Compositions and methods for treating schizophrenia

Abstract

The disclosure provides a novel polymorph of Compound (I):2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one monohydrochloride dihydrate, i.e., Form (A) of Compound (I)-HCl-2H2O. Pharmaceutical compositions comprising Form (A) of Compound (I)-HCl-2H2O and related methods of treatment are also disclosed.

What is claimed is: 
     
         1 . A crystalline form of Compound (I); 
       
         
           
           
               
               
           
         
       
       comprising a polymorph form (A) of Compound (I)-HCl-2H 2 O, and wherein the form (A) has a X-ray powder diffraction pattern with at least one major peak substantially similar to at least one major peak shown in  FIG.  11   . 
     
     
         2 . The crystalline form of  claim 1 , wherein the form (A) has X-ray powder diffraction pattern peaks at approximately 7.6 and 14.3°2θ using Cu Kα radiation. 
     
     
         3 . The crystalline form of  claim 1  or  2 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 14.3, and 14.7°2θ using Cu Kα radiation. 
     
     
         4 . The crystalline form of any one of  claims 1 - 3 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 14.3, and 27.5°2θ using Cu Kα radiation. 
     
     
         5 . The crystalline form of any one of  claims 1 - 4 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, and 27.5°2θ using Cu Kα radiation. 
     
     
         6 . The crystalline form of any one of  claims 1 - 5 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, 18.6, and 27.5°2θ using Cu Kα radiation. 
     
     
         7 . The crystalline form of any one of  claims 1 - 6 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, 14.9, 18.6, 27.5 and 30.1°2θ using Cu Kα radiation. 
     
     
         8 . The crystalline form of any one of  claims 1 - 7 , wherein the form (A) has X-ray powder diffraction peaks at approximately 7.6, 11.2, 14.3, 14.7, 14.9, 18.6, 22.0, 25.9, 27.5 and 30.1°2θ using Cu Kα radiation. 
     
     
         9 . A pharmaceutical formulation comprising Compound (I); 
       
         
           
           
               
               
           
         
       
       wherein the formulation comprises a release modifier that provides a maximum plasma concentration (C max ) of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O below 50 ng/mL when a dose of between about 1-100 mg of the formulation is administered to a human. 
     
     
         10 . The pharmaceutical formulation of  claim 9 , when Compound (I) is present as the polymorph form (A) of Compound (I)-HCl-2H 2 O. 
     
     
         11 . The pharmaceutical formulation of  claim 10 , comprising about 10-75 mg of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O. 
     
     
         12 . The pharmaceutical formulation of  claim 10 , comprising about 15-65 mg of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O. 
     
     
         13 . The pharmaceutical formulation of  claim 10 , comprising about 16 mg, about 32 mg, about 40 mg, or about 64 mg of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O. 
     
     
         14 . The pharmaceutical formulation of  claim 10 , wherein the release modifier is a hypromellose. 
     
     
         15 . The pharmaceutical formulation any one of  claims 9 - 14 , further comprising a filler, a glidant, and a lubricant. 
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein the filler is microcrystalline cellulose, lactose, or a combination thereof. 
     
     
         17 . The pharmaceutical formulation of  claim 15 , wherein the glidant is silica colloidal anhydrous. 
     
     
         18 . The pharmaceutical formulation of  claim 15 , wherein the lubricant is magnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or a combination thereof. 
     
     
         19 . The pharmaceutical formulation of any one of  claims 9 - 18 , wherein the formulation provides a maximum plasma concentration (C max ) of BFB-520 below 10.0 ng/mL, preferably below 5.0 ng/mL. 
     
     
         20 . The pharmaceutical formulation of any one of  claims 9 - 19 , wherein the formulation provides a maximum plasma concentration (C max ) of BFB-999 below 5.0 ng/mL. 
     
     
         21 . The pharmaceutical formulation of any one of  claims 9 - 20 , wherein the formulation provides an AUC of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O below 400 hr*ng/mL. 
     
     
         22 . The pharmaceutical formulation of any one of  claims 9 - 21 , wherein the formulation provides an AUC of BFB-520 below 40 hr*ng/mL. 
     
     
         23 . The pharmaceutical formulation of any one of  claims 9 - 22 , wherein the formulation provides an AUC of BFB-999 below 40 hr*ng/mL. 
     
     
         24 . The pharmaceutical formulation of any one of  claims 9 - 23 , wherein the formulation is suitable for chronic administration. 
     
     
         25 . The pharmaceutical formulation of any one of  claims 9 - 24 , wherein the formulation is in an immediate release form. 
     
     
         26 . The pharmaceutical formulation of any one of  claims 9 - 25 , wherein the formulation is in a controlled release form. 
     
     
         27 . The pharmaceutical formulation of any one of  claims 9 - 26 , wherein substantially all of the administered dose of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O is released from the pharmaceutical formulation over 16-24 hours. 
     
     
         28 . A method of treating a neuropsychiatric disease or disorder, comprising administering a therapeutically effective amount of the pharmaceutical formulation of any one of  claims 9 - 27  to a subject in need thereof. 
     
     
         29 . The method of  claim 28 , wherein the neuropsychiatric disease or disorder is schizophrenia. 
     
     
         30 . The method of  claim 28  or  29 , wherein the pharmaceutical formulation is administered once daily. 
     
     
         31 . The method of any one of  claims 28 - 30 , wherein the amount of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O administered is in the range of about 1-100 mg. 
     
     
         32 . The method of  claim 31 , wherein the amount of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O administered is in the range of about 10-75 mg. 
     
     
         33 . The method of  claim 32 , wherein the amount of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O administered is in the range of about 15-65 mg. 
     
     
         34 . The method of  claim 31 , wherein the amount of Compound (I) or the polymorph form (A) of Compound (I)-HCl-2H 2 O administered is about 16 mg, about 32 mg, about 40 mg, or about 64 mg. 
     
     
         35 . The method of  claim 28 , wherein at least one symptom of schizophrenia is treated or diminished. 
     
     
         36 . The method of  claim 35 , wherein the symptom is associated with the negative and/or positive symptoms of schizophrenia, cognitive function, sleep architecture and continuity, and social functioning. 
     
     
         37 . The method of  claim 28 , wherein at least one condition or disorder associated with depression is treated. 
     
     
         38 . A method of treating a sleep disorder, comprising administering a therapeutically effective amount of the pharmaceutical formulation of any one of  claims 9 - 37  to a subject in need thereof. 
     
     
         39 . The method of  claim 38 , wherein at least one aspect of a sleep disorder is treated or diminished. 
     
     
         40 . The method of  claim 39  wherein the at least one aspect of a sleep disorder is selected from sleep period time, one or more segments of sleep period time, overall sleep continuity, and sleep architecture. 
     
     
         41 . The method of  claim 38 , wherein the sleep disorder is associated with schizophrenia. 
     
     
         42 . A kit comprising the pharmaceutical formulation of any one of  claims 9 - 41 , and instructions for use.