Pharmaceutical formulations of bruton's tyrosine kinase inhibitor

Abstract

To provide high-load solid tablet formulations of 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 (ibrutinib).SOLUTION: A high-load solid tablet formulation comprises ibrutinib and one or more pharmaceutically acceptable excipients, wherein the high-load solid tablet formulation comprises at least 50% w / w of ibrutinib.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] 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 by reference in their entireties.

[0002] Described herein are 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 pharma- ceutically acceptable salts thereof, as well as pharmaceutical formulations comprising the Btk inhibitors, and methods of using the Btk inhibitor compositions or formulations in the treatment of diseases or conditions in which inhibition of Btk activity would be beneficial. [Background technology]

[0003] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a major signaling enzyme expressed in all hematopoietic cells except T lymphocytes and natural killer cells. Btk plays an essential role in the B cell signaling pathway, linking cell surface B cell receptor (BCR) stimulation to downstream intracellular responses.

[0004] Btk is a key regulator of B cell development, activation, signaling, and survival. In addition, Btk plays a role in several other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B lineage lymphoid cells, and collagen-stimulated platelet aggregation.

[0005] 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 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one, or 2-propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-one, and has been given the USAN name ibrutinib. The various names given for ibrutinib are used interchangeably herein. Summary of the Invention

[0006] Described herein is the 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 pharma- ceutically acceptable compositions, formulations, and methods of use thereof. Also described are pharma- ceutically acceptable compositions and formulations of the 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 for use in the manufacture of a medicament for the treatment of a disease or condition associated with Btk activity. 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 an irreversible Btk inhibitor. Pharmaceutical compositions and formulations of the 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 and methods of using the Btk inhibitor in the treatment of diseases or conditions, including diseases or conditions in which irreversible inhibition of Btk provides a therapeutic benefit to a mammal having the disease or condition, are further described.

[0007] Also described herein is a process for preparing a pharmaceutical composition of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one by wet granulation.Further described is a pharmaceutical formulation comprising a pharmaceutical composition of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one prepared by wet granulation.

[0008] In one embodiment, a pharmaceutical composition comprising ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1:

[0009] [ka] The pharmaceutical composition comprises at least 50% (w / w) ibrutinib.

[0010] In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises from about 50% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises from about 50% (w / w) to about 80% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises from about 60% (w / w) to about 80% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises from about 60% (w / w) to about 75% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising at least 50% (w / w) ibrutinib, the pharmaceutical composition comprises intragranular and extragranular components. In another embodiment, the pharmaceutical composition comprises at least 50% (w / w) ibrutinib, wherein the pharmaceutical composition is prepared using a wet granulation method. In another embodiment, the pharmaceutical composition comprises at least 50% (w / w) ibrutinib, further comprising at least one pharma- ceutically acceptable excipient.

[0011] In another embodiment is a high load solid tablet formulation comprising a pharmaceutical composition 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. In another embodiment is a high load solid tablet formulation comprising a pharmaceutical composition 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 pharma- ceutically 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, the 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 pharma- ceutically acceptable excipients, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, the at least one excipient is a binder. In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipient comprises, consists essentially of, or consists of lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the excipient comprises, consists essentially of, or consists of lactose, polyvinylpyrrolidone, sodium lauryl sulfate, crospovidone, colloidal silicon dioxide, and magnesium stearate.

[0013] In another embodiment is 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 intragranular and extragranular excipients, wherein the intragranular excipients comprise, consist essentially of, or consist of lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, 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, wherein the intragranular excipient is lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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 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 intragranular and extragranular excipients, wherein the intragranular excipients comprise lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, 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, wherein the intragranular excipient is Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0 to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0 to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0 to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount 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] In another embodiment, a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 2% (w / w) to about 5% (w / w) microcrystalline cellulose; d) about 1% (w / w) to about 3% (w / w) polyvinylpyrrolidone; e) about 6% (w / w) to about 8% (w / w) croscarmellose sodium; f) about 1% (w / w) to about 4% (w / w) sodium lauryl sulfate; g) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; h) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0016] In another embodiment, a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose monohydrate; c) about 5% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 1% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) About 0.5% (w / w) magnesium stearate.

[0017] In another embodiment, a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose monohydrate; c) about 2% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 4% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) About 0.5% (w / w) magnesium stearate.

[0018] In another embodiment, a) about 70% (w / w) ibrutinib; b) about 16% (w / w) lactose; c) about 2% (w / w) polyvinylpyrrolidone; d) about 1% (w / w) sodium lauryl sulfate; e) about 10% (w / w) crospovidone; f) about 0.5% (w / w) colloidal silicon dioxide; g) About 0.5% (w / w) magnesium stearate.

[0019] In another embodiment, a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 13% (w / w) to about 15% (w / w) microcrystalline cellulose; d) about 4% (w / w) to about 6% (w / w) croscarmellose sodium; e) about 5% (w / w) to about 7% (w / w) sodium lauryl sulfate; f) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; g) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0020] In some embodiments, the total weight of the tablet is about 934 mg.

[0021] In another embodiment, a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 14% (w / w) lactose; c) about 13% (w / w) to about 14% (w / w) microcrystalline cellulose; d) about 2% (w / w) to about 3% (w / w) of croscarmellose sodium (intragranular); e) about 0.8% (w / w) to about 1.2% (w / w) hydroxypropyl cellulose; f) about 2% (w / w) to about 3% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0022] In some embodiments, the total weight of the tablet is about 934 mg. In another embodiment, a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 8% (w / w) to about 9% (w / w) lactose; c) about 8 to about 9% (w / w) microcrystalline cellulose; d) about 2.5 to about 3.5% (w / w) croscarmellose sodium (intragranular); e) about 2.5 to about 3.5% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0023] Lactose as used herein may be anhydrous lactose and / or hydrous lactose, such as lactose monohydrate. In some embodiments, lactose is anhydrous lactose. In some particular embodiments, lactose is hydrous lactose. In more particular embodiments, lactose is lactose monohydrate.

[0024] In some embodiments, the total weight of the tablet is about 800 mg.

[0025] In some embodiments of the highly loaded solid tablet formulations described herein, ibrutinib is in an amount of about 35 mg to about 840 mg per tablet. In some embodiments of the highly loaded solid tablet formulations described herein, ibrutinib is in an amount of about 140 mg to about 840 mg per tablet. In some embodiments of the highly loaded solid tablet formulations described herein, ibrutinib is in an amount of 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 highly loaded solid tablet formulations described herein, ibrutinib is in an amount of about 560 mg. In some embodiments of the highly loaded solid tablet formulations described herein, ibrutinib is in a particulate form. In some embodiments of the highly loaded solid tablet formulations described herein, the formulation is used for once-daily administration. In some embodiments of the high load solid tablet formulations described herein, the formulation is an oral dosage form containing a therapeutically effective amount of ibrutinib.

[0026] In another embodiment is a method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0027] In another embodiment is a method of treating an autoimmune disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein, hi some embodiments, the autoimmune disease is rheumatoid arthritis or lupus.

[0028] In another embodiment is a method of treating a heteroimmune disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0029] In another embodiment, a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a 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 a B cell malignancy 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 lymphoma, leukemia, or a solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphoblastic acute leukemia, lymphoplasmacytic lymphoma / Waldenstrom's 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 effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis.

[0030] In another embodiment is a method of treating mastocytosis in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0031] In another embodiment is a method of treating osteoporosis or a bone resorption disorder in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0032] In another embodiment is a method of treating an inflammatory disease or condition in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0033] In another embodiment is a method of treating lupus in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0034] In some embodiments, the formulations and methods described herein can be used to treat brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovarian, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, intraepithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epithelial carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's and non-Hodgkin's disease, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or indolent smoldering multiple myeloma.

[0035] In some embodiments, the formulations and methods described herein can be used to treat central nervous system (CNS) malignancies. In some embodiments, the CNS malignancies are primary CNS lymphomas. In some embodiments, the primary CNS lymphomas are gliomas. In some embodiments, the gliomas are astrocytomas, ependymoma, oligodendroglioma. In some embodiments, the CNS malignancy is an astrocytic tumor, e.g., juvenile hairy cell, subependymal, well-differentiated or moderately differentiated anaplastic astrocytoma; anaplastic astrocytoma; glioblastoma multiforme; ependymal tumor, e.g., myxopapillary ventricular and well-differentiated ependymoma, anaplastic ependymoma, ependymoblastoma; oligodendroglial tumors, including well-differentiated oligodendroglioma and anaplastic oligodendroglioma; mixed tumors, e.g., mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed ependymoma-oligodendroglioma; or medulloblastoma.

[0036] In some embodiments, the formulations and methods described herein can be used to treat hematological malignancies, including, but not limited to, leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancies, or B-cell malignancies. In some embodiments, the hematological malignancies are treatment-naïve hematological malignancies. In some embodiments, the hematological malignancies are relapsed or refractory hematological malignancies.

[0037] In some embodiments, the hematological malignancy is a T-cell malignancy. In some embodiments, the T-cell malignancy is peripheral T-cell lymphoma, not otherwise specified type (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type intestinal T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphoma, or therapy-related T-cell lymphoma. In some embodiments, the T-cell malignancy is a relapsed or refractory T-cell malignancy. In some embodiments, the T-cell malignancy is a therapy-naive T-cell malignancy.

[0038] In some embodiments, the hematological malignancy is a B-cell proliferative disorder. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, non-CLL / SLL lymphoma, or prolymphocytic leukemia (PLL). In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, DLBCL is further classified into the 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 embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myeloid (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia. In some embodiments, the B-cell proliferative disorder is a relapsed or refractory B-cell proliferative disorder. In some embodiments, the B-cell proliferative disorder is a treatment-naive B-cell proliferative disorder.

[0039] 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, pulmonary chronic GVHD, or hepatic chronic GVHD. In some embodiments, the fibrosis is fibrosis of the liver, lung, pancreas, kidney, bone marrow, heart, skin, intestine, or joints. In some embodiments, the fibrosis is fibrosis of the liver. In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the fibrosis is fibrosis of the pancreas. In some embodiments, the patient is suffering from cirrhosis of the liver, chronic pancreatitis, or cystic fibrosis.

[0040] In another aspect, a process for preparing a pharmaceutical composition or tablet formulation comprising ibrutinib as described herein, the process comprising a wet granulation process.

[0041] In another embodiment, a high load solid tablet formulation comprising ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1:

[0042] [ka] Each tablet contains approximately 560 mg of ibrutinib.

[0043] In another embodiment, the high-load solid tablet formulation, ibrutinib is in a particulate 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 30 microns or less than 30 microns. In one embodiment, ibrutinib is in a particulate form, the particle size is about 1-30 microns. In another embodiment, the particle size is about 10 microns or less than 10 microns. In another embodiment, the particle size is less than 1 micron. In another embodiment, the high-load solid tablet formulation, the tablet is used for once-daily oral administration.

[0044] In another aspect, provided herein are methods for treating a patient by administering Compound 1. In some embodiments, provided herein are methods for inhibiting tyrosine kinase(s), such as Btk, or treating a disease, disorder, or condition in a mammal in which inhibition of tyrosine kinase(s), such as Btk, would be beneficial, comprising administering to the mammal a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, pharma-ceutically active metabolite, pharma-ceutically acceptable prodrug, or pharma-ceutically acceptable solvate.

[0045] In another aspect, provided herein is the use of Compound 1 for inhibiting Bruton's tyrosine kinase (Btk) activity or for treating a disease, disorder, or condition in which inhibition of Bruton's tyrosine kinase (Btk) activity would be beneficial.

[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, a pharmaceutical composition comprising crystalline Compound 1 is administered orally. In some embodiments, a pharmaceutical composition comprising amorphous Compound 1 is administered orally.

[0048] In some embodiments, a pharmaceutical composition comprising crystalline Compound 1 is used to formulate a medicament for the inhibition of tyrosine kinase activity. In some other embodiments, a pharmaceutical composition comprising crystalline Compound 1 is used to formulate a medicament for the inhibition of Bruton's tyrosine kinase (Btk) activity. In some embodiments, a pharmaceutical composition comprising amorphous Compound 1 is used to formulate a medicament for the inhibition of tyrosine kinase activity. In some other embodiments, a pharmaceutical composition comprising amorphous Compound 1 is used to formulate a medicament for the inhibition of 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 pharma- ceutically 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 pharma- ceutically acceptable salt or solvate thereof, is replaced with a) a lower chiral purity of compound 1, or a pharma- ceutically acceptable salt or solvate thereof, 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 pharma- ceutically acceptable salt or solvate 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 pharma- ceutically acceptable salt or solvate thereof.

[0050] Any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.) utilize amorphous Compound 1. Any of the embodiments disclosed herein (including compositions, methods, uses, formulations, combination therapies, etc.) utilize crystalline Compound 1.

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

[0052] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the detailed description set forth below. However, it should be understood that the detailed description and specific examples, while illustrating certain embodiments, are given for illustrative purposes only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, papers, books, manuals, and articles, are expressly incorporated herein by reference in their entirety and for all purposes.

[0053] Incorporation by Reference All publications and patent applications mentioned herein are incorporated by reference to the extent applicable and relevant. [Brief description of the drawings]

[0054] [Figure 1] 1 shows the mean plasma concentration-time profiles of ibrutinib following a single oral administration (dose=140 mg) of a capsule formulation versus three different wet tablet formulations to fasted beagle dogs. [Diagram 2]1 shows the mean plasma concentration-time profiles of ibrutinib following a single oral administration (dose=140 mg) of a capsule formulation versus two different dry tablet formulations to fasted beagle dogs. [Diagram 3] (A) Photographs of examples of a capsule containing 140 mg of ibrutinib (Formulation A) and tablets of the invention containing 560 mg, 420 mg, 280 mg, and 140 mg of ibrutinib, respectively (B-E). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The diverse roles played by Btk signaling in various hematopoietic cell functions, e.g., B cell receptor activation, suggest that small molecule Btk inhibitors such as compound 1 may be useful in reducing the risk of or treating a variety of diseases that are affected by or affect many cell types of the hematopoietic system, e.g., autoimmune diseases, xenoimmune conditions or diseases, inflammatory diseases, cancers (e.g., B cell proliferative disorders), and thromboembolic disorders. Additionally, irreversible Btk inhibitor compounds such as compound 1 can be used to inhibit a small subset of other tyrosine kinases that share homology with Btk by possessing cysteine ​​residues (including the cysteine ​​481 residue) that can form covalent bonds with the irreversible inhibitor.

[0056] In some embodiments, a composition or tablet formulation comprising Compound 1 can be used to treat an autoimmune disease in a mammal, including rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, rigidity, and the like. These include, but are not limited to, idiopathic spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.

[0057] In some embodiments, a composition or tablet formulation comprising Compound 1 can be used to treat a heteroimmune disease or condition in a mammal, including, but not limited to, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach calyx), Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0058] In some embodiments, a composition or tablet formulation comprising Compound 1 can be used to treat inflammatory diseases in a mammal, including 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, These include, but are not limited to, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. In some embodiments, the inflammatory disease is asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, hepatitis, suppurative sweat gland inflammation, or the like. inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myocarditis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibodies. syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0059] In yet other embodiments, the methods described herein can be used to treat cancer, e.g., B-cell proliferative disorders, including, but not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphoblastic acute leukemia, lymphoplasmacytic lymphoma / Waldenstrom's 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 effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0060] In further embodiments, the methods described herein can be used to treat thromboembolic disorders, including, but not limited to, myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[0061] Hematological malignancies In certain embodiments, disclosed herein are methods for treating hematological malignancies in an individual in need of treatment, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1.

[0062] In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's high-grade B-cell lymphoma, or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or precursor B-cell acute lymphoblastic leukemia. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is multiple myeloma (MM). In some embodiments, the hematological malignancy is Burkitt's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL). In some embodiments, the hematological malignancy is transformed follicular lymphoma. In some embodiments, the hematological malignancy is marginal zone lymphoma.

[0063] In some embodiments, the hematological malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological 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 Waldenstrom's macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkitt's high-grade B-cell lymphoma, relapsed or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory acute or chronic myeloid (or 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 embodiments, the hematological malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematological malignancy is relapsed or refractory Burkitt's lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory follicular lymphoma (FL).

[0064] In some embodiments, the hematological malignancy is a hematological malignancy classified as high risk. In some embodiments, the hematological malignancy is high risk CLL or high risk SLL.

[0065] B-cell lymphoproliferative disorders (BCLDs) are hematological tumors, including non-Hodgkin's lymphoma, multiple myeloma, and leukemia, among others. BCLDs can arise in either lymphoid tissue (as in lymphomas) or bone marrow (as in leukemia and myeloma), all of which are associated with uncontrolled growth of lymphocytes or white blood cells. There are many subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The disease course and treatment of BCLD depend on the BCLD subtype; however, even within each subtype, the clinical manifestations, morphological appearance, and response to treatment are heterogeneous.

[0066] Malignant lymphoma is a malignant transformation of cells that reside predominantly in lymphoid tissues. The two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma invade tissues of the reticuloendothelial system. However, they differ in the neoplastic cell of origin, the site of disease, the presence of systemic symptoms, and response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (approved publication of the American Cancer Society, BC Decker Inc., Hamilton, Ontario, 2003).

[0067] Non-Hodgkin lymphoma In certain embodiments, disclosed herein are methods for treating non-Hodgkin's lymphoma in an individual in need of treatment, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1.

[0068] Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of Compound 1. In some embodiments, the 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.

[0069] Non-Hodgkin's lymphoma (NHL) is a diverse group of malignant tumors that are predominantly of B-cell origin. 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 lymphadenopathy, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formation classification system, NHLs are divided into low-grade, intermediate-grade, or high-grade categories according to their natural history (see "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135). Low-grade lymphomas are indolent and have a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475). Chemotherapy can induce remission in the majority of indolent lymphomas, but cures are rare and most patients eventually relapse and require further treatment. Intermediate and high-grade lymphomas are more aggressive tumors, but they have a greater chance for cure with chemotherapy. However, a significant proportion of these patients will relapse and require further treatment.

[0070] A non-exclusive list of B-cell NHL includes Burkitt lymphoma (e.g., endemic Burkitt lymphoma and sporadic Burkitt lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse mixed small and large cell lymphoma, diffuse small round cell, diffuse small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small round cell (grade 1), follicular mixed small and large round cell (grade 2), follicular large cell (grade 3), intravascular large B-cell lymphoma, intravascular lymphomatosis, large immunoblastic lymphoma, large lymphoma, large lymphocytic lymphoma, large ... Non-Hodgkin's lymphomas include large cell lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-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 cell B-cell lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenstrom's macroglobulinemia, and primary central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are contemplated within the scope of the present invention and will be apparent to one of skill in the art.

[0071] DLBCL Disclosed herein, in certain embodiments, is a method for treating DLCBL in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory DLCBL in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising a therapeutically effective amount of Compound 1.

[0072] As used herein, the term "diffuse large B-cell lymphoma (DLBCL)" refers to a neoplasm of germinal center B lymphocytes with a diffuse growth pattern and a high-moderate proliferation index. DLBCL represents approximately 30% of all lymphomas and can exist with a variety of morphologic variants, including germinal center cell, immunoblastic, T cell / histiocyte-rich, anaplastic, and plasmablastic subtypes. Genetic testing has shown that different subtypes of DLBCL exist. These subtypes appear to have different appearances (prognosis) and responses to treatment. DLBCL can affect any age group, but most often occurs in older adults (the average age is in the mid-60s).

[0073] Disclosed herein, in certain embodiments, is a method for treating diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL) in an individual in need thereof, comprising administering to the individual an irreversible Btk inhibitor in an amount of 300 mg / day to 1000 mg / day. Diffuse large B-cell lymphoma of the ABC subtype (ABC-DLBCL) is thought to arise from post-germinal center B cells that are arrested during plasma differentiation. DLBCL of the ABC subtype (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. It is considered the most difficult to treat DLBCL molecular subtype, and patients diagnosed with ABC-DLBCL typically display significantly reduced survival rates compared to individuals with other types of DLBCL. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate the germinal center master regulator BCL6 and with inactivating mutations in the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0074] A particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is that mediated by the nuclear factor (NF)-κB transcription complex. The NF-κB family includes five members (p50, p52, p65, c-rel, and RelB), which form homodimers and heterodimers and function as transcription factors mediating various proliferation, apoptosis, inflammatory, and immune responses, and are important for the growth and survival of canonical B cells. NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB initiates the expression of genes that keep cells proliferating and protect them from conditions that would cause them to die via apoptosis.

[0075] The dependency of ABC DLBCLs on NF-kB varies depending on the signaling pathway upstream of IkB kinase, which consists of CARD11, BCL10, and MALT1 (CBM complex). Interference with the CBM pathway abolishes NF-kB signaling in ABC DLBCL cells and induces apoptosis. Although the molecules underlying the constitutive activity of the NF-kB pathway are the subject of current research, several somatic mutations to the genome of ABC DLBCLs explicitly invoke this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCLs enable this signaling scaffold protein to spontaneously nucleate from protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-kB activation. Constitutive activity of the B cell receptor signaling pathway is linked to the activation of NF-kB in ABC DLBCLs by wild-type CARD11, which is related to mutations within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating mutations in the signaling adaptor MYD88 activate NF-kB and synergize with B cell receptor signaling in sustaining ABC DLBCL cell survival. In addition, inactivating mutations in a negative regulator of the NF-kB pathway (A20) occur almost exclusively in ABC DLBCL.

[0076] Indeed, genetic alterations affecting multiple components of the NF-κB signaling pathway have been identified in recent years in more than 50% of ABC-DLBCL patients, where these lesions promote constitutive NF-κB activation and thereby contribute to lymphoma proliferation. These include mutations in CARD11 (approximately 10% of cases), a lymphocyte-specific cytoplasmic scaffolding protein that, together with MALT1 and BCL10, forms the BCR signalosome, which relays signals from antigen receptors to downstream mediators of NF-κB activation. Even a larger fraction of cases (approximately 30%) carry biallelic genetic lesions that inactivate the negative NF-κB regulator A20. Moreover, high levels of expression of NF-κB target genes have been observed in ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008), Nature Reviews Immunology 8:22-23; RE Davis et al., (2001), Journal of Experimental Medicine 194:1861-1874; G. Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature 459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).

[0077] DLBCL cells of the ABC subtype, such as OCI-Ly10, have 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 proliferation of OCI-Ly10 (EC 50 Continuous exposure = 10 nM, EC 50(1 hour pulse = 50 nM). In addition, induction of apoptosis, as shown by capsase activation, Annexin-V flow cytometry, and increased sub-G0 fraction, is observed in OCILy10. Sensitive and resistant cells express Btk at similar levels, and the active site of Btk is fully occupied by the inhibitor in both, as shown using a fluorescently labeled affinity probe. OCI-Ly10 cells are shown to have chronically active BCR signaling to NF-kB, a dose dependent inhibition by the Btk inhibitors described herein. The activity of Btk inhibitors in the cell lines discussed herein is also characterized by comparing signal transduction profiles (Btk, PLCγ, ERK, NF-kB, AKT), cytokine secretion profiles, and mRNA expression profiles with and without BCR stimulation, and significant differences in these profiles are observed that lead to clinical biomarkers that identify patient populations most sensitive to Btk inhibitor treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the contents of which are incorporated by reference in their entireties.

[0078] Follicular lymphoma Disclosed herein, in certain embodiments, is a method for treating follicular lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory follicular lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0079] As used herein, the term "follicular lymphoma" refers to any of the various types of non-Hodgkin's lymphoma in which lymphoma cells are clustered in nodules or follicles. The cells tend to grow in a circular or nodular pattern in the lymph nodes, hence the term "follicular." The average age of people with this lymphoma is about 60 years old.

[0080] CLL / SLL Disclosed herein, in certain embodiments, is a method for treating CLL or SLL in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory CLL or SLL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0081] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are generally thought of as the same disease with slightly different symptoms. Where the cancer cells collect determines whether it is called CLL or SLL. If the cancer cells are found primarily in the lymph nodes (lima bean-shaped structures in the lymphatic system (a system of small blood vessels found primarily in the body)), it is called SLL. SLL accounts for about 5%-10% of all lymphomas. If most of the cancer cells are in the bloodstream and bone marrow, it is called CLL.

[0082] Both CLL and SLL are slow-growing diseases, but CLL, which is much more common, tends to be slow-growing. CLL and SLL are treated in the same way. They are not usually considered curable with standard treatments, but most patients live longer than 10 years, depending on the stage and growth rate of the disease. Sometimes over time, these slow-growing lymphomas can transform into more aggressive forms of lymphoma.

[0083] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. It is estimated that 100,760 people in the United States are living with or in remission from CLL. Most people (over 75%) newly diagnosed with CLL are over the age of 50. Currently, CLL treatment focuses on controlling the disease and its symptoms, rather than definitive treatment. CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplant. Symptoms are sometimes treated surgically (splenectomy for splenomegaly) or with radiation therapy (to "debulk" lymphadenopathy). CLL progresses slowly in most cases, but is generally considered untreatable. Certain CLLs 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 with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0084] CLL treatment is typically administered when a patient's clinical symptoms or blood counts indicate that the disease has progressed to a point that may affect the patient's quality of life.

[0085] Small lymphocytic leukemia (SLL) is very similar to CLL mentioned above and is also a cancer of B cells. In SLL, abnormal lymphocytes primarily affect 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 cases of non-Hodgkin's lymphoma. It can occur any time from adolescence to old age, but is rare under the age of 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly and patients tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to various chemotherapy agents, it is generally considered incurable. Cases and deaths from SLL are split equally between men and women, although some cancers tend to occur more frequently in one gender or the other. The average age at diagnosis is 60 years.

[0086] SLL is indolent but permanently progressive. The usual pattern of the disease is a period of disease remission with high response rates to radiation and / or chemotherapy. This is followed by months or years with inevitable relapse. Retreatment again leads to response, but the disease will recur again. This means that while the short-term prognosis for SLL is fairly good, over time many patients will progress to the fatal complications of recurrent disease. Given the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease with minimal side effects that does not interfere with the patient's quality of life. The present invention fulfills this long-standing need in the art.

[0087] Mantle cell lymphoma Disclosed herein, in certain embodiments, is a method for treating mantle cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising a therapeutically effective amount of Compound 1.

[0088] As used herein, the term "mantle cell lymphoma" refers to a subtype of B cell lymphoma due to CD5 positive antigen-naive pre-germinal center B cells within the mantle zone surrounding the standard germinal center follicle. MCL cells typically overexpress cyclin D1 due to a t(11:14) chromosomal translocation in DNA. More specifically, the translocation is at t(11;14)(q13;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Humans are most frequently affected. The average age of patients is in the early 60s. Lymphoma is usually extensive at diagnosis, involving lymph nodes, bone marrow, and very frequently the spleen. Mantle cell lymphoma is not a very fast-growing lymphoma, but it is difficult to treat.

[0089] Marginal zone B-cell lymphoma Disclosed herein, in certain embodiments, is a method for treating marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising a therapeutically effective amount of Compound 1.

[0090] As used herein, the term "marginal zone B-cell lymphoma" refers to a group of related B-cell neoplasms that involve lymphoid tissue in the marginal zone (the patchy area outside the follicular mantle). Marginal zone lymphomas account for approximately 5%-10% of lymphomas. The cells in these lymphomas appear small under a microscope. There are three main types of marginal zone lymphoma, including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

[0091] MALT Disclosed herein, in certain embodiments, is a method for treating MALT in an individual in need thereof, comprising administering to the individual an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory MALT in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 or a composition or tablet formulation described herein.

[0092] The term "mucosa-associated lymphoid tissue (MALT) lymphoma" as used herein refers to the extranodal manifestations of marginal zone lymphoma. Most MALT lymphomas are low grade, but a small number either initially manifest as intermediate grade non-Hodgkin's lymphoma (NHL) or evolve from a low grade form. Most MALT lymphomas arise in the stomach, and approximately 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Various cytogenetic abnormalities have been identified, the most common being trisomy or t(11;18). Many of these other MALT lymphomas have also been associated with infections with bacteria or viruses. The average age of patients with MALT lymphoma is approximately 60 years.

[0093] Nodal marginal zone B-cell lymphoma Disclosed herein, in certain embodiments, is a method for treating nodal marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0094] The term "nodal marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma that is mostly found in lymph nodes. The disease is rare, accounting for only 1% of all non-Hodgkin's lymphomas (NHL). It is most commonly diagnosed in older patients, and women are more likely to be affected than men. Because the mutation occurs in the marginal zone of B cells, the disease is classified as marginal zone lymphoma. Because of its restriction in lymph nodes, the disease is also classified as nodal.

[0095] Splenic marginal zone B-cell lymphoma Disclosed herein, in certain embodiments, is a method for treating splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0096] The term "splenic marginal zone B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma incorporated in the World Health Organization classification. Characteristic features are a moderate lymphocytosis of splenomegaly with villous morphology, intrasinusoidal pattern of involvement of various organs, especially bone marrow, and relative indolent periods. Tumor progression with increasing blast morphology and aggressive behavior is observed in a minority of patients. Molecular and cytogenetic studies have shown mixed results, probably due to the lack of standardized diagnostic criteria.

[0097] Burkitt Lymphoma Disclosed herein, in certain embodiments, is a method for treating Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1, in certain embodiments, is a composition or tablet formulation described herein comprising a therapeutically effective amount of Compound 1.

[0098] The term "Burkitt lymphoma" refers to a type of non-Hodgkin's lymphoma (NHL) that commonly affects children. It is a highly aggressive type of B-cell lymphoma that frequently begins in and involves parts of the body other than lymph nodes. Despite its fast-growing nature, Burkitt lymphoma is usually treatable with modern intensive care. There are two widespread types of Burkitt lymphoma: sporadic and endemic variants.

[0099] Endemic Burkitt's lymphoma: This disease affects children much more than adults and is associated with Epstein-Barr virus (EBV) infection in 95% of cases. It originates in equatorial Africa, where about half of all childhood cancers are Burkitt's lymphoma. It characteristically has a high probability of involvement of the jawbone, a rather distinctive feature that is rare in sporadic Burkitt's. It also commonly involves the abdomen.

[0100] Sporadic Burkitt lymphoma: The type of Burkitt lymphoma that affects the rest of the world, including Europe and the Americas, is the sporadic type. Again, it is primarily a disease of children. Direct evidence of Epstein-Barr virus (EBV) infection is present in one in five patients, but the link between EBV is not as strong as in the endemic variant. More than lymph node involvement, the abdomen is prominently affected in over 90% of children. Bone marrow involvement is more common than in the sporadic variant.

[0101] Waldenström macroglobulinemia Disclosed herein, in certain embodiments, is a method for treating Waldenstrom's macroglobulinemia in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory Waldenstrom's macroglobulinemia in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising a therapeutically effective amount of Compound 1.

[0102] Also known as lymphoplasmacytic lymphoma, the term "Waldenström's macroglobulinemia" is a cancer involving a subtype of white blood cells called lymphocytes. It is characterized by uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells that make an antibody called immunoglobulin M (IgM). IgM antibodies circulate in the blood in large quantities, thickening the liquid portion of the blood like syrup. This can lead to reduced blood flow to many organs, which can cause problems with vision (due to poor circulation in the blood vessels behind the eyes) and neurological problems caused by insufficient blood flow in the brain (such as headaches, dizziness, and confusion). Other symptoms can include a feeling of fatigue and weakness, as well as a tendency to bleed easily. Although the underlying etiology is not fully understood, many risk factors have been identified, including the location 6p21.3 on chromosome 6. There is a 2-3 fold increased risk of developing WM in people with a personal history of autoantibodies and particularly high-risk autoimmune diseases associated with hepatitis, human immunodeficiency virus, and rickettsiosis.

[0103] Multiple myeloma Disclosed herein, in certain embodiments, is a method for treating myeloma in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory myeloma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0104] Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (after Otto Kahler), is a cancer of the white blood cells known as plasma cells. Plasma cells, a type of B cell, are an important part of the immune system in humans and other vertebrates, responsible for antibody production. They are produced in the bone marrow and transported through the lymphatic system.

[0105] leukemia Disclosed herein, in certain embodiments, is a method for treating leukemia in an individual in need thereof, comprising administering to the individual a composition or tablet formulation described herein comprising an amount of Compound 1. Disclosed herein further, in certain embodiments, is a method for treating relapsed or refractory leukemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition or tablet formulation described herein comprising Compound 1.

[0106] Leukemia is a cancer of the blood or bone marrow, characterized by an abnormal increase in blood cells, usually leukocytes (white blood cells). Leukemia is a broad term that encompasses a range of diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by a rapid increase in immature blood cells. This crowding causes the bone marrow to fail to produce healthy blood cells. Urgent treatment is required for acute leukemia due to the rapid progression and accumulation of malignant cells, which then spread to the bloodstream and other organs of the body. The acute form of leukemia is the most common form of leukemia in children; (ii) chronic leukemia is recognized by the excessive accumulation of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much faster rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but theoretically can occur in any age group. In addition, the disease is subdivided according to which blood cell types are affected, into lymphoblastic or lymphocytic leukemia, and myeloid or osteosarcomatous leukemia: (i) lymphoblastic or lymphocytic leukemia, in which the cancerous changes occur in a type of bone marrow cell that normally progresses to form lymphocytes, immune system cells that fight off infection; (ii) myeloid or osteosarcomatous leukemia, in which the cancerous changes occur in a type of bone marrow cell that normally progresses to form red blood cells, several other types of white blood cells, and platelets.

[0107] Within these major categories, there are various subcategories, including, but not limited to, acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Thus, in certain embodiments, disclosed herein is a method for treating acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL) in an individual in need of such treatment, comprising administering to the individual an amount of Compound 1. In some embodiments, the leukemia is relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called 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).

[0108] Symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known. See, e.g., Harrison's Principles of Internal Medicine (c) " 16th ed., 2004, The McGraw-Hill Companies, Inc. See Dey et al. (2006), Cytojournal 3(24), and the "Revised European American Lymphoma" (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

[0109] A number of animal models are useful for establishing an effective dose range of an irreversible Btk inhibitor compound, such as Compound 1, for the treatment of any of the aforementioned diseases.

[0110] Compound 1 therapeutic effect for any one of the aforementioned diseases can be optimized during the course of treatment. For example, a subject being treated can undergo diagnostic evaluation to correlate the alleviation of disease symptoms or disease conditions with the inhibition of in vivo Btk activity achieved by administration of 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, since activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phosphospecific immunocytochemical staining of P-Y223 or P-Y551 positive cells can be used to detect or quantify the activation of Btk in a cell population (e.g., by FACS analysis of stained versus unstained cells). See, for example, Nishitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the Btk inhibitor compound administered to a subject can be increased or decreased as necessary to maintain an optimal level of Btk inhibition to treat the subject's condition.

[0111] Compound 1 irreversibly inhibits Btk and can be used to treat mammals suffering from 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. Compound 1 has demonstrated efficacy in a wide variety of diseases and conditions, as described herein.

[0112] In some embodiments, Compound 1 is used in the manufacture of a medicament for treating any of the aforementioned conditions (e.g., an autoimmune disease, an inflammatory disease, an allergic disorder, a B cell proliferative disorder, or a thromboembolic disorder).

[0113] Compound 1 and its pharma- ceutically acceptable salts The Btk inhibitor compounds described herein (i.e., Compound 1) are selective for Btk and kinases that have a cysteine ​​residue at the amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine ​​481 in Btk. The Btk inhibitor compounds can form a covalent bond with cysteine ​​481 of Btk (e.g., via a Michael reaction).

[0114] "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-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one" or "2-propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl" or ibrutinib, or other suitable names, have the structure:

[0115] [ka] It refers to a compound having the formula:

[0116] A wide variety of pharma- ceutically acceptable salts may be formed from Compound 1, including the following: - acid addition salts formed by reacting compound 1 with organic acids (including fatty acid mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, fatty and aromatic sulfonic acids, amino acids, etc.) 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. - Acid addition salts formed by reacting compound 1 with inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0117] With respect to Compound 1, the term "pharmaceutically acceptable salt" refers to a salt of Compound 1 that does not cause significant irritation to a mammal to which it is administered and that does not significantly abrogate the biological activity and properties of the compound.

[0118] It should be understood that a reference to a pharma-ceutically acceptable salt includes its solvent addition forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of solvate and are formed during the process of product formation or isolation with pharma-ceutically acceptable solvents (water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc.). In one embodiment, solvates are formed using, but not limited to, Class 3 solvent(s). Solvent categories are defined, for example, in 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). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of Compound 1, or a pharma- ceutically acceptable salt thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of Compound 1, or a pharma- ceutically acceptable salt thereof, are anhydrous. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is in a nonsolvated form. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is in a nonsolvated form and is anhydrous.

[0119] In yet other embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is prepared in various forms, including, but not limited to, amorphous phase, crystalline form, milled form, and nanoparticulate form. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is crystalline and anhydrous.

[0120] In some embodiments, compound 1 is prepared as outlined in US Pat. No. 7,514,444.

[0121] Certain technologies 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 belongs. It is to be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and are not limiting of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" is open-ended, as are other forms such as "include," "includes," and "included."

[0122] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, papers, books, manuals, and articles, are expressly incorporated herein by reference in their entirety and for all purposes.

[0123] The term "about" when used before a numerical value means that the value can vary within a reasonable range, such as within ±10%, ±5%, or ±1% of the stated value.

[0124] As used herein, the term "comprising" or grammatical variations thereof is intended to mean that the compositions, methods, etc., include the recited elements, but do not exclude others. "Consisting essentially of" or grammatical variations thereof, when used to define compositions and methods, is intended to mean excluding other elements of any essential significance to the combination for the intended use, but not excluding elements that do not materially affect the characteristics or characteristics of the composition or method. "Consisting of" or grammatical variations thereof is intended to mean not excluding elements not specifically mentioned. The embodiments defined by each of these transition terms are within the scope of the invention. For example, when a formulation is described as including components A, B, and C, a formulation consisting essentially of A, B, and C, as well as a formulation consisting of A, B, and C, are independently within the scope of the invention.

[0125] As used herein, the term "acceptable" or "pharmaceutical acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the general health of the subject being treated or abrogating the biological activity or properties of the compound, and is relatively non-toxic.

[0126] As used herein, the term "agonist" refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity that results from the presence of a naturally occurring ligand for the protein, e.g., Btk.

[0127] As used herein, the term "partial agonist" refers to a compound, the presence of which results in the same type, but to a lesser extent, of biological activity of a protein that would result from the presence of a naturally occurring ligand for the protein.

[0128] As used herein, the term "antagonist" refers to a compound, the presence of which results in a decrease in the degree of biological activity of a protein. In certain embodiments, the presence of an antagonist results in complete inhibition of the biological activity of a protein, such as, for example, Btk. In certain embodiments, an antagonist is an inhibitor.

[0129] As used herein, "alleviation" of symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any lessening in severity, delay in onset, slowing in progression, or shortening in duration (whether permanent or temporary, lasting or transient) that can result from or be associated with the administration of the compound or composition.

[0130] "Bioavailability" refers to the percentage of administered Compound 1 that is delivered to the systemic circulation of the animal or human being studied. The total exposure of the drug when administered intravenously (AUC (0-∞) ) is usually defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is administered orally, as compared to intravenous injection.

[0131] "Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that due to variability in metabolism and / or possible interactions with other therapeutic agents, the plasma concentration of Compound 1 may vary significantly between subjects. In accordance with one embodiment disclosed herein, the plasma concentration of Compound 1 may vary from subject to subject. Similarly, the maximum plasma concentration (C max ) or maximum plasma concentration (T max ) or the total area under the plasma concentration-time curve (AUC (0-∞) ) may vary from subject to subject. Because of this variability, the amount necessary to constitute a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

[0132] As used herein, the term "Bruton's tyrosine kinase" refers to Bruton's tyrosine kinase from Homo sapiens, disclosed, for example, in US Pat. No. 6,326,469 (GenBank Accession No. NP_000052).

[0133] As used herein, terms such as "co-administration" are meant to encompass administration of selected therapeutic agents to a patient and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, terms such as "co-administration" are meant to encompass administration of selected therapeutic agents in the same cycle(s). In these embodiments, the selected therapeutic agents may be administered in cycle(s) of the same or different days.

[0134] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, in therapeutic applications, an "effective amount" is the amount of a composition containing a compound disclosed herein that is required to clinically sufficiently reduce the disease symptoms without causing undue adverse side effects. An appropriate "effective amount" for any individual may be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, an amount that is effective for prophylaxis. An "effective amount" of a compound disclosed herein is an amount that is effective to achieve a desired pharmacological effect or therapeutic improvement without causing undue adverse side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of Compound 1, body weight, the general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount may be determined by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0135] The term "enhance" or "enhancing" means to increase or prolong a desired effect, either in potency or duration. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, either in potency or duration, the effect of the therapeutic agent in treating a disease, disorder, or condition. As used herein, an "enhancing-effective amount" refers to an amount adequate to enhance the effect of a therapeutic agent in treating a disease, disorder, or condition. When used in a patient, the amount effective for this use will vary depending on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status, and response to the drug, and the judgment of the treating physician.

[0136] As used herein, "inhibit," "inhibiting," or an "inhibitor" of a kinase refers to the inhibition of the phosphotransferase activity of the enzyme.

[0137] As used herein, the term "irreversible inhibitor" refers to a compound that contacts a target protein (e.g., a kinase) and causes the formation of a new covalent bond with or within the protein, whereby one or more of the biological activities of the target protein (e.g., phosphotransferase activity) is reduced or abolished regardless of the subsequent presence or absence of the irreversible inhibitor.

[0138] As used herein, the term "irreversible Btk inhibitor" refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk. In one embodiment, an irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk, and in certain embodiments, an irreversible inhibitor can form a covalent bond with the Cys481 residue of Btk (or a homolog thereof), or a cysteine ​​residue at a homologous corresponding position of another tyrosine kinase.

[0139] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0140] As used herein, the term "modulator" refers to a compound that changes the activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of the activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that reduces the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0141] As used herein, "prophylactically effective amount" refers to the amount of the composition applied to a patient that will relieve to some extent one or more symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amount may vary depending on the patient's health condition, weight, etc. It is considered to be well within the skill of the art to determine such prophylactically effective amount by routine experimentation, including but not limited to dose escalation clinical trials.

[0142] As used herein, "individual," "subject," or "patient" refers to an animal that is the object of treatment, observation, or experiment. By way of example only, a subject may be, but is not limited to, a mammal, including, but not limited to, a human.

[0143] As used herein, the term "wet granulation" refers to the formation of granulations using a granulation liquid (water, organic solvent, or solution).

[0144] As used herein, the term "dry granulation" refers to the formation of granulations without the use of a granulation liquid (water, organic solvent, or solution).

[0145] As used herein, the term "high load solid tablet formulation" refers to a solid tablet formulation that contains at least 50% (w / w) ibrutinib per tablet.

[0146] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures such a response.

[0147] As used herein, EC 50 refers to the dose, concentration, or amount of a particular test compound that elicits a dose-dependent response with 50% maximal expression of a particular response induced, caused, or potentiated by the particular test compound.

[0148] Pharmaceutical Compositions / Formulations As used herein, a pharmaceutical composition or pharmaceutical formulation refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to a mammal. The compound may be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0149] As used herein, the term "pharmaceutical 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" refers to the fact that both active ingredients, e.g., Compound 1 and co-drug, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to the fact that the active ingredients, e.g., Compound 1 and co-drug, are administered to a patient as separate entities, simultaneously, concurrently, or sequentially, without any particular time limit for interruption, such that such administration provides an effective level of the two compounds to the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0150] In some embodiments, crystalline Compound 1 is incorporated into pharmaceutical compositions to provide solid oral dosage forms, such as powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0151] Ibrutinib is currently used in clinics at unit doses of 420 mg or 560 mg, orally administered in capsules of 3 or 4 tablets containing 140 mg of ibrutinib per capsule. High-load tablet formulations may allow administration of one tablet per dose. However, high-load tablet formulations that meet pharmacologic acceptable properties such as suitable compressibility when administered, compression molding, granular flowability, granular density, integrity during manufacturing, shipping, and storage, appropriate hardness, stability, swallowability, and disintegration properties are considered to be more difficult to prepare than capsule formulations due to the limited amount of excipients that can be used to meet tablet properties. Furthermore, tablet formulations, especially for ibrutinib, which has very low water solubility, have a higher C-value than capsule formulations due to the process of disintegration and absorption after administration. max tends to be low. max It is difficult to prepare a highly loaded tablet formulation of ibrutinib that has both pharmacologic acceptable and desirable PK properties.

[0152] In some embodiments, the pharmaceutical composition comprises ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1:

[0153] [ka] The pharmaceutical composition comprises at least 50% (w / w) ibrutinib.

[0154] In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises at least about 20% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 20% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 30% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 40% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 50% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 40% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 50% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 60% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 50% (w / w) to about 75% (w / w) of ibrutinib. In another embodiment, a pharmaceutical composition comprising ibrutinib, the pharmaceutical composition comprises about 60% (w / w) to about 75% (w / w) of ibrutinib. In another embodiment, a pharmaceutical composition comprising at least 50% (w / w) ibrutinib, the pharmaceutical composition comprising intragranular and extragranular components. In another embodiment, a pharmaceutical composition comprising at least 50% (w / w) ibrutinib, the pharmaceutical composition being prepared using a wet granulation method. In another embodiment, a pharmaceutical composition comprising at least 50% (w / w) ibrutinib, further comprising at least one pharma- ceutical acceptable excipient.

[0155] In some embodiments, the pharmaceutical compositions described herein are prepared by a process comprising wet granulation.

[0156] In another embodiment, the solid tablet formulation comprises ibrutinib, the solid tablet formulation comprises at least about 20% (w / w) ibrutinib. In another embodiment, the solid tablet formulation comprises ibrutinib, the solid tablet formulation comprises about 20% (w / w) to about 90% (w / w) ibrutinib. In another embodiment, the solid tablet formulation comprises a high load of ibrutinib, at least 20% (w / w) or 30% (w / w) and one or more pharma- ceutically acceptable excipients. In another embodiment, the solid tablet formulation comprises a high load of ibrutinib, at least 40% (w / w) and one or more pharma-ceutically acceptable excipients. In another embodiment, the solid tablet formulation comprises a high load of ibrutinib, at least 50% (w / w) and one or more pharma-ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 30% (w / w) to about 90% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 40% (w / w) to about 90% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 40% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 50% (w / w) to about 75% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients. In another embodiment, the formulation is a high-load solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients.

[0157] In another embodiment, the high-load solid tablet formulation comprises at least 50% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 10% (w / w) to about 50% (w / w). In another embodiment, the high-load solid tablet formulation comprises about 50% (w / w) to about 90% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 10% (w / w) to about 50% (w / w). In another embodiment, the high-load solid tablet formulation comprises about 60% (w / w) to about 80% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more 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 comprising about 60% (w / w) to about 75% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 25% (w / w) to about 40% (w / w).

[0158] In another embodiment, the solid tablet formulation is a high-loading formulation comprising at least 50% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the one or more excipients being selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose (e.g., Dipac®), dextrose, dextrates, maltodextrin, mannitol, xylitol (e.g., Xylitab®), sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose (e.g., Avicel®), microcellulose, and talc. In some embodiments, the diluent is cellulose. In some embodiments, 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methylcellulose (e.g., Methocel®), croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, PVP K25, PVP K30, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12). In some embodiments, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose.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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0159] In another embodiment is a high load solid tablet formulation comprising at least 50% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients are lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0160] In another embodiment, a high load solid tablet formulation comprises at least 50% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0161] In another embodiment, the high load solid tablet formulation comprises about 50% (w / w) to about 90% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, 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, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant.In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0162] In another embodiment, a high load solid tablet formulation comprises about 50% (w / w) to about 90% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0163] In another embodiment, a high load solid tablet formulation comprises about 50% (w / w) to about 90% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0164] In another embodiment, the high load solid tablet formulation comprises about 50% (w / w) to about 80% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, 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, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant.In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0165] In another embodiment, a high load solid tablet formulation comprises about 50% (w / w) to about 80% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0166] In another embodiment, a high load solid tablet formulation comprises about 50% (w / w) to about 80% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0167] In another embodiment, the high load solid tablet formulation comprises about 60% (w / w) to about 80% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, 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, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant.In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0168] In another embodiment, a high load solid tablet formulation comprises about 60% (w / w) to about 80% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0169] In another embodiment, a high load solid tablet formulation comprises about 60% (w / w) to about 80% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0170] In another embodiment, the high load solid tablet formulation comprises about 60% (w / w) to about 75% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, 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, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant.In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0171] In another embodiment, a high load solid tablet formulation comprises about 60% (w / w) to about 75% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0172] In another embodiment, a high load solid tablet formulation comprises about 60% (w / w) to about 75% (w / w) ibrutinib and intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the intragranular excipients comprise: Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0173] In another embodiment, the high load solid tablet formulation comprises: a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose monohydrate; c) about 2% (w / w) to about 5% (w / w) microcrystalline cellulose; d) about 1% (w / w) to about 3% (w / w) polyvinylpyrrolidone; e) about 6% (w / w) to about 8% (w / w) croscarmellose sodium; f) about 1% (w / w) to about 4% (w / w) sodium lauryl sulfate; g) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; h) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0174] In another embodiment, the high load solid tablet formulation comprises: a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose monohydrate; c) about 5% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 1% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) about 0.5% (w / w) magnesium stearate.

[0175] In one embodiment, the tablet formulation is as described above, and the croscarmellose sodium is within about 5% and is greater than or equal to about 2%. In another embodiment, the sodium lauryl sulfate is within about 1% and is greater than or equal to about 0%.

[0176] In another embodiment, the high load solid tablet formulation comprises: a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose monohydrate; c) about 2% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 4% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) about 0.5% (w / w) magnesium stearate.

[0177] In one embodiment, the tablet formulation is as described above, and the croscarmellose sodium is within about 5% and is greater than or equal to about 2%. In another embodiment, the sodium lauryl sulfate is within about 1% and is greater than or equal to about 3%.

[0178] In another embodiment, the high load solid tablet formulation comprises lactose, polyvinylpyrrolidone, sodium lauryl sulfate, crospovidone, colloidal silicon dioxide, and magnesium stearate. a) about 65% (w / w) to about 75% (w / w), or about 70% (w / w) ibrutinib; b) about 14% (w / w) to about 18% (w / w), or about 16% (w / w) lactose monohydrate; c) about 1% (w / w) to about 3% (w / w), or about 2% (w / w) polyvinylpyrrolidone; d) about 0.5% (w / w) to about 1.5% (w / w), or about 1% (w / w) sodium lauryl sulfate; e) about 5% (w / w) to about 15% (w / w), or about 10% (w / w) crospovidone; f) about 0.3% (w / w) to about 0.7% (w / w), or about 0.5% (w / w) colloidal silicon dioxide; g) about 0.3% (w / w) to about 0.7% (w / w), or about 0.5% (w / w) magnesium stearate.

[0179] In another embodiment, the high load solid tablet formulation comprises: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 13% (w / w) to about 15% (w / w) microcrystalline cellulose; d) about 4% (w / w) to about 6% (w / w) croscarmellose sodium; e) about 5% (w / w) to about 7% (w / w) sodium lauryl sulfate; f) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; g) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0180] In some embodiments, the total weight of the tablet is about 934 mg.

[0181] In another embodiment, the high load solid tablet formulation comprises: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 14% (w / w) lactose; c) about 13% (w / w) to about 14% (w / w) microcrystalline cellulose; d) about 2% (w / w) to about 3% (w / w) of croscarmellose sodium (intragranular); e) about 0.8% (w / w) to about 1.2% (w / w) hydroxypropyl cellulose; f) about 2% (w / w) to about 3% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0182] In some embodiments, the total weight of the tablet is about 934 mg.

[0183] In another embodiment, the high load solid tablet formulation comprises: a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 8% (w / w) to about 9% (w / w) lactose; c) about 8 to about 9% (w / w) microcrystalline cellulose; d) about 2.5 to about 3.5% (w / w) croscarmellose sodium (intragranular); e) about 2.5 to about 3.5% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0184] In some embodiments of the tablets described herein, the total weight of the tablet is about 50 mg to about 1.2 g, e.g., 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, including the endpoints. In some embodiments, the total weight of the tablet is about 800 mg.

[0185] In some embodiments of the high-load solid tablet formulations described herein, ibrutinib is in an amount of about 35 mg to about 840 mg per tablet, for example, 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 formulations described herein, ibrutinib is in an amount of about 560 mg. In some embodiments of the high-load solid tablet formulations described herein, ibrutinib is in a particulate form. In some embodiments of the high-load solid tablet formulations described herein, the formulation is used for once-daily administration. In some embodiments of the high-load solid tablet formulations described herein, the formulation is an oral dosage form containing a therapeutically effective amount of ibrutinib.

[0186] In some embodiments, the high load solid tablet formulations described herein are prepared by a process including wet granulation.

[0187] In another embodiment is a method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0188] In another embodiment, a method of treating an autoimmune disease in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In some embodiments, the autoimmune disease is rheumatoid arthritis or lupus. In another embodiment, a method of treating rheumatoid arthritis in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating lupus in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0189] In another embodiment is a method of treating a heteroimmune disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0190] In another embodiment, a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a 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.

[0191] In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being a B cell malignancy, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In some embodiments, the cancer is a B cell proliferative disorder and a B cell malignancy 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 proliferative disorder and the B cell malignancy is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). In some embodiments, the cancer is a B cell proliferative disorder and the B cell malignancy is mantle cell lymphoma (MCL). In some embodiments, the cancer is a B cell proliferative disorder and the B cell malignancy is diffuse large B cell lymphoma (DLBCL). In some embodiments, the cancer is a B cell proliferative disorder and the B cell malignancy is multiple myeloma.

[0192] In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being lymphoma, leukemia, or solid tumor, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being leukemia, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being a solid tumor, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0193] In another embodiment is a method of treating cancer in a patient in need of treatment which is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphoblastic acute leukemia, lymphoplasmacytic lymphoma / Waldenstrom's 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 effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being diffuse large B-cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being follicular lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being chronic lymphocytic lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being chronic lymphocytic leukemia, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being B-cell prolymphoblastic acute leukemia, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment is a method of treating cancer in a patient in need of such treatment, wherein the cancer is lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being splenic marginal zone lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being plasma cell myeloma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being plasmacytoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being extranodal marginal zone B-cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being nodal marginal zone B-cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being mantle cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being mediastinal (thymic) large B-cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being intravascular large B-cell lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being primary effusion lymphoma, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating cancer in a patient in need of treatment, the cancer being Burkitt's lymphoma / leukemia, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.In another embodiment is a method of treating cancer in a patient in need thereof, said cancer being lymphomatoid granulomatosis, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0194] In some embodiments, the composition is for use in the treatment of sarcoma or carcinoma. In some embodiments, the composition is for use in the treatment of sarcoma. In some embodiments, the composition is for use in the treatment of carcinoma. In some embodiments, the sarcoma is selected from the group consisting of alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, nasal neuroblastoma, Ewing's sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi's sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, In some embodiments, the carcinoma is selected from: malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasm(s) with perivascular epithelioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm(s) with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraskeletal Ewing's tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, telangiectatic osteosarcoma. In some embodiments, the carcinoma is selected from: adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the solid tumor is selected from anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain cancer, breast cancer, HER2-amplified breast cancer, cervical cancer, colon cancer, cancer of unknown primary (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, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, or vulvar cancer. In some embodiments, the carcinoma 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 carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer.In some embodiments, the colorectal cancer is an 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 carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell, or adenocarcinoma. In some embodiments, the carcinoma 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 carcinoma, or large cell lung carcinoma. In some embodiments, the non-small cell lung cancer is large cell lung carcinoma. In some embodiments, the lung cancer is small cell lung carcinoma. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is proximal cholangiocarcinoma or distal cholangiocarcinoma.

[0195] In another embodiment is a method of treating mastocytosis in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0196] In another embodiment, a method of treating osteoporosis or a bone resorption disorder in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating osteoporosis in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In another embodiment, a method of treating bone resorption disorder in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0197] In another embodiment is a method of treating an inflammatory disease or condition in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0198] In another embodiment is a method of treating lupus in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0199] In another aspect, a process for preparing a pharmaceutical composition described herein, the process comprising a wet granulation process.

[0200] In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1:

[0201] [ka] The process comprises a wet granulation process and the pharmaceutical composition comprises at least 50% (w / w) ibrutinib.

[0202] In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 30% (w / w) to about 90% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 40% (w / w) to about 90% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 50% (w / w) to about 90% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 40% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 50% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 60% (w / w) to about 80% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 50% (w / w) to about 75% (w / w) of ibrutinib. In another embodiment, a process for preparing a pharmaceutical composition comprising ibrutinib, the process comprises a wet granulation method, and the pharmaceutical composition comprises about 60% (w / w) to about 75% (w / w) of ibrutinib.

[0203] In another embodiment, there is provided a process for preparing a highly loaded 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 pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising at least 30% (w / w) ibrutinib, and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising at least 40% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising at least 50% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 30% (w / w) to about 90% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 40% (w / w) to about 90% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 40% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process.In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, a process is provided for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 75% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients, the process comprising a wet granulation process.

[0204] In another embodiment, there is provided a process 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 pharma- ceutically acceptable excipients present in an amount of about 10% (w / w) to about 50% (w / w) total weight, the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising at least 50% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients present in a total weight of about 50% (w / w) or less, the process comprising a wet granulation process.In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) ibrutinib and one or more pharma-ceutically acceptable excipients present in a total weight of about 10% (w / w) to about 50% (w / w), the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma- ceutically acceptable excipients present at about 20% (w / w) to about 50% (w / w) total weight, the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib and one or more pharma-ceutically acceptable excipients present at about 20% (w / w) to about 40% (w / w) total weight, the process comprising a wet granulation process. In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) ibrutinib and one or more pharma- ceutically acceptable excipients present in a total weight range of about 25% (w / w) to about 40% (w / w), wherein the process comprises a wet granulation process.

[0205] 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 pharma- ceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants, the process comprising a wet granulation process. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0206] In another embodiment, there is provided a process for preparing a high-load solid tablet formulation comprising at least 50% (w / w) ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a high-load solid tablet formulation comprising at least 50% (w / w) ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0207] In another embodiment, there is provided a process for preparing a high-load solid tablet formulation comprising at least 50% (w / w) ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a high-load solid tablet formulation comprising at least 50% (w / w) ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0208] 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 pharma- ceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants. In some embodiments, the at least one excipient is a diluent and the process comprises a wet granulation process. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0209] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0210] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 90% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0211] 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 pharma- ceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants, the process comprising a wet granulation process. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0212] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0213] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 50% (w / w) to about 80% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0214] 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 pharma- ceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants, the process comprising a wet granulation process. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0215] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0216] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 80% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0217] 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 pharma- ceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants, the process comprising a wet granulation process. In some embodiments, the at least one excipient is a diluent. In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 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). In some embodiments, the diluent is lactose, and the 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, and gums. In some embodiments, the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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, 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). In some embodiments, the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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). In some embodiments, the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropylcellulose. 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 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). In some embodiments, at least one excipient is a glidant. In some embodiments, the glidant is silica (colloidal silicon dioxide). In some embodiments, the glidant is silica (colloidal silicon dioxide), and the silica (colloidal silicon dioxide) 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). 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 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). In some embodiments, the excipients include lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

[0218] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising lactose in an amount 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 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); croscarmellose sodium in an amount 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 an amount 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), Extragranular excipients are: croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

[0219] In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) of ibrutinib and intragranular and extragranular excipients, the process comprising a wet granulation process, the intragranular excipients comprising lactose, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In another embodiment, there is provided a process for preparing a highly loaded solid tablet formulation comprising about 60% (w / w) to about 75% (w / w) of ibrutinib, the process comprising a wet granulation process, the intragranular excipients comprising Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); Microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); Extragranular excipients are: Croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

[0220] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 2% (w / w) to about 5% (w / w) microcrystalline cellulose; d) about 1% (w / w) to about 3% (w / w) polyvinylpyrrolidone; e) about 6% (w / w) to about 8% (w / w) croscarmellose sodium; f) about 1% (w / w) to about 4% (w / w) sodium lauryl sulfate; g) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; h) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0221] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose; c) about 5% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 1% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) about 0.5% (w / w) magnesium stearate.

[0222] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 70% (w / w) ibrutinib; b) about 14% (w / w) lactose; c) about 2% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 4% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; h) about 0.5% (w / w) magnesium stearate.

[0223] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 65% (w / w) to about 75% (w / w), or about 70% (w / w) ibrutinib; b) about 14% (w / w) to about 18% (w / w), or about 16% (w / w) lactose monohydrate; c) about 1% (w / w) to about 3% (w / w), or about 2% (w / w) polyvinylpyrrolidone; d) about 0.5% (w / w) to about 1.5% (w / w), or about 1% (w / w) sodium lauryl sulfate; e) about 5% (w / w) to about 15% (w / w), or about 10% (w / w) crospovidone; f) about 0.3% (w / w) to about 0.7% (w / w), or about 0.5% (w / w) colloidal silicon dioxide; g) about 0.3% (w / w) to about 0.7% (w / w), or about 0.5% (w / w) magnesium stearate.

[0224] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 13% (w / w) to about 15% (w / w) microcrystalline cellulose; d) about 4% (w / w) to about 6% (w / w) croscarmellose sodium; e) about 5% (w / w) to about 7% (w / w) sodium lauryl sulfate; f) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; g) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate. In some embodiments, the total weight of the tablet is about 934 mg.

[0225] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 14% (w / w) lactose; c) about 13% (w / w) to about 14% (w / w) microcrystalline cellulose; d) about 2% (w / w) to about 3% (w / w) of croscarmellose sodium (intragranular); e) about 0.8% (w / w) to about 1.2% (w / w) hydroxypropyl cellulose; f) about 2% (w / w) to about 3% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0226] In some embodiments, the total weight of the tablet is about 934 mg.

[0227] In another embodiment, there is provided a process for preparing a high load solid tablet formulation comprising ibrutinib, the process comprising a wet granulation process, the formulation comprising: a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 8% (w / w) to about 9% (w / w) lactose; c) about 8 to about 9% (w / w) microcrystalline cellulose; d) about 2.5 to about 3.5% (w / w) croscarmellose sodium (intragranular); e) about 2.5 to about 3.5% (w / w) croscarmellose sodium (extragranular); g) about 5.5 to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

[0228] In some embodiments, the total weight of the tablet is about 800 mg.

[0229] In some embodiments of the high-load solid tablet formulations described herein that contain ibrutinib and are prepared using wet granulation, ibrutinib is in an amount of about 560 mg. In some embodiments of the high-load solid tablet formulations described herein that contain ibrutinib and are prepared using wet granulation, ibrutinib is in particulate form. In some embodiments of the high-load solid tablet formulations described herein that contain ibrutinib and are prepared using wet granulation, the formulation is used for once-daily administration. In some embodiments of the high-load solid tablet formulations described herein that contain ibrutinib and are prepared using wet granulation, the formulation is an oral dosage form that contains a therapeutically effective amount of ibrutinib.

[0230] Furthermore, the pharmaceutical compositions described herein that include Compound 1 can be formulated into any suitable dosage form, including, but not limited to, solid oral dosage forms, controlled release formulations, fast dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations. In some embodiments, the tablets described herein are for immediate release and do not contain a viscosity increasing agent such as proxamer or glyceryl behenate.

[0231] In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets, including suspension tablets, fast-disintegrating tablets, bite-disintegration tablets, rapid-disintegration tablets, effervescent tablets, or caplets. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast-disintegrating tablet. Furthermore, the solid dosage forms 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.

[0232] 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 blend composition. When such a bulk blend composition is said to be homogeneous, it means that the particles of Compound 1 are uniformly distributed 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 when taken orally or when contacted with a diluent.

[0233] In some embodiments, the wet granulation process involves granulating a mixture of ibrutinib and intragranular excipients with a granulation liquid, such as purified water, under granulation conditions, such as high shear granulation conditions, to form granules.

[0234] In some embodiments, a composition or formulation described herein is prepared by a process comprising: (1) mixing ibrutinib with intragranular excipients, such as fillers, binders, disintegrants, and surfactants; (2) granulating the mixture of ibrutinib and intragranular excipients with purified water or an aqueous binder solution under high shear granulation conditions to form granules; (3) drying the granules to form dry granules; (4) milling the dried granules; (5) blending the milled granules with extragranular excipients, such as fillers, disintegrants, surfactants, and lubricants; and (6) compressing the mixture of milled granules and extragranular excipients to form a tablet.

[0235] The pharmaceutical compositions or formulations described herein may further comprise a flavoring agent, a sweetener, a coloring agent, an antioxidant, a preservative, or one or more combinations thereof.In yet another aspect, a film coating is provided around the formulation of Compound 1 using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).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 neither microencapsulated nor coated.

[0236] Suitable antioxidants for use in the compositions or formulations described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0237] It should be understood that there is considerable overlap between the additives used in the solid dosage forms described herein.Therefore, the above additives should be taken as merely illustrative and not limiting of the types of additives that can be included in the compositions or formulations described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0238] Compressed tablets are solid dosage forms prepared by compressing the formulation of the bulk blend described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, a film coating can provide delayed release of Compound 1 from the formulation. In other embodiments, a film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, are typically about 1%-about 3% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0239] In some embodiments, the compositions or formulations described herein can be formulated as enteric-coated delayed release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form can be a (coated or uncoated) compressed or molded or extruded tablet / form containing granules, powders, pellets, beads, or particles of the active ingredient and / or other composition ingredients, which are themselves coated or uncoated. The enteric-coated oral dosage form can also be a (coated or uncoated) capsule containing pellets, beads, or granules of the solid carrier or composition, which are themselves coated or uncoated.

[0240] As used herein, the term "delayed release" refers to delivery such that release may occur at some generally predictable location in the intestinal tract that is more distal from where it would have occurred if the delayed release change had not occurred. In some embodiments, the method for delaying release is a coating. Any coating should be applied to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH above about 5. It is expected that any anionic polymer that exhibits a pH-dependent solubility profile may 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, the polymers and their compatible mixtures, as well as some of their properties, include, but are not limited to:

[0241] 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 above 7.

[0242] Acrylic polymers. The performance of acrylic polymers (mainly their solubility in biological fluids) can vary based on the degree and type of substitution. Suitable acrylic polymers include, for example, methacrylic acid copolymers and ammonia methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract, but are permeable and are primarily used to target the colon. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach, but dissolve in the intestine.

[0243] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; a reaction mixture of partial acetate esters of cellulose with phthalic anhydride. Performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at a pH above 6. Aquateric (FMC) is a spray-dried CAP pseudolatex that is water-based and contains particles less than 1 μm. Other ingredients in Aquateric may include Pluronics, Tweens, and acetyl monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance may vary based on the degree and type of substitution. For example, grades of HPMCP such as HP-50, HP-55, HP-55S, HP-55F, etc. are suitable. Performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are provided as granules for aqueous dispersion, or as fine powders. Polyvinyl acetate phthalate (PVAP). PVAP dissolves at a pH above 5 and is less permeable to water vapor and gastric juices.

[0244] In some embodiments, the coating can, and typically does, contain a plasticizer and possibly other coating excipients known in the art, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. Specifically, anionic carboxylic acrylic polymers will usually contain 10-25% by weight of a plasticizer, particularly 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 should be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the intestinal tract.

[0245] Colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) can be added to the coating to solubilize or disperse the coating materials, improve coating performance and the coated product.

[0246] In other embodiments, the formulations described herein that contain Compound 1 are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate release pulses at a predetermined time point or at a specific site after a controlled lag time. 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 polymer-based systems such as polylactic and polyglycolic acids, polyanhydrides, and polycaprolactones; porous matrices; non-polymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters, and fatty acids, or neutral fats, such as mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets, using conventional binders, and the like. For example, see Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 751-753 (2002), U.S. Pat. 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.

[0247] In some embodiments, a pharmaceutical formulation is provided that includes particles of Compound 1 and at least one dispersing or suspending agent for oral administration to a subject. The formulation can be a powder and / or granules for suspension, which upon mixing with water results in a substantially uniform suspension.

[0248] It should be understood that there is overlap between the above additives used in the aqueous dispersion or suspension described herein, because a given additive is often classified differently by different practitioners in this field or is common in any of several different functions.Therefore, the above additives should be taken as merely illustrative and not limiting for the types of additives that can be included in the formulations described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0249] Medication and Treatment Regimens In some embodiments, the amount of Compound 1 administered to the mammal is 300 mg / day to 1000 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is 420 mg / day to 840 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 420 mg / day. In some embodiments, the amount of Compound 1 administered to the mammal is about 560 mg / day. In some embodiments, the AUC 0~24 is about 150 to about 3500 ng*h / mL. In some embodiments, the AUC 0~24 is about 500 to about 1100 ng*h / mL. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once a day, twice a day, or three times a day. In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered once a day. In some embodiments, Compound 1 is administered every other day. In some embodiments, Compound 1 is a maintenance therapy.

[0250] Compound 1 may be used in the preparation of a medicament for the treatment of a disease or condition in which inhibition of Btk or a homolog thereof, or inhibition of Btk or a homolog thereof, would be beneficial, at least in part, including in subjects diagnosed with a hematological malignancy. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of treatment includes administering to the subject a therapeutically effective amount of a pharmaceutical composition containing Compound 1, or a pharma- ceutical acceptable salt, a pharma-ceutical acceptable N-oxide, a pharma-ceutical active metabolite, a pharma-ceutical acceptable prodrug, or a pharma-ceutical acceptable solvate thereof.

[0251] The composition containing Compound 1 may be administered for prophylaxis, treatment, or maintenance treatment. In some embodiments, the composition containing Compound 1 is administered for therapeutic applications (e.g., administered to a subject diagnosed with a hematological malignancy). In some embodiments, the composition containing Compound 1 is administered for therapeutic applications (e.g., administered to a subject susceptible to or otherwise at risk of developing a hematological malignancy). In some embodiments, the composition containing Compound 1 is administered to a patient in remission as a maintenance therapy.

[0252] The amount of compound 1 will vary depending on the use (e.g., treatment, prevention, or maintenance). The amount of compound 1 will vary depending on the severity and course of the disease or condition, previous therapy, the patient's health, weight, and response to the drug, and the judgment of the treating physician. It is considered well within the skill of the art to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, dose escalation clinical trials). In some embodiments, the amount of compound 1 is 300 mg / day to 1000 mg / day. In some embodiments, the amount of compound 1 is 420 mg / day to 840 mg / day. In some embodiments, the amount of compound 1 is 400 mg / day to 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 between 2 mg / kg / day and 13 mg / kg / day. In some embodiments, the amount of Compound 1 is between 2.5 mg / kg / day and 8 mg / kg / day. In some embodiments, the amount of Compound 1 is between 2.5 mg / kg / day and 6 mg / kg / day. In some embodiments, the amount of Compound 1 is between 2.5 mg / kg / day and 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.

[0253] In one embodiment, a tablet formulation of the present invention containing a 140 mg dose in dogs has a C of about 260-400 ng / mL (fed) and about 300-400 ng / mL (fasted). max In another embodiment, the formulation produces a C of about 280-380 ng / mL (fed) and about 360-380 ng / mL (fasted). max In certain embodiments, the formulation produces a C of about 290 ng / mL (fed) and about 370 ng / mL (fasted). max In another specific embodiment, the formulation produces a C of about 370 ng / mL (fed) and about 370 ng / mL (fasted). maxIn 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).

[0254] In one embodiment, a tablet formulation of the present invention comprising a 140 mg dose in dogs produces an AUC of about 850-1050 ng*h / mL (fed) and about 850-1050 ng*h / mL (fasted). In another embodiment, the formulation produces an AUC of about 870-1050 ng*h / mL (fed) and about 840-1000 ng*h / mL (fasted). In a particular embodiment, the formulation produces an AUC of about 875 ng*h / mL (fed) and about 1000 ng*h / mL (fasted). In another particular embodiment, the formulation produces an AUC of about 1000 ng*h / mL (fed) and about 850 ng*h / mL (fasted). 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).

[0255] In one embodiment, a tablet formulation of the present invention containing a 140 mg dose in dogs has an F of about 150-250 (fed) and 100-160 (fasted). rel (%)(tablet / capsule)(C max In certain embodiments, the formulation produces an F value of about 170 (fed) and about 110 (fasted). rel (%)(tablet / capsule)(C max In another particular embodiment, the formulation produces an F value of about 230 (fed) and about 150 (fasted). rel (%)(tablet / capsule)(C max) values. 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).

[0256] In one embodiment, a tablet formulation of the present invention containing a 140 mg dose in dogs has an F of about 110-150 (fed) and 100-140 (fasted). rel (%) (tablet / capsule) (AUC) values ​​of about 120 (fed) and about 110 (fasted). rel In another particular embodiment, the formulation produces an F(%)(tablet / capsule)(AUC) value of about 150 (fed) and about 130 (fasted). rel (%) (tablet / capsule) (AUC) values ​​are generated. 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).

[0257] In one embodiment, a tablet formulation of the present invention containing a 140 mg dose in dogs has an F of about 90 to 105. rel (%)(Fed / Fasted)(C max In certain embodiments, the formulation produces an F value of about 95. rel (%)(Fed / Fasted)(C max In another particular embodiment, the formulation produces an F value of about 100. rel (%)(Fed / Fasted)(C max ) values. 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).

[0258] In one embodiment, a tablet formulation of the present invention containing a 140 mg dose in dogs has an F of about 90 to 140. rel In certain embodiments, the formulation produces an F of about 100. rel (%) (fed / fasted) (AUC) values ​​are generated. 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).

[0259] In some embodiments, the pharmaceutical compositions described herein contain about 140 mg of Compound 1. In some embodiments, a tablet formulation containing about 140 mg of Compound 1 is prepared. In some embodiments, 2, 3, 4, or 5 tablets of the tablet formulation are administered daily. In some embodiments, 3 or 4 capsules are administered daily. In some embodiments, a tablet is administered once a day. In some embodiments, a capsule is administered once a day. In other embodiments, a tablet is administered multiple times a day.

[0260] In another embodiment, a high load solid tablet formulation comprising ibrutinib, wherein ibrutinib is a compound having the structure of Compound 1:

[0261] [ka] Each tablet contains approximately 560 mg of ibrutinib.

[0262] In another embodiment, the high-load solid tablet formulation is used for once-daily oral administration. The high-load solid tablet formulation described herein allows for administration of one tablet once a day and contains a large amount of ibrutinib per tablet, such as about 420 mg to about 840 mg, for example, about 420 mg, about 560 mg, or about 840 mg, or any range between any two of these values, including the end points. In another embodiment, the high-load solid tablet formulation is used, and the tablet contains 560 mg of ibrutinib. In another embodiment, the high-load solid tablet formulation is used, and the ibrutinib is in a particulate form.

[0263] In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered every other day.

[0264] In some embodiments, Compound 1 is administered once a day. In some embodiments, Compound 1 is administered twice a day. In some embodiments, Compound 1 is administered three times a day. In some embodiments, Compound 1 is administered four times a day.

[0265] In some embodiments, Compound 1 is administered until disease progression, unacceptable toxicity, or personal choice. In some embodiments, Compound 1 is administered daily until disease progression, unacceptable toxicity, or personal choice. In some embodiments, Compound 1 is administered every other day until disease progression, unacceptable toxicity, or personal choice.

[0266] If the patient's condition improves, at the discretion of the physician, administration of the compound may be continued; alternatively, the dose of the administered drug may be temporarily reduced or temporarily discontinued for a certain period of time (i.e., a "drug holiday"). The length of the drug holiday may vary between 2 days and 1 year, and includes, by way of 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. Dose reductions between drug holidays can be from 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0267] Once improvement of the patient's condition has occurred, a maintenance dose is administered as necessary.The dosage or frequency of administration, or both, can then be reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained.However, the patient may require long-term intermittent treatment upon recurrence of any symptoms.

[0268] The amount of a given agent that would correspond to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the identity (e.g., body weight) of the subject or host requiring treatment, but can nevertheless be routinely determined in a manner well known in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated. In general, however, doses employed for adult treatment will typically be within the range of 0.02 to 5000 mg per day, or about 1 to 1500 mg per day. The desired dose may conveniently be present as a single dose or divided doses, and may be administered simultaneously (or over a short period of time) or at suitable intervals, e.g., two, three, four or more subdoses per day.

[0269] The pharmaceutical compositions or formulations described herein may be in unit dosage form suitable for single administration of precise dosage amounts. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses may be in the form of packages containing individual 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-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is typical to include a preservative in the composition. In some embodiments, each unit dosage form contains 140 mg of Compound 1. In some embodiments, an individual is administered one unit dosage form per day. In some embodiments, an individual is administered two unit dosage forms per day. In some embodiments, an individual is administered three unit dosage forms per day. In some embodiments, an individual is administered four unit dosage forms per day.

[0270] The foregoing ranges are merely suggestive, since the number of variables for each individual treatment regimen is large and it is not uncommon for there to be substantial deviations from these recommendations. Such dosages may vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0271] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including the LD 50 (Lethal dose for 50% of the population) and ED 50 These include, but are not limited to, the determination of the dose effective to treat 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably at least about 100 mg / kg / day with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed, and the route of administration utilized.

[0272] Combination therapy In some cases, it may be appropriate to administer Compound 1 in combination with another therapeutic agent.

[0273] In one embodiment, the compositions and methods described herein are also used in conjunction with other therapeutic agents selected for their particular utility for the condition being treated. Generally, in embodiments where combination therapy is used, the compositions described herein and the other agents do not need to be administered in the same pharmaceutical composition, but are administered by different routes due to different physical and chemical characteristics. In one embodiment, initial administration is performed according to an established protocol, with further modifications based on observed effects, mode of administration, and time of administration.

[0274] In various embodiments, the compounds are administered concurrently (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the condition of the patient, and the actual choice of compounds used. In certain embodiments, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based on an evaluation of the disease being treated and the condition of the patient.

[0275] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, and the like.

[0276] The individual compounds of such combinations are administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be understood by those skilled in the art.

[0277] The combinations referred to herein are conveniently presented for use in the form of a pharmaceutical composition, together with a pharma- ceutically acceptable diluent(s) or carrier(s).

[0278] In certain embodiments, disclosed herein are methods for treating cancer in an individual in need thereof, comprising administering to the individual an amount of Compound 1. In some embodiments, the method further comprises administering a second cancer treatment regimen.

[0279] In some embodiments, administering a Btk inhibitor prior to a second cancer treatment regimen reduces an immune-mediated response to the second cancer treatment regimen. In some embodiments, administering compound 1 prior to ofatumumab reduces an immune-mediated response to ofatumumab.

[0280] In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCγ inhibitor, a PKCβ inhibitor, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises an antibody, a B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, an immunochemotherapy, a radioimmunotherapeutic agent, a DNA damaging agent, a proteosome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jak1 / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[0281] In some embodiments, the second cancer treatment regimen is selected from the group consisting of chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, 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.

[0282] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab.

[0283] In some embodiments, the second cancer treatment regimen comprises bendamustine and rituximab.

[0284] In some embodiments, the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.

[0285] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab.

[0286] In some embodiments, the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally rituximab.

[0287] In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.

[0288] In some embodiments, the second cancer treatment regimen comprises a proteasome inhibitor. In some embodiments, the second cancer treatment regimen comprises bortezomib. In some embodiments, the second cancer treatment regimen comprises an epoxyketone. In some embodiments, the second cancer treatment regimen comprises epoxomicin. In some embodiments, the second cancer treatment regimen comprises a tetrapeptide epoxyketone. In some embodiments, the second cancer treatment regimen comprises carfilzomib. In some embodiments, the second cancer treatment regimen comprises disulfuram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

[0289] In some embodiments, the second cancer treatment regimen comprises a Cyp3A4 inhibitor. In some embodiments, the second cancer treatment regimen comprises indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone. In some embodiments, the second cancer treatment regimen comprises ketoconazole.

[0290] In some embodiments, the second cancer treatment regimen comprises a Janus kinase (JAK) inhibitor. In some embodiments, the second treatment comprises lestaurtinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or pacritinib.

[0291] In some embodiments, the second cancer treatment regimen comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment regimen comprises a hydroxamic acid (or hydroxamate) such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic tetrapeptide such as trapoxin B, a depsipeptide, a benzamide such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), an electrophilic ketone, or a fatty acid compound such as phenylbutyrate and valproic acid.

[0292] Further cancer treatment regimens include nitrogen mustards, such as, for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trophosphamide; alkyl sulfonates, such as, for example, busulfan, mannosulfan, treosulfan; ethylenimines, such as, for example, carboquone, thiotepa, triaziquone; nitrosoureas, such as, for example, carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; epoxides, such as, for example, etoglucide; Other alkylating agents such as bronitrile, pipobroman, temozolomide; folic acid analogues such as methotrexate, permetrexed, pralatrexate, raltitrexed; purine analogues such as cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, thioguanine; pyrimidine analogues such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; vinblastine, vincristine, vindesine, vinflunine, vinoreclone, vinoxacillin ... Vinca alkaloids such as rubin; podophyllotoxin derivatives such as etoposide, teniposide; colchicine derivatives such as demecolcine; taxanes such as docetaxel, paclitaxel, paclitaxel poliglumex; other plant alkaloids and natural products such as trabectedin; actinomycins such as dactinomycin; anthracyclines such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubicin; bleomycin, other cytotoxic antibiotics such as ixabepilone, mitomycin, plicamycin; platinum compounds such as carboplatin, cisplatin, oxaliplatin, satraplatin; methylhydrazines such as procarbazine; sensitizers such as aminolevulinic acid, efaproxiral, methylaminolevulinate, porfimer sodium, temoporfin; protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus;For example, alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosine, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimagine seradenovec, tiazofurin, and topotecan. other antineoplastic agents such as diethylstilbenol, ethinyl estradiol, fosfestrol, polyestradiol phosphate; progestogens such as gestnorone, medroxyprogesterone, megestrol; gonadotropin releasing hormone analogues such as buserelin, goserelin, leuprorelin, triptorelin; fulvestrant, tamoxifen, toremife anti-estrogens such as bicalutamide, flutamide, nilutamide, etc.; enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, vorozole; other hormone antagonists such as abarelix, degarelix, etc.; immunostimulants such as histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, thymopentin, etc.; Immunosuppressants such as flunomide, mycophenolic acid, sirolimus; calcineurin inhibitors such as cyclosporine, tacrolimus; other immunostimulants such as azathioprine, lenalidomide, methotrexate, thalidomide; calcineurin inhibitors such as cyclosporine, tacrolimus; other immunosuppressants such as azathioprine, lenalidomide, methotrexate, thalidomide; radiopharmaceuticals such as iobenguane;

[0293] Additional cancer treatment regimens include interferons, interleukins, tumor necrosis factors, growth factors, and the like.

[0294] Further cancer treatment regimens include immune stimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim; interferons such as interferon alpha natural, interferon alpha-2a, interferon alpha-2b, interferon alfacon-1, interferon alpha-n1, interferon beta natural, interferon beta-1a, interferon beta-1b, interferon gamma, peginterferon alpha-2a, peginterferon alpha-2b; interleukins such as aldesleukin, oprelvekin; and interleukins such as BCG vaccine, glutiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly I Other immunostimulants such as CLC, rokinimex, tasonermin, thymopentin; immunosuppressants such as abatacept, avetimus, alefacept, antilymphocyte immunoglobulin (horse), antithymic immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3, mycophenolate, natalizumab, sirolimus; adalimumab, afelimomab, certolizumab TNF-alpha inhibitors such as pegol, etanercept, golimumab, infliximab; interleukin inhibitors such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, ustekinumab; calcineurin inhibitors such as cyclosporine, tacrolimus; other immunosuppressants such as azathioprine, lenalidomide, methotrexate, thalidomide.

[0295] Additional cancer treatment regimens include adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, and the like, or combinations thereof.

[0296] Further cancer treatment regimens include, for example, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, immunosuppressants, monoclonal antibodies such as eculizumab, efalizumab, muromab-CD3, natalizumab; TNF-alpha inhibitors such as liximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab, radiopharmaceuticals, ibritumomab tiuxetan, tositumomab; such as abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMAb, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, b Lentuximab vedotin, capromab pendetide, cixutumumab, clodicimab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glenbatumumab, ibritumomab, inotuzumab, ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab Other monoclonal antibodies include mab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necituzumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramaclimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0297] Additional cancer treatment regimens include agents that affect the tumor microenvironment, such as intracellular signaling networks (e.g., the phosphatidylinositol 3-kinase (PI3K) signaling pathway of signaling from the B cell receptor and the IgE receptor). In some embodiments, the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syk inhibitor is R788. In another embodiment, it is a PKCγ inhibitor, such as, by way of example only, enzastaurin.

[0298] In some embodiments, the additional therapeutic agent comprises a pain reliever, such as acetaminophen.

[0299] In some embodiments, the additional therapeutic agent comprises an agent selected from an inhibitor of LYN, SYK, JAK, PI3K, PLCγ, MAPK, MEK, or NFκB.

[0300] Examples of agents that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, such as protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pasonanib, sorafenib, sunitinib, temsirolimus; other angiogenesis inhibitors such as GT-111, JI-101, R1530; AC220, AC480, ACE-041, AMG900, AP24534, Arry-614, AT7519, AT9283, AV-951, Axitinib, AZD1152, AZD7762, AZD8055, AZD8931, Bafetinib, BAY73-4506, BGJ398, BGT226, BI811283, BI6727, BIBF1120, BIBW2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, Dinaciclib, Dovitinib lactate, E7050, EMD1214063, ENMD-2076, Fostamatinib dinat um, GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON01919.Na, OSI-027, OSI-930, Btk inhibitors, PF-00562271, PF-02341066, PF-03814735, PF-0421790 Other kinase inhibitors include 3, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281RO5126766, XL418, and XL765.

[0301] Further examples of anti-cancer agents for use in combination with the 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).

[0302] Other anticancer drugs that can be used in combination with the Btk inhibitor compounds include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldeslureukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; Visafide dimesylate;Bizelesin;Bleomycin sulfate;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carbucin hydrochloride;Carzelesin;Cedefingol;Chlorambucil;Silormycin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Desaguanine;Desaguanine mesylate;Diazicon;Doxorubicin;Doxol hydrochloride Bicine;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamiturcin;Enloplatin;Empromate;Epiropropidine;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine sodium phosphate;Etanidazole;Etoposide;Etoposide phosphate;Ethaprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Flurocitabine;Pho Sukidon; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; interleukin Il (including recombinant interleukin II or rlL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;Lometrexol sodium; Lomustine; Rosoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mintidomi; Mitocalcine; Mitochromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenol Acid;Nocodazole;Nogalamycin;Ormaplatin;Oxisuran;Pegaspargase;Paliomycin;Pentamastine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Riboprin;Rogletimide;Safingol;Safi hydrochloride Ngol;Semustine;Simtrazene;Sparphosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestron acetate ;triciribine phosphate;trimetrexate;trimetrexate triglucuronate;triptorelin;tubrozole hydrochloride;uracil mustard;uredepa;vapreotide;verteporfin;vinblastine sulfate;vincristine sulfate;vindesine;vindesine sulfate;binepidine sulfate;vinglisinate sulfate;vinleurosine sulfate;vinorelbine tartrate;vinrocidine sulfate;vinzolidine sulfate;vorozole;zeniplatin;zinostatin;zorubicin hydrochloride salts. ;

[0303] Other anti-cancer drugs that can be used in combination with Btk inhibitor compounds include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambasmustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing Morphogenetic protein-1;Antiandrogens, prostate cancer;Antiestrogens;Antineoplastic drugs;Antisense oligonucleotides;Aphidicolin glycinate;Apoptosis gene regulators;Apoptosis regulators;Apurinic acid;ara-CDP-DL-PTBA;Arginine deaminase;Asulaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxins;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorid benzoylstaurosporine;beta-lactam derivatives;beta-arretin;beta-aclamycin B;betulinic acid;bFGF inhibitors;bicalutamide;bisantrene;bisaziridinyl spermine;bisnafide;bistratin A;bizelesin;brefrait;bropirimine;budotitanium;buthionine sulfoximine;calcipotriol;calphostin C;camptothecin derivatives;canarypox IL-2;capecitabine;carboxamide-amino-triazoles;carboxyamidotriazoles;CaRestM3;CARN700;cartilage derived inhibitors;ca Luzeresin;Casein kinase inhibitors (ICOS);Castanospermine;Cecropin B;Cetrorelix;Clorance;SulfonamidesChloroquinoxalines;Sulfonamides;Cicaprost;Cis-porphyrins;Cladribine;Clomiphene analogs;Clotrimazole;Colismycin A;Colismycin B;Combretastatin A4;Combretastatin analogs;Conagenin;Crambesidin 816;Crysnatol;Cryptophycin 8;Cryptophycin A derivatives;Cracin A;Cyclopentaanthraquinones;Cycloplatam;Sipemycin;Cytarabine ocfosfate;Cytolytic factors;Cytostatin;Dacliximab;Decitabine;Dehydrodidemnin B;Deslorelin;Dexamethasone;Dexyphosphamide;Dexrazoxane;Dexaverapamil;Diazicon;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-dioxamycin;Diphenylspiromustine;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrcoloma b;eflornithine;elemene;emitefur;epirubicin;epristeride;estramus analogs;estrogen agonists;estrogen antagonists;etanidazole;etoposide phosphate;exemestane;fadrozole;fazarabine;fenretinide;filgrastim;finasteride;flavopiridol;frezelastine;fluasterone;fludarabine;fluorodaunornithine hydrochloride;forphenimex;formestane;fostriecin;fotemustine;gadolinium texaphyrin;gallium nitrate;gallocitabine;ga Nirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfam;Heregulin;Hexamethylene bisacetamide;Hypericin;Ibandronic acid;Idarubicin;Idoxifene;Idramantone;Irmofosine;Ilomastat;Imidazoacridone;Imiquimod;Immunostimulating peptides;Insulin such as growth factor-1 receptor inhibitors;Interferon agonists;Interferons;Interleukins;Iobenguane;Iododoxorubicin;Ipomeanol, 4-;Ilopract;Irsogladine;Isobengazone Le;Isohomohalichondrin B;Itasetron;Jasplakinolide;Kahalalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leuprorelin;Levamisole;Liarozole;Linear polyamine analogs;Lipophilic disaccharide peptides;Lipophilic platinum compounds;Lissoclinamide 7;Lovaplatin;Lombricine;Lometrexol;Lonidamine;Losoxantrone;Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Lytic peptides; Maytansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrilysine inhibitors; Matrix metalloproteinase inhibitors; Menogaril; Melbarone; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Millimostim; Mismatched double-stranded RNA; Mitoguazone; Mitolactol; Mitomycin analogs; Mitonafide; Mitotoxin fibroblast growth factor-saporin ;mitoxantrone;mofalotene;molgramostim;monoclonal antibodies, human chorionic gonadotropin;monophosphoryl lipid A + myobacterium cell wall sk;mopidamol;multidrug resistance gene inhibitors;multiple tumor suppressors 1-based therapy;mustard anticancer drugs;mycaperoxide B;mycobacterial cell wall extract;myriaporone;N-acetyldinaline;N-substituted benzamides;nafarelin;nagressib;naloxone + pentazocine;napavine;nafterpine;nartograstim;nedaplatin;nemorubicin;neridronic acid;neutral endopeptida azeta;nilutamide;nisamycin;nitric oxide regulators;nitroxide antioxidants;nitrulline;O6-benzylguanine;octreotide;oxenone;oligonucleotides;onapristone;ondansetron;ondansetron;oracin;oral cytokine inducers;ormaplatin;osaterone;oxaliplatin;oxaunomycin;palauamine;palmitoyl rhizoxin;pamidronic acid;panaxytriol;panomiphen;parabactin;pazeliptin;pegaspargase;perdecin;pentosan polysulfate sodium;pen Tostatin;Pentrozole;Perflubron;Perfosfamide;Perillyl alcohol;Phenazinomycin;Phenylacetic acid;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Pracetin A;Pracetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Propyl bis-acridone;Prostaglandin J2;Proteasome inhibitors;Protein A-based immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors;purpurin;pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugates;raf antagonists;raltitrexed;ramosetron;ras farnesyl protein transferase inhibitors;ras inhibitors, ras-GAP inhibitors;demethylated reterliptin;rhenium Re186 etidronic acid;rhizoxin;ribozymes;RII retinamide;logretimide;rohitukine;romurtide;roquinimex;rubiginone B1;ruboxil;safingol;saintpin;SarCNU;sarcophytol A;sargramostim;Sdi 1 mimetics;semustine;senescence-derived inhibitor 1;sense oligonucleotides;signal transduction inhibitors;signal transduction modulators;single-chain antigen-binding proteins;sizofiran;sobuzoxane;sodium borocaptate;sodium phenylacetate;sorberol;somatomedin binding proteins;sonermin;sparfosic acid;spicamycin D;spiromustine;splenopentin;spongistatin 1;squalamine;stem cell inhibitors;stem cell division inhibitors;stypiamide;stromelysin inhibitors;sulfinozine;superactive vasoactive intestinal peptide antagonists;sladista;suramin;swainsonine;synthetic glycosaminoglycans;tallimustine;tamoxifen methiodide;tauromustine;tazarotene;tecogalan sodium;tegafur;terlapyrylium;telome lase inhibitors;temoporfin;temozolomide;teniposide;tetrachlorodecaoxide;tetrazomine;thaliblastine;thiocoraline;thrombopoietin;thrombopoietin mimetics;thymalfasin;thymopoietin receptor agonists;thymotrinan;thyroid stimulating hormone;tin ethyl etiopurpurin;tirapazamine;titanocene dichloride;topsentin;toremifene;totipotent stem cell factor;translation inhibitors;tretinoin;triacetyluridine;triciribine;trimetrexate;triptorelin;tropisetron;turosteride;tyrosine kinase inhibitors;tyrphostins;UBC inhibitors;ubenimex;urogenital sinus-derived growth inhibitor;urokinase receptor antagonists;vapreotide;variolin B;vector systems, erythrocyte gene therapy;veraresol;These include veramine, verudine, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, dilasconob, and zinostatin stimalamer.

[0304] Still other anti-cancer agents that can be used in combination with the Btk inhibitor compounds include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonic acids (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0305] Examples of alkylating agents that can be used in combination with the Btk inhibitor compounds include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0306] Examples of hormones and antagonists include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medoxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0307] Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenal cortical suppressants (e.g., mitotane, aminogluetimide).

[0308] Examples of anti-cancer agents that act by arresting cells in the G2-M phase by stabilizing microtubules and that can be used in combination with Btk inhibitor compounds are elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbotson et al., J. Med. 2002), and cyclosporine (ALS)-10 (ALS). tt, also known as E-7010), altritoltin (such as altritoltin A and altritoltin C), spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothiloneF and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Croptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), bitilebuamide, tubulysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas StateUniversity), oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), ereutherobin (including desmethylereutherobin, desacetylereutherobin, isoereutherobin A, and Z-ereutherobin), carbaeoside, carbaeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozozstatin, (-)-phenylahistine (also known as NSCL-96F037), D-68838 (AstaMarketed and investigational drugs include, but are not limited to, the following: AstraZeneca (Medica), D-68836 (AstaMedica), myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbelastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0309] The formulation can be used in any combination with one or more other antithrombotic agents to treat or prevent thromboembolic disorders (e.g., stroke).Examples of antithrombotic agents include, but are not limited to, thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, doraparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.

[0310] In some embodiments, the additional anti-cancer agent is a Bcl-2 inhibitor.

[0311] In some embodiments, the additional anti-cancer agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is programmed death-ligand 1 (PD-L1, also known as B7-H1, CD274), programmed death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86 , CD137, CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDO1, IDO2, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagen-like structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, VTCN1, or any combination thereof. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-L2.

[0312] In some embodiments, the formulation is administered in combination with a CD20 inhibitor. Exemplary CD20 inhibitors include, but are not limited to, ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab, and obinutuzumab.

[0313] In some embodiments, the additional anti-cancer agent used in combination with the formulations described herein comprises a CDK4 inhibitor (e.g., palbociclib).

[0314] In some embodiments, the additional cancer agent is a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from bortezomib or carfilzomib.

[0315] In some embodiments, the additional cancer drug that can be administered in combination with the formulation is an HDAC inhibitor. In some embodiments, the HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HCl. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.

[0316] In some embodiments, the additional cancer agent that may be administered in combination with the formulation is a MALT1 inhibitor, an MCL-1 inhibitor, an IDH1 inhibitor, a TLR inhibitor, or a PIM inhibitor.

[0317] In some embodiments, an additional anti-cancer agent that may be administered in combination with the formulation is an immunomodulatory agent. Exemplary immunomodulatory agents include, but are not limited to, lenalidomide, thalidomide, and pomalidomide.

[0318] If an individual suffers from or is at risk of suffering from an autoimmune, inflammatory, or allergic disease, Compound 1 may be used with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g., sarcoids, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), steroids (e.g., sarcoids, cyclosporine, rapamycin, methotrexate, cyclophosphamide, methotrexate, cyclosporine ... licylates, arylalkanoates, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulfonanilides), Cox-2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurophine, sulfasalazine, hydroxychloroquine, minocycline, TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, anti-leukotrienes, beta-agonists, theophylline, and anticholinergics.

[0319] Kits / Products Kits and products are also described herein for use in the therapeutic methods of use described herein. Such kits include carriers, packages, or containers that are compartmentalized to accommodate one or more containers, such as vials, tubes, etc., each of the containers (including multiple containers) containing one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from various materials, such as glass or plastic.

[0320] The products provided herein include packaging materials. Packaging materials used for packaging pharmaceutical formulations include, for example, those described in U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0321] In some embodiments, the compounds or compositions described herein are presented in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein are packaged alone or together with another compound or another ingredient or additive. In some embodiments, the package contains one or more containers filled with one or more of the components of the pharmaceutical composition. In some embodiments, the package comprises metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration, such as instructions for administering the compound or composition to treat a neoplastic disease. In some embodiments, the package or dispenser is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the agency of the drug form for human or veterinary administration. In some embodiments, such notice is, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In some embodiments, compositions comprising a compound described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0322] For example, the container(s) optionally contain Compound 1 in a composition or in combination with another agent disclosed herein. Such kits optionally include an identifying instruction or label or instructions for its use in the methods described herein.

[0323] The kit typically includes a label listing the contents and / or instructions for use, as well as a package insert containing the instructions for use. A set of instructions will also typically be included.

[0324] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other features that form the label are attached, molded, or engraved on the container itself; the label is associated with the container when it is present in a receptacle or carrier that holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also indicates instructions for the use of the contents, such as in the methods described herein.

[0325] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the drug form for human or veterinary administration. Such notice is, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In one embodiment, compositions containing the compounds provided herein, formulated in a compatible pharmaceutical carrier, are also prepared, placed in a suitable container, and labeled for treatment of an indicated condition. EXAMPLES

[0326] The following ingredients, formulations, processes, and procedures for carrying out the methods disclosed herein correspond to those described above.

[0327] Example 1: Wet granulation method for preparation of high-load tablet formulation of ibrutinib A high shear mixer is charged with ibrutinib and intragranular ingredients such as lactose monohydrate, optionally microcrystalline cellulose, and optionally croscarmellose sodium and hydroxypropylcellulose in the W / W ratios listed in Tables 1A-1F. These ingredients are then mixed and water (or aqueous binder solution) is gradually added. Once granulated, the wet granules are dried in a fluid bed dryer at an inlet temperature of 60° C. until the loss on drying (LOD) is less than 1.5%. The dried granulated material is then passed through a co-mill equipped with a 0.04 inch screen. The extragranular ingredients such as croscarmellose sodium, sodium lauryl sulfate, and colloidal silicon dioxide are then mixed with the granules in the mixer for 20 minutes. Magnesium stearate is charged into the mixer. The final blend is blended for an additional 2 minutes. The final blend is then removed and compressed into tablets. The tablets are stored at room temp...

Claims

1. A high-load solid tablet formulation comprising ibrutinib and one or more pharma- ceutically acceptable excipients, wherein ibrutinib is a compound having the structure of Compound 1; 【Chemistry 1】 A highly loaded solid tablet formulation, wherein said highly loaded solid tablet formulation comprises at least 50% (w / w) ibrutinib.

2. 2. The highly loaded solid tablet formulation of claim 1, wherein the highly loaded solid tablet formulation comprises from about 50% (w / w) to about 90% (w / w) of ibrutinib.

3. 2. The highly loaded solid tablet formulation of claim 1, wherein the highly loaded solid tablet formulation comprises from about 50% (w / w) to about 80% (w / w) of ibrutinib.

4. 2. The highly loaded solid tablet formulation of claim 1, wherein the highly loaded solid tablet formulation comprises from about 60% (w / w) to about 80% (w / w) of ibrutinib.

5. 2. The highly loaded solid tablet formulation of claim 1, wherein the highly loaded solid tablet formulation comprises about 60% (w / w) to about 75% (w / w) of ibrutinib.

6. 6. The highly loaded solid tablet formulation of any one of claims 1 to 5, wherein the highly loaded solid tablet formulation comprises intragranular and extragranular components.

7. 7. The high load solid tablet formulation of any one of claims 1 to 6, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, and surfactants.

8. The high load solid tablet formulation of any one of claims 1 to 7, wherein at least one excipient is a diluent.

9. 9. The high load solid tablet formulation of claim 8, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc.

10. 9. The high load solid tablet formulation of claim 8, wherein the diluent is cellulose.

11. 9. The high load solid tablet formulation of claim 8, wherein 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).

12. 9. The high load solid tablet formulation of claim 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).

13. 9. The high load solid tablet formulation of claim 8, wherein said diluent is microcrystalline cellulose.

14. 14. The high load solid tablet formulation of claim 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).

15. 14. The high load solid tablet formulation of claim 13, wherein the microcrystalline cellulose is present in an amount of about 8.5% (w / w) or about 14% (w / w).

16. 9. The high load solid tablet formulation of claim 8, wherein the diluents are lactose and microcrystalline cellulose.

17. 17. The high load solid tablet formulation of claim 16, wherein the lactose is present in an amount from about 10% (w / w) to about 15% (w / w) and the microcrystalline cellulose is present in an amount from about 1% (w / w) to about 6% (w / w).

18. 17. The high load solid tablet formulation of claim 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).

19. The high load solid tablet formulation of any one of claims 1 to 18, wherein at least one excipient is a disintegrant.

20. 20. The high load solid tablet formulation of claim 19, wherein the disintegrant is selected from the group consisting of native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays, and gums.

21. 20. The high load solid tablet formulation of claim 19, wherein the disintegrant is croscarmellose sodium, and the croscarmellose sodium is present in an amount 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).

22. 22. The high load solid tablet formulation of any one of claims 1 to 21, wherein at least one excipient is a binder.

23. 23. The high load solid tablet formulation of claim 22, wherein the binder is hydroxypropylcellulose, and the hydroxypropylcellulose 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).

24. 24. The high load solid tablet formulation of any one of claims 1 to 23, wherein the solid tablet formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose.

25. 23. The high load solid tablet formulation of claim 22, wherein the binder is polyvinylpyrrolidone.

26. 26. The high load solid tablet formulation of claim 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).

27. 27. The high load solid tablet formulation of any one of claims 1 to 26, wherein at least one excipient is a surfactant.

28. 28. The high load solid tablet formulation of claim 27, wherein the surfactant is sodium lauryl sulfate.

29. 29. The high load solid tablet formulation of claim 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).

30. 30. The high load solid tablet formulation of any one of claims 1 to 29, wherein the solid tablet formulation further comprises one or more glidants.

31. 31. The high load solid tablet formulation of claim 30, wherein the glidant is silica (colloidal silicon dioxide).

32. 32. The high load solid tablet formulation of claim 31, wherein the silica (colloidal silicon dioxide) 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).

33. The high load solid tablet formulation of any one of claims 1 to 32, wherein at least one excipient is a lubricant.

34. 34. The high load solid tablet formulation of claim 33, wherein the lubricant is magnesium stearate.

35. 35. The high load solid tablet formulation of claim 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).

36. 36. The high load solid tablet formulation of any one of claims 1-22 and 25-35, wherein the excipients comprise lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

37. 6. The high load solid tablet formulation of any one of claims 1 to 5, wherein the solid tablet formulation comprises intragranular and extragranular excipients, the intragranular excipients comprising lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

38. The intragranular excipient is lactose in an amount 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 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); croscarmellose sodium in an amount 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); hydroxypropylcellulose in an amount 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); The extragranular excipient is croscarmellose sodium in an amount 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 an amount 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 silicon dioxide in an amount 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 an amount 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).

39. 6. The high load solid tablet formulation of any one of claims 1 to 5, wherein the solid tablet formulation comprises intragranular and extragranular excipients, the intragranular excipients comprising lactose, sodium lauryl sulfate, polyvinylpyrrolidone, and croscarmellose sodium, and the extragranular excipients comprising croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

40. The intragranular excipient is Lactose in an amount of about 10% (w / w) to about 20% (w / w) or about 12% (w / w) to about 15% (w / w); polyvinylpyrrolidone in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); croscarmellose sodium in an amount of about 1% (w / w) to about 10% (w / w) or about 3% (w / w) to about 7% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w); The extragranular excipient is croscarmellose sodium in an amount of about 0% (w / w) to about 5% (w / w), about 1% (w / w) to about 3% (w / w); sodium lauryl sulfate in an amount of about 0% (w / w) to about 10% (w / w) or about 0% (w / w) to about 4% (w / w); microcrystalline cellulose in an amount of about 1% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w); Colloidal silicon dioxide in an amount 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 an amount of about 0.4% (w / w) to about 0.8% (w / w) or about 0.5% (w / w) to about 0.6% (w / w).

41. a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose monohydrate; c) about 2% (w / w) to about 5% (w / w) microcrystalline cellulose; d) about 1% (w / w) to about 3% (w / w) polyvinylpyrrolidone; e) about 6% (w / w) to about 8% (w / w) croscarmellose sodium; f) about 1% (w / w) to about 4% (w / w) sodium lauryl sulfate; g) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; and h) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

42. a) about 70% (w / w) ibrutinib; and b) about 14% (w / w) lactose monohydrate; c) about 5% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 1% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; and h) about 0.5% (w / w) magnesium stearate.

43. a) about 70% (w / w) ibrutinib; and b) about 14% (w / w) lactose monohydrate; c) about 2% (w / w) microcrystalline cellulose; d) about 2% (w / w) polyvinylpyrrolidone; e) about 7% (w / w) croscarmellose sodium; f) about 4% (w / w) sodium lauryl sulfate; g) about 0.5% (w / w) colloidal silicon dioxide; and h) about 0.5% (w / w) magnesium stearate.

44. The solid tablet formulation comprises: a) about 65% (w / w) to about 75% (w / w) ibrutinib; b) about 14% (w / w) to about 18% (w / w) lactose monohydrate; c) about 1% (w / w) to about 3% (w / w) polyvinylpyrrolidone; d) about 0.5% (w / w) to about 1.5% (w / w) sodium lauryl sulfate; e) about 5% (w / w) to about 15% (w / w) of crospovidone; and f) about 0.3% (w / w) to about 0.7% (w / w) colloidal silicon dioxide; g) about 0.3% (w / w) to about 0.7% (w / w) magnesium stearate.

45. The solid tablet formulation comprises: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 15% (w / w) lactose; c) about 13% (w / w) to about 15% (w / w) microcrystalline cellulose; d) about 4% (w / w) to about 6% (w / w) croscarmellose sodium; e) about 5% (w / w) to about 7% (w / w) sodium lauryl sulfate; f) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; g) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

46. The solid tablet formulation comprises: a) about 59% (w / w) to about 61% (w / w) ibrutinib; b) about 13% (w / w) to about 14% (w / w) lactose; c) about 13% (w / w) to about 14% (w / w) microcrystalline cellulose; d) about 2% (w / w) to about 3% (w / w) croscarmellose sodium (intragranular); e) about 0.8% (w / w) to about 1.2% (w / w) hydroxypropylcellulose; f) about 2% (w / w) to about 3% (w / w) croscarmellose sodium (extragranular); g) about 5.5% (w / w) to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; 2. The high load solid tablet formulation of claim 1, comprising: i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

47. The solid tablet formulation comprises: a) about 69% (w / w) to about 71% (w / w) ibrutinib; b) about 8% (w / w) to about 9% (w / w) lactose; c) about 8% (w / w) to about 9% (w / w) microcrystalline cellulose; d) about 2.5% (w / w) to about 3.5% (w / w) croscarmellose sodium (intragranular); e) about 2.5% (w / w) to about 3.5% (w / w) croscarmellose sodium (extragranular); g) about 5.5% (w / w) to about 6.5% (w / w) sodium lauryl sulfate; h) about 0.4% (w / w) to about 0.6% (w / w) colloidal silicon dioxide; 2. The high load solid tablet formulation of claim 1, comprising: i) about 0.4% (w / w) to about 0.6% (w / w) magnesium stearate.

48. 48. The high load solid tablet formulation of any one of claims 1-47, wherein ibrutinib is in an amount of about 420 or about 560 mg.

49. 49. The high-load solid tablet formulation of any one of claims 1 to 48, wherein the high-load solid tablet formulation is used for administration of one tablet once daily.

50. 50. The highly loaded solid tablet formulation of any one of claims 1 to 49, wherein the highly loaded solid tablet formulation is prepared using a process comprising wet granulation.

51. 50. A method of treating a disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the high load solid tablet formulation of any one of claims 1-49.

52. A process for preparing the high load solid tablet formulation of any one of claims 1 to 49, comprising a wet granulation process.

53. 53. The process of claim 52, wherein the wet granulation method comprises granulating a mixture of ibrutinib and the intragranular excipients with a granulation fluid to form granules.

54. 54. The process of claim 52 or 53, comprising: (1) mixing ibrutinib with the intragranular excipients; (2) granulating the mixture of ibrutinib and the intragranular excipients with purified water or an aqueous binder solution to form granules; (3) drying the granules to form dry granules; (4) milling the dried granules; (5) blending the milled granules with the extragranular excipients; and (6) compressing the mixture of milled granules and the extragranular excipients to form a tablet of the high load solid tablet formulation.

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