached to an entity refers to one or more of that entity; for example, a "compound" refers to one or more compounds, or at least one compound, unless otherwise stated. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein.

[0107] As used herein, the term "about" or "approximately" means approximately, in the region of, in the general area of, or in the region of. When the term "about" is used in connection with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value that varies by 5% above and below the stated value.

[0108] As used herein, “Compound (I)” refers to the (E) isomer, (Z) isomer, and mixtures 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)- It refers to a mixture of the (R) and (S) enantiomers of 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, or 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 following structure: [ka] (In the formula, * C is a stereochemical center)

[0109] When compound (I) is expressed 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 may 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. Thus, when compound (I) is expressed as 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, the amount of the (R) or (S) enantiomer in the mixture is greater than 1% by weight. Similarly, when compound (I) is expressed as the (E) isomer, it may contain less than 1% by weight of the corresponding (Z) isomer as an impurity. Thus, when compound (I) is expressed as a mixture of the (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 the (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0110] In some embodiments, compound (I) is 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.

[0111] 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%, e.g., at least about 80%, at least about 85%, at least about 90%, or at least about 95% by weight 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. 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.

[0112] Compound (I) may be referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0113] As used herein, the term "solution" in reference to a form of topical pharmaceutical composition includes emulsions in which the API is dissolved in a vehicle.

[0114] As used herein, the term "suspension" in reference to a form of topical pharmaceutical composition includes formulations in which the API is dispersed / suspended in a vehicle.

[0115] As used herein, "substantially pure" with respect to geometric isomeric forms refers to a compound, such as Compound (I), in which greater than 70% by weight or greater than 70% by mole of the compound is present as a given isomeric form. For example, the phrase "Compound (I) is a substantially pure (E) isomer" refers to Compound (I) having at least 70% by weight or 70% by mole of the (E) isomeric form, and the phrase "Compound (I) is a substantially pure (Z) isomer" refers to Compound (I) having at least 70% by weight or 70% by mole of the (Z) isomeric form. In some embodiments, at least 80% by weight or 80% by mole of Compound (I) is the (E) form, or at least 80% by weight or 80% by mole of Compound (I) is the (Z) form. In some embodiments, at least 85% by weight or 85% by mole of Compound (I) is the (E) form, or at least 85% by weight or 85% by mole of Compound (I) is the (Z) form. In some embodiments, at least 90% by weight or 90% by mole of Compound (I) is in the (E) form, or at least 90% by weight or 90% by mole of Compound (I) is in the (Z) form. In some embodiments, at least 95% by weight or 95% by mole of Compound (I) is in the (E) form, or at least 95% by weight or 95% by mole of Compound (I) is in the (Z) form. In some embodiments, at least 97% by weight or 97% by mole, or 98% by weight or 98% by mole of Compound (I) is in the (E) form, or at least 97% by weight or 97% by mole, or 98% by weight or 98% by mole of Compound (I) is in the (Z) form. In some embodiments, at least 99% by weight or 99% by mole of Compound (I) is in the (E) form, or at least 99% by weight or 99% by mole of Compound (I) is in the (Z) form. The relative amounts of the (E) and (Z) isomers in a solid mixture can be determined according to standard methods and techniques known in the art.

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

[0117] In some embodiments, compound (I) is a substantially pure (E) isomer 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. In some embodiments, compound (I) is at least about 75%, e.g., at least about 80%, at least about 85%, at least about 90%, or at least about 95% by weight of the (E) isomer 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. 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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

[0118] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic salt form of the compound of the present disclosure. Pharmaceutically acceptable salts of Compound (I) of the present 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, for example, those disclosed in Berge, SM et al., J. Pharma. Sci. 66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in the above documents include acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycolyl arsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; maleate; mandelate; mesyl Acid salts include methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, monoacetate, succinate, sulfate, tannate, tartrate, teociate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0119] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate 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 using other methods used in the art, such as ion exchange. Additional non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxybenzoate, benzoic acid ... ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1~4Examples of pharmaceutically acceptable salts include alkali metal salts and alkaline earth metal salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further 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 alkali sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0120] As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient that is useful in preparing a pharmaceutical composition. For example, pharmaceutically acceptable excipients include carriers and excipients that are generally regarded as safe and acceptable for pharmaceutical use in mammals.

[0121] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or a significant decrease in the baseline activity of a biological activity or process.

[0122] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in improvement of the disorder or condition, e.g., alleviation, reduction, modulation, amelioration, or elimination. Improvement or reduction in the severity of any symptom of a disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0123] As used herein, "mammal" refers to domestic animals (e.g., dogs, cats, and horses) as well as humans. In some embodiments, the mammal is a human.

[0124] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0125] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also called thermogravimetric) analysis.

[0126] As used herein, particle size is expressed in terms of particle size distribution (PSD) (e.g., D 10 Value, D 50 value, and D 90 The particle size distribution can be affected by the hydration state of the particles. For example, the wet particle size distribution can differ from the dry particle size distribution, resulting in a correspondingly different characteristic D 10 Value, D 50 value, and D 90 It has a value.

[0127] As will be appreciated by those skilled in the art, the 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 measured by laser diffraction (e.g., D 10 Value, D 50 value, and D 90 value).

[0128] As used herein, "D 50 " refers to the median diameter of the particle size distribution.

[0129] As used herein, "D 10 " means that 10% of the particle population is D 10 It refers to particle sizes having the following particle sizes:

[0130] As used herein, "D 90 " means that 90% of the particle population is D 90 It refers to particle sizes having the following particle sizes:

[0131] Example embodiment 1: Non-limiting embodiments of the present disclosure include: 1. A topical pharmaceutical composition for application to the skin of a subject, comprising: 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)-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 at least one pharmaceutically acceptable excipient Including, A topical pharmaceutical composition in a form selected from a suspension, a solution, and a combination thereof. 2. A topical pharmaceutical composition described in embodiment 1, in the form of a suspension. 3. A topical pharmaceutical composition according to embodiment 1, which is a formulation selected from a gel, an ointment, and a cream. 4. A topical pharmaceutical composition according to embodiment 2, comprising: 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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (I)), or a pharmaceutically acceptable salt thereof. Including, The at least one pharmaceutically acceptable excipient is a vehicle, individually or in combination, that does not substantially dissolve Compound (I) or a pharmaceutically acceptable salt thereof; a moisturizing and / or emollient for retaining Compound (I) or a pharmaceutically acceptable salt thereof on the skin; a wetting agent to keep Compound (I) or a pharmaceutically acceptable salt thereof deaggregated; and thickener 1. A topical pharmaceutical composition comprising: 5. The topical pharmaceutical composition of embodiment 4, wherein Compound (I) or a pharmaceutically acceptable salt of Compound (I) is micronized. 6. Compound (I) or a pharmaceutically acceptable salt of Compound (I) is dispersed in a particle size distribution D in the range of 5 to 10 microns. 90 5. The topical pharmaceutical composition of embodiment 4, having 7. A topical pharmaceutical composition according to any one of embodiments 4 to 6, comprising: The vehicle is selected from water, mineral oil, and combinations thereof; The humectant and / or emollient comprises at least one of propylene glycol, glycerin, medium chain triglycerides, and combinations thereof; The wetting agent comprises at least one of polyethoxylated sorbitan and oleic acid (polysorbate 80), dimethicone (polydimethylsiloxane), and combinations thereof; A topical pharmaceutical composition, wherein the thickening agent comprises at least one of a cross-linked polyacrylic acid polymer (Carbopol® polymer), hydrogenated castor oil, microcrystalline wax, and combinations thereof. 8. A topical pharmaceutical composition according to any one of embodiments 4 to 7, comprising: about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); about 0.1% to about 20% by weight of natural glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.01% to about 0.5% by weight of methylparaben; about 0.01% to about 0.2% by weight of propylparaben; about 0.1% to about 4% by weight of a cross-linked polyacrylic acid polymer (Carbopol® 980 polymer); 10% (w / w) sodium hydroxide solution in an amount to adjust the pH to about 3.5 to about 8.5; and Add enough water to make up to 100ml 1. A topical pharmaceutical composition comprising: 9. The topical pharmaceutical composition of 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. 10. A topical pharmaceutical composition according to embodiment 8 or 9, comprising: about 0.1%, 0.5%, 2%, 5%, or 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; approximately 2% by weight of medium-chain triglycerides; approximately 2% by weight of polyethoxylated sorbitan and oleic acid (polysorbate 80); Approximately 5% by weight of natural glycerin; about 10% by weight propylene glycol; approximately 0.20% by weight of methylparaben; approximately 0.05% by weight propylparaben; about 0.75% by weight of cross-linked polyacrylic acid polymer (Carbopol® 980); 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to about 5.0±0.5; and Add enough water to make up to 100ml 1. A topical pharmaceutical composition comprising: 11. A topical pharmaceutical composition according to any one of embodiments 8 to 10, which is a gel formulation. 12. The topical pharmaceutical composition of any one of embodiments 4 to 6, about 0.1% to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of a microcrystalline wax; about 0.1% to about 10% by weight of hydrogenated castor oil; about 0.01% to about 10% by weight of dimethicone; and Mineral oil (up to 100%) 1. A topical pharmaceutical composition comprising: 13. The topical pharmaceutical composition of embodiment 12, wherein 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. 14. A topical pharmaceutical composition according to embodiment 12 or 13, comprising: about 0.1%, 0.5%, 2%, 5%, or 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; approximately 10% by weight of medium-chain triglycerides; about 5% by weight of microcrystalline wax; approximately 2% by weight of hydrogenated castor oil; about 3% by weight of dimethicone; and Mineral oil (up to 100%) 1. A topical pharmaceutical composition comprising: 15. A topical pharmaceutical composition described in embodiment 14, wherein the dimethicone has a viscosity of 12,500 centistokes (cSt). 16. A topical pharmaceutical composition described in any one of embodiments 12 to 14, which is an ointment formulation. 17. A topical pharmaceutical composition in the form of a cream for application to the skin of a subject, comprising: about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 1% to about 45% by weight of oleic acid; about 0.1% to about 20% by weight of glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.1% to about 5% by weight of benzyl alcohol; Acrylic acid and C crosslinked with allylpentaerythritol (Pemulen™ polymer) 10 ~C 30 about 0.1% to about 5% by weight of a high molecular weight copolymer of an alkyl acrylate; 10% (w / w) sodium hydroxide solution in an amount to adjust the pH to about 3.5 to about 8.5; and Add enough water to make up to 100ml 1. A topical pharmaceutical composition comprising: 18. A topical pharmaceutical composition according to embodiment 18, wherein the Pemulen™ polymer is Pemulen™ TR-1. 19. A topical pharmaceutical composition according to embodiment 17 or 18, comprising: about 0.2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof; about 25% by weight of oleic acid; about 5% by weight glycerin; about 5% by weight propylene glycol; about 1% by weight of benzyl alcohol; about 0.75% by weight of Pemulen™ TR-1 polymer; 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to about 4.5 to about 5.5; and Add enough water to make up to 100ml 1. A topical pharmaceutical composition comprising: 20. A topical pharmaceutical composition according to any one of embodiments 1 to 19, wherein the 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-enenitrile (Compound (I)) in free base form. 21. A topical pharmaceutical composition according to any one of embodiments 1 to 20, wherein the 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-enenitrile (Compound (I)), in amorphous or crystalline form, or a pharmaceutically acceptable salt thereof. 22. A topical pharmaceutical composition according to embodiment 21, wherein the crystalline form is crystalline form I or crystalline form II of the free base (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)). 23. A 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)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (I)) is the (E) isomer. 24. A method of treating a skin disorder mediated by Bruton's tyrosine kinase (BTK) in a mammal in need thereof, comprising: Topically administering to the skin of a mammal a topical pharmaceutical composition according to any one of embodiments 1 to 23. A method comprising: 25. In mammals requiring it, 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 dermatographia, alopecia, alopecia areata, vitiligo vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome 1. A method of treating a skin disorder selected from: erythematous rosacea, erythematous rosacea, papulopustular rosacea, neutrophilic dermatosis, chronic kidney disease-associated pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet's syndrome, comprising administering to said skin a therapeutically effective amount of steroids to said skin. Topically administering to the skin of a mammal a topical pharmaceutical composition according to any one of embodiments 1 to 23. A method comprising: 26. The method of embodiment 24 or 25, wherein the mammal is a human.

[0132] Example 2: Non-limiting embodiments of the present disclosure include: 1. at least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and at least one pH-dependent gelling agent 1. A pharmaceutical composition comprising: A pharmaceutical composition in the form of a gel. 2. The pharmaceutical composition of embodiment 1, comprising about 0.1% to about 4% by weight of at least one pH-dependent gelling agent. 3. The pharmaceutical composition of embodiment 1 or 2, wherein at least one pH-dependent gelling agent is selected from Carbopol® polymers. 4. A pharmaceutical composition described in any one of embodiments 1 to 3, wherein at least one pH-dependent gelling agent is a Carbopol® 980 polymer. 5. A pharmaceutical composition according to any one of embodiments 1 to 4, wherein at least one compound is at least partially suspended in a gel. 6. A pharmaceutical composition described in any one of embodiments 1 to 5, wherein at least one compound is substantially suspended in a gel. 7. A pharmaceutical composition according to any one of embodiments 1 to 6, wherein at least one compound is suspended in a gel. 8. A pharmaceutical composition described in any one of embodiments 1 to 7, further comprising at least one emollient or humectant. 9. The pharmaceutical composition of embodiment 8, comprising from about 0.1% to about 65% by weight of at least one emollient or humectant. 10. A pharmaceutical composition described in embodiment 8 or 9, wherein the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. 11. A pharmaceutical composition according to any one of embodiments 8 to 10, wherein at least one emollient or humectant is glycerin and propylene glycol. 12. A pharmaceutical composition described in any one of embodiments 1 to 11, further comprising at least one preservative. 13. The pharmaceutical composition of embodiment 12, comprising about 0.01% to about 0.7% by weight of at least one preservative. 14. The pharmaceutical composition of embodiment 12 or 13, wherein the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof. 15. A pharmaceutical composition according to any one of embodiments 12 to 14, wherein at least one preservative is methylparaben and propylparaben. 16. A pharmaceutical composition described in any one of embodiments 1 to 15, further comprising at least one lubricant. 17. The pharmaceutical composition of embodiment 16, comprising about 0.1% to about 20% by weight of at least one lubricant. 18. A pharmaceutical composition according to embodiment 16 or 17, wherein at least one lubricant is selected from medium-chain triglycerides. 19. A pharmaceutical composition described in any one of embodiments 1 to 18, further comprising at least one wetting agent. 20. The pharmaceutical composition of embodiment 19, comprising about 0.1% to about 20% by weight of at least one wetting agent. 21. A pharmaceutical composition described in embodiment 19 or 20, wherein at least one wetting agent is polysorbate 80. 22. A pharmaceutical composition described in any one of embodiments 1 to 21, further comprising at least one vehicle. 23. A pharmaceutical composition according to embodiment 22, wherein at least one vehicle is selected from an aqueous solution. 24. A pharmaceutical composition according to embodiment 22 or 23, wherein at least one vehicle is purified water. 25. A pharmaceutical composition described in any one of embodiments 1 to 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. 26. A pharmaceutical composition described in embodiment 25, wherein the value is in the range of about 4 to about 6. 27. A pharmaceutical composition described in embodiment 25 or 26, wherein the value is in the range of about 4.5 to about 5.5. 28. A pharmaceutical composition described in any one of embodiments 25 to 27, wherein the value is about 5. 29. The pharmaceutical composition of embodiment 4, about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of polysorbate 80; about 0.1% to about 20% by weight of glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.01% to about 0.5% by weight of methylparaben; about 0.01% to about 0.2% by weight of propylparaben; about 0.1% to about 4% by weight of Carbopol® 980 polymer; 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 Appropriate amount of purified water up to 100 A pharmaceutical composition comprising: 30. The pharmaceutical composition of embodiment 29, approximately 2% by weight of medium-chain triglycerides; approximately 2% by weight polysorbate 80; about 5% by weight glycerin; about 10% by weight propylene glycol; approximately 0.2% by weight of methylparaben; approximately 0.05% by weight of propylparaben; about 0.75% by weight of Carbopol® 980 polymer; 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 Appropriate amount of purified water up to 100 A pharmaceutical composition comprising: 31. At least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and At least one saturated hydrocarbon 1. A pharmaceutical composition comprising: A pharmaceutical composition in the form of an ointment. 32. The pharmaceutical composition of embodiment 31, wherein the at least one saturated hydrocarbon is selected from mineral oil, hydrogenated castor oil, and combinations thereof. 33. A pharmaceutical composition according to embodiment 31 or 32, wherein at least one saturated hydrocarbon is mineral oil and hydrogenated castor oil. 34. A pharmaceutical composition according to embodiment 32 or 33, wherein the mineral oil is selected from white mineral oils. 35. A pharmaceutical composition described in any one of embodiments 32 to 34, wherein the mineral oil is Kaydol white mineral oil. 36. A pharmaceutical composition according to any one of embodiments 31 to 35, wherein at least one compound is at least partially suspended in an ointment. 37. A pharmaceutical composition according to any one of embodiments 31 to 36, wherein at least one compound is substantially suspended in an ointment. 38. A pharmaceutical composition according to any one of embodiments 31 to 37, wherein at least one compound is suspended in an ointment. 39. A pharmaceutical composition described in any one of embodiments 31 to 38, further comprising at least one viscosity modifier. 40. The pharmaceutical composition of embodiment 39, comprising about 0.1% to about 20% by weight of at least one viscosity modifier. 41. A pharmaceutical composition described in embodiment 39 or 40, wherein at least one viscosity modifier is a microcrystalline wax. 42. A pharmaceutical composition according to any one of embodiments 31 to 41, further comprising at least one dispersing agent. 43. The pharmaceutical composition of embodiment 42, comprising about 0.01% to about 30% by weight of at least one dispersing agent. 44. A pharmaceutical composition described in embodiment 42 or 43, wherein at least one dispersing agent is selected from dimethicone, medium-chain triglycerides, and combinations thereof. 45. A pharmaceutical composition described in any one of embodiments 42-44, wherein at least one dispersing agent is dimethicone and a medium-chain triglyceride. 46. ​​A pharmaceutical composition described in embodiment 44 or 45, wherein the dimethicone has a viscosity of 12,500 centistokes (cSt). 47. A pharmaceutical composition according to embodiment 32, comprising: about 0.1% to about 20% by weight of medium-chain triglycerides; about 0.1% to about 20% by weight of a microcrystalline wax; about 0.1% to about 10% by weight of hydrogenated castor oil; about 0.01% to about 10% by weight of dimethicone; and 100g of white mineral oil A pharmaceutical composition comprising: 48. A pharmaceutical composition according to embodiment 47, comprising: approximately 10% by weight of medium-chain triglycerides; about 5% by weight of microcrystalline wax; approximately 2% by weight of hydrogenated castor oil; about 3% by weight of dimethicone; and 100g of white mineral oil A pharmaceutical composition comprising: 49. At least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and At least one lytic agent 1. A pharmaceutical composition comprising: A pharmaceutical composition in the form of a cream. 50. The pharmaceutical composition of embodiment 49, comprising about 1% to about 45% by weight of at least one dissolution agent. 51. A pharmaceutical composition described in embodiment 49 or 50, wherein at least one dissolution agent is oleic acid. 52. A pharmaceutical composition according to any one of embodiments 49 to 51, wherein at least one compound is at least partially dissolved in the cream. 53. A pharmaceutical composition described in any one of embodiments 49-52, wherein at least one compound is substantially dissolved in the cream. 54. A pharmaceutical composition described in any one of embodiments 49 to 53, wherein at least one compound is dissolved in a cream. 55. A pharmaceutical composition described in any one of embodiments 49 to 54, further comprising at least one gelling emulsifier. 56. A pharmaceutical composition described in embodiment 55, comprising about 0.1% by weight to about 5% by weight of at least one gelling emulsifier. 57. A pharmaceutical composition according to embodiment 55 or 56, wherein at least one gelling emulsifier is selected from Pemulen™ polymers. 58. A pharmaceutical composition described in any one of embodiments 55 to 57, wherein at least one gelling emulsifier is Pemulen™ TR-1. 59. A pharmaceutical composition described in any one of embodiments 49 to 58, further comprising at least one alcohol. 60. A pharmaceutical composition described in embodiment 59, comprising about 0.1% to about 5% by weight of at least one alcohol. 61. A pharmaceutical composition according to embodiment 59 or 60, wherein at least one alcohol is benzyl alcohol. 62. A pharmaceutical composition described in any one of embodiments 49 to 61, further comprising at least one emollient or humectant. 63. A pharmaceutical composition described in embodiment 62, comprising about 0.1% to about 65% by weight of at least one emollient or humectant. 64. A pharmaceutical composition described in embodiment 62 or 63, wherein at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof. 65. A pharmaceutical composition described in any one of embodiments 62-64, wherein at least one emollient or humectant is glycerin and propylene glycol. 66. A pharmaceutical composition described in any one of embodiments 49 to 65, further comprising at least one vehicle. 67. A pharmaceutical composition according to embodiment 66, wherein at least one vehicle is selected from an aqueous solution. 68. A pharmaceutical composition according to embodiment 66 or 67, wherein at least one vehicle is purified water. 69. A pharmaceutical composition described in any one of embodiments 49 to 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. 70. A pharmaceutical composition described in embodiment 69, wherein the value is in the range of about 4 to about 6. 71. A pharmaceutical composition described in embodiment 69 or 70, wherein the value is in the range of about 4.5 to about 5.5. 72. A pharmaceutical composition described in any one of embodiments 69 to 71, wherein the value is about 5. 73. A pharmaceutical composition according to embodiment 49, comprising: about 1% to about 45% by weight of oleic acid; about 0.1% to about 20% by weight of glycerin; about 0.1% to about 45% by weight of propylene glycol; about 0.1% to about 5% by weight of benzyl alcohol; about 0.1% to about 5% by weight of Pemulen™ polymer; 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 Appropriate amount of purified water up to 100 A pharmaceutical composition comprising: 74. A pharmaceutical composition according to embodiment 73, comprising: about 10% by weight of oleic acid; about 5% by weight glycerin; about 5% by weight propylene glycol; about 1% by weight of benzyl alcohol; about 0.75% by weight of Pemulen™ polymer; 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 Appropriate amount of purified water up to 100 A pharmaceutical composition comprising: 75. A pharmaceutical composition described in any one of embodiments 49 to 74, comprising from about 0.01% to about 2% by weight of at least one compound. 76. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 0.1% to about 10% by weight of at least one compound. 77. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 0.5% by weight of at least one compound. 78. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising at least about 0.5% by weight of at least one compound. 79. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 1% by weight of at least one compound. 80. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 2% by weight of at least one compound. 81. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 5% by weight of at least one compound. 82. A pharmaceutical composition described in any one of embodiments 1 to 74, comprising about 10% by weight of at least one compound. 83. The pharmaceutical composition of any one of embodiments 1-82, wherein at least about 95% by weight of 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-enenitrile. 84. A pharmaceutical composition according to any one of embodiments 1-83, wherein at least about 95% by weight of at least one compound is the (E) isomer. 85. The pharmaceutical composition of embodiment 83 or 84, wherein at least one compound is substantially amorphous. 86. A pharmaceutical composition according to any one of embodiments 83-85, wherein at least one compound is micronized. 87. At least one compound has a particle size distribution D in the range of about 5 to about 10 microns. 90 87. The pharmaceutical composition of embodiment 86, having the formula: 88. The pharmaceutical composition of any one of embodiments 1-84, wherein at least one compound is crystalline. 89. The pharmaceutical composition of any one of embodiments 1-88, wherein at least one compound is in crystalline form (I). 90. The pharmaceutical composition of embodiment 89, wherein the crystalline form (I) is characterized by an X-ray powder diffraction pattern having signals 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. 91. The pharmaceutical composition of embodiment 89, wherein the crystalline form (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1. 92. The pharmaceutical composition of any one of embodiments 89-91, wherein the crystalline form (I) is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 177°C to about 178°C. 93. The pharmaceutical composition of any one of embodiments 89-92, wherein crystalline form (I) is characterized by a DSC thermogram showing an onset of melting at about 174.8°C to about 175.2°C. 94. The pharmaceutical composition according to embodiment 89, wherein the crystalline form (I) is adding 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; stirring the solution to form a precipitate; and Isolating the crystalline form (I) by filtration A pharmaceutical composition produced by a method comprising: 95. A pharmaceutical composition described in any one of embodiments 1-88, wherein at least one compound is in crystalline form (II). 96. The pharmaceutical composition of embodiment 95, wherein the crystalline form (II) is characterized by an X-ray powder diffraction pattern having signals 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. 97. The pharmaceutical composition of embodiment 95, wherein crystalline form (II) is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 3. 98. The pharmaceutical composition of any one of embodiments 95 to 97, wherein crystalline form (II) is characterized by a DSC thermogram having an endothermic peak (melting temperature) at about 170.0°C to about 170.2°C. 99. The pharmaceutical composition of any one of embodiments 95-98, wherein crystalline form (II) is characterized by a DSC thermogram showing an onset of melting at about 167.2°C to about 167.6°C. 100. A pharmaceutical composition described in any one of embodiments 95 to 99, wherein crystalline form (II) is characterized by a mass loss of less than 1.5 wt.% between 35°C and 220°C by thermogravimetric analysis. 101. The pharmaceutical composition according to embodiment 95, wherein the crystalline form (II) is 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 t-butyl ether to form a solution; stirring the solution to form a precipitate; and Isolating the crystalline form (II) by filtration A pharmaceutical composition produced by a method comprising: 102. A method for treating a skin disorder in a mammal in need thereof, comprising topically administering to at least a portion of the skin of the mammalian subject at least one topical pharmaceutical composition described in any one of embodiments 1 to 101. 103. The method of embodiment 102, wherein the skin disorder is mediated by BTK. 104. Skin disorders include 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 dermatographia, alopecia, alopecia areata, vitiligo vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, in mammals requiring it. 104. The method of embodiment 102 or 103, wherein the skin rash is selected from the group consisting of erythematous ulcerative colitis, inflammatory bowel disease (IGF), ... 105. A pharmaceutical composition described in any one of embodiments 102 to 104, wherein the skin disorder is pemphigus vulgaris. 106. A pharmaceutical composition described in any one of embodiments 102 to 104, wherein the skin disorder is pemphigus foliaceus. 107. A pharmaceutical composition described in any one of embodiments 102 to 104, wherein the skin disorder is atopic dermatitis. 108. A pharmaceutical composition described in any one of embodiments 102 to 107, wherein the mammal is a human. 109. A pharmaceutical composition described in any one of embodiments 102 to 107, wherein the mammal is a dog. 110. A pharmaceutical composition described in any one of embodiments 102 to 107, wherein the mammal is a cat. 111. A pharmaceutical composition described in any one of embodiments 102 to 107, wherein the mammal is not a human.

[0133] Compound (I) in crystalline form (I) In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising Compound (I) in crystalline form (I). [ka]

[0134] FIG. 1 shows the X-ray powder diffraction diagram for compound (I) in crystalline form (I).

[0135] 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 an endothermic peak (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 an 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 an onset of melting at about 174.8°C to about 175.2°C. In some embodiments, the associated enthalpy is about 85 J / g (ΔH=85 J / g).

[0136] In some embodiments, crystalline form (I) of Compound (I) is characterized by a DSC thermogram substantially similar to that of FIG.

[0137] FIG. 2 also shows the TGA thermal curve of Compound (I) in crystalline form (I).

[0138] In some embodiments, Compound (I) in crystalline form (I) is a white solid.

[0139] In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 1.

[0140] [Table 1-1] [Table 1-2]

[0141] In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.3±0.2°2-theta. In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 12.6±0.2°2-theta. In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.2±0.2°2-theta. In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.6±0.2°2-theta. In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.2±0.2°2-theta. In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.4±0.2°2-theta. In some embodiments, Compound (I) in crystalline form (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.1±0.2 degrees two-theta.

[0142] In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern having signals 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.

[0143] In some embodiments, crystalline form (I) of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG.

[0144] In some embodiments, the topical pharmaceutical composition comprises Compound (I) in crystalline form (I) prepared by a process comprising adding 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. In some embodiments, the process further comprises stirring the solution to form a precipitate. In some embodiments, the process further comprises isolating crystalline form (I) by filtration.

[0145] A method for making crystalline form (I) of Compound (I) is disclosed in Example 1.

[0146] Crystalline Form II of Compound (I) In some embodiments, the present disclosure provides a topical pharmaceutical composition comprising crystalline form (II) of Compound (I). [ka]

[0147] FIG. 3 shows the X-ray powder diffraction diagram for crystalline form (II) of compound (I).

[0148] 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 an endothermic peak (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 an 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 (ΔH=68 J / g).

[0149] In some embodiments, crystalline form (II) of Compound (I) is characterized by a DSC thermogram substantially similar to that of FIG.

[0150] 4 also shows the TGA thermal curve 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.

[0151] Crystalline form (II) cannot be converted to crystalline form (I) by heating or cooling.

[0152] In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis with an incident beam of Cu-Kα radiation having signals substantially similar to those set forth in Table 2.

[0153] [Table 2-1] [Table 2-2]

[0154] In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.3±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.2±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.0±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.6±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.0±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.8±0.2°2-theta. In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 27.5±0.2°2-theta.

[0155] In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffractogram having signals 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.

[0156] In some embodiments, crystalline form (II) of Compound (I) is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG.

[0157] In some embodiments, the topical pharmaceutical composition comprises crystalline form (II) of Compound (I) prepared by a process comprising 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 t-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 crystalline form (II) by filtration.

[0158] A method for making crystalline form (II) of Compound (I) is disclosed in Example 2.

[0159] Topical Pharmaceutical Compositions Compound (I), pharmaceutically acceptable salts thereof, and solid forms of Compound (I) (e.g., crystalline forms of Compound (I)) described herein are useful as active pharmaceutical ingredients (APIs) and as materials for preparing topical pharmaceutical compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration to mammals, such as human subjects (e.g., topical administration to the skin). In some embodiments, these topical pharmaceutical compositions are pharmaceutical products, such as, for example, suspensions, solutions, or combinations thereof.

[0160] 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 crystalline Form (I) and crystalline 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 crystalline Form (I) and crystalline Form (II), and at least one pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable," in the sense of being compatible with the subject composition and not harmful to the patient. Use of any conventional pharmaceutically acceptable excipient is considered within the scope of the present disclosure unless it is incompatible with Compound (I), such as by producing any undesirable biological effect or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.

[0161] 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.

[0162] 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.

[0163] In some embodiments, the topical pharmaceutical composition comprises at least one pharmaceutically acceptable additive. Pharmaceutically acceptable additives include different classes of ingredients, such as, but not limited to, vehicles, humectants, emollients, moisturizers, thickeners, fillers, surfactants, excipients, binders, glidants, lubricants, and any combination thereof. Some non-limiting examples of materials that can serve as pharmaceutically acceptable additives include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, 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; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0164] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, D.B. Troy, ed., Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C.B. Boylan, eds., 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.

[0165] The pharmaceutical compositions disclosed herein can be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.

[0166] The topical pharmaceutical composition may be in the form of a suitable gel, ointment, or cream.

[0167] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof can be suspended or dissolved in at least one additive to form an ointment. Additives for topical administration include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.

[0168] 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 Carbopol® polymers. In some embodiments, the Carbopol® polymer is Carbopol® 980 polymer. In some embodiments, the gel further comprises at least one preservative. In some embodiments, the at least one preservative is selected from 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 humectant. In some embodiments, the at least one humectant is selected from 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 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 an aqueous solution. In some embodiments, the aqueous solution is purified water. In some embodiments, the at least one vehicle does not substantially dissolve Compound (I) or a pharmaceutically acceptable salt thereof.

[0169] 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.

[0170] 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.

[0171] In some embodiments, the gel comprising Compound (I) or a pharmaceutically acceptable salt thereof is at least one pH-dependent gelling agent; At least one emollient or moisturizer; at least one preservative; At least one lubricant; at least one wetting agent; and At least one vehicle and further comprising 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:

[0172] In some embodiments, the at least one pH-dependent gelling agent is selected from Carbopol® polymers. In some embodiments, the Carbopol® polymer is Carbopol® 980 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.

[0173] 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.

[0174] 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.

[0175] In some embodiments, the gel comprising Compound (I) or a pharmaceutically acceptable salt thereof is at least one pH-dependent gelling agent; At least one emollient or moisturizer; at least one preservative; At least one lubricant; at least one wetting agent; and At least one vehicle Further includes:

[0176] In some embodiments, the at least one pH-dependent gelling agent is selected from Carbopol® polymers. In some embodiments, the Carbopol® polymer is Carbopol® 980 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.

[0177] 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.

[0178] 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.

[0179] In some embodiments, the gel comprising Compound (I) or a pharmaceutically acceptable salt thereof is about 0.1% to about 4% by weight of at least one pH-dependent gelling agent; about 0.1% to about 65% by weight of at least one emollient or humectant; about 0.01% to about 0.7% by weight of at least one preservative; about 0.1% to about 20% by weight of at least one lubricant; about 0.1% to about 20% by weight of at least one humectant; and At least one vehicle further comprising It contains about 0.1% by weight to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the at least one pH-dependent gelling agent is selected from Carbopol® polymers. In some embodiments, the Carbopol® polymer is Carbopol® 980 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.

[0181] 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.

[0182] 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.

[0183] In some embodiments, the topical pharmaceutical compositions disclosed herein can be formulated in a suitable lotion or cream containing Compound (I) or a pharmaceutically acceptable salt thereof suspended or dissolved in at least one pharmaceutically acceptable excipient, including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, polysorbate 80, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0184] In some embodiments, the topical pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof is 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 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 dimethicone, medium-chain triglycerides, and combinations thereof.

[0185] In some embodiments, the ointment contains about 0.5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 1% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0186] 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.

[0187] In some embodiments, an ointment comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises at least one saturated hydrocarbon; at least one viscosity modifier; and at least one dispersant Further comprising at least one (e.g., one, two, three, or at least two) component selected from:

[0188] In some embodiments, the at least one saturated hydrocarbon is selected from 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 dimethicone, medium-chain triglycerides, and combinations thereof.

[0189] In some embodiments, the ointment contains about 0.5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 1% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0190] 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.

[0191] In some embodiments, an ointment comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises at least one saturated hydrocarbon; at least one viscosity modifier; and at least one dispersant Further includes:

[0192] In some embodiments, the at least one saturated hydrocarbon is selected from 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 dimethicone, medium-chain triglycerides, and combinations thereof.

[0193] In some embodiments, the ointment contains about 0.5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 1% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0194] 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.

[0195] In some embodiments, an ointment comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises at least one saturated hydrocarbon; about 0.1% to about 20% by weight of at least one viscosity modifier; and about 0.01% to about 30% by weight of at least one dispersing agent further comprising It contains about 0.1% by weight to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the at least one saturated hydrocarbon is selected from 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 dimethicone, medium-chain triglycerides, and combinations thereof.

[0197] In some embodiments, the ointment contains about 0.5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 1% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 5% by weight of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ointment contains about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0198] 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.

[0199] 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™ polymers. In some embodiments, the Pemulen™ polymer is Pemulen™ 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 an aqueous solution. In some embodiments, the aqueous solution is purified water.

[0200] In some embodiments, the cream comprises about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0201] 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.

[0202] 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.

[0203] In some embodiments, a cream comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises at least one lytic agent; at least one gelling emulsifier; At least one alcoholic beverage; at least one emollient or moisturizer; and At least one vehicle Further comprising at least one (e.g., 1, 2, 3, 4, 5, at least 2, at least 3, or at least 4) component selected from:

[0204] In some embodiments, the at least one solubilizing agent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen™ polymers. In some embodiments, the Pemulen™ polymer is Pemulen™ 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 vehicle is selected from an aqueous solution. In some embodiments, the aqueous solution is purified water.

[0205] In some embodiments, the cream comprises about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0206] 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.

[0207] 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.

[0208] In some embodiments, a cream comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises at least one lytic agent; at least one gelling emulsifier; At least one alcoholic beverage; at least one emollient or moisturizer; and At least one vehicle Further includes:

[0209] In some embodiments, the at least one solubilizing agent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen™ polymers. In some embodiments, the Pemulen™ polymer is Pemulen™ 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 vehicle is selected from an aqueous solution. In some embodiments, the aqueous solution is purified water.

[0210] In some embodiments, the cream comprises about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0211] 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.

[0212] 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.

[0213] In some embodiments, a cream comprising Compound (I) or a pharmaceutically acceptable salt thereof comprises about 1% to about 45% by weight of at least one solubilizing agent; about 0.1% to about 5% by weight of at least one gelling emulsifier; about 0.1% to about 5% by weight of at least one alcohol; about 0.1% to about 65% by weight of at least one emollient or humectant; and At least one vehicle further comprising It contains about 0.01% by weight to about 10% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the at least one solubilizing agent is oleic acid. In some embodiments, the at least one gelling emulsifier is selected from Pemulen™ polymers. In some embodiments, the Pemulen™ polymer is Pemulen™ 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 vehicle is selected from an aqueous solution. In some embodiments, the aqueous solution is purified water.

[0215] In some embodiments, the cream comprises about 0.01% to about 2% by weight of Compound (I) or a pharmaceutically acceptable salt thereof.

[0216] 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.

[0217] 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.

[0218] index The topical pharmaceutical compositions described herein may be useful for treating skin conditions mediated by BTK activity in mammals, such as skin disorders. In some embodiments, the topical pharmaceutical compositions can be used to treat humans or non-humans. In some embodiments, the topical pharmaceutical compositions can be used to treat humans. In some embodiments, the topical pharmaceutical compositions can be used to treat non-humans. In some embodiments, the topical pharmaceutical compositions can be used to treat dogs. In some embodiments, the topical pharmaceutical compositions can be used to treat cats.

[0219] 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 vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Johnson syndrome, TEN (toxic epidermal necrolysis), drug rash, folliculitis barbae, pseudofolliculitis barbae, leukocytoclastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, dermatitis herpetiformis, rosacea, erythema rosacea, papulopustular rosacea, neutrophilic dermatosis, chronic kidney disease-associated pruritus, end-stage renal disease-induced pruritus, acne, mycosis fungoides, and Sweet's syndrome.

[0220] 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.

[0221] In some embodiments, the skin disorder is atopic dermatitis.

[0222] dosage Generally, the effective dose of the topical pharmaceutical compositions of the present disclosure for any particular mammal (e.g., any particular human) will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the particular pharmaceutical composition utilized; the mammal's age, weight, general health, sex, and diet; the time of administration, the duration of treatment; and similar factors well known in the medical arts. A therapeutically effective amount of Compound (I) may range, for example, from 0.01 to 500 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Suitable dosage levels may be, for example, from 0.01 to 250 mg / kg per day, from 0.05 to 100 mg / kg per day, or from 0.1 to 50 mg / kg per day. Within this range, in some embodiments, the dosage may be from 0.05 to 0.5, from 0.5 to 5, or from 5 to 50 mg / kg per day.

[0223] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0224] A claim or description including "or" or "and / or" between at least one member of a group is deemed to be satisfied when one, more than one, or all of the group members are present in, utilized in, or relevant to a given product or process, unless indicated to the contrary or clear from the context. The present disclosure includes embodiments in which exactly one member of a group is present in, utilized in, or relevant to a given product or process. The present disclosure includes embodiments in which two or more or all group members are present in, utilized in, or relevant to a given product or process.

[0225] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, any claim that depends on another claim can be amended to include at least one limitation found in any other claim that depends from the same basic claim. When elements are presented as a list, for example, in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the present disclosure or aspects of the disclosure are referred to as including particular elements and / or features, it should be understood that embodiments of the disclosure or aspects of the disclosure consist of or consist essentially of such elements and / or features. For simplicity, these embodiments are not specifically described in these terms herein. When ranges are presented, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any specific value or subrange within the ranges described in different embodiments of this disclosure, down to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [Example]

[0226] The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way.

[0227] Common methods: Screening of crystalline forms of Compound (I) was performed using multiple solvents and three different crystallization techniques to obtain multiple crystalline forms of Compound (I), e.g., crystalline Form (I) and crystalline Form (II). Briefly, the three different crystallization techniques were thermal cycling (TC), rapid cooling (RC), and slow evaporation (EV). To prepare crystalline forms of Compound (I) by thermal cycling, a slurry containing Compound (I) was temperature cycled between 5°C and 40°C for 36 hours, followed by equilibration at 25°C for 8 hours. To prepare crystalline forms of Compound (I) through rapid cooling, a clarified saturated solution of Compound (I) was rapidly cooled from 25°C to 4°C and held at 4°C for 48 hours. To prepare crystalline forms of Compound (I) by slow evaporation, a solution containing Compound (I) was subjected to slow evaporation for up to 10 days. The solvents and solvent systems used to obtain crystalline forms (I) and (II) are shown in Table 3 below.

[0228] [Table 3-1] [Table 3-2] [Example]

[0229] Preparation of crystalline form I of compound (I) 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)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (1.0 g) and stirred to form a solution. After approximately 5 minutes of stirring, a precipitate began to form. Additional MIBK (10 mL) was charged and the slurry was stirred. After approximately 10 days, the solid was filtered and rinsed with MIBK (10 mL). The solid was dried under vacuum with heating to give approximately 0.5 g of crystalline form (I) 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 as a white solid. XRPD (2theta): 12.6, 15.7, 16.2, 18.3, 18.4, 22.1; DSC: onset 175° C., melt 177.6° C. [Example]

[0230] Preparation of crystalline form II of compound (I) 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 (1.0 g) was dissolved in methyl t-butyl ether (MTBE, 4 mL). The solution was stirred at room temperature. After approximately 5 minutes, a precipitate began to form. To the slurry was charged additional MTBE (approximately 10 mL). The solid was filtered and dried under vacuum to obtain approximately 0.7 g of crystalline Form II 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. XRPD (2 theta): 15.2, 16.6, 17.6, 20.0, 24.8; DSC: onset 167°C, melt 170°C. [Example]

[0231] Rat Arthus test The IgG-mediated acute Arthus rat model was utilized as an in vivo pharmacological screen, with commercial betamethasone used as a control. Two endpoints were assessed: (1) measurement of pigment diameter after dosing; and (2) measurement of pigment density after dosing.

[0232] Thirty female SD rats (120-130 g) were received, housed individually, and quarantined. The rats' ears were dissected for rat identification purposes. Following quarantine, the rats selected for testing were assigned to six groups of five rats each; each group had approximately the same average body weight.

[0233] On day 1, the rats' backs were shaved, and their weights were recorded on day 0. Three hours after anesthesia and intradermal injection of rabbit anti-ovalbumin IgG (T=-3 hours), the rats were fitted with an Elizabethan collar and topically dosed with Compound (I) in Carbopol gel suspension 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].

[0234] [Table 4]

[0235] At T=0, rats in the study were anesthetized and injected intradermally with rabbit anti-ovalbumin IgG (50 μg in 25 μL) at three different sites on one side of the back and with isotype rabbit IgG at three different sites on the other side of the back. Four hours later, rats were euthanized, and the skin was peeled from the rat's back and everted. The diameter of the EBD leakage was measured for area calculations, and punch biopsies (approximately 8 mm) centered near the injection site were incubated overnight at 80°C in 2 mL of formamide to remove the EBD. 610nm The topical pharmaceutical formulation of a suspending gel showed promising results in this study.

[0236] Promising results were also observed at extended time points to 16 hours prior to antibody challenge (multiple-day dosing study). In a single-day dosing study, the topical formulation demonstrated steroid-like efficacy at 3 and 16 hours with 1% Compound (I) in a gel formulation. Steroid-like efficacy was also observed in a 3-day dosing study with 0.5% Compound (I) in a gel formulation at 3 and 16 hours, comparable to betamethasone after 3 days of application.

[0237] 5A and 5B show the results of IgG (FcgR) inhibition in a rat Arthus (macrophage / neutrophil) model at 3 hours in a 3-day dosing study. The data demonstrate that topical pharmaceutical suspension gel formulations of the present disclosure provide steroid-like efficacy at 0.5% or greater Compound (I) in the gel formulation following multi-day dosing with the final dose 3 hours prior to IgG challenge.

[0238] The IgG-mediated acute Arthus rat model was also used to screen certain ointment suspension formulations of Compound (I). Figures 6A and 6B show the results of the ointment suspension in a 1-day dosing study, and Figures 7A and 7B show the results of the ointment suspension in a 3-day dosing study. [Example]

[0239] Skin penetration of compound (I) into the dermis and epidermis Compound (I) can penetrate human abdominal skin (500±50 μm) from elective surgery into the dermis and epidermis at 10 mg / cm using skin from one donor (n=4-5 replicates per condition) and a receptor solution containing phosphate / citrate buffer at pH 5.6 with 0.01% Brij 98. 2A dose of Compound (I) was applied in one of three 2% Compound (I) gel formulations containing crystalline Form (I), amorphous Compound (I), or one of crystalline Form (II). Samples were collected every 3 hours for 24 hours. Residual formulation was removed from the skin surface before separating the epidermis and dermis. The skin surface was then tape-stripped up to five times to remove residual formulation and the upper surface layer of the skin (stratum corneum). The dermis and epidermis were separated by heating to 60°C for 2 minutes, followed by manual separation using forceps. The extraction solution used was 90:10 acetonitrile:water containing 0.1% BHT. The epidermal and dermal samples were homogenized, then shaken at 130 RPM overnight and transferred to a LoBind DW96 plate.

[0240] Table 5 and Figure 8 show the average amount (ng) of Compound (I) delivered to the epidermis and dermis 24 hours after application of three 2% formulation variants containing crystalline form (I) of Compound (I), amorphous Compound (I), and one of crystalline form (II) of Compound (I). No significant differences in skin penetration ability were observed between the different formulations containing different forms of Compound (I) (the two crystalline forms and the amorphous form), even when Compound (I) was in the form of a suspension.

[0241] [Table 5] [Example]

[0242] Carbopol Gel Suspension Example Exemplary formulations containing Compound (I) and Carbopol in the form of a gel suspension were prepared as shown below in Table 6. Carbopol is a high molecular weight synthetic polymer of acrylic acid that acts as a pH-dependent gelling agent.

[0243] [Table 6]

[0244] Methylparaben and propylparaben were added as preservatives. Propylene glycol acted as a good solvent to dissolve the preservatives. Polysorbate 80 acts as a humectant to aid in the disaggregation of Compound (I), typically in suspension. Medium-chain triglycerides were added as lubricants, while glycerin and propylene glycol were added as skin moisturizers. [Example]

[0245] Ointment suspension example Examples of formulations containing Compound (I) in the form of an ointment suspension are shown in Table 7 below.

[0246] [Table 7]

[0247] The mineral oil / hydrogenated castor oil suspension of Compound (I) exhibited excellent high-temperature suspension properties. Dimethicone and medium-chain triglycerides were added to disperse Compound (I), while microcrystalline wax was added as a viscosity modifier. [Example]

[0248] Cream formulation example An example of a formulation containing Compound (I) in the form of a dissolved cream is shown below in Table 8. Pemulen™ TR-1 was selected as the gelling emulsifier for the cream formulation so that the product could be manufactured at room temperature, avoiding potential heat-causing degradation during the manufacturing process.

[0249] [Table 8] [Example]

[0250] Stability testing The formulations in Tables 6-8 were prepared and placed in scintillation vials for safety monitoring at 25°C and 40°C. Non-micronized Compound (I) was used in the safety studies. During 2.5 months of safety testing at 25°C and 40°C, total impurities did not exceed 1% for the Carbopol gel and ointment containing Compound (I).

[0251] [Table 9]

[0252] Additional stability studies were conducted on both ointment and gel suspensions containing micronized Compound (I). Safety data for the formulation examples are summarized in Table 10.

[0253] [Table 10]

[0254] The formulations were stable for 3 months at 25°C, and both 5% formulations were stable for 3 months at 40°C, although some phase separation was observed between the vehicle and drug particles for the ointment suspension at 40°C.

[0255] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. at least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and At least one pH-dependent gelling agent 1. A pharmaceutical composition comprising: The pharmaceutical composition is in the form of a gel.

2. 10. The pharmaceutical composition of claim 1, comprising 0.1±0.005% to 4±0.2% by weight of at least one pH-dependent gelling agent.

3. 3. The pharmaceutical composition of claim 1, wherein at least one pH-dependent gelling agent is a Carbopol® polymer.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the at least one compound is suspended in a gel.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, further comprising at least one emollient or humectant.

6. 6. The pharmaceutical composition of claim 5, comprising 0.1±0.005% to 65±3.25% by weight of at least one emollient or humectant.

7. 7. The pharmaceutical composition of claim 5 or 6, wherein the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, further comprising at least one preservative.

9. 9. The pharmaceutical composition of claim 8, comprising 0.01±0.0005% to 0.7±0.035% by weight of at least one preservative.

10. 10. The pharmaceutical composition of claim 8 or 9, wherein the at least one preservative is selected from methylparaben, propylparaben, and combinations thereof.

11. The pharmaceutical composition according to any one of claims 1 to 10, further comprising at least one lubricant.

12. 12. The pharmaceutical composition of claim 11, comprising 0.1±0.005% to 20±1% by weight of at least one lubricant.

13. 13. The pharmaceutical composition of claim 11 or 12, wherein at least one lubricant is selected from medium chain triglycerides.

14. The pharmaceutical composition according to any one of claims 1 to 13, further comprising at least one wetting agent.

15. 15. The pharmaceutical composition of claim 14, comprising 0.1±0.005% to 20±1% by weight of at least one wetting agent.

16. 16. The pharmaceutical composition of claim 14 or 15, wherein at least one wetting agent is polysorbate 80.

17. The pharmaceutical composition according to any one of claims 1 to 16, further comprising at least one vehicle.

18. 2. The pharmaceutical composition of claim 1, 0.1±0.005% to 20±1% by weight of medium chain triglycerides; 0.1±0.005% to 20±1% by weight of polysorbate 80; 0.1±0.005% to 20±1% by weight of glycerin; 0.1±0.005% to 45±2.25% by weight of propylene glycol; 0.01±0.0005% to 0.5±0.025% by weight of methylparaben; 0.01±0.0005% to 0.2±0.01% by weight of propylparaben; 0.1±0.005% to 4±0.2% by weight of Carbopol® 980 polymer; 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 4±0.2 to 6±0.3; and Appropriate amount of purified water up to 100 The pharmaceutical composition comprising:

19. at least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and at least one saturated hydrocarbon 1. A pharmaceutical composition comprising: The pharmaceutical composition is in the form of an ointment.

20. The at least one saturated hydrocarbon is selected from mineral oil, hydrogenated castor oil, and combinations thereof. The pharmaceutical composition of claim 19.

21. 21. The pharmaceutical composition of claim 19 or 20, wherein the at least one compound is suspended in an ointment.

22. The pharmaceutical composition according to any one of claims 19 to 21, further comprising at least one viscosity modifier.

23. 23. The pharmaceutical composition of claim 22, comprising 0.1±0.005% to 20±1% by weight of at least one viscosity modifier.

24. 24. The pharmaceutical composition of claim 22 or 23, wherein at least one viscosity modifier is a microcrystalline wax.

25. The pharmaceutical composition according to any one of claims 19 to 24, further comprising at least one dispersing agent.

26. 26. The pharmaceutical composition of claim 25, comprising 0.01±0.0005% to 30±1.5% by weight of at least one dispersing agent.

27. 27. The pharmaceutical composition of claim 25 or 26, wherein the at least one dispersing agent is selected from dimethicone, medium chain triglycerides, and combinations thereof.

28. 20. The pharmaceutical composition of claim 19, 0.1±0.005% to 20±1% by weight of medium chain triglycerides; 0.1±0.005% to 20±1% by weight of microcrystalline wax; 0.1±0.005% to 10±0.5% by weight of hydrogenated castor oil; 0.01±0.0005% to 10±0.5% by weight of dimethicone; and White mineral oil (approximately 100%) The pharmaceutical composition comprising:

29. at least one compound 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-enenitrile, and pharmaceutically acceptable salts thereof; and At least one lysis agent 1. A pharmaceutical composition comprising: The pharmaceutical composition is in the form of a cream.

30. 30. The pharmaceutical composition of claim 29, comprising 1±0.05% to 45±2.25% by weight of at least one dissolution agent.

31. 31. The pharmaceutical composition of claim 29 or 30, wherein at least one dissolution agent is oleic acid.

32. The pharmaceutical composition according to any one of claims 29 to 31, wherein the at least one compound is dissolved in a cream.

33. 33. The pharmaceutical composition of any one of claims 29 to 32, further comprising at least one gelling emulsifier.

34. 34. The pharmaceutical composition of claim 33, comprising 0.1±0.005% to 5±0.25% by weight of at least one gelling emulsifier.

35. 35. The pharmaceutical composition of claim 33 or 34, wherein at least one gelling emulsifier is Pemulen™ TR-1.

36. 36. The pharmaceutical composition of any one of claims 29 to 35, further comprising at least one alcohol.

37. 37. The pharmaceutical composition of claim 36, comprising 0.1±0.005% to 5±0.25% by weight of at least one alcohol.

38. 38. The pharmaceutical composition of any one of claims 29 to 37, further comprising at least one emollient or humectant.

39. 39. The pharmaceutical composition of claim 38, comprising 0.1±0.005% to 65±3.25% by weight of at least one emollient or humectant.

40. 40. The pharmaceutical composition of claim 38 or 39, wherein the at least one emollient or humectant is selected from glycerin, propylene glycol, and combinations thereof.

41. The pharmaceutical composition according to any one of claims 29 to 40, further comprising at least one vehicle.

42. 30. The pharmaceutical composition of claim 29, 1±0.05% to 45±2.25% by weight of oleic acid; 0.1±0.005% to 20±1% by weight of glycerin; 0.1±0.005% to 45±2.25% by weight of propylene glycol; 0.1±0.005% to 5±0.25% by weight of benzyl alcohol; 0.1±0.005% to 5±0.25% by weight of Pemulen™ polymer; a 10% (w / w) sodium hydroxide solution in an amount sufficient to adjust the pH to a value in the range of 4±0.2 to 6±0.3; and Appropriate amount of purified water up to 100 The pharmaceutical composition comprising:

43. 43. The pharmaceutical composition of any one of claims 1 to 42, comprising 0.1±0.005% to 10±0.5% by weight of at least one compound.

44. 44. The pharmaceutical composition of any one of claims 1 to 43, comprising at least 0.5±0.025% by weight of the at least one compound.

45. 45. The pharmaceutical composition of any one of claims 1 to 44, comprising 1±0.05% by weight of at least one compound.

46. 45. The pharmaceutical composition of any one of claims 1 to 44, comprising 2±0.1% by weight of at least one compound.

47. At least 95±4.75% by weight of at least one compound is (R)-2-(3-( The pharmaceutical composition of any one of claims 1 to 46, which is 4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.

48. 48. The pharmaceutical composition of any one of claims 1 to 47, wherein at least 95±4.75% by weight of at least one compound is the (E) isomer.

49. 49. The pharmaceutical composition of any one of claims 47 or 48, wherein at least one compound is micronized.

50. At least one compound has a particle size distribution D in the range of 5±0.25 to 10±0.5 microns 90 50. The pharmaceutical composition of claim 49, having the formula:

51. The pharmaceutical composition of any one of claims 1 to 48, wherein at least one compound is crystalline.

52. 52. The pharmaceutical composition of claim 51, wherein at least one compound is in crystalline form (I).

53. 53. The pharmaceutical composition of claim 52, wherein crystalline form (I) is characterized by an X-ray powder diffraction pattern having signals 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.

54. 52. The pharmaceutical composition of claim 51, wherein at least one compound is in crystalline form (II).

55. 55. The pharmaceutical composition of claim 54, wherein crystalline form (II) is characterized by an X-ray powder diffraction pattern having signals 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.

56. 56. A pharmaceutical composition comprising at least one topical pharmaceutical composition according to any one of claims 1 to 55 for treating a skin disorder in a mammal in need thereof.

57. Skin disorders include 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 dermatomyositis, alopecia, alopecia areata, vitiligo vulgaris, pyoderma gangrenosum, mucous membrane pemphigoid, epidermolysis bullosa acquisita, Stevens-Jones syndrome, and pemphigoid vulgaris in mammals requiring it.

57. The pharmaceutical composition of claim 56, wherein the disease is selected from the group consisting of rheumatoid arthritis, ...

58. 58. The pharmaceutical composition of claim 56 or 57, wherein the skin disorder is pemphigus vulgaris or pemphigus foliaceus.

59. 58. The pharmaceutical composition of claim 56 or 57, wherein the skin disorder is atopic dermatitis.

60. The pharmaceutical composition according to any one of claims 56 to 59, wherein the mammal is a human.

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