Pharmaceutical formulations of abiraterone acetate and niraparib

Abstract

The present disclosure relates to a combination of abiraterone acetate and niraparib, free-dose and fixed-dose combinations of abiraterone acetate and niraparib, and methods of treatment of prostate cancer with said combinations.

1 - 64 . (canceled) 
     
     
         65 . A granule composition comprising abiraterone acetate, niraparib tosylate monohydrate, and a pharmaceutically acceptable carrier;
 wherein the granules consist essentially of abiraterone acetate, niraparib tosylate monohydrate, and a pharmaceutically acceptable carrier;   wherein the pharmaceutically acceptable carrier of the granules comprises a wetting agent, a diluent, a disintegrant;   wherein the wetting agent is sodium lauryl sulfate;   and wherein the disintegrant is crospovidone.   
     
     
         66 . The granule composition of  claim 65 , wherein the pharmaceutically acceptable carrier of the granules further comprises a glidant, a lubricant, and a binder. 
     
     
         67 . The granule composition of  claim 65 , wherein the granules have a particle size distribution with a d 50  of about 200 to about 500 μm, or of about 231 to about 396 μm; a d 10  of about 50 to about 250 μm, or of about 93 to about 192 μm; and/or a d 90  of about 500 to about 900 μ, or of about 616 to about 723 μm. 
     
     
         68 . The granule composition of  claim 65 , wherein the diluent is lactose, and wherein lactose is also used as a binder. 
     
     
         69 . The granule composition of  claim 66 , wherein the glidant is colloidal anhydrous silica. 
     
     
         70 . The granule composition of  claim 66 , wherein the lubricant is magnesium stearate. 
     
     
         71 . The granule composition of  claim 66 , wherein the binder is HPMC 2910 15 mPa·s. 
     
     
         72 . An oral dosage form comprising the granule composition of  claim 65 . 
     
     
         73 . The oral dosage form of  claim 72 , wherein the oral dosage form comprises about 50 mg eq. niraparib and about 500 mg abiraterone acetate; about 100 mg eq. niraparib and about 500 mg abiraterone acetate; about 50 mg eq. niraparib and about 375 mg abiraterone acetate; about 100 mg eq. niraparib and about 375 mg abiraterone acetate; about 50 mg eq. niraparib and about 250 mg abiraterone acetate; about 100 mg eq. niraparib and about 250 mg abiraterone acetate; about 33 mg eq. niraparib and about 333 mg abiraterone acetate; or about 67 mg eq. niraparib and about 333 mg abiraterone acetate. 
     
     
         74 . The oral dosage form of  claim 72 , wherein said oral dosage form is a tablet, wherein the pharmaceutically acceptable carrier comprises a wetting agent, a diluent, a disintegrant, a glidant, and a lubricant. 
     
     
         75 . The oral dosage form of  claim 74 , wherein the pharmaceutically acceptable carrier further comprises a binder and a coating material. 
     
     
         76 . The oral dosage form of  claim 74 , wherein the wetting agent is sodium lauryl sulfate (SLS) and is present in the dosage form in a percentage from about 3 to 6% (w/w). 
     
     
         77 . The oral dosage form of  claim 74 , wherein the wetting agent is SLS and is present in the final dosage forms in a by weight ratio versus abiraterone acetate of about 0.05: 1 to 0.2: I (SLS:abiraterone acetate), about 0.1: 1, about 0.11: 1, about 0.12: 1, or about 0.123: 1. 
     
     
         78 . The oral dosage form of  claim 74 , wherein SLS is present both in the intragranular and extragranular phases of the tablet. 
     
     
         79 . The oral dosage form of  claim 74 , wherein the disintegrant is crospovidone and is present both in the intragranular and extragranular phases of the tablet. 
     
     
         80 . The oral dosage form of  claim 74 , wherein the diluent of the extragranular phase is silicified microcrystalline cellulose. 
     
     
         81 . The oral dosage form of  claim 74 , wherein the tablet has a hardness of 250 to 350 N. 
     
     
         82 . The oral dosage form of  claim 74 , wherein the tablet has a stratified content uniformity from 75% to 125%, or from 90% to 110%. 
     
     
         83 . The oral dosage form of  claim 74 , wherein the tablet has a blend uniformity with a relative standard deviation up to 3%. 
     
     
         84 . A process for preparing the granule composition as defined in  claim 65  comprising the steps of:
 (a) preparing a binder solution comprising a wetting agent; 
 (b) blending the binder solution of step (a) with abiraterone acetate, niraparib tosylate monohydrate, and a diluent; 
 (c) wet granulating the blend obtained from step (b); 
 (d) drying the product obtained from step (c). 
 
     
     
         85 . The process of  claim 84 , wherein step (b) is in the presence of a disintegrant. 
     
     
         86 . The process of  claim 84 , wherein the binder solution comprises a binder, the wetting agent, and a solvent. 
     
     
         87 . The process of  claim 84 , wherein the inlet air temperature during the wet granulating of step (c), is from 25° C. to 65° C. 
     
     
         88 . The process of  claim 84 , wherein the spray rate during the wet granulating of step (c), is from 190 to 300 g/min. 
     
     
         89 . The process of  claim 84 , wherein the inlet air flow during the wet granulating of step (c), is from 800 to 1300 m 3 /h. 
     
     
         90 . A method for the treatment of prostate cancer in a patient, said method comprising administering to the patient the oral dosage form of  claim 72 . 
     
     
         91 . The method of  claim 90 , wherein the prostate cancer is first-line (LI) metastatic castration resistant prostate cancer (mCRPC) and the patient is positive for homologous recombination repair (HRR) defects. 
     
     
         92 . The method of  claim 90 , wherein the prostate cancer is deleterious germline or somatic HRR gene-mutated metastatic castration sensitive prostate cancer (mCSPC). 
     
     
         93 . The method of  claim 90 , wherein the method comprises administering 1, 2, or 3 dosage forms per day. 
     
     
         94 . The method of  claim 90 , wherein the method comprises administering the dosage form(s) once a day (q.d.) or two times a day (b.i.d.). 
     
     
         95 . The method of  claim 94 , wherein the method comprises administering the dosage form(s) once a day at least 1 hour before a meal or at least two hours after a meal. 
     
     
         96 . The method of  claim 90 , wherein the method comprises administering separately 10 mg/day of prednisone or prednisolone.