COMPOSITIONS AND METHODS FOR TREATING SCHIZOPHRENIA
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-2H 2 O. Pharmaceutical compositions comprising Form (A) of Compound (I)-HCl-2H 2 O and related methods of treatment are also disclosed.
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.