Compositions Containing Ibrutinib

Abstract

Discussed herein are pharmaceutical compositions containing Ibrutinib and processes for preparing them. The compositions may be utilized in the treatment of a variety of conditions including, without limitation, B-cell proliferative disorders such as non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma, or leukemia. These compositions are designed for oral ingestion. The compositions are contained within a capsule such as a standard or sprinkle or in a liquid formulation such as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. 
     
     
         2 . The pharmaceutical composition of  claim 1  comprising about 40 to about 45% by weight of Ibrutinib. 
     
     
         3 . The pharmaceutical composition of  claim 1 , comprising about 50 to about 140 mg of Ibrutinib. 
     
     
         4 . The pharmaceutical composition of  claim 1 , comprising about 44 to about 47% by weight of microcrystalline cellulose. 
     
     
         5 . The pharmaceutical composition of  claim 1 , comprising about 6 to about 8% by weight of croscarmellose sodium. 
     
     
         6 . The pharmaceutical composition of  claim 1 , comprising about 3 to about 5% by weight of intragranular croscarmellose sodium. 
     
     
         7 . The pharmaceutical composition of  claim 1 , comprising about 2 to about 4% by weight of extragranular croscarmellose sodium 
     
     
         8 . The pharmaceutical composition of  claim 1 , comprising about 1 to about 5% by weight of sodium lauryl sulfate. 
     
     
         9 . The pharmaceutical composition of  claim 8 , comprising about 2.5 to about 3% by weight of intragranular sodium lauryl sulfate. 
     
     
         10 . The pharmaceutical composition of  claim 8 , comprising about 1.2 to about 1.6% by weight of extragranular sodium lauryl sulfate. 
     
     
         11 . The pharmaceutical composition of  claim 1 , comprising about 0.4 to about 0.6% by weight of magnesium stearate. 
     
     
         12 . The pharmaceutical composition of  claim 1 , comprising about 0.45 to about 0.5% by weight of magnesium stearate. 
     
     
         13 . The pharmaceutical composition of  claim 1 , comprising about 0.2 to about 0.3% by weight of intragranular magnesium stearate. 
     
     
         14 . The pharmaceutical composition of  claim 1 , comprising about 0.2 to about 0.3% by weight of extragranular magnesium stearate. 
     
     
         15 . The pharmaceutical composition of  claim 1  comprising an intragranulation comprising Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. 
     
     
         16 . The pharmaceutical composition of  claim 1 , comprising an extragranulation comprising croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. 
     
     
         17 . A pharmaceutical composition comprising:
 (i) about 40 to about 45% by weight of Ibrutinib;   (ii) about 44 to about 47% by weight of microcrystalline cellulose;   (iii) about 6 to about 8% by weight of croscarmellose sodium;   (iv) about 1 to about 5% by weight of sodium lauryl sulfate; and   (v) about 0.2 to about 0.3% by weight of magnesium stearate.   
     
     
         18 . A pharmaceutical composition comprising:
 (i) about 140 mg of Ibrutinib;   (ii) about 151 mg of microcrystalline cellulose;   (iii) about 23 mg of croscarmellose sodium;   (iv) about 14 mg of sodium lauryl sulfate; and   (v) about 1.6 mg of magnesium stearate.   
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein said croscarmellose sodium comprises about 13 mg of intragranular croscarmellose sodium and about 9.9 mg of extragranular croscarmellose sodium. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein said sodium lauryl sulfate comprises about 9.4 mg of intragranular sodium lauryl sulfate and about 4.6 mg of extragranular sodium lauryl sulfate. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein said magnesium stearate comprises about 0.8 mg of intragranular magnesium stearate and about 0.8 mg of extragranular magnesium stearate. 
     
     
         22 . A pharmaceutical composition comprising:
 (i) about 50 mg of Ibrutinib;   (ii) about 54 mg of microcrystalline cellulose;   (iii) about 8 mg of croscarmellose sodium;   (iv) about 5 mg of sodium lauryl sulfate; and   (v) about 0.6 mg of magnesium stearate.   
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein said croscarmellose sodium comprises about 4.6 mg of intragranular croscarmellose sodium and about 3.5 mg of extragranular croscarmellose sodium. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein said sodium lauryl sulfate comprises about 3.3 mg of intragranular sodium lauryl sulfate and about 1.6 mg of extragranular sodium lauryl sulfate. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein said magnesium stearate comprises about 0.3 mg of intragranular magnesium stearate and about 0.3 mg of extragranular magnesium stearate. 
     
     
         26 . A capsule comprising the pharmaceutical composition of  claim 1 . 
     
     
         27 . The capsule of  claim 26 , which is a gelatin capsule. 
     
     
         28 . The capsule of  claim 26 , which is a hard gelatin capsule. 
     
     
         29 . The capsule of  claim 26 , which is a standard or sprinkle capsule. 
     
     
         30 . The capsule of  claim 26 , which is Swedish orange capsule. 
     
     
         31 . The capsule of  claim 26 , which is a size 0 capsule. 
     
     
         32 . A pharmaceutical composition comprising Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water. 
     
     
         33 . The pharmaceutical composition of  claim 32 , comprising about 30 to about 80 mg/mL of Ibrutinib. 
     
     
         34 . The pharmaceutical composition of  claim 32 , comprising about 30 to about 50 mg/mL of Ibrutinib. 
     
     
         35 . The pharmaceutical composition of  claim 32 , comprising about 60 to about 80 mg/mL of Ibrutinib. 
     
     
         36 . The pharmaceutical composition of  claim 32 , comprising about 12 to about 15 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         37 . The pharmaceutical composition of  claim 32 , comprising about 13 to about 15 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         38 . The pharmaceutical composition of  claim 32 , comprising about 12 to about 14 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         39 . The pharmaceutical composition of  claim 32 , comprising about 0.5 to about 3 mg/mL of hydroxypropylmethylcellulose. 
     
     
         40 . The pharmaceutical composition of  claim 32 , comprising about 2 to about 3 mg/mL of hydroxypropylmethylcellulose. 
     
     
         41 . The pharmaceutical composition of  claim 32 , comprising about 0.5 to about 1.5 mg/mL of hydroxypropylmethylcellulose. 
     
     
         42 . The pharmaceutical composition of  claim 32 , comprising about 1.4 to about 1.7 mg/mL of citric acid monohydrate. 
     
     
         43 . The pharmaceutical composition of  claim 32 , comprising about 1.4 mg/mL of disodium hydrogen phosphate. 
     
     
         44 . The pharmaceutical composition of  claim 32 , comprising about 0.5 to about 1.5 mg/mL of sucralose. 
     
     
         45 . The pharmaceutical composition of  claim 32 , comprising about 1 to about 1.5 mg/mL of sodium methyl parahydroxybenzoate. 
     
     
         46 . The pharmaceutical composition of  claim 32 , comprising about 0.5 to about 0.7 mg/mL of sodium ethyl parahydroxybenzoate. 
     
     
         47 . The pharmaceutical composition of  claim 32 , comprising a sufficient amount of concentrated hydrochloric acid to sustain a pH of about 6. 
     
     
         48 . The pharmaceutical composition of  claim 32 , comprising a sufficient amount of sodium hydroxide to sustain a pH of about 6. 
     
     
         49 . The pharmaceutical composition of  claim 32 , comprising a sufficient amount of water to ensure a total volume of 1 mL. 
     
     
         50 . The pharmaceutical composition of  claim 32 , which is a liquid suspension. 
     
     
         51 . The pharmaceutical composition of  claim 32 , comprising:
 (i) about 70 mg/mL of Ibrutinib;   (ii) about 13 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium;   (iii) about 2.5 mg/mL of hydroxypropylmethylcellulose;   (iv) about 1.5 mg/mL of citric acid monohydrate;   (v) about 1.4 mg/mL of disodium hydrogen phosphate;   (vi) about 1 mg/mL of sucralose;   (vii) about 1 mg/mL of sodium methyl parahydroxybenzoate; and   (viii) about 0.6 mg/mL of sodium ethyl parahydroxybenzoate.   
     
     
         52 . The pharmaceutical composition of  claim 32 , comprising:
 (i) about 40 mg/mL of Ibrutinib;   (ii) about 14 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium;   (iii) about 1 mg/mL of hydroxypropylmethylcellulose;   (iv) about 1.6 mg/mL of citric acid monohydrate;   (v) about 1.4 mg/mL of disodium hydrogen phosphate;   (vi) about 0.5 mg/mL of sucralose;   (vii) about 1.4 mg/mL of sodium methyl parahydroxybenzoate; and   (viii) about 0.7 mg/mL of sodium ethyl parahydroxybenzoate.   
     
     
         53 . A method for treating a B-cell proliferative disorder comprising administering a pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         54 . The method of  claim 53 , wherein said B-cell proliferative disorder is a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, or chronic lymphocytic leukemia. 
     
     
         55 . The method of  claim 54 , wherein the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and burkitt lymphoma. 
     
     
         56 . The method of  claim 53 , wherein the composition is administered orally. 
     
     
         57 . A method for treating a lymphoma comprising administering a composition of  claim 1  to a subject in need thereof. 
     
     
         58 . A method of treating a leukemia, said method comprising administering a composition of  claim 1  to a subject in need thereof. 
     
     
         59 . A method for treating mantle cell lymphoma in a subject who has already received at least one prior therapy for mantle cell lymphoma, said method comprising administering to the subject a composition of  claim 1  once per day. 
     
     
         60 . The method of  claim 53 , wherein the subject is a human. 
     
     
         61 . The method of  claim 53 , wherein the composition is scattered into food. 
     
     
         62 . The method of  claim 61 , wherein the food is soft food. 
     
     
         63 . The method of  claim 61 , wherein the subject is a human child. 
     
     
         64 . A process for preparing a composition of  claim 1 , said process comprising:
 (a) blending the microcrystalline cellulose, a first portion of sodium lauryl sulfate, and a first portion of croscarmellose sodium;   (b) blending the product of step (a) with a first portion of Ibrutinib;   (c) blending the product of step (b) with a second portion of Ibrutinib;   (d) blending the product of step (c) with a first portion of magnesium stearate;   (e) roller compacting the product of step (d);   (f) milling the ribbons produced in step (e);   (g) blending the granules produced in step (0 with a second portion of sodium lauryl sulfate and croscarmellose sodium; and   (h) blending the product of step (g) with a second portion of magnesium stearate.   
     
     
         65 . The process of  claim 64 , further comprising:
 (i) adding the product of step (h) to a capsule.   
     
     
         66 . A process for preparing a composition of  claim 32 , said process comprising:
 (a) mixing water, microcrystalline cellulose croscarmellose sodium;   (b) mixing water and with hydroxypropylmethylcellulose;   (c) mixing the product of step (b) with Ibrutinib;   (d) mixing the product of steps (a) and (c);   (e) mixing the product of step (d) with sucralose;   (f) mixing the product of step (e) with sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate;   (g) mixing the product of step (f) with monohydrate citric acid; and   (h) mixing the product of step (g) with anhydrous disodium hydrogen phosphate.