Pharmaceutical formulations of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1h-imidazo [4, 5-c] pyridine-2 (3h)-one

Abstract

The present disclosure relates to the field of therapeutic Bruton's tyrosine kinase (BTK) inhibitors. Pharmaceutical formulations of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one are described, as well as methods for preparing the pharmaceutical formulations.

Description

Cross - Reference to Related Applications

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 433,824, filed on December 20, 2022, the entire content of which is incorporated herein by reference for any purpose. Technical Field

[0002] The present disclosure relates to pharmaceutical formulations of (R)-1-(1 - acryloylpiperidin - 3 - yl)-4 - amino - 3-(4 - phenoxyphenyl)-1H - imidazo[4,5 - c]pyridin - 2(3H)-one, methods of preparing such formulations, and methods of using the same. Background Art

[0003] As a member of the Tec family of non - receptor tyrosine kinases, BTK is essential for B - cell signaling downstream of the B - cell receptor. It is expressed in B cells and other hematopoietic cells such as monocytes, macrophages, and mast cells. It plays a role in various aspects of B - cell function that maintain the B - cell repertoire (see Gauld S.B. et al., B cell antigen receptor signaling: roles in cell development and disease. Science, 296:1641 - 2, 2002). B cells are involved in rheumatoid arthritis (see Perosa F., et al., CD20 - depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 267:260 - 77, 2010 and T, et al. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther. 125:464-75. 2010 and Honigberg, L., et al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen induced arthritis. Clin. Immunol. 127S1:S111. 2008) and other autoimmune diseases, such as systemic lupus erythematosus and cancer (see Shlomchik M.J., et al., The role of B cells in lpr / lpr-induced autoimmunity. J. Exp Med. 180:1295-1306. 1994; Honigberg L.A., The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. 107:13075-80. 2010; and Mina-Osorio P, et al., Suppression of glomerulonephritis in lupus-prone NZB x NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 65:2380-91. 2013).

[0004] BTK inhibitors are also potentially useful in the treatment of allergic diseases (see Honigberg, L. et al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen induced arthritis. Clin. Immunol. 127S1:S111. 2008). Note that irreversible inhibitors inhibit the passive cutaneous anaphylaxis (PCA) in mice induced by the IgE antigen complex. These findings are consistent with those in BTK mutant mast cells and knockout mice, and suggest that BTK inhibitors can be used to treat asthma, an IgE-dependent airway allergic disease.

[0005] The compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (hereinafter also referred to as "Compound 1") depicted below is a BTK inhibitor: It is also known as "tolebrutinib", and 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one having the following structure:

[0006] One factor in evaluating whether a compound is suitable as a therapeutic agent is whether the compound can be synthesized in a manner suitable for large-scale manufacture and isolation, with minimal product waste and impurities. This factor is often considered when reviewing whether a laboratory-scale method is suitable for preparing larger quantities required for commercial production. For example, Compound (1) and the method for preparing it are disclosed in Example 3 of U.S. Patent No. 9,688,676, reproduced below:

[0007] Place (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equivalent), DCM-CH3OH (6 mL), and TEA (113 mg, 1.12 mmol, 3.00 equivalents) into a 100-mL round-bottom flask. Subsequently, add prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equivalents) dropwise with stirring at 0 °C for 5 min. Stir the resulting solution at 0 °C for 2 h. Concentrate the resulting mixture under vacuum. Apply the residue onto a silica gel column with dichloromethane / methanol (30:1). Purify the crude product (100 mg) by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase: water (containing 0.05% TFA) and ACN (from 25.0% ACN to 45.0% in 8 min)). As mentioned above, this synthesis provided 100 mg of the crude compound (1), which had to be purified by column chromatography to give 54.5 mg of the purified compound (1), which may have polymorphic form 1 as described below.

[0008] Another desired aspect to be achieved is that the compound as a therapeutic agent can be administered in a form that is readily absorbed by the human body and is also storage-stable. The pharmaceutically active substance for preparing the treatment should be as pure as possible, and its stability during long-term storage under various environmental conditions should be ensured. These characteristics help prevent the emergence of unplanned degradation products in the pharmaceutical composition, which may be potentially toxic or simply result in a reduction in the potency of the composition.

[0009] A major concern in the large-scale production of pharmaceutical compounds is that the active substance should have a stable crystalline form to ensure consistent processing parameters and drug quality. If an unstable polymorphic form is used, the crystal form may change during manufacturing and / or storage, leading to quality control problems and formulation irregularities. Such changes may affect the reproducibility of the manufacturing method and thus result in the final formulation not meeting the high-quality and strict requirements imposed on pharmaceutical composition formulations. In this regard, it is generally considered that any change to the solid state of a pharmaceutical composition that improves its physical and chemical stability has a significant advantage over the same drug in a less stable form.

[0010] When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism". Each crystal form is a "polymorph". Although the polymorphs of a given substance have the same chemical composition, they may differ from each other in one or more physical properties such as solubility, dissociation, true density, dissolution rate, melting point, crystal form, compaction performance, flow characteristics, and / or solid-state stability. Summary of the Invention

[0011] Accordingly, the present disclosure seeks to address the deficiencies of the prior art. Disclosed herein are tablets comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and pharmaceutically acceptable salts thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0012] Also disclosed herein is a method of treating a BTK-mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a tablet comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1).

[0013] Also disclosed herein is the use of a pharmaceutical delivery form (such as a tablet) for treating a disease involving a BTK receptor-mediated disease, the pharmaceutical delivery form comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1). Brief Description of the Drawings

[0014] Figure 1 A graph showing torque versus water quantity / mixing weight is shown.

[0015] Figure 2 A graph showing the granulation curve, where torque varies with granulation time, is shown.

[0016] Figure 3 A comparison of the wetting curves of placebo batch 1 and formulation A batches 1 and 2 is shown.

[0017] Figure 4 A comparison of the wetting curves of placebo batches 1 and 2 and formulation A batch 3 is shown.

[0018] Figure 5 A comparison of the wetting curves of formulation A batches 1, 2, and 3 is shown.

[0019] Figure 6 The wetting curve of formulation B batch 2 is shown.

[0020] Figure 7 The wetting curve and granulation of formulation B batch 2 with different percentages of water added are shown.

[0021] Figure 8Shows a comparison of the wetting curves and granulation curves for batches 1 and 2 of formulation B.

[0022] Figure 9A 、 Figure 9B and Figure 9C Shows a comparison diagram of the wetting curves and granulation curves for batch 2 of formulation B and batch 2 of formulation C.

[0023] Figure 10 Shows a comparison diagram of the wetting curves and granulation curves for batches 1 and 2 of formulation C.

[0024] Figure 11 Shows the wetting curves and granulation for batch 1 of formulation E, batch 3 of formulation C, batch 1 of formulation D, and batch 2 of formulation E.

[0025] Figure 12A 、 Figure 12B and Figure 12C Respectively show diagrams of the percentage of particle size distribution varying with the sieve for batch 1 of formulation E, batch 3 of formulation C, and batch 2 of formulation E.

[0026] Figure 13 Shows a spider web diagram for batch 1 of formulation E, batch 3 of formulation C, and batch 1 of formulation D.

[0027] Figure 14 Shows the variation of the hardness curve and disintegration time over time for 10 mg dose strength tablets of batch 2 of formulation E.

[0028] Figure 15 Shows the variation of the hardness curve and disintegration time over time for 60 mg dose strength tablets of batch 2 of formulation E.

[0029] Figure 16 Shows a comparison of 60 mg dose strength core tablets for batch 1 of formulation E, batch 3 of formulation C, and batch 1 of formulation D.

[0030] Figure 17 Shows a comparison of the core and film-coated 10 mg dose strength tablets of batch 1 of formulation E.

[0031] Figure 18 Shows a comparison of the core and film-coated 60 mg dose strength tablets of batch 1 of formulation E. Detailed Description

[0032] Now, certain embodiments will be described in detail, and their examples are illustrated in the accompanying drawings. Although the present disclosure provides illustrative embodiments, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the appended patent application scope.

[0033] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter in any way. In the event of any conflict between any document incorporated by reference and any term defined in this specification, this specification shall control. Although the teachings of the invention are described in conjunction with various embodiments, it is not intended that the teachings of the invention be limited to these embodiments. On the contrary, as will be understood by those skilled in the art, the teachings of the invention cover various alternatives, modifications, and equivalents. I. Definitions

[0034] Unless otherwise noted, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0035] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element.

[0036] The term "about" is used in this disclosure to indicate and encompass the indicated value and ranges above and below that value. In certain embodiments, the term "about" indicates ±10%, ±5%, or ±1% of the specified value. In certain embodiments, where applicable, the term "about" means one or more specified values ± one standard deviation of the one or more values.

[0037] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean "and" or "or".

[0038] The terms "article" and "kit" are used synonymously.

[0039] As used herein, "BTK inhibitor", "BTK inhibitor compound", "compound of formula (1)", "compound (1)", "tolebrutinib", and "the compound" refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure: which is also known as 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one having the following structure: and / or a pharmaceutically acceptable salt thereof.

[0040] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes carriers or excipients acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes one and more than one such excipient.

[0041] As used herein, the term "crystalline" or "crystalline solid form" refers to a solid form that is substantially free of any amorphous solid form.

[0042] In some embodiments, "substantially free" 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 crystal forms and amorphous compounds of the compound. In some embodiments, "substantially free" means a non-detectable amount of other crystal forms and amorphous compounds of the compound.

[0043] As used herein, the term "substantially pure" or "substantially crystalline" means that the crystalline form contains by weight at least 90%, such as at least 95%, such as at least 97% and even at least 99% of the indicated crystalline form compared to the total weight of all forms of the compound.

[0044] Alternatively, it will be understood that "substantially pure" or "substantially crystalline" means that the crystalline form contains by weight less than 10%, such as less than 5%, such as less than 3% and even less than 1% of impurities (including other polymorphs, solvates or amorphous forms) compared to the total weight of all forms of the compound.

[0045] As used herein, the term "amorphous" refers to a solid material that has no long-range order in its molecular positions. Amorphous solids are generally supercooled liquids in which the molecules are arranged randomly such that there is no definite arrangement (e.g., molecular packing) and no long-range order. For example, an amorphous material is a solid material that does not have one or more sharp characteristic signals in its X-ray powder diffraction pattern (i.e., is determined by XRPD not to be crystalline). Instead, one or more broad peaks (e.g., a halo) appear in its diffraction pattern. Broad peaks are characteristic of amorphous solids.

[0046] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in its molecular positions. For example, a substantially amorphous material has a crystallinity of less than 15% (e.g., less than 10% or less than 5% crystallinity). "Substantially amorphous" includes the descriptor "amorphous", which refers to a material having no (0%) crystallinity.

[0047] "Treating" or "treatment" of a disease includes: (1) Preventing the disease, e.g., causing a mammalian subject that may be exposed to or is susceptible to the disease but has not yet experienced or exhibited symptoms of the disease to not develop clinical symptoms of the disease; (2) Inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or (3) Relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0048] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the instance where the event or circumstance occurs and the instance where it does not.

[0049] "Therapeutically effective amount" means an amount of a BTK inhibitor compound that, when administered to a mammalian subject for treating a disease, is sufficient to effect such treatment of the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammalian subject to be treated.

[0050] Before describing the teachings of the present invention in detail, it is to be understood that the present disclosure is not limited to specific compositions or method steps, as these may vary.

[0051] It should be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a conjugate" includes a plurality of conjugates, and reference to "a cell" includes a plurality of cells, and the like.

[0052] Numerical ranges include the numbers defining the range. Taking into account significant figures and errors associated with measurements, measured values and measurable values should be understood as approximate values. Additionally, the use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" is not intended to be limiting. It should be understood that the foregoing Summary of the Invention and Detailed Description are merely exemplary and explanatory and are not limiting of the teachings of the present invention.

[0053] Unless specifically indicated otherwise in the foregoing specification, embodiments recited in this specification that list "comprising" various components are also contemplated as "consisting of" or "consisting essentially of" the recited components; embodiments recited in this specification that list "consisting of" various components are also contemplated as "comprising" or "consisting essentially of" the recited components; and embodiments recited in this specification that list "consisting essentially of" various components are also contemplated as "consisting of" or "comprising" the recited components (such interchangeability does not apply to the use of these terms in the claims).

[0054] As used herein, the terms "or a combination thereof" and "or combinations thereof" refer to any and all permutations and combinations of the terms listed prior to such terms. For example, "A, B, C, or a combination thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB if order is important in a particular context. Continuing with this example, combinations that contain repeats of one or more items are expressly included, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. One of ordinary skill in the art will understand that, unless otherwise apparent from the context, there is typically no limit to the number of items in any combination.

[0055] Unless the context requires otherwise, "or" is used in an inclusive sense, i.e., equivalent to "and / or". II. BTK Inhibitor Compounds

[0056] BTK inhibitor compounds can be prepared according to the methods and protocols described, for example, in U.S. Patent No. 9,688,676B2 (specifically, the content from column 62, line 8 to column 65, line 32, and column 67, line 28 to column 69, which is incorporated herein by reference).

[0057] The following preparation of the compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided to enable those skilled in the art to prepare BTK inhibitor compounds. The synthetic route should not be regarded as limiting the scope of the present disclosure, but merely illustrative and representative.

[0058] Exemplary synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one:

[0059] Place (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equivalent), DCM-CH3OH (6 mL), and TEA (113 mg, 1.12 mmol, 3.00 equivalents) in a 100 mL round-bottom flask. Subsequently, add prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equivalents) dropwise, with stirring at 0 °C for 5 min. Stir the resulting solution at 0 °C for 2 h. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column with dichloromethane / methanol (30:1). Purify the crude product (100 mg) by preparative HPLC under the following conditions (column: XBridge Prep C 18 OBD column, 5 μm, 19 * 150 mm; mobile phase: water (containing 0.05% TFA) and ACN (25.0% ACN up to 45.0% in 8 min)). Obtain 54.5 mg of the product (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one as a white solid. LC-MSm / z: 465.2 (M+1). III. Tablet Formulation

[0060] A tablet comprising compound 1 or a pharmaceutically acceptable salt thereof is provided.

[0061] In some embodiments, the provided tablets comprise: at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and its pharmaceutically acceptable salts; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0062] In some embodiments, the tablet further comprises at least one glidant.

[0063] In some embodiments, the tablet comprises an intragranular core and an extragranular portion.

[0064] In some embodiments, the at least one diluent is selected from lactose monohydrate and microcrystalline cellulose. In some embodiments, the at least one diluent is present in a total amount in the range of from about 70% to about 90% by weight. In some embodiments, the at least one diluent is present in a total amount in the range of from about 50% to about 70% by weight in the intragranular core. In some embodiments, the at least one diluent is present in a total amount in the range of from about 10% to about 30% by weight in the extragranular portion.

[0065] In some embodiments, the at least one binder is hydroxypropyl methylcellulose (hypromellose). In some embodiments, the at least one binder is present in a total amount in the range of from about 0.1% to about 5% by weight.

[0066] In some embodiments, the at least one disintegrant is cross-linked polyvinylpyrrolidone (crospovidone). In some embodiments, the at least one disintegrant is present in a total amount in the range of from about 0.1% to about 5% by weight. In some embodiments, the at least one disintegrant is present in a total amount in the range of from about 0.5% to about 3% by weight in the intragranular core. In some embodiments, the at least one disintegrant is present in a total amount in the range of from about 0.5% to about 3% by weight in the extragranular portion.

[0067] In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the at least one lubricant is present in a total amount in the range of from about 0.1% to about 5% by weight. In some embodiments, the at least one lubricant is present in a total amount of about 0.35% by weight.

[0068] In some embodiments, the at least one glidant is talc. In some embodiments, the at least one glidant is present in a total amount in the range of from about 1% to about 5% by weight.

[0069] In some embodiments, the intragranular core comprises at least one diluent, at least one binder, and at least one disintegrant.

[0070] In some embodiments, the extragranular portion comprises at least one diluent, at least one disintegrant, and at least one lubricant.

[0071] In some embodiments, Compound 1 is present in at least 50% crystalline form, 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.

[0072] In some embodiments, Compound 1 is present in an amount of from about 0.9 mg to about 125 mg. In some embodiments, Compound 1 is present in an amount of about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg and about 125 mg. In some embodiments, Compound 1 is present in an amount of about 10 mg. In some embodiments, Compound 1 is present in an amount of about 60 mg. In some embodiments, Compound 1 is present in an amount of about 120 mg. In some embodiments, Compound 1 is present in an amount of about 5% to 25% by weight.

[0073] In some embodiments, the tablet further comprises at least one coating layer. In some embodiments, the coating layer comprises a polyethylene glycol-polyvinyl alcohol graft copolymer, optionally further comprising talc and titanium dioxide. In some embodiments, the coating layer comprises hydroxypropyl methylcellulose. In some embodiments, the coating layer further comprises at least one of titanium dioxide and polyethylene glycol (macrogol polyethylene glycol). In some embodiments, the coating layer further comprises at least one of copovidone and titanium dioxide.

[0074] In some embodiments, the tablet comprises: about 15% to about 45% by weight of lactose monohydrate, about 35% to about 60% by weight of microcrystalline cellulose, about 1% to about 5% by weight of hydroxypropyl methylcellulose, about 1% to about 5% by weight of crospovidone, and about 0.1% to about 3% by weight of magnesium stearate.

[0075] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises from about 20% to about 40% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises from about 15% to about 25% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises from about 0.5% to about 2.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises from about 0.5% to about 2.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of from about 5% to 25% by weight.

[0076] In some embodiments, the tablet comprises: from about 30% to about 40% by weight of lactose monohydrate, from about 40% to about 50% by weight of microcrystalline cellulose, from about 1% to about 3% by weight of hypromellose, from about 2% to about 4% by weight of crospovidone, and from about 0.1% to about 1% by weight of magnesium stearate.

[0077] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises from about 20% to about 30% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises from about 15% to about 25% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises from about 0.5% to about 2.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises from about 0.5% to about 2.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of from about 10% to 20% by weight.

[0078] In some embodiments, the tablet comprises: about 35.0% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.5% by weight of magnesium stearate.

[0079] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises 21.0% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises about 1.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises about 1.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0080] In some embodiments, the tablet comprises: about 28.8% by weight of lactose monohydrate, about 55.8% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0081] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 34.8% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises 21.0% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises about 1.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises about 1.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of about 10% by weight.

[0082] In some embodiments, the tablet comprises: about 23.5% by weight of lactose monohydrate, about 56.2% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0083] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 35.2% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises 21.0% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises about 1.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises about 1.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0084] In some embodiments, the tablet comprises: about 35.2% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0085] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises 21.0% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises about 1.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises about 1.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0086] In some embodiments, the tablet comprises: about 32.2% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, about 0.4% by weight of magnesium stearate; and about 3.0% by weight of talc.

[0087] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% by weight of microcrystalline cellulose. In some embodiments, the extragranular portion comprises 21.0% by weight of microcrystalline cellulose. In some embodiments, the intragranular core comprises about 1.5% by weight of crospovidone. In some embodiments, the extragranular portion comprises about 1.5% by weight of crospovidone. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0088] In some embodiments, the tablet further comprises a film coating agent. In some embodiments, the film coating is present in an amount of about 2% to about 5% relative to the total weight of the tablet. In some embodiments, the film coating is present in an amount of about 3% relative to the total weight of the tablet.

[0089] In some embodiments, the ratio of lactose to intragranular microcrystalline cellulose is about 40:60 by weight. In some embodiments, the ratio of lactose to intragranular microcrystalline cellulose is about 50:50 by weight. In some embodiments, the ratio of lactose to intragranular microcrystalline cellulose is about 60:40 by weight.

[0090] In some embodiments, the coating layer comprises a polyethylene glycol-polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl monocaprylate / glyceryl monostearate / glyceryl distearate / fatty acid glyceride type 1, yellow iron oxide, partially hydrolyzed polyvinyl alcohol, and red iron oxide.

[0091] In some embodiments, the coating layer comprises hypromellose, titanium dioxide, polyethylene glycol (macrogol polyethylene glycol), yellow iron oxide, and red iron oxide.

[0092] In some embodiments, the coating layer comprises hypromellose, copovidone, titanium dioxide, polyethylene glycol, yellow iron oxide, indigo carmine aluminum lake, and glyceryl caprylate / caprate.

[0093] The present disclosure also relates to a method of treating a BTK-mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a tablet comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and pharmaceutically acceptable salts thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0094] The present disclosure also relates to the use of a tablet for treating a disease involving a BTK receptor-mediated disease, the tablet comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and pharmaceutically acceptable salts thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0095] A diluent is a chemical compound used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize the compound as they can provide a more stable environment. Salts dissolved in a buffer solution (which can also provide pH control or maintenance) are used as diluents in the art herein, including but not limited to phosphate buffered saline solutions. In some embodiments, the diluent increases the volume of the composition to facilitate compression or to produce a sufficient volume of a homogeneous blend for capsule filling. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextran; microcrystalline cellulose, such as calcium hydrogen phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugar, such as (Amstar); hydroxypropylmethylcellulose; hydroxypropylmethylcellulose acetate stearate; sucrose-based diluents; confectioner's sugar; calcium bisulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite, etc.

[0096] In some embodiments, the tablet comprises at least one diluent selected from mannitol, lactose monohydrate, anhydrous lactose, microcrystalline cellulose, starch, sorbitol, dextrose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, calcium phosphate, pregelatinized starch, compressible sugar, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar, calcium dihydrogen sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, glucose binder, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite.

[0097] Binders impart adhesiveness and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ), and microcrystalline cellulose (e.g., ); microcrystalline dextrin; amylose; magnesium aluminum silicate; polygalacturonic acid; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth; dextrin; sugars such as sucrose (e.g., ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ), and lactose; natural or synthetic gums such as gum arabic, tragacanth, Indian gum mucilage of isapol bark; polyvinylpyrrolidone (e.g., CL, CL, XL-10); larch arabinogalactan; polyethylene glycol; polyethylene oxide; wax; sodium alginate, etc.

[0098] 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 the method involves blending, dry granulation, or wet granulation. For example, dry granulation can involve compaction to form dry granules, followed by the addition of excipients at a later time. Wet granulation can involve forming a weight gain phase and a granulation phase, i.e., specific excipients are added to specific phases, and then once the phases are mixed, drying is carried out to obtain granules. If wet granulation is chosen, specific excipients can be selected to facilitate the method (including the use of binders). Of course, as those skilled in the art will understand, it can be modified (such as adding materials at a later time).

[0099] In some embodiments, the at least one binder is selected from alginic acid, carboxymethyl cellulose, methyl cellulose (e.g., ) Hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ) ethyl cellulose (e.g., ) microcrystalline cellulose (e.g., ), microcrystalline dextrin, amylose, magnesium aluminum silicate, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin, sucrose (e.g., ), glucose, dextrin, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose; gum arabic, tragacanth gum, Indian gum mucilage of isapol bark; polyvinylpyrrolidone (e.g., CL, CL, XL-10), larch arabinogalactan, polyethylene glycol, poly(ethylene oxide) and sodium alginate.

[0100] Disintegrants assist both the dissolution and dispersion of the dosage form upon contact with gastrointestinal fluids. Disintegrating agents or disintegrants promote the disintegration of tablets and granules and thus affect the release of the active pharmaceutical ingredient. Examples of disintegrating agents include starch, e.g., natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551, or sodium starch glycolate (e.g., or ); cellulose such as wood products, methylcrystalline cellulose (e.g., PH101, PH 102, PH105, P100, and ), methylcellulose, crosslinked carboxymethyl cellulose or crosslinked cellulose (such as sodium crosslinked carboxymethyl cellulose crosslinked carboxymethyl cellulose or crosslinked carboxymethylcellulose); crosslinked starch (such as sodium starch glycolate); crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone), crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean gum, karaya gum, pectin or tragacanth gum; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch, etc.

[0101] In some embodiments, the at least one disintegrant is selected from sodium starch glycolate, croscarmellose sodium, corn starch, potato starch, pregelatinized starch, methylcellulose crystalline, methylcellulose, cross-linked carboxymethylcellulose, croscarmellose sodium, cross-linked carboxymethylcellulose, croscarmellose, crospovidone, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, magnesium aluminum silicate, agar, guar gum, locust bean, karaya gum, pectin, tragacanth, bentonite, citrus pulp, and sodium lauryl sulfate.

[0102] Lubricants are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons (such as mineral oil or hydrogenated vegetable oils (such as hydrogenated soybean oil)), higher fatty acids and their alkali and alkaline earth metal salts (such as aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, glycerol, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG4000) or methoxypolyethylene glycol (such as )), sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica (such as ), starch (such as corn starch), silicone oil, surfactants, etc.

[0103] In some embodiments, the at least one lubricant is selected from magnesium stearate, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, mineral oil, hydrogenated soybean oil, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearate, glycerol, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, methoxypolyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, magnesium lauryl sulfate, sodium lauryl sulfate, colloidal silica, corn starch, silicone oil, and surfactants.

[0104] In some embodiments, the tablet comprises at least one glidant. In some embodiments, the glidant is silica or talc.

[0105] In some embodiments, the tablet may include at least one pH regulator and / or buffer, for example, acids such as acetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate, sodium bicarbonate, ammonium chloride, etc. Such buffers used as bases may have other counterions besides sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. The amounts of such acids, bases, and buffers required to maintain the pH of the composition within an acceptable range are included.

[0106] In some embodiments, the tablets may also include at least one antifoaming agent to reduce foaming that may cause coagulation of the aqueous dispersion, the appearance of air bubbles in the finished film, or generally impair processing during processing. Exemplary antifoaming agents include silicone emulsions or sorbitan sesquioleate.

[0107] In some embodiments, the tablets may also include at least one salt in an amount required to bring the osmotic pressure of the composition to an acceptable range. 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.

[0108] In some embodiments, the tablets may also include at least one antioxidant, such as non-thiol antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivatives, and tocopherol or its derivatives. In certain embodiments, the antioxidant enhances chemical stability when needed. Other reagents such as citric acid or citrate or EDTA may also be added to slow down oxidation.

[0109] In some embodiments, the tablets may also include at least one preservative to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate (merfen) and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0110] In some embodiments, the tablets may also include at least one dispersant and / or viscosity modifier. Dispersants and / or viscosity modifiers include materials that control the diffusion and uniformity of the drug through the liquid medium or granulation method or blending method. In some embodiments, these reagents also contribute to the effectiveness of the coating or erodible matrix. Exemplary diffusion promoters / dispersants include, for example, hydrophilic polymers, electrolytes, 60 or 80, polyvinylpyrrolidone (PVP; commercially known as ), triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), polymer of 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., and 8, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic also known as Poloxamine It is a tetrafunctional block copolymer obtained by sequentially adding propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, New Jersey), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polysorbate-80, gums (such as gum tragacanth and gum arabic, guar gum, xanthan gum-like (including xanthan gum)), polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate and carbomer. Dispersants particularly useful for liposome dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate. Generally, a binder level of about 10% to about 70% is used in powder-filled gelatin capsule formulations. The binder usage levels in tablet formulations vary whether direct compression, wet granulation, roller compaction or other excipients (such as fillers, which can themselves act as moderate binders) are used. A skilled formulator in the art can determine the binder level of the formulation, but binder usage levels of up to 90%, more typically up to 70%, are common in tablet formulations.

[0111] In some embodiments, the tablet may further comprise at least one erosion promoter. Erosion promoters include materials that control the erosion of specific materials in gastrointestinal fluids. Erosion promoters are generally known to those of ordinary skill in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

[0112] In some embodiments, the tablet may further comprise at least one filler, the at least one filler comprising compounds such as glucose binders, dextran, sucrose, xylitol, lactitol and the like.

[0113] In some embodiments, the tablet may further comprise at least one flavoring agent and / or sweetening agent, such as gum arabic syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cold cherry, cold citrus, cyclamate, cyclamate, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizate, glycyrrhiza / licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizate, maltol, maple, marshmallow, menthol, mint cream, mixed berries, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, powder, raspberry, root beer, rum, saccharin, safrole, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, talin, xylitol, sucralose, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring components, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof.

[0114] In some embodiments, the tablet may further comprise at least one solubilizer, the at least one solubilizer comprising compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, hydroxypropyl cyclodextrin (e.g. ), ethanol, n-butanol, isopropanol, cholesterol, bile salts, tetrahydrofurfuryl polyethylene glycol ether, diethylene glycol monoethyl ether and isosorbide dimethyl ether. In one embodiment, the solubilizer is vitamin E TPGS and / or or β-hydroxypropyl cyclodextrin.

[0115] In some embodiments, the tablet may further comprise at least one suspending agent, which includes compounds such as vinylpyrrolidone / vinyl acetate copolymer (S630), polysorbate - 80, hydroxyethyl cellulose, gums (such as tragacanth and gum arabic, guar gum, xanthan gums (including xanthan gum)), polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, etc.

[0116] In some embodiments, the tablet may further comprise at least one surfactant, which includes compounds such as sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., (BASF)), etc. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., octylphenol polyether 10, octylphenol polyether 40). In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0117] In some embodiments, the tablet may further comprise at least one wetting agent, which includes compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts, etc.

[0118] The pharmaceutical formulations disclosed herein can be obtained by mixing at least one solid excipient described herein with Compound 1 described herein, optionally grinding the resulting mixture, and (if necessary) processing the granule mixture after adding suitable excipients to obtain tablets.

[0119] The pharmaceutical preparations disclosed herein also include capsules made of gelatin and soft-sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). The capsules can also be made of polymers such as hypromellose (i.e., hydroxypropyl methylcellulose). The capsules can contain the active ingredient, optionally a mixture of the active ingredient with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In the soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, lipid, solubilizer, or liquid polyethylene glycol). In addition, a stabilizer can be added. The dosage of all the preparations for oral administration should be suitable for such administration.

[0120] These preparations can be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, (6) melting, or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Edition (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (such as wurster coating), tangential coating, top spraying, tableting, extrusion, extrusion / spheronization, etc.

[0121] It should be understood that there is a significant overlap among the excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be considered merely exemplary rather than restrictive of the types of excipients that can be included in the solid dosage forms described herein. The type and amount of such excipients can be readily determined by those skilled in the art according to the specific properties desired.

[0122] In addition to the plasticizer, colorants, surfactants, anti-sticking agents, defoaming agents, lubricants (such as carnauba wax or PEG), and other additives can be added to the coating to dissolve or disperse the coating material and improve the coating properties and the coated product.

[0123] In some embodiments, the tablets are packaged in a blister pack. The blister pack can be made of any suitable material. Examples include polyvinyl-chlorotrifluoroethylene in a formed film and a hardened aluminum foil (as a cap). IV. Liquid Preparations

[0124] A liquid suspension can be prepared by adding the tablets to water and crushing the tablets to disperse them in the water.

[0125] In some embodiments, a syringe comprising a liquid suspension of comminuted tablets can be provided. The syringe can be used to connect to a gastric tube and empty into the gastric tube. V. Treatment Methods

[0126] Provided herein are methods of treating a BTK-mediated disease or disorder, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof, the BTK inhibitor compound comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the therapeutically effective amount is from about 1 to about 125 mg. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject has one or more of the following symptoms prior to treatment: (i) multiple sclerosis (MS), including relapsing forms of MS, non-relapsing secondary progressive multiple sclerosis (NRSPMS), and primary progressive multiple sclerosis (PPMS); (ii) myasthenia gravis (MG); or (iii) myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and the treatment reduces or eliminates the one or more symptoms. In some embodiments, the subject suffers from inflammation, pain, loss of mobility, and muscle weakness caused by MS, MG, or MOGAD.

[0127] In some embodiments, a subject with MS has had at least one documented relapse in the past year, and / or at least two documented relapses in the past two years, and / or at least one active Gd-enhancing brain lesion on an MRI scan in the past year and prior to screening.

[0128] In some embodiments, a dose of about 5 - 10 mg, 10 - 15 mg, 15 - 20 mg, 20 - 25 mg, 25 - 30 mg, 30 - 35 mg, 35 - 40 mg, 40 - 45 mg, 45 - 50 mg, 50 - 55 mg, 55 - 60 mg, 60 - 65 mg, 65 - 70 mg, 70 - 75 mg, 75 - 80 mg, 80 - 85 mg, 85 - 90 mg, 90 - 95 mg, 95 - 100 mg, 100 - 105 mg, 105 - 110 mg, 110 - 115 mg, 115 - 120 mg or 120 - 125 mg is administered. In some embodiments, the dose is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg or about 125 mg. In some embodiments, the dose is about 5 mg. In some embodiments, the dose is about 10 mg. In some embodiments, the dose is about 20 mg. In some embodiments, the dose is about 30 mg. In some embodiments, the dose is about 60 mg. In some embodiments, the dose is about 120 mg.

[0129] In some embodiments, the dose is administered daily. The daily dose can 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., about every 24 hours). In some embodiments, the dose is administered twice a day. In some embodiments, the dose is divided into two portions for twice-daily administration (e.g., about every 12 hours). In some embodiments, the dose is divided into three portions for three-times-daily administration (e.g., about every 8 hours). In some embodiments, the dose is divided into four portions for four-times-daily administration (e.g., about every 6 hours).

[0130] In some embodiments, the dose is administered orally. In some embodiments, the dose is administered in the form of a tablet. In some embodiments, the dose is administered in the form of a pill, capsule, semi-solid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0131] In some embodiments, a BTK inhibitor compound is administered to a subject for a period of about 4, 8, 12, 16, 20, 24, or 26 weeks. In some embodiments, a BTK inhibitor compound is administered to a subject for a period of about 6, 12, 18, 24, 30, 36, 42, or 48 months. In some embodiments, the dose is once daily.

[0132] In some embodiments, the BTK inhibitor compound is administered as a monotherapy. In some embodiments, the method comprises administering a BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent can be administered concurrently or sequentially with the BTK inhibitor compound.

[0133] The determination of the frequency of administration can be made by one of ordinary skill in the art (such as the attending physician) based on considerations of the disorder being treated, the age of the subject being treated, the severity of the disorder being treated, the general health status of the subject being treated, etc. In some embodiments, the BTK inhibitor compound is administered in a therapeutically effective amount for the treatment of MS, MG, or MOGAD. A therapeutically effective amount generally depends on the weight of the subject being treated, their physical or health condition, the extent of the disorder to be treated, or the age of the subject being treated, the method of formulation of the drug and / or the method of administration (e.g., time of administration and route of administration).

[0134] For purposes of clarity and understanding, the foregoing disclosure has been described in some detail by way of illustration and example. Accordingly, it should be understood that the above description is intended to be illustrative and not restrictive. Thus, the scope of the present disclosure should not be determined with reference to the above description, but rather should be determined with reference to the full scope of the appended claims and their equivalents. Examples

[0135] The following examples are provided to illustrate certain disclosed embodiments and should not be construed as limiting the scope of the present disclosure in any way. In the examples discussed below, the BTK inhibitor as defined above may also be interchangeably referred to as "Compound 1", "Compound", "Tolebrutinib", or "Drug".

[0136] Example 1: Preparation of tablets containing Compound 1.

[0137] The development of the tablet formulation described in this example involved experiments to determine: · The concentration of the active ingredient to be used, · Whether to use hypromellose (HPMC) in the dry blend or in an aqueous binding solution, · The ratio of lactose to microcrystalline cellulose to be used, and · The effect of adding silica or other test glidants (such as talc).

[0138] The method also involves adjustments: · Adjusting the wetting time by adjusting the flow rate of the mooring solution · The volume of mooring water · The granulation time

[0139] For the Phase IIb formulation, the dried granules as a whole will be directly calibrated and compared with the following two steps: screening the dry granules and then calibrating the unswirled granules. The excipients used in this study are shown in Table 1. Table 1. Excipients Used a orange QX 321A230043 consists of 40.0% polyethylene glycol-polyvinyl alcohol graft copolymer (Ph.Eur.-NF), 27.5% talc (Ph.Eur.-USP), 20.2% titanium dioxide (E171) (Ph.Eur.-USP), 4% glycerol monocaprylate / glycerol monoesters / glycerol diesters (Food Chemical Codex) / fatty acid glycerides of type 1, 3.8% yellow iron oxide (E172) (NF), 3.5% partially hydrolyzed polyvinyl alcohol (Ph.Eur.-USP), and 1.0% red iron oxide (E172) (NF).

[0140] Wetting and Granulation Studies

[0141] To achieve comparable wetting and granulation curves by limiting the consumption of the active ingredient and to allow for rapid and efficient implementation, two wetting and granulation methods, namely the multiple addition method and the variable mixing time method, were tested on a small scale as described below. These two methods were tested with a placebo mixture or a mixture containing Compound 1. The excipients used in this study are described in Table 1.

[0142] The percentage compositions of the placebo and Compound 1 formulations used in this study are described in Tables 2 and 3, respectively. Table 2. Percentage Composition of the Placebo Formulation Table 3. Percentage Composition of the Compound 1 Formulation

[0143] Wetting and granulation tests were carried out on a Caleva granulator on a scale of approximately 25 g. The placebo mixture was on a scale of 1000 g, and the compound 1 mixture was on a scale of 75 g or 250 g. These mixtures were then separated to carry out granulation tests at 25 g and evaluate the reproducibility of the same initial batches.

[0144] The internal phase mixture was prepared as follows.

[0145] Step 1: Weigh all components according to the compositions in Tables 2 and 3.

[0146] Step 2: Prepare a solution of 8% hypromellose in demineralized water the day before under strong stirring, and dilute the solution to the required hypromellose concentration. This step is not carried out when adding hypromellose to the dry mixture.

[0147] Step 3 for the placebo mixture: Sieve the first half of the lactose monohydrate together with microcrystalline cellulose and crospovidone type A. Then rinse the sieve with the second half of the lactose monohydrate through a sieve with a 0.6 mm mesh.

[0148] Step 3 for the compound 1 mixture: Sieve compound 1 together with the first half of the lactose monohydrate, then microcrystalline cellulose, hypromellose 6 mPa.s, and crospovidone type A. Then rinse the sieve with the second half of the lactose monohydrate through a sieve with a 0.6 mm mesh.

[0149] Step 4 for the placebo mixture: Mix the sieved excipients from Step 3 in a CMA rotary mixer equipped with a 5 L tank at 7 rpm for 10 minutes.

[0150] Step 4 for the compound 1 mixture: Mix the sieved excipients from Step 3 in a mixer at 32 rpm for 10 minutes.

[0151] Two wetting and granulation methods were tested, namely the multiple addition method and the variable mixing time method, as described below.

[0152] Multiple addition method: Fill the Caleva tank with the required amount of powder (V0 = 0.412 mass powder = 24.7 g), and prepare a 4.42% HPMC solution in demineralized water. This method uses the following parameters: - Rotor speed = 50 rpm - Mixing time = 30 seconds - Log time = 30 seconds - Number of runs = 33 - Test duration = 35 minutes - Add 1 mL of HPMC solution every 60 seconds

[0153] Total added volume = 31 mL

[0154] Variable mixing time method: The Caleva pot was filled with the required amount of powder (V0 = 0.412 mass powder = 24.7 g) and wetted with HPMC solutions in deionized water prepared at different concentrations. The method used the following parameters: - Rotor speed = 50 rpm - Mixing time = 40 seconds - Log time = 20 seconds - Run number = 12 - Stirring time = 10 minutes - The minimum of HPMC was: 8%, 5.51%, 4.42%, 3.63%, 2.91%, and the volume was adjusted to have 2% HPMC in the final formulation.

[0155] The granules were dried in a tray dryer at approximately 50 °C for batches of approximately 25 g.

[0156] The compound 1 mixtures were tested by testing several batches of the active ingredient and different formulations (Formulations A, B, and C as described in Table 3) and two different modes of introducing HPMC (in wetting liquid A or in dry mixture B), as described in Table 4A. Table 4B describes the placebo batches. The extensometry of the active pharmaceutical ingredient (API) batches is described in Table 4C. Table 4A. Formulations with different modes of introducing HPMC Table 4B. Description of placebo batches

[0157] According to Figure 1 and Figure 2 The results were analyzed according to the reference wetting and granulation curves shown. Different granulation states (pendulum-like, ribbon-like, capillary-like, and droplet-like) were obtained by plotting the blade power (torque, N·m) against time or the amount of water added relative to the weight of the mixture.

[0158] Internal phase mixtures of 250 g or 75 g were prepared for each active ingredient and tested at a 25 g scale to evaluate repeatability (n = 3). The concentration of the wetting HPMC solution was calculated to obtain (approximately) 2% HPMC in the final formulation.

[0159] Figure 3 It was shown that the performance of the mixtures of Formulation A Batch 1 and Batch 2 was equivalent to that of the placebo with an aqueous HPMC solution.

[0160] Figure 4 It is shown that the performance of the placebo and the formulation A batch 3 mixture is equivalent for the granulation step.

[0161] Figure 5 It is shown that the performance of the mixtures of three batches of formulation A shown in Table 4A is equivalent for the granulation step in which HPMC is in the wetting liquid, and the observed granulation plateau is at a ratio of 0.7 g / mL. For this step, the variability in the particle size of the active ingredient (ranging from 10 to 120 μm) does not seem to have an effect. The low density of the active pharmaceutical ingredient (API) validates the study of the granulation method aimed at densifying the mixture for compression. As shown in Table 4C, it was found that the active ingredient batches used had poor rearrangement, poor cohesion, and little tendency to adhere (ejection pressure). The active ingredient from the batches used was quite plastic and had very little elasticity. Table 4C. API batch extensibility determination at 150 MPa

[0162] Comparison of batch wettability, angle of fall: · API batch 5: 66° + / - 3° · API batch 1: 69° + / - 3° · API batch 2: 67° + / - 2° · API batch 3: 90° + / - 10° · API batch 4: 77° + / - 3°

[0163] Figure 6 It is shown the granulation plateau observed for the formulation B batch 2 mixture in Table 4A at a water addition ratio of 0.6 mL / g. It is slightly deviated from Figure 3 and Figure 4 the results shown. This difference is because the percentage of compound 1 in formulation B is 15% compared to the batches of formulation A containing 10% compound 1. The active ingredient batches, i.e., API batch 2, are also different, and these properties can have an impact on the performance in wetting and granulation.

[0164] Figure 7 Analysis of the curves in leads to the selection of approximately 45% water for anchoring. Formulation B batch 2 contains a lactose / cellulose ratio equal to 40 / 60, is wetted with water, and HPMC is in the dry internal phase mixture.

[0165] Figure 8Formulation B batch 1 and Formulation B batch 2 were compared. They have the same formulation, including a lactose / cellulose ratio of 40 / 60, but hydroxypropyl methylcellulose (HPMC) was introduced into the wetting solution in Formulation B batch 1 and into the dry mixture in Formulation B batch 2. Since the slopes of the curves are the same, for the purpose of simplifying the method and industrial practice, adding HPMC directly to the powder mixture was chosen.

[0166] Figure 9A , Figure 9B and Figure 9C The curves of Formulation B batch 2 (lactose / cellulose ratio 40 / 60) and Formulation C batch 2 (lactose / cellulose ratio 60 / 40) were compared. These graphs show that for formulations with different lactose / cellulose ratios, the wetting and granulation curves are not similar. The ideal amount is approximately 35% for a 60 / 40 lactose / cellulose ratio and approximately 45% for a 40 / 60 ratio. Based on these results, a lactose / cellulose ratio of 60 / 40 was chosen to give the mixture greater cohesiveness and compressibility. Another advantage of this ratio is a shorter drying time because less water is required. The differences in performance were evaluated during the compression step.

[0167] Batch repeatability was evaluated by testing Formulation C batches 1 and 2 using the same method and 35% water. The results are shown in Figure 10 .

[0168] For Formulation B batch 2 and Formulation C batch 1, the final mixtures were manufactured and compression tests were carried out on a Stylcam with a simulation of Korsch XL100, a speed of 20 rpm, forced feed, and a punch engraved with '6' of size 7×3.8 mm. The characteristics of the core tablets are shown in Tables 5 and 6. Table 5. Characteristics of 10 mg core tablets of Formulation B batch 2 at 5, 7, 9 kN on the Stylcam Table 6. Characteristics of 10 mg core tablets of Formulation C batch 1 at 5, 7, 9 kN on the Stylcam

[0169] The compression profiles show that the Formulation B batch 2 mixture (40 / 60 ratio) has a hardness drop at 8 - 9 kN force compared to the Formulation C batch 1 mixture.

[0170] Based on the granule and final blend properties of the formulations described in this example and the compression results, the following selections were made in the preparation of the formulation: a lactose / cellulose ratio of 60 / 40 and 35% water was used during the wetting step of the internal phase mixture of Compound 1 containing HPMC in the dry mixture.

[0171] Example 2: Method for preparing film-coated tablets containing Compound 1.

[0172] Five tablet formulations were developed, as shown in Table 7. Table 7. Batch comparison of Compound 1 tablets

[0173] Several batches of formulations with different qualitative and quantitative aspects were manufactured at a scale of 300 g in a 1 L granulation tank to compare the characteristics of the mixtures and tablets. These were Batch 1 of Formulation E, Batch 3 of Formulation C, Batch 1 of Formulation D, and Batch 2 of Formulation E. The excipients used in this study are described in Table 1.

[0174] Step 1: Weigh all components according to the tablet formulation in Table 1.

[0175] Step 2: Sieve Compound 1 together with the first half of the lactose monohydrate, then microcrystalline cellulose, hypromellose 6 mPa.s, and crospovidone Type A, and then pass through a sieve with an opening of 0.6 mm with the second half of the lactose monohydrate.

[0176] Step 3: Load the sieved components into the granulator tank at high shear speed and mix for 5 min, with the bottom blade of the tank at 250 r / min and the chopper at 0 r / min.

[0177] Step 4: Wet the components by mixing with water at a flow rate of about 80 mL / min to about 100 mL / min (fast flow) and about 35% (w / w), with the bottom blade of the tank at 250 r / min and the chopper at 0 r / min, and granulate at a speed of 1500 r / min for about 2 minutes.

[0178] Step 5: Dry the obtained granules in a fluidized air bed at an inlet temperature of 60 °C and an air flow rate of about 40 m 3 / h until the water content is close to the amount before granulation, for example, in the range of about 23 minutes to about 35 minutes, to obtain a loss on drying (LOD) in the range of about 1.48% to about 1.94% or in the range of about 1.5% to about 1.9%, equivalent to the initial dry mixture.

[0179] Step 6: Calibrate the obtained granules on an open grid of 0.991 mm using a minimum rotor speed of 750 rpm.

[0180] Step 7: Sieve the external phase excipients (microcrystalline cellulose 90 μm and crospovidone) on a sieve with an opening of 0.6 mm.

[0181] Step 8: Add the external phase excipients to the granules calibrated in Step 6 and mix in a blender at 10 r / min for 20 minutes.

[0182] Step 9: Sieve the magnesium stearate through a sieve with an opening of 0.6 mm.

[0183] Step 10: Add the sieved magnesium stearate to the calibrated granules and mix at 6 r / min for 10 minutes to obtain a homogeneous mixture.

[0184] Step 11: Compress the lubricated granules on a Korsch XL 100 tablet press equipped with 4 punches. The tablets with a 10 mg dose strength are 3.8×7 mm, and the tablets with a 60 mg dose strength are 12.65×5.75 mm. The feeder speed used is 10 rpm, and the turntable speed is 20 rpm.

[0185] Step 12: Prepare a 30% Opadry QX film coating suspension.

[0186] Step 13: For batches 1 and 2 of formulation E, film coat the tablets with a 10 mg dose strength and a 60 mg dose strength using the following parameters to achieve a 3% weight gain: 1.2 mm nozzle, inlet temperature of 60 °C, air flow rate of 50 m 3 / h, roller speed of 2 rpm during preheating (where the speed is adjusted according to the tablet bed), suspension flow rate of approximately <5 g / min, spray pressure of 1.3 bar, and angular pressure of 1.3 bar.

[0187] Table 8 shows the manufacturing parameters used during batch manufacturing.

[0188] Testing and evaluation procedures

[0189] Perform the following tests on the final mixture prepared in Step 10: - Test 1 g of the mixture for 20 minutes at 95 °C using a heat balancer to determine the residual moisture by loss on drying (Ph.Eur. 2.2.32). - Test the homogeneity of the mixture on 3 samples: high, medium, and low. - Determine the bulk density (m / V, in g / mL) according to the volume of 100 g of powder obtained in a 250 mL graduated sample before sedimentation and after 10, 500, and 1250 sedimentations (Ph.Eur. 2.9.34). - The compressibility index (or Carr's index) (%) is calculated according to the following formula: 100x[(V0 - V f) / V0], where V0 is the apparent uncompacted volume, and V f is the final volume after the powder has settled until a constant volume is obtained. The Hausner index is calculated according to the following formula: V0 / V f . According to Ph.Eur. 2.9.36, the generally accepted scale of flowability is presented in Table 9. - Test the flow of 100 g of powder (Ph.Eur. 2.9.16). - On a Flodex apparatus, for 50 g of powder, determine the flow index (mm) through the orifice (Ph.Eur. 2.9.36) based on the smallest orifice diameter through which the sample can flow in 3 consecutive tests. - Conduct a sieve analysis for particle size distribution on 25 g of powder (Ph.Eur. 2.9.38), using sieves with opening sizes of 850, 425, 250, 180, 150, 106.75, <75 μm. The results are expressed as the percentage (w / w) of the powder not retained on the sieve. Table 9. Scale of flowability

[0190] Perform the following tests on the core tablets prepared in step 11: - Test the average mass of 10 compressed tablets - Test the mass uniformity of 20 tablets during compression (Ph.Eur. 2.9.5) - Test the hardness in 10 longitudinal compression directions during compression (Ph.Eur. 2.9.8) - Measure the thickness of 10 tablets during the compression process - Perform the friability test (Ph.Eur. 2.9.7) on tablets weighing not less than 6.5 g at the start, middle, and end of compression, for 4 minutes at 25 r / min and for 30 minutes. - Perform the disintegration test on 10 tablets at the start, middle, and end of compression (Ph.Eur. 2.9.1) - Perform the dissolution test on 6 tablets according to the method described in this example.

[0191] Perform the following tests on the film-coated tablets prepared in step 13: - Test the average mass of 10 compressed tablets - Test the mass uniformity of 20 tablets during compression (Ph.Eur. 2.9.5) - Test the hardness of 10 tablets in the length orientation during compression (Ph.Eur. 2.9.8) - Measure the thickness of 10 compressed tablets - Perform friability testing (Ph.Eur. 2.9.7) on tablets weighing not less than 6.5 g at the start, middle, and end of compression, continuously at 25 r / min for 4 minutes and 30 minutes - Perform disintegration on 10 tablets at the start, middle, and end of compression (Ph.Eur. 2.9.1) - Perform dissolution testing on 6 tablets according to the method described in this example

[0192] The following evaluation criteria were applied · Process monitoring based on defined parameters · Granulation state: ribbon / capillary · Characteristics of calibrated granules: density, particle size · Characteristics of the final mixture: flow, density, particle size · Analysis of Carr's index value and Hausner ratio · Good compressibility of the final mixture · During the film coating stage, in terms of aesthetics, control the following: uniform color, smooth surface, distinct engraving · Characteristics of core tablets and film-coated tablets: mass uniformity, thickness, hardness, friability, and disintegration time

[0193] Analysis results of film-coated tablets containing Compound 1: content uniformity and dissolution curve (according to the immediate release curve)

[0194] Dissolution method

[0195] The operating conditions of the dissolution method are as follows

[0196] Dissolution: 6 tablets in Stage I + 6 tablets in Stage II

[0197] Perform dissolution analysis according to USP <711> and Ph.Eur. 2.9.3 a. Apparatus i. Type 2 tray equipment ii. Visible UV spectrophotometer b. Dissolution conditions · Rotation speed: 75 rpm for 30 minutes, then 150 rpm from 30 minutes (completed) to 45 minutes · Medium: Citric acid and sodium citrate solution, pH = 3.5 · Volume: 900 mL · Bath temperature: 37 °C · Sampling: Every 5 minutes until 45 minutes · Wavelogger: 300 nm · Number of units tested: minimum 6 units (“Phase I”) to 24 units (“Phase III”) (if necessary)

[0198] Results Table 10. Comparison of batches containing Compound 1 Tablets with a dose of 10 mg (batch size 136 g) and 60 mg (batch size: 97 g) were film-coated with orange film coating agent QX

[0199] Based on Formulation C loaded with 15% Compound 1 and having an optimized ratio of 60 / 40 lactose / cellulose, studies were conducted to determine the effect of changing the percentage of magnesium stearate or adding talc to the formulation on the properties of the granulation mixture and tablets. The addition of colloidal silica was also considered for the purpose of improving flow, but no studies on colloidal silica were conducted.

[0200] The applied method was preliminarily simplified and optimized: · The flow rate of the wetting suspension (water) was about 100 ml / min fast · The percentage of water was 35% · The speed of the chopper was 1500 rpm fast · The dry granules were directly fully calibrated using a calibrator equipped with a 0.991 mm grid

[0201] For these batches, the final granules and mixtures were either partially characterized or not properly recorded or characterized. For some batches, poor sampling was performed, so the data are not described as they are not interpretable.

[0202] For comparison, only the characterization of 10 mg and 60 mg tablets manufactured at a force of 7 kN or 12 kN is presented in this example.

[0203] According to the method of Example 2 and the process parameters described in Table 8, the granulation step was carried out with 35% water.

[0204] As Figure 11 shown, the wetting curves of Formulation E Batch 1, Formulation C Batch 3, and Formulation D Batch 1 overlap. For Formulation E Batch 2, the curve is slightly different. The power is lower after 2 minutes of granulation, and the growth of the granulation cost slows down, which may be preferred when scaling up to control this step. The analyzed differences are related to the batches of the active ingredient. The effect of the physical quality of the active ingredient was studied in the method optimization study.

[0205] As shown in Table 11, the drying time varied between 23 and 35 minutes to obtain an LOD between 1.48% and 1.94%, equivalent to the initial dry mixture. Considering the temperature and humidity data, the drying conditions were similar.

[0206] Table 12 and Figure 12A and Figure 12 describe the characterization of the final mixture. Figure 12C

[0207] Table 13 shows that the characterized batches had similar D10, D50, and D90 values. Table 13. Particle Size of Batches Containing Compound 1 Compared by Sieving Analysis

[0208] Figure 13 An extensibility profile analysis was performed on the final mixtures of Batch 1 of Formulation E, Batch 3 of Formulation C, Batch 1 of Formulation D, and Batch 2 of Formulation E. The results are shown in and Table 14.

[0209] A comprehensive analysis of the extensibility profiles at 150 MPa showed that these batches had the following characteristics: - Appropriate density (about 0.47 g / cm3) / good rearrangement (<25%), resulting in easy flow of the three formulations. - Considerably plastic compound at break (Dr > 0.6) - Acceptable elasticity as it was below the limit of 2.4 J / g, - Good powder cohesion for Batch 1 of Formulation E / Batch 3 of Formulation C (Prd of 2.44 and 2.46 MPa > 2 MPa), while slightly poor powder cohesion for Batch 1 of Formulation D (Prd of 1.71 Mpa < 2 Mpa) - good demolding as < 2 MPa: no significant adhesion risk is expected

[0210] In summary, based on the extensibility characteristics at 150 MPa, the two formulations, Batch 1 of Formulation E and Batch 3 of Formulation C, are similar, and Batch 1 of Formulation D containing talc is slightly inferior due to a significant loss of cohesion.

[0211] ​The 10 mg and 60 mg tablets have the desired characteristics. At the end of the study, a lactose / cellulose ratio of 60 / 40 and 0.5% magnesium stearate were selected based on the results of the granulation step, mixing, and compression products, considering scale-up and processability. This formulation corresponds to batches 1 and 2 of Formulation E.

[0212] Tables 17A - 17C show the composition of the tablets prepared using this method. Table 17A. Composition of 10 mg and 60 mg dosage strength tablets containing Compound 1 (Formulation E) a Orange QX 321A230043 consists of 40.0% polyethylene glycol - polyvinyl alcohol graft copolymer (Ph.Eur.-NF), 27.5% talc (Ph.Eur.-USP), 20.2% titanium dioxide (E171) (Ph.Eur.-USP), 4% glyceryl monocaprylate / glyceryl monostearate / glyceryl distearate (Food Chemicals Codex) / fatty acid glycerides of type 1, 3.8% yellow iron oxide (E172) (NF), 3.5% partially hydrolyzed polyvinyl alcohol (Ph.Eur.-USP), and 1.0% red iron oxide (E172) (NF). Table 17B. Composition of 60 mg dosage strength tablets containing Compound 1 (Formulation E) a. When referring to the pharmacopoeia, this means applying the current version of that pharmacopoeia. b. Removed during the manufacturing process. c. From plant source. d. Using Aquarius TM Prime Orange BAP313104. Aquarius TM Prime Orange BAP313104 consists of 62.50% hypromellose 2910 (Ph.Eur.-USP), 19.45% titanium dioxide (E171) [CI77891] (Ph.Eur.-USP), 12.50% polyethylene glycol (macrogol - polyethylene glycol) (Ph.Eur.-USP), 4.32% yellow iron oxide (E172) [CI 77492] (NF), and 1.23% red iron oxide (E172) [CI 77491] (NF). Table 17C. Composition of 120 mg dosage strength tablets containing Compound 1 (Formulation E) a. When referring to a pharmacopoeia, this means applying the current version of that pharmacopoeia. b. Removed during the manufacturing process. c. From a plant source. d. Using Aquarius TM Preferred HSP BPP316076Green. Aquarius TM Preferred HSPBPP316076Green consists of 34.50% hypromellose 2910 (Ph.Eur.-USP), 28.00% copovidone NF (Ph.Eur.), 18.36% titanium dioxide (E171) (Ph.Eur.-USP), 9.50% polyethylene glycol (Ph.Eur.-USP), 3.48% yellow iron oxide (E172) (NF), 3.16% FD&C Blue No. 2 indigo carmine aluminum lake E132, and 3.00% caprylic / capric triglyceride NF (Ph.Eur.).

[0213] Example 3: Small-scale film coating tests for 10 mg and 60 mg doses

[0214] Film coat the Batch 2 of Formulation E according to the procedure of Example 2 and using the method parameters described in Table 18. Table 18. Characteristics of 10 mg film-coated tablets of Batch 2 of Formulation E Table 19. Characteristics of 60 mg film-coated tablets of Batch 2 of Formulation E

[0215] Considering the color uniformity, smooth appearance, and absence of defects, the film-coated tablets of both batches have suitable galenic characteristics and good film coating quality. Between the compression step and the film coating step, the hardness and disintegration time of both 10 mg and 60 mg doses increase.

[0216] The study was conducted as follows: These batches of T0 film-coated tablets were characterized and then for three consecutive days: The tablets were stored in open vials in the compression chamber at ambient temperature and humidity. It was observed that the hardness values and disintegration times decreased over time and reached a plateau for both doses.

[0217] Figure 14 and Figure 15Shows the hardness curves and disintegration times of 10 mg and 60 mg dosage strength tablets of Formulation E, Batch 2.

[0218] Example 4: Dissolution profiles of 10 mg and 60 mg dosage strength tablets containing Compound 1

[0219] As Figure 16 shown, the dissolution profiles of the 60 mg dosage strength tablets are comparable to those of the tablets of Formulation E, Batch 1, Formulation C, Batch 3, Formulation D, Batch 1, and Formulation E, Batch 2. The addition of talc and the amount of magnesium stearate have no effect on dissolution, and 80% release is achieved before 20 minutes.

[0220] The dissolution of 10 mg and 60 mg dosage strength tablets of Formulation E, Batch 1 is shown in Figure 17 and Figure 18 .

[0221] Comparison of the curves of the core tablets and film-coated tablets shows that the curves of the orange QX film coating agent are similar regardless of whether the dosage of the tablets is 10 mg or 60 mg.

[0222] The present disclosure includes any one or combination of the following embodiments, for example:

[0223] Embodiment 1: A tablet comprising at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and its pharmaceutically acceptable salts; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0224] Embodiment 2: The tablet according to Embodiment 1, further comprising at least one glidant.

[0225] Embodiment 3: The tablet according to any one of the foregoing embodiments, wherein the tablet comprises an intragranular core and an extragranular portion.

[0226] Embodiment 4: The tablet according to Embodiment 3, wherein the at least one diluent is selected from lactose monohydrate and microcrystalline cellulose.

[0227] Embodiment 5: The tablet according to Embodiment 4, wherein the at least one diluent is present in a total amount in the range of from about 70% to about 90% by weight.

[0228] Embodiment 6: The tablet according to Embodiment 5, wherein the at least one diluent is present in a total amount in the range of from about 50% to about 70% by weight in the intragranular core.

[0229] Embodiment 7: The tablet according to Embodiment 5 or 6, wherein the at least one diluent is present in the extra-granular portion in a total amount in the range of from about 10% to about 30% by weight.

[0230] Embodiment 8: The tablet according to any one of the foregoing embodiments, wherein the at least one binder is hydroxypropyl methylcellulose (hypromellose).

[0231] Embodiment 9: The tablet according to Embodiment 8, wherein the at least one binder is present in a total amount in the range of from about 0.1% to about 5% by weight.

[0232] Embodiment 10: The tablet according to Embodiment 3, wherein the at least one disintegrant is cross-linked polyvinylpyrrolidone (crospovidone). Embodiment 11: The tablet according to Embodiment 10, wherein the at least one disintegrant is present in a total amount of from about 0.1% to about 5% by weight.

[0233] Embodiment 12: The tablet according to Embodiment 11, wherein the at least one disintegrant is present in the inner core of the granule in a total amount in the range of from about 0.5% to about 3% by weight.

[0234] Embodiment 13: The tablet according to Embodiment 11 or 12, wherein the at least one disintegrant is present in the extra-granular portion in a total amount in the range of from about 0.5% to about 3% by weight.

[0235] Embodiment 14: The tablet according to any one of the foregoing embodiments, wherein the at least one lubricant is magnesium stearate.

[0236] Embodiment 15: The tablet according to Embodiment 14, wherein the at least one lubricant is present in a total amount in the range of from about 0.1% to about 5% by weight.

[0237] Embodiment 16: The tablet according to Embodiment 2, wherein the at least one glidant is talc.

[0238] Embodiment 17: The tablet according to Embodiment 16, wherein the at least one glidant is present in a total amount in the range of from about 1% to about 5% by weight.

[0239] Embodiment 18: The tablet according to Embodiment 3, wherein the inner core of the granule contains at least one diluent, at least one binder and at least one disintegrant.

[0240] Embodiment 19: The tablet according to Embodiment 3 or 18, wherein the extra-granular portion contains at least one diluent, at least one disintegrant and at least one lubricant.

[0241] Embodiment 20: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in at least 50% crystalline form, 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.

[0242] Embodiment 21: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount ranging from about 0.9 mg to about 125 mg.

[0243] Embodiment 22: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, and about 125 mg.

[0244] Embodiment 23: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 10 mg.

[0245] Embodiment 24: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 60 mg.

[0246] Embodiment 25: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 120 mg.

[0247] Embodiment 26: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

[0248] Embodiment 27: The tablet according to any one of the foregoing embodiments, the tablet further comprising at least one coating layer.

[0249] Embodiment 28: The tablet according to Embodiment 27, wherein the coating layer comprises a polyethylene glycol-polyvinyl alcohol graft copolymer, optionally further comprising talc and titanium dioxide.

[0250] Embodiment 29: The tablet according to Embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose.

[0251] Embodiment 30: The tablet according to Embodiment 29, wherein the coating layer further comprises at least one of titanium dioxide and polyethylene glycol.

[0252] Embodiment 31: The tablet according to Embodiment 29, wherein the coating layer further comprises at least one of copovidone and titanium dioxide.

[0253] Embodiment 32: The tablet according to Embodiment 1, wherein the tablet comprises: about 15% to about 45% by weight of lactose monohydrate, about 35% to about 60% by weight of microcrystalline cellulose, about 1% to about 5% by weight of hypromellose, about 1% to about 5% by weight of crospovidone, and about 0.1% to about 3% by weight of magnesium stearate.

[0254] Embodiment 33: The tablet according to Embodiment 32, wherein the tablet comprises an intragranular core and an extragranular portion.

[0255] Embodiment 34: The tablet according to Embodiment 33, wherein the intragranular core comprises about 20% to about 40% by weight of microcrystalline cellulose.

[0256] Embodiment 35: The tablet according to Embodiment 33, wherein the extragranular portion comprises about 15% to about 25% by weight of microcrystalline cellulose.

[0257] Embodiment 36: The tablet according to Embodiment 33, wherein the intragranular core comprises about 0.5% to about 2.5% by weight of crospovidone.

[0258] Embodiment 37: The tablet according to Embodiment 33, wherein the extragranular portion comprises about 0.5% to about 2.5% by weight of crospovidone.

[0259] Embodiment 38: The tablet according to any one of Embodiments 32 - 37, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

[0260] Embodiment 39: The tablet according to Embodiment 1, wherein the tablet comprises: about 30% to about 40% by weight of lactose monohydrate, about 40% to about 50% by weight of microcrystalline cellulose, about 1% to about 3% by weight of hypromellose, about 2% to about 4% by weight of crospovidone, and about 0.1% to about 1% by weight of magnesium stearate.

[0261] Embodiment 40: The tablet according to Embodiment 39, wherein the tablet comprises an intragranular core and an extragranular portion.

[0262] Embodiment 41: The tablet according to Embodiment 40, wherein the intra-granular core comprises about 20% to about 30% by weight of microcrystalline cellulose.

[0263] Embodiment 42: The tablet according to Embodiment 40, wherein the extra-granular portion comprises about 15% to about 25% by weight of microcrystalline cellulose.

[0264] Embodiment 43: The tablet according to Embodiment 40, wherein the intra-granular core comprises about 0.5% to about 2.5% by weight of crospovidone.

[0265] Embodiment 44: The tablet according to Embodiment 40, wherein the extra-granular portion comprises about 0.5% to about 2.5% by weight of crospovidone.

[0266] Embodiment 45: The tablet according to any one of Embodiments 39-44, wherein Compound 1 is present in an amount of about 10% to 20% by weight.

[0267] Embodiment 46: The tablet according to Embodiment 1, wherein the tablet comprises: about 35.0% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.5% by weight of magnesium stearate.

[0268] Embodiment 47: The tablet according to Embodiment 46, wherein the tablet comprises an intra-granular core and an extra-granular portion.

[0269] Embodiment 48: The tablet according to Embodiment 47, wherein the intra-granular core comprises 23.5% by weight of microcrystalline cellulose.

[0270] Embodiment 49: The tablet according to Embodiment 47, wherein the extra-granular portion comprises 21.0% by weight of microcrystalline cellulose.

[0271] Embodiment 50: The tablet according to Embodiment 47, wherein the intra-granular core comprises about 1.5% by weight of crospovidone.

[0272] Embodiment 51: The tablet according to Embodiment 47, wherein the extra-granular portion comprises about 1.5% by weight of crospovidone.

[0273] Embodiment 52: The tablet according to any one of Embodiments 46-51, wherein Compound 1 is present in an amount of about 15% by weight.

[0274] Embodiment 53: The tablet according to Embodiment 1, wherein the tablet comprises: about 28.8% by weight of lactose monohydrate, about 55.8% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0275] Embodiment 54: The tablet according to Embodiment 53, wherein the tablet comprises an intragranular core and an extragranular portion.

[0276] Embodiment 55: The tablet according to Embodiment 54, wherein the intragranular core comprises 34.8% by weight of microcrystalline cellulose.

[0277] Embodiment 56: The tablet according to Embodiment 54, wherein the extragranular portion comprises 21.0% by weight of microcrystalline cellulose.

[0278] Embodiment 57: The tablet according to Embodiment 54, wherein the intragranular core comprises about 1.5% by weight of crospovidone.

[0279] Embodiment 58: The tablet according to Embodiment 54, wherein the extragranular portion comprises about 1.5% by weight of crospovidone.

[0280] Embodiment 59: The tablet according to any one of Embodiments 53 - 58, wherein Compound 1 is present in an amount of about 10% by weight.

[0281] Embodiment 60: The tablet according to Embodiment 1, wherein the tablet comprises: about 23.5% by weight of lactose monohydrate, about 56.2% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0282] Embodiment 61: The tablet according to Embodiment 60, wherein the tablet comprises an intragranular core and an extragranular portion.

[0283] Embodiment 62: The tablet according to Embodiment 61, wherein the intragranular core comprises 35.2% by weight of microcrystalline cellulose.

[0284] Embodiment 63: The tablet according to Embodiment 61, wherein the extragranular portion comprises 21.0% by weight of microcrystalline cellulose.

[0285] Embodiment 64: The tablet according to Embodiment 61, wherein the intragranular core comprises about 1.5% by weight of crospovidone.

[0286] Embodiment 65: The tablet according to Embodiment 61, wherein the extra-granular portion contains about 1.5% by weight of crospovidone.

[0287] Embodiment 66: The tablet according to any one of Embodiments 60 - 65, wherein Compound 1 is present in an amount of about 15% by weight.

[0288] Embodiment 67: The tablet according to Embodiment 1, wherein the tablet contains: about 35.2% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

[0289] Embodiment 68: The tablet according to Embodiment 67, wherein the tablet contains an intra-granular core and an extra-granular portion.

[0290] Embodiment 69: The tablet according to Embodiment 68, wherein the intra-granular core contains 23.5% by weight of microcrystalline cellulose.

[0291] Embodiment 70: The tablet according to Embodiment 68, wherein the extra-granular portion contains 21.0% by weight of microcrystalline cellulose.

[0292] Embodiment 71: The tablet according to Embodiment 68, wherein the intra-granular core contains about 1.5% by weight of crospovidone.

[0293] Embodiment 72: The tablet according to Embodiment 68, wherein the extra-granular portion contains about 1.5% by weight of crospovidone.

[0294] Embodiment 73: The tablet according to any one of Embodiments 67 - 72, wherein Compound 1 is present in an amount of about 15% by weight.

[0295] Embodiment 74: The tablet according to Embodiment 2, wherein the tablet contains: about 32.2% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hypromellose, about 3.0% by weight of crospovidone, about 0.4% by weight of magnesium stearate; and about 3.0% by weight of talc.

[0296] Embodiment 75: The tablet according to Embodiment 74, wherein the tablet contains an intra-granular core and an extra-granular portion.

[0297] Embodiment 76: The tablet according to Embodiment 75, wherein the intra-granular core contains 23.5% by weight of microcrystalline cellulose.

[0298] Embodiment 77: The tablet according to Embodiment 75, wherein the extra-granular portion comprises 21.0% by weight of microcrystalline cellulose.

[0299] Embodiment 78: The tablet according to Embodiment 75, wherein the intra-granular core comprises about 1.5% by weight of crospovidone.

[0300] Embodiment 79: The tablet according to Embodiment 75, wherein the extra-granular portion comprises about 1.5% by weight of crospovidone.

[0301] Embodiment 80: The tablet according to any one of the foregoing embodiments, wherein Compound 1 is present in an amount of about 15% by weight.

[0302] Embodiment 81: The tablet according to any one of Embodiments 32 - 80, the tablet further comprising a film coating agent.

[0303] Embodiment 82: The tablet according to Embodiment 81, wherein the film coating is present in an amount of about 2% to about 5% relative to the total weight of the tablet.

[0304] Embodiment 83: The tablet according to Embodiment 82, wherein the film coating is present in an amount of about 3% relative to the total weight of the tablet.

[0305] Embodiment 84: The tablet according to any one of Embodiments 53 - 66, wherein the ratio of lactose to intra-granular microcrystalline cellulose is about 40:60 by weight.

[0306] Embodiment 85: The tablet according to any one of Embodiments 46 - 52 and 67 - 79, wherein the ratio of lactose to intra-granular microcrystalline cellulose is about 60:40 by weight.

[0307] Embodiment 86: The tablet according to Embodiment 27, wherein the coating layer comprises a polyethylene glycol-polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl monocaprylate / glyceryl monostearate / glyceryl distearate / fatty acid glyceride type 1, yellow iron oxide, partially hydrolyzed polyvinyl alcohol, and red iron oxide.

[0308] Embodiment 87: The tablet according to Embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, yellow iron oxide, and red iron oxide.

[0309] Embodiment 88: The tablet according to Embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose, copovidone, titanium dioxide, polyethylene glycol, yellow iron oxide, indigo carmine aluminum lake, and glyceryl trioctanoate / glyceryl tridecanoate.

[0310] Embodiment 89: A method of treating a BTK-mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a tablet according to any one of Embodiments 1 to 88.

[0311] Embodiment 90: Use of a tablet according to any one of Embodiments 1-88 for the treatment of a disease involving a BTK receptor-mediated disease.

Claims

1. A tablet, the tablet comprising: at least one compound selected from (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound 1) and pharmaceutically acceptable salts thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

2. The tablet according to claim 1, the tablet further comprising: at least one glidant.

3. The tablet according to any one of the preceding claims, wherein the tablet comprises an intragranular core and an extragranular portion.

4. The tablet according to claim 3, wherein the at least one diluent is selected from lactose monohydrate and microcrystalline cellulose.

5. The tablet according to claim 4, wherein the at least one diluent is present in a total amount in the range of from about 70% to about 90% by weight.

6. The tablet according to claim 5, wherein the at least one diluent is present in a total amount in the range of from about 50% to about 70% by weight in the intragranular core.

7. The tablet according to claim 5 or 6, wherein the at least one diluent is present in a total amount in the range of from about 10% to about 30% by weight in the extragranular portion.

8. The tablet according to any one of the preceding claims, wherein the at least one binder is hydroxypropyl methylcellulose (hypromellose).

9. The tablet according to claim 8, wherein the at least one binder is present in a total amount in the range of from about 0.1% to about 5% by weight.

10. The tablet according to claim 3, wherein the at least one disintegrant is crospovidone.

11. The tablet according to claim 10, wherein the at least one disintegrant is present in a total amount in the range of from about 0.1% to about 5% by weight.

12. The tablet according to claim 11, wherein the at least one disintegrant is present in a total amount in the range of from about 0.5% to about 3% by weight in the intragranular core.

13. The tablet according to claim 11 or 12, wherein the at least one disintegrant is present in a total amount in the range of from about 0.5% to about 3% by weight in the extragranular portion.

14. The tablet according to any one of the preceding claims, wherein the at least one lubricant is magnesium stearate.

15. The tablet according to claim 14, wherein the at least one lubricant is present in a total amount in the range of from about 0.1% to about 5% by weight.

16. The tablet according to claim 2, wherein the at least one glidant is talc.

17. The tablet according to claim 16, wherein the at least one glidant is present in a total amount in the range of from about 1% to about 5% by weight.

18. The tablet according to claim 3, wherein the intragranular core comprises at least one diluent, at least one binder and at least one disintegrant.

19. The tablet according to claim 3 or 18, wherein the extragranular portion comprises at least one diluent, at least one disintegrant and at least one lubricant.

20. The tablet according to any one of the preceding claims, wherein Compound 1 is present in at least 50% crystalline form, 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.

21. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount ranging from about 0.9 mg to about 125 mg.

22. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, and about 125 mg.

23. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of about 10 mg.

24. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of about 60 mg.

25. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of about 120 mg.

26. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

27. The tablet according to any one of the preceding claims, wherein the tablet further comprises at least one coating layer.

28. The tablet according to claim 27, wherein the coating layer comprises a polyethylene glycol - polyvinyl alcohol graft copolymer, optionally further comprising talc and titanium dioxide.

29. The tablet according to claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose.

30. The tablet according to claim 29, wherein the coating layer further comprises at least one of titanium dioxide and polyethylene glycol.

31. The tablet according to claim 29, wherein the coating layer further comprises at least one of copovidone and titanium dioxide.

32. The tablet according to claim 1, wherein the tablet comprises: about 15% to about 45% by weight of lactose monohydrate, about 35% to about 60% by weight of microcrystalline cellulose, about 1% to about 5% by weight of hydroxypropyl methylcellulose, about 1% to about 5% by weight of crospovidone, and about 0.1% to about 3% by weight of magnesium stearate.

33. The tablet according to claim 32, wherein the tablet comprises an intra - granule core and an extra - granule portion.

34. The tablet according to claim 33, wherein the intra - granule core comprises about 20% to about 40% by weight of microcrystalline cellulose.

35. The tablet according to claim 33, wherein the extra - granule portion comprises about 15% to about 25% by weight of microcrystalline cellulose.

36. The tablet according to claim 33, wherein the inner core of the granule contains about 0.5% to about 2.5% by weight of crospovidone.

37. The tablet according to claim 33, wherein the outer part of the granule contains about 0.5% to about 2.5% by weight of crospovidone.

38. The tablet according to any one of claims 32 - 37, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

39. The tablet according to claim 1, wherein the tablet comprises: about 30% to about 40% by weight of lactose monohydrate, about 40% to about 50% by weight of microcrystalline cellulose, about 1% to about 3% by weight of hydroxypropyl methylcellulose, about 2% to about 4% by weight of crospovidone, and about 0.1% to about 1% by weight of magnesium stearate.

40. The tablet according to claim 39, wherein the tablet comprises an inner core of the granule and an outer part of the granule.

41. The tablet according to claim 40, wherein the inner core of the granule contains about 20% to about 30% by weight of microcrystalline cellulose.

42. The tablet according to claim 40, wherein the outer part of the granule contains about 15% to about 25% by weight of microcrystalline cellulose.

43. The tablet according to claim 40, wherein the inner core of the granule contains about 0.5% to about 2.5% by weight of crospovidone.

44. The tablet according to claim 40, wherein the outer part of the granule contains about 0.5% to about 2.5% by weight of crospovidone.

45. The tablet according to any one of claims 39 - 44, wherein Compound 1 is present in an amount of about 10% to 20% by weight.

46. The tablet according to claim 1, wherein the tablet comprises: about 35.0% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hydroxypropyl methylcellulose, about 3.0% by weight of crospovidone, and about 0.5% by weight of magnesium stearate.

47. The tablet according to claim 46, wherein the tablet comprises an inner core of the granule and an outer part of the granule.

48. The tablet according to claim 47, wherein the inner core of the granule contains 23.5% by weight of microcrystalline cellulose.

49. The tablet according to claim 47, wherein the outer part of the granule contains 21.0% by weight of microcrystalline cellulose.

50. The tablet according to claim 47, wherein the inner core of the granule contains about 1.5% by weight of crospovidone.

51. The tablet according to claim 47, wherein the outer part of the granule contains about 1.5% by weight of crospovidone.

52. The tablet according to any one of claims 46 - 51, wherein Compound 1 is present in an amount of about 15% by weight.

53. The tablet according to claim 1, wherein the tablet comprises: about 28.8% by weight of lactose monohydrate, about 55.8% by weight of microcrystalline cellulose, about 2.0% by weight of hydroxypropyl methylcellulose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

54. The tablet according to claim 53, wherein the tablet comprises an intragranular core and an extragranular part.

55. The tablet according to claim 54, wherein the intragranular core comprises 34.8% by weight of microcrystalline cellulose.

56. The tablet according to claim 54, wherein the extragranular part comprises 21.0% by weight of microcrystalline cellulose.

57. The tablet according to claim 54, wherein the intragranular core comprises about 1.5% by weight of crospovidone.

58. The tablet according to claim 54, wherein the extragranular part comprises about 1.5% by weight of crospovidone.

59. The tablet according to any one of claims 53 - 58, wherein Compound 1 is present in an amount of about 10% by weight.

60. The tablet according to claim 1, wherein the tablet comprises: about 23.5% by weight of lactose monohydrate, about 56.2% by weight of microcrystalline cellulose, about 2.0% by weight of hydroxypropyl methylcellulose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

61. The tablet according to claim 60, wherein the tablet comprises an intragranular core and an extragranular part.

62. The tablet according to claim 61, wherein the intragranular core comprises 35.2% by weight of microcrystalline cellulose.

63. The tablet according to claim 61, wherein the extragranular part comprises 21.0% by weight of microcrystalline cellulose.

64. The tablet according to claim 61, wherein the intragranular core comprises about 1.5% by weight of crospovidone.

65. The tablet according to claim 61, wherein the extragranular part comprises about 1.5% by weight of crospovidone.

66. The tablet according to any one of claims 60 - 65, wherein Compound 1 is present in an amount of about 15% by weight.

67. The tablet according to claim 1, wherein the tablet comprises: about 35.2% by weight of lactose monohydrate, about 44.5% by weight of microcrystalline cellulose, about 2.0% by weight of hydroxypropyl methylcellulose, about 3.0% by weight of crospovidone, and about 0.4% by weight of magnesium stearate.

68. The tablet according to claim 67, wherein the tablet comprises an intragranular core and an extragranular part.

69. The tablet according to claim 68, wherein the intragranular core comprises 23.5% by weight of microcrystalline cellulose.

70. The tablet according to claim 68, wherein the extragranular part comprises 21.0% by weight of microcrystalline cellulose.

71. The tablet according to claim 68, wherein the intragranular core comprises about 1.5% by weight of crospovidone.

72. The tablet according to claim 68, wherein the extragranular part comprises about 1.5% by weight of crospovidone.

73. The tablet according to any one of claims 67 - 72, wherein Compound 1 is present in an amount of about 15% by weight.

74. The tablet according to claim 2, wherein the tablet comprises: about 32.2% by weight of lactose monohydrate, Approximately 44.5% microcrystalline cellulose by weight, Approximately 2.0% hydroxypropyl methylcellulose by weight, Approximately 3.0% crospovidone by weight, Approximately 0.4% magnesium stearate by weight; and Approximately 3.0% talc by weight.

75. The tablet according to claim 74, wherein the tablet comprises an intragranular core and an extragranular portion.

76. The tablet according to claim 75, wherein the intragranular core comprises 23.5% microcrystalline cellulose by weight.

77. The tablet according to claim 75, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

78. The tablet according to claim 75, wherein the intragranular core comprises approximately 1.5% crospovidone by weight.

79. The tablet according to claim 75, wherein the extragranular portion comprises approximately 1.5% crospovidone by weight.

80. The tablet according to any one of the preceding claims, wherein Compound 1 is present in an amount of approximately 15% by weight.

81. The tablet according to any one of claims 32 - 80, the tablet further comprising a film coating agent.

82. The tablet according to claim 81, wherein the film coating is present in an amount of approximately 2% to approximately 5% relative to the total weight of the tablet.

83. The tablet according to claim 82, wherein the film coating is present in an amount of approximately 3% relative to the total weight of the tablet.

84. The tablet according to any one of claims 53 - 66, wherein the ratio of lactose to intragranular microcrystalline cellulose is approximately 40:60 by weight.

85. The tablet according to any one of claims 46 - 52 and 67 - 79, wherein the ratio of lactose to intragranular microcrystalline cellulose is approximately 60:40 by weight.

86. The tablet according to claim 27, wherein the coating layer comprises a polyethylene glycol - grafted polyvinyl alcohol copolymer, talc, titanium dioxide, monoglyceride / diglyceride / fatty acid glyceride type 1, yellow iron oxide, partially hydrolyzed polyvinyl alcohol, and red iron oxide.

87. The tablet according to claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, yellow iron oxide, and red iron oxide.

88. The tablet according to claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose, copovidone, titanium dioxide, polyethylene glycol, yellow iron oxide, indigo aluminum lake, and triglyceride caprylate / caprate.

89. A method of treating a BTK - mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a tablet according to any one of claims 1 to 88.

90. Use of a tablet according to any one of claims 1 - 88 for the treatment of a disease involving a BTK receptor - mediated disease.

Images