Pharmaceutical formula of Bruton's tyrosine kinase inhibitor

Abstract

The invention relates to a pharmaceutical formula of a Bruton's tyrosine kinase inhibitor. Described herein are pharmaceutical formulations of the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one. Also disclosed are methods of using Btk inhibitors, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Description

[0001] This application is a divisional of application number 2016800167100, filed March 2, 2016, having the title "Pharmaceutical Formulations of Bruton's Tyrosine Kinase Inhibitors."

[0002] Cross Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 127,717, filed March 3, 2015, and U.S. Provisional Application No. 62 / 193,518, filed July 16, 2015, which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including pharmaceutical compositions, solvates, and pharmaceutically acceptable salts thereof, as well as pharmaceutical formulations including the Btk inhibitor and methods of using the Btk inhibitor compositions or formulations to treat diseases or conditions that would benefit from inhibition of Btk activity. BACKGROUND

[0004] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a critical signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays an indispensable role in the B cell signaling pathway that links cell surface B cell receptor (BCR) stimulation to downstream intracellular responses.

[0005] Btk is a critical regulator of B cell development, activation, signaling, and survival. In addition, Btk plays a role in many other hematopoietic cell signaling pathways, for example, Toll-like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (FcsRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.

[0006] 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1- one is also known by its IUPAC name as 1-{(3 R )-3-[4-amino-3-(4-phenoxyphenyl)-1 H -pyrazolo[3,4- d1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin- 1 -yl)prop-2-en-1 -one or 1 -[(3 R )-3-[4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl]piperidin-1 - yl]prop-2-en-1 -one or 1 -[(3 H -3-[4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl]piperidin-1 - yl]prop-2-en-1 -one or 1 -[(3 d )-3-[4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl]piperidin-1 - yl]prop-2-en-1 -one or 1 -[(3 SUMMARY

[0007] Described herein is the Btk inhibitor 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one, including pharmaceutically acceptable compositions, formulations, and methods of use thereof. Also described are pharmaceutically acceptable compositions and formulations of the Btk inhibitor 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one for use in the manufacture of a medicament for treating a disease or condition associated with Btk activity. 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one is an irreversible Btk inhibitor. Further described are pharmaceutical compositions and formulations of the Btk inhibitor 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one, and methods of using the Btk inhibitor to treat a disease or condition, including diseases or conditions for which irreversible inhibition of Btk provides a therapeutic benefit in a mammal suffering from the disease or condition.

[0008] Also described herein is a process for preparing a pharmaceutical composition of 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one by a wet granulation process. Further described are pharmaceutical formulations comprising a pharmaceutical composition of 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one prepared by a wet granulation process.

[0009] In one aspect is a pharmaceutical composition comprising ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1, Compound 1 ; and wherein the pharmaceutical composition comprises at least 50% w / w of ibrutinib.

[0010] In another embodiment is a pharmaceutical composition comprising ibrutinib, wherein the pharmaceutical composition comprises about 50% w / w to about 90% w / w of ibrutinib. In another embodiment is a pharmaceutical composition comprising ibrutinib, wherein the pharmaceutical composition comprises about 50% w / w to about 80% w / w of ibrutinib. In another embodiment is a pharmaceutical composition comprising ibrutinib, wherein the pharmaceutical composition comprises about 60% w / w to about 80% w / w of ibrutinib. In another embodiment is a pharmaceutical composition comprising ibrutinib, wherein the pharmaceutical composition comprises about 60% w / w to about 75% w / w of ibrutinib. In another embodiment is a pharmaceutical composition comprising at least 50% w / w of ibrutinib, wherein the pharmaceutical composition comprises intra-granular and extra-granular ingredients. In another embodiment is a pharmaceutical composition comprising at least 50% w / w of ibrutinib, wherein the pharmaceutical composition is prepared using a wet granulation method. In another embodiment is a pharmaceutical composition comprising at least 50% w / w of ibrutinib, further comprising at least one pharmaceutically acceptable excipient.

[0011] In another embodiment is a high-load solid tablet formulation comprising a pharmaceutical composition comprising at least 50% w / w of ibrutinib, about 50% w / w to about 90% w / w of ibrutinib, about 50% w / w to about 80% w / w of ibrutinib, about 60% w / w to about 80% w / w of ibrutinib, or about 60% w / w to about 75% w / w of ibrutinib, and one or more pharmaceutically acceptable excipients. In another embodiment is a high-load solid tablet formulation comprising a pharmaceutical composition comprising at least 50% w / w of ibrutinib, about 50% w / w to about 90% w / w of ibrutinib, about 50% w / w to about 80% w / w of ibrutinib, about 60% w / w to about 80% w / w of ibrutinib, or about 60% w / w to about 75% w / w of ibrutinib, and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 10% w / w to about 50% w / w.

[0012] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose dextrorates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in amounts of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and microcrystalline cellulose is present in amounts of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w, or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant.In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, croscarmellose sodium, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose, sodium alginate, clay, and gums. In some embodiments, the disintegrant is croscarmellose sodium; and croscarmellose sodium is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1 to about 5% w / w, or about 2% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w.In some embodiments, the excipient comprises, is substantially composed of, or is composed of: lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the excipient comprises, is substantially composed of, or is composed of: lactose, polyvinylpyrrolidone, sodium lauryl sulfate, crospovidone, colloidal silica, and magnesium stearate.

[0013] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise, substantially comprise, or comprise of lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, wherein the in-particle excipient comprises Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0 to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0014] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, wherein the in-particle excipient comprises Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of approximately 0 to approximately 2% w / w, approximately 0.5% w / w to approximately 1.5% w / w; and External excipients for particulate matter contain Sodium coscammeler in amounts of approximately 0 to approximately 5% w / w, approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0 to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0015] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose of approximately 2% w / w to approximately 5% w / w d) Polyvinylpyrrolidone, approximately 1% w / w to approximately 3% w / w e) Sodium coscammeler at approximately 6% w / w to approximately 8% w / w f) Sodium lauryl sulfate, approximately 1% w / w to approximately 4% w / w g) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and h) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0016] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 5% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 1% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0017] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 2% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 4% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0018] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 70% w / w b) Approximately 16% w / w lactose, c) Approximately 2% w / w polyvinylpyrrolidone, d) Approximately 1% w / w sodium lauryl sulfate, e) Approximately 10% w / w cropovidone, f) Approximately 0.5% w / w colloidal silica, and g) Approximately 0.5% w / w magnesium stearate.

[0019] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 15% w / w d) Sodium coscammeler, approximately 4% w / w to approximately 6% w / w e) Sodium lauryl sulfate at approximately 5% w / w to approximately 7% w / w f) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and g) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0020] In some implementations, the total weight of the tablet is approximately 934 mg.

[0021] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose at approximately 13% w / w to approximately 14% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 14% w / w d) Sodium coscammeler (in granules) of approximately 2% w / w to approximately 3% w / w. e) Hydroxypropyl cellulose, approximately 0.8% w / w to approximately 1.2% w / w f) Sodium coscammeler (extragranular) at approximately 2% w / w to approximately 3% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0022] In some implementations, the total weight of the tablet is approximately 934 mg.

[0023] Another embodiment is a high-load solid tablet formulation containing a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose at approximately 8% w / w to approximately 9% w / w c) Approximately 8 to 9% w / w microcrystalline cellulose, d) Sodium coscamelles (in granules) at approximately 2.5 to approximately 3.5% w / w. e) Sodium coscammeler (extragranular) at approximately 2.5 to approximately 3.5% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0024] The lactose used herein can be anhydrous lactose and / or hydrated lactose, such as lactose monohydrate. In some embodiments, the lactose is anhydrous lactose. In some specific embodiments, the lactose is hydrated lactose. In more specific embodiments, the lactose is lactose monohydrate.

[0025] In some implementations, the total weight of the tablet is approximately 800 mg.

[0026] In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is from about 35 mg to about 840 mg per tablet. In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is from about 140 mg to about 840 mg per tablet. In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg per tablet, or any range between any two of these values, including the endpoints. In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is about 560 mg. In some embodiments of the high-load solid tablet formulation described herein, ibrutinib is in a micronized form. In some embodiments of the high-load solid tablet formulation described herein, the formulation is for once-daily dosing. In some embodiments of the high-load solid tablet formulation described herein, the formulation is an oral dosage form containing a therapeutically effective amount of ibrutinib.

[0027] In another embodiment, it is a method of treating a disease in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0028] In another embodiment, a method of treating an autoimmune disease in a patient requiring treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein. In some embodiments, the autoimmune disease is rheumatoid arthritis or lupus.

[0029] In another embodiment, it is a method of treating a patient with a xenoimmune disease in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0030] In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein. In some embodiments, the cancer is a B-cell proliferative disorder. In some embodiments, the cancer is a B-cell proliferative disorder and the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. In some embodiments, the cancer is lymphoma, leukemia, or a solid tumor. In some implementations, cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.

[0031] In another embodiment, it is a method of treating mastocytosis in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0032] In another embodiment, it is a method of treating osteoporosis or bone resorption in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0033] In another embodiment, it is a method of treating an inflammatory disease or condition in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0034] In another embodiment, it is a method of treating lupus in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0035] In some implementations, the formulations and methods described herein can be used to treat cancers of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas; glioblastomas; neuroblastomas; multiple myeloma; gastrointestinal cancers, especially colon cancer or colorectal adenomas; tumors of the neck and head; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; vesicles; vesicles with epithelial features; adenomas; adenocarcinomas; keratoacanthomas; epidermoid carcinomas; large cell carcinomas; non-small cell lung cancers; Hodgkin's and non-Hodgkin's lymphomas; breast cancers; follicular carcinomas; undifferentiated carcinomas; papillary carcinomas; seminomas; melanomas; or the smoldering form of indolent multiple myeloma.

[0036] In some embodiments, the formulations and methods described herein can be used to treat malignant diseases of the central nervous system (CNS). In some embodiments, the CNS malignancy is primary CNS lymphoma. In some embodiments, the primary CNS lymphoma is glioma. In some embodiments, the glioma is astrocytoma, ependymoma, or oligodendroglioma. In some implementations, CNS malignancies are astrocytic tumors, such as juvenile pilocytic, subependymal, well-differentiated, or moderately differentiated anaplastic astrocytomas; anaplastic astrocytomas; glioblastomas multiforme; ependymal tumors, such as myxoid papillary and well-differentiated ependymomas, anaplastic ependymomas, and ependymoblastomas; oligodendroglial tumors, including well-differentiated oligodendrogliomas and anaplastic oligodendrogliomas; mixed tumors, such as mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed astrocytoma-ependymoma-oligodendroglioma; or medulloblastomas.

[0037] In some embodiments, the formulations and methods described herein can be used to treat hematologic malignancies such as (but not limited to) leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancy, or B-cell malignancy. In some embodiments, the hematologic malignancy is a treatment-naïve hematologic malignancy. In some embodiments, the hematologic malignancy is a relapsed or refractory hematologic malignancy.

[0038] In some implementations, the hematologic malignancy is a T-cell malignancy. In some implementations, the T-cell malignancy is a nonspecific peripheral T-cell lymphoma (PTCL-NOS), anaplastic large cell lymphoma, angioblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), primitive NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematologic splenic γ-δ T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphoma, or treatment-related T-cell lymphoma. In some implementations, the T-cell malignancy is a relapsed or refractory T-cell malignancy. In some implementations, the T-cell malignancy is a treatment-naïve T-cell malignancy.

[0039] In some implementations, the hematologic malignancy is a B-cell proliferative disorder. In some implementations, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, non-CLL / SLL lymphoma, or prolymphocytic leukemia (PLL). In some implementations, cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis. In some implementations, DLBCL is further subdivided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and double-hit (DH) DLBCL. In some implementations, ABC-DLBCL is characterized by a CD79B mutation. In some implementations, ABC-DLBCL is characterized by a CD79A mutation. In some implementations, ABC-DLBCL is characterized by mutations in MyD88, A20, or a combination thereof. In some implementations, the cancer is acute or chronic myeloid (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia. In some implementations, the B-cell proliferative disorder is relapsed or refractory B-cell proliferative disorder. In some implementations, the B-cell proliferative disorder is treatment-naïve B-cell proliferative disorder.

[0040] In some embodiments, the formulations and methods described herein can be used to treat fibrosis. In some embodiments, the fibrosis is not associated with graft-versus-host disease (GVHD). In some embodiments, the fibrosis is not associated with scleroderma GVHD, chronic pulmonary GVHD, or chronic hepatic GVHD. In some embodiments, the fibrosis is fibrosis of the liver, lungs, pancreas, kidneys, bone marrow, heart, skin, intestines, or joints. In some embodiments, the fibrosis is liver fibrosis. In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the fibrosis is pancreatic fibrosis. In some embodiments, the patient has cirrhosis, chronic pancreatitis, or cystic fibrosis.

[0041] In another aspect, there is a process for preparing a pharmaceutical composition or tablet formulation comprising ibrutinib as described herein, wherein such process includes a wet granulation method.

[0042] In another aspect, there is a high-load solid tablet formulation containing ibrutinib, wherein ibrutinib is a compound having the structure of compound 1. Compound 1; The tablet contains approximately 560 mg of ibrutinib.

[0043] In another embodiment, a high-load solid tablet formulation is provided, wherein ibrutinib is in a micronized form. In another embodiment, ibrutinib is in a spray-dried form. In another embodiment, ibrutinib is not in a spray-dried form. In another embodiment, the particle size is about or less than 30 micrometers. In one embodiment, ibrutinib is in a micronized form and the particle size is about 1-30 micrometers. In another embodiment, the particle size is about or less than 10 micrometers. In another embodiment, the particle size is < 1 micrometer. In another embodiment, a high-load solid tablet formulation is provided, wherein the tablet is for once-daily oral administration.

[0044] In another aspect, this document provides a method for treating a patient by administering compound 1. In some embodiments, this document provides a method for inhibiting the activity of a tyrosine kinase, such as Btk, in a mammal, or for treating a disease, condition, or symptom that would benefit from the inhibition of a tyrosine kinase, such as Btk, comprising administering to a mammal a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate.

[0045] In another respect, this article provides the use of compound 1 for inhibiting Bruton's tyrosine kinase (Btk) activity or for treating diseases, conditions, or symptoms that would benefit from inhibition of Bruton's tyrosine kinase (Btk) activity.

[0046] In some embodiments, a pharmaceutical composition comprising crystalline compound 1 is administered to a human. In some embodiments, a pharmaceutical composition comprising amorphous compound 1 is administered to a human.

[0047] In some embodiments, the pharmaceutical composition comprising crystalline compound 1 is administered orally. In some embodiments, the pharmaceutical composition comprising amorphous compound 1 is administered orally.

[0048] In some embodiments, a pharmaceutical composition comprising crystalline compound 1 is used in the formulation of an agent for inhibiting tyrosine kinase activity. In other embodiments, a pharmaceutical composition comprising crystalline compound 1 is used in the formulation of an agent for inhibiting Bruton's tyrosine kinase (Btk) activity. In some embodiments, a pharmaceutical composition comprising amorphous compound 1 is used in the formulation of an agent for inhibiting tyrosine kinase activity. In other embodiments, a pharmaceutical composition comprising amorphous compound 1 is used in the formulation of an agent for inhibiting Bruton's tyrosine kinase (Btk) activity.

[0049] In some embodiments, in any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), compound 1 or a pharmaceutically acceptable salt or solvate thereof is optically pure (i.e., greater than 99% chiral purity, by HPLC). In some embodiments, in any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), compound 1 or a pharmaceutically acceptable salt or solvation thereof is replaced by: a) a compound 1 or a pharmaceutically acceptable salt or solvation thereof of lower chiral purity; b) 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt or solvation thereof of any optical purity; or c) racemic 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt or solvation thereof.

[0050] In any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), amorphous compound 1 is used. In any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), crystalline compound 1 is used.

[0051] In some embodiments, in any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), compound 1 or a pharmaceutically acceptable salt thereof is replaced with an active metabolite of compound 1. In some embodiments, the active metabolite is in crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In other embodiments, the metabolite is separated. In some embodiments, in any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.), compound 1 or a pharmaceutically acceptable salt thereof is replaced with a prodrug of compound 1, or a deuterated analog of compound 1 or a pharmaceutically acceptable salt thereof.

[0052] Other objectives, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific embodiments indicate particular implementations, they are given by way of illustration only, as various variations and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description. Section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter. All documents or portions thereof cited in this application, including (but not limited to) patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated in their entirety for any purpose.

[0053] This application provides the following: A high-load solid tablet formulation comprising ibrutinib and one or more pharmaceutically acceptable excipients, wherein ibrutinib is a compound having the structure of compound 1. Compound 1; Furthermore, the high-load solid tablet formulation contains at least 50% w / w ibrutinib.

[0054] 2. The high-load solid tablet formulation as described in Embodiment 1, wherein the high-load solid tablet formulation comprises about 50% w / w to about 90% w / w ibrutinib.

[0055] 3. The high-load solid tablet formulation as described in Embodiment 1, wherein the high-load solid tablet formulation comprises about 50% w / w to about 80% w / w ibrutinib.

[0056] 4. The high-load solid tablet formulation as described in Embodiment 1, wherein the high-load solid tablet formulation comprises about 60% w / w to about 80% w / w ibrutinib.

[0057] 5. A high-load solid tablet formulation as described in Embodiment 1, wherein the high-load solid tablet formulation comprises about 60% w / w to about 75% w / w ibrutinib.

[0058] 6. A high-load solid tablet formulation as described in any one of embodiments 1 to 5, wherein the high-load solid tablet formulation comprises in-particle and extra-particle components.

[0059] 7. A high-load solid tablet formulation as described in any one of embodiments 1 to 6, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants.

[0060] 8. A high-load solid tablet formulation as described in any one of embodiments 1 to 7, wherein at least one excipient is a diluent.

[0061] 9. The high-load solid tablet formulation as described in Embodiment 8, wherein the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binder, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose and talc.

[0062] 10. The high-load solid tablet formulation as described in embodiment 8, wherein the diluent is cellulose.

[0063] 11. The high-load solid tablet formulation as described in embodiment 8, wherein the diluent is lactose; and the lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w.

[0064] 12. The high-load solid tablet formulation as described in embodiment 8, wherein the diluent is lactose; and the lactose is present in an amount of about 8.5% w / w or about 14% w / w.

[0065] 13. The high-load solid tablet formulation as described in embodiment 8, wherein the diluent is microcrystalline cellulose.

[0066] 14. The high-load solid tablet formulation as described in embodiment 13, wherein the microcrystalline cellulose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w.

[0067] 15. The high-load solid tablet formulation as described in embodiment 13, wherein the microcrystalline cellulose is present in an amount of about 8.5% w / w or about 14% w / w.

[0068] 16. The high-load solid tablet formulation as described in embodiment 8, wherein the diluent is lactose and microcrystalline cellulose.

[0069] 17. The high-load solid tablet formulation as described in embodiment 16, wherein the lactose is present in an amount of about 10% w / w to about 15% w / w and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w.

[0070] 18. The high-load solid tablet formulation as described in embodiment 16, wherein the lactose is present in an amount of about 14% w / w and the microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w.

[0071] 19. A high-load solid tablet formulation as described in any one of embodiments 1 to 18, wherein at least one excipient is a disintegrant.

[0072] 20. The high-load solid tablet formulation of embodiment 19, wherein the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.

[0073] 21. The high-load solid tablet formulation of embodiment 19, wherein the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w.

[0074] 22. A high-load solid tablet formulation as described in any one of embodiments 1 to 21, wherein at least one excipient is a binder.

[0075] 23. The high-load solid tablet formulation of embodiment 22, wherein the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in an amount of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w.

[0076] 24. A high-load solid tablet formulation as described in any one of embodiments 1 to 23, wherein the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose.

[0077] 25. The high-load solid tablet formulation as described in embodiment 22, wherein the binder is polyvinylpyrrolidone.

[0078] 26. The high-load solid tablet formulation of embodiment 25, wherein the polyvinylpyrrolidone is present in an amount of about 0 to about 10% w / w, about 1 to about 5% w / w, or about 2% w / w.

[0079] 27. A high-load solid tablet formulation as described in any one of embodiments 1 to 26, wherein at least one excipient is a surfactant.

[0080] 28. The high-load solid tablet formulation as described in embodiment 27, wherein the surfactant is sodium lauryl sulfate.

[0081] 29. The high-load solid tablet formulation of embodiment 28, wherein the sodium lauryl sulfate is present in an amount of about 0 to about 10% w / w, about 0.5 to about 5% w / w, about 1 to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w.

[0082] 30. A high-load solid tablet formulation as described in any one of embodiments 1 to 29, wherein the formulation further comprises one or more flow aids.

[0083] 31. The high-load solid tablet formulation as described in embodiment 30, wherein the flow aid is silica (colloidal silica).

[0084] 32. The high-load solid tablet formulation of embodiment 31, wherein the silica (colloidal silica) is present in an amount of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0085] 33. A high-load solid tablet formulation as described in any one of embodiments 1 to 32, wherein at least one excipient is a lubricant.

[0086] 34. The high-load solid tablet formulation as described in embodiment 33, wherein the lubricant is magnesium stearate.

[0087] 35. The high-load solid tablet formulation of embodiment 34, wherein the magnesium stearate is present in an amount of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w.

[0088] 36. A high-load solid tablet formulation as described in any one of embodiments 1 to 22 and 25 to 35, wherein the excipient comprises lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0089] 37. A high-load solid tablet formulation as described in any one of embodiments 1 to 5, wherein the formulation comprises in-particle and out-of-particle excipients; and the in-particle excipient comprises lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipient comprises sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0090] 38. A high-load solid tablet formulation as described in any one of embodiments 1 to 5, wherein... The in-particle excipient comprises: Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0 to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and The excipient for particulate matter contains Sodium saccharin in amounts of about 0 to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0091] 39. A high-load solid tablet formulation as described in any one of embodiments 1 to 5, wherein the formulation comprises in-particle and out-of-particle excipients; and the in-particle excipient comprises lactose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipient comprises sodium coscamelles, sodium lauryl sulfate, microcrystalline cellulose, colloidal silica, and magnesium stearate.

[0092] 40. A high-load solid tablet formulation as described in any one of embodiments 1 to 5, wherein... The in-particle excipient comprises: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and The excipient for particulate matter contains Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0093] 41. The high-load solid tablet formulation as described in Embodiment 1, comprising: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Approximately 13% w / w to approximately 15% w / w lactose monohydrate, c) Microcrystalline cellulose of approximately 2% w / w to approximately 5% w / w d) Polyvinylpyrrolidone, approximately 1% w / w to approximately 3% w / w e) Sodium coscammeler at approximately 6% w / w to approximately 8% w / w f) Sodium lauryl sulfate, approximately 1% w / w to approximately 4% w / w g) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and h) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0094] 42. The high-load solid tablet formulation as described in Embodiment 1, comprising: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 5% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 1% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0095] 43. The high-load solid tablet formulation as described in Embodiment 1, comprising: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 2% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 4% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0096] 44. A high-load solid tablet formulation as described in Embodiment 1, wherein the formulation comprises: a) Ibrutinib at approximately 65% ​​w / w to approximately 75% w / w b) Approximately 14% w / w to approximately 18% w / w lactose monohydrate c) Polyvinylpyrrolidone of approximately 1% w / w to approximately 3% w / w d) Sodium lauryl sulfate, approximately 0.5% w / w to approximately 1.5% w / w. e) Approximately 5% w / w to approximately 15% w / w of cropovidone. f) Colloidal silica of approximately 0.3% w / w to approximately 0.7% w / w, and g) Magnesium stearate of about 0.3% w / w to about 0.7% w / w.

[0097] 45. A high-load solid tablet formulation as described in Embodiment 1, wherein the formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 15% w / w d) Sodium coscammeler, approximately 4% w / w to approximately 6% w / w e) Sodium lauryl sulfate at approximately 5% w / w to approximately 7% w / w f) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and g) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0098] 46. ​​A high-load solid tablet formulation as described in Embodiment 1, wherein the formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose at approximately 13% w / w to approximately 14% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 14% w / w d) Sodium coscammeler (in granules) of approximately 2% w / w to approximately 3% w / w. e) Hydroxypropyl cellulose, approximately 0.8% w / w to approximately 1.2% w / w f) Sodium coscammeler (extragranular) at approximately 2% w / w to approximately 3% w / w. g) Sodium lauryl sulfate, approximately 5.5% w / w to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0099] 47. A high-load solid tablet formulation as described in Embodiment 1, wherein the formulation comprises: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose at approximately 8% w / w to approximately 9% w / w c) Microcrystalline cellulose of approximately 8% w / w to approximately 9% w / w d) Sodium coscammeler (in granules) of approximately 2.5% w / w to approximately 3.5% w / w. e) Sodium coscammeler (extragranular) at approximately 2.5% w / w to approximately 3.5% w / w. g) Sodium lauryl sulfate, approximately 5.5% w / w to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0100] 48. A high-load solid tablet formulation as described in any one of embodiments 1 to 47, wherein the amount of ibrutinib is about 420 or about 560 mg.

[0101] 49. A high-load solid tablet formulation as described in any one of embodiments 1 to 48, wherein the high-load solid tablet formulation is used for one tablet, administered once daily.

[0102] 50. A high-load solid tablet formulation as described in any one of embodiments 1 to 49, wherein the high-load solid tablet formulation is prepared using a process including a wet granulation method.

[0103] 51. A method of treating a disease in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of a high-load solid tablet formulation as described in any one of embodiments 1 to 49.

[0104] 52. A process for preparing a high-load solid tablet formulation as described in any one of embodiments 1 to 49, wherein the process includes a wet granulation method.

[0105] 53. The process as described in embodiment 52, wherein the wet granulation method comprises granulating a mixture of ibrutinib and the intraparticle excipient with a granulation liquid to form particles.

[0106] 54. The process as described in embodiment 52 or 53, comprising (1) mixing ibrutinib with the intragranular excipient; (2) granulating the mixture of ibrutinib and the intragranular excipient with purified water or an aqueous binder solution to form granules; (3) drying the granules to form dried granules; (4) grinding the dried granules; (5) blending the ground granules with the extragranular excipient; and (6) compressing the mixture of the ground granules and the extragranular excipient to form tablets of the high-load solid tablet formulation.

[0107] Incorporation by Reference All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. Attached Figure Description

[0108] Figure 1 The mean plasma concentration-time profile of ibrutinib is shown after a single oral dose of 140 mg was administered to fasted beagle dogs, comparing the capsule formulation with three different wet tablet formulations.

[0109] Figure 2 The mean plasma concentration-time profile of ibrutinib is shown after a single oral dose of two different dry tablet formulations was administered to fasted beagle dogs (dose = 140 mg) in a comparison of the capsule formulation and the two dry tablet formulations.

[0110] Figure 3 The following are photographs of the embodiments: (A) capsules containing 140 mg ibrutinib (Formula A), and tablets of the present invention designed to contain 560 mg, 420 mg, 280 mg and 140 mg ibrutinib respectively (BE). Detailed Implementation

[0111] The diverse roles of Btk signaling in various hematopoietic cell functions, such as B cell receptor activation, suggest that small molecule Btk inhibitors, such as compound 1, are suitable for reducing the risk of or treating a variety of diseases affecting or influencing many cell types of the hematopoietic lineage, including, for example, autoimmune diseases, xenoimmune conditions or diseases, inflammatory diseases, cancers (e.g., B cell proliferation disorders), and thromboembolic disorders. Furthermore, irreversible Btk inhibitor compounds, such as compound 1, can be used to inhibit other tyrosine kinases that share homology with Btk through cysteine ​​residues (including Cys 481 residues) that can form covalent bonds with irreversible inhibitors.

[0112] In some embodiments, compositions or tablet formulations comprising compound 1 may be used to treat autoimmune diseases in mammals, including (but not limited to) rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, and Goodpasture's syndrome. (Syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, mild autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic nervous system disorders, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, and vulvar pain.

[0113] In some embodiments, the composition or tablet formulation containing compound 1 can be used to treat xenoimmune diseases or conditions in mammals, including (but not limited to) graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies (e.g., allergies to plant pollen, milk, drugs, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0114] In some embodiments, compositions or tablet formulations comprising compound 1 can be used to treat inflammatory diseases in mammals, including (but not limited to) asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, and fibrositis. Inflammation of tissues, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. In some implementations, inflammatory diseases include asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In some implementation schemes, autoimmune diseases include inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Auder's thyroiditis, Graves' disease, Shoegrange syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, and antiphospholipid antibody syndrome. Comorbidities, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpass syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome, Goran's arteritis, temporal arteritis, mild autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system disorders, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, or vulvar pain.

[0115] In other embodiments, the methods described herein can be used to treat cancers such as B-cell proliferative disorders, including (but not limited to) diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis.

[0116] In other embodiments, the methods described herein can be used to treat thromboembolic conditions, including (but not limited to) myocardial infarction, angina pectoris (including unstable angina), re-occlusion or restenosis after angioplasty or aortocoronary shunt, stroke, transient ischemic attack, peripheral artery occlusion, pulmonary embolism, and deep vein thrombosis.

[0117] Hematological malignancies In some embodiments, this document discloses a method for treating a blood malignancy in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1.

[0118] In some implementations, the hematologic malignancy is non-Hodgkin's lymphoma (NHL). In some implementations, the hematologic malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some implementations, the hematologic malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, non-Burkkitt high-grade B-cell lymphoma, or extranodal marginal zone B-cell lymphoma. In some implementations, the hematologic malignancy is acute or chronic myeloid (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or precursor B-cell acute lymphoblastic leukemia. In some implementations, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is the DLBCL ABC subtype. In some embodiments, the hematologic malignancy is the DLBCL GCB subtype. In some embodiments, the hematologic malignancy is Waldenström's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is multiple myeloma (MM). In some embodiments, the hematologic malignancy is Burkitt's lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (FL). In some embodiments, the hematologic malignancy is transformed follicular lymphoma. In some embodiments, the hematologic malignancy is marginal zone lymphoma.

[0119] In some implementations, the hematologic malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some implementations, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenström's macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkkitt high-grade B-cell lymphoma, or relapsed or refractory extranodal marginal zone B-cell lymphoma. In some implementations, the hematologic malignancy is relapsed or refractory acute or chronic myeloid leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia, or relapsed or refractory precursor B-cell acute lymphoblastic leukemia. In some implementations, the hematologic malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some implementations, the hematologic malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some implementations, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some implementations, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ABC subtype. In some implementations, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL) GCB subtype. In some implementations, the hematologic malignancy is relapsed or refractory Waldenström macroglobulinemia (WM). In some implementations, the hematologic malignancy is relapsed or refractory multiple myeloma (MM). In some implementations, the hematologic malignancy is relapsed or refractory Burkitt lymphoma. In some implementations, the hematologic malignancy is relapsed or refractory follicular lymphoma (FL).

[0120] In some implementations, hematologic malignancies are classified as high-risk hematologic malignancies. In some implementations, hematologic malignancies are high-risk CLL or high-risk SLL.

[0121] B-cell lymphoproliferative disorders (BCLD) are bloodborne diseases and particularly include non-Hodgkin's lymphoma, multiple myeloma, and leukemia. BCLD can originate in lymphoid tissue (as in the case of lymphoma) or bone marrow (as in the case of leukemia and myeloma), and all are associated with the uncontrolled growth of lymphocytes or white blood cells. Many subtypes of BCLD exist, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The course and treatment of BCLD depend on the BCLD subtype; however, even within each subtype, clinical presentation, morphological appearance, and response to therapy vary.

[0122] Malignant lymphomas are neoplastic transformations of cells that primarily reside in lymphoid tissue. There are two groups of malignant lymphomas: Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma infiltrate reticuloendothelial tissue. However, they differ in the neoplastic cells of origin, the location of the disease, the presence of systemic symptoms, and the response to treatment (Freedman et al., Non-Hodgkin's Lymphomas, Chapter 134, Cancer Medicine (authorized publication by the American Cancer Society), BCDecker Inc., Hamilton, Ontario, 2003).

[0123] Non-Hodgkin's lymphoma In some embodiments, this document discloses a method for treating non-Hodgkin's lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1.

[0124] In some embodiments, this document further discloses a method for treating relapsed or refractory non-Hodgkin's lymphoma in an individual of need, comprising: administering a therapeutically effective amount of compound 1 to the individual. In some embodiments, non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, or relapsed or refractory CLL.

[0125] Non-Hodgkin's lymphoma (NHL) is a diverse group of malignancies primarily originating from B cells. NHL can develop in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is often characterized by enlarged lymph nodes, fever, and weight loss. NHL is classified as B-cell or T-cell NHL. Lymphomas associated with lymphoproliferative disorders following bone marrow or stem cell transplantation are typically B-cell NHL. In the Working Formulation classification scheme, NHL has been divided into low, intermediate, and high-level categories based on its natural history (see The Non-Hodgkin's Lymphoma Pathologic Classification Project, Cancer 49(1982):2112-2135). Low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984), *New England Journal of Medicine* 311:1471-1475). Although chemotherapy can induce remission in the vast majority of indolent lymphomas, a cure is rare and most patients eventually relapse, requiring further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors, but they have a greater chance of being cured with chemotherapy. However, a significant proportion of these patients will relapse and require further treatment.

[0126] The non-restricted list of B-cell NHL includes Burkitt's lymphoma (e.g., endemic Burkitt's lymphoma and sporadic Burkitt's lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse mixed small and large cell lymphoma, diffuse small cleavage cell lymphoma, diffuse small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small cleavage cell (grade 1), follicular mixed small cleavage and large cell (grade 2), follicular large cell (grade 3), intravascular large B-cell lymphoma, intravascular lymphomatosis, large cell immunoblastic lymphoma, and large cell lymphoma. This includes lymphoblastic lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lymphoma-mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenström's macroglobulinemia, and primary central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are contemplated within the scope of this invention and will be apparent to those skilled in the art.

[0127] DLBCL In some embodiments, this document discloses a method for treating relapsed or refractory DLCBL in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory DLCBL in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0128] As used in this article, "diffuse large B-cell lymphoma (DLBCL)" refers to a proliferation of germinal center B lymphocytes with a diffuse growth pattern and a high-to-medium proliferation index. DLBCL represents approximately 30% of all lymphomas and can present with several morphological variants, including centroblastic, immunoblastic, T-cell-rich / histocyte-rich, anaplastic, and plasmablastic subtypes. Genetic testing has revealed the existence of different subtypes of DLBCL. These subtypes appear to have different prospects (prognosis) and treatment responses. DLBCL can affect any age group, but it occurs most frequently in older adults (mean age mid-60 years).

[0129] In some embodiments, this document discloses a method for treating individuals with diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL), comprising administering to the individual an irreversible Btk inhibitor at a dose of 300 mg / day to, and including, 1000 mg / day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is believed to arise from post-germinal center B cells that have arrested during cytoplasmic differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. It is considered the least curable molecular subtype of DLBCL, and thus, patients diagnosed with ABC-DLBCL typically exhibit significantly lower survival rates compared to individuals with other types of DLBCL. ABC-DLBCL is most commonly associated with chromosomal translocations that dysregulate the germinal center master regulator BCL6 and with mutations that inactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0130] In the pathogenesis of ABC-DLBCL, a particularly relevant signaling pathway is mediated by the nuclear factor (NF)-κB transcriptional complex. The NF-κB family comprises five members (p50, p52, p65, c-rel, and RelB), which form homodimers and heterodimers and function as transcription factors to mediate various proliferation, apoptosis, inflammation, and immune responses, and are crucial for normal B cell development and survival. NF-κB is widely used in eukaryotic cells as a regulator of genes controlling cell proliferation and survival. Thus, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB activates gene expression that maintains cell proliferation and protects cells from pathogens that would otherwise lead to cell death via apoptosis.

[0131] The dependence of ABC DLBCL on NF-κB depends on a signaling pathway upstream of the IκB kinase, which includes CARD11, BCL10, and MALT1 (CBM complex). Disruption of the CBM pathway suppresses NF-κB signaling in ABC DLBCL cells and induces apoptosis. The molecular basis of constitutive activity of the NF-κB pathway is the subject of this study, but some somatic variations in the ABC DLBCL genome clearly circumvent this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCL enable this signaling scaffold protein to spontaneously nucleate with protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-κB activation. Constitutive activity of the B cell receptor signaling pathway has been involved in NF-κB activation in ABC DLBCL with wild-type CARD11, and this is associated with mutations in the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activation mutations in the signal transduction aptamer MYD88 activate NF-κB and synergistically work with B cell receptor signaling to maintain the survival of ABC DLBCL cells. Furthermore, inactivating mutations in A20, a negative regulator of the NF-κB pathway, occur almost exclusively in ABC DLBCLs.

[0132] Indeed, genetic variations affecting multiple components of the NF-κB signaling pathway have recently been identified in more than 50% of ABC-DLBCL patients, with these impairments promoting constitutive NF-κB activation, thus contributing to lymphoma growth. These include mutations in the lymphocyte-specific cytoplasmic scaffold protein CARD11 (in approximately 10% of cases), which, along with MALT1 and BCL10, forms the BCR signalingsome, which transmits signals from the antigen receptor to downstream mediators of NF-κB activation. Even a larger percentage (approximately 30%) carry biallelic gene damage, inactivating the negative NF-κB regulator A20. Furthermore, high expression levels of NF-κB target genes have been observed in ABC-DLBCL tumor samples. See, for example, U. Klein et al., (2008), *Nature Immunology Review*. Nature Reviews Immunology )》 8:22-23; RE Davis et al., (2001), Journal of Experimental Medicine ( Journal of Experimental Medicine )》 194:1861-1874; G. Lentz et al., (2008), Science ( Science )》 319:1676-1679; M. Compagno et al., (2009), Nature ( Nature )》 459:712-721; and L. Srinivasan et al., (2009), Cell ( Cell)》 139:573-586).

[0133] ABC subtypes of DLBCL cells, such as OCI-Ly10, possess chronically active BCR signaling and are highly sensitive to the Btk inhibitors described herein. The irreversible Btk inhibitors described herein potently and irreversibly inhibit the growth of OCI-Ly10 cells (ECG). 50 Continuous exposure = 10 nM, EC 50 1-hour pulse = 50 nM. Furthermore, apoptosis induction, as indicated by caspase activation, annexin V flow cytometry, and increased sub-G0 fraction, was observed in OCI-Ly10 cells. Both sensitive and resistant cells expressed Btk at similar levels, and the active sites of Btk, as indicated by fluorescently labeled affinity probes, were completely occupied by inhibitors in both. OCI-Ly10 cells exhibited chronically active BCR signaling to NF-κB, which was dose-dependently inhibited by the Btk inhibitors described herein. The activity of Btk inhibitors in the cell lines studied was also characterized by comparisons of signal transduction morphologies (Btk, PLCγ, ERK, NF-κB, AKT), cytokine secretion morphologies, and mRNA expression morphologies (with and without BCR stimulation), and significant differences observed in these morphologies generated clinical biomarkers that identified the patient population most sensitive to Btk inhibitor treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, January 7, 2010, pp. 88-92, the contents of which are incorporated herein by reference in their entirety.

[0134] Follicular lymphoma In some embodiments, this document discloses a method for treating follicular lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory follicular lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0135] As used in this article, the term "follicular lymphoma" refers to any of several types of non-Hodgkin's lymphoma in which lymphoma cells aggregate into nodules or follicles. The term "follicular" is used because the cells tend to grow in a ring-like or nodular pattern within the lymph nodes. The average age of people with this type of lymphoma is approximately 60 years.

[0136] CLL / SLL In some embodiments, this document discloses a method for treating CLL or SLL in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory CLL or SLL in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0137] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are often considered the same disease with slightly different presentations. The location where cancer cells cluster determines whether it is called CLL or SLL. When cancer cells are primarily found in lymph nodes, the lima bean-shaped structures of the lymphatic system (a system primarily composed of tiny blood vessels found throughout the body), it is called SLL. SLL accounts for approximately 5% to 10% of all lymphomas. When most cancer cells are in the bloodstream and bone marrow, it is called CLL.

[0138] Both CLL and SLL are slow-growing diseases, although the more common CLL tends to grow even more slowly. CLL and SLL are treated in the same way. They are generally not considered curable with standard treatment, but depending on the stage and growth rate of the disease, most patients survive for more than 10 years. Occasionally, over time, these slow-growing lymphomas may transform into more aggressive types of lymphoma.

[0139] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. An estimated 100,760 people in the United States live with or are in remission of CLL. The majority (>75%) newly diagnosed with CLL are over 50 years of age. Currently, CLL treatment focuses on controlling the disease and its symptoms rather than achieving a complete cure. CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy to remove an enlarged spleen) or with radiation therapy (“mass resection” of swollen lymph nodes). Although CLL progresses slowly in most cases, it is generally considered incurable. Some types of CLL are classified as high-risk. As used herein, “high-risk CLL” means CLL characterized by at least one of the following: 1) 17p13-; 2) 11q22-; 3) unmutated IgVH along with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0140] CLL is typically treated when a patient’s clinical symptoms or blood cell count indicate that the disease has progressed to a point where it may affect the patient’s quality of life.

[0141] Small lymphocytic leukemia (SLL) is very similar to CLL as described above and is also a B-cell cancer. In SLL, the abnormal lymphocytes primarily affect the lymph nodes. However, in CLL, the abnormal cells primarily affect the blood and bone marrow. The spleen can be affected in both conditions. SLL accounts for approximately 1 in 25 of all non-Hodgkin's lymphomas. It can occur at any time from adolescence to old age, but is rare before the age of 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and patients tend to survive for many years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to a variety of chemotherapy drugs, it is generally considered incurable. Although some cancers tend to occur more frequently in one sex or the other, cases and deaths from SLL are evenly distributed between men and women. The average age at diagnosis is 60 years.

[0142] Although SLL is indolent, it is continuously progressing. The typical pattern of this disease is one of the high response rates to radiation and / or chemotherapy, accompanied by a period of disease remission. This is followed by an inevitable relapse after months or years. Retreatment induces another response, but the disease will relapse again. This means that although the short-term prognosis for SLL is fairly good, many patients develop fatal complications from relapsed disease over time. Given the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for simple and effective treatments with minimal side effects that do not impair the patient's quality of life. This invention addresses this long-standing need in the art.

[0143] mantle cell lymphoma In some embodiments, this document discloses a method for treating mantle cell lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory mantle cell lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0144] As used in this article, “mantle cell lymphoma” refers to a subtype of B-cell lymphoma, attributed to CD5-positive pregerminal center B cells within the mantle region surrounding normal germinal center follicles. MCL cells are generally attributed to an overexpression of cyclin D1 due to a t(11:14) chromosomal translocation in the DNA. More specifically, the translocation occurs at t(11;14)(q13;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Men are most commonly affected. The average age of patients is in their early 60s. Lymphomas are usually widely distributed when diagnosed, involving lymph nodes, bone marrow, and often the spleen. Mantle cell lymphoma is not a fast-growing lymphoma, but it is difficult to treat.

[0145] Marginal zone B-cell lymphoma In some embodiments, this document discloses a method for treating marginal zone B-cell lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0146] As used herein, the term "marginal zone B-cell lymphoma" refers to a group of associated B-cell vegetations that involve lymphoid tissue in the marginal zone, i.e., the plaque-like region outside the follicular mantle. Marginal zone lymphomas account for approximately 5% to 10% of all lymphomas. The cells in these lymphomas appear very small under a microscope. There are three main types of marginal zone lymphomas: extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

[0147] MALT In some embodiments, this document discloses a method for treating MALT in an individual in need, comprising administering an amount of compound 1 to the individual. In some embodiments, this document further discloses a method for treating relapsed or refractory MALT in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0148] As used in this article, “mucosa-associated lymphoid tissue (MALT) lymphoma” refers to the extranodal manifestation of marginal zone lymphoma. Most MALT lymphomas are low-grade, although a minority initially present as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from low-grade forms. Most MALT lymphomas occur in the stomach, and approximately 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(11;18). Many of these other MALT lymphomas have also been associated with bacterial or viral infections. The average age of patients with MALT lymphoma is approximately 60 years.

[0149] Nodal marginal zone B-cell lymphoma In some embodiments, this document discloses a method for treating nodal marginal zone B-cell lymphoma in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0150] The term "marginal zone B-cell lymphoma" refers to an indolent type of B-cell lymphoma primarily found in lymph nodes. This disease is rare and accounts for only 1% of all non-Hodgkin's lymphomas (NHL). It is most commonly diagnosed in older patients, and women are more susceptible than men. This disease is classified as marginal zone lymphoma because the mutation occurs in the marginal zone of B cells. Due to its confinement to lymph nodes, this disease is also classified as nodal.

[0151] Splenic marginal zone B-cell lymphoma In some embodiments, this document discloses a method for treating splenic marginal zone B-cell lymphoma in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0152] The term "marginal zone B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma included in the World Health Organization classification. Characteristic features include splenomegaly, moderate lymphocytosis with villous morphology, a sinusoidal luminal pattern involving various organs (especially the bone marrow), and a relatively indolent course. Tumor progression with blast crisis and invasive behavior has been observed in a minority of patients. Molecular and cytogenetic studies have shown mixed results, likely due to the lack of standardized diagnostic criteria.

[0153] Burkitt lymphoma In some embodiments, this document discloses a method for treating Burkitt lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory Burkitt lymphoma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0154] The term "Burkett lymphoma" refers to a type of non-Hodgkin's lymphoma (NHL) that typically affects children. It is a highly aggressive type of B-cell lymphoma that often begins and affects parts of the body other than the lymph nodes. Despite its rapidly growing nature, Burkitt's lymphoma is often curable with today's intensive therapies. There are two main types of Burkitt's lymphoma – sporadic and endemic varieties: Endemic Burkitt's lymphoma: This disease affects far more children than adults and is associated with Epstein-Barr virus (EBV) infection in 95% of cases. It primarily occurs in equatorial Africa, where approximately half of all childhood cancers are Burkitt's lymphoma. It is characteristically associated with a high chance of affecting the jawbone, a rather unique feature rarely seen in sporadic Burkitt's lymphoma. It also frequently involves the abdomen.

[0155] Sporadic Burkitt's lymphoma: The type of Burkitt's lymphoma affecting other parts of the world, including Europe and the Americas, is sporadic. Here as well, it is primarily a childhood disease. The link to Epstein-Barr virus (EBV) is not as strong as in the endemic variety, although direct evidence of EBV infection exists in one unidentified patient. More significant involvement than lymph nodes is in the abdomen, which is markedly affected in over 90% of children. Bone marrow involvement is more common than in the sporadic variety.

[0156] Waldenström macroglobulinemia In some embodiments, this document discloses a method for treating Waldenström macroglobulinemia in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of Compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory Waldenström macroglobulinemia in an individual of need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of Compound 1.

[0157] The term "Waldenström macroglobulinemia," also known as lymphoplasmacytic lymphoma, is a subtype of white blood cells called lymphocytes. It is characterized by the uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells that produce antibodies called immunoglobulin M (IgM). IgM antibodies circulate extensively in the blood, causing the fluid portion of the blood to thicken, becoming syrupy. This can lead to reduced blood flow to many organs, causing vision problems (due to poor circulation in the blood vessels of the retina) and neurological problems (such as headaches, dizziness, and fainting) caused by poor blood flow in the brain. Other symptoms can include feeling tired and weak, and a tendency to bleed easily. The underlying cause is not fully understood, but many risk factors have been identified, including locus 6p21.3 on chromosome 6. The risk of developing WM is increased 2 to 3 times in individuals with a personal history of autoimmune diseases with autoantibodies, and is particularly elevated in association with hepatitis, human immunodeficiency virus (HIV), and rickettsial diseases.

[0158] Multiple myeloma In some embodiments, this document discloses a method for treating multiple myeloma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory multiple myeloma in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0159] Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (after Otto Kahler), is a cancer of white blood cells called plasma cells. A type of B cell, plasma cells, are a key part of the immune system responsible for producing antibodies in humans and other vertebrates. They are produced in the bone marrow and transported via the lymphatic system.

[0160] leukemia In some embodiments, this document discloses a method for treating leukemia in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing an amount of compound 1. In some embodiments, this document further discloses a method for treating relapsed or refractory leukemia in an individual in need, comprising administering to the individual a composition or tablet formulation described herein containing a therapeutically effective amount of compound 1.

[0161] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells (leukocytes). Leukemia is a broad term that covers a range of diseases. The first classification is between its acute and chronic forms: (i) Acute leukemia is characterized by a rapid increase in immature blood cells. This accumulation prevents the bone marrow from producing healthy blood cells. Acute leukemia requires immediate treatment due to the rapid progression and accumulation of malignant cells, which then leak into the bloodstream and spread to other organs of the body. The acute form of leukemia is the most common form of leukemia in children; (ii) Chronic leukemia is distinguished by an excessive accumulation of relatively mature but still abnormal white blood cells. Progression typically takes months or years, and these cells are produced at a much higher rate than normal cells, resulting in a large number of abnormal white blood cells in the blood. Chronic leukemia primarily occurs in older adults but can theoretically occur in any age group. Additionally, the disease is subdivided based on which blood cells are affected. This classification divides leukemia into lymphoblastic or lymphocytic leukemia and myeloid or bone marrow leukemia: (i) lymphoblastic or lymphocytic leukemia, in which cancerous transformation occurs in myeloid cell types of lymphocytes that normally continue to form immune system cells that fight infection; and (ii) myeloid or bone marrow leukemia, in which cancerous transformation occurs in myeloid cell types that normally continue to form red blood cells, some other types of white blood cells, and platelets.

[0162] Within these main categories, there are several subcategories, including (but not limited to) acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Therefore, in some embodiments, this document discloses a method for treating an individual in need of acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL), comprising: administering a specified amount of compound 1 to the individual. In some embodiments, the leukemia is relapsed or refractory leukemia. In some implementations, leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B-lymphoblastic leukemia), relapsed or refractory acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or relapsed or refractory hairy cell leukemia (HCL).

[0163] The symptoms, diagnostic tests, and prognostic tests for each of the conditions mentioned above are known. See, for example, Harrison's Principles of Internal Medicine. © ( Harrison's Principles of Internal Medicine © )》, 16th edition, 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the Revised European American Lymphoma (REAL) classification system (see, for example, the website maintained by the National Cancer Institute).

[0164] Many animal models are suitable for establishing the range of effective therapeutic doses of irreversible Btk inhibitor compounds, such as compound 1, for treating any of the aforementioned diseases.

[0165] The therapeutic efficacy of Compound 1 for any of the aforementioned diseases can be optimized during the treatment process. For example, a subject undergoing treatment may undergo diagnostic assessments to correlate the reduction of disease symptoms or morbidity with the inhibition of in vivo Btk activity achieved by administering a given dose of Compound 1. Cellular assays known in the art can be used to determine the in vivo activity of Btk in the presence or absence of an irreversible Btk inhibitor. For example, because activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phosphorylation-specific immunocytochemical staining of P-Y223 or P-Y551 positive cells can be used to detect or quantify Btk activation in a cell population (e.g., by contrasting staining with FACS analysis of unstained cells). See, for example, Nisitani et al. (1999), Proceedings of the National Academy of Sciences (NASS). Proc. Natl. Acad. Sci )》, USA 96:2221-2226. Therefore, the amount of Btk inhibitor compound administered to the subject can be increased or decreased as needed to maintain the optimal level of Btk inhibition for the subject's disease condition.

[0166] Compound 1 can irreversibly inhibit Btk and can be used to treat Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase-mediated conditions or diseases, including (but not limited to) cancer, autoimmune diseases, and other inflammatory diseases in mammals. Compound 1 has shown efficacy in a wide variety of diseases and conditions described herein.

[0167] In some embodiments, compound 1 is used to manufacture an agent for treating any of the aforementioned conditions (e.g., autoimmune diseases, inflammatory diseases, allergic diseases, B-cell proliferation disorders, or thromboembolic diseases).

[0168] Compound 1 and its pharmaceutically acceptable salt The Btk inhibitor compound described herein (i.e., compound 1) is selective for Btk and kinases having cysteine ​​residues at amino acid sequence positions of tyrosine kinases homologous to the amino acid sequence position of cysteine ​​481 in Btk. The Btk inhibitor compound can form a covalent bond with Cys 481 of Btk (e.g., via the Michael reaction).

[0169] "Compound 1" or "1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one" or "1-{(3 R )-3-[4-amino-3-(4-phenoxyphenyl)-1H -pyrazolo[3,4- d ]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one” or “1-[(3 R )-3-[4-amino-3-(4-phenoxyphenyl)-1 H -pyrazolo[3,4- d "[Pyrimidin-1-yl]-1-piperidinyl-2-propen-1-one" or ibrutinib or any other suitable name refers to a compound having the following structure: A wide variety of pharmaceutically acceptable salts are formed from compound 1 and include: - An acid addition salt formed by reacting compound 1 with an organic acid, including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. - An acid addition salt is formed by reacting compound 1 with an inorganic acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0170] The term “medically acceptable salt” for Compound 1 refers to a salt of Compound 1 that does not cause significant irritation to the mammals to which it is administered and does not substantially eliminate the biological activity and properties of the compound.

[0171] It should be understood that references to pharmaceutically acceptable salts include solvation forms (solvents). Solvents contain stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of product formation or separation from pharmaceutically acceptable solvents. These solvents include water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In one aspect, solvates are formed using (but not limited to) Class 3 solvents. The categories of solvents are defined, for example, by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. In some embodiments, a solvate of compound 1 or a pharmaceutically acceptable salt thereof is conveniently prepared or formed during the process described herein. In some embodiments, the solvate of compound 1 is anhydrous. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in an unsolvated form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in an unsolvated form and is anhydrous.

[0172] In other embodiments, compound 1 or its pharmaceutically acceptable salt is prepared in various forms, including (but not limited to) amorphous phase, crystalline form, milled form, and nanoparticle form. In some embodiments, compound 1 or its pharmaceutically acceptable salt is amorphous. In some embodiments, compound 1 or its pharmaceutically acceptable salt is amorphous and anhydrous. In some embodiments, compound 1 or its pharmaceutically acceptable salt is crystalline. In some embodiments, compound 1 or its pharmaceutically acceptable salt is crystalline and anhydrous.

[0173] In some embodiments, compound 1 is prepared as outlined in U.S. Patent No. 7,514,444.

[0174] certain terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the above general description and the following detailed description are merely illustrative and explanatory and do not limit any of the claimed subject matter. In this application, the singular is used to include the plural unless otherwise specified. It must be noted that the singular forms “a / an” and “the” as used in this specification and the appended claims include plural indicators unless the context clearly indicates otherwise. In this application, the use of “or” means “and / or” unless otherwise specified. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0175] The chapter headings used herein are for organizational purposes only and are not intended to limit the subject matter described. All references or portions thereof cited in this application, including (but not limited to) patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated in their entirety for any purpose.

[0176] The term “about” when used before a numerical value indicates that the value can vary within a reasonable range, such as within ±10%, ±5%, or ±1% of the specified value.

[0177] As used herein, the term "comprising" or its grammatical variations are intended to mean that compositions and methods, etc., include the listed elements, but do not exclude others. "consistently composed of" or its grammatical variations, when used to define compositions and methods, should mean excluding other elements that have any fundamental effect on the combination for its intended use, but do not exclude elements that do not substantially affect the characteristics of the composition or method. "Constituted of" or its grammatical variations should mean excluding elements not specifically listed. Embodiments defined by each of these transitional terms are within the scope of this invention. For example, when a formulation is described as comprising ingredients A, B, and C, formulations consisting essentially of A, B, and C and formulations consisting of A, B, and C are independently within the scope of this invention.

[0178] As used herein, the terms “acceptable” or “medically acceptable” regarding formulations, compositions or ingredients mean that they do not have a lasting harmful effect on the general health of the subject being treated or do not eliminate the biological activity or properties of the compound, and are relatively non-toxic.

[0179] As used in this article, the term "agonist" refers to a compound whose presence results in the same biological activity of a protein as that produced by the presence of a ligand of a protein, such as Btk, which is naturally present.

[0180] As used in this article, the term "partial agonist" refers to a compound whose presence results in the same type of biological activity of a protein as that produced by a naturally occurring ligand of the protein, but at a lower level.

[0181] As used herein, the term "antagonist" refers to a compound whose presence reduces the biological activity of a protein by an order of magnitude. In some embodiments, the presence of an antagonist completely inhibits the biological activity of a protein, such as Btk. In some embodiments, the antagonist is an inhibitor.

[0182] As used herein, “improvement” in a particular disease, condition, or symptom by application of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, slowing of progression, or shortening of duration attributable to or associated with the application of the compound or composition, whether permanent or temporary, lasting or transient.

[0183] "Bioavailability" refers to the percentage of the administered compound 1 delivered into the systemic circulation of the animal or human being under study. When administered intravenously, the total exposure (AUC) of the drug is also considered. (0-∞) ) is usually defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is administered orally compared to when administered intravenously.

[0184] "Plasma concentration" refers to the concentration of compound 1 in the plasma components of a subject's blood. It should be understood that the plasma concentration of compound 1 can vary significantly among subjects due to variability in metabolism and / or potential interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of compound 1 may vary from subject to subject. Similarly, maximum plasma concentrations (C0) can also vary. max or the time to reach maximum plasma concentration (T) max ) or the total area under the plasma concentration-time curve (AUC) (0-∞) The value of ) may vary from subject to subject. Due to this variability, the amount required to constitute a “therapeuticly effective amount” of compound 1 may vary from subject to subject.

[0185] As used herein, the term “Bruton’s tyrosine kinase” refers to Bruton’s tyrosine kinase from Homo sapiens, as disclosed, for example, in U.S. Patent No. 6,326,469 (GenBank Accession No. NP_000052).

[0186] As used herein, the term "co-administration," etc., is intended to encompass the administration of a selected therapeutic agent to a single patient and to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times. In some embodiments, the term "co-administration," etc., is intended to encompass the administration of the selected therapeutic agent within the same cycle. In these embodiments, the selected therapeutic agent may be administered on the same or different days of the cycle.

[0187] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of a drug or compound being administered that will reduce one or more symptoms of the disease or condition being treated to a certain degree. The result may be a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising compounds as disclosed herein that is necessary to provide a clinically significant reduction in the symptoms of a disease without excessive adverse side effects. The appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutic effective amount" includes, for example, a prophylactic effective amount. An "effective amount" of the compounds disclosed herein is the amount that effectively achieves the desired pharmacological effect or therapeutic improvement without excessive adverse side effects. It should be understood that the "effective amount" or "therapeutic effective amount" may vary from subject to changes in the metabolism of compound 1, the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the prescribing physician's judgment. For example, the effective therapeutic dose can be determined through routine experiments, including (but not limited to) dose-escalation clinical trials.

[0188] The term "enhancement" means to increase or prolong the potency or duration of a desired effect. For example, "enhancing" the effect of a therapeutic agent refers to its ability to increase or prolong the potency or duration of its effect during the treatment of a disease, condition, or symptom. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of the therapeutic agent in the treatment of a disease, condition, or symptom. When used in a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or symptom, prior therapy, the patient's health status and response to the drug, and the judgment of the treating physician.

[0189] As used in this article, the term "inhibition" or "inhibitor" of a kinase refers to the inhibition of enzyme-mediated phosphotransferase activity.

[0190] As used herein, the term "irreversible inhibitor" refers to a compound that, upon contact with a target protein (e.g., a kinase), forms a new covalent bond with or within the protein, thereby reducing or eliminating one or more of the target protein's biological activities (e.g., phosphotransferase activity), regardless of the presence or absence of a subsequent irreversible inhibitor.

[0191] As used herein, the term "irreversible Btk inhibitor" refers to a Btk inhibitor that can form a covalent bond with an amino acid residue of Btk. In one embodiment, the irreversible Btk inhibitor can form a covalent bond with a Cys residue of Btk; in a particular embodiment, the irreversible inhibitor can form a covalent bond with a Cys 481 residue of Btk (or a homolog thereof) or a cysteine ​​residue at the homologous position of another tyrosine kinase.

[0192] As used herein, the term “modulation” means directly or indirectly interacting with a target to alter its activity, including (by way of example only) enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0193] As used herein, the term "modifier" refers to a compound that alters the activity of a molecule. For example, a modifier can increase or decrease the magnitude of a certain activity of a molecule compared to the magnitude of activity in the absence of the modifier. In some embodiments, the modifier is an inhibitor that reduces the magnitude of one or more activities of a molecule. In some embodiments, an inhibitor completely inhibits one or more activities of a molecule. In some embodiments, the modifier is an activator that increases the magnitude of at least one activity of a molecule. In some embodiments, the presence of the modifier produces an activity that would not occur in the absence of the modifier.

[0194] As used herein, the term "preventative effective dose" refers to an amount of composition applied to a patient that will reduce one or more symptoms of the disease, condition, or ailment being treated to a certain degree. In such preventative applications, this dose may depend on the patient's health status, weight, etc. It is well understood within the art that such preventative effective doses are determined through routine experiments, including (but not limited to) dose-escalation clinical trials.

[0195] As used herein, the terms “individual,” “subject,” or “patient” refer to an animal that is the subject of treatment, observation, or experimentation. For example only, a subject can be (but is not limited to) a mammal, including (but not limited to) humans.

[0196] As used in this article, “wet granulation” refers to the formation of granules using a granulation liquid (water, organic solvent, or solution).

[0197] As used in this article, "dry granulation" refers to the formation of granules without the use of granulation liquids (water, organic solvents, or solutions).

[0198] As used herein, the term "high-load solid tablet formulation" refers to a solid tablet formulation containing at least 50% w / w ibrutinib per tablet.

[0199] As used in this article, IC 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the reaction in a test that measures the maximum response, such as the inhibition of Btk.

[0200] As used in this article, EC 50 This refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximum expression of a specific response induced, initiated, or enhanced by the specific test compound.

[0201] Pharmaceutical Compositions / Formulations As used herein, a pharmaceutical composition or formulation refers to a mixture of Compound 1 with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates the administration of the compound to mammals. The compound may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0202] As used herein, the term "medical combination" refers to a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, such as compound 1, and the co-agent are administered simultaneously to the patient as a single entity or dose. The term "non-fixed combination" means that the active ingredient, such as compound 1, and the co-agent are administered to the patient as independent entities simultaneously, in parallel, or sequentially without a specific time interval, where such administration provides an effective level of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0203] In some embodiments, crystalline compound 1 is incorporated into a pharmaceutical composition to provide fixed oral dosage forms, such as powders, immediate-release formulations, controlled-release formulations, rapid-melting formulations, tablets, capsules, pills, delayed-release formulations, long-release formulations, pulsed-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0204] Ibrutinib is currently used clinically in unit doses of 420 mg or 560 mg, administered orally in three or four capsules containing 140 mg of ibrutinib per capsule. High-load tablet formulations would allow for one tablet per dose. However, high-load tablet formulations, which meet pharmaceutically acceptable properties such as suitable compressibility, compactibility, particle flowability, particle density, integrity during manufacturing, transport, and storage, appropriate hardness, stability, swallowability at administration, and disintegration properties, appear to be more difficult to prepare than capsule forms, due to the limited amount of excipients available to adjust tablet properties. Furthermore, tablet formulations tend to have lower C60 values ​​compared to capsule formulations.max This is attributed to its disintegration and absorption process after administration, especially for ibrutinib, which has extremely low water solubility. Preparation is required to achieve pharmaceutically acceptable properties with the desired PK characteristics, such as high C60 content. max High-load tablet formulations of ibrutinib are challenging.

[0205] In some embodiments, a pharmaceutical composition comprising ibrutinib is provided, wherein ibrutinib is a compound having the structure of compound 1. Compound 1; Furthermore, this pharmaceutical composition contains at least 50% w / w ibrutinib.

[0206] In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises at least about 20% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 20% w / w to about 90% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 30% w / w to about 90% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 40% w / w to about 90% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 50% w / w to about 90% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 40% w / w to about 80% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 50% w / w to about 80% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 60% w / w to about 80% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 50% w / w to about 75% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib is provided, wherein the pharmaceutical composition comprises about 60% w / w to about 75% w / w ibrutinib. In another embodiment, a pharmaceutical composition comprising at least 50% w / w ibrutinib is provided, wherein the pharmaceutical composition comprises both intraparticle and extraparticle components. In another embodiment, a pharmaceutical composition comprising at least 50% w / w ibrutinib is provided, wherein the pharmaceutical composition is prepared using a wet granulation method. In another embodiment, a pharmaceutical composition comprising at least 50% w / w ibrutinib, further comprising at least one pharmaceutically acceptable excipient.

[0207] In some embodiments, the pharmaceutical compositions described herein are prepared by a process including a wet granulation method.

[0208] In another embodiment, a solid tablet formulation comprising ibrutinib is provided, wherein the solid tablet formulation comprises at least about 20% w / w ibrutinib. In another embodiment, a solid tablet formulation comprising ibrutinib is provided, wherein the solid tablet formulation comprises about 20% w / w to about 90% w / w ibrutinib. In another embodiment, a high-load solid tablet formulation comprises at least 20% w / w or 30% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises at least 40% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 30% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 40% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 40% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients. In yet another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients.

[0209] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the excipients are present in an amount of about 10% w / w to about 50% w / w. In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the excipients are present in an amount of about 10% w / w to about 50% w / w. In another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the excipients are present in an amount of about 20% w / w to about 40% w / w. In another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 25% w / w to about 40% w / w.

[0210] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from lactose, sucrose (e.g., Dipac), etc. ® ), glucose, glucose binding agents, maltodextrin, mannitol, xylitol (e.g., Xylitab) ® ), sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose (e.g., Avicel) ®The diluent comprises the group consisting of cellulose, microcrystalline cellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w, or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose (e.g., Methocel). ® The group comprises: coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums. In some embodiments, the disintegrant is sodium coscamelles; and sodium coscamelles is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone (e.g., PVP K15, PVP K19, PVPK25, PVP K30, Povidone). ® CL, Kollidon ® CL, Polyplasdone ®XL-10 and Povidone ® (K-12). In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1 to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate (SLS). In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients comprise lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0211] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0212] In another embodiment, a high-load solid tablet formulation comprises at least 50% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0213] In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0214] In another embodiment, a high-load solid tablet formulation comprises approximately 50% w / w to approximately 90% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0215] In another embodiment, a high-load solid tablet formulation comprises approximately 50% w / w to approximately 90% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0216] In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0217] In another embodiment, a high-load solid tablet formulation comprises approximately 50% w / w to approximately 80% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0218] In another embodiment, a high-load solid tablet formulation comprises about 50% w / w to about 80% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, microcrystalline cellulose, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0219] In another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0220] In another embodiment, a high-load solid tablet formulation comprises approximately 60% w / w to approximately 80% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0221] In another embodiment, a high-load solid tablet formulation comprises approximately 60% w / w to approximately 80% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0222] In another embodiment, a high-load solid tablet formulation comprises about 60% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein these excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeler, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0223] In another embodiment, a high-load solid tablet formulation comprises approximately 60% w / w to approximately 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0224] In another embodiment, a high-load solid tablet formulation comprises approximately 60% w / w to approximately 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the in-particle excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles; and the out-of-particle excipients comprise sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, the in-particle excipients comprise: Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and The excipients for the particulate matter include: Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0225] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Approximately 13% w / w to approximately 15% w / w lactose monohydrate, c) Microcrystalline cellulose of approximately 2% w / w to approximately 5% w / w d) Polyvinylpyrrolidone, approximately 1% w / w to approximately 3% w / w e) Sodium coscammeler at approximately 6% w / w to approximately 8% w / w f) Sodium lauryl sulfate, approximately 1% w / w to approximately 4% w / w g) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and h) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0226] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 5% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 1% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0227] In one embodiment, the tablet formulation is as described above, with sodium coscammeler at about 5% internal and about 2% external. In another embodiment, sodium lauryl sulfate is at about 1% internal and about 0% external.

[0228] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose monohydrate, c) Approximately 2% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 4% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0229] In one embodiment, the tablet formulation is as described above, with sodium coscammeler at about 5% inner and about 2% outer. In another embodiment, sodium lauryl sulfate is at about 1% inner and about 3% outer.

[0230] In another embodiment, the high-load solid tablet comprises lactose, polyvinylpyrrolidone, sodium lauryl sulfate, crospovidone, colloidal silica, and magnesium stearate. In yet another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 65% ​​w / w to approximately 75% w / w, or approximately 70% w / w. b) Approximately 14% w / w to approximately 18% w / w, or approximately 16% w / w, of lactose monohydrate. c) Polyvinylpyrrolidone of about 1% w / w to about 3% w / w, or about 2% w / w d) Sodium lauryl sulfate, approximately 0.5% w / w to approximately 1.5% w / w, or approximately 1% w / w. e) Approximately 5% w / w to approximately 15% w / w, or approximately 10% w / w, of cropovidone. f) Colloidal silica of about 0.3% w / w to about 0.7% w / w, or about 0.5% w / w, and g) Magnesium stearate of about 0.3% w / w to about 0.7% w / w, or about 0.5% w / w.

[0231] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 15% w / w d) Sodium coscammeler, approximately 4% w / w to approximately 6% w / w e) Sodium lauryl sulfate at approximately 5% w / w to approximately 7% w / w f) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and g) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0232] In some implementations, the total weight of the tablet is approximately 934 mg.

[0233] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose at approximately 13% w / w to approximately 14% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 14% w / w d) Sodium coscammeler (in granules) of approximately 2% w / w to approximately 3% w / w. e) Hydroxypropyl cellulose, approximately 0.8% w / w to approximately 1.2% w / w f) Sodium coscammeler (extragranular) at approximately 2% w / w to approximately 3% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0234] In some implementations, the total weight of the tablet is approximately 934 mg.

[0235] In another embodiment, a high-load solid tablet formulation comprises: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose at approximately 8% w / w to approximately 9% w / w c) Approximately 8 to 9% w / w microcrystalline cellulose, d) Sodium coscamelles (in granules) at approximately 2.5 to approximately 3.5% w / w. e) Sodium coscammeler (extragranular) at approximately 2.5 to approximately 3.5% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Approximately 0.4% w / w to approximately 0.6% w / w of magnesium stearate.

[0236] In some embodiments of the tablets described herein, the total weight of the tablet is from about 50 mg to about 1.2 g, such as about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1.2 g, or any range between any two of these values, with the endpoints included. In some embodiments, the total weight of the tablet is about 800 mg.

[0237] In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is from about 35 mg to about 840 mg per tablet, such as about 35 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg, or any range between any two of these values, including the endpoints. In some embodiments of the high-load solid tablet formulation described herein, the amount of ibrutinib is about 560 mg. In some embodiments of the high-load solid tablet formulation described herein, ibrutinib is in a micronized form. In some embodiments of the high-load solid tablet formulation described herein, the formulation is for once-daily dosing. In some embodiments of the high-load solid tablet formulation described herein, the formulation is an oral dosage form containing a therapeutically effective amount of ibrutinib.

[0238] In some implementations, the high-load solid tablet formulations described herein are prepared by a process including a wet granulation method.

[0239] In another embodiment, it is a method of treating a disease in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0240] In another embodiment, a method for treating an autoimmune disease in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient. In some embodiments, the autoimmune disease is rheumatoid arthritis or lupus. In another embodiment, a method for treating rheumatoid arthritis in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient. In another embodiment, a method for treating lupus in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient.

[0241] In another embodiment, it is a method of treating a patient with a xenoimmune disease in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0242] In another embodiment, a method of treating cancer in a patient requiring treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein. In some embodiments, the cancer is a B-cell proliferative disorder. In some embodiments, the cancer is a B-cell proliferative disorder and the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. In some embodiments, the cancer is a B-cell proliferative disorder and the B-cell proliferative disorder is diffuse large B-cell lymphoma. In some embodiments, the cancer is a B-cell proliferative disorder and the B-cell proliferative disorder is follicular lymphoma.

[0243] In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is mantle cell lymphoma (MCL). In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is a B-cell malignancy and the B-cell malignancy is multiple myeloma.

[0244] In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is lymphoma, leukemia, or a solid tumor. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is leukemia. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is a solid tumor.

[0245] In another embodiment, a method of treating cancer in a patient requiring treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis. In another embodiment, a method of treating cancer in a patient requiring treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is diffuse large B-cell lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is follicular lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is chronic lymphocytic lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is chronic lymphocytic leukemia. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is B-cell prolymphocytic leukemia. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is lymphoplasmacytic lymphoma / Waldenström macroglobulinemia. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is splenic marginal zone lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is plasmacytoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is plasmacytoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is extranodal marginal zone B-cell lymphoma.In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is a nodal marginal zone B-cell lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is a mantle cell lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is a mediastinal (thymic) large B-cell lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is an intravascular large B-cell lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is a primary exudative lymphoma. In another embodiment, a method of treating cancer in a patient in need of treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient, wherein the cancer is Burkitt lymphoma / leukemia. In another embodiment, it is a method of treating cancer in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein, wherein the cancer is lymphomatoid granulomatosis.

[0246] In some embodiments, the composition is used to treat sarcomas or carcinomas. In some embodiments, the composition is used to treat sarcomas. In some embodiments, the composition is used to treat carcinomas. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft tissue sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; soft tissue clear cell sarcoma; dedifferentiated liposarcoma; desmoid fibroma; connective tissue proliferative small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; sensory neuroblastoma; Ewing sarcoma; extrarenal rhabdomyosarcoma; extraosseous myxoid chondrosarcoma; extraosseous osteosarcoma; fibrosarcoma; giant cell tumor; hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi's sarcoma; bone leiomyosarcoma; liposarcoma; osteoliposarcoma; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma of bone (MFH); malignant mesenchymal tumor; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxoid fibrosarcoma; myxoid liposarcoma; myxoid inflammatory fibroblastic sarcoma; vegetations with perivascular epithelioid cell differentiation; osteosarcoma; periosseous osteosarcoma; vegetations with perivascular epithelioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET / extraosseous Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; capillary dilatational osteosarcoma. In some embodiments, the tumor is selected from adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the solid tumor is selected from anal cancer; appendix cancer; cholangiocarcinoma (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; HER2-amplified breast cancer; cervical cancer; colon cancer; unexplained primary cancer (CUP); esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer; renal cell carcinoma; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; pancreatic ductal carcinoma; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; gastric cancer; testicular cancer; laryngeal cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the tumor is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the tumor is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma or islet cell carcinoma. In some embodiments, the tumor is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colonic polyp. In some embodiments, the colonic polyp is associated with familial adenomatous polyposis. In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.In some embodiments, the tumor is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the tumor is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the tumor is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the tumor is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct cancer or distal bile duct cancer.

[0247] In another embodiment, it is a method of treating mastocytosis in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0248] In another embodiment, a method for treating osteoporosis or bone resorption in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient. In another embodiment, a method for treating osteoporosis in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient. In another embodiment, a method for treating bone resorption in a patient requiring treatment includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient.

[0249] In another embodiment, it is a method of treating an inflammatory disease or condition in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0250] In another embodiment, it is a method of treating lupus in a patient who requires treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein.

[0251] In another aspect, there is a process for preparing the pharmaceutical compositions described herein, wherein such process includes a wet granulation method.

[0252] In another aspect, there is a process for preparing a pharmaceutical composition comprising ibrutinib, wherein ibrutinib is a compound having the structure of compound 1. Compound 1; This process includes a wet granulation method; and the pharmaceutical composition contains at least 50% w / w ibrutinib.

[0253] In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 30% w / w to about 90% w / w ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 40% w / w to about 90% w / w ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 50% w / w to about 90% w / w ibrutinib. In yet another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 40% w / w to about 80% w / w ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 50% w / w to about 80% w / w ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 60% w / w to about 80% w / w ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 50% w / w to about 75% w / w ibrutinib. In yet another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib is provided, wherein the process includes a wet granulation method and the pharmaceutical composition comprises about 60% w / w to about 75% w / w ibrutinib.

[0254] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 30% w / w ibrutinib, and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In yet another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 40% w / w ibrutinib, and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In another embodiment, a process for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib and one or more pharmaceutically acceptable excipients is provided, wherein the process includes a wet granulation method. In another embodiment, a process for preparing a high-load solid tablet formulation comprising about 30% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients is provided, wherein the process includes a wet granulation method. In another embodiment, a process for preparing a high-load solid tablet formulation comprising about 40% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients is provided, wherein the process includes a wet granulation method. In yet another embodiment, a process for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients is provided, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 40% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In yet another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method.In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method. In yet another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients, wherein the process includes a wet granulation method.

[0255] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, about 50% w / w to about 90% w / w ibrutinib, about 50% w / w to about 80% w / w ibrutinib, about 60% w / w to about 80% w / w ibrutinib, or about 60% w / w to about 75% w / w ibrutinib, and one or more pharmaceutically acceptable excipients present in an amount of about 10% w / w to about 50% w / w, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, and one or more pharmaceutically acceptable excipients present in an amount not exceeding about 50% w / w, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib and one or more pharmaceutically acceptable excipients present in a total amount of about 10% w / w to about 50% w / w, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients present in a total amount of about 20% w / w to about 50% w / w, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib and one or more pharmaceutically acceptable excipients present in a total amount of about 20% w / w to about 40% w / w, wherein the process includes a wet granulation method. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib and one or more pharmaceutically acceptable excipients present in a total amount of about 25% w / w to about 40% w / w, wherein the process includes a wet granulation method.

[0256] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib and one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants, wherein the process includes a wet granulation method. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0257] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0258] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising at least 50% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0259] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants. In some embodiments, at least one excipient is a diluent, wherein the process includes a wet granulation method. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0260] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0261] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0262] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants, wherein the process includes a wet granulation method. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0263] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib and in-particle and out-of-particle excipients, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0264] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib, and in-particle and out-of-particle excipients, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0265] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants, wherein the process includes a wet granulation method. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0266] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib, and in-particle and out-of-particle excipients, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0267] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib, and in-particle and out-of-particle excipients, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In yet another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0268] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, flow aids, and surfactants, wherein the process includes a wet granulation method. In some embodiments, at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, glucose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is lactose; and lactose is present in an amount of about 8.5% w / w or about 14% w / w. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 1% w / w to about 2% w / w, about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w. In some embodiments, the diluent is microcrystalline cellulose and the microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w, or about 8.5% w / w or about 14% w / w. In some embodiments, the diluent comprises lactose and microcrystalline cellulose. In some embodiments, lactose is present in an amount of about 10% w / w to about 15% w / w and microcrystalline cellulose is present in an amount of about 1% w / w to about 6% w / w. In some embodiments, lactose is present in an amount of about 14% w / w and microcrystalline cellulose is present in an amount of about 2% w / w to about 5% w / w. In some embodiments, at least one excipient is a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, coscamelles, sodium coscamelles, croscarmellose sodium, croscarmellose, croscarmellose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crospovidone, croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums.In some embodiments, the disintegrant is sodium coscammeler; and sodium coscammeler is present in amounts of about 0 to about 20% w / w, about 1% w / w to about 10% w / w, about 5% w / w to about 10% w / w, about 6% w / w to about 8% w / w, about 4% w / w to about 6% w / w, or about 2% w / w to about 4% w / w. In some embodiments, at least one excipient is a binder. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in amounts of about 0 to about 10% w / w, about 1% to about 5% w / w, or about 2% w / w. In some embodiments, the binder is hydroxypropyl cellulose; and the hydroxypropyl cellulose is present in amounts of about 0 to about 10% w / w, about 0 to about 5% w / w, about 0 to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w. In some embodiments, the formulation comprises lactose, microcrystalline cellulose, sodium coscammeles, and hydroxypropyl cellulose. In some embodiments, at least one excipient is a surfactant. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate in amounts of about 0 to about 10% w / w, about 0.5% to about 5% w / w, about 1% to about 4% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w. In some embodiments, at least one excipient is a flow aid. In some embodiments, the flow aid is silica (colloidal silica). In some embodiments, the flow aid is silica (colloidal silica) and the silica (colloidal silica) is present in amounts of about 0 to about 5% w / w, 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, at least one excipient is a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and the magnesium stearate is present in amounts of about 0.01% w / w to about 5% w / w, 0.01% w / w to about 2% w / w, 0.1% w / w to about 0.7% w / w, or about 0.5% w / w to about 0.6% w / w. In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate.

[0269] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium coscamelles, and hydroxypropyl cellulose; and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 15% w / w, or about 8% w / w to about 14% w / w; Microcrystalline cellulose in amounts of about 5% w / w to about 20% w / w, about 8% w / w to about 20% w / w, or about 8% w / w to about 15% w / w; Sodium coscammeler in amounts of about 0% w / w to about 10% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 4% w / w; and Hydroxypropyl cellulose in amounts of about 0% w / w to about 2% w / w, about 0.1% w / w to about 1.1% w / w, or about 0.1% w / w to about 1% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of about 0% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 2% w / w to about 5% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w, about 4% w / w to about 8% w / w, or about 5% w / w to about 6% w / w; Colloidal silica in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.1% w / w to about 1.5% w / w, about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0270] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib, and in-particle and out-of-particle excipients; wherein the process includes a wet granulation method, the in-particle excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and sodium coscamelles, and the out-of-particle excipients comprising sodium coscamelles, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w ibrutinib, wherein the process includes a wet granulation method, the in-particle excipients comprising... Lactose in amounts of approximately 10% w / w to approximately 20% w / w, or approximately 12% w / w to approximately 15% w / w; Microcrystalline cellulose in amounts of approximately 1% w / w to approximately 10% w / w and approximately 2% w / w to approximately 5% w / w; Polyvinylpyrrolidone in amounts of about 0% w / w to about 5% w / w and about 1% w / w to about 3% w / w; Sodium coscammeler in amounts of about 1% w / w to about 10% w / w, or about 3% w / w to about 7% w / w; and Sodium lauryl sulfate in amounts of about 0% w / w to about 2% w / w and about 0.5% w / w to about 1.5% w / w; and External excipients for particulate matter contain Sodium saccharin in amounts of approximately 0% w / w to approximately 5% w / w and approximately 1% w / w to approximately 3% w / w; Sodium lauryl sulfate in amounts of about 0% w / w to about 10% w / w or about 0% w / w to about 4% w / w; Colloidal silica in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w; and Magnesium stearate in amounts of about 0.4% w / w to about 0.8% w / w, or about 0.5% w / w to about 0.6% w / w.

[0271] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and the formulation comprises: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose of approximately 2% w / w to approximately 5% w / w d) Polyvinylpyrrolidone, approximately 1% w / w to approximately 3% w / w e) Sodium coscammeler at approximately 6% w / w to approximately 8% w / w f) Sodium lauryl sulfate, approximately 1% w / w to approximately 4% w / w g) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and h) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0272] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and the formulation comprises: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose, c) Approximately 5% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 1% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0273] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and the formulation comprises: a) Ibrutinib at approximately 70% w / w b) Approximately 14% w / w lactose, c) Approximately 2% w / w microcrystalline cellulose, d) Approximately 2% w / w polyvinylpyrrolidone, e) Approximately 7% w / w of Coscamelles sodium, f) Approximately 4% w / w sodium lauryl sulfate, g) Approximately 0.5% w / w colloidal silica, and h) Approximately 0.5% w / w magnesium stearate.

[0274] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and wherein the formulation comprises: a) Ibrutinib at approximately 65% ​​w / w to approximately 75% w / w, or approximately 70% w / w. b) Approximately 14% w / w to approximately 18% w / w, or approximately 16% w / w, of lactose monohydrate. c) Polyvinylpyrrolidone of about 1% w / w to about 3% w / w, or about 2% w / w d) Sodium lauryl sulfate, approximately 0.5% w / w to approximately 1.5% w / w, or approximately 1% w / w. e) Approximately 5% w / w to approximately 15% w / w, or approximately 10% w / w, of cropovidone. f) Colloidal silica of about 0.3% w / w to about 0.7% w / w, or about 0.5% w / w, and g) Magnesium stearate of about 0.3% w / w to about 0.7% w / w, or about 0.5% w / w.

[0275] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and wherein the formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose from approximately 13% w / w to approximately 15% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 15% w / w d) Sodium coscammeler, approximately 4% w / w to approximately 6% w / w e) Sodium lauryl sulfate at approximately 5% w / w to approximately 7% w / w f) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and g) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0276] In some implementations, the total weight of the tablet is approximately 934 mg.

[0277] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and wherein the formulation comprises: a) Ibrutinib at approximately 59% w / w to approximately 61% w / w b) Lactose at approximately 13% w / w to approximately 14% w / w c) Microcrystalline cellulose, approximately 13% w / w to approximately 14% w / w d) Sodium coscammeler (in granules) of approximately 2% w / w to approximately 3% w / w. e) Hydroxypropyl cellulose, approximately 0.8% w / w to approximately 1.2% w / w f) Sodium coscammeler (extragranular) at approximately 2% w / w to approximately 3% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0278] In some implementations, the total weight of the tablet is approximately 934 mg.

[0279] In another embodiment, a process is provided for preparing a high-load solid tablet formulation comprising ibrutinib, wherein the process includes a wet granulation method, and wherein the formulation comprises: a) Ibrutinib at approximately 69% w / w to approximately 71% w / w b) Lactose at approximately 8% w / w to approximately 9% w / w c) Approximately 8 to 9% w / w microcrystalline cellulose, d) Sodium coscamelles (in granules) at approximately 2.5 to approximately 3.5% w / w. e) Sodium coscammeler (extragranular) at approximately 2.5 to approximately 3.5% w / w. g) Sodium lauryl sulfate, approximately 5.5% to approximately 6.5% w / w. h) Colloidal silica of about 0.4% w / w to about 0.6% w / w, and i) Magnesium stearate of about 0.4% w / w to about 0.6% w / w.

[0280] In some implementations, the total weight of the tablet is approximately 800 mg.

[0281] In some embodiments of the high-load solid tablet formulation described herein, which comprises ibrutinib and is prepared using a wet granulation method, the amount of ibrutinib is approximately 560 mg. In some embodiments of the high-load solid tablet formulation described herein, which comprises ibrutinib and is prepared using a wet granulation method, ibrutinib is in a micronized form. In some embodiments of the high-load solid tablet formulation described herein, which comprises ibrutinib and is prepared using a wet granulation method, the formulation is intended for once-daily dosing. In some embodiments of the high-load solid tablet formulation described herein, which comprises ibrutinib and is prepared using a wet granulation method, the formulation is an oral dosage form containing a therapeutically effective amount of ibrutinib.

[0282] Furthermore, the pharmaceutical compositions described herein, including compound 1, can be formulated into any suitable dosage form, including (but not limited to) solid oral dosage forms, controlled-release formulations, rapid-melting formulations, effervescent formulations, tablets, powders, pills, capsules, delayed-release formulations, long-release formulations, pulsatile-release formulations, multi-particle formulations, and hybrid instantaneous and controlled-release formulations. In some embodiments, the tablets described herein are intended for instantaneous release and do not contain thickeners such as poloxamer or glyceryl behenate.

[0283] In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets, including suspension tablets, fast-melting tablets, chewable tablets, rapidly disintegrating tablets, effervescent tablets, or capsules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In other embodiments, the pharmaceutical formulation is in the form of tablets, including (but not limited to) fast-melting tablets. Additionally, the pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in two, three, or four tablets.

[0284] In some embodiments, the compositions described herein are prepared by mixing particles of Compound 1 with one or more pharmaceutical excipients to form a bulk blended composition. When these bulk blended compositions are referred to as homogeneous, it means that the particles of Compound 1 are uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit doses may also include a film coating that disintegrates upon oral ingestion or upon contact with a diluent.

[0285] In some embodiments, the wet granulation method includes granulating a mixture of ibrutinib and an intragranular excipient under granulation conditions, such as high-shear granulation conditions, with a granulation liquid, such as purified water, to form granules.

[0286] In some embodiments, the compositions or formulations described herein are prepared by methods comprising (1) mixing ibrutinib with intragranular excipients, such as fillers, binders, disintegrants, and surfactants; (2) granulating the mixture of ibrutinib and intragranular excipients under high-shear granulation conditions with purified water or an aqueous binder solution to form granules; (3) drying the granules to form dry granules; (4) grinding the dry granules; (5) blending the ground granules with extragranular excipients, such as fillers, disintegrants, surfactants, and lubricants; and (6) compressing the mixture of ground granules and extragranular excipients to form tablets.

[0287] The pharmaceutical compositions or formulations described herein may further include flavoring agents, sweeteners, coloring agents, antioxidants, preservatives, or one or more combinations thereof. In other respects, standard coating procedures are used, such as those outlined in Remington's Pharmaceutical Sciences (…). Remington's Pharmaceutical Sciences The formulations of Compound 1 described in the 20th edition (2000) of the [Journal Name] provide film coatings. In one embodiment, some or all of the particles of Compound 1 are coated. In another embodiment, some or all of the particles of Compound 1 are microencapsulated. In yet another embodiment, the particles of Compound 1 are not microencapsulated and are not coated.

[0288] Suitable antioxidants used in the compositions or formulations described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0289] It should be understood that there is considerable overlap among the additives used in the solid dosage forms described herein. Therefore, the additives listed above should be considered merely illustrative and do not limit the types of additives that may be included in the compositions or formulations described herein. The amount of such additives can be readily determined by those skilled in the art based on the specific properties required.

[0290] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulation described above. In various embodiments, the compressed tablets, designed to dissolve in the mouth, will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, film coating may provide a delayed release of compound 1 from the formulation. In other embodiments, film coating may contribute to patient compliance (e.g., Opadry). ® Coating or sugar coating). Including Opaldy. ® The film coating typically ranges from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablet includes one or more excipients.

[0291] In some embodiments, the compositions or formulations described herein can be formulated into enteric-coated delayed-release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize enteric coating to influence release in the small intestine of the gastrointestinal tract. Enteric-coated dosage forms can be compressed or molded or extruded tablets / molds (coated or uncoated) containing granules, powders, pellets, beads, or particles that are themselves coated or uncoated as active ingredients and / or other components. Enteric-coated oral dosage forms can also be capsules (coated or uncoated) containing pellets, beads, or granules containing themselves coated or uncoated as solid carriers or compositions.

[0292] As used herein, the term "delayed release" refers to delivery intended to achieve release at a generally predictable location in the gut, more distal than a release would have been achieved without the presence of a delayed release variation. In some embodiments, a method for delayed release is coating. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at pH below about 5, but dissolves at pH about 5 and above. Any anionic polymer intended to exhibit a pH-dependent solubility pattern can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, some of the polymers and their compatible mixtures, and their properties, include (but are not limited to): Shellac, also known as purified lac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH > 7. Acrylic polymers. The properties of acrylic polymers (primarily their solubility in biofluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylic acid copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as soluble in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and primarily used for colonic targeting. Eudragit series E is soluble in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach but soluble in the intestine. Cellulose derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of cellulose with phthalic anhydride metaacetate. Properties can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) is soluble at pH > 6. Aquateric (FMC) is an aqueous system and a spray-dried CAP pseudo-latex with particles < 1 μm. Other components in Aquateric may include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose succinate (e.g., AQOAT (ShinEtsu)). Properties can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable. Performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose succinate include (but are not limited to) AS-LG (LF), soluble at pH 5; AS-MG (MF), soluble at pH 5.5; and AS-HG (HF), soluble at higher pH levels. These polymers are provided as granules or as fine powders for aqueous dispersions; polyvinyl acetate phthalate (PVAP). PVAP is soluble at pH > 5 and has much lower permeability to water vapor and gastric juices.

[0293] In some embodiments, the coating may and typically contains plasticizers and other coating excipients, such as colorants, talc, and / or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetylated triethyl citrate (Citroflex A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers will typically contain 10-25% by weight of plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray or pan coating, are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of local delivery in the intestine.

[0294] In addition to plasticizers, colorants, anti-sticking agents, surfactants, defoamers, and lubricants (such as carnuba wax or PEG) can be added to the coating to dissolve or disperse the coating material and improve the coating performance and the coated product.

[0295] In other embodiments, formulations including Compound 1 described herein utilize pulsatile dosage forms for delivery. Pulsatile dosage forms are capable of providing one or more instantaneous release pulses at a predetermined time point after a controlled lag time or at a specific site. Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices; non-polymer-based systems that are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or natural fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax-coated, biocorrosive dosage forms, compressed tablets using conventional adhesives, etc. See, for example, Liberman et al., Pharmaceutical Dosage Forms (… Pharmaceutical Dosage Forms ), 2nd edition, Volume 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Medical Technology ( Encyclopedia of Pharmaceutical Technology ), 2nd edition, pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is specifically incorporated by reference.

[0296] In some embodiments, a pharmaceutical formulation is provided comprising particles of compound 1 and at least one dispersant or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, and upon mixing with water, yields a substantially homogeneous suspension.

[0297] It should be understood that there is overlap among the additives listed above used in the aqueous dispersions or suspensions described herein, because given additives are often classified differently by different practitioners in the field, or are generally used for any of several different functions. Therefore, the additives listed above should be considered merely illustrative and do not limit the types of additives that may be included in the formulations described herein. The amount of such additives can be readily determined by those skilled in the art based on the specific properties required.

[0298] Dosage and treatment regimen In some embodiments, the amount of compound 1 administered to mammals is from 300 mg / day to and includes 1000 mg / day. In some embodiments, the amount of compound 1 administered to mammals is from 420 mg / day to and includes 840 mg / day. In some embodiments, the amount of compound 1 administered to mammals is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of compound 1 administered to mammals is about 420 mg / day. In some embodiments, the amount of compound 1 administered to mammals is about 560 mg / day. In some embodiments, the AUC of compound 1... 0-24 The concentration ranges from approximately 150 to approximately 3500 ng•h / mL. In some embodiments, the AUC of compound 1 is... 0-24 The concentration is between approximately 500 and approximately 1100 ng•h / mL. In some embodiments, compound 1 is administered orally. In some embodiments, compound 1 is administered once daily, twice daily, or three times daily. In some embodiments, compound 1 is administered daily. In some embodiments, compound 1 is administered once daily. In some embodiments, compound 1 is administered every other day. In some embodiments, compound 1 is a maintenance therapy.

[0299] Compound 1 can be used to prepare pharmaceutical agents for inhibiting Btk or its homologs, or for treating diseases or conditions that would at least partially benefit from inhibition of Btk or its homologs, including subjects diagnosed with hematologic malignancies. Additionally, methods of treating any of the diseases or conditions described herein in subjects requiring treatment involve administering a pharmaceutical composition containing Compound 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate to said subject in a therapeutically effective amount.

[0300] The composition containing compound 1 can be administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the composition containing compound 1 is administered for therapeutic use (e.g., to a subject diagnosed with a hematologic malignancy). In some embodiments, the composition containing compound 1 is administered for therapeutic use (e.g., to a subject who is susceptible to or otherwise at risk of developing a hematologic malignancy). In some embodiments, the composition containing compound 1 is administered as maintenance therapy to a patient in remission.

[0301] The amount of compound 1 will depend on the intended use (e.g., therapeutic, prophylactic, or maintenance). The amount of compound 1 will depend on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. It is well understood within the art that an effective amount for such treatment will be determined through routine experimental procedures, including (but not limited to) dose-escalation clinical trials. In some embodiments, the amount of compound 1 is from 300 mg / day to and includes 1000 mg / day. In some embodiments, the amount of compound 1 is from 420 mg / day to and includes 840 mg / day. In some embodiments, the amount of compound 1 is from 400 mg / day to and includes 860 mg / day. In some embodiments, the amount of compound 1 is about 360 mg / day. In some embodiments, the amount of compound 1 is about 420 mg / day. In some embodiments, the amount of compound 1 is about 560 mg / day. In some embodiments, the amount of compound 1 is about 840 mg / day. In some embodiments, the amount of compound 1 is from 2 mg / kg / day to 13 mg / kg / day. In some embodiments, the amount of compound 1 is from 2.5 mg / kg / day to 8 mg / kg / day. In some embodiments, the amount of compound 1 is from 2.5 mg / kg / day to 6 mg / kg / day. In some embodiments, the amount of compound 1 is from 2.5 mg / kg / day to 4 mg / kg / day. In some embodiments, the amount of compound 1 is about 2.5 mg / kg / day. In some embodiments, the amount of compound 1 is about 8 mg / kg / day.

[0302] In one embodiment, a tablet formulation of the present invention with a dose of 140 mg in dogs produces approximately 260 to 400 ng / mL (on an empty stomach) and approximately 300 to 400 ng / mL (fasting) C. max In another embodiment, the formulation produces approximately 280 to 380 ng / mL (feeding) and approximately 360 to 380 ng / mL (fasting) of C. max In one particular implementation, the formulation produces approximately 290 ng / mL (feeding) and approximately 370 ng / mL (fasting) of C. max In another specific embodiment, the formulation produces approximately 370 ng / mL (feeding) and approximately 370 ng / mL (fasting) of C. max In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In a particular embodiment, the tablet formulation is formulation BK21A. In another particular embodiment, the tablet formulation is formulation BK21B. (Tables 1E and 1F).

[0303] In one embodiment, a tablet formulation of the present invention with a dose of 140 mg in dogs produces an AUC of about 850 to 1050 ng·h / mL (on an empty stomach) and about 850 to 1050 ng·h / mL (fasting). In another embodiment, the formulation produces an AUC of about 870 to 1050 ng·h / mL (on an empty stomach) and about 840 to 1000 ng·h / mL (fasting). In a particular embodiment, the formulation produces an AUC of about 875 ng·h / mL (on an empty stomach) and about 1000 ng·h / mL (fasting). In another particular embodiment, the formulation produces an AUC of about 1000 ng·h / mL (on an empty stomach) and about 850 ng·h / mL (fasting). In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In a particular embodiment, the tablet formulation is formulation BK21A. In another specific embodiment, the tablet formulation is formulation BK21B (Tables 1E and 1F).

[0304] In one embodiment, the tablet formulation of the present invention with a dose of 140 mg in dogs produces approximately 150-250 (on an empty stomach) and 100-160 (on a fasting stomach). rel (Tablets / Capsules) (C) max ) values. In one particular implementation, the formulation produces approximately 170 (feeding) and approximately 110 (fasting) %F. rel (Tablets / Capsules) (C) max In another specific embodiment, the formulation produces approximately 230 (feeding) and approximately 150 (fasting) %F. rel (Tablets / Capsules) (C) max Value. In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In one particular embodiment, the tablet formulation is formulation BK21A. In another particular embodiment, the tablet formulation is formulation BK21B. (Tables 1E and 1F).

[0305] In one embodiment, the tablet formulation of the present invention with a dose of 140 mg in dogs produces approximately 110-150 (on an empty stomach) and 100-140 (on a fasting stomach). rel (Tablets / capsules) (AUC) values. In one particular embodiment, the formulation produces approximately 120 (eaten) and approximately 110 (fasting) %F rel (Tablets / capsules) (AUC) value. In another specific embodiment, the formulation produces approximately 150 (eaten) and approximately 130 (fasting) %F. rel(Tablet / Capsule) (AUC) value. In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In one particular embodiment, the tablet formulation is formulation BK21A. In another particular embodiment, the tablet formulation is formulation BK21B. (Tables 1E and 1F).

[0306] In one embodiment, the tablet formulation of the present invention having a dose of 140 mg in dogs produces approximately 90-105% F. rel (Eating / Fasting) (C) max ) value. In one particular implementation, the formulation produces approximately 95% F. rel (Eating / Fasting) (C) max ) value. In another specific embodiment, the formulation produces approximately 100%F rel (Eating / Fasting) (C) max Value. In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In one particular embodiment, the tablet formulation is formulation BK21A. In another particular embodiment, the tablet formulation is formulation BK21B. (Tables 1E and 1F).

[0307] In one embodiment, the tablet formulation of the present invention having a dose of 140 mg in dogs produces approximately 90-140% F. rel (Feeding / Fasting) (AUC) value. In one particular implementation, the formulation produces approximately 100% F rel (Fasting / Intake) (AUC) value. In one embodiment, the formulation is a wet granulation formulation. In one embodiment, the tablet formulation is formulation BK02, BK21A, or BK21B. In one particular embodiment, the tablet formulation is formulation BK21A. In another particular embodiment, the tablet formulation is formulation BK21B. (Tables 1E and 1F).

[0308] In some embodiments, the pharmaceutical composition described herein comprises about 140 mg of compound 1. In some embodiments, a tablet formulation comprising about 140 mg of compound 1 is prepared. In some embodiments, two, three, four, or five tablets are administered daily. In some embodiments, three or four capsules are administered daily. In some embodiments, the tablets are administered once daily. In some embodiments, the capsules are administered once daily. In other embodiments, the tablets are administered multiple times daily.

[0309] In another aspect, there is a high-load solid tablet formulation containing ibrutinib, wherein ibrutinib is a compound having the structure of compound 1. Compound 1; The tablet contains approximately 560 mg of ibrutinib.

[0310] In another embodiment, a high-load solid tablet formulation is provided, wherein the tablet is for once-daily oral administration. The high-load solid tablet formulation described herein enables administration of one tablet per day and each tablet contains a large amount of ibrutinib, such as about 420 mg to about 840 mg, including values ​​such as about 420 mg, about 560 mg, or about 840 mg, or any range between these values, with the endpoints included. In another embodiment, a high-load solid tablet formulation is provided, wherein the tablet contains 560 mg of ibrutinib. In another embodiment, a high-load solid tablet formulation is provided, wherein ibrutinib is in a micronized form.

[0311] In some embodiments, compound 1 is administered daily. In some embodiments, compound 1 is administered every other day.

[0312] In some embodiments, compound 1 is administered once daily. In some embodiments, compound 1 is administered twice daily. In some embodiments, compound 1 is administered three times daily. In some embodiments, compound 1 is administered three times daily.

[0313] In some embodiments, compound 1 is administered until disease progression, unacceptable toxicity, or individual choice. In some embodiments, compound 1 is administered daily until disease progression, unacceptable toxicity, or individual choice. In some embodiments, compound 1 is administered every other day until disease progression, unacceptable toxicity, or individual choice.

[0314] If the patient's condition improves, the compound may be administered continuously upon the physician's judgment; alternatively, the dosage of the currently administered drug may be temporarily reduced or discontinued for a certain period of time (i.e., a "withdrawal period"). The length of the withdrawal period can vary between 2 days and 1 year, including (for example only) 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the withdrawal period can be 10%-100%, including (for example only) 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0315] Once the patient's symptoms have improved, a maintenance dose is administered if necessary. Subsequently, the dose or frequency, or both, may be reduced as symptoms change until the improved condition, symptom, or symptom is maintained at a level that allows the patient to maintain the improvement. The patient may then require long-term intermittent treatment following any recurrence of symptoms.

[0316] The amount of medication administered corresponding to such a quantity will vary depending on factors such as the specific compound, the severity of the disease, and the identity of the subject or host requiring treatment (e.g., weight), but can still be routinely determined in a manner known in the art based on the specific circumstances surrounding the case, including, for example, the specific medication being administered, the route of administration, and the subject or host being treated. Generally, however, the dosage used for adult treatment will typically range from 0.02 to 5000 mg daily or about 1 to 1500 mg daily. The required dosage can conveniently be presented as a single dose or as multiple doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, two, three, four, or more sub-dose daily.

[0317] The pharmaceutical compositions or formulations described herein may be in unit dosage forms suitable for precise single-dose administration. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses may be in packaging containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-resealable containers. Alternatively, multi-dose, resealable containers may be used, in which case a preservative is typically included in the composition. In some embodiments, each unit dosage form contains 140 mg of compound 1. In some embodiments, one unit dosage form is administered to an individual daily. In some embodiments, two unit dosage forms are administered to an individual daily. In some embodiments, three unit dosage forms are administered to an individual daily. In some embodiments, four unit dosage forms are administered to an individual daily.

[0318] The aforementioned ranges are merely illustrative, as the number of variables relating to individual treatment regimens is substantial, and considerable deviations from these recommended values ​​are not uncommon. Such dosages can vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's needs, the severity of the disease or condition being treated, and the physician's judgment.

[0319] The toxicity and efficacy of these treatment regimens can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, including (but not limited to) LD50. 50 (The dose that would cause 50% mortality in the population) and ED 50Determination of the effective dose (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index and can be expressed as LD50. 50 With ED 50 The ratio between these values. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to determine the range of dosages for human use. The dosage of such compounds is preferably within the range of the optimal therapeutic index (EDI) with minimal toxicity. 50 The circulating concentration range. Depending on the dosage form and route of administration, the dosage can vary within this range.

[0320] Combination therapy In some cases, it is appropriate to administer compound 1 in combination with another therapeutic agent.

[0321] In one embodiment, the compositions and methods described herein are also used in combination with other therapeutic agents selected for their specific suitability for the condition being treated. Generally, the compositions described herein, and other agents employed in embodiments employing combination therapy, do not necessarily need to be administered in the same pharmaceutical composition, and are therefore administered via different routes due to their different physical and chemical characteristics. In one embodiment, initial administration is performed according to a predetermined regimen, and then the dosage, administration pattern, and timing are further modified based on observed effects.

[0322] In various implementations, compounds are administered in parallel (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially, depending on the nature of the disease, the patient's condition, and the actual choice of compounds used. In some implementations, the determination of the order of administration and the number of times each therapeutic agent is administered during the treatment regimen are based on an assessment of the disease being treated and the patient's condition.

[0323] For the combination therapy described in this article, the dosage of the co-administered compounds varies depending on the type of co-drug used, the specific drug used, the disease or condition being treated, and so on.

[0324] Individual compounds in such combinations are administered sequentially or simultaneously in pharmaceutical formulations, either alone or in combination. In one embodiment, individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate dosages of known therapeutic agents will be understood by those skilled in the art.

[0325] The combinations mentioned herein are conveniently presented together with pharmaceutically acceptable diluents or carriers for use in the form of pharmaceutical compositions.

[0326] In some embodiments, this document discloses a method for treating cancer in an individual in need, comprising: administering a measured amount of compound 1 to the individual. In some embodiments, this method further comprises administering a second cancer treatment regimen.

[0327] In some implementations, administering a Btk inhibitor prior to a second cancer treatment reduces the immune-mediated response to the second treatment. In some implementations, administering compound 1 prior to ofatumumab reduces the immune-mediated response to ofatumumab.

[0328] In some embodiments, the second cancer treatment regimen includes chemotherapy agents, steroids, immunotherapy agents, targeted therapy, or combinations thereof. In some embodiments, the second cancer treatment regimen includes a B-cell receptor pathway inhibitor. In some embodiments, the B-cell receptor pathway inhibitor is a CD79A inhibitor, CD79B inhibitor, CD19 inhibitor, Lyn inhibitor, Syk inhibitor, PI3K inhibitor, Blnk inhibitor, PLCγ inhibitor, PKCβ inhibitor, or a combination thereof. In some embodiments, the second cancer treatment regimen includes antibodies, B-cell receptor signaling inhibitors, PI3K inhibitors, IAP inhibitors, mTOR inhibitors, immunochemotherapy, radioimmunotherapy agents, DNA damaging agents, proteasome inhibitors, Cyp3A4 inhibitors, histone deacetylase inhibitors, protein kinase inhibitors, hedgehog inhibitors, Hsp90 inhibitors, telomerase inhibitors, Jak1 / 2 inhibitors, protease inhibitors, PKC inhibitors, PARP inhibitors, or combinations thereof.

[0329] In some implementation schemes, the second cancer treatment regimen includes chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, oframumab, rituximab, dexamethasone, and prednisone. nisone), CAL-101, isobramomab, tositumomab, bortezomib, pentostatin, endostatin, EPOCH-R, DA-EPOCH-R, rifampin, selinexor, gemcitabine, obinutuzumab, carmustine, cytarabine, melphalan, ublituximab, palbociclib, ACP-196 (Acerta Pharma BV), TGR-1202 (TG Therapeutics, Inc.), TEDDI, TEDD, MEDI4736 (AstraZeneca), ABT-0199 (AbbVie), CC-122 (Celgene Corporation), LD-AraC, ketoconazole, etoposide, carboplatin, moxifloxacin, citrovorum, methotrexate, filgrastim, mesna, vincristine, cyclophosphamide, erythromycin, voriconazole, nivolumab, or combinations thereof.

[0330] In some implementations, the second cancer treatment regimen includes cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab.

[0331] In some implementations, the second cancer treatment regimen includes bendamustine and rituximab.

[0332] In some implementations, the second cancer treatment regimen includes fludarabine, cyclophosphamide, and rituximab.

[0333] In some implementations, the second cancer treatment regimen includes cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.

[0334] In some implementations, the second cancer treatment regimen includes etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally, rituximab.

[0335] In some implementations, the second cancer treatment regimen includes dexamethasone and lenalidomide.

[0336] In some embodiments, the second cancer treatment comprises a proteasome inhibitor. In some embodiments, the second treatment comprises bortezomib. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises tetrapeptide epoxomib. In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulfram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

[0337] In some implementations, the second cancer treatment includes a Cyp3A4 inhibitor. In some implementations, the second cancer treatment includes indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, or nefazodone. In some implementations, the second cancer treatment includes ketoconazole.

[0338] In some implementations, the second cancer treatment includes a Janus kinase (JAK) inhibitor. In some implementations, the second treatment includes lettaurtinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or parcritinib.

[0339] In some implementations, the second cancer treatment comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some implementations, the second cancer treatment comprises isohydroxamic acid (or isohydroxamic acid salt), such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589); cyclic tetrapeptides, such as trapoxin B; phenyl condensates; benzamides, such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103); electrophilic ketones; or fatty acid compounds, such as phenylbutyrate and valproic acid.

[0340] Additional cancer treatment options include nitrogen mustards, such as bendamustine, chlormethicone, chlormethicone, cyclophosphamide, ifosfamide, melphalan, prednimustine, and trofosfamide; alkyl sulfonates, such as busulfan, mannosulfan, and treosulfan; ethyleneimines, such as carboquone, thiotepa, and triaziquone; and nitrosoureas, such as... Carmustine, formustine, lomustine, nimustine, ranimustine, semustine, streptozocin; epoxides, such as etoglucid; other alkylating agents, such as dacarbazine, mitobronitol, pipebroman, temozolomide; folic acid analogs, such as methotrexate, pemetrexed. Permetrexed, pralatrexate, raltitrexed; purine analogs, such as cladribine, clofarabine, fludarabine, mecaptopurine, nelarabine, tioguanine; pyrimidine analogs, such as azacitidine, capecitabine, carmofur, cytarabine, decitabine. Podophyllin derivatives, such as vinblastine, vindesine, vinflunine, and vinorelbine; podophyllotoxin derivatives, such as etoposide and teniposide; colchicine derivatives, such as demecolcine; taxanes, such as docetaxel, paclitaxel, and polyglutamate paclitaxel; and other plant alkaloids and natural products, such as trabectedin.Actinomycines, such as dactinomycin; anthracyclines, such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubincin; and other fine... Cytotoxic antibiotics, such as bleomycin, ixabepilone, mitomycin, and plicamycin; platinum compounds, such as carboplatin, cisplatin, oxaliplatin, and satraplatin; methylhydrazine, such as procarbazine; sensitizers, such as aminolevulinic acid, efaproxiral, methyl aminolevulinate, and porfimer. Sodium), temoporfin; protein kinase inhibitors, such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, tesimolimus;Other anti-hypertrophic agents include alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, and denileukin. Diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosein, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimageneceradenovec, tiazofurine, topotecan, tretinoin, vorinostatin; estrogens, such as diethylstilbenol, ethinylestradiol, fosfestrol, polyestradiol. Phosphate); progestins, such as gestonorone, medroxyprogesterone, and megestrol; gonadotropin-releasing hormone analogs, such as buserelin, goserelin, leuprorelin, and triptorelin; antiestrogens, such as fulvestrant, tamoxifen, and toremifene; antiandrogens, such as bicalutamide, flutamide, and nilutamide; enzyme inhibitors, such as aminoglutethimide, anastrozole, exemestane, formestane, letrozole, and vorozole; and other hormone antagonists, such as abarrelix and degarelix.Immunostimulants, such as histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, and thymopentin; immunosuppressants, such as everolimus, gusperimus, leflunomide, mycophenolic acid, and sirolimus; calcineurin inhibitors, such as cyclosporin and tacrolimus; other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, and thalidomide; and radiopharmaceuticals, such as iobenguane.

[0341] Additional cancer treatment options include interferon, interleukin, tumor necrosis factor, growth factors, and so on.

[0342] Additional cancer treatment options include immunostimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostim; interferons such as natural interferon α, interferon α-2a, interferon α-2b, interferon alfacon-1, interferon α-n1, natural interferon β, interferon β-1a, interferon β-1b, interferon γ, pegylated interferon α-2a, and pegylated interferon α-2b; interleukins such as aldesleukin and oprelvekin; and other immunostimulants such as BCG vaccine, glatirameracetate, histamine dihydrochloride, immunocyanin, and lentinan. Melanoma vaccine, mifamulin, pegademase, pidotimod, praxaviva, polyI:C, polyICLC, roquine mifat, tasonermin, thymopentin; immunosuppressants such as abatacept, abetimus, alefacept, anti-lymphocyte immunoglobulin (equine), anti-thymocyte immunoglobulin (rabbit), eculizumab, efalizumab. Everolimus, guaniolimus, leflunomide, muromab-CD3, mycophenolate mofetil, natalizumab, sirolimus; TNFα inhibitors, such as adalimumab, afelimomab, pegylated certolizumab, etanercept, golimumab, infliximab; interleukin inhibitors Drugs such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, and ustekinumab; calcineurin inhibitors such as cyclosporine and tacrolimus; and other immunosuppressants such as azathioprine, lenalidomide, methotrexate, and thalidomide.

[0343] Additional cancer treatment options include adalimumab, alemtuzumab, baliximab, bevacizumab, cetuximab, pegylated cetuzumab, daliximab, eculizumab, efazolinumab, gemtuzumab, isobrimumomabtiuxetan, infliximab, muromonab-CD3, nateximab, panitumumab, ranibizumab, rituximab, tosimomab, trastuzumab, etc., or combinations thereof.

[0344] Additional cancer treatment options include monoclonal antibodies such as alemtuzumab, bevacizumab, catutuxomab, cetuximab, edrecolomab, gemtuzumab, ofamumab, panitumumab, rituximab, trastuzumab; immunosuppressants such as eculizumab, efazolinumab, murazumab-CD3, natezumab; TNFα inhibitors such as adalimumab, afemoramab, pegylated cetuzumab, golimumab, infliximab; interleukin inhibitors such as balithimab, konnabumab, dalizumab, mepolizumab, tocilizumab, uterotumab; radiopharmaceuticals such as isbemumab / tetan, tosimomab; and other monoclonal antibodies.Examples of monoclonal antibodies include abagovomab, adecatumumab, alenumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, baliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, and capromab. Pendetide, Cixutumumab, Claudiximab, Conatumumab, Dacetuzumab, Denosumab, Iculizumab, Epratuzumab, Epratuzumab, Ertumaxomab, Etaracizumab, Figitumumab, Fresolimumab, Galiximab, Ganitumab, Gemtuzumab ozogamicin, Glembatumumab, Ibexomab, Intuzumab ozogamicin ozogamicin, ipilimumab, lexatumumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, oflamumab, oregovomab, pertuzumab The following are listed: zumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tosimomab, trastuzumab, tremelimumab, tucotuzumabcelmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0345] Additional cancer treatment options include agents that affect the tumor microenvironment, such as cell signaling networks (e.g., the phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from B-cell receptors and IgE receptors). In some embodiments, the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syc inhibitor is R788. In another embodiment, it is a PKCγ inhibitor, such as (by way of example) enzastaurin.

[0346] In some implementations, the additional therapeutic agent includes analgesics such as acetaminophen.

[0347] In some implementations, the additional therapeutic agent comprises an inhibitor selected from the following: LYN, SYK, JAK, PI3K, PLCγ, MAPK, MEK, or NFκB.

[0348] Examples of drugs that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, and protein kinase inhibitors, such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, parzonalib, sorafenib, sunitinib, and tesiromoximib; other angiogenesis inhibitors, such as GT-111, JI-101, and R1530; and other kinase inhibitors, such as AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, and BI. 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinacilib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076, fostamatinib disodium disodium), GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib (lini fanib), LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281RO5126766, XL418, XL765. .

[0349] Other examples of anticancer agents used in combination with Btk inhibitor compounds include inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[0350] Other anticancer agents that can be used in combination with Btk inhibitor compounds include adriamycin, actinomycin D, bleomycin, vincristine, cisplatin, acivicin; azorubicin; acodazole hydrochloride; acronine; adozelesin; interleukin; hexamethylmelamine; ambomycin; ametatrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; and bisnafide dimethylsulfonate. dimesylate); bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin C; calusterone; caracemide; carbetimer; carplatin; carmustine; carrubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine mesylate mesylate); diziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate.Eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; fluxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium sodium); gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II or rlL2); interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-la; interferon γ-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride hydrochloride); maserophenol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; mefarin; menogaril.Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitoclomin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotan; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoie; Nogalamycin; Ormaplatin; Oxisuran; Pepsisparin; Peliomycin; Pentamustine; Peplomycin sulfate sulfate); perfosfamide; pipesobromide; piposulfan; piroxantrone hydrochloride; plocamestane; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride hydrochloride); spiromustine; spiroplatin; streptonigrin; streptozotocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temopofol; teniposide; teroxirone; testolactone; thiamiprine; thioguanine.Thiazofamid; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tobaccochloride hydrochloride; uracil mustard; uredepa; vapreotide; vertepofluorfin; vinblastine sulfate; vincristine sulfate; vindesine sulfate; vinpidine sulfate; vinpyrine sulfate; vinleurosine sulfate; vinorelbine tartrate tartrate); vinrosidine sulfate; vinzolidine sulfate; vortexilazole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0351] Other anticancer agents that can be used in combination with Btk inhibitor compounds include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; arubicin; acylfulvene; adenypenol; adorexin; interleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; aifostine; aminolevulinic acid; amrubicin; acridine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1. Protein-1); anti-androgen, prostate cancer; anti-estrogen; anti-tumor ketone (antineoplaston); antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis modulator; apurinic acid; vidarabine-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III III) Derivatives; Balanol; Bamastastat; BCR / ABL antagonists; Benzochlorin; Benzoylstaurosporine; β-lactam derivatives; Beta-alethine; Beta-clarithromycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bistratene A; Breflate; Brompirimine; Budotitan; Butthionine sulfoximine; Calcipotriol; Calphostin CCamptothecin derivatives; canarypox IL-2; capecitabine; formamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; chondroitin inhibitors; canzelexin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorln; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; cromifene analogs; clotrimazole; colismycin A; colismycin B; comprbetastatin A4 A4); compretastatin analogues; conagenin; crabescidin 816; cristatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B B); deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diazoquinone; didennin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; dolasetol; dolastron; doxifluridine; droloxifen; dronabinolDuocarmycin SA SA); ebselen; ecomustine; edelfosine; eflornithine; elemene; emitefur; epirubicin; epristeride; estradiol analogues; estrogen agonists; estrogen antagonists; estradiol; etoposide phosphate; exemestane; fadrozole; fazalaline; retinoic acid; filgrastim; finasteride; flovipirol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestain; fostriecin; formustine; gadolinium Tetraphyrin); Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethylene diacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifen; Idramantone; Ilmofosine; Ilomastat; Imidazocone; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Iodobenzylguanidine; Iododoxorubicin; 4-Ipomocarboxylic acid 4-); Iroplact; Irsogladine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Legosteen; Lentinan sulfate;Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprolide; Levamisole; Liarozole; Linear polyamine analog; Lipophilic disaccharide peptide; Lipophilic platinum compound; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Clonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Cleavage peptide; Maitansine; Mannostatin A A); marimastat; masoprolol; mastin; matrixlysin inhibitor; matrix metalloproteinase inhibitor; menostatin; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saponin Factor-saporin); Mitoxantrone; Mofarotene; Moraxetin; Monoclonal antibody, Human chorionic gonadotropin; Monophosphoryl lipid A+ Mycobacterium cell wall SK; Mopidamol; Multidrug resistance gene inhibitor; Therapies based on multiple tumor suppressor factor 1; Mustard anticancer agents; Indian Ocean sponge B; Mycobacterium cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamide; Nafarelin; Nagrestip; Naloxone+pentazocine; Napavin; Naphterpin; Nartograstim.Nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilumethicone; nisamycin; nitric oxide regulator; nitrooxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; omaliplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid); panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; pephosphatamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitor; picibanil; pirocarpine hydrochloride; pirarubicin; piritrixim; placetin A; placetin B; platinum activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porphyrin sodium; pofibromycin; prednisone; propyl diacinone Bis-acridone); prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; RAF antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors;Demethylated retelliptine; rhenium Re 186 etidronate; rhizoxin; ribozyme; RII retinamide; rohitukine; romurtide; roquimetac; rubiginone B1; ruboxyl; safungo; saintopin; SarCNU; sarcophytol A; saxaglastine; Sdi 1. Analog; Semustine; Senescence-related inhibitor 1; Significant oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single-chain antigen-binding protein; Sizofiran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solvent; Somatostatin-binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongistatin 1 1) Squalamine; stem cell inhibitors; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; potent vasoactive intestinal peptide antagonists; suradista; suramin; swainsonine; synthetic glucosamine; tallimustine; tamoxifen methyliodide methiodide); tauromustine; tazarotene; tecogallan sodium; tegafur; tellurapyrylium; telomerase inhibitor; temopofol; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimics; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid-stimulating hormone; tin ethyletiopurpurpurin; teirazamine; titaniumocene bichloride.Topsentin; toremifene; pluripotent stem cell factor; translation inhibitors; retinoic acid; triacetyluridine; triciribine; trimethoprim; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitors; urokinase receptor antagonists; vapeptide; variolin B; vector systems; erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorazole; zanoterone; zilascorb; and zinostatin stimalamer.

[0352] Other anticancer agents that can be used in combination with Btk inhibitor compounds include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustard (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazines (e.g., decarbazine, etc.). Examples of antimetabolites include (but are not limited to) folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0353] Examples of alkylating agents that can be used in combination with Btk inhibitor compounds include (but are not limited to) nitrogen mustard (e.g., dichloromethyldiethylamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.), or triazines (azinimide, etc.). Examples of antimetabolites include (but are not limited to) folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, fluxouridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0354] Examples of hormones and antagonists include (but are not limited to) corticosteroids (e.g., prednisone), progestins (e.g., hydroxypro...

Claims

1. An immediate release solid tablet formulation comprising: a) about 69% w / w to about 71% w / w of ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1, Compound 1; b) about 13% w / w to about 15% w / w of lactose monohydrate; c) about 2% w / w to about 5% w / w of microcrystalline cellulose; d) about 1% w / w to about 3% w / w of polyvinylpyrrolidone; e) about 6% w / w to about 8% w / w of sodium croscarmellose; f) about 1% w / w to about 4% w / w of sodium lauryl sulfate; g) about 0.4% w / w to about 0.6% w / w of colloidal silicon dioxide; and h) about 0.4% w / w to about 0.6% w / w of one or more lubricants; wherein the solid tablet is prepared using a process comprising a wet granulation method.

2. The solid tablet formulation of claim 1, comprising: a) about 70% w / w of ibrutinib, b) about 14% w / w of lactose monohydrate, c) about 5% w / w of microcrystalline cellulose, d) about 2% w / w of polyvinylpyrrolidone, e) about 7% w / w of sodium croscarmellose, f) about 1% w / w of sodium lauryl sulfate, g) about 0.5% w / w of colloidal silicon dioxide, and h) about 0.5% w / w of one or more lubricants.

3. The solid tablet formulation of claim 1, comprising: a) about 70% w / w of ibrutinib, b) about 14% w / w of lactose monohydrate, c) about 2% w / w of microcrystalline cellulose, d) about 2% w / w of polyvinylpyrrolidone, e) about 7% w / w of sodium croscarmellose, f) about 4% w / w of sodium lauryl sulfate, g) about 0.5% w / w of colloidal silicon dioxide, and h) about 0.5% w / w of one or more lubricants.

4. An immediate release solid tablet formulation comprising: a) about 65% w / w to about 75% w / w of ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1, Compound 1; b) about 14% w / w to about 18% w / w of lactose monohydrate, c) about 1% w / w to about 3% w / w of polyvinylpyrrolidone, d) about 0.5% w / w to about 1.5% w / w of sodium lauryl sulfate, e) about 5% w / w to about 15% w / w of crospovidone, f) about 0.3% w / w to about 0.7% w / w of colloidal silicon dioxide, and g) about 0.3% w / w to about 0.7% w / w of one or more lubricants; wherein the solid tablet is prepared using a process comprising a wet granulation method.

5. The solid tablet formulation of any one of claims 1-4, wherein the amount of ibrutinib in the tablet is about 420 mg or about 560 mg.

6. The solid tablet formulation of claim 5, wherein the amount of ibrutinib in the tablet is about 560 mg.

7. The solid tablet formulation of any one of claims 1-4, wherein the ibrutinib is in a micronized form and the particle size of the micronized ibrutinib is about 30 microns or less.

8. The solid tablet formulation of claim 7, wherein the particle size of the micronized ibrutinib is about 10 microns or less.

9. The solid tablet formulation of any one of claims 1-4, wherein the one or more lubricants is a stearate salt, a polyethylene glycol (PEG), or a wax.

10. The solid tablet formulation of claim 9, wherein the one or more lubricants is a stearate salt.

11. The solid tablet formulation of any one of claims 1-4, wherein the formulation is for one tablet, administered once a day.

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