Formulation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-C]pyridin-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]pyridin-2(3H)-one are described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 433,824, filed December 20, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] The present disclosure relates to formulations of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, processes for preparing the formulations, and methods of use thereof. [Background technology]

[0003] BTK, a member of the Tec family of non-receptor tyrosine kinases, 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 functions in various aspects of B cell function, maintaining the B cell repertoire (see Gauld SB et al., B cell antigen receptor signaling: roles in cell development and disease. Science, 296:1641-2. 2002). B cells play a role in rheumatoid arthritis (Perosa F., et al., CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 267:260-77. 2010 and Doerner 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-indicated arthritis. Clin. Immunol. 127 S1:S111. 2008), as well as other autoimmune diseases such as systemic lupus erythematosus and cancer (Shlomchik MJ, et. al., The role of B cells in lpr / lpr-induced autoimmunity. J. Exp. Med.180:1295-1306.1994;Honigberg LA, 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 also have potential for treating allergic diseases (see Honigberg, L., et al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen-indicated arthritis. Clin. Immunol. 127 S1:S111. 2008). An irreversible inhibitor was shown to suppress passive cutaneous anaphylaxis (PCA) induced by IgE-antigen complexes in mice. These findings are consistent with those observed in BTK-mutant mast cells and knockout mice, suggesting that BTK inhibitors may be useful for treating asthma, an IgE-mediated allergic disease of the airways.

[0005] The compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one shown below (hereinafter also referred to as "Compound 1") is a BTK inhibitor: [ka] (which is also known as "trebrutinib"), and the following structure: [ka] 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 formula:

[0006] One factor in assessing a compound's suitability as a therapeutic agent is whether the compound can be synthesized in a manner suitable for large-scale production and isolation with minimal waste and impurities. This factor is often taken into consideration when considering the suitability of a bench-scale process for producing the larger quantities required for commercial production. For example, compound (1) and a method for preparing it are disclosed in Example 3 of U.S. Pat. No. 9,688,676 and are as follows:

[0007] In a 100 mL round-bottom flask, (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 equiv.), DCM-CHOH (6 mL), and TEA (113 mg, 1.12 mmol, 3.00 equiv.) were added. Then, over a period of 5 minutes, prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv.) was added dropwise with stirring at 0° C. The resulting solution was stirred at 0° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was loaded onto a silica gel column using dichloromethane / methanol (30:1). The crude product (100 mg) was purified using the following conditions (column: XBridge Prep C18 OBD Column, 5 μm, 19 *The mixture was purified by preparative HPLC using a 150 mm mobile phase containing 0.05% TFA and ACN in water (25.0% ACN to 45.0% ACN in 8 minutes). As described above, this synthesis yielded 100 mg of crude Compound (1), which had to be purified by column chromatography to yield 54.5 mg of purified Compound (1), which may have crystalline Form 1 as described herein below.

[0008] Another desirable aspect to be realized is that the compound as a therapeutic agent can be administered in a form that is easily absorbed by the body and is also storage stable. The pharmaceutically active substance used to prepare the therapeutic agent should be as pure as possible, and its stability during long-term storage should be guaranteed under various environmental conditions. These properties are useful for preventing the appearance of unintended degradation products in the pharmaceutical composition, which may be potentially toxic or simply reduce the efficacy of the composition.

[0009] A primary concern for large-scale production of pharmaceutical compounds is that the active substance should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, the crystalline morphology may change during production and / or storage, resulting in quality control issues and formulation variability. Such changes may affect the reproducibility of the manufacturing process, thereby resulting in a final formulation that does not meet the high quality and stringent requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should generally be noted that any changes to the solid state of a pharmaceutical composition that can improve its physical and chemical stability will generally provide a significant advantage over less stable forms of the same drug.

[0010] When a compound crystallizes from a solution or slurry, it may crystallize in a variety of spatial lattice arrangements, a property called "polymorphism." Each crystalline form is a "polymorph." Polymorphs of a given substance have the same chemical composition, but they may differ from each other with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystalline shape, compaction behavior, flowability, and / or solid-state stability. Summary of the Invention [Means for solving the problem]

[0011] Therefore, the present disclosure seeks to address the shortcomings of the art. Disclosed herein is 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.

[0012] Also disclosed herein is a method of treating a disease or condition mediated by BTK in a patient in need thereof, 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 drug delivery form, such as 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), for treating diseases mediated by the BTK receptor. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows a representation of torque as a function of water / mix weight. [Figure 2] 1 shows a representation of the granulation curve with torque as a function of granulation time. [Figure 3] A comparison of the wetting curves of placebo batch 1 and Formula A batches 1 and 2 is shown. [Figure 4] A comparison of the wetting curves of placebo batches 1 and 2 and formulation A batch 3 is shown. [Figure 5] 1 shows a comparison of the wetting curves of Formulation A Batches 1, 2, and 3. [Figure 6] 1 shows the wetting curve for Formulation B Batch 2. [Figure 7] Figure 1 shows the wetting curves and granulation at various percentages of water addition for Formulation B Batch 2. [Figure 8] 1 shows a comparison of wetting and granulation curves for Formulation B batches 1 and 2. [Figure 9A] 1 shows a comparative representation of the wetting and granulation curves for Formulation B Batch 2 and Formulation C Batch 2. [Figure 9B] 1 shows a comparative representation of the wetting and granulation curves for Formulation B Batch 2 and Formulation C Batch 2. [Figure 9C] 1 shows a comparative representation of the wetting and granulation curves for Formulation B Batch 2 and Formulation C Batch 2. [Figure 10] 1 shows a comparative representation of the wetting and granulation curves for Formulation C Batches 1 and 2. [Figure 11] 1 shows the wetting curves and granulation of Formula E Batch 1, Formula C Batch 3, Formula D Batch 1, and Formula E Batch 2. [Figure 12A] 1 shows particle size distribution as a function of sieve, expressed as a percentage, for Formula E Batch 1, Formula C Batch 3, and Formula E Batch 2, respectively. [Figure 12B] 1 shows particle size distribution as a function of sieve, expressed as a percentage, for Formula E Batch 1, Formula C Batch 3, and Formula E Batch 2, respectively. [Figure 12C]1 shows particle size distribution as a function of sieve, expressed as a percentage, for Formula E Batch 1, Formula C Batch 3, and Formula E Batch 2, respectively. [Figure 13] 1 shows the spider-like representation of Formula E Batch 1, Formula C Batch 3, and Formula D Batch 1. [Figure 14] 1 shows the hardness curve and disintegration time as a function of time for 10 mg dosage strength tablets of Formulation E Batch 2. [Figure 15] 1 shows the hardness curve and disintegration time as a function of time for Formulation E Batch 2 60 mg dosage strength tablets. [Figure 16] 1 shows a comparison of 60 mg dosage strength core tablets for Formulation E Batch 1, Formulation C Batch 3, and Formulation D Batch 1. [Figure 17] 1 shows a comparison of Formulation E Batch 1 cores and film coated 10 mg dosage strength tablets. [Figure 18] 1 shows a comparison of Formulation E Batch 1 core and film coated 60 mg dosage strength tablets. DETAILED DESCRIPTION OF THE INVENTION

[0015] Reference will now be made in detail to specific embodiments which are illustrated in the accompanying drawings. While the present disclosure provides illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present disclosure as defined by the appended claims.

[0016] The section headings used herein are for organizational purposes only and should not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined herein, the present specification shall control. While the present teachings will be described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0017] I. Definition Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0018] The articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0019] The term "about" is used in this disclosure to indicate and encompass a stated value as well as a range above and below that value. In certain embodiments, the term "about" refers to the specified value ±10%, ±5%, or ±1%. In certain embodiments, where applicable, the term "about" refers to the specified value ±1 standard deviation of that value.

[0020] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise stated.

[0021] The terms "article of manufacture" and "kit" are used synonymously.

[0022] As used herein, "BTK inhibitor," "BTK inhibitor compound," "compound of Formula (1)," "compound (1)," "trebrutinib," 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: [ka] It has the following structure: [ka] 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 and / or a pharmaceutically acceptable salt thereof.

[0023] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0024] As used herein, the term "crystalline" or "crystalline solid form" refers to a solid form that is substantially free of any amorphous solid form.

[0025] In some embodiments, "substantially free" refers to less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of other crystalline forms of the compound and amorphous compounds. In some embodiments, "substantially free" refers to undetectable amounts of other crystalline forms of the compound and amorphous compounds.

[0026] As used herein, the terms "substantially pure" or "substantially crystalline" mean that the crystalline form contains at least 90 percent, such as at least 95 percent, such as at least 97 percent, or even at least 99 percent, by weight of the indicated crystalline form compared to the total weight of all forms of the compound.

[0027] Alternatively, "substantially pure" or "substantially crystalline" will be understood to mean that the crystalline form contains less than 10 percent by weight, such as less than 5 percent, for example less than 3 percent, or even less than 1 percent, of impurities, including other polymorphs, solvates, or amorphous forms, relative to the total weight of the compound in all forms.

[0028] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which molecules are arranged in a random manner so that there is no clearly defined arrangement, such as molecular packing and long-range order. For example, an amorphous material is a solid material that does not have a sharp characteristic signal in its X-ray powder diffraction (power diffractogram) (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in the diffractogram. Broad peaks are characteristic of amorphous solids.

[0029] As used herein, the term "substantially amorphous" refers to a solid material that has little long-range order in the position of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). "Substantially amorphous" includes the descriptor "amorphous," which refers to a substance that has no crystallinity (0% crystallinity).

[0030] "Treating" a disease or "treatment" of a disease includes: (1) To prevent disease, e.g., to prevent the development of clinical symptoms of disease in a mammal that may be exposed to or predisposed to the disease but has not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, e.g., preventing or reducing the onset of the disease or its clinical symptoms; (3) Alleviating the disease, e.g., reversing the disease or its clinical symptoms.

[0031] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0032] A "therapeutically effective amount" means the amount of a BTK inhibitor compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0033] Before describing the present teachings in detail, it is to be understood that this disclosure is not limited to particular compositions or process steps, as such may vary.

[0034] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "complex" includes a plurality of complexes, reference to a "cell" includes a plurality of cells, and so forth.

[0035] Numerical ranges are inclusive of the numbers defining the range. Measurements and measurable values ​​are understood to be approximations, taking into account significant digits and error associated with the measurements. Also, the use of "comprise," "comprises," "comprising," "contain," "contains," "containing," and "include," "includes," "including" are not intended to be limiting. It is to be understood that both the foregoing general and detailed descriptions are exemplary and explanatory only and are not restrictive of the teachings.

[0036] Unless otherwise stated in the specification above, embodiments herein that recite various components as "comprising" are also contemplated as "consisting of" or "consisting essentially of" the recited components; embodiments herein that recite various components as "consisting of" are also contemplated as "comprising" or "consisting essentially of" the recited components; and embodiments herein that recite various components as "consisting essentially of" are also contemplated as "consisting of" or "comprising" the recited components (this interchangeability does not apply to the use of such terms in the claims).

[0037] As used herein, the terms "or a combination thereof" and "or combinations thereof" refer to any and all permutations and combinations of the listed terms preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, where order is important in a particular situation, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, combinations including repeats of one or more items or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Those of skill in the art will understand that typically there is no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0038] "Or" is used in its inclusive sense, ie, equivalent to "and / or," unless the context requires otherwise.

[0039] II. BTK Inhibitor Compounds BTK inhibitor compounds can be prepared, for example, according to the methods and schemes described in U.S. Pat. No. 9,688,676 B2, particularly column 62, line 8 to column 65, line 32 and column 67, lines 28 to 69, which are incorporated herein by reference.

[0040] To enable one of ordinary skill in the art to prepare BTK inhibitor compounds, the preparation of the following compound, (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, is shown below. The synthetic routes should not be construed as limiting the scope of the present disclosure, but are merely illustrative and representative thereof.

[0041] Exemplary Synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one: [ka]

[0042] In a 100 mL round-bottom flask, (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 equiv.), DCM-CH3OH (6 mL), and TEA (113 mg, 1.12 mmol, 3.00 equiv.) were added. Subsequently, prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv.) was added dropwise with stirring at 0°C for 5 minutes. The resulting solution was stirred at 0°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column using dichloromethane / methanol (30:1). The crude product (100 mg) was purified by Prep-HPLC (column, XBridge Prep C) under the following conditions: 18 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). 54.5 mg of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m / z: 465.2 (M+1).

[0043] III. Tablet Formulations Tablets containing Compound 1 or a pharmaceutically acceptable salt thereof are provided.

[0044] In some embodiments, a tablet is provided that includes 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.

[0045] In some embodiments, the tablet further comprises at least one flow agent.

[0046] In some embodiments, the tablet comprises an intragranular core and an extragranular portion.

[0047] 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 ranging from about 70% to about 90% by weight. In some embodiments, the at least one diluent is present in the intragranular core in a total amount ranging from about 50% to about 70% by weight. In some embodiments, the at least one diluent is present in the extragranular portion in a total amount ranging from about 10% to about 30% by weight.

[0048] 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 ranging from about 0.1% to about 5% by weight.

[0049] In some embodiments, at least one disintegrant is cross-linked polyvinyl N-pyrrolidone (crospovidone). In some embodiments, the at least one disintegrant is present in a total amount ranging from about 0.1% to about 5% by weight. In some embodiments, the at least one disintegrant is present in the intragranular core in a total amount ranging from about 0.5% to about 3% by weight. In some embodiments, the at least one disintegrant is present in the extragranular portion in a total amount ranging from about 0.5% to about 3% by weight.

[0050] 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 ranging 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.

[0051] In some embodiments, the at least one flow agent is talc. In some embodiments, the at least one flow agent is present in a total amount ranging from about 1% to about 5% by weight.

[0052] In some embodiments, the intragranular core comprises at least one diluent, at least one binder, and at least one disintegrant.

[0053] In some embodiments, the extragranular portion comprises at least one diluent, at least one disintegrant, and at least one lubricant.

[0054] In some embodiments, Compound 1 is present in at least 50% crystalline form, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% crystalline.

[0055] In some embodiments, Compound 1 is present in an amount ranging 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.

[0056] In some embodiments, the tablet further comprises at least one coating layer. In some embodiments, the coating layer comprises macrogol polyvinyl alcohol graft copolymer, optionally further comprising talc with 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 macrogol polyethylene glycol. In some embodiments, the coating layer further comprises at least one of copovidone and titanium dioxide.

[0057] In some embodiments, the tablet comprises about 15% to about 45% by weight lactose monohydrate, about 35% to about 60% by weight microcrystalline cellulose, about 1% to about 5% by weight hydroxypropyl methylcellulose, about 1% to about 5% by weight crospovidone, and about 0.1% to about 3% by weight magnesium stearate.

[0058] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises about 20% to about 40% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 0.5% to about 2.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 5% to 25% by weight.

[0059] In some embodiments, the tablet comprises about 30% to about 40% by weight lactose monohydrate, about 40% to about 50% by weight microcrystalline cellulose, about 1% to about 3% by weight hydroxypropyl methylcellulose, about 2% to about 4% by weight crospovidone, and about 0.1% to about 1% by weight magnesium stearate.

[0060] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises about 20% to about 30% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 0.5% to about 2.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 10% to 20% by weight.

[0061] In some embodiments, the tablet comprises about 35.0% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.5% by weight magnesium stearate.

[0062] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises 21.0% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 1.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 1.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0063] In some embodiments, the tablet comprises about 28.8% by weight lactose monohydrate, about 55.8% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0064] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 34.8% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises 21.0% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 1.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 1.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 10% by weight.

[0065] In some embodiments, the tablet comprises about 23.5% by weight lactose monohydrate, about 56.2% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0066] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 35.2% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises 21.0% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 1.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 1.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0067] In some embodiments, the tablet comprises about 35.2% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0068] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises 21.0% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 1.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 1.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0069] In some embodiments, the tablet comprises about 32.2% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, about 0.4% by weight magnesium stearate, and about 3.0% by weight talc.

[0070] In some embodiments, the tablet comprises an intragranular core and an extragranular portion. In some embodiments, the intragranular core comprises 23.5% microcrystalline cellulose by weight. In some embodiments, the extragranular portion comprises 21.0% microcrystalline cellulose by weight. In some embodiments, the intragranular core comprises about 1.5% crospovidone by weight. In some embodiments, the extragranular portion comprises about 1.5% crospovidone by weight. In some embodiments, Compound 1 is present in an amount of about 15% by weight.

[0071] In some embodiments, the tablet further comprises a film coating. In some embodiments, the film coating is present in an amount of about 2% to about 5% by total tablet weight. In some embodiments, the film coating is present in an amount of about 3% by total tablet weight.

[0072] In some embodiments, the weight ratio of lactose to intragranular microcrystalline cellulose is about 40:60. In some embodiments, the weight ratio of lactose to intragranular microcrystalline cellulose is about 50:50. In some embodiments, the weight ratio of lactose to intragranular microcrystalline cellulose is about 60:40.

[0073] In some embodiments, the coating layer comprises macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, fatty acid monocaprylocapriate glycerol type 1 / mono / diglyceride / glycerol, yellow ferric oxide, partially hydrolyzed polyvinyl alcohol, and red ferric oxide.

[0074] In some embodiments, the coating layer comprises hydroxypropyl methylcellulose, titanium dioxide, macrogol polyethylene glycol, yellow ferric oxide, and red ferric oxide.

[0075] In some embodiments, the coating layer comprises hydroxypropyl methylcellulose, copovidone, titanium dioxide, polyethylene glycol, yellow ferric oxide, indigo carmine aluminum lake, and caprylic / capric triglyceride.

[0076] The present disclosure also relates to a method of treating a disease or condition mediated by BTK, comprising administering to a 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.

[0077] The present disclosure also relates to the use of 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 for treating a disease involving mediation of the BTK receptor.

[0078] Diluents are compounds used to dilute the compound of interest before delivery. Diluents can also be used to stabilize the compound, as they can provide a more stable environment (which can also provide pH control or maintenance). Salts dissolved in buffer solutions are used as diluents in the art, including but not limited to phosphate buffered saline. In some embodiments, diluents increase the bulk of the composition to facilitate compression or create sufficient bulk for a homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, calcium diphosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectioners' sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates; hydrolyzed grain solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0079] In some embodiments, the tablet comprises at least one diluent selected from mannitol, lactose monohydrate, anhydrous lactose, microcrystalline cellulose, starch, sorbitol, dextrose, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, pregelatinized starch, compressible sugar, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed grain solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, and bentonite.

[0080] Binders impart cohesiveness and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinyl-pyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatin; sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as acacia, tragacanth, gum ghatti mucilage from isapol husk, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegun®, polyethylene glycol, polyethylene oxide, waxes, and sodium alginate.

[0081] Those skilled in the art will understand that the selection of excipients may depend on the process used to manufacture tablets before compression, whether it involves blending, dry granulation, or wet granulation. For example, dry granulation may involve compression to form dry granules, followed by the addition of excipients. Wet granulation may involve forming a weighted phase and a granulation phase, with specific excipients added to a specific phase, followed by mixing of the phases and drying to obtain granules. If wet granulation is selected, specific excipients may be selected to facilitate this process, including the use of binders. Of course, modifications of this, such as the addition of materials later, may be made, as will be understood by those skilled in the art.

[0082] In some embodiments, the at least one binder is selected from the group consisting of alginic acid, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, gelatin, polyvinyl-pyrrolidone / vinyl acetate copolymer; crospovidone, povidone, starch The sugars and / or sugar-soluble cellulose are selected from the group consisting of cellulose, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose; acacia, tragacanth, ghatti gum mucilage of isapol husk, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegun®, polyethylene glycol, polyethylene oxide, and sodium alginate.

[0083] Disintegrants contribute to both the dissolution and dispersion of the dosage form when in contact with gastrointestinal fluids. Disintegrants (or disintegrants) promote the disintegration of tablets and granules, thereby influencing the release of the active pharmaceutical ingredient. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methylcrystalline celluloses such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked celluloses such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, and the like. crosslinked cellulose such as cellulose or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crosslinked polyvinyl N-pyrrolidone (crospovidone), crosslinked polyvinylpyrrolidone, alginates, for example alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate complex starch, and the like.

[0084] In some embodiments, the at least one disintegrant is chosen from sodium starch glycolate, croscarmellose sodium, corn starch, potato starch, pregelatinized starch, methyl crystalline cellulose, methylcellulose, croscarmellose, cross-linked sodium carboxymethyl-cellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, crospovidone, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, magnesium aluminum silicate, agar, guar, locust bean, karaya, pectin, tragacanth, bentonite, citrus pulp, and sodium lauryl sulfate.

[0085] 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 cellulose, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil, higher fatty acids and their alkali metal salts 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 Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica such as Syloid® or Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, etc.

[0086] In some embodiments, the at least one lubricant is chosen from magnesium stearate, stearic acid, calcium hydroxide, talc, sodium stearyl lumellinate, mineral oil, hydrogenated soybean oil, aluminum, calcium, magnesium, zinc, 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.

[0087] In some embodiments, the tablet comprises at least one flow agent, hi some embodiments, the flow agent is silica or talc.

[0088] In some embodiments, the tablet may contain one or more pH adjusters and / or buffers, such as 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-hydroxymethylaminomethane; and buffers such as citrate, sodium bicarbonate, and ammonium chloride. Such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0089] In some embodiments, the tablet may also include at least one antifoaming agent to reduce foaming during processing, which can result in coagulation of the aqueous dispersion, air bubbles in the finished film, or generally impair processing. Exemplary antifoaming agents include silicone emulsion or sorbitan sesquioleate.

[0090] In some embodiments, the tablet may also contain at least one salt in an amount necessary to bring the osmolality of the composition into 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.

[0091] In some embodiments, the tablet may also contain at least one antioxidant, such as a non-thiol antioxidant, 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 as needed. Other agents, such as citric acid or citrate salts or EDTA, may also be added to retard oxidation.

[0092] In some embodiments, the tablet may also contain at least one preservative to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0093] In some embodiments, the tablet may also contain at least one dispersant and / or viscosity modifier. Dispersants or viscosity modifiers include materials that control the diffusion and uniformity of the drug through the liquid medium and / or granulation or blending process. In some embodiments, these agents also promote the effectiveness of the coating or eroding matrix. Exemplary diffusion facilitators / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymers of ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F10®8, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Chemicals, Inc.). Examples of suitable dispersing agents include polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polysorbate-80, gums such as tragacanth gum and gum arabic, guar gum, xanthan gum, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, and carbomer. Particularly useful dispersing agents for liposomal and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl myristate. Generally, binder levels of about 10% to about 70% are used in powder-filled gelatin capsule formulations.Binder usage levels in tablet formulations vary with either direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that can themselves act as moderate binders. While one skilled in the art can determine binder levels for a formulation, binder usage levels of up to 90%, more typically up to 70%, are common in tablet formulations.

[0094] In some embodiments, the tablet may also contain at least one erosion enhancer. Erosion enhancers include materials that control the erosion of a particular material in gastrointestinal fluids. Erosion enhancers are generally known to those skilled in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0095] In some embodiments, the tablet may also include at least one filler, which may include, for example, compounds such as dextrates, dextran, sucrose, xylitol, lactitol, and the like.

[0096] In some embodiments, the tablet also contains at least one flavoring and / or sweetening agent, such as acacia 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, cool cherry, cool citrus, cyclamate, cyclamate, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizinate, glycyrrhizic acid (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin. The flavoring ingredients may include menthol 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, talc, xylitol, sucralose, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, sweet cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, 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.

[0097] In some embodiments, the tablet may also contain at least one solubilizing agent, including compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, hydroxypropyl cyclodextrin, e.g., Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, glycofurol, transcutol, and dimethyl isosorbide. In one embodiment, the solubilizing agent is vitamin E TPGS and / or Captisol® or β-hydroxypropyl cyclodextrin.

[0098] In some embodiments, the tablet may also include at least one suspending agent, such as vinylpyrrolidone / vinyl acetate copolymer (S630), polysorbate-80, hydroxyethylcellulose, gums such as tragacanth and gum arabic, guar gum, xanthan, including xanthan gum, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, and other compounds.

[0099] In some embodiments, the tablet may also contain at least one surfactant, including compounds such as docusate sodium, Tween 20, 60, or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., Octoxynol 10, Octoxynol 40. In some embodiments, a surfactant may be included to enhance physical stability or for other purposes.

[0100] In some embodiments, the tablet may also include at least one wetting agent, such as compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and the like.

[0101] The pharmaceutical preparations 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 desired, adding suitable excipients, followed by processing the granulated mixture to obtain tablets.

[0102] The pharmaceutical preparations disclosed herein also include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules may also be made of polymers such as hypromellose (i.e., hydroxypropylmethylcellulose). Capsules may contain the active ingredient, optionally mixed with a binder such as lactose or starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, lipids, solubilizers, or liquid polyethylene glycol. Additionally, stabilizers may be added. All preparations intended for oral administration should be in a form suitable for such administration.

[0103] These formulations can be manufactured by conventional pharmaceutical techniques, including, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, (6) fusion, or (7) extrusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy, 3 rd ed. (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tabletting, extrusion, extrusion / spheronization, and the like.

[0104] It should be recognized that there is considerable overlap between the excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be construed as merely exemplary and not limiting of the types of excipients that can be included in the solid dosage forms described herein. The types and amounts of such excipients can be easily determined by those skilled in the art according to the specific properties desired.

[0105] In addition to plasticizers, colorants, surfactants, anti-adherents, anti-foaming agents, lubricants (e.g., carnauba wax or PEG), and other additives may be added to the coating to solubilize or disperse the coating materials and improve coating performance and the coated product.

[0106] In some embodiments, the tablets are packaged in a blister pack. The blister pack can be made of any suitable material. Examples include polyvinyl-polychlorotrifluoroethylene in the forming film and hardened aluminum foil as the lid.

[0107] IV. Liquid Formulations A liquid suspension can be prepared by adding the tablet to water, crushing the tablet and dispersing it in the water.

[0108] In some embodiments, a syringe containing a liquid suspension of crushed tablets can be provided, which can be used to connect to and empty into a gastric tube.

[0109] V. Treatment method Provided herein are methods for treating a disease or condition mediated by BTK, comprising administering to a subject in need thereof a therapeutically effective amount of a BTK inhibitor compound comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is 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, prior to treatment, one or more symptoms of: (i) multiple sclerosis (MS) (including relapsing forms of MS, non-relapsing secondary progressive multiple sclerosis (NRSPMS), primary progressive multiple sclerosis (PPMS)); (ii) myasthenia gravis (MG); or (iii) myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and the treatment reduces or eliminates one or more symptoms. In some embodiments, the subject is suffering from inflammation, pain, loss of motor function, and muscle weakness caused by MS, MG, or MOGAD.

[0110] In some embodiments, subjects with MS have at least one documented relapse within the past year and / or at least two documented relapses within the past two years, and / or have at least one active Gd-enhancing brain lesion in the past year and on an MRI scan prior to screening.

[0111] 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.

[0112] In some embodiments, the dose is administered daily. The daily dose can be administered as a single dose or in multiple doses. 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 subdivided into two portions that are administered twice a day (e.g., about every 12 hours). In some embodiments, the dose is subdivided into three portions that are administered three times a day (e.g., about every 8 hours). In some embodiments, the dose is subdivided into four portions that are administered four times a day (e.g., about every 6 hours).

[0113] 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, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0114] In some embodiments, the subject is administered a BTK inhibitor compound for a period of about 4, 8, 12, 16, 20, 24, or 26 weeks. In some embodiments, the subject is administered a BTK inhibitor compound for a period of about 6, 12, 18, 24, 30, 36, 42, or 48 months. In some embodiments, the dose is once daily.

[0115] In some embodiments, the BTK inhibitor compound is administered as monotherapy. In some embodiments, the method comprises administering a BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent may be administered simultaneously or sequentially with the BTK inhibitor compound.

[0116] The determination of the frequency of administration can be made by one of ordinary skill in the art, such as an attending physician, taking into consideration the condition being treated, the age of the subject being treated, the severity of the condition being treated, the general health 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. The therapeutically effective amount typically depends on the weight of the subject being treated, their physical or health condition, the extent of the condition being treated, or the age of the subject being treated, the pharmaceutical formulation method, and / or the method of administration (e.g., the time and route of administration).

[0117] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It is therefore to be understood that the foregoing description is intended to be illustrative and not limiting. The scope of the present disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. [Example]

[0118] 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 defined above may be referred to interchangeably as "Compound 1," "Compound," "trebrutinib," or "drug."

[0119] Example 1: Preparation of tablets containing Compound 1 The development of the tablet formulation described in this example involved experiments to determine: the concentration of the active ingredient to be used, Whether used as a dry mix or aqueous binder solution, hydroxypropyl methylcellulose (HPMC) the ratio of lactose to microcrystalline cellulose to be used, and · The effect of adding other test flow agents such as silica or talc.

[0120] This process further involved adjusting: Wetting time by adjusting the flow rate of the mooring liquid Amount of mooring water Granulation time

[0121] The Zentite hand calibration of the dried granules was directly compared to the two steps of the Phase IIb formulation: sieving of the dried granules, followed by calibration of the removed granules. The excipients used in this study are listed in Table 1.

[0122] [Table 1] aOpadry® orange QX 321A230043 is composed of 40.0% macrogol polyvinyl alcohol graft copolymer (Ph.Eur.-NF), 27.5% talc (Ph.Eur.-USP), 20.2% titanium dioxide (E171) (Ph.Eur.-USP), 4% monocaprylocaprinate glycerol type 1 (Ph.Eur.-NF) / mono / diglycerides (Food Chemical Codex) / glycerol of fatty acids, 3.8% yellow ferric oxide (E172) (NF), 3.5% partially hydrolyzed polyvinyl alcohol (Ph.Eur.-USP), and 1.0% red ferric oxide (E172) (NF).

[0123] Wetting and Granulation Studies To compare wetting and granulation curves by limiting active ingredient consumption and to allow for rapid and efficient implementation, two wetting and granulation methods, the multiple addition method and the variable mixing time method, were tested on a small scale, as described below. The two methods were tested using a placebo mixture or a mixture containing Compound 1. The excipients used in this study are listed in Table 1.

[0124] The percentage compositions of the placebo and Compound 1 formulations used in this study are listed in Tables 2 and 3, respectively.

[0125] [Table 2]

[0126] [Table 3]

[0127] Wetting and granulation tests were carried out at approximately 25 g scales using a Caleva-type granulator. The placebo mixture was at a 1000 g scale, and the Compound 1 mixture was at a 75 g or 250 g scale. These mixtures were then subjected to granulation tests at 25 g and divided to assess reproducibility with the same initial batch.

[0128] The internal phase mixture was prepared as follows.

[0129] Step 1: All ingredients were weighed according to the compositions in Tables 2 and 3.

[0130] Step 2: An 8% solution of hypromellose in demineralized water was prepared the day before with vigorous stirring and the solution was diluted to the desired concentration of hypromellose. This step was not performed if hypromellose was added to the dry mix.

[0131] Step 3 for the placebo mixture: The first half of the lactose monohydrate was sieved together with the microcrystalline cellulose and crospovidone form A. The sieve was then rinsed with the second half of the lactose monohydrate which had been passed through a sieve with 0.6 mm mesh openings.

[0132] Step 3 for Compound 1 mixture: Compound 1 was sieved with the first half of the lactose monohydrate, followed by microcrystalline cellulose, hypromellose 6 mPa.s, and crospovidone type A. The sieve was then rinsed with the second half of the lactose monohydrate, which had been passed through a sieve with 0.6 mm mesh openings.

[0133] Step 4 for Placebo Mix: The sieved excipients from step 3 were mixed in a CMA gyratory mixer equipped with a 5 L tank for 10 minutes at 7 rpm.

[0134] Step 4 for Compound 1 mixture: The sieved excipients from step 3 were mixed in a Turbula® mixer at 32 rpm for 10 minutes.

[0135] Two wetting and granulation methods, a multiple addition method and a variable mix time method were tested, as described below.

[0136] Multiple addition method: A Caleva tank was filled with the desired amount of powder (V = 0.412 mass powder = 24.7 g) to prepare a 4.42% HPMC solution in demineralized water. The method used the following parameters: - Rotor speed = 50 rpm - Mixing time = 30 seconds - Log time = 30 seconds - Number of runs = 33 - Test duration: 35 minutes - 1 mL of HPMC solution was added every 60 seconds

[0137] Amount of compound added = 31 mL

[0138] Variable Mixing Time Method: A Caleva tank was filled with the desired amount of powder (V = 0.412 mass powder = 24.7 g) and wetted with HPMC solutions in demineralized water prepared at different concentrations. The method used the following parameters: - Rotor speed = 50 rpm - Mixing time = 40 seconds - Log time = 20 seconds - Number of runs = 12 - Mixing time = 10 minutes - HPMC bed: 8%, 5.51%, 4.42%, 3.63%, 2.91%, the volume was adjusted to have 2% HPMC in the final formulation.

[0139] Granule drying was carried out in a tray dryer at about 50°C on batches of about 25g.

[0140] Testing was performed on Compound 1 mixtures 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 HPMC introduction (in wet liquid A or in dry mixture B), as described in Table 4A. Table 4B describes the placebo batch. The active pharmaceutical ingredient (AOI) batch elongation measurement method is described in Table 4C.

[0141] [Table 4]

[0142] [Table 5]

[0143] The analysis of the results was carried out according to the reference wetting and granulation curves shown in Figures 1 and 2. The different states of granulation (pendulum, funicular, capillary and drop) were obtained by plotting the curves of blade power (torque, Nm) as a function of time or amount of water added against the weight of the mixture.

[0144] A 250 g or 75 g internal phase mixture was prepared for each active ingredient and testing was performed at the 25 g scale to assess reproducibility (n=3). The concentration of the HPMC wetting solution was calculated to give (approximately) 2% HPMC in the final formulation.

[0145] FIG. 3 shows that the mixture of Batch 1 and Batch 2 of Formulation A performed similarly to the placebo with HPMC in aqueous solution.

[0146] Figure 4 shows that the placebo and Formulation A Batch 3 mixtures behaved similarly in the granulation process.

[0147] Figure 5 shows that the behavior of the three batch mixtures of Formulation A shown in Table 4A is comparable for a granulation process where HPMC is present in the wetting liquid and the observed granulation plateau is at a ratio of 0.7 g / mL. For this process, variation in the particle size of the active ingredient (API) in the 10-120 μm range appears to have no effect. Because the active pharmaceutical ingredient (API) has a low density, the granulation process is explored with the goal of compacting the mixture for compression. As shown in Table 4C, the batches of active ingredient used exhibited poor redistribution, poor cohesion, and little tendency to bind (discharge pressure). The active ingredient from the batches used was rather plastic and had little elasticity.

[0148] [Table 6]

[0149] Relative batch wettability, drop angle: 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°

[0150] Figure 6 shows that the granulation plateau observed for the Formula B Batch 2 mixture in Table 4A is at a rate of 0.6 mL / g added water ratio. This offsets slightly from the results shown in Figures 3 and 4. This difference is due to the 15% Compound 1 in Formula B compared to the Formula A batch containing 10% Compound 1. The batch of active ingredient, API Batch 2, also differs, and these properties may affect wetting and granulation behavior.

[0151] A water percentage of approximately 45% for anchorage was selected after analyzing the curves in Figure 7. Formulation B Batch 2 contained a lactose / cellulose ratio equal to 40 / 60, wetting was performed with water, and HPMC was in the dry internal phase mixture.

[0152] Figure 8 compares Formula B Batch 1 and Formula B Batch 2, which had the same formulation with a 40 / 60 lactose / cellulose ratio, but in which HPMC was introduced in the wetting solution in Formula B Batch 1 and in the dry mix in Formula B Batch 2. Because the slopes of the curves are the same, adding HPMC directly to the powder mix was chosen for process simplicity and industrial implementation purposes.

[0153] Figures 9A, 9B, and 9C compare the curves for Formulation B Batch 2 (lactose / cellulose ratio 40 / 60) and Formulation C Batch 2 (lactose / cellulose ratio 60 / 40). These figures show that the wetting and granulation curves are not similar for formulations with different lactose / cellulose ratios. The ideal amount is approximately 35% for the 60 / 40 lactose / cellulose ratio, while it is approximately 45% for the 40 / 60 ratio. Based on these results, a 60 / 40 lactose / cellulose ratio was selected to provide more cohesiveness and compressibility to the mixture. Another advantage of this ratio is that less water is required, resulting in shorter drying times. The differences in behavior were evaluated during the compression process.

[0154] Batch reproducibility was assessed by testing Formulation C Batch 1 and Batch 2 using the same process and 35% water, and the results are shown in Figure 10.

[0155] For Formulation B Batch 2 and Formulation C Batch 1, final blends were produced and compression tests were carried out on a Stylcam using a simulated Korsch XL100, speed 20 rpm, forced feed and stamped "6" punches of size 7 x 3.8 mm. The core tablet properties are shown in Tables 5 and 6.

[0156] [Table 7]

[0157] [Table 8]

[0158] The compression profile shows a decrease in hardness at a force of 8-9 kN for the Formula B Batch 2 mixture (40 / 60 ratio) compared to the Formula C Batch 1 mixture.

[0159] Based on the granule and final blend properties and compression results of the formulations described in this example, the following choices were used in the preparation of the formulations: a 60 / 40 lactose / cellulose ratio and use of 35% water during the wetting step of the Compound 1 internal phase mixture containing HPMC in the dry mix.

[0160] Example 2: Process for preparing film-coated tablets containing Compound 1. Five tablet formulations were developed, as shown in Table 7.

[0161] [Table 9]

[0162] To compare the properties of the blends and tablets, several batches with qualitatively and quantitatively different formulations were manufactured at a 300 g scale in a 1 L granulation tank: Formulation E Batch 1, Formulation C Batch 3, Formulation D Batch 1, and Formulation E Batch 2. The excipients used in this study are listed in Table 1.

[0163] Step 1: Weigh out all ingredients according to the tablet formulation in Table 1.

[0164] Step 2: Compound 1 was sieved with the first half of the lactose monohydrate, then with microcrystalline cellulose, hypromellose 6 mPa.s, and crospovidone type A, and then the second half of the lactose monohydrate was sieved through a sieve with 0.6 mm openings.

[0165] Step 3: The sieved ingredients were charged into the granulator tank at high shear rate and mixed for 5 minutes at 250 r / min for the blade at the bottom of the tank and 0 r / min for the chopper.

[0166] Step 4: The ingredients were wetted by mixing with about 35% (w / w) water at a flow rate of about 80 mL / min to about 100 mL / min (high flow) at 250 r / min for the blade at the bottom of the tank and 0 r / min for the chopper, and granulated for about 2 minutes at a speed of 1500 r / min for the chopper.

[0167] Step 5: The resulting granules are dried in a fluidized air bed at an inlet temperature of 60°C and an air flow of about 40 m3 / hr until the moisture content approaches the pre-granulation amount, for example, in the range of about 23 minutes to about 35 minutes, to obtain a loss on drying (LOD) corresponding to the initial dry mix in the range of about 1.48% to about 1.94%, or about 1.5% to about 1.9%.

[0168] Step 6: The resulting granules were calibrated on a 0.991 mm open grid using a minimum rotor speed of 750 rpm.

[0169] Step 7: The external phase excipients (microcrystalline cellulose 90 μm and crospovidone) were sieved over a sieve with 0.6 mm openings.

[0170] Step 8: The external phase excipients were added to the granules calibrated in step 6 and mixed in a blender at 10 r / min for 20 minutes.

[0171] Step 9: The magnesium stearate was sieved on a sieve with 0.6 mm openings.

[0172] Step 10: The sieved magnesium stearate was added to the calibrated granules and mixed at 6 r / min for 10 minutes to obtain a uniform mixture.

[0173] Step 11: The lubricated granulation was compressed in a Korsch XL 100 press equipped with four punches, 3.8 x 7 mm for 10 mg dosage strength tablets and 12.65 x 5.75 mm for 60 mg dosage strength tablets, using a feeder speed of 10 rpm and a turret speed of 20 rpm.

[0174] Step 12: A 30% Opadry QX film coating suspension was prepared.

[0175] Step 13: For Formulation E Batches 1 and 2, 10 mg and 60 mg dosage strength tablets were film coated to achieve a 3% mass gain using the following parameters: 1.2 mm nozzle, 60° C. inlet temperature, 50 m 3 / h air flow, drum speed 2 rpm when preheated at a rate adjusted according to the tablet bed, suspension flow rate of about <5 g / min, atomization pressure of 1.3 bar, and angular pressure of 1.3 bar.

[0176] Table 8 shows the manufacturing parameters used during batch manufacturing.

[0177] [Table 10]

[0178] [Table 11]

[0179] [Table 12]

[0180] Testing and Evaluation Procedures The following tests were performed on the final mixture prepared in step 10: Residual moisture by loss on drying (Ph.Eur.2.2.32) was carried out on 1 g of the mixture at 95°C for 20 minutes using a thermobalance. - Mixture homogeneity was performed on three samples: high, medium and low. - The bulk density (m / V in g / mL) (Ph.Eur.2.9.34) was determined from the volume of 100 g of powder obtained in 250 mL incremental specimens before settling and after 10, 500 and 1250 settlings. The compressibility (or Carr index) (%) is calculated according to the following formula: 100 × [(V0 - Vf ) / V0] (V0 is the apparent unfilled volume and V f (V is the final volume the powder is allowed to settle until a constant volume is obtained). The Hausner index is calculated according to the following formula: V / V f A generally accepted scale of liquidity is presented in Table 9 in accordance with Ph.Eur.2.9.36. - Flow (Ph.Eur.2.9.16) was performed on 100 g of powder. - The flow index (Ph.Eur.2.9.36) through an orifice (mm) was determined on a Flodex apparatus from the smallest orifice diameter through which a sample of 50 g of powder could flow over three successive tests. - Particle size distribution by sieving (Ph.Eur.2.9.38) was carried out on 25 g of powder using sieves with opening sizes of 850, 425, 250, 180, 150, 106.75 and <75 μm.

[0181] The results are expressed as the percentage (w / w) of powder not retained on the sieve.

[0182] [Table 13]

[0183] The following tests were performed on the core tablets prepared in step 11: - Average mass was measured on 10 tablets being compressed - Mass uniformity (Ph.Eur.2.9.5) was performed on 20 tablets during compression. - Hardness (Ph.Eur.2.9.8) was performed on 10 compressed tablets along their length during compression. - Thickness was measured on 10 tablets during the compression process - Friability tests (Ph.Eur.2.9.7) were carried out on tablets of 6.5 g or more after 4 and 30 minutes at 25 r / min at the beginning, middle and end of compression. - Deflocculation (Ph.Eur.2.9.1) was carried out on 10 tablets at the beginning, middle and end of compression. - Dissolution testing was carried out on 6 tablets according to the method described in this example.

[0184] The following tests were performed on the film-coated tablets prepared in step 13: - Average mass was measured on 10 tablets being compressed - Mass uniformity (Ph.Eur.2.9.5) was performed on 20 tablets during compression. - Hardness (Ph.Eur.2.9.8) was performed on 10 tablets in the length direction during compression. - Thickness was measured on 10 compressed tablets - Friability tests (Ph.Eur.2.9.7) were carried out on tablets of 6.5 g or more after 4 and 30 minutes at 25 r / min at the beginning, middle and end of compression. - Deflocculation (Ph.Eur.2.9.1) was carried out on 10 tablets at the beginning, middle and end of compression. - Dissolution testing was carried out on 6 tablets according to the method described in this example.

[0185] The following evaluation criteria were applied: Process monitoring according to defined parameters Granulation state: Funicular / Capillary Calibrated granule properties: density, particle size Final mixture properties: flow, density, particle size Carr index and Hausner ratio analysis Good compressibility of the final mixture In the film coating stage, from an aesthetic point of view, the control is as follows: uniform color, smooth surface, clear imprint · Core tablet and film-coated tablet characteristics: uniformity of mass, thickness, hardness, friability and disintegration time.

[0186] Analytical results for film-coated tablets containing Compound 1: content uniformity and dissolution profile according to immediate release profile.

[0187] Elution method The operating conditions for the elution method are as follows:

[0188] Dissolution: 6 tablets in Stage I + 6 tablets in Stage II

[0189] USP <711> and dissolution analysis according to Ph.Eur.2.9.3 a. Equipment: i. Type 2 pallet device ii. Visible UV spectrophotometer b. Elution conditions: Rotation speed: 75 rpm for 30 minutes, then 150 rpm for 30 minutes (complete) to 45 minutes Test solution: pH 3.5 solution of citric acid and trisodium citrate Volume: 900mL ·Bath temperature: 37℃ Sampling: Every 5 minutes up to 45 minutes Wavelogger: 300nm Number of units tested: minimum 6 units ("Stage I") to 24 units ("Stage III"), as needed

[0190] result

[0191] [Table 14]

[0192] Based on Formulation C with a loading of 15% Compound 1 and an optimized ratio of 60 / 40 lactose / cellulose, studies were conducted to determine the effect of varying 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 to improve flowability, but colloidal silica was not studied.

[0193] The applied processes are simplified and optimized in a preliminary way: The flow rate of the wet suspension (water) is high, about 100 ml / min. The percentage of water is 35% The chopper speed is as high as 1500 rpm Complete direct calibration of dry granules using a calibrator with a 0.991 grid

[0194] In these batches, the final granules and blends were either partially characterized or not properly recorded or characterized. In some batches, poor sampling was performed so the data was not interpretable and is not listed.

[0195] For comparison, only the characterization of 10 mg and 60 mg tablets produced at 7 kN or 12 kN forces is presented in this example.

[0196] The granulation process was carried out using 35% water according to the process of Example 2 and the process parameters set out in Table 8.

[0197] As shown in Figure 11, the wetting curves of Formulation E Batch 1, Formulation C Batch 3, and Formulation D Batch 1 are superimposed. The curves are slightly different for Formulation E Batch 2. The output is lower after 2 minutes of granulation, and the granulation cost is lower, which may be preferable to master this step during scale-up. The analyzed differences are related to the batch of active ingredient. The influence of the physical quality of the active ingredient was examined in the process optimization study.

[0198] Drying times vary between 23 and 35 minutes to obtain LODs corresponding to initial dry mixes between 1.48% and 1.94%, as shown in Table 11. Drying conditions are similar considering temperature and humidity data.

[0199] A description of the properties of the final mixtures is provided in Table 12 and Figures 12A, 12B, and 12C.

[0200] [Table 15]

[0201] [Table 16]

[0202] Table 13 shows that the batches characterized have similar values ​​for D10, D50, and D90.

[0203] [Table 17] Extensometry profiles were performed on the final blends of the following batches: Formulation E Batch 1, Formulation C Batch 3, Formulation D Batch 1, and Formulation E Batch 2. The results are shown in Figure 13 and Table 14.

[0204] Composite analysis of the extensometry profiles at 150 MPa shows that the batch has the following properties: - Correct density (approximately 0.47 g / cm3) / good redistribution (<25%) allows easy flow of the three formulations. - Rather, it is a plastic compound at fracture (DR>0.6). - acceptable elasticity since it is below the limit of 2.4 J / g, - Good powder cohesion for Formulation E Batch 1 / Formulation C Batch 3 (Prd of 2.44 and 2.46 MPa > 2 MPa) and somewhat poor powder cohesion for Formulation D Batch 1 (Prd of 1.71 MPa, 2 MPa) - Good drainage due to <2Mpa: no significant risk of bonding is expected

[0205] In summary, based on the extensometry properties at 150 MPa, the two formulations Formulation E Batch 1 and Formulation C Batch 3 are similar, while Formulation D Batch 1, which contains talc, is somewhat inferior due to a significant loss of cohesion.

[0206] [Table 18]

[0207] [Table 19]

[0208] [Table 20]

[0209] The 10 mg and 60 mg tablets have the desired properties. At the end of the study, based on the results of the granulation process, blending, and compression product, a 60 / 40 lactose / cellulose ratio and 0.5% magnesium stearate were selected for scale-up and processability considerations. This formulation corresponds to Formulation E batches 1 and 2.

[0210] Tables 17A-17C show the compositions of tablets prepared using this method.

[0211] [Table 21]

[0212] [Table 22]

[0213] [Table 23]

[0214] [Table 24]

[0215] [Table 25]

[0216] Example 3: Small scale film coating study of 10 mg and 60 mg doses Film coating was carried out according to the procedure of Example 2 and using the process parameters listed in Table 18 for Formulation E Batch 2.

[0217] [Table 26]

[0218] [Table 27]

[0219] Both batches of film-coated tablets have suitable galenic properties and good quality film coating, given the uniformity of color, smooth appearance and absence of defects. There was an increase in hardness and disintegration time for both the 10 mg and 60 mg doses between the compression and film-coating steps.

[0220] The TO film-coated tablets of these batches were characterized and then investigated daily for three days: the tablets were stored in open vials in a compression chamber at ambient temperature and humidity. A decrease in hardness and disintegration time values ​​appeared to be observed over time until a plateau was reached for both doses.

[0221] Figures 14 and 15 show the hardness curves and disaggregation times for 10 mg and 60 mg dosage strength tablets of Formulation E Batch 2.

[0222] Example 4: Dissolution of 10 mg and 60 mg Dosage Strength Tablets Containing Compound 1 As shown in Figure 16, the dissolution profile of the 60 mg dosage strength tablets is comparable to tablets of Formula E Batch 1, Formula C Batch 3, Formula D Batch 1, and Formula E Batch 2. The addition of talc and the amount of magnesium stearate did not affect dissolution, reaching 80% release after 20 minutes.

[0223] The dissolution of 10 mg and 60 mg dosage strength tablets of Formulation E Batch 1 is shown in Figures 17 and 18.

[0224] Comparison of the profiles of core tablets versus film-coated tablets shows similarity to the profile for the orange Opadry® QX film-coated tablet, regardless of whether the tablet is 10 mg or 60 mg dose.

[0225] The present disclosure includes, for example, any one or combination of the following embodiments:

[0226] 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 pharmaceutically acceptable salts thereof; at least one diluent; at least one binder; at least one disintegrant; and at least one lubricant.

[0227] Embodiment 2: The tablet of embodiment 1, further comprising at least one flow agent.

[0228] Embodiment 3: The tablet of any one of the preceding embodiments, wherein the tablet comprises an intragranular core and an extragranular portion.

[0229] Embodiment 4: The tablet of embodiment 3, wherein at least one diluent is selected from lactose monohydrate and microcrystalline cellulose.

[0230] Embodiment 5: The tablet of embodiment 4, wherein the at least one diluent is present in a total amount ranging from about 70% to about 90% by weight.

[0231] Embodiment 6: The tablet of embodiment 5, wherein the at least one diluent is present in the intragranular core in a total amount ranging from about 50% to about 70% by weight.

[0232] Embodiment 7: The tablet of embodiment 5 or 6, wherein the at least one diluent is present in the extragranular portion in a total amount ranging from about 10% to about 30% by weight.

[0233] Embodiment 8: The tablet of any one of the preceding embodiments, wherein at least one binder is hydroxypropyl methylcellulose (hypromellose).

[0234] Embodiment 9: The tablet of embodiment 8, wherein the at least one binder is present in a total amount ranging from about 0.1% to about 5% by weight.

[0235] Embodiment 10: The tablet of embodiment 3, wherein the at least one disintegrant is cross-linked polyvinyl N-pyrrolidone (crospovidone).Embodiment 11: The tablet of embodiment 10, wherein the at least one disintegrant is present in a total amount ranging from about 0.1% to about 5% by weight.

[0236] Embodiment 12: The tablet of embodiment 11, wherein the at least one disintegrant is present in the intragranular core in a total amount ranging from about 0.5% to about 3% by weight.

[0237] Embodiment 13: The tablet of embodiment 11 or 12, wherein the at least one disintegrant is present in the extragranular portion in a total amount ranging from about 0.5% to about 3% by weight.

[0238] Embodiment 14: The tablet of any one of the preceding embodiments, wherein at least one lubricant is magnesium stearate.

[0239] Embodiment 15: The tablet of embodiment 14, wherein the at least one lubricant is present in a total amount ranging from about 0.1% to about 5% by weight.

[0240] Embodiment 16: The tablet of embodiment 2, wherein at least one flow agent is talc.

[0241] Embodiment 17: The tablet of embodiment 16, wherein the at least one flow agent is present in a total amount ranging from about 1% to about 5% by weight.

[0242] Embodiment 18: A tablet according to embodiment 3, wherein the intragranular core comprises at least one diluent, at least one binder, and at least one disintegrant.

[0243] Embodiment 19: The tablet of embodiment 3 or 18, wherein the extragranular portion comprises at least one diluent, at least one disintegrant, and at least one lubricant.

[0244] Embodiment 20: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in at least 50% crystalline form, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% crystalline.

[0245] Embodiment 21: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount ranging from about 0.9 mg to about 125 mg.

[0246] Embodiment 22: The tablet of any one of the preceding 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.

[0247] Embodiment 23: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount of about 10 mg.

[0248] Embodiment 24: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount of about 60 mg.

[0249] Embodiment 25: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount of about 120 mg.

[0250] Embodiment 26: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

[0251] Embodiment 27: A tablet according to any one of the preceding embodiments, further comprising at least one coating layer.

[0252] Embodiment 28: The tablet of embodiment 27, wherein the coating layer comprises a macrogol polyvinyl alcohol graft copolymer, optionally further comprising talc with titanium dioxide.

[0253] Embodiment 29: The tablet of embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose.

[0254] Embodiment 30: The tablet of embodiment 29, wherein the coating layer further comprises at least one of titanium dioxide and macrogol polyethylene glycol.

[0255] Embodiment 31: The tablet of embodiment 29, wherein the coating layer further comprises at least one of copovidone and titanium dioxide.

[0256] Embodiment 32: The tablet of embodiment 1, wherein the tablet comprises about 15% to about 45% by weight lactose monohydrate, about 35% to about 60% by weight microcrystalline cellulose, about 1% to about 5% by weight hydroxypropyl methylcellulose, about 1% to about 5% by weight crospovidone, and about 0.1% to about 3% by weight magnesium stearate.

[0257] Embodiment 33: The tablet of embodiment 32, wherein the tablet comprises an intragranular core and an extragranular portion.

[0258] Embodiment 34: The tablet of embodiment 33, wherein the intragranular core comprises about 20% to about 40% microcrystalline cellulose by weight.

[0259] Embodiment 35: The tablet of embodiment 33, wherein the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight.

[0260] Embodiment 36: The tablet of embodiment 33, wherein the intragranular core comprises about 0.5% to about 2.5% crospovidone by weight.

[0261] Embodiment 37: The tablet of embodiment 33, wherein the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight.

[0262] Embodiment 38: The tablet of any one of embodiments 32 to 37, wherein Compound 1 is present in an amount of about 5% to 25% by weight.

[0263] Embodiment 39: The tablet of embodiment 1, wherein the tablet comprises about 30% to about 40% by weight lactose monohydrate, about 40% to about 50% by weight microcrystalline cellulose, about 1% to about 3% by weight hydroxypropyl methylcellulose, about 2% to about 4% by weight crospovidone, and about 0.1% to about 1% by weight magnesium stearate.

[0264] Embodiment 40: The tablet of embodiment 39, wherein the tablet comprises an intragranular core and an extragranular portion.

[0265] Embodiment 41: The tablet of embodiment 40, wherein the intragranular core comprises about 20% to about 30% microcrystalline cellulose by weight.

[0266] Embodiment 42: The tablet of embodiment 40, wherein the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight.

[0267] Embodiment 43: The tablet of embodiment 40, wherein the intragranular core comprises about 0.5% to about 2.5% crospovidone by weight.

[0268] Embodiment 44: The tablet of embodiment 40, wherein the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight.

[0269] Embodiment 45: The tablet of any one of embodiments 39 to 44, wherein Compound 1 is present in an amount of about 10% to 20% by weight.

[0270] Embodiment 46: The tablet of embodiment 1, wherein the tablet comprises about 35.0% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.5% by weight magnesium stearate.

[0271] Embodiment 47: The tablet of embodiment 46, wherein the tablet comprises an intragranular core and an extragranular portion.

[0272] Embodiment 48: The tablet of embodiment 47, wherein the intragranular core comprises 23.5% microcrystalline cellulose by weight.

[0273] Embodiment 49: The tablet of embodiment 47, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

[0274] Embodiment 50: The tablet of embodiment 47, wherein the intragranular core comprises about 1.5% crospovidone by weight.

[0275] Embodiment 51: The tablet of embodiment 47, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

[0276] Embodiment 52: The tablet of any one of embodiments 46 to 51, wherein Compound 1 is present in an amount of about 15% by weight.

[0277] Embodiment 53: The tablet of embodiment 1, wherein the tablet comprises about 28.8% by weight lactose monohydrate, about 55.8% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0278] Embodiment 54: The tablet of embodiment 53, wherein the tablet comprises an intragranular core and an extragranular portion.

[0279] Embodiment 55: The tablet of embodiment 54, wherein the intragranular core comprises 34.8% microcrystalline cellulose by weight.

[0280] Embodiment 56: The tablet of embodiment 54, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

[0281] Embodiment 57: The tablet of embodiment 54, wherein the intragranular core comprises about 1.5% crospovidone by weight.

[0282] Embodiment 58: The tablet of embodiment 54, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

[0283] Embodiment 59: The tablet of any one of embodiments 53 to 58, wherein Compound 1 is present in an amount of about 10% by weight.

[0284] Embodiment 60: The tablet of embodiment 1, wherein the tablet comprises about 23.5% by weight lactose monohydrate, about 56.2% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0285] Embodiment 61: The tablet of embodiment 60, wherein the tablet comprises an intragranular core and an extragranular portion.

[0286] Embodiment 62: A tablet according to embodiment 61, wherein the intragranular core comprises 35.2% microcrystalline cellulose by weight.

[0287] Embodiment 63: The tablet of embodiment 61, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

[0288] Embodiment 64: The tablet of embodiment 61, wherein the intragranular core comprises about 1.5% crospovidone by weight.

[0289] Embodiment 65: The tablet of embodiment 61, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

[0290] Embodiment 66: The tablet of any one of embodiments 60 to 65, wherein Compound 1 is present in an amount of about 15% by weight.

[0291] Embodiment 67: The tablet of embodiment 1, wherein the tablet comprises about 35.2% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, and about 0.4% by weight magnesium stearate.

[0292] Embodiment 68: A tablet according to embodiment 67, wherein the tablet comprises an intragranular core and an extragranular portion.

[0293] Embodiment 69: A tablet according to embodiment 68, wherein the intragranular core comprises 23.5% microcrystalline cellulose by weight.

[0294] Embodiment 70: The tablet of embodiment 68, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

[0295] Embodiment 71: The tablet of embodiment 68, wherein the intragranular core comprises about 1.5% crospovidone by weight.

[0296] Embodiment 72: The tablet of embodiment 68, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

[0297] Embodiment 73: The tablet of any one of embodiments 67 to 72, wherein Compound 1 is present in an amount of about 15% by weight.

[0298] Embodiment 74: The tablet of embodiment 2, wherein the tablet comprises about 32.2% by weight lactose monohydrate, about 44.5% by weight microcrystalline cellulose, about 2.0% by weight hydroxypropyl methylcellulose, about 3.0% by weight crospovidone, about 0.4% by weight magnesium stearate, and about 3.0% by weight talc.

[0299] Embodiment 75: The tablet of embodiment 74, wherein the tablet comprises an intragranular core and an extragranular portion.

[0300] Embodiment 76: The tablet of embodiment 75, wherein the intragranular core comprises 23.5% microcrystalline cellulose by weight.

[0301] Embodiment 77: The tablet of embodiment 75, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

[0302] Embodiment 78: The tablet of embodiment 75, wherein the intragranular core comprises about 1.5% crospovidone by weight.

[0303] Embodiment 79: The tablet of embodiment 75, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

[0304] Embodiment 80: The tablet of any one of the preceding embodiments, wherein Compound 1 is present in an amount of about 15% by weight.

[0305] Embodiment 81: A tablet according to any one of embodiments 32 to 80, further comprising a film coating.

[0306] Embodiment 82: The tablet of embodiment 81, wherein the film coating is present in an amount of about 2% to about 5% based on the total weight of the tablet.

[0307] Embodiment 83: A tablet according to embodiment 82, wherein the film coating is present in an amount of about 3% based on the total weight of the tablet.

[0308] Embodiment 84: A tablet according to any one of embodiments 53 to 66, wherein the weight ratio of lactose to intragranular microcrystalline cellulose is about 40:60.

[0309] Embodiment 85: A tablet according to any one of embodiments 46 to 52 and 67 to 79, wherein the weight ratio of lactose to intragranular microcrystalline cellulose is about 60:40.

[0310] Embodiment 86: The tablet of embodiment 27, wherein the coating layer comprises macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, glycerol monocaprylocarate type 1 / mono / diglyceride / glycerol of fatty acids, yellow ferric oxide, partially hydrolyzed polyvinyl alcohol, and red ferric oxide.

[0311] Embodiment 87: The tablet of embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose, titanium dioxide, macrogol polyethylene glycol, yellow ferric oxide, and red ferric oxide.

[0312] Embodiment 88: The tablet of embodiment 27, wherein the coating layer comprises hydroxypropyl methylcellulose, copovidone, titanium dioxide, polyethylene glycol, yellow ferric oxide, indigo carmine aluminum lake, and caprylic / capric triglyceride.

[0313] Embodiment 89: A method of treating a disease or condition mediated by BTK in a patient in need thereof, comprising administering to the patient a tablet of any one of embodiments 1 to 88.

[0314] Embodiment 90: Use of a tablet according to any one of embodiments 1 to 88 for treating a disease involving BTK receptor mediation.

Claims

1. 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. 10. The tablet of claim 1, further comprising at least one flow agent.

3. 3. The tablet of claim 1 or 2, wherein the tablet comprises an intragranular core and an extragranular portion.

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

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

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

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

8. 8. The tablet of claim 1, wherein the at least one binder is hydroxypropyl methylcellulose (hypromellose).

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

10. 4. The tablet of claim 3, wherein the at least one disintegrant is cross-linked polyvinyl N-pyrrolidone (crospovidone).

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

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

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

14. 14. The tablet of any one of claims 1 to 13, wherein the at least one lubricant is magnesium stearate.

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

16. 3. The tablet of claim 2, wherein the at least one flow agent is talc.

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

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

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

20. 20. The tablet of any one of claims 1 to 19, wherein Compound 1 is present in at least 50% crystalline form, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% crystalline.

21. 21. The tablet of any one of claims 1 to 20, wherein Compound 1 is present in an amount ranging from about 0.9 mg to about 125 mg.

22. 22. The tablet of any one of claims 1 to 21, 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. 23. The tablet of any one of claims 1 to 22, wherein Compound 1 is present in an amount of about 10 mg.

24. 24. The tablet of any one of claims 1 to 23, wherein Compound 1 is present in an amount of about 60 mg.

25. 25. The tablet of any one of claims 1 to 24, wherein Compound 1 is present in an amount of about 120 mg.

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

27. 27. The tablet of any one of claims 1 to 26, further comprising at least one coating layer.

28. 28. The tablet of claim 27, wherein the coating layer comprises a macrogol polyvinyl alcohol graft copolymer further comprising talc optionally with titanium dioxide.

29. 28. The tablet of claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose.

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

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

32. The tablet 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; about 0.1% to about 3% by weight of magnesium stearate; The tablet of claim 1, comprising:

33. 33. The tablet of claim 32, wherein the tablet comprises an intragranular core and an extragranular portion.

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

35. 34. The tablet of claim 33, wherein the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight.

36. 34. The tablet of claim 33, wherein the intragranular core comprises from about 0.5% to about 2.5% crospovidone by weight.

37. 34. The tablet of claim 33, wherein the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight.

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

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

40. 40. The tablet of claim 39, wherein the tablet comprises an intragranular core and an extragranular portion.

41. 41. The tablet of claim 40, wherein the intragranular core comprises about 20% to about 30% microcrystalline cellulose by weight.

42. 41. The tablet of claim 40, wherein the extragranular portion comprises about 15% to about 25% microcrystalline cellulose by weight.

43. 41. The tablet of claim 40, wherein the intragranular core comprises about 0.5% to about 2.5% crospovidone by weight.

44. 41. The tablet of claim 40, wherein the extragranular portion comprises about 0.5% to about 2.5% crospovidone by weight.

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

46. The tablet About 35.0% by weight lactose monohydrate; about 44.5% by weight microcrystalline cellulose; about 2.0% by weight of hydroxypropyl methylcellulose; about 3.0% by weight of crospovidone; about 0.5% by weight of magnesium stearate; The tablet of claim 1, comprising:

47. 47. The tablet of claim 46, wherein the tablet comprises an intragranular core and an extragranular portion.

48. 48. The tablet of claim 47, wherein the intragranular core comprises 23.5% microcrystalline cellulose by weight.

49. 48. The tablet of claim 47, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

50. 48. The tablet of claim 47, wherein the intragranular core comprises about 1.5% crospovidone by weight.

51. 48. The tablet of claim 47, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

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

53. The tablet About 28.8% lactose monohydrate by weight; about 55.8% by weight microcrystalline cellulose; about 2.0% by weight of hydroxypropyl methylcellulose; about 3.0% by weight of crospovidone; about 0.4% by weight of magnesium stearate; The tablet of claim 1, comprising:

54. 54. The tablet of claim 53, wherein the tablet comprises an intragranular core and an extragranular portion.

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

56. 55. The tablet of claim 54, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

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

58. 55. The tablet of claim 54, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

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

60. The tablet About 23.5% by weight of lactose monohydrate; about 56.2% by weight microcrystalline cellulose; about 2.0% by weight of hydroxypropyl methylcellulose; about 3.0% by weight of crospovidone; about 0.4% by weight of magnesium stearate; The tablet of claim 1, comprising:

61. 61. The tablet of claim 60, wherein the tablet comprises an intragranular core and an extragranular portion.

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

63. 62. The tablet of claim 61, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

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

65. 62. The tablet of claim 61, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

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

67. The tablet About 35.2% lactose monohydrate by weight; about 44.5% by weight microcrystalline cellulose; about 2.0% by weight of hydroxypropyl methylcellulose; about 3.0% by weight of crospovidone; about 0.4% by weight of magnesium stearate; The tablet of claim 1, comprising:

68. 68. The tablet of claim 67, wherein the tablet comprises an intragranular core and an extragranular portion.

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

70. 69. The tablet of claim 68, wherein the extragranular portion comprises 21.0% microcrystalline cellulose by weight.

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

72. 69. The tablet of claim 68, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

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

74. The tablet About 32.2% lactose monohydrate by weight; about 44.5% by weight microcrystalline cellulose; about 2.0% by weight of hydroxypropyl methylcellulose; about 3.0% by weight of crospovidone; about 0.4% by weight of magnesium stearate; about 3.0% talc; The tablet of claim 2, comprising:

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

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

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

78. 76. The tablet of claim 75, wherein the intragranular core comprises about 1.5% crospovidone by weight.

79. 76. The tablet of claim 75, wherein the extragranular portion comprises about 1.5% crospovidone by weight.

80. 80. The tablet of any one of claims 1 to 79, wherein Compound 1 is present in an amount of about 15% by weight.

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

82. 82. The tablet of claim 81, wherein the film coating is present in an amount of about 2% to about 5% based on the total weight of the tablet.

83. 83. The tablet of claim 82, wherein the film coating is present in an amount of about 3% based on the total weight of the tablet.

84. 67. The tablet of any one of claims 53 to 66, wherein the weight ratio of lactose to intragranular microcrystalline cellulose is about 40:

60.

85. 80. The tablet of any one of claims 46 to 52 and 67 to 79, wherein the weight ratio of lactose to intragranular microcrystalline cellulose is about 60:

40.

86. 28. The tablet of claim 27, wherein the coating layer comprises macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, fatty acid monocaprylocapriate glycerol type 1 / mono / diglyceride / glycerol, yellow ferric oxide, partially hydrolyzed polyvinyl alcohol, and red ferric oxide.

87. 28. The tablet of claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose, titanium dioxide, macrogol polyethylene glycol, yellow ferric oxide, and red ferric oxide.

88. 28. The tablet of claim 27, wherein the coating layer comprises hydroxypropyl methylcellulose, copovidone, titanium dioxide, polyethylene glycol, yellow ferric oxide, indigo carmine aluminum lake, and caprylic / capric triglyceride.

89. 90. A method of treating a disease or condition mediated by BTK in a patient in need thereof, 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 to 88 for treating a disease in which BTK receptor mediation is involved.

Images