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)piperidin-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.

What is claimed is: 
     
         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, 
       
         
           
           
               
               
           
         
       
       and wherein the high-load solid tablet formulation comprises at least 50% w/w of ibrutinib. 
     
     
         2 . The high-load solid tablet formulation of  claim 1 , wherein the high-load solid tablet formulation comprises about 50% w/w to about 90% w/w of ibrutinib. 
     
     
         3 . The high-load solid tablet formulation of  claim 1 , wherein the high-load solid tablet formulation comprises about 50% w/w to about 80% w/w of ibrutinib. 
     
     
         4 . The high-load solid tablet formulation of  claim 1 , wherein the high-load solid tablet formulation comprises about 60% w/w to about 80% w/w of ibrutinib. 
     
     
         5 . The high-load solid tablet formulation of  claim 1 , wherein the high-load solid tablet formulation comprises about 60% w/w to about 75% w/w of ibrutinib. 
     
     
         6 . The high-load solid tablet formulation of any one of  claims 1 - 5 , wherein the high-load solid tablet formulation comprises intragranular and extragranular ingredients. 
     
     
         7 . The high-load solid tablet formulation of any one of  claims 1 - 6 , wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrating agents, lubricants, glidants, and surfactants. 
     
     
         8 . The high-load solid tablet formulation of any one of  claims 1 - 7 , wherein at least one excipient is a diluent. 
     
     
         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, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, and talc. 
     
     
         10 . The high-load solid tablet formulation of  claim 8 , wherein the diluent is cellulose. 
     
     
         11 . The high-load solid tablet formulation of  claim 8 , wherein the diluent is lactose; and lactose is present 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. 
     
     
         12 . The high-load solid tablet formulation of  claim 8 , wherein the diluent is lactose; and lactose is present in an amount of about 8.5% w/w or about 14% w/w. 
     
     
         13 . The high-load solid tablet formulation of  claim 8 , wherein the diluent is microcrystalline cellulose. 
     
     
         14 . The high-load solid tablet formulation of  claim 13 , wherein the microcrystalline cellulose is present 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. 
     
     
         15 . 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 . The high-load solid tablet formulation of  claim 8 , wherein the diluent is lactose and microcrystalline cellulose. 
     
     
         17 . The high-load solid tablet formulation of  claim 16 , wherein the lactose is present in an amount of about 10% w/w to about 15% w/w and microcrystalline cellulose is present in an amount from about 1% w/w to about 6% w/w. 
     
     
         18 . The high-load solid tablet formulation of  claim 16 , wherein the lactose is present in an amount of about 14% w/w and microcrystalline cellulose is present in an amount from about 2% w/w to about 5% w/w. 
     
     
         19 . The high-load solid tablet formulation of any one of  claims 1 - 18 , wherein at least one excipient is a disintegrating agent. 
     
     
         20 . The high-load solid tablet formulation of  claim 19 , 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 such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum. 
     
     
         21 . The high-load solid tablet formulation of  claim 19 , wherein the disintegrating agent is croscarmellose sodium; and croscarmellose sodium is present in an amount from 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 . The high-load solid tablet formulation of any one of  claims 1 - 21 , wherein at least one excipient is a binder. 
     
     
         23 . The high-load solid tablet formulation of  claim 22 , wherein the binder is hydroxypropyl cellulose; and hydroxypropyl cellulose is present in an amount from 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 . The high-load solid tablet formulation of any one of  claims 1 - 23 , wherein the formulation comprises lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose. 
     
     
         25 . The high-load solid tablet formulation of  claim 22 , wherein the binder is polyvinylpyrrolidone. 
     
     
         26 . The high-load solid tablet formulation of  claim 25 , wherein, the polyvinylpyrrolidone is present in an amount from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2% w/w. 
     
     
         27 . The high-load solid tablet formulation of any one of  claims 1 - 26 , wherein at least one excipient is a surfactant. 
     
     
         28 . The high-load solid tablet formulation of  claim 27 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         29 . The high-load solid tablet formulation of  claim 28 , wherein the sodium lauryl sulfate is present in an amount from 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 . The high-load solid tablet formulation of any one of  claims 1 - 29 , wherein the formulation further comprises one or more glidants. 
     
     
         31 . The high-load solid tablet formulation of  claim 30 , wherein the glidant is silica (colloidal silicon dioxide). 
     
     
         32 . The high-load solid tablet formulation of  claim 31 , wherein the silica (colloidal silicon dioxide) is present in an amount from 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 - 32 , wherein at least one excipient is a lubricant. 
     
     
         34 . The high-load solid tablet formulation of  claim 33 , wherein the lubricant is magnesium stearate. 
     
     
         35 . The high-load solid tablet formulation of  claim 34 , wherein the magnesium stearate is present in an amount from 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 . 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 . The high-load solid tablet formulation of any one of  claims 1 - 5 , wherein the formulation comprises 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. 
     
     
         38 . The high-load solid tablet formulation of any one of  claims 1 - 5 , wherein the intragranular excipients comprise:
 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   the extragranular excipients comprise   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.   
     
     
         39 . The high-load solid tablet formulation of any one of  claims 1 - 5 , wherein the formulation comprises 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. 
     
     
         40 . The high-load solid tablet formulation of any one of  claims 1 - 5 , wherein the intragranular excipients comprise:
 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, 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, about 0.5% w/w to about 1.5% w/w; and   the extragranular excipients comprise   croscarmellose sodium in an amount from about 0 w/w to about 5% w/w, 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, 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.   
     
     
         41 . 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.   
     
     
         42 . 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.   
     
     
         43 . 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.   
     
     
         44 . 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.   
     
     
         45 . 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.   
     
     
         46 . 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 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.   
     
     
         47 . The high-load solid tablet formulation of  claim 1 , 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),   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.   
     
     
         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 . The high-load solid tablet formulation of any one of  claims 1 - 48 , wherein the high-load solid tablet formulation is used for one tablet once a day dosing. 
     
     
         50 . The high-load solid tablet formulation of any one of  claims 1 - 49 , wherein the high-load solid tablet formulation is prepared using a process comprising a wet granulation method. 
     
     
         51 . A method of treating a disease in a patient in need of such treatment, comprising administering to the 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 - 49 , wherein the process comprises a wet granulation method. 
     
     
         53 . The process of  claim 52 , wherein the wet granulation method comprises granulating a mixture of ibrutinib and the intragranular excipients with a granulation liquid to form granules. 
     
     
         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 dried 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 tablets of the high-load solid tablet formulation.