Claims for Patent: 9,655,857

Summary for Patent: 9,655,857

Title:	Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
Abstract:	Described herein are pharmaceutical formulations of 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. Also disclosed are 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):	Chong; Ching W. (Fremont, CA), Kuehl; Robert (San Francisco, CA), Tan; Heow (Cupertino, CA), Atluri; Harisha (Palo Alto, CA)
Assignee:	Pharmacyclics LLC (Sunnyvale, CA)
Application Number:	15/060,010
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,655,857
Patent Claims:	1. A high-load solid tablet formulation comprising ibrutinib and one or more pharmaceutically acceptable excipients, wherein ibrutinib is a compound with the structure of Compound 1, ##STR00007## and wherein the high-load solid tablet formulation comprises at least 50% w/w of ibrutinib, and the excipients comprise one or more diluents selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, and talc; one or more disintegrating agents 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; one or more binders selected from the group consisting of hydroxypropyl cellulose and polyvinylpyrrolidone; sodium laurel sulfate; silica; and magnesium stearate. 2. The high-load solid tablet formulation of claim 1, wherein the one or more disintegrating agents are 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, sodium starch glycolate, crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum. 3. The high-load solid tablet formulation of claim 1, wherein the one or more diluents are lactose or microcrystalline cellulose, or a combination thereof. 4. The high-load solid tablet formulation of claim 1, wherein the excipients comprise lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and magnesium stearate. 5. The high-load solid tablet formulation of claim 1, wherein the excipients comprise intragranular and extragranular excipients; and the intragranular excipients comprise lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. 6. The high-load solid tablet formulation of claim 1, wherein the excipients comprise intragranular excipients comprising: lactose in an amount from 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 from 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 from 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 from about 0 to about 2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1% w/w; and extragranular excipients comprising: croscarmellose sodium in an amount from 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 from 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 from 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 from 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. 7. The high-load solid tablet formulation of claim 1, wherein the excipients comprise intragranular and extragranular excipients; and the intragranular excipients comprise lactose, sodium lauryl sulfate, polyvinylpyrrolidone and croscarmellose sodium; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. 8. The high-load solid tablet formulation of claim 1, wherein the excipients comprise intragranular excipients comprising: lactose in an amount from about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w; polyvinylpyrrolidone in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w; croscarmellose sodium in an amount from about 1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and sodium lauryl sulfate in an amount from about 0% w/w to about 2% w/w, or about 0.5% w/w to about 1.5% w/w; and extragranular excipients comprising: croscarmellose sodium in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w; sodium lauryl sulfate in an amount from about 0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; microcrystalline cellulose in an amount from about 1% w/w to about 10% w/w, or about 2% w/w to about 5% w/w; colloidal silicon dioxide in an amount from 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 from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w. 9. The high-load solid tablet formulation of claim 1, comprising: a) about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 10. The high-load solid tablet formulation of claim 1, comprising: a) about 70% w/w of ibrutinib, b) about 14% w/w of lactose monohydrate, c) about 5% w/w of microcrystalline cellulose, d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of croscarmellose sodium, f) about 1% w/w of sodium lauryl sulfate, g) about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w of magnesium stearate. 11. The high-load solid tablet formulation of claim 1, comprising: a) about 70% w/w of ibrutinib, b) about 14% w/w of lactose monohydrate, c) about 2% w/w of microcrystalline cellulose, d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of croscarmellose sodium, f) about 4% w/w of sodium lauryl sulfate, g) about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w of magnesium stearate. 12. The high-load solid tablet formulation of claim 1, wherein the formulation comprises: a) about 65% w/w to about 75% w/w of ibrutinib, b) about 14% w/w to about 18% w/w of lactose monohydrate, c) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, d) about 0.5% w/w to about 1.5% w/w of sodium lauryl sulfate, e) about 5% w/w to about 15% w/w of crospovidone, f) about 0.3% w/w to about 0.7% w/w of colloidal silicon dioxide, and g) about 0.3% w/w to about 0.7% w/w of magnesium stearate. 13. The high-load solid tablet formulation of claim 1, wherein the formulation comprises: a) about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose, c) about 13% w/w to about 15% w/w of microcrystalline cellulose, d) about 4% w/w to about 6% w/w of croscarmellose sodium, e) about 5% w/w to about 7% w/w of sodium lauryl sulfate, f) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and g) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 14. The high-load solid tablet formulation of claim 8, wherein the formulation comprises: a) about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to about 14% w/w of lactose, c) about 13% w/w to about 14% w/w of 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 of hydroxypropyl cellulose, f) about 2% w/w to about 3% w/w of croscarmellose sodium (extragranular), g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and i) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 15. The high-load solid tablet formulation of claim 8, wherein the formulation comprises: a) about 69% w/w to about 71% w/w of ibrutinib, b) about 8% w/w to about 9% w/w of lactose, c) about 8% w/w to about 9% w/w of microcrystalline cellulose, d) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (intragranular), e) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (extragranular), f) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 16. The high-load solid tablet formulation of claim 1, wherein ibrutinib is in an amount of about 140 mg, about 420 mg, or about 560 mg. 17. The high-load solid tablet formulation of claim 1, wherein the high-load solid tablet formulation is used for one tablet once a day dosing. 18. The high-load solid tablet formulation of claim 1, wherein ibrutinib is in an amount of about 70 mg to about 840 mg. 19. The high-load solid tablet formulation of claim 3, wherein the high-load solid tablet formulation comprises about 60% w/w to about 80% w/w of ibrutinib. 20. The high-load solid tablet formulation of claim 19, wherein ibrutinib is in an amount of about 70 mg to about 840 mg. 21. The high-load solid tablet formulation of claim 19, wherein ibrutinib is in an amount of about 140 mg, about 420 mg, or about 560 mg. 22. The high-load solid tablet formulation of claim 4, wherein the high-load solid tablet formulation comprises about 60% w/w to about 80% w/w of ibrutinib. 23. The high-load solid tablet formulation of claim 22, wherein ibrutinib is in an amount of about 70 mg to about 840 mg. 24. The high-load solid tablet formulation of claim 22, wherein ibrutinib is in an amount of about 140 mg, about 420 mg, or about 560 mg. 25. A solid tablet formulation comprising ibrutinib, intragranular excipients and extragranular excipients; wherein the intragranular excipients comprise: lactose in an amount from about 10% w/w to about 20% w/w; polyvinylpyrrolidone in an amount from about 0% w/w to about 5% w/w; croscarmellose sodium in an amount from about 1% w/w to about 10% w/w; and sodium lauryl sulfate in an amount from about 0% w/w to about 2% w/w; and the extragranular excipients comprise: croscarmellose sodium in an amount from about 0% w/w to about 5% w/w; sodium lauryl sulfate in an amount from about 0% w/w to about 10% w/w; microcrystalline cellulose in an amount from about 1% w/w to about 10% w/w; colloidal silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w; and magnesium stearate in an amount from about 0.4% w/w to about 0.8% w/w; wherein ibrutinib is a compound with the structure of Compound 1, ##STR00008## and is present at about 60% w/w to about 80% w/w and in an amount of about 70 mg to about 840 mg. 26. The solid tablet formulation of claim 25, wherein the intragranular excipients comprise: lactose in an amount from about 12% w/w to about 15% w/w; polyvinylpyrrolidone in an amount from about 1% w/w to about 3% w/w; croscarmellose sodium in an amount from about 3% w/w to about 7% w/w; and sodium lauryl sulfate in an amount from about 0.5% w/w to about 1.5% w/w; and the extragranular excipients comprise: croscarmellose sodium in an amount from about 1% w/w to about 3% w/w; sodium lauryl sulfate in an amount from about 0% w/w to about 4% w/w; microcrystalline cellulose in an amount from about 2% w/w to about 5% w/w; colloidal silicon dioxide in an amount from about 0.5% w/w to about 0.6% w/w; and magnesium stearate in an amount from about 0.5% w/w to about 0.6% w/w. 27. A solid tablet formulation comprising about 50% w/w to about 90% w/w of ibrutinib; about 10% w/w to about 15% w/w lactose; about 1% w/w to about 6% w/w microcrystalline cellulose; about 1% w/w to about 5% w/w polyvinylpyrrolidone; about 1% w/w to about 10% w/w croscarmellose sodium; about 0.5% w/w to about 5% w/w sodium lauryl sulfate; about 0.1% w/w to about 1.5% w/w silica; about 0.01% w/w to about 2% w/w magnesium stearate; wherein ibrutinib is a compound with the structure of Compound 1, ##STR00009## and is in an amount of about 70 mg to about 840 mg. 28. The solid tablet formulation of claim 27 comprising a) about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 29. The high-load solid tablet formulation of claim 1, consisting essentially of: a) about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 30. The high-load solid tablet formulation of claim 1, consisting essentially of: a) about 70% w/w of ibrutinib, b) about 14% w/w of lactose monohydrate, c) about 5% w/w of microcrystalline cellulose, d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of croscarmellose sodium, f) about 1% w/w of sodium lauryl sulfate, g) about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w of magnesium stearate. 31. The high-load solid tablet formulation of claim 1, consisting essentially of: a) about 70% w/w of ibrutinib, b) about 14% w/w of lactose monohydrate, c) about 2% w/w of microcrystalline cellulose, d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of croscarmellose sodium, f) about 4% w/w of sodium lauryl sulfate, g) about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w of magnesium stearate. 32. The high-load solid tablet formulation of claim 1, wherein the formulation consists essentially of: a) about 65% w/w to about 75% w/w of ibrutinib, b) about 14% w/w to about 18% w/w of lactose monohydrate, c) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, d) about 0.5% w/w to about 1.5% w/w of sodium lauryl sulfate, e) about 5% w/w to about 15% w/w of crospovidone, f) about 0.3% w/w to about 0.7% w/w of colloidal silicon dioxide, and g) about 0.3% w/w to about 0.7% w/w of magnesium stearate. 33. The high-load solid tablet formulation of claim 1, wherein the formulation consists essentially of: a) about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose, c) about 13% w/w to about 15% w/w of microcrystalline cellulose, d) about 4% w/w to about 6% w/w of croscarmellose sodium, e) about 5% w/w to about 7% w/w of sodium lauryl sulfate, f) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and g) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 34. The high-load solid tablet formulation of claim 8, wherein the formulation consists essentially of: a) about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to about 14% w/w of lactose, c) about 13% w/w to about 14% w/w of 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 of hydroxypropyl cellulose, f) about 2% w/w to about 3% w/w of croscarmellose sodium (extragranular), g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and i) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 35. The high-load solid tablet formulation of claim 8, wherein the formulation consists essentially of: a) about 69% w/w to about 71% w/w of ibrutinib, b) about 8% w/w to about 9% w/w of lactose, c) about 8% w/w to about 9% w/w of microcrystalline cellulose, d) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (intragranular), e) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (extragranular), f) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate. 36. A solid tablet formulation consisting essentially of about 50% w/w to about 90% w/w of ibrutinib; about 10% w/w to about 15% w/w lactose; about 1% w/w to about 6% w/w microcrystalline cellulose; about 1% w/w to about 5% w/w polyvinylpyrrolidone; about 1% w/w to about 10% w/w croscarmellose sodium; about 0.5% w/w to about 5% w/w sodium lauryl sulfate; about 0.1% w/w to about 1.5% w/w silica; about 0.01% w/w to about 2% w/w magnesium stearate; wherein ibrutinib is a compound with the structure of Compound 1, ##STR00010## and is in an amount of about 70 mg to about 840 mg. 37. The solid tablet formulation of claim 27 consisting essentially of a) about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.