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, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising about 30 to about 80 mg/mL of Ibrutinib. 
     
     
         3 . The pharmaceutical composition of  claim 1 , comprising about 30 to about 50 mg/mL of Ibrutinib. 
     
     
         4 . The pharmaceutical composition of  claim 1 , comprising about 60 to about 80 mg/mL of Ibrutinib. 
     
     
         5 . The pharmaceutical composition of  claim 1 , comprising about 12 to about 15 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         6 . The pharmaceutical composition of  claim 1 , comprising about 13 to about 15 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         7 . The pharmaceutical composition of  claim 1 , comprising about 12 to about 14 mg/mL of microcrystalline cellulose and carboxymethylcellulose sodium. 
     
     
         8 . The pharmaceutical composition of  claim 1 , comprising about 0.5 to about 3 mg/mL of hydroxypropylmethylcellulose. 
     
     
         9 . The pharmaceutical composition of  claim 1 , comprising about 2 to about 3 mg/mL of hydroxypropylmethylcellulose. 
     
     
         10 . The pharmaceutical composition of  claim 1 , comprising about 0.5 to about 1.5 mg/mL of hydroxypropylmethylcellulose. 
     
     
         11 . The pharmaceutical composition of  claim 1 , comprising about 1.4 to about 1.7 mg/mL of citric acid monohydrate. 
     
     
         12 . The pharmaceutical composition of  claim 1 , comprising about 1.4 mg/mL of disodium hydrogen phosphate. 
     
     
         13 . The pharmaceutical composition of  claim 1 , comprising about 0.5 to about 1.5 mg/mL of sucralose. 
     
     
         14 . The pharmaceutical composition of  claim 1 , comprising about 1 to about 1.5 mg/mL of sodium methyl parahydroxybenzoate. 
     
     
         15 . The pharmaceutical composition of  claim 1 , comprising about 0.5 to about 0.7 mg/mL of sodium ethyl parahydroxybenzoate. 
     
     
         16 . The pharmaceutical composition of  claim 1 , comprising a sufficient amount of concentrated hydrochloric acid to sustain a pH of about 6. 
     
     
         17 . The pharmaceutical composition of  claim 1 , comprising a sufficient amount of sodium hydroxide to sustain a pH of about 6. 
     
     
         18 . The pharmaceutical composition of  claim 1 , comprising a sufficient amount of water to ensure a total volume of 1 mL. 
     
     
         19 . The pharmaceutical composition of  claim 1 , which is a liquid suspension. 
     
     
         20 . The pharmaceutical composition of  claim 1 , 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.   
     
     
         21 . The pharmaceutical composition of  claim 1 , 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.   
     
     
         22 . A method for treating a B-cell proliferative disorder comprising administering a pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         23 . The method of  claim 22 , wherein said B-cell proliferative disorder is a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, or chronic lymphocytic leukemia. 
     
     
         24 . The method of  claim 23 , 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. 
     
     
         25 . The method of  claim 22 , wherein the composition is administered orally. 
     
     
         26 . A method for treating a lymphoma comprising administering a composition of  claim 1  to a subject in need thereof. 
     
     
         27 . A method of treating a leukemia, said method comprising administering a composition of  claim 1  to a subject in need thereof. 
     
     
         28 . 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. 
     
     
         29 . The method of  claim 1 , wherein the subject is a human. 
     
     
         30 . The method of  claim 1 , wherein the composition is scattered into food. 
     
     
         31 . The method of  claim 30 , wherein the food is soft food. 
     
     
         32 . The method of  claim 31 , wherein the subject is a human child. 
     
     
         33 . A process for preparing a composition of  claim 1 , 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.