Formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- D]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]- pent-2-ene nitrile

Abstract

Disclosed herein are novel formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2- enenitrile, including formulations comprising various solid forms thereof. Also disclosed are methods for making formulations of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2- enenitrile.

Description

Technical Field

[0001] This document discloses novel formulations (including various solid forms) of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]-pent-2-enonitriles and methods for their preparation. The 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]-pent-2-enonitrile, referred to herein as rilzabrutinib, is also known as the compound of formula (I), having the following structure: Background Technology

[0002] The compound described by formula (I) is an inhibitor of Bruton's tyrosine kinase (BTK) and may be used to treat disorders and conditions mediated by BTK activity. BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in B cell development and activation and is involved in multiple signaling pathways in a wide variety of immune-mediated diseases. BTK activity is involved in the pathogenesis of several disorders and conditions, such as B cell-related blood cancers (e.g., non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjögren's syndrome, pemphigus, inflammatory bowel disease, lupus, and asthma).

[0003] Example 31 of WO 2014 / 039899 discloses a compound of formula (I). The synthesis of the compound of formula (I) disclosed in WO 2014 / 039899 requires purification by column chromatography, and after solvent removal, a foam is provided, which can be crushed into a powder. WO 2021 / 150723 discloses crystalline solid forms A, B, and C characterized as compounds of formula (I), and methods for their preparation.

[0004] One factor in assessing the suitability of a compound as a therapeutic agent is whether it can be administered in a formulation that is readily absorbed by the body and also has good storage stability. The pharmaceutically active substance used to prepare the formulation should be guaranteed to maintain stability under various environmental conditions during long-term storage to prevent the formation of unexpected degradation products in the pharmaceutical composition. Such degradation products may have potential toxicity or simply lead to a reduction in the potency and / or efficacy of the composition.

[0005] Another challenge in the large-scale manufacturing of pharmaceutical compounds is producing therapeutic substances through consistent, highly reproducible manufacturing processes. Using unstable or unoptimized formulations can lead to quality control problems and formulation irregularities. Such variations can affect the reproducibility of the manufacturing process, resulting in final formulations that do not meet the high-quality and stringent requirements for pharmaceutical composition formulations. In this regard, it should generally be considered that any modifications to the formulation of a pharmaceutical composition that improve its physical and chemical stability offer significant advantages over less stable formulations.

[0006] Optimizing the physical properties of formulations presents another set of challenges, which can influence the choice of solid form, excipients, and manufacturing processes for therapeutic agents. It is impossible to predict definitively which solid form(s) of a therapeutic agent will have favorable physical properties in a particular formulation (e.g., tablets) until the actual preparation and characterization of the formulation (both in vitro and in vivo). Nor is it possible to predict how certain excipients might affect the physical properties of a particular formulation (e.g., tablets) or its processability.

[0007] Certain combinations of the solid form of a therapeutic agent with excipients can impart physical and biological advantages relative to other combinations. To name just a few, without limitation, such advantages can include better processability during manufacturing, solubility, or shelf-life stability. In particular, such advantages can include improved flowability, tablet release characteristics, and / or tablet physical properties. The flowability of a material during the manufacturing process can be affected by the type and amount of therapeutic agents and excipients contained in the material. Flowability characteristics can affect tablet stiffness, tablet crush resistance, and the pressure required to compress the material to form a tablet. Poor flowability can also lead to unacceptable variability in tablet weight.

[0008] Another goal in pharmaceutical manufacturing is to limit the amount of excipients used in formulations. This simplifies the manufacturing process and provides formulations containing a greater proportion of therapeutic substances compared to the proportion of excipients. This can benefit, for example, improved patient compliance. Simple and stable formulations are desired, which can be manufactured reproducibly and efficiently, and can provide tablets with beneficial physical and biological characteristics.

[0009] This disclosure relates to formulations comprising 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enyl nitrile and at least one pharmaceutically acceptable excipient. For compounds intended for use in pharmaceutical compositions, formulations should be suitable for large-scale manufacturing and separation, and the physical properties of the formulations should ensure that they do not negatively impact the manufacturing process, efficacy, or cost of the active ingredient. This disclosure addresses such needs. Summary of the Invention

[0010] This article discloses novel formulations of compounds of formula (I) and methods for their preparation.

[0011] It has been unexpectedly discovered that the solid form of the compound of formula (I) used in formulations can affect the flowability and / or physical properties of the formulation. In particular, the use of the amorphous solid form of the compound of formula (I) in formulations can impart different physical characteristics to tablets compared to formulations containing the crystalline solid form of the compound of formula (I).

[0012] It has also been unexpectedly discovered that certain combinations of excipients used in formulations containing compounds of formula (I) can affect the flowability and / or physical properties of the formulations containing compounds of formula (I). In particular, the type and amount of disintegrants (such as cropovidone), flow aids (such as colloidal anhydrous silica), diluents (such as microcrystalline cellulose), and / or lubricants (such as magnesium stearate) contained in the formulations can advantageously influence the characteristics of tablets containing compounds of formula (I). Useful methods for producing formulations of compounds of formula (I) have also been discovered. Optimized formulations can impart beneficial physical characteristics to formulations of compounds of formula (I).

[0013] This document discloses formulations that can provide tablets comprising a compound of formula (I) or any pharmaceutically acceptable salt thereof, in combination with at least one diluent, at least one disintegrant, at least one lubricant, and optionally at least one flow aid.

[0014] Also disclosed are formulations that can provide tablets comprising a compound of formula (I) or any pharmaceutically acceptable salt thereof, wherein the tablets contain about 45% to about 55% by weight of an amorphous solid form of formula (I), about 35% to about 40% by weight of microcrystalline cellulose, about 5% to about 15% by weight of cropovidone, and about 0.5% to about 5% by weight of sodium stearoyl fumarate.

[0015] Further disclosed is a formulation that can provide tablets comprising a compound of formula (I) or any pharmaceutically acceptable salt thereof, wherein the tablets comprise, by weight, about 60% to about 70% of the compound of formula (I) in crystalline solid form, about 25% to about 35% of microcrystalline cellulose, about 0.5% to about 5% of cropovidone, about 0.1% to about 5% of magnesium stearate, and about 0.1% to about 5% of colloidal silica, wherein the colloidal silica has a density of about 200 μm. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g. 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g.

[0016] Additionally, a formulation for providing tablets is disclosed, the tablets comprising at least one compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof, at least one diluent present in an amount ranging from about 10% to about 50% by weight, at least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight, at least one lubricant present in an amount ranging from about 0.01% to about 5% by weight, and optionally at least one flow aid. Attached Figure Description

[0017] Various aspects of this disclosure are set forth in the appended claims. The features and advantages of this disclosure will be better understood by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments utilizing the principles of this disclosure, in which:

[0018] Figure 1 The mean (+SD) plasma concentration-time curves (linear scale) of rizarutinib following a single oral administration of the two formulations in healthy participants under fasting or eating conditions are shown.

[0019] Figure 2 The mean (+SD) plasma concentration-time curves (semi-log scale) of rizarutinib following a single oral administration of the two formulations in healthy participants under fasting or eating conditions are shown. Detailed Implementation

[0020] Reference will now be made in detail to certain embodiments. While this disclosure provides illustrative embodiments, it should be understood that they are not intended to limit the invention to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined by the appended claims.

[0021] The chapter headings used herein are for organizational purposes only and should not be construed as limiting the intended subject matter in any way. In the event of any conflict between any terminology defined in this specification and any references incorporated herein by reference, this specification shall prevail. Although this instruction has been described in conjunction with various embodiments, it is not intended to limit this instruction to such embodiments. Rather, as those skilled in the art will understand, the instruction encompasses a variety of alternatives, modifications, and equivalents. definition

[0022] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0023] Unless otherwise stated, as used herein, “a / a(a)” or “a / a(an)” means one or more of the entities, for example, “a compound” means one or more compounds or at least one compound. Therefore, the terms “a / a(a)” (or “a / a(an)”), “one or more” and “at least one” are used interchangeably herein.

[0024] As used herein, the term "about" means approximately, within a region, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the value. Generally, the term "about" is used herein to modify a value to be 5% higher or lower than the value. In some embodiments, the term "about" indicates a specified value ± 10%, ± 5%, or ± 1%. In some embodiments, where applicable, the term "about" indicates one or more specified values ​​± one standard deviation of those values.

[0025] Unless otherwise indicated, the term “and / or” is used in this disclosure to mean “and” or “or”.

[0026] As used herein, “2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]pent-2-enonitrile,” “rizarutinib,” and “compounds of formula (I)” are used interchangeably and refer to compounds having the following structures: It is also known as: 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]-(E and Z)-pent-2-enonitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]pent-2-enonitrile;(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetane)-1-piperazinyl] [Propylene]-β-oxo-1-piperidinpropionitrile; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]pent-2-enonitrile; and according to the International Nonproprietary Name (INN) published by the World Health Organization (https: / / cdn.who.int / media / docs / default-source / international-nonproprietary-names-(inn) / pl121.pdf?sfvrsn=69617906_15&download=true), it has the following structure: . Compounds of formula (I) include E and Z isomers, as indicated by the wavy bonds in the structure shown above. Compounds of formula (I) may exist as salts.

[0027] In some embodiments, the compound of formula (I) is a compound of formula (I-(E)), that is, an E isomer of the compound of formula (I). In some embodiments, the compound of formula (I-(E)) has the following structure:

[0028] In some embodiments, the compound of formula (I) is a compound of formula (I-(Z)), that is, the Z isomer of the compound of formula (I). In some embodiments, the compound of formula (I-(Z)) has the following structure:

[0029] In some embodiments, the compound of formula (I) comprises the compound of formula (I-(Z)). In some embodiments, the compound of formula (I) comprises the compound of formula (I-(E)). In some embodiments, the compound of formula (I) comprises a mixture of the compound of formula (I-(Z)) and the compound of formula (I-(E)).

[0030] The dosage of the (E) isomer of a compound of formula (I) may include less than about 10% by weight (e.g., less than about 5% by weight, less than about 2% by weight, and less than about 1% by weight) of the corresponding (Z) isomer. When a compound of formula (I) is represented as a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile, it means that the amount of the (E) isomer or (Z) isomer in the mixture is greater than about 2% by weight. In some embodiments, when a compound of formula (I) is represented as a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutan-3-yl)piperazin-1-yl]pent-2-enonitrile, it means that the amount of the (Z) isomer in the mixture is equal to or less than about 10% by weight, such as equal to or less than about 5% by weight, equal to or less than about 2% by weight, or equal to or less than about 1% by weight.

[0031] The dosage of the (Z) isomer of a compound of formula (I) may comprise less than about 10% by weight (e.g., less than about 5% by weight, less than about 2% by weight, and less than about 1% by weight) of the corresponding (E) isomer. In some embodiments, when a compound of formula (I) is represented as a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile, it means that the amount of the (E) isomer in the mixture is equal to or less than about 10% by weight, such as equal to or less than about 5% by weight, equal to or less than about 2% by weight, or equal to or less than about 1% by weight.

[0032] In some embodiments, the molar ratio of the (E) isomer to the (Z) isomer of the compound of formula (I) is 8:2. In some embodiments, the molar ratio of the (E) isomer to the (Z) isomer of the compound of formula (I) is 9:1. In some embodiments, the molar ratio of the (E) isomer to the (Z) isomer of the compound of formula (I) is 98:2. In some embodiments, the molar ratio of the (E) isomer to the (Z) isomer of the compound of formula (I) is 99:1.

[0033] Compounds of formula (I) may also exist in salt form, in other words, in combination with one or more cations or anions. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0034] As used herein, a “pharmaceutically acceptable salt” of a compound of formula (I) means an acid addition salt that is pharmaceutically acceptable and has the desired pharmacological activity of the compound from which the salt is prepared. Such salts include salts formed with: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; or organic acids, such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, etc.

[0035] As used herein, “pharmaceuticalally acceptable excipient” means a carrier or excipient that can be used to prepare a pharmaceutical composition. For example, pharmaceutically acceptable excipients are generally safe and include carriers and excipients that are generally considered pharmaceutically acceptable for mammals.

[0036] As used herein, the term “crystallization” or “crystalline solid form” refers to a solid form that is substantially free of any amorphous solid form.

[0037] In some embodiments, "substantially free of" means less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of other crystalline and amorphous forms of the compound. In some embodiments, "substantially free of" means undetectable amounts of other crystalline and amorphous forms of the compound.

[0038] As used herein, the terms “substantially pure” or “substantially crystalline” mean that, relative to the total weight of all forms of the compound, the crystalline form contains at least 90% (e.g., at least 95%, such as at least 97%, and even at least 99%) of the indicated crystalline form by weight.

[0039] Alternatively, "substantially pure" or "substantially crystalline" will be understood to mean that the crystalline form contains less than 10% (e.g., less than 5%, less than 3%, and even less than 1%) of impurities (including other polymorphic or amorphous forms) by weight compared to the total weight of all forms of the compound.

[0040] As used herein, the term "amorphous" refers to a solid material that lacks long-range order in its molecular positions. Amorphous solids are typically supercooled liquids in which molecules are arranged randomly, resulting in no defined arrangement (e.g., molecular packing) and no long-range order. For example, an amorphous material is a solid material whose X-ray powder diffraction pattern lacks one or more sharp characteristic signals (i.e., it is not crystalline, as determined by XRPD). Instead, it exhibits one or more broad peaks (e.g., halo) in its diffraction pattern. Broad peaks are characteristic of amorphous solids.

[0041] As used herein, the term "substantially amorphous" means that a solid material has virtually no long-range order in its molecular positions. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% or less than 5%). "Substantially amorphous" includes the descriptive phrase "amorphous," which means that the material has no (0%) crystallinity.

[0042] "Therapeutic effective amount" means the amount of a BTK inhibitor compound that, when administered to a mammal for the treatment of a disease, is sufficient to achieve such treatment of the disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, species, etc., of the mammal to be treated. For example, the mammal to be treated could be a human. In embodiments, the term "therapeutic effective amount" means the amount of a BTK inhibitor compound that, when administered to a human for the treatment of a disease, is sufficient to achieve such treatment of the disease.

[0043] As used herein, the terms “treat,” “treating,” or “treatment,” when used in conjunction with a disorder or condition, include any effect that results in improvement of said disorder or condition, such as relief, reduction, modulation, improvement, or elimination of said disorder or condition. Any improvement in the symptoms of a disorder or condition, or a reduction in its severity, can be readily assessed according to standard methods and techniques known in the art.

[0044] As used herein, the term "XRPD" refers to an analytical characterization method for X-ray powder diffraction. XRPD spectra can be recorded using a diffractometer under ambient conditions with transmission or reflection geometry.

[0045] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifically describing the presence of the mentioned features or components, but do not exclude the presence or addition of one or more features or components or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples covered by the term “composed of”. Therefore, the term “composed of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments of the compounds and / or methods disclosed herein.

[0046] The term "composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the said features or components that constitute it. In another embodiment, the term "composed of" excludes any other features or components from the scope of any subsequent description, except for those features or components that are not essential to the technical effect to be achieved.

[0047] As used herein, the term "or" should be interpreted as inclusive "or," meaning any one or any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition only arise when a combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0048] In this specification, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the range, and, where appropriate, to include fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated. Furthermore, any numerical ranges listed herein relating to any physical characteristic (such as polymer subunits, size, or thickness) shall be understood to include any integer within the listed range, unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated.

[0049] It should be noted that if there is a discrepancy between the described structure and its name, the described structure shall prevail.

[0050] While various features of the compounds and methods disclosed herein may be described in the context of individual embodiments, these features may also be provided individually or in any suitable combination. Conversely, although the compounds and methods disclosed herein may be described in the context of individual embodiments for clarity, they may also be implemented in individual embodiments. The solid form of the compound of formula (I)

[0051] BTK inhibitor compounds can be prepared according to, for example, the methods and procedures described in WO 2014 / 039899. Alternatively, BTK inhibitor compounds can be prepared as described in WO 2021 / 150723.

[0052] In some embodiments, this document provides a solid form of a compound of formula (I) or a salt thereof. In some embodiments, a salt of a compound selected from the compounds in Table 1 is provided. In some embodiments, a crystalline form of a compound selected from the compounds in Table 1 or a salt thereof is provided. In some embodiments, a crystalline form B of a compound selected from the compounds in Table 1 or a salt thereof is provided. In some embodiments, an amorphous form of a compound selected from the compounds in Table 1 or a salt thereof is provided.

[0053] Although some compounds described in this disclosure (including in Table 1) are presented in a particular stereoisomer and / or in a non-stereochemical form, it should be understood that any or all stereochemical forms (including any enantiomers or diastereomers) of any compound described herein (including in Table 1) as well as any tautomers or other forms are described herein. Table 1. Or its salt.

[0054] The solid forms of compounds of formula (I) include crystalline form A, crystalline form B and crystalline form C, as well as any of their salts.

[0055] The crystalline form A of the compound of formula (I) can be identified and / or characterized by a variety of features, including differential scanning calorimetry (DSC), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG-FTIR), and X-ray powder diffraction (XRPD).

[0056] In some embodiments, the crystalline form A of the compound of formula (I) is characterized by an endothermic peak (melting temperature) in its DSC thermogram at about 146ºC to about 147ºC. In some embodiments, the crystalline form A of the compound of formula (I) is characterized by a DSC thermogram showing melting / decomposition beginning at about 140.6ºC to about 141.2ºC. In some embodiments, the crystalline form A of the compound of formula (I) is characterized by a DSC thermogram showing melting beginning at about 140.6ºC to about 141.2ºC. In some embodiments, the relevant enthalpy is about 52 J / g (∆H = 52 J / g).

[0057] In some embodiments, the crystalline form A of the compound of formula (I) is characterized by a mass loss of less than 1.0 wt.% between 25ºC and 200ºC, as determined by thermogravimetric analysis. In some embodiments, this mass loss corresponds to the loss of isopropyl acetate released near the melting temperature. In some embodiments, decomposition is observed at higher temperatures (starting from about 220ºC to about 230ºC). In some embodiments, the crystalline form A of the compound of formula (I) is characterized by a water content of less than 1% when stored at 95% relative humidity (RH).

[0058] In some embodiments, the crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis of an incident beam irradiated with Cu Kα, which has a signal at at least three 2θ values ​​selected from the following: 5.6 ± 0.2, 12.7 ± 0.2, 16.5 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 22.2 ± 0.2, and 24.4 ± 0.2.

[0059] The crystalline form B of the compound of formula (I) can be identified and / or characterized by a variety of features, including differential scanning calorimetry (DSC), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG-FTIR), and X-ray powder diffraction (XRPD).

[0060] In some embodiments, the crystalline form B of the compound of formula (I) is characterized by an endothermic peak (melting temperature) in its DSC thermogram at about 141ºC to about 142ºC. In some embodiments, the crystalline form B of the compound of formula (I) is characterized by an endothermic peak (melting temperature) in its DSC thermogram at about 144ºC to about 146ºC. In some embodiments, the crystalline form B of the compound of formula (I) is characterized by a DSC thermogram showing melting at about 131.8ºC to about 132.4ºC. In some embodiments, the crystalline form B of the compound of formula (I) is characterized by a DSC thermogram showing melting at about 139.3ºC. In some embodiments, the crystalline form B of the compound of formula (I) is characterized by a water content of less than 1.3% when stored at 95% relative humidity (RH). In some embodiments, the relevant enthalpy is about 54.9 J / g (∆H = 54.9 J / g).

[0061] In some embodiments, the crystalline form B of the compound of formula (I) is characterized by a mass loss of less than 0.8 wt.% between 25ºC and 162ºC, as determined by thermogravimetric analysis. In some embodiments, in addition to the aforementioned mass loss, a further mass loss of less than 0.8 wt.% exists between 162ºC and 250ºC, as determined by thermogravimetric analysis. In some embodiments, this further mass loss corresponds to the removal of ethyl acetate. In some embodiments, decomposition is observed at higher temperatures (starting from about 250ºC to about 253ºC).

[0062] In some embodiments, the crystalline form B of the compound of formula (I) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis of an incident beam irradiated with Cu Kα, which has a signal at at least three 2θ values ​​selected from the following: 10.8 ± 0.2, 15.3 ± 0.2, 16.3 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 22.0 ± 0.2, and 22.9 ± 0.2.

[0063] The crystalline form C of the compound of formula (I) can be identified and / or characterized by a variety of features, including differential scanning calorimetry (DSC), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG-FTIR), and X-ray powder diffraction (XRPD).

[0064] In some embodiments, the crystalline form C of the compound of formula (I) is characterized by a DSC thermogram showing an endothermic peak (melting temperature) from about 118.5ºC to about 119ºC, wherein the DSC scan rate is 15ºC / min. In some embodiments, the crystalline form C of the compound of formula (I) is characterized by a DSC thermogram showing melting at about 115.6ºC to about 116.0ºC, wherein the DSC scan rate is 15ºC / min. In some embodiments, the crystalline form C of the compound of formula (I) is characterized by a DSC thermogram showing an endothermic peak (melting temperature) from about 120.5ºC to about 121ºC, wherein the DSC scan rate is 10ºC / min. In some embodiments, the crystalline form C of the compound of formula (I) is characterized by a DSC thermogram showing melting / decomposition at about 118.0ºC to about 118.5ºC, wherein the DSC scan rate is 10ºC / min.

[0065] In some embodiments, crystalline form C is characterized by a mass loss of less than 5% on the TGA thermal profile between 25ºC and 150ºC. In some embodiments, crystalline form C is characterized by a mass loss of less than 5 wt.% between 25ºC and 145ºC. In some embodiments, the mass loss is due to the removal of acetonitrile.

[0066] In some embodiments, the crystalline form C of the compound of formula (I) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis of an incident beam irradiated with Cu Kα, which has a signal at at least three 2θ values ​​selected from the following: 9.8 ± 0.2, 10.2 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, and 21.6 ± 0.2. Preparations and methods for their preparation

[0067] According to this disclosure, compounds of formula (I) can be incorporated into formulations prepared by one or more of the following methods. As those skilled in the art will understand, the methods described herein can be combined in any suitable order.

[0068] solid preparations

[0069] This article discloses tablets containing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0070] In some embodiments, the tablet comprises at least one compound selected from formula (I) or a pharmaceutically acceptable salt thereof, as well as at least one diluent, at least one disintegrant, at least one lubricant, and optionally at least one flow aid.

[0071] In some embodiments, the tablet comprises an internal phase and an external phase. In some embodiments, the tablet comprises two phases. In some embodiments, the tablet comprises at least two phases. In some embodiments, the tablet comprises at least two phases and a film coating.

[0072] In some embodiments, the tablet comprises at least one diluent selected from the following: lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropyl methylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite. The diluent may be microcrystalline cellulose, such as 50 µm microcrystalline cellulose, 180 µm microcrystalline cellulose, or both. The diluent may be present in the tablet in a total amount ranging from about 75 mg to about 400 mg. The diluent may be present in a total amount ranging from about 10% to about 50% by weight of the tablet. The diluent may be present in the intraparticle phase of the tablet in a total amount ranging from about 15% to about 45% by weight. The diluent may be present in the extraparticle phase in a total amount ranging from about 0% to about 15% by weight.

[0073] In some embodiments, the tablet comprises at least one flow aid selected from colloidal silica and talc. The flow aid may have a density of approximately 200 μm. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 A mixture of colloidal silica with an average specific surface area of ​​approximately 200 m² / g. The flow aid may contain a mixture of colloidal silica with an average specific surface area of ​​approximately 200 m² / g. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 Colloidal silica with an average specific surface area of ​​ / g or both. The gliding agent may be present in the tablet in a total amount ranging from 0 mg to about 50 mg. The gliding agent may be present in a total amount ranging from about 0% to about 5% by weight of the tablet. The gliding agent may be present in the internal phase of the tablet in a total amount ranging from about 0% to about 5% by weight. The gliding agent may be present in the external phase of the tablet in a total amount ranging from about 0% to about 5% by weight.

[0074] In some embodiments, the tablet comprises at least one disintegrant selected from: starch, cross-linked starch, cellulose, cross-linked cellulose, cross-linked polymers, alginate, clay, gum, glycolate, bentonite, natural sponge, surfactant, resin, citrus pomace, and sodium lauryl sulfate. The disintegrant may include cross-linked polyvinyl N-pyrrolidone (crosspovidone) and cross-linked carboxymethyl cellulose (cross-linked carboxymethyl cellulose). The disintegrant may include cross-linked polyvinyl N-pyrrolidone (crosspovidone), cross-linked carboxymethyl cellulose (cross-linked carboxymethyl cellulose), or both crosspovidone and cross-linked carboxymethyl cellulose. The disintegrant may be present in the tablet in a total amount ranging from 1 mg to about 125 mg. The disintegrant may be present in the tablet in a total amount ranging from about 0.1% to about 15% by weight of the tablet. The disintegrant may be present in the internal phase of the tablet in a total amount ranging from about 0.1% to about 10% by weight of the tablet. The disintegrant may be present in the external phase of the tablet in a total amount ranging from about 0% to about 10% by weight of the tablet.

[0075] In some embodiments, the tablet comprises at least one lubricant selected from: stearic acid, calcium hydroxide, talc, hydrocarbons, hydrogenated vegetable oils, higher fatty acids, stearates, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxy polyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch, silicone oil, and surfactants. At least one lubricant may be selected from magnesium stearate and sodium stearoyl fumarate. At least one lubricant may be selected from magnesium stearate, sodium stearoyl fumarate, or both. At least one lubricant may be magnesium stearate. At least one lubricant may be sodium stearoyl fumarate. The lubricant may be present in the tablet in a total amount ranging from 0.1 mg to about 50 mg. The lubricant may be present in a total amount ranging from about 0.01% to about 5% by weight of the tablet. The lubricant is present in the internal phase of the tablet particles in a total amount ranging from about 0.1% to about 5% by weight. The lubricant may also be present in the external phase of the tablet particles in a total amount ranging from about 0% to about 5% by weight.

[0076] In some embodiments, the tablet comprises an internal phase containing at least one diluent, at least one disintegrant, and at least one lubricant. The diluent in the internal phase of the tablet may be 50 µm microcrystalline cellulose. The lubricant in the internal phase of the tablet may be magnesium stearate. The lubricant in the internal phase of the tablet may be sodium stearoyl fumarate. The disintegrant in the internal phase of the tablet may be cross-linked polyvinyl N-pyrrolidone (crosspovidone). The internal phase of the tablet may further contain at least one flow aid. The flow aid in the internal phase of the tablet may have a particle size of about 200 µm. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g, or may be colloidal silica with an average specific surface area of ​​approximately 300 m² / g.2 Colloidal silica with an average specific surface area of ​​ / g.

[0077] In some embodiments, the tablet comprises an extrapartic phase containing at least one lubricant. The lubricant in the extrapartic phase of the tablet may be magnesium stearate. The lubricant in the extrapartic phase of the tablet may be sodium stearoyl fumarate. The extrapartic phase of the tablet may further comprise at least one diluent. The diluent in the extrapartic phase of the tablet may be 180 µm microcrystalline cellulose. The extrapartic phase of the tablet may further comprise at least one flow aid. The flow aid in the extrapartic phase of the tablet may be a microcrystalline cellulose having a particle size of about 200 µm. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g, or may be colloidal silica with an average specific surface area of ​​approximately 300 m² / g. 2 Colloidal silica with an average specific surface area of ​​ / g. The extragranular phase of the tablet may further contain at least one disintegrant. The disintegrant in the extragranular phase of the tablet may be cross-linked polyvinyl N-pyrrolidone (crosspovidone).

[0078] In some embodiments, the compound of formula (I) present in the tablet is in a solid form that is at least 50% crystalline (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100% crystalline). The compound of formula (I) present in the tablet may be present in an amount ranging from about 200 mg to about 650 mg. The compound of formula (I) present in the tablet may be present in the following amounts: about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg. mg, about 630 mg, about 640 mg, or about 650 mg. For example, the compound of formula (I) may be present in the tablet in an amount of about 300 mg. Alternatively, the compound of formula (I) may be present in the tablet in an amount of about 500 mg. Alternatively, the compound of formula (I) may be present in the tablet in an amount of about 600 mg. The compound of formula (I) present in the tablet may be present in an amount of about 40% to about 75% by weight of the tablet. For example, the compound of formula (I) may be present in an amount of about 50% by weight of the tablet. Alternatively, the compound of formula (I) may be present in the tablet in an amount of about 65% by weight of the tablet.

[0079] In some embodiments, the tablet comprising the compound of formula (I) further comprises at least one coating layer. The coating layer may comprise a flavor masking agent. The weight of the coating layer may be included in the total weight of the tablet. Alternatively, the weight of the tablet may exclude the weight of the coating layer.

[0080] In other embodiments, the tablet comprises about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of cropovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0081] In some embodiments, a tablet comprising a compound of formula (I) has an internal phase and an external phase. The compound of formula (I) may be present in the internal phase of the tablet. The compound of formula (I) may be present in at least one of the internal or external phases of the tablet.

[0082] In a further embodiment, the tablet has an internal particle phase comprising about 65% by weight of the compound of formula (I), about 31% by weight of the microcrystalline cellulose, about 2% by weight of the cyclopovidone, about 0.25% by weight of the magnesium stearate, and about 1% by weight of the colloidal silica. In some embodiments, the tablet has an external particle phase comprising about 1% by weight of the magnesium stearate.

[0083] In some embodiments, the tablet has a compound of formula (I) present in the tablet as an amorphous solid. The tablet may have a compound of formula (I) present in the tablet as a crystalline solid. The tablet may have a compound of formula (I) present in the tablet in a crystalline form, said crystalline form being at least one of crystalline form A, crystalline form B, and crystalline form C. The crystalline form of the compound of formula (I) present in the tablet may be form A. The crystalline form of the compound of formula (I) present in the tablet may be form B. The crystalline form of the compound of formula (I) present in the tablet may be form C.

[0084] In a further embodiment, the tablet comprises about 45% to about 55% by weight of an amorphous compound of formula (I), about 35% to about 40% by weight of microcrystalline cellulose, about 5% to about 15% by weight of cropovidone, and about 0.5% to about 5% by weight of sodium stearoyl fumarate.

[0085] The internal phase of the tablet may contain about 50% by weight of the compound of formula (I), about 38% by weight of microcrystalline cellulose, about 10% by weight of chapovidone, and about 2% by weight of sodium stearoyl fumarate. The external phase of the tablet may contain about 5% by weight of chapovidone and about 1% by weight of sodium stearoyl fumarate.

[0086] In another embodiment, the tablet has the compound of formula (I) present in the tablet in an amount of about 270 mg. The tablet may contain about 300 mg or about 400 mg of the compound of formula (I). The tablet may contain about 300 mg of the compound of formula (I). The tablet may contain about 400 mg of the compound of formula (I). The compound of formula (I) present in the tablet may be present in an amount of about 400 mg or about 450 mg. The compound of formula (I) present in the tablet may be present in an amount of about 450 mg. The compound of formula (I) may be present in the tablet in an amount of about 500 mg. The compound of formula (I) may be present in the tablet in an amount of about 550 mg. The compound of formula (I) may be present in the tablet in an amount of about 600 mg. The compound of formula (I) may be present in the tablet in an amount of about 650 mg.

[0087] In another embodiment, the tablet comprises about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 20% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 10% by weight of a disintegrant, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica. The tablet may contain a disintegrant comprising at least one of crospovidone and cross-linked carboxymethyl cellulose.

[0088] The internal phase of the tablet may comprise about 65% by weight of the compound of formula (I), about 23% to about 31% by weight of the microcrystalline cellulose, about 2.0% to about 4.0% by weight of the disintegrant, about 0.5% to about 1.0% by weight of the magnesium stearate, and about 0.9% by weight of the colloidal silica. The external phase of the tablet may comprise about 1.5% by weight of the microcrystalline cellulose, about 0% to about 2.0% by weight of the disintegrant, about 0.2% to about 1.0% by weight of the magnesium stearate, and about 0.4% by weight of the colloidal silica.

[0089] In yet another embodiment, the tablet comprises about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of cropovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0090] The internal phase of the particles may comprise about 65% of the compound of formula (I) by weight of tablets, about 31% of microcrystalline cellulose by weight of tablets, about 2.0% of cropovidone by weight of tablets, about 0.25% of magnesium stearate by weight of tablets, and about 0.9% of colloidal silica by weight of tablets. The external phase of the particles may comprise about 1.0% of magnesium stearate by weight of tablets and about 0.4% of colloidal silica by weight of tablets.

[0091] In a further embodiment, the tablet comprises about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of cropovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0092] The internal phase of the tablet may comprise about 65% by weight of the compound of formula (I), about 30% by weight of microcrystalline cellulose, about 2.0% by weight of cropovidone, about 0.5% by weight of magnesium stearate, and about 0.9% by weight of colloidal silica. The external phase of the tablet may comprise about 1.0% by weight of magnesium stearate and about 0.4% by weight of colloidal silica.

[0093] In another embodiment, the tablet comprises about 60% to about 70% by weight of a crystalline compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of cropovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica. The colloidal silica may include a silica having a surface area of ​​about 200 μm. 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 At least one of the following colloidal silicas with an average specific surface area of ​​approximately 200 m² / g: [The text abruptly ends here, so the translation stops as well.] 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g. 2 Colloidal silica with an average specific surface area of ​​ / g.

[0094] The internal phase of the tablet may comprise about 65% by weight of the crystalline solid form of the compound of formula (I), about 20% to about 30% by weight of the tablet, about 2.0% by weight of the tablet, about 0.25% by weight of the tablet, about 0.7% to about 0.9% by weight of the tablet, and colloidal silica. The external phase of the tablet may comprise about 1.0% by weight of the tablet, about 0% to about 10% by weight of the tablet, and about 0.4% to about 0.6% by weight of the tablet, and colloidal silica.

[0095] In another embodiment, the tablet comprising the compound of formula (I) comprises a film coating agent. The film coating may be present in an amount of about 2% to about 5% by weight relative to the total weight of the tablet. The film coating may be present in an amount of about 3% by weight relative to the total weight of the tablet. The weight of the film coating layer may be included in the total weight of the tablet. Alternatively, the weight of the tablet may not include the weight of the film coating agent.

[0096] Tablets containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in methods of treating BTK-mediated diseases or conditions in patients in need. Methods of treating BTK-mediated diseases or conditions in patients in need may include administering tablets containing a compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient.

[0097] The patient's possible BTK-mediated disease or condition may be selected from at least one of the following: acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosa, pemphigoid membranaceus, acquired epidermolysis bullosa, Stevens-Johnson syndrome.Syndrome), toxic epidermal necrolysis (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitis, antiphospholipid antibody syndrome, vasculitis, Guillain-Barré syndrome, scleroderma, Wechsler's granulomatosis, psoriasis, granulomatous polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate to severe asthma, mild asthma, moderate asthma, severe asthma, poorly controlled asthma, autoimmune hepatitis, Behcet's disease, Graves' disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis Dermatitis, drug eruption, drug-induced thrombocytopenia (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis-related alopecia, pseudofolliculitis of the beard, leukocytospastic vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, mycosis fungoides, Sweet's syndrome, follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walter's macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma. Mediastinal (thymic) large B-cell lymphoma, non-Hodgkin's lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin's lymphoma, idiopathic thrombocytopenic purpura, IgG4-related disease (IgG4-RD) and its acute exacerbation, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenic purpura, inflammatory bowel disease, pruritus associated with atopic dermatitis, lupus, cutaneous lupus, cutaneous lupus erythematosus. Lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, acute lung injury caused by sepsis, diffuse alveolar injury (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary cholangiosclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), IgA urticaria, and IgA nephropathy.

[0098] Tablets containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to treat diseases or conditions mediated by BTK receptors. Methods of treating diseases or conditions mediated by BTK receptors may include administering to a patient a tablet containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] Solid formulations may contain the range of components shown in Table 2 below: Table 2: Components of an exemplary formulation

[0100] In some embodiments, the compound of formula (I) is present in a crystalline form at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100% crystalline. In some embodiments, the compound of formula (I) is present in an amorphous form. In some embodiments, the compound of formula (I) is present in a crystalline form B.

[0101] The compound of formula (I) may be present in the tablet in a total amount ranging from about 40% to about 75% by weight of the tablet. In some embodiments, the compound of formula (I) is present in the tablet in a total amount ranging from about 50% to about 65% by weight of the tablet. In some embodiments, the compound of formula (I) is present in the tablet in a total amount of about 50% by weight. In some embodiments, the compound of formula (I) is present in the tablet in a total amount of about 65% by weight. In some embodiments, the compound of formula (I) is present in an amorphous form in a total amount of about 50% by weight of the tablet. In some embodiments, the compound of formula (I) is present in a crystalline form in a total amount of about 65% by weight of the tablet. In some embodiments, the compound of formula (I) is present in crystalline form B in a total amount of about 65% by weight of the tablet.

[0102] In some embodiments, the tablets contain a compound of formula (I) in an amount ranging from about 200 mg to about 650 mg. In some embodiments, the compound of formula (I) is present in amounts of: about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg. mg, about 630 mg, about 640 mg, or about 650 mg. In some embodiments, the compound of formula (I) is present in an amount of about 300 mg. In some embodiments, the compound of formula (I) is present in an amount of about 500 mg. In some embodiments, the compound of formula (I) is present in an amount of about 550 mg. In some embodiments, the compound of formula (I) is present in an amount of about 600 mg. In some embodiments, the compound of formula (I) is present in an amount of about 650 mg.

[0103] A diluent is a chemical compound used to dilute a target compound prior to delivery. Diluents can also be used to stabilize compounds, as they provide a more stable environment. Salts dissolved in buffer solutions (which can also provide pH control or maintenance) are used in the art as diluents, including but not limited to phosphate-buffered saline solutions. In some embodiments, diluents increase the volume of the composition to facilitate tableting or to provide sufficient volume for homogeneous blends used for capsule filling. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose, such as Avicel®; dicalcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugars, such as Di-Pac® (Amstar); hydroxypropyl methylcellulose; hydroxypropyl methylcellulose acetate stearate; sucrose-based diluents; confectioner's sugar; calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; glucose binders; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite, etc.

[0104] Diluents can have different particle sizes, and particle size can affect the physical properties of the formulation. Microcrystalline cellulose of a certain particle size can act as a rounding aid to help withstand pressure during tableting. Microcrystalline cellulose can also help provide particle size uniformity in the formulation, and larger particle sizes can improve particle flowability. Microcrystalline cellulose particle sizes that can provide beneficial physical properties (including flowability) to formulations include particles with an average diameter of about 10 µm to about 300 µm (e.g., about 50 µm, about 90 µm, and about 180 µm).

[0105] In some embodiments, the tablet comprises at least one diluent selected from: lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropyl methylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite. In some embodiments, the tablet comprises at least one diluent selected from: mannitol, spray-dried mannitol, lactose monohydrate, anhydrous lactose, and microcrystalline cellulose. In some embodiments, the tablet comprises at least one diluent selected from anhydrous lactose and microcrystalline cellulose. In some embodiments, the tablet comprises microcrystalline cellulose. In some embodiments, the tablet comprises at least one microcrystalline cellulose selected from 50 µm microcrystalline cellulose, 90 µm microcrystalline cellulose, and 180 µm microcrystalline cellulose. In some embodiments, the tablet comprises at least one microcrystalline cellulose selected from 50 µm microcrystalline cellulose and 90 µm microcrystalline cellulose. In some embodiments, the tablet comprises at least one microcrystalline cellulose selected from 50 µm microcrystalline cellulose and 180 µm microcrystalline cellulose. In some embodiments, the tablet comprises at least one microcrystalline cellulose selected from 90 µm microcrystalline cellulose and 180 µm microcrystalline cellulose. In some embodiments, the tablet comprises 50 µm microcrystalline cellulose. In some embodiments, the tablet comprises 90 µm microcrystalline cellulose. In some embodiments, the tablet comprises 180 µm microcrystalline cellulose.

[0106] The total amount of diluent present in the tablet ranges from about 10% to about 50% by weight. In some embodiments, the total amount of diluent present in the tablet ranges from about 15% to about 45% by weight. In some embodiments, the total amount of diluent present in the tablet ranges from about 18% to about 40% by weight. In some embodiments, the total amount of diluent present in the tablet is about 20%, about 21%, about 30%, about 31%, about 23%, or about 38% by weight.

[0107] In some embodiments, the tablet comprises microcrystalline cellulose. In some embodiments, the amount of microcrystalline cellulose in the tablet ranges from about 15% to about 45% by weight. In some embodiments, the amount of microcrystalline cellulose in the tablet ranges from about 18% to about 40% by weight, about 20% by weight, about 21% by weight, about 30% by weight, about 31% by weight, about 23% by weight, or about 38% by weight. In some embodiments, the amount of microcrystalline cellulose in the tablet is about 30.5% by weight. In some embodiments, the amount of microcrystalline cellulose in the tablet is about 38% by weight.

[0108] In some embodiments, the tablet comprises about 15% to about 45% by weight, or about 18% to about 40% by weight, of microcrystalline cellulose selected from at least one of 50 µm microcrystalline cellulose and 180 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 15% to about 45% by weight, or about 18% to about 40% by weight, of microcrystalline cellulose selected from at least one of 50 µm microcrystalline cellulose, 90 µm microcrystalline cellulose, and 180 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 30.5% by weight of 50 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 30.5% by weight of 90 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 20.5% by weight of 50 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 20.5% by weight of 90 µm microcrystalline cellulose. In some embodiments, the tablet comprises about 10% by weight of 180 µm microcrystalline cellulose. In some implementations, the tablets contain about 10% by weight of 90 µm microcrystalline cellulose.

[0109] In some embodiments, the tablet contains a diluent in a total amount from about 75 mg to about 400 mg. In some embodiments, the tablet contains microcrystalline cellulose in a total amount from about 75 mg to about 400 mg. In some embodiments, the tablet contains microcrystalline cellulose in a total amount of about 128 mg, about 142 mg, about 152 mg, about 209 mg, about 234 mg, about 235 mg, or about 304 mg. In some embodiments, the tablet contains about 234 mg of 50 µm microcrystalline cellulose. In some embodiments, the tablet contains about 157 mg of 50 µm microcrystalline cellulose. In some embodiments, the tablet contains about 77 mg of 180 µm microcrystalline cellulose. In some embodiments, the tablet contains about 157 mg of 50 µm microcrystalline cellulose and about 77 mg of 180 µm microcrystalline cellulose.

[0110] Gliders are compounds that reduce interparticle attraction, decrease agglomeration, and enhance powder flow during tablet preparation. They are also called flow agents because they are used to optimize the flow properties of powders. Gliders can improve powder flowability by correcting surface irregularities, reducing interparticle friction, and reducing surface charge.

[0111] In some embodiments, the tablet contains at least one flow aid. In some embodiments, the tablet optionally contains at least one flow aid. In some embodiments, the tablet does not contain a flow aid. In some embodiments, the flow aid is selected from colloidal silica and talc. In some embodiments, the flow aid is colloidal silica, also known as colloidal silica.

[0112] Colloidal silica (also known as colloidal anhydrous silica) can be obtained as particles with different average specific surface areas, such as Aerosil® 200 and Aeroperl® 300, which have approximately 200 μm² of specific surface area. 2 / g and approximately 300 m 2 / g average specific surface area.

[0113] The total amount of the gliding agent present in the tablet ranges from about 0 to about 5% by weight. In some embodiments, the total amount of the gliding agent present in the tablet ranges from about 0 to about 5% by weight, such as from about 0.1% to about 2% by weight, from about 0.1% to about 1.5% by weight, or from about 0.1% to about 1% by weight. In some embodiments, the total amount of the gliding agent present in the tablet is about 0.9% by weight. In some embodiments, the total amount of the gliding agent present in the tablet is about 1.3% by weight.

[0114] In some embodiments, the gliding agent is colloidal silica. In some embodiments, the amount of colloidal silica present in the tablet ranges from 0 to about 5% by weight. In some embodiments, the amount of colloidal silica present in the tablet ranges from about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, about 0.1% to about 1.5% by weight, or about 0.1% to about 1% by weight. In some embodiments, the amount of colloidal silica present in the tablet is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 0.4%, or about 1.5% by weight.

[0115] In some implementations, the flow aid is selected from those having a flow rate of approximately 200 m 2Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g. In some embodiments, the colloidal silica is anhydrous. In some embodiments, the tablets contain a total amount of about 1.3% by weight of colloidal silica with an average specific surface area of ​​about 200m². 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, the tablets contain a total amount of about 1.3% by weight of colloidal silica with an average specific surface area of ​​about 300 m². 2 / g of colloidal silica with an average specific surface area. In some embodiments, the tablets contain a total amount ranging from about 0.5% to about 1.5% by weight of colloidal silica.

[0116] In some embodiments, the tablet contains a total amount of a flow aid ranging from about 0 mg to about 50 mg. In some embodiments, the tablet contains a total amount of a flow aid ranging from about 0 mg to about 20 mg. In some embodiments, the tablet contains a total amount of a flow aid ranging from about 0 mg to about 10 mg. In some embodiments, the tablet contains a total amount of about 3.7 mg of a flow aid. In some embodiments, the tablet contains a total amount of about 8.0 mg of a flow aid. In some embodiments, the tablet contains a total amount of about 9.0 mg of a flow aid. In some embodiments, the tablet contains a total amount of about 10 mg of a flow aid.

[0117] Disintegrants aid in the dissolution and dispersion of dosage forms upon contact with gastrointestinal fluids. Disintegrants or disintegrants promote the disintegration of tablets and granules, thus affecting the release of the active pharmaceutical ingredient. Examples of disintegrants include starches, such as natural starches (e.g., corn starch or potato starch), pregelatinized starches (e.g., National 1551), or sodium starch glycolate (e.g., Promogel® or Explotab®); celluloses, such as wood products, methyl crystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®), methyl cellulose, croscarmellose cellulose, or cross-linked cellulose (e.g., croscarmellose sodium carboxymethyl cellulose (Ac-Di-Sol®), croscarmellose cellulose, or croscarmellose carboxymethyl cellulose); cross-linked starches (e.g., sodium starch glycolate); cross-linked polymers, such as cross-linked polyvinyl N-pyrrolidone (crosspovidone), cross-linked polyvinylpyrrolidone; alginates, such as alginic acid or salts of alginic acid (e.g., sodium alginate); and clays, such as Veegum®. HV (magnesium aluminum silicate); gums, such as agar, guar gum, locust bean gum, ebony gum, pectin, or astragalus gum; sodium starch glycolate; bentonite; natural sponges; surfactants; resins, such as cation exchange resins; citrus pomace; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch, etc. In some embodiments, at least one disintegrant is selected from starch, cross-linked starch, cellulose, cross-linked cellulose, cross-linked polymers, alginate, clay, gums, glycolates, bentonite, natural sponges, surfactants, resins, citrus pomace, and sodium lauryl sulfate.

[0118] In some embodiments, at least one disintegrant is selected from croscarmellose sodium, croscarmellose, croscarmellose sodium, croscarmellose, croscarmellose carboxymethyl cellulose, cross-linked croscarmellose, cross-linked croscarmellose, cross-linked polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone. In some embodiments, at least one disintegrant is selected from cross-linked polyvinyl N-pyrrolidone (croscarmellose) and cross-linked carboxymethyl cellulose (croscarmellose). In some embodiments, at least one disintegrant comprises cross-linked polyvinyl N-pyrrolidone (croscarmellose) and cross-linked carboxymethyl cellulose (croscarmellose). In some embodiments, at least one disintegrant comprises cross-linked polyvinyl N-pyrrolidone (croscarmellose). In some embodiments, at least one disintegrant comprises cross-linked carboxymethyl cellulose (croscarmellose). In some embodiments, at least one disintegrant comprises croscarmellose sodium. In some embodiments, at least one disintegrant comprises type A croscarmellose.

[0119] The total amount of disintegrant in the tablet ranges from about 0.1% to about 15% by weight. In some embodiments, the total amount of disintegrant in the tablet ranges from about 0.5% to about 15% by weight, about 0.1% to about 10% by weight, or about 2.0% to about 5.0% by weight. In some embodiments, the total amount of disintegrant in the tablet is about 2.0% by weight, about 3.0% by weight, about 4.0% by weight, about 5.0% by weight, about 6.0% by weight, about 7.0% by weight, about 8.0% by weight, about 9.0% by weight, or about 10% by weight. In some embodiments, the total amount of disintegrant in the tablet is about 2.0% by weight.

[0120] In some embodiments, the tablet contains about 2.0% crospovidone by weight. In some embodiments, the tablet contains about 4.0% crospovidone by weight. In some embodiments, the tablet contains about 10.0% crospovidone by weight. In some embodiments, the tablet contains about 4.0% crospovidone by weight and about 2.0% croscarmellose sodium by weight.

[0121] In some embodiments, the tablet contains a total amount of disintegrant from about 1 mg to about 125 mg. In some embodiments, the tablet contains a total amount of disintegrant from about 10 mg to about 100 mg. In some embodiments, the tablet contains a total amount of disintegrant from about 80 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 80 mg. In some embodiments, the tablet contains a total amount of disintegrant from about 15 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 15 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 15 mg. In some embodiments, the tablet contains a total amount of disintegrant from about 14 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 14 mg. In some embodiments, the tablet contains a total amount of disintegrant from about 8 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 8 mg. In some embodiments, the tablet contains a total amount of crospovidone from about 25 mg and a total amount of crospovidone sodium from about 14 mg.

[0122] Lubricants are compounds that prevent, reduce, or inhibit the adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearoyl fumarate, hydrocarbons (such as mineral oil), or hydrogenated vegetable oils (such as hydrogenated soybean oil), higher fatty acids and their alkali metal and alkaline earth metal salts (such as aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, glycerin, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG4000) or methoxy polyethylene glycol (such as Carbowax®), sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica (such as Syloid®, Cab-O-Sil®), starch (such as corn starch), silicone oil, surfactants, etc. In some embodiments, at least one lubricant is selected from stearic acid, calcium hydroxide, talc, hydrocarbons, hydrogenated vegetable oils, higher fatty acids, stearates, glycerin, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxy polyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch, silicone oil, and surfactants.

[0123] In some embodiments, at least one lubricant is selected from magnesium stearate and sodium stearoyl fumarate. In some embodiments, at least one lubricant is magnesium stearate. In some embodiments, at least one lubricant is sodium stearoyl fumarate. In some embodiments, the tablet does not contain magnesium stearate. In some embodiments, the tablet does not contain sodium stearoyl fumarate.

[0124] In some embodiments, the total amount of lubricant in the tablet ranges from about 0.01% to about 5% by weight. In some embodiments, the total amount of lubricant in the tablet ranges from about 0.1% to about 5% by weight. In some embodiments, the total amount of lubricant in the tablet is about 1% by weight. In some embodiments, the total amount of lubricant in the tablet is about 1.25% by weight. In some embodiments, the total amount of lubricant in the tablet is about 1.2% by weight. In some embodiments, the total amount of lubricant in the tablet is about 1.5% by weight. In some embodiments, the total amount of lubricant in the tablet is about 2.0% by weight.

[0125] In some embodiments, the tablet comprises magnesium stearate. In some embodiments, the amount of magnesium stearate in the tablet ranges from about 0 to about 1.5% by weight. In some embodiments, the amount of magnesium stearate in the tablet is about 1.2% by weight. In some embodiments, the amount of magnesium stearate in the tablet is about 1.25% by weight. In some embodiments, the amount of magnesium stearate in the tablet is about 1.5% by weight. In some embodiments, the amount of magnesium stearate in the tablet ranges from about 0 to about 20 mg. In some embodiments, the amount of magnesium stearate in the tablet is about 3.5 mg. In some embodiments, the amount of magnesium stearate in the tablet is about 7.2 mg. In some embodiments, the amount of magnesium stearate in the tablet is about 9.6 mg. In some embodiments, the amount of magnesium stearate in the tablet is about 11.5 mg.

[0126] In some embodiments, the tablet contains sodium stearoyl fumarate. In some embodiments, the amount of sodium stearoyl fumarate in the tablet ranges from about 0 to about 2.0% by weight. In some embodiments, the amount of sodium stearoyl fumarate in the tablet ranges from about 0 to about 20 mg. In some embodiments, the amount of sodium stearoyl fumarate in the tablet is about 16 mg.

[0127] During the preparation of tablets of compounds of formula (I), some components may be mixed separately and then combined later during processing. For example, a group of components may be blended and compacted to form dry granules. Subsequently, those intermediate dry granules may be further blended with other components and then compressed to form tablets, which may be coated with a film coating. The intermediate dry granules may have a certain size or shape that advantageously provides one or more improved processing characteristics, such as, for example, providing a particle size of a flowable powder that resists aggregation. The intermediate dry granules may undergo blending with a group of other components to form a solid material having at least two discrete phases, wherein the dry granules form an intragranular phase and the other components form an extragranular phase. The presence of discrete phases can provide beneficial properties to the resulting tablets and during processing, including, for example, improved dissolution, friability, hardness characteristics, flowability, and tablet quality reproducibility. Particles containing two phases can be larger and have a more uniform particle size compared to particles with only one phase, which can lead to improved flow characteristics. In some embodiments, the tablets comprise an intragranular phase and an extragranular phase.

[0128] The internal phase of the particles may include a compound of formula (I), at least one diluent, at least one disintegrant, at least one lubricant, and optionally at least one flow aid.

[0129] In some embodiments, at least one diluent is present in the internal phase of the particles in a total amount ranging from about 15% to about 45% by weight (e.g., about 20.5% or about 30.5% by weight). In some embodiments, at least one diluent is present in the external phase of the particles in a total amount ranging from about 0% to about 15% by weight (e.g., about 10% by weight). In some embodiments, at least one diluent present in the internal phase of the particles comprises 50 µm microcrystalline cellulose. In some embodiments, at least one diluent present in the internal phase of the particles comprises 90 µm microcrystalline cellulose. In some embodiments, at least one diluent present in the external phase of the particles comprises 180 µm microcrystalline cellulose. In some embodiments, at least one diluent present in the internal phase of the particles comprises about 30.5% of 50 µm microcrystalline cellulose in total. In some embodiments, at least one diluent present in the internal phase of the particles comprises about 20.5% of 50 µm microcrystalline cellulose in total. In some embodiments, at least one diluent present in the internal phase of the particles comprises about 30.5% of 90 µm microcrystalline cellulose in total. In some embodiments, at least one diluent present in the internal phase of the particles comprises about 20.5% of 90 µm microcrystalline cellulose in total. In some embodiments, at least one diluent present in the external phase of the particles comprises about 10% of 180 µm microcrystalline cellulose in total. In some embodiments, the external phase of the particles does not contain a diluent.

[0130] In some embodiments, at least one disintegrant is present in the internal phase of the particles in a total amount ranging from about 1.0% to about 10% by weight (e.g., about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, or about 10.0% by weight). In some embodiments, at least one disintegrant is present in the internal phase of the particles in a total amount of about 2.0% by weight. In some embodiments, at least one disintegrant is present in the internal phase of the particles in a total amount of about 4.0% by weight. In some embodiments, at least one disintegrant is present in the internal phase of the particles in a total amount of about 5.0% by weight. In some embodiments, the at least one disintegrant present in the internal phase of the particles is selected from cross-linked polyvinyl N-pyrrolidone (crosspovidone) and cross-linked carboxymethyl cellulose (cross-linked carboxymethyl cellulose). In some embodiments, at least one disintegrant present in the internal phase of the particles is about 2.0% by weight of crospovidone. In some embodiments, at least one disintegrant present in the internal phase of the particles is about 5.0% by weight of crospovidone. In some embodiments, at least one disintegrant present in the internal phase of the particles is about 3.0% by weight of crospovidone and about 1.0% by weight of cross-linked carboxymethyl cellulose.

[0131] In some embodiments, at least one disintegrant is present in the external phase of the particles in a total amount ranging from about 1.0% to about 10% by weight (e.g., about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, or about 10.0% by weight). In some embodiments, at least one disintegrant is present in the external phase of the particles in a total amount of about 2.0% by weight. In some embodiments, at least one disintegrant is present in the external phase of the particles in a total amount of about 5.0% by weight. In some embodiments, the external phase of the particles does not contain a disintegrant. In some embodiments, at least one disintegrant in the external phase of the particles is selected from cross-linked polyethylene N-pyrrolidone (crosspovidone) and cross-linked carboxymethyl cellulose (cross-linked carboxymethyl cellulose). In some embodiments, at least one disintegrant present in the internal phase of the particles is about 2.0% by weight of cropovidone. In some embodiments, at least one disintegrant present in the external phase of the particles is about 2.0% by weight of cropovidone. In some embodiments, at least one disintegrant present in the external phase of the particles is about 5.0% by weight of cropovidone. In some embodiments, at least one disintegrant present in the external phase of the particles is about 1.0% by weight of cropovidone and about 1.0% by weight of cross-linked carboxymethyl cellulose.

[0132] In some embodiments, at least one lubricant is present in the intraparticle phase in a total amount ranging from about 0.01% to about 10% by weight (e.g., about 0.1% to about 5% by weight, such as about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1.0% by weight). In some embodiments, at least one lubricant is present in the intraparticle phase in a total amount of about 0.25% by weight. In some embodiments, at least one lubricant is present in the intraparticle phase in a total amount of about 0.5% by weight. In some embodiments, at least one lubricant is present in the intraparticle phase in a total amount of about 1.0% by weight. In some embodiments, the at least one lubricant present in the intraparticle phase comprises magnesium stearate or sodium stearoyl fumarate. In some embodiments, the at least one lubricant present in the intraparticle phase comprises magnesium stearate. In some embodiments, at least one lubricant present in the internal phase of the particles comprises about 0.5% magnesium stearate in total. In some embodiments, at least one lubricant present in the internal phase of the particles comprises about 1.0% magnesium stearate in total. In some embodiments, at least one lubricant present in the internal phase of the particles comprises sodium stearoyl fumarate. In some embodiments, at least one lubricant present in the internal phase of the particles comprises about 1.0% sodium stearoyl fumarate in total.

[0133] In some embodiments, at least one lubricant is present in the external phase of the particulate matter in a total amount ranging from about 0 to about 5% by weight (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1.0% by weight). In some embodiments, at least one lubricant is present in the external phase of the particulate matter in a total amount of about 0.2% by weight. In some embodiments, at least one lubricant is present in the external phase of the particulate matter in a total amount of about 0.25% by weight. In some embodiments, at least one lubricant is present in the external phase of the particulate matter in a total amount of about 1.0% by weight. In some embodiments, the at least one lubricant present in the external phase of the particulate matter comprises magnesium stearate or sodium stearoyl fumarate. In some embodiments, the at least one lubricant present in the external phase of the particulate matter comprises magnesium stearate. In some embodiments, at least one lubricant present in the particulate phase comprises about 0.2% magnesium stearate in total. In some embodiments, at least one lubricant present in the particulate phase comprises about 1.0% magnesium stearate in total. In some embodiments, at least one lubricant present in the particulate phase comprises sodium stearoyl fumarate. In some embodiments, at least one lubricant present in the particulate phase comprises about 1.0% sodium stearoyl fumarate in total.

[0134] In some embodiments, at least one flow aid is present in the intraparticle phase in a total amount ranging from about 0% to about 5% by weight (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight). In some embodiments, at least one flow aid is present in the intraparticle phase in a total amount of about 0.9% by weight. In some embodiments, at least one flow aid is present in the intraparticle phase in a total amount of about 0.7% by weight.

[0135] In some embodiments, at least one flow aid present in the intraparticle phase comprises a flow rate of about 200 m 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the internal phase of the particles comprises approximately 0.9% by weight of a material having a surface area of ​​approximately 200 m². 2Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the internal phase of the particles comprises about 0.7% by weight of a particle with an average specific surface area of ​​about 200 m². 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the internal phase of the particles comprises a total amount of about 0.9% by weight of colloidal silica with an average specific surface area of ​​about 300 m. 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the internal phase of the particles comprises about 0.7% by weight of a silica with an average specific surface area of ​​about 300 m². 2 Colloidal silica with an average specific surface area of ​​ / g.

[0136] In some embodiments, at least one flow aid is present in the external phase of the particles in a total amount ranging from about 0% to about 5% by weight (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight). In some embodiments, at least one flow aid is present in the external phase of the particles in a total amount of about 0.4% by weight. In some embodiments, at least one flow aid is present in the external phase of the particles in a total amount of about 0.6% by weight.

[0137] In some embodiments, at least one flow aid present in the particulate external phase comprises a flow rate of about 200 m 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the particulate external phase comprises approximately 0.4% by weight of a material having a surface area of ​​approximately 200 m². 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the particulate external phase comprises a total amount of about 0.6% by weight of colloidal silica with an average specific surface area of ​​about 200 m. 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the particulate external phase comprises a total amount of about 0.4% by weight of colloidal silica with an average specific surface area of ​​about 300 m. 2 Colloidal silica with an average specific surface area of ​​ / g. In some embodiments, at least one flow aid present in the particulate external phase comprises a total amount of about 0.6% by weight of colloidal silica with an average specific surface area of ​​about 300 m. 2 Colloidal silica with an average specific surface area of ​​ / g.

[0138] In some embodiments, the tablet comprises at least one compound selected from a compound of formula (I) and a pharmaceutically acceptable salt thereof, at least one diluent present in an amount ranging from about 10% to about 50% by weight, at least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight, at least one lubricant present in an amount ranging from about 0.01% to about 5% by weight, and optionally at least one flow aid. In embodiments in which at least one flow aid is present, the flow aid is present in an amount greater than 0% to about 5% by weight (e.g., in an amount ranging from about 0.01% to about 5% by weight).

[0139] In some embodiments, the intraparticle phase comprises a compound of formula (I), microcrystalline cellulose, crosspovidone, magnesium stearate, and colloidal silica. In some embodiments, the extraparticle phase comprises magnesium stearate. In some embodiments, the intraparticle phase comprises a compound of formula (I), microcrystalline cellulose, crosspovidone, and sodium stearoyl fumarate. In some embodiments, the extraparticle phase comprises sodium stearoyl fumarate. In some embodiments, the intraparticle phase comprises a compound of formula (I), at least one of microcrystalline cellulose, crosspovidone, and cross-linked carboxymethyl cellulose, magnesium stearate, and colloidal silica. In some embodiments, the extraparticle phase comprises at least one of microcrystalline cellulose, crosspovidone, and cross-linked carboxymethyl cellulose, magnesium stearate, and colloidal silica.

[0140] In some embodiments, the internal phase of the particles comprises a compound of formula (I), microcrystalline cellulose, cross-povidone, magnesium stearate, and colloidal silica. In some embodiments, the external phase of the particles comprises magnesium stearate and colloidal silica.

[0141] The adhesive imparts cohesiveness and includes, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g., Methocel®), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; cross-linked viscosine; povidone; starch; pregelatinized starch; astragalus gum; dextrin; sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as gum arabic, astragalus gum, ghatti gum, and mucilage of isapol husks; polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon®). CL, Polyplasdone® XL-10); larch arabinogalactan; Veegum®; polyethylene glycol; polyethylene oxide; wax; sodium alginate, etc.

[0142] Those skilled in the art will understand that the choice of excipients can depend on the method used to prepare the tablets prior to compression, whether that method involves blending or dry granulation. For example, dry granulation can involve compaction to form dry granules, followed by the addition of excipients, including binders. Of course, this can be modified, as those skilled in the art will understand, such as by adding materials later.

[0143] In some embodiments, at least one adhesive is selected from alginate, carboxymethyl cellulose, methyl cellulose (e.g., Methocel®), hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose, HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer; cross-linked povidone, povidone, starch, pregelatinized starch, astragalus gum, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose; gum arabic, astragalus gum, solanum, psyllium husk mucus, and polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10). In some embodiments, the adhesive includes hydroxypropyl cellulose.

[0144] Methods for preparing formulations

[0145] The pharmaceutical formulations disclosed herein can be obtained by mixing at least one solid excipient described herein with a compound of formula (I) described herein in solid form, optionally grinding the resulting mixture, and processing the mixture into granules after adding a suitable excipient (if desired) to obtain tablets.

[0146] Other steps include one or a combination of the following methods: (1) dry mixing, (2) direct tableting, (3) milling, (4) dry or non-aqueous granulation, (5) melt processing, or (6) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd ed. (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, extrusion / spheronization, etc.

[0147] In some embodiments, the preparation of tablets disclosed herein includes weighing, sieving, mixing, compacting, tableting, and film coating steps.

[0148] In some embodiments, tablets prepared using the formulations disclosed herein are compacted at a pressure ranging from about 30 to about 60 bar (e.g., about 36 bar). In some embodiments, tablets prepared using the formulations disclosed herein have an average crush resistance of 250 N ± 50 N. In some embodiments, tablets prepared using the formulations disclosed herein have a friability of < 1% after 4 minutes and 30 minutes. In some embodiments, tablets prepared using the formulations disclosed herein have a disintegration time of < 15 minutes. In some embodiments, tablets prepared using the formulations disclosed herein have at least one of the following characteristics: an average crush resistance of 250 N ± 50 N, a friability of < 1% after 4 minutes and 30 minutes, and a disintegration time of < 15 minutes.

[0149] In some embodiments, the tablet comprises at least one coating layer. In some embodiments, the coating layer is a film coating layer. The coating layer may comprise hydroxypropyl methylcellulose, also known as hydroxypropyl methylcellulose. In some embodiments, the coating layer comprises at least one of titanium dioxide and polyethylene glycol. In some embodiments, the coating layer comprises titanium dioxide and polyethylene glycol. In some embodiments, the coating layer comprises hydroxypropyl methylcellulose. In some embodiments, the coating layer may mask or enhance the taste of the tablet and may include a flavor masking agent.

[0150] In some embodiments, the coating layer comprises about 1% to about 8% of the tablet by weight. In some embodiments, the coating layer comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, or about 8% of the tablet by weight.

[0151] In some embodiments, the coating layer comprises 36% lactose monohydrate, 28% hydroxypropyl methylcellulose (15 mPa·s), 26% titanium dioxide (E171), and 10% macrogol 3000-polyethylene glycol 3000 in an amount of about 2% to 4% by weight of the tablet. In some embodiments, the coating layer comprises lactose monohydrate, hydroxypropyl methylcellulose, titanium dioxide, and macrogol 3000-polyethylene glycol 3000 in an amount of about 3% by weight of the tablet.

[0152] In some embodiments, the coating layer comprises 40% hydrolyzed polyvinyl alcohol, 20.2% macrogol / PEG, 21.5% titanium dioxide, 14.8% talc, and 3.5% FD&C No. 6 Yellow (Sunset Yellow FCF Aluminum Lake, US FDA Pigment Certification No. AZ7623, Regulation (EC) No. 1333 / 2008). In some embodiments, the coating layer comprises hydrolyzed polyvinyl alcohol, macrogol / PEG, titanium dioxide, talc, and pigment in an amount of approximately 3% by weight of the tablet.

[0153] In some implementations, the pharmaceutical formulation does not contain titanium dioxide.

[0154] In addition to plasticizers, colorants, surfactants, anti-sticking agents, defoamers, lubricants (e.g., carnauba wax or PEG), and other additives can be added to the coating to dissolve or disperse the coating material and improve coating performance and the coated product. In some embodiments, the coating layer is white. In some embodiments, the coating layer is orange.

[0155] In some implementations, the tablets are packaged in blister packs. Blister packs can be made of any suitable material. Examples include polyethylene-polyvinyl chloride in a molded film and hardened aluminum foil as a cap.

[0156] In some implementations, the tablets are packaged in a bottle. The bottle can be made of any suitable material.

[0157] Treatment

[0158] This document provides a method for treating a BTK-mediated disease or condition, the method comprising administering to a subject in need a formulation comprising a therapeutically effective amount of a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]pent-2-enenoner or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient. In some embodiments, the therapeutically effective amount is from about 50 mg to about 900 mg. In some embodiments, the therapeutically effective amount is about 200 mg. In some embodiments, the therapeutically effective amount is about 300 mg. In some embodiments, the therapeutically effective amount is about 400 mg. In some embodiments, the therapeutically effective amount is about 500 mg. In some embodiments, the therapeutically effective amount is about 600 mg. In some embodiments, the therapeutically effective amount is about 800 mg. In some implementations, the subjects are mammals. In some implementations, the mammals are humans.

[0159] This document also provides the use of a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for the manufacture of an agent for treating a disease or condition mediated by BTK. In some embodiments, the use of a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enenyl nitrile or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for manufacturing an agent for treating a BTK-mediated disease or condition includes the use of a therapeutically effective amount of a compound of formula (I). In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 50 mg to about 900 mg. In some embodiments, the therapeutically effective amount is about 200 mg. In some embodiments, the therapeutically effective amount is about 300 mg. In some embodiments, the therapeutically effective amount is about 400 mg. In some embodiments, the therapeutically effective amount is about 500 mg. In some embodiments, the therapeutically effective amount is about 600 mg. In some embodiments, the therapeutically effective dose is approximately 800 mg. In some embodiments, the agent is intended for use in treating mammals. In some embodiments, the mammal is a human.

[0160] This document further provides the use of a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enenoner or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for the treatment of diseases or conditions mediated by BTK. In some embodiments, the use of a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enenyl nitrile or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for the treatment of BTK-mediated diseases or conditions includes the use of a therapeutically effective amount of a compound of formula (I). In some embodiments, a therapeutically effective amount of a compound of formula (I) is from about 50 mg to about 900 mg. In some embodiments, a therapeutically effective amount is about 200 mg. In some embodiments, a therapeutically effective amount is about 300 mg. In some embodiments, a therapeutically effective amount is about 400 mg. In some embodiments, a therapeutically effective amount is about 500 mg. In some embodiments, a therapeutically effective amount is about 600 mg. In some embodiments, the therapeutically effective dose is approximately 800 mg. In some embodiments, the use is for the treatment of mammals. In some embodiments, the mammal is a human.

[0161] This document further provides a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutan-3-yl)piperazin-1-yl]pent-2-enenoner or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for use in the treatment of diseases or conditions mediated by BTK. This document also provides a compound of formula (I) (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient for use in the manufacture of a medicament for treating a disease or condition mediated by BTK.

[0162] In some embodiments, the dosage is approximately 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 800-850 mg, or 850-900 mg. In some embodiments, the dosage is approximately 200 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, or approximately 1000 mg. In some embodiments, the dosage is approximately 200 mg. In some embodiments, the dosage is approximately 300 mg. In some embodiments, the dose is about 400 mg or about 500 mg. In some embodiments, the dose is about 600 mg. In some embodiments, the dose is about 800 mg. In some embodiments, the dose is about 900 mg.

[0163] In some embodiments, the dose is administered daily. The daily dose may be delivered as a single dose or divided into multiple portions. For example, in some embodiments, the dose is administered once a day (e.g., approximately every 24 hours). In some embodiments, the dose is administered twice daily. In some embodiments, the dose is divided into two portions for administration twice daily (e.g., approximately every 12 hours). In some embodiments, the dose is divided into three portions for administration three times daily (e.g., approximately every 8 hours). In some embodiments, the dose is divided into four portions for administration four times daily (e.g., approximately every 6 hours).

[0164] In some embodiments, the dosage is administered orally. In some embodiments, the dosage is administered in tablet form. In some embodiments, the dosage is administered in the form of pills, capsules, semi-solid dosage forms, powders, sustained-release formulations, or any other suitable combination.

[0165] In some embodiments, the BTK inhibitor compound of formula (I) is administered to the subject for a period of approximately 4, 8, 12, 16, 20, 24, or 26 weeks. In some embodiments, the BTK inhibitor compound of formula (I) is administered to the subject for a period of approximately 6, 12, 18, 24, 30, 36, 42, or 48 months. In some embodiments, the dose is once daily. In some embodiments, the dose is twice daily.

[0166] In some embodiments, the BTK inhibitor compound of formula (I) is administered as a single therapy. In some embodiments, the method includes administering the BTK inhibitor compound of formula (I) and at least one additional therapeutic agent. The additional therapeutic agent may be administered in parallel or sequentially with the compound of formula (I).

[0167] The frequency of administration can be determined by a person skilled in the art (such as an attending physician) based on the following considerations: the condition being treated, the age of the subject being treated, the severity of the condition being treated, and the general health status of the subject being treated.

[0168] In some implementations, a therapeutically effective amount of the compound of formula (I) is administered to treat a variety of conditions or diseases, such as at least one of the following: acne, allergies, alopecia areata, vitiligo, pyoderma gangrenosa, pemphigoid membranaceus, acquired epidermolysis bullosa, Schwarz-Jones syndrome, toxic epidermolysis bullosa (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitis, antiphospholipid syndrome, vasculitis, Guillain-Barré syndrome, scleroderma, Wechsler's granulomatosis, psoriasis, granulomatous polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate to severe asthma, mild asthma, moderate asthma, severe asthma, poorly controlled asthma, autoimmune hepatitis, leukemia. Severe's disease, Graves' disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruption, drug-induced thrombocytopenic purpura (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis-associated alopecia, pseudofolliculitis of the beard, leukocytospinal vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, mycosis fungoides, Sweet's syndrome, follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walter's macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma. Extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, non-Hodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related disease (IgG4-RD) and its acute exacerbation, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenic purpura, inflammatory bowel disease, pruritus associated with atopic dermatitis. Lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, acute lung injury caused by sepsis, diffuse alveolar injury (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary cholangiosclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), IgA urticaria, and IgA nephropathy.

[0169] The effective therapeutic dose typically depends on the weight of the subject being treated, their physical or health condition, the extent of the condition to be treated, or the age of the subject being treated, the method of drug formulation and / or method of administration (e.g., timing and route of administration).

[0170] In some embodiments, the dosage is administered with food. In some embodiments, the dosage is administered once daily with food. In some embodiments, the dosage is 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg with food. In some embodiments, the dosage is 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg with food once daily. In some embodiments, the dosage is 400 mg with food once daily. In some embodiments, the dosage is 600 mg with food once daily. In some embodiments, the dosage is administered in tablet form. In some embodiments, the dosage is administered in tablet form with food. In some embodiments, the dosage is administered once daily in tablet form. In some embodiments, the dosage is 400 mg with tablet form. In some embodiments, the dosage is 400 mg with tablet form with food. In some embodiments, the dosage is 400 mg with tablet form once daily in tablet form. In some embodiments, the dosage is 600 mg with tablet form. In some embodiments, a 600 mg tablet is administered with food. In some embodiments, a 600 mg tablet is administered once daily. In some embodiments, a 600 mg tablet is administered once daily with food.

[0171] In some embodiments, the dose is administered twice daily with food. In some embodiments, a dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered twice daily with food. In some embodiments, a dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered twice daily with food. In some embodiments, a dose of 400 mg is administered twice daily with food. In some embodiments, a dose of 600 mg is administered twice daily with food. In some embodiments, the dose is administered in tablet form. In some embodiments, the dose is administered in tablet form with food. In some embodiments, the dose is administered in tablet form twice daily. In some embodiments, the dose is administered in tablet form twice daily with food. In some embodiments, the dose is administered in tablet form twice daily with food. In some embodiments, the dose is administered in tablet form twice daily with food.

[0172] In some embodiments, the dose is administered without food. In some embodiments, the dose is administered once daily without food. In some embodiments, doses of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered without food. In some embodiments, doses of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered once daily without food. In some embodiments, a dose of 400 mg is administered once daily without food. In some embodiments, a dose of 600 mg is administered once daily without food. In some embodiments, the dose is administered in tablet form without food. In some embodiments, the dose is administered once daily without food. In some embodiments, a dose of 400 mg is administered in tablet form without food. In some embodiments, a dose of 400 mg is administered once daily without food. In some embodiments, a dose of 600 mg is administered in tablet form without food. In some embodiments, a dose of 600 mg is administered once daily without food.

[0173] In some embodiments, the dose is administered twice daily without food. In some embodiments, a dose of 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg is administered twice daily without food. In some embodiments, a dose of 400 mg is administered twice daily without food. In some embodiments, a dose of 600 mg is administered twice daily without food. In some embodiments, the dose is administered twice daily in tablet form without food. In some embodiments, a dose of 400 mg is administered twice daily in tablet form without food. In some embodiments, a dose of 600 mg is administered twice daily in tablet form without food.

[0174] In some embodiments, the dosage is 400 mg administered once daily. In some embodiments, the dosage is 600 mg administered once daily.

[0175] In some embodiments, the dosage is 400 mg administered twice daily. In some embodiments, the dosage is 600 mg administered twice daily.

[0176] For purposes of clarity and understanding, the foregoing disclosure has been described in detail by way of illustration and example. Therefore, it should be understood that the above description is intended to be illustrative and not restrictive. Consequently, the scope of this disclosure should not be determined by reference to the above description, but rather by reference to the following appended claims and the full scope of their equivalents. Example

[0177] The following embodiments are presented in an illustrative rather than limiting manner. Those skilled in the art can modify the procedures shown in the illustrative embodiments to obtain desired products.

[0178] According to this disclosure, formulations comprising a compound of formula (I) can be prepared as described herein.

[0179] Example 1: Immediate-release tablet formulation (400 mg, amorphous)

[0180] Film-coated tablets containing 400 mg of amorphous rizarutinib were prepared, the components of which are listed in Table 3 below. A homothetical formulation containing 300 mg of amorphous rizarutinib was used in Example 7. Table 3. Composition of 400 mg amorphous rizarutinib film-coated tablets a. Adjust the amount of microcrystalline cellulose to compensate for the weight of rizarutinib active pharmaceutical ingredient. b. During the method, purified water from the spray-coated suspension is removed by drying. c indicates a 3% weight increase in the tablet core weight. Opadry II 85F130006 or Opadry II 85F18422 (white) can be used.

[0181] Microcrystalline cellulose. Microcrystalline cellulose (MCC) is used as a diluent for direct tableting and roll compression. In approved tablet pharmaceutical products, microcrystalline cellulose is primarily used as a diluent in oral tablet formulations. In addition to its use as a diluent, microcrystalline cellulose possesses good compressibility properties, making it suitable for tableting. In the manufacture of rizarutinib tablets, MCC is added to the formulation to provide good compaction / compressibility and adhesion.

[0182] The MCC used in the rizarutinib tablets described in this article is Avicel PH101.

[0183] Chloroprene. Chloroprene is a water-insoluble, cross-linked polyvinyl N-pyrrolidone. It is a nonionic disintegrant and dissolution enhancer that can be used in tablets prepared by direct compression and dry granulation. It is considered a superdisintegrant because it rapidly exhibits high capillary activity and significant hydration capacity. In the formulations described herein, rizarutinib is designed as an immediate-release tablet to allow for rapid disintegration to ensure maximum bioavailability.

[0184] The particle size of cropovidone affects the disintegration process, with larger particles providing faster disintegration. As size increases, intraparticle porosity increases, leading to greater water absorption and faster disintegration. Disintegrants can be more effective when used both inside and outside the particle. Generally, disintegrants added only inside the particle are less effective than those added outside. For rizarutinib tablets, cropovidone is used at a 5% level inside the particle, with an additional 5% added outside. This ensures rapid tablet disintegration and improved dissolution.

[0185] The product uses type A crosspovidone, which is a multi-pharmacographa grade crosspovidone, characterized by large particle size, swelling pressure, and rapid disintegration time.

[0186] Sodium stearoyl fumarate. Sodium stearoyl fumarate (SSF) is a tablet lubricant designed for formulations requiring high-speed direct compression of tablets. SSF can be used to minimize the adhesion of blends to the rollers and promote tablet release during compression. The use of SSF is advantageous compared to other lubricants, such as magnesium stearate, with benefits including high drug compatibility and robustness against over-lubrication. Furthermore, SSF can be superior to magnesium stearate because it can improve dissolution rates, produce harder tablets, and prevent over-blending.

[0187] The SSF used in rizarutinib tablets is a multi-pharmacographa grade SSF manufactured by JRS Pharma.

[0188] Film coating agent. The ready-to-use orange film coating agent Opadry II 85F130006 is manufactured by Colorcon and consists of a mixture containing polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and aluminum lake pigment FD&C 6 Yellow.

[0189] In the tablet formulation described herein, a coating agent is dispersed in purified water and then sprayed onto the tablet core to form a water-soluble film coating, which is an aesthetic coating and allows the tablet to disintegrate immediately to rapidly release rizarutinib.

[0190] A tablet containing 400 mg of amorphous rizarutinib has a total core tablet mass of 800 mg per tablet (excluding film coating). This is shown in Table 4 below. Table 4. Composition of amorphous rizarutinib preparation (400 mg) a. During the method, purified water from the spray-coated suspension is removed by drying. b indicates the theoretical amount, corresponding to a target weight increase of 3% of the core tablet weight. Once the weight increase reaches approximately 3%, immediately stop spraying. c. Ready-to-use orange film coating; can be used with the Opadry II® complete film coating system 85F130006.

[0191] Example 2: Crystallized preparation (270 mg)

[0192] Tablets containing 270 mg of crystalline form B of rizalutinib were prepared, and the components are listed in Table 5 below. Table 5. 270 mg Rizalutinib Tablets (Crystals)

[0193] The final tablet weight was 416 mg ± 3% (404-428 mg).

[0194] The methods for preparing the tablets described herein include the steps of weighing, sieving, mixing, compacting, tableting, and film coating.

[0195] Example 3: Crystallized formulations (400 mg, 450 mg)

[0196] Two formulations containing crystalline form B rizarutinib tablets were prepared, one containing 400 mg of active pharmaceutical ingredient (API) and the other containing 450 mg of API. The components of these two formulations are listed in Table 6 below. The figures in the table represent the percentage of each component by weight relative to the total weight of the tablets. Table 6. Composition of Rizarutinib Preparations *TiO2-free

[0197] In this study, it was determined that hydroxypropyl cellulose can be removed from the formulation without adversely affecting the physical characteristics of the tablets. Furthermore, it was determined that a disintegrant is sufficient, and that magnesium stearate and silica are adequate for the external phase of the particles. The use of magnesium stearate in the external phase reduces material adhesion during processing, and a TiO2-free white film coating agent can be used.

[0198] Example 4: Another crystalline preparation (500 mg)

[0199] A formulation containing 500 mg of crystalline rizarutinib B was prepared. The components of this formulation are listed in Table 7 below. Table 7. Composition of 500 mg crystalline rizarutinib formulation Opadry® II 32F38977 is composed of 36% lactose monohydrate, 28% hydroxypropyl methylcellulose (15 mPa.s), 26% titanium dioxide (E171), and 10% macrogol 3000 (polyethylene glycol 3000). b. During the method, purified water from the spray-coated suspension is removed by drying.

[0200] Example 5: Another 500 mg crystalline exemplary formulation

[0201] Further formulations were prepared containing 500 mg of crystalline rizarutinib B tablets. The components of this formulation are listed in Table 8 below. Table 8. Crystallized formulation of 500 mg rizalutinib

[0202] Tablets were prepared using the formulations shown in Table 8. Additional batches were prepared with 0.50% by weight magnesium stearate in the granule phase. The tablet mass was 769.23 ± 3%.

[0203] Using a white coating with titanium dioxide was found to be beneficial for achieving a suitable tablet color. Material flow issues existed during the tableting process.

[0204] Example 6: Changes in colloidal silica / MCC (400 mg crystals)

[0205] Six additional formulations containing 400 mg of crystalline form B rizarutinib were prepared to evaluate the effects of changing the type of colloidal silica and microcrystalline cellulose (MCC) used in the tablets. The components of these formulations are listed in Table 9 below. Table 9. Additional formulations of 400 mg crystalline rizalutinib tablets

[0206] These formulations containing 400 mg of crystalline rizarutinib tablets will determine the optimal formulation for future use.

[0207] Example 7: Food effects and relative bioavailability of rizarutinib in healthy participants.

[0208] A randomized, open-label, single-dose, phase 4, 4-sequence, crossover phase I relative bioavailability study was conducted to compare crystalline formulation tablets of rizarutinib with a reference amorphous formulation tablets under fasting and eating conditions in healthy male and female participants. IMP = Investigational drug.

[0209] The amorphous formulation was studied at two doses of 300 mg amorphous tablets (total dose of 600 mg rizarutinib; IMP1), and the crystalline formulation was studied at a dose of one 500 mg crystalline tablet (IMP2).

[0210] This study was conducted using healthy volunteers.

[0211] Study Design Summary. This is a randomized, open-label, single-dose, phase 4, 4-sequence, crossover phase I relative bioavailability study comparing crystalline formulation tablets of rizarutinib with a reference amorphous formulation tablets under fasting and eaten (high-fat meal) conditions in healthy male and female participants aged 18 to 55 years.

[0212] The total study duration for each participant was approximately 36 days, including:

[0213] Screening: 28 days (from day -28 to day -1).

[0214] Treatment period: Once screening is successful, enrolled participants will be randomly assigned to one of four treatment sequences with four single-dose treatment periods. Duration of each period in a participant's study: 1 day of treatment followed by 1 day of washout.

[0215] Washout: Washout is planned for one day after each treatment period, so there will be a 2-day interval between doses.

[0216] Safety follow-up: Participants were required to participate in the study end safety assessment upon discharge from the clinical study unit (i.e., on day 8 of the study, one day after the last IMP administration on day 1 of the fourth treatment period).

[0217] Primary study objective: To evaluate the relative bioavailability of crystalline formulation tablets of rizarutinib compared to a reference amorphous formulation tablets in healthy male and female participants under fasting conditions.

[0218] Secondary study objectives: To evaluate the relative bioavailability of crystalline rizarutinib tablets compared to a reference amorphous tablets in healthy male and female participants under eating conditions; to evaluate the food effects of crystalline rizarutinib tablets and a reference amorphous tablets in healthy male and female participants; and to evaluate the safety and tolerability of a single oral dose of 600 mg amorphous rizarutinib (reference formulation) and a single oral dose of 500 mg crystalline rizarutinib (test formulation) administered under eating and fasting conditions.

[0219] The scope of the experiment includes safety and pharmacokinetic studies.

[0220] The four groups in the study are shown in Table 10 below. Table 10. The four groups studied.

[0221] Eligible participants were randomly assigned according to a Latin square design to receive the following study intervention in one of four sequences:

[0222] Treatment A: Rizalutinib, an amorphous tablet formulation, is administered orally in a single dose of 600 mg via 2 x 300 mg tablets on an empty stomach (= Reference under empty stomach conditions).

[0223] Treatment B: A single oral dose of 500 mg of crystalline tablet formulation rizarutinib is administered under fasting conditions (= test under fasting conditions).

[0224] Treatment C: Rizalutinib, a formulation of amorphous tablets, is administered orally in a single dose of 600 mg at the time of feeding (2 x 300 mg tablets = reference under feeding conditions).

[0225] Treatment D: Rizarutinib crystalline tablet formulation, administered orally once at a time under eating conditions, is a 500 mg dose of crystal tablets (= Test under eating conditions).

[0226] On day 1, the following sequences were randomly assigned in a ratio of 1:1:1:1:

[0227] Each administration of the investigational drug (IMP) was separated by a washout process lasting 2 days (1 day of treatment with a single dose followed by 1 day of washout).

[0228] The trial ended with the last visit (LSLV) of the last participant.

[0229] Study population: Healthy volunteers, all sexes, with a minimum age of 18 years and a maximum age of 55 years. Number of participants (planning and analysis): 28 healthy adult male and female participants were randomly assigned to the study intervention as planned.

[0230] Inclusion criteria: Men weighing between 50.0 and 100.0 kg (inclusive), and women weighing between 40.0 and 90.0 kg (inclusive), with a body mass index (BMI) between 18.0 and 32.0 kg / m². 2 Between (inclusive). Willing to abstain from tobacco or nicotine-containing products or alcohol from admission (Day -1) until discharge at the end of the study visit. Willing to abstain from any prescription drugs, dietary supplements, or over-the-counter drugs for 14 days or 5 half-lives (whichever is longer) before the first dose of the study drug, until the follow-up telephone call. Hormonal contraceptives and aspirin (≤ 2000 mg / day) or ibuprofen (≤ 1200 mg / day) are permitted before and during the study. Negative urine drug / alcohol tests are required at screening and admission (Day -1). A screening urine drug / alcohol test may be repeated if deemed appropriate by the research center investigator. Willing to abstain from products containing grapefruit, star fruit, or lime from 14 days before the first dose of the study drug until discharge from the clinical research unit.

[0231] Exclusion criteria: Any history or present condition or signs of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematologic, neurological, musculoskeletal, joint, psychiatric, systemic, ocular, gynecological (if female), or infectious disease. Participants must have had clinical signs and symptoms consistent with COVID-19 within the last 4 weeks prior to screening, such as fever, dry cough, dyspnea, loss of taste and smell, sore throat, fatigue, or infection confirmed by appropriate laboratory testing. Participants must have had a severe COVID-19 course (i.e., hospitalization, extracorporeal membrane oxygenation [ECMO], mechanical ventilation). Participants must have tested positive for SARS-CoV-2 (measured via real-time reverse transcriptase polymerase chain reaction [RT-PCR] or rapid antigen test [RAT]).

[0232] Frequent headaches and / or migraines, recurrent nausea and / or vomiting (vomiting only: more than twice a month). Donated blood (any volume) within 1 month prior to selection. Symptomatic orthostatic hypotension, regardless of whether blood pressure drops; or asymptomatic orthostatic hypotension, defined as a drop in systolic blood pressure of <30 mmHg within 3 minutes of changing from a supine to a standing position.

[0233] Drug allergy or a current condition or history of an allergic disease diagnosed and treated by a physician. Participants with a known allergy to any component of the IMP formulation or a current condition diagnosed and treated by a physician. History or current condition of drug or alcohol abuse (regular daily alcohol consumption exceeding 40 g). Regular intake of nicotine (via patches, smoking, e-cigarettes, or other forms) exceeding 10 mg daily (based on an average nicotine content of 10–12 mg per cigarette and an inhalation dose of up to 2 mg per cigarette) and inability to quit smoking during the study period (occasional smokers may be included). Excessive consumption of beverages containing xanthine (more than 4 cups or 4 glasses per day). If female, pregnant (defined as a positive β-HCG blood test) or breastfeeding.

[0234] Any medication administered within 14 days prior to enrollment or within five times the elimination half-life or pharmacodynamic half-life of the drug (including St. John's wort or ginseng), except aspirin / ibuprofen, hormonal contraceptives, and menopausal hormone replacement therapy. Any vaccination administered within the last 28 days prior to enrollment (except for COVID-19 vaccination, see below) and any biologics (antibodies or their derivatives) administered within four months prior to enrollment. Inactive vaccines, including COVID-19: the last administration of the vaccine within four weeks prior to randomization. Live vaccines: the last administration of the vaccine within three months prior to randomization.

[0235] A positive result for any of the following tests: Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibody, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab); a positive result for urine drug screening (amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, opioids); a positive breathalyzer or urine alcohol test; a positive pregnancy test; or Gilbert's syndrome.

[0236] Specific vulnerable groups: Women of childbearing potential who use contraception.

[0237] Intervention. See Table 11 below. Table 11. Intervention

[0238] Endpoints. See Tables 12-13 below. The primary endpoint was the relative bioavailability of rizarutinib as assessed by plasma PK parameters (e.g., Cmax, AUClast, AUC) after administration of the test and reference formulations in a fasting state. Secondary endpoints were the relative bioavailability of rizarutinib as assessed by plasma PK parameters (e.g., Cmax, AUClast, AUC) after administration of the test and reference formulations in a fed state; the food effect of rizarutinib as assessed by plasma PK parameters (e.g., Cmax, AUClast, AUC) after administration of the test and reference formulations in both fed and fasting states; and the safety of the test and reference formulations as assessed by physical examination, vital signs, 12-lead ECG, clinical laboratory tests (clinical chemistry, hematology, coagulation, and urinalysis), and adverse events.

[0239] Abbreviations: AUC = Area under the plasma concentration-time curve extrapolated to infinity; AUClast = Area under the plasma concentration-time curve from time zero to the last measurable concentration; Cmax = Maximum plasma concentration; ECG = Electrocardiogram; PK = Pharmacokinetics. Table 12. Primary endpoints Table 13. Secondary endpoints

[0240] Statistical methods. Statistical considerations.

[0241] Primary endpoint: Pharmacokinetics. With and without dose normalization, the relative bioavailability (Frel) of the crystalline formulation compared to the amorphous formulation under fasting conditions was assessed using a linear model based on logarithmic transformation parameters, targeting the maximum plasma concentration (Cmax), the AUC up to the last time point using quantifiable concentrations (AUClast), and the area under the plasma concentration-time curve extrapolated to infinity (AUC). The formulation ratio (geometric mean ratio) and 90% confidence interval (CI) were estimated based on the model.

[0242] Primary and secondary endpoints.

[0243] Pharmacokinetics. The relative bioavailability (with and without dose normalization) of crystalline formulations compared to amorphous formulations under food conditions was assessed using a linear model based on log-transformed parameters, targeting Cmax, AUClast, and AUC, as well as the food effect of each formulation. The test / reference ratio (geometric mean ratio) and 90% CI for the PK parameters after log-transformation were estimated for different formulations and food conditions.

[0244] Safety. Secondary endpoints included adverse events (AEs), laboratory parameters, vital signs, and electrocardiograms (ECGs). Analysis was based on review and descriptive statistics of individual values. Safety analyses focused on treatment-occurring (TE) periods, defined as the time from the first IMP administration during the study period until the next study period (excluding the next study period) or until the end-of-study visit of the last study period (including the visit). AEs were coded according to the Medication Dictionary of Regulatory Activities (MedDRA). Their severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The percentage of participants who experienced treatment-occurring TEAEs was summarized. Potentially clinically significant abnormalities (PCSAs) in clinical laboratory findings, vital signs, and ECGs were labeled and summarized using a frequency table.

[0245] Results summary.

[0246] Participant Disposition: A total of 28 participants were randomized and exposed to rizarutinib in one of four treatment sequences (ABCD, BCDA, CDAB, or DABC). 27 of the 28 participants completed the study, while one participant withdrew their consent on day 6 for personal reasons (sequence randomized to ABCD, no exposure to D).

[0247] Analysis population: All participants (N = 28) were evaluable for the security assessment and PK parameters.

[0248] Demographic and other baseline characteristics: 18 of the 28 participants (64.3%) were male and 10 of the 28 participants (35.7%) were female. The median (min-max) age at enrollment was 31.5 (range 19-53) years.

[0249] Exposure: Except for one participant, all participants (27 of 28) received four single doses of rizarutinib: 600 mg of the amorphous formulation (reference formulation) with and without food, and 500 mg of the crystalline formulation (test formulation) with and without food. One subject withdrew from the study before completing treatment sequence 1 and received a single dose of the 600 mg amorphous formulation with and without food, and a single dose of the 500 mg crystalline formulation (fasting). This participant was not replaced.

[0250] Safety results: Rizarutinib was safe and well-tolerated in both formulations. Overall, 21 of the 28 participants (75%) experienced a total of 60 adverse events (AEs) (58 TEAEs and 2 post-treatment AEs). Of the 58 reported TEAEs, 41 (70.6%) were gastrointestinal in nature. There were no deaths, serious adverse events (SAEs), or withdrawal from the study due to TEAEs.

[0251] No other significant changes in clinical vital signs, ECG, or laboratory parameters were observed.

[0252] The most common TEAEs among subjects who recently received both amorphous and crystalline formulations were of a gastrointestinal nature.

[0253] Following administration of the amorphous preparation (A) on an empty stomach, 15 of the 28 participants (53.6%) reported 20 gastrointestinal TEAEs, including 8 cases of Grade 1 diarrhea, 4 cases of Grade 1 nausea, 2 cases of Grade 1 abdominal pain, 1 case of Grade 1 vomiting, and 1 case of Grade 1 dyspepsia. One participant reported Grade 2 nausea and Grade 2 abdominal pain; one participant reported Grade 2 nausea; and one participant reported Grade 2 diarrhea. All TEAEs resolved with only the addition of oral fluids.

[0254] Following administration of the crystalline formulation (B) on an empty stomach, 11 of the 28 participants (39.3%) reported 14 gastrointestinal TEAEs, including 8 cases of Grade 1 diarrhea, 4 cases of Grade 1 nausea, 1 case of Grade 1 abdominal pain, and 1 case of Grade 1 flatulence. All TEAEs resolved without treatment.

[0255] Gastrointestinal TEAEs were less frequent in each formulation when the patient was eating: after receiving the amorphous formulation (C), 4 out of 28 participants (14.3%) reported 3 cases of Grade 1 nausea and 1 case of Grade 1 abdominal pain, and after receiving the crystalline formulation (D), 3 out of 27 participants (11.1%) reported 2 cases of Grade 1 nausea and 1 case of Grade 1 diarrhea.

[0256] Pharmacokinetic results. A total of 28 participants were enrolled in the PK analysis cohort. One participant discontinued early, therefore there are no data available for the “500 mg crystallization via food” intervention.

[0257] The mean rizalutinib plasma concentration-time curve after a single SC dose is shown in Figure 1 (Linear scale) and Figure 2 (Semi-logarithmic scale). The plasma PK parameters of rizalutinib following a single oral dose of 500 mg crystalline or 600 mg amorphous rizalutinib under fasting or eating conditions are summarized in Table 14. Table 14. Mean ± SD (geometric mean) [CV%] of pharmacokinetic parameters of rizalutinib in healthy participants after a single oral administration of the two formulations under fasting or eating conditions. a. Median (Min, Max) b N = 26. For the two participants in the “500 mg crystal fasting” study, the log-linear terminal phase was not adequately characterized. cN = 27. For one participant in the “600 mg amorphous fasting” group, the log-linear terminal phase was not adequately characterized.

[0258] The geometric mean ratios and 90% CIs of the main PK parameters are summarized in Tables 15 and 16, the latter presenting dose-normalized PK parameters. Table 15 - Main Analysis - Relative Bioavailability and Food Effect - Point Estimates and 90% Confidence Intervals for Treatment Ratios of Rizarutinib Cmax, AUClast, and AUC - PK Population Treatment A: Rizarutinib 600 mg amorphous, fasting. Treatment B: Rizarutinib 500 mg crystalline, fasting. Treatment C: Rizarutinib 600 mg amorphous, with food. Treatment D: Rizarutinib 500 mg crystalline, with food. CI: Confidence Interval The main analysis includes all available PK parameters. Table 16 - Main Analysis - Relative Bioavailability and Food Effects of Rizalutinib Cmax, AUClast, and AUC - Treatment Ratio Point Estimation and 90% Confidence Intervals for Dose-Normalized PK Parameters - PK Population Treatment A: Rizarutinib 600 mg amorphous, fasting. Treatment B: Rizarutinib 500 mg crystalline, fasting. Treatment C: Rizarutinib 600 mg amorphous, with food. Treatment D: Rizarutinib 500 mg crystalline, with food. CI: Confidence Interval The main analysis includes all available PK parameters.

[0259] Under fasting conditions, the exposure of 600 mg amorphous rizarutinib was similar in terms of Cmax and slightly higher in terms of AUC compared with 500 mg crystalline rizarutinib (Table 14), with trial / reference ratios of 0.93 (90% CI: 0.73 to 1.19) and 0.85 (90% CI: 0.69 to 1.05), respectively (Table 15). Under fed conditions, the exposure of 600 mg amorphous rizarutinib was slightly higher in terms of both Cmax and AUC compared with 500 mg crystalline rizarutinib (Table 14), with trial / reference ratios of 0.83 (90% CI: 0.65 to 1.07) and 0.85 (90% CI: 0.69 to 1.04), respectively (Table 15).

[0260] Dose-normalized exposures were similar between the two formulations, indicating similar bioavailability after adjustment for dose differences (Table 16). For Cmax and AUC, the dose-normalized point estimates (90% CI) of the crystal / amorphous ratio were 1.12 (90% CI: 0.88 to 1.43) and 1.02 (90% CI: 0.83 to 1.26) under fasting conditions, and 1.00 (90% CI: 0.78 to 1.28) and 1.02 (90% CI: 0.83 to 1.25) under eating conditions, respectively. All 90% CIs for the geometric mean ratio include 1 (Tables 15 and 16).

[0261] Following oral administration of 500 mg crystalline or 600 mg amorphous rizarutinib under fasting conditions, the median tmax of rizarutinib was similar (1.50 h). When rizarutinib was administered with food, the median tmax was delayed, but similar for both formulations (2.50 h). The mean t1 / 2z of rizarutinib was similar between 500 mg crystalline and 600 mg amorphous rizarutinib under both fasting and food conditions, with mean values ​​ranging from 2.66 to 3.21 hours.

[0262] For both formulations, exposure to rizarutinib was lower in terms of Cmax and AUC when administered after eating compared to when administered on an empty stomach (Table 14). Point estimates for the eating / fasting ratios for Cmax and AUC were 0.77 (90% CI: 0.58 to 1.02) and 0.85 (90% CI: 0.67 to 1.07) for 500 mg crystalline rizarutinib, and 0.86 (90% CI: 0.65 to 1.14) and 0.85 (90% CI: 0.67 to 1.07) for 600 mg amorphous rizarutinib, respectively (Table 15).

[0263] The total variability (based on CV%) of plasma rizarutinib systemic exposure parameters was generally high (56% to 114%) under fasting or eating conditions, and showed a generally similar pattern between the two formulations (Table 14).

[0264] Conclusions. Under fasting conditions, after dose normalization, the bioavailability of rizarutinib was similar after a single dose of the 500 mg crystalline tablet formulation to that of the 600 mg amorphous tablet. For both formulations, a high-fat diet resulted in a mean reduction of exposure (AUC) of 15% compared to the fasting condition.

[0265] Overall, rizarutinib was safe and well-tolerated in healthy participants, administered as a single dose of 600 mg amorphous formulation and 500 mg crystalline formulation, in both fasting and eating states. Gastrointestinal adverse events were common and more frequently observed in fasting states and with the use of amorphous formulations.

[0266] Example 8: Another crystalline preparation (600 mg)

[0267] A formulation containing 600 mg of crystalline rizarutinib B in an immediate-release film-coated tablet form was prepared. Tablets for oral administration were prepared, and these tablets were white to off-white oval film-coated tablets. The components of this formulation are listed in Table 17 below. Table 17. Composition of 600 mg crystalline rizalutinib tablets a. Adjust the amount of microcrystalline cellulose to compensate for the weight of rizarutinib active pharmaceutical ingredient. b indicates a 3% weight increase in the core tablet mass. c. Ready-to-use Opadry® II 32F38977 is composed of 36% lactose monohydrate, 28% hydroxypropyl methylcellulose (15 mPa.s), 26% titanium dioxide (E171), and 10% macrogol 3000 (polyethylene glycol 3000). d. Prepare an aqueous suspension for spraying using purified water with the film coating agent. Water is considered a processing agent and is removed during processing.

[0268] Although this disclosure has been described in detail by way of illustration and example for purposes of clarity, such description and example should not be construed as limiting the scope of the invention. All disclosures of patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

[0269] Implementation plan:

[0270] The non-limiting embodiments of this disclosure include:

[0271] Implementation Scheme 1. A tablet comprising: at least one compound selected from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile (compounds of formula (I)) and pharmaceutically acceptable salts thereof; at least one diluent; at least one disintegrant; at least one lubricant; and optionally at least one flow aid.

[0272] Implementation Scheme 2. The tablet according to Implementation Scheme 1, wherein the tablet comprises an internal phase and an external phase.

[0273] Implementation Scheme 3. The tablet according to Implementation Scheme 1 or Implementation Scheme 2, wherein the at least one diluent is selected from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropyl methylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite.

[0274] Implementation Scheme 4. The tablet according to Implementation Scheme 3, wherein the at least one diluent comprises microcrystalline cellulose.

[0275] Implementation Scheme 5. The tablet according to Implementation Scheme 3, wherein the at least one diluent is selected from 50 µm microcrystalline cellulose, 90 µm microcrystalline cellulose and 180 µm microcrystalline cellulose.

[0276] Implementation Scheme 6. The tablet according to Implementation Scheme 3, wherein the at least one diluent is present in a total amount ranging from about 75 mg to about 400 mg.

[0277] Implementation Scheme 7. The tablet according to Implementation Scheme 3, wherein the at least one diluent is present in a total amount ranging from about 10% to about 50% by weight.

[0278] Implementation Scheme 8. The tablet according to Implementation Scheme 7, wherein the at least one diluent is present in the intraparticle phase in a total amount ranging from about 15% to about 45% by weight.

[0279] Implementation Scheme 9. The tablet according to Implementation Scheme 7 or Implementation Scheme 8, wherein the at least one diluent is present in the external phase of the particles in a total amount ranging from about 0% to about 15% by weight.

[0280] Implementation Scheme 10. The tablet according to Implementation Scheme 1 or Implementation Scheme 2, wherein the at least one flow aid is selected from colloidal silica and talc.

[0281] Implementation Scheme 11. The tablet according to Implementation Scheme 10, wherein the at least one gliding agent comprises at least one of colloidal silica having an average specific surface area of ​​about 200 m² / g and colloidal silica having an average specific surface area of ​​about 300 m² / g.

[0282] Implementation Scheme 12. The tablet according to Implementation Scheme 10, wherein the at least one gliding agent is present in a total amount ranging from 0 mg to about 50 mg.

[0283] Implementation Scheme 13. The tablet according to Implementation Scheme 10, wherein the at least one gliding agent is present in a total amount ranging from about 0% to about 5% by weight.

[0284] Implementation Scheme 14. The tablet according to Implementation Scheme 13, wherein the at least one gliding agent is present in the intraparticle phase in a total amount ranging from about 0% to about 5% by weight.

[0285] Implementation Scheme 15. The tablet according to Implementation Scheme 13, wherein the at least one gliding agent is present in the external phase of the particles in a total amount ranging from about 0% to about 5% by weight.

[0286] Implementation Scheme 16. The tablet according to Implementation Scheme 1 or Implementation Scheme 2, wherein the at least one disintegrant is selected from starch, cross-linked starch, cellulose, cross-linked cellulose, cross-linked polymer, alginate, clay, gum, glycolate, bentonite, natural sponge, surfactant, resin, citrus pomace and sodium lauryl sulfate.

[0287] Implementation Scheme 17. The tablet according to Implementation Scheme 16, wherein the at least one disintegrant is selected from cross-linked polyvinyl N-pyrrolidone (crosspovidone) and cross-linked carboxymethyl cellulose (cross-linked carboxymethyl cellulose).

[0288] Implementation Scheme 18. The tablet according to Implementation Scheme 16, wherein the at least one disintegrant is present in a total amount ranging from 1 mg to about 125 mg.

[0289] Implementation Scheme 19. The tablet according to Implementation Scheme 16, wherein the at least one disintegrant is present in a total amount ranging from about 0.1% to about 15% by weight.

[0290] Implementation Scheme 20. The tablet according to Implementation Scheme 19, wherein the at least one disintegrant is present in the intraparticle phase in a total amount ranging from about 0.1% to about 10% by weight.

[0291] Implementation Scheme 21. The tablet according to Implementation Scheme 19, wherein the at least one disintegrant is present in the external phase of the particles in a total amount ranging from about 0% to about 10% by weight.

[0292] Implementation Scheme 22. The tablet according to Implementation Scheme 1 or Implementation Scheme 2, wherein the at least one lubricant is selected from stearic acid, calcium hydroxide, talc, hydrocarbon, hydrogenated vegetable oil, higher fatty acids, stearates, glycerin, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxy polyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch, silicone oil and surfactant.

[0293] Implementation Scheme 23. The tablet according to Implementation Scheme 22, wherein the at least one lubricant is selected from magnesium stearate and sodium stearoyl fumarate.

[0294] Implementation Scheme 24. The tablet according to Implementation Scheme 22, wherein the at least one lubricant is present in a total amount ranging from 0.1 mg to about 50 mg.

[0295] Implementation Scheme 25. The tablet according to Implementation Scheme 22, wherein the at least one lubricant is present in a total amount ranging from about 0.01% to about 5% by weight.

[0296] Implementation Scheme 26. The tablet according to Implementation Scheme 25, wherein the at least one lubricant is present in the intraparticle phase in a total amount ranging from about 0.1% to about 5% by weight.

[0297] Implementation Scheme 27. The tablet according to Implementation Scheme 25, wherein the at least one lubricant is present in the external phase of the particles in a total amount ranging from about 0% to about 5% by weight.

[0298] Implementation Scheme 28. The tablet according to Implementation Scheme 2, wherein the intraparticle phase comprises at least one compound selected from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile (compounds of formula (I)) and pharmaceutically acceptable salts thereof, at least one diluent, at least one disintegrant, and at least one lubricant.

[0299] Implementation Scheme 29. The tablet according to Implementation Scheme 28, wherein the at least one diluent comprises 50 µm microcrystalline cellulose.

[0300] Implementation Scheme 30. The tablet according to Implementation Scheme 28, wherein the at least one lubricant comprises magnesium stearate.

[0301] Implementation Scheme 31. The tablet according to Implementation Scheme 28, wherein the at least one lubricant comprises sodium stearoyl fumarate.

[0302] Implementation Scheme 32. The tablet according to Implementation Scheme 28, wherein the at least one disintegrant comprises cross-linked polyvinyl N-pyrrolidone (crosspovidone).

[0303] Implementation Scheme 33. The tablet according to Implementation Scheme 28, wherein the intraparticle phase further comprises at least one flow aid.

[0304] Implementation Scheme 34. The tablet according to Implementation Scheme 33, wherein the at least one gliding agent comprises at least one of colloidal silica having an average specific surface area of ​​about 200 m² / g and colloidal silica having an average specific surface area of ​​about 300 m² / g.

[0305] Implementation Scheme 35. The tablet according to Implementation Scheme 2, wherein the extraparticle phase comprises at least one lubricant.

[0306] Implementation Scheme 36. The tablet according to Implementation Scheme 35, wherein the at least one lubricant comprises magnesium stearate.

[0307] Implementation Scheme 37. The tablet according to Implementation Scheme 35, wherein the at least one lubricant comprises sodium stearoyl fumarate.

[0308] Implementation Scheme 38. The tablet according to Implementation Scheme 35, wherein the external phase of the particles further comprises at least one diluent.

[0309] Implementation Scheme 39. The tablet according to Implementation Scheme 38, wherein the at least one diluent comprises 180 µm microcrystalline cellulose.

[0310] Implementation Scheme 40. The tablet according to Implementation Scheme 35, wherein the external phase of the particles further comprises at least one flow aid.

[0311] Implementation Scheme 41. The tablet according to Implementation Scheme 40, wherein the at least one gliding agent comprises at least one of colloidal silica having an average specific surface area of ​​about 200 m² / g and colloidal silica having an average specific surface area of ​​about 300 m² / g.

[0312] Implementation Scheme 42. The tablet according to Implementation Scheme 35, wherein the external phase of the particles further comprises at least one disintegrant.

[0313] Implementation Scheme 43. The tablet according to Implementation Scheme 42, wherein the at least one disintegrant comprises cross-linked polyvinyl N-pyrrolidone (crosspovidone).

[0314] Implementation Scheme 44. The tablet according to any one of the preceding embodiments, wherein the compound of formula (I) comprises an amorphous form.

[0315] Implementation Scheme 45. A tablet according to any one of Implementation Schemes 1-43, wherein the compound of Formula (I) is present in a crystalline form of at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100%.

[0316] Implementation Scheme 46. The tablet according to Implementation Scheme 45, wherein the compound of formula (I) comprises crystalline form B.

[0317] Implementation Scheme 47. The tablet according to any one of the preceding embodiments, wherein the compound of formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

[0318] Implementation Scheme 48. A tablet according to any one of the foregoing embodiments, wherein the compound of formula (I) is present in amounts of: about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg. mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, or approximately 650 mg.

[0319] Implementation Scheme 49. The tablet according to Implementation Scheme 48, wherein the compound of formula (I) is present in an amount of about 300 mg.

[0320] Implementation Scheme 50. The tablet according to Implementation Scheme 48, wherein the compound of formula (I) is present in an amount of about 500 mg.

[0321] Implementation Scheme 51. The tablet according to Implementation Scheme 48, wherein the compound of formula (I) is present in an amount of about 600 mg.

[0322] Implementation Scheme 52. The tablet according to any one of the preceding embodiments, wherein the compound of formula (I) is present in an amount of about 40% to about 75% by weight.

[0323] Implementation Scheme 53. The tablet according to Implementation Scheme 52, wherein the compound of formula (I) is present in an amount of about 50% by weight.

[0324] Implementation Scheme 54. The tablet according to Implementation Scheme 52, wherein the compound of formula (I) is present in an amount of about 65% by weight.

[0325] Implementation Scheme 55. The tablet according to Implementation Scheme 52, wherein the compound of formula (I) is present in the intraparticle phase.

[0326] Implementation Scheme 56. The tablet according to any one of the foregoing embodiments, wherein the tablet further comprises at least one coating layer.

[0327] Implementation Scheme 57. The tablet according to Implementation Scheme 56, wherein the coating layer comprises a flavor masking agent.

[0328] Implementation Scheme 58. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0329] Implementation Scheme 59. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate and about 0.1% to about 5% by weight of colloidal silica.

[0330] Implementation Scheme 60. The tablet according to Implementation Scheme 58 or 59, wherein the tablet comprises an internal phase and an external phase.

[0331] Implementation Scheme 61. The tablet according to Implementation Scheme 60, wherein the intraparticle phase comprises about 65% by weight of the compound of formula (I), about 31% by weight of microcrystalline cellulose, about 2% by weight of cropovidone, about 0.25% by weight of magnesium stearate and about 1% by weight of colloidal silica.

[0332] Implementation Scheme 62. The tablet according to Implementation Scheme 60, wherein the particulate phase comprises about 1% magnesium stearate by weight.

[0333] Implementation Scheme 63. A tablet according to any one of Implementation Schemes 58-62, wherein the compound of Formula (I) is present in an amount of about 270 mg.

[0334] Implementation Scheme 64. The tablet according to any one of Implementation Schemes 59-63, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0335] Implementation Scheme 65. A tablet according to any one of Implementation Schemes 59-63, wherein the compound of formula (I) comprises an amorphous form.

[0336] Implementation Scheme 66. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 45% to about 55% by weight of an amorphous compound of formula (I), about 35% to about 40% by weight of microcrystalline cellulose, about 5% to about 15% by weight of cropovidone, and about 0.5% to about 5% by weight of sodium stearoyl fumarate.

[0337] Implementation Scheme 67. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 45% to about 55% by weight of the compound of formula (I), about 35% to about 40% by weight of microcrystalline cellulose, about 5% to about 15% by weight of cropovidone and about 0.5% to about 5% by weight of sodium stearoyl fumarate.

[0338] Implementation Scheme 68. The tablet according to Implementation Scheme 66 or 67, wherein the tablet comprises an internal phase and an external phase.

[0339] Implementation Scheme 69. The tablet according to Implementation Scheme 68, wherein the intraparticle phase comprises about 50% by weight of the compound of formula (I), about 38% by weight of microcrystalline cellulose, about 10% by weight of cropovidone, and about 2% by weight of sodium stearoyl fumarate.

[0340] Implementation Scheme 70. The tablet according to Implementation Scheme 68, wherein the particulate phase comprises about 5% by weight of cropovidone and about 1% by weight of sodium stearoyl fumarate.

[0341] Implementation Scheme 71. A tablet according to any one of Implementation Schemes 66-70, wherein the compound of Formula (I) is present in an amount of about 300 mg or about 400 mg.

[0342] Implementation Scheme 72. The tablet according to any one of Implementation Schemes 67-71, wherein the compound of formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0343] Implementation Scheme 73. The tablet according to any one of Implementation Schemes 67-71, wherein the compound of formula (I) comprises an amorphous form.

[0344] Implementation Scheme 74. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of crystalline form B of the compound of formula (I), about 20% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 10% by weight of disintegrant, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica, wherein the disintegrant comprises at least one of crosspovidone and crosslinked carboxymethyl cellulose.

[0345] Implementation Scheme 75. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of formula (I), about 20% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 10% by weight of disintegrant, about 0.1% to about 5% by weight of magnesium stearate and about 0.1% to about 5% by weight of colloidal silica, wherein the disintegrant comprises at least one of crosspovidone and crosslinked carboxymethyl cellulose.

[0346] Implementation Scheme 76. The tablet according to Implementation Scheme 74 or 75, wherein the tablet comprises an internal phase and an external phase.

[0347] Implementation Scheme 77. The tablet according to Implementation Scheme 76, wherein the intraparticle phase comprises about 65% by weight of the compound of formula (I), about 23% to about 31% by weight of microcrystalline cellulose, about 2.0% to about 4.0% by weight of disintegrant, about 0.5% to about 1.0% by weight of magnesium stearate and about 0.9% by weight of colloidal silica.

[0348] Implementation Scheme 78. The tablet according to Implementation Scheme 76, wherein the particulate phase comprises about 1.5% microcrystalline cellulose by weight, about 0% to about 2.0% disintegrant by weight, about 0.2% to about 1.0% magnesium stearate and about 0.4% colloidal silica by weight.

[0349] Implementation Scheme 79. A tablet according to any one of Implementation Schemes 74-78, wherein the compound of Formula (I) is present in an amount of about 400 mg or about 450 mg.

[0350] Implementation Scheme 80. A tablet according to any one of Implementation Schemes 75-79, wherein the compound of formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0351] Implementation Scheme 81. A tablet according to any one of Implementation Schemes 75-79, wherein the compound of formula (I) comprises an amorphous form.

[0352] Implementation Scheme 82. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0353] Implementation Scheme 83. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate and about 0.1% to about 5% by weight of colloidal silica.

[0354] Implementation Scheme 84. The tablet according to Implementation Scheme 82 or 83, wherein the tablet comprises an internal phase and an external phase.

[0355] Implementation Scheme 85. The tablet according to Implementation Scheme 84, wherein the intraparticle phase comprises about 65% by weight of the compound of formula (I), about 31% by weight of microcrystalline cellulose, about 2.0% by weight of cropovidone, about 0.25% by weight of magnesium stearate and about 0.9% by weight of colloidal silica.

[0356] Implementation Scheme 86. The tablet according to Implementation Scheme 84, wherein the particulate phase comprises about 1.0% magnesium stearate and about 0.4% colloidal silica by weight.

[0357] Implementation Scheme 87. A tablet according to any one of Implementation Schemes 82-86, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[0358] Implementation Scheme 88. A tablet according to any one of Implementation Schemes 83-87, wherein the compound of formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0359] Implementation Scheme 89. A tablet according to any one of Implementation Schemes 84-87, wherein the compound of Formula (I) comprises an amorphous form.

[0360] Implementation Scheme 90. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica.

[0361] Implementation Scheme 91. The tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate and about 0.1% to about 5% by weight of colloidal silica.

[0362] Implementation Scheme 92. The tablet according to Implementation Scheme 90 or 91, wherein the tablet comprises an internal phase and an external phase.

[0363] Implementation Scheme 93. The tablet according to Implementation Scheme 92, wherein the intraparticle phase comprises about 65% by weight of the compound of formula (I), about 30% by weight of microcrystalline cellulose, about 2.0% by weight of cropovidone, about 0.5% by weight of magnesium stearate and about 0.9% by weight of colloidal silica.

[0364] Implementation Scheme 94. The tablet according to Implementation Scheme 92, wherein the particulate phase comprises about 1.0% magnesium stearate and about 0.4% colloidal silica by weight.

[0365] Implementation Scheme 95. A tablet according to any one of Implementation Schemes 90-94, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[0366] Implementation Scheme 96. The tablet according to any one of Implementation Schemes 91-95, wherein the compound of formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0367] Implementation Scheme 97. A tablet according to any one of Implementation Schemes 91-95, wherein the compound of formula (I) comprises an amorphous form.

[0368] Implementation Scheme 98. A tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of a crystalline compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica, wherein the colloidal silica comprises having a molecular weight of about 200 μm 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g.

[0369] Implementation Scheme 99. A tablet according to Implementation Scheme 1, wherein the tablet comprises: about 60% to about 70% by weight of a compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of cropovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica, wherein the colloidal silica comprises having a molecular weight of about 200 μm 2 Colloidal silica with an average specific surface area of ​​approximately 300 m² / g and a specific surface area of ​​approximately 300 m² / g. 2 At least one of the following: colloidal silica with an average specific surface area of ​​ / g.

[0370] Implementation Scheme 100. A tablet according to Implementation Scheme 98 or 99, wherein the tablet comprises an internal phase and an external phase.

[0371] Implementation Scheme 101. The tablet according to Implementation Scheme 100, wherein the intraparticle phase comprises about 65% by weight of the compound of formula (I), about 20% to about 30% by weight of microcrystalline cellulose, about 2.0% by weight of cropovidone, about 0.25% by weight of magnesium stearate and about 0.7% to about 0.9% by weight of colloidal silica.

[0372] Implementation Scheme 102. The tablet according to Implementation Scheme 100, wherein the particulate phase comprises, by weight, about 1.0% magnesium stearate, about 0% to about 10% microcrystalline cellulose and about 0.4% to about 0.6% colloidal silica.

[0373] Implementation Scheme 103. A tablet according to any one of Implementation Schemes 98-102, wherein the compound of Formula (I) is present in an amount of about 500 mg.

[0374] Implementation Scheme 104. A tablet according to any one of Implementation Schemes 98-102, wherein the compound of Formula (I) is present in an amount of about 600 mg.

[0375] Implementation Scheme 105. The tablet according to any one of Implementation Schemes 99-104, wherein the compound of Formula (I) comprises a crystalline form, and preferably comprises crystalline form B.

[0376] Implementation Scheme 106. A tablet according to any one of Implementation Schemes 99-104, wherein the compound of Formula (I) comprises an amorphous form.

[0377] Implementation Scheme 107. A tablet according to any one of Implementation Schemes 1-43, 45-64, 67-72, 74-80, 82-88, 90-96 and 98-105, wherein the compound of formula (I) comprises crystalline form B.

[0378] Implementation Scheme 108. The tablet according to any one of Implementation Schemes 1-107, wherein the tablet further comprises a film coating agent.

[0379] Implementation Scheme 109. The tablet according to Implementation Scheme 108, wherein the film coating is present in an amount of about 2% to about 5% relative to the total weight of the tablet.

[0380] Implementation Scheme 110. The tablet according to Implementation Scheme 109, wherein the film coating is present in an amount of about 3% relative to the total weight of the tablet.

[0381] Implementation Scheme 111. A method for treating a BTK-mediated disease or condition in a patient in need, the method comprising administering to the patient a tablet according to any one of Implementation Schemes 1 to 110.

[0382] Implementation Scheme 112. The method according to Implementation Scheme 111, wherein the BTK-mediated disease or condition is selected from at least one of the following: acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosa, pemphigoid membranaceus, acquired epidermolysis bullosa, Schwarz-Jones syndrome, toxic epidermolysis bullosa (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitis, antiphospholipid syndrome, vasculitis, Guillain-Barré syndrome, scleroderma, Wechsler granulomatosis, psoriasis, granulomatous polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate to severe asthma, mild asthma, moderate asthma, severe asthma, poorly controlled asthma. Asthma, autoimmune hepatitis, Behcet's disease, Graves' disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruption, drug-induced thrombocytopenic purpura (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis-associated alopecia, pseudofolliculitis of the beard, leukocytospinal vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, mycosis fungoides, Sweet's syndrome, follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walter's macroglobulinemia, marginal zone lymphoma of the spleen, plasmacytic myelopathic disease. Tumors, plasmacytomas, extranodal marginal zone B-cell lymphomas, intranodal marginal zone B-cell lymphomas, mantle cell lymphomas, mediastinal (thymic) large B-cell lymphomas, non-Hodgkin lymphomas, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related disease (IgG4-RD) and its acute exacerbations, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenic purpura, inflammatory bowel disease, and atopic dermatitis-related diseases. Itching, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, acute lung injury caused by sepsis, diffuse alveolar injury (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary cholangiosclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), A1 urticaria, and IgA nephropathy.

[0383] Implementation Scheme 113. Use of the tablet according to any one of Implementation Schemes 1 to 110 for the treatment of diseases mediated by BTK receptors.

[0384] Implementation Scheme 114. A tablet comprising: at least one compound selected from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pent-2-enonitrile (compounds of formula (I)) and pharmaceutically acceptable salts thereof; at least one diluent present in an amount ranging from about 10% to about 50% by weight; at least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight; at least one lubricant present in an amount ranging from about 0.01% to about 5% by weight; and optionally at least one flow aid.

[0385] Implementation Scheme 115. The tablet according to Implementation Scheme 114, wherein the tablet comprises an internal phase and an external phase.

[0386] Implementation Scheme 116. The tablet according to Implementation Scheme 114 or 115, wherein: the at least one diluent is selected from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropyl methylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite; the at least one disintegrant is selected from starch, cross-linked starch, cellulose, cross-linked cellulose, cross-linked polymers, alginate, clay, gum, glycolate, bentonite, natural The lubricant comprises a sponge, a surfactant, a resin, citrus pomace, and sodium lauryl sulfate; the at least one lubricant is selected from stearic acid, calcium hydroxide, talc, hydrocarbons, hydrogenated vegetable oils, higher fatty acids, stearates, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxy polyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch, silicone oil, and surfactants; and if present, the at least one flow aid is selected from colloidal silica and talc.

[0387] Implementation Scheme 117. The tablet according to any one of Implementation Schemes 114-116, wherein the at least one gliding agent is present in an amount greater than 0% to about 5% by weight.

[0388] Implementation Scheme 118. A tablet according to any one of Implementation Schemes 114-117, wherein the compound of Formula (I) comprises an amorphous form.

[0389] Implementation Scheme 119. The tablet according to any one of Implementation Schemes 114-117, wherein the compound of Formula (I) is present in a crystalline form of at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100%.

[0390] Implementation Scheme 120. A tablet according to any one of Implementation Schemes 114-119, wherein the compound of Formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

[0391] Implementation Scheme 121. The tablet according to Implementation Scheme 120, wherein the compound of formula (I) is present in an amount of about 400 mg.

[0392] Implementation Scheme 122. The tablet according to Implementation Scheme 120, wherein the compound of formula (I) is present in an amount of about 600 mg.

[0393] Implementation Scheme 123. The tablet according to any one of Implementation Schemes 114-122, wherein the compound of Formula (I) is present in an amount of about 40% to about 75% by weight.

[0394] Implementation Scheme 124. The tablet according to Implementation Scheme 123, wherein the compound of formula (I) is present in the intraparticle phase.

[0395] Implementation Scheme 125. A tablet according to any one of Implementation Schemes 114-117, wherein the tablet comprises: about 45% to about 55% by weight of an amorphous compound of formula (I), about 35% to about 40% by weight of microcrystalline cellulose, about 5% to about 15% by weight of cropovidone, and about 0.5% to about 5% by weight of sodium stearoyl fumarate, preferably wherein the compound of formula (I) is present in an amount of about 400 mg.

[0396] Implementation Scheme 126. A tablet according to any one of Implementation Schemes 114-117, wherein the tablet comprises: about 60% to about 70% by weight of the crystalline form B of the compound of formula (I), about 25% to about 35% by weight of microcrystalline cellulose, about 0.5% to about 5% by weight of crospovidone, about 0.1% to about 5% by weight of magnesium stearate, and about 0.1% to about 5% by weight of colloidal silica, preferably wherein the compound of formula (I) is present in an amount of about 600 mg.

[0397] Implementation Scheme 127. The tablet according to any one of Implementation Schemes 114-126, wherein the tablet further comprises a film coating agent.

[0398] Implementation Scheme 128. A method for treating a BTK-mediated disease or condition in a patient in need, the method comprising administering to the patient a tablet according to any one of Implementation Schemes 114-127.

[0399] Implementation Scheme 129. The method according to Implementation Scheme 128, wherein the BTK-mediated disease or condition is selected from at least one of the following: acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosa, pemphigoid membranaceus, acquired epidermolysis bullosa, Schwarz-Jones syndrome, toxic epidermolysis bullosa (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitis, antiphospholipid syndrome, vasculitis, Guillain-Barré syndrome, scleroderma, Wechsler granulomatosis, psoriasis, granulomatous polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate to severe asthma, mild asthma, moderate asthma, severe asthma, poorly controlled asthma. Asthma, autoimmune hepatitis, Behcet's disease, Graves' disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruption, drug-induced thrombocytopenic purpura (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis-associated alopecia, pseudofolliculitis of the beard, leukocytospinal vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, mycosis fungoides, Sweet's syndrome, follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walter's macroglobulinemia, marginal zone lymphoma of the spleen, plasmacytic myelopathic disease. Tumors, plasmacytomas, extranodal marginal zone B-cell lymphomas, intranodal marginal zone B-cell lymphomas, mantle cell lymphomas, mediastinal (thymic) large B-cell lymphomas, non-Hodgkin lymphomas, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related disease (IgG4-RD) and its acute exacerbations, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenic purpura, inflammatory bowel disease, and atopic dermatitis-related diseases. Itching, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, acute lung injury caused by sepsis, diffuse alveolar injury (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary cholangiosclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), A1 urticaria, and IgA nephropathy.

[0400] Implementation Scheme 130. Use of the tablet according to any one of Implementation Schemes 114-127 for the treatment of diseases involving BTK receptor-mediated diseases.

Claims

1. A tablet comprising: At least one compound selected from (2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazin-1-yl]pent-2-enonitrile (compounds of formula (I)) and pharmaceutically acceptable salts thereof; At least one diluent present in an amount ranging from about 10% to about 50% by weight; At least one disintegrant present in an amount ranging from about 0.1% to about 15% by weight; At least one lubricant present in an amount ranging from about 0.01% to about 5% by weight; and optionally at least one flow aid.

2. The tablet according to claim 1, wherein the tablet comprises an internal phase and an external phase.

3. The tablet according to claim 1 or claim 2, wherein: The at least one diluent is selected from lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium phosphate, hydroxypropyl methylcellulose, sucrose, calcium sulfate, calcium lactate, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite; The at least one disintegrant is selected from starch, cross-linked starch, cellulose, cross-linked cellulose, cross-linked polymers, alginate, clay, gum, glycolate, bentonite, natural sponge, surfactant, resin, citrus pomace and sodium lauryl sulfate. The at least one lubricant is selected from stearic acid, calcium hydroxide, talc, hydrocarbons, hydrogenated vegetable oils, higher fatty acids, stearates, glycerin, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxy polyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch, silicone oil, and surfactants; and If present, the at least one flow aid is selected from colloidal silica and talc.

4. The tablet according to any one of the preceding claims, wherein the at least one gliding agent is present in an amount greater than 0% to about 5% by weight.

5. The tablet according to any one of the preceding claims, wherein the compound of formula (I) comprises an amorphous form.

6. The tablet according to any one of claims 1 to 4, wherein the compound of formula (I) is present in a crystalline form of at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5%, or 100%.

7. The tablet according to any one of the preceding claims, wherein the compound of formula (I) is present in an amount ranging from about 200 mg to about 650 mg.

8. The tablet according to claim 7, wherein the compound of formula (I) is present in an amount of about 400 mg.

9. The tablet according to claim 7, wherein the compound of formula (I) is present in an amount of about 600 mg.

10. The tablet according to any one of the preceding claims, wherein the compound of formula (I) is present in an amount of about 40% to about 75% by weight.

11. The tablet according to claim 10, wherein the compound of formula (I) is present in the intraparticle phase.

12. The tablet according to any one of claims 1 to 4, wherein the tablet comprises: Amorphous compounds of formula (I) comprising approximately 45% to approximately 55% by weight. Microcrystalline cellulose, approximately 35% to 40% by weight. By weight, approximately 5% to approximately 15% crospovidone, and Sodium stearoyl fumarate, approximately 0.5% to approximately 5% by weight. Preferably, the compound of formula (I) is present in an amount of about 400 mg.

13. The tablet according to any one of claims 1 to 4, wherein the tablet comprises: The crystalline form B of the compound of formula (I) comprises about 60% to about 70% by weight. Microcrystalline cellulose, approximately 25% to 35% by weight By weight, approximately 0.5% to approximately 5% crospovidone. Magnesium stearate, by weight, is approximately 0.1% to approximately 5%; Colloidal silica, approximately 0.1% to approximately 5% by weight. Preferably, the compound of formula (I) is present in an amount of about 600 mg.

14. The tablet according to any one of the preceding claims, wherein the tablet further comprises a film coating agent.

15. A method for treating a BTK-mediated disease or condition in a patient in need, the method comprising administering to the patient a tablet according to any one of claims 1 to 14.

16. The method of claim 15, wherein the BTK-mediated disease or condition is selected from at least one of the following: acne, allergy, alopecia areata, vitiligo, pyoderma gangrenosa, pemphigoid membranaceus, acquired epidermolysis bullosa, Schwarz-Jones syndrome, toxic epidermolysis bullosa (TEN), pemphigus vulgaris, pemphigus foliaceus, ankylosing spondylitis, antiphospholipid syndrome, vasculitis, Guillain-Barré syndrome, scleroderma, Wechsler's granulomatosis, psoriasis, granulomatous polyangiitis, thrombotic thrombocytopenic purpura, polyarteritis nodosa, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, asthma, moderate to severe asthma, mild asthma, moderate asthma, severe asthma, poorly controlled asthma. Asthma, autoimmune hepatitis, Behcet's disease, Graves' disease, nephritis, pancreatitis, primary biliary cirrhosis, ulcerative colitis, colitis, conjunctivitis, dermatitis, atopic dermatitis, drug eruption, drug-induced thrombocytopenic purpura (DITP), vaccine-induced thrombosis and thrombocytopenia (VITT), eczema, folliculitis-associated alopecia, pseudofolliculitis of the beard, leukocytospinal vasculitis, hidradenitis suppurativa, palmoplantar pustulosis, lichenoid dermatitis, mycosis fungoides, Sweet's syndrome, follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walter's macroglobulinemia, marginal zone lymphoma of the spleen, plasmacytic osteoporosis Myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, non-Hodgkin lymphoma, warm autoimmune hemolytic anemia (wAIHA), B-cell acute lymphoblastic leukemia (B-ALL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, B-cell non-Hodgkin lymphoma, idiopathic thrombocytopenic purpura, IgG4-related disease (IgG4-RD) and its acute exacerbation, antiphospholipid syndrome (APS), membranous nephropathy (MN), immune thrombocytopenic purpura, inflammatory bowel disease, and atopic dermatitis-related diseases. Itching, lupus, cutaneous lupus, cutaneous lupus erythematosus, lupus nephritis, mixed connective tissue disease, multiple myeloma, multiple sclerosis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), sepsis, acute lung injury caused by sepsis, diffuse alveolar injury (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), cutaneous form of systemic sclerosis (CREST), cryoglobulinemia, primary cholangiosclerosis, sclerosing cholangitis, urticaria, chronic spontaneous urticaria (CSU), chronic idiopathic urticaria (CIU), A1 urticaria, and IgA nephropathy.

17. Use of the tablet according to any one of claims 1 to 14 for the treatment of diseases mediated by BTK receptors.

Images