Details for Patent: 9,713,617

Title:	Crystalline forms of a Bruton's tyrosine kinase inhibitor
Abstract:	Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Inventor(s):	Purro; Norbert (Los Gatos, CA), Smyth; Mark Stephen (Foster City, CA), Goldman; Erick (Concord, CA), Wirth; David D. (Oak Ridge, NC)
Assignee:	Pharmacyclics LLC (Sunnyvale, CA)
Filing Date:	Dec 21, 2016
Application Number:	15/386,118
Claims:	1. A pharmaceutical formulation for oral administration comprising: (a) about 40 mgs to about 200 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) about 40 wt % to about 50 wt % of a diluent; (c) about 3 wt % to about 10 wt % of a disintegrating agent; (d) about 2 wt % to about 7 wt % of a surfactant; and (e) about 0.2 wt % to about 1.0 wt % of a lubricant. 2. The pharmaceutical formulation of claim 1, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. 3. The pharmaceutical formulation of claim 2, wherein the diluent is microcrystalline cellulose. 4. The pharmaceutical formulation of claim 1, wherein the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum. 5. The pharmaceutical formulation of claim 4, wherein the disintegrating agent is croscarmellose sodium. 6. The pharmaceutical formulation of claim 1, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. 7. The pharmaceutical formulation of claim 6, wherein the surfactant is sodium lauryl sulfate. 8. The pharmaceutical formulation of claim 1, wherein the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. 9. The pharmaceutical formulation of claim 8, wherein the lubricant is magnesium stearate. 10. The pharmaceutical formulation of claim 1 comprising: (a) 140 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) 45.9 wt % of microcrystalline cellulose; (c) 7.0 wt % of croscarmellose sodium; (d) 4.2 wt % of sodium lauryl sulfate; and (e) 0.5 wt % of magnesium stearate. 11. The pharmaceutical formulation of claim 1, wherein the dosage form is a hard gelatin capsule. 12. A package comprising one or more discrete blister pockets, wherein each blister pocket comprises a unit dosage form comprising: a) about 40 mgs to about 200 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of a diluent; c) about 3 wt % to about 10 wt % of a disintegrating agent; d) about 2 wt % to about 7 wt % of a surfactant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant; wherein each blister pocket comprises metal or plastic foil. 13. The package of claim 12 wherein each unit dosage comprises: a) 140 mgs 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; b) 45.9 wt % of microcrystalline cellulose; c) 7.0 wt % of croscarmellose sodium; and d) 4.2 wt % of sodium lauryl sulfate; and e) 0.5 wt % of magnesium stearate. 14. The pharmaceutical formulation of claim 10, wherein the dosage form is a hard gelatin capsule. 15. The pharmaceutical formulation of claim 1 comprising: (a) about 40 wt % to about 50 wt % of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) about 40 wt % to about 50 wt % of microcrystalline cellulose; (c) about 3 wt % to about 10 wt % of croscarmellose sodium; (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate; and (e) about 0.2 wt % to about 1.0 wt % of magnesium stearate. 16. The pharmaceutical formulation of claim 15, wherein the dosage form is a hard gelatin capsule. 17. A pharmaceutical formulation comprising: (a) 140 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) 151.4 mgs of microcrystalline cellulose; (c) 23.0 mgs of croscarmellose sodium; (d) 14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate. 18. The pharmaceutical formulation of claim 17, wherein the dosage form is a hard gelatin capsule. 19. The pharmaceutical formulation of claim 1, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, xylitol, sorbitol, calcium phosphate, starches, modified starches, microcrystalline cellulose, and microcellulose. 20. The pharmaceutical formulation of claim 1, wherein the diluent is selected from the group consisting of lactose, sucrose, mannitol, calcium phosphate, starches, modified starches, and microcrystalline cellulose. 21. The pharmaceutical formulation of claim 1, wherein the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, crospovidone, sodium alginate, a clay, and a gum. 22. The pharmaceutical formulation of claim 1, wherein the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, and crospovidone. 23. The pharmaceutical formulation of claim 1, wherein the disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone. 24. The pharmaceutical formulation of claim 1, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, copolymers of ethylene oxide and propylene oxide. 25. The pharmaceutical formulation of claim 1, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamers, copolymers of ethylene oxide and propylene oxide. 26. The pharmaceutical formulation of claim 1, wherein the lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, magnesium stearate, and zinc stearate. 27. The pharmaceutical formulation of claim 1, wherein the lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, and magnesium stearate. 28. The pharmaceutical formulation of claim 1, wherein: the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc; the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum; the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide; and the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearates, magnesium stearate, zinc stearate, and waxes. 29. The pharmaceutical formulation of claim 28, wherein the dosage form is a hard gelatin capsule. 30. The pharmaceutical formulation of claim 1, wherein: the diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, xylitol, sorbitol, calcium phosphate, starches, modified starches, microcrystalline cellulose, and microcellulose; the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, and crospovidone; the surfactant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, copolymers of ethylene oxide and propylene oxide; and the lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, magnesium stearate, and zinc stearate. 31. The pharmaceutical formulation of claim 30, wherein the dosage form is a hard gelatin capsule. 32. The pharmaceutical formulation of claim 1, wherein: the diluent is selected from the group consisting of lactose, sucrose, mannitol, calcium phosphate, starches, modified starches, and microcrystalline cellulose; the disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone; the surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamers, copolymers of ethylene oxide and propylene oxide; and the lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, and magnesium stearate. 33. The pharmaceutical formulation of claim 32, wherein the dosage form is a hard gelatin capsule. 34. A pharmaceutical formulation consisting essentially of: (a) about 40 wt % to about 50 wt % of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) about 40 wt % to about 50 wt % of microcrystalline cellulose; (c) about 3 wt % to about 10 wt % of croscarmellose sodium; (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate; and (e) about 0.2 wt % to about 1.0 wt % of magnesium stearate. 35. The pharmaceutical formulation of claim 34, wherein the dosage form is a hard gelatin capsule. 36. A pharmaceutical formulation consisting essentially of: (a) 140 mgs 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; (b) 151.4 mgs of microcrystalline cellulose; (c) 23.0 mgs of croscarmellose sodium; (d) 14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate. 37. The pharmaceutical formulation of claim 36, wherein the dosage form is a hard gelatin capsule. 38. A pharmaceutical formulation consisting of: (a) about 40 wt % to about 50 wt % of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) about 40 wt % to about 50 wt % of microcrystalline cellulose; (c) about 3 wt % to about 10 wt % of croscarmellose sodium; (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate; and (e) about 0.2 wt % to about 1.0 wt % of magnesium stearate. 39. The pharmaceutical formulation of claim 38, wherein the dosage form is a hard gelatin capsule. 40. A pharmaceutical formulation consisting of: (a) 140 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi- peridin-1-yl)prop-2-en-1-one; (b) 151.4 mgs of microcrystalline cellulose; (c) 23.0 mgs of croscarmellose sodium; (d) 14.0 mgs of sodium lauryl sulfate; and (e) 1.6 mgs of magnesium stearate. 41. The pharmaceutical formulation of claim 40, wherein the dosage form is a hard gelatin capsule.