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)•HC1•2H 2 O. Pharmaceutical compositions comprising Form (A) of Compound (I)•HC1•2H 2 O and related methods of treatment are also disclosed.
1. A pharmaceutical formulation comprising Compound I:
wherein the formulation comprises a release modifier that provides a maximum plasma concentration (Cmax) of Compound I below 35 ng/ml when a dose of 32 mg of Compound I is administered to a human.
2. The formulation of claim 1 , which comprises the polymorph form (A) of Compound I HC 1 •2H 2 O.
3. The formulation of claim 1 , which comprises a hypromellose.
4. The formulation of claim 3 , which comprises between 15-65 mg of Compound I.
5. The pharmaceutical formulation of claim 4 , which comprises 32 mg of Compound I.
6. The pharmaceutical formulation of claim 4 , which comprises 64 mg of Compound I.
7. The pharmaceutical formulation of claim 1 , wherein the formulation provides an AUC of Compound I below 400 hr*ng/mL when a dose of 32 mg of Compound I is administered to a human.
8. A method of treating or diminishing at least one negative symptom of schizophrenia in a subject in need thereof, comprising administering to the subject between 10-75 mg of Compound I in the pharmaceutical formulation of claim 1 .
9. The method of claim 8 , wherein the formulation is administered once daily.
10. The method of claim 9 , wherein 16 mg of Compound I, 32 mg of Compound I, 40 mg of Compound I, or 64 mg of Compound I is administered.
11. The method of claim 9 , wherein 32 mg of Compound I is administered.
12. The method of claim 9 , wherein 64 mg of Compound I is administered.
13. The method of claim 8 , wherein the formulation comprises a hypromellose.
14. The method of claim 8 , wherein the formulation is administered at least 4 hours after the subject has taken a meal, at least 6 hours after the subject has taken a meal, at least 8 hours after the subject has taken a meal, at least 10 hours after the subject has taken a meal, or at least 12 hours after the subject has taken a meal.
15. A method of treating or diminishing at least one negative symptom of schizophrenia in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation comprising Compound I:
wherein the formulation comprises a release modifier that provides a maximum plasma concentration (Cmax) of Compound I below 30 ng/ml when a dose of 32 mg of Compound I is administered to a human.
16. The method of claim 15 , wherein the formulation is administered to the subject once daily.
17. The method of claim 16 , wherein the formulation comprises a hypromellose and 32 mg of Compound I, 40 mg of Compound I, or 64 mg of Compound I.
18. The method of claim 17 , wherein the formulation comprises 32 mg of Compound I.
19. The method of claim 17 , wherein the formulation comprises 64 mg of Compound I.
20. The method of claim 17 , wherein the formulation is administered to the subject once daily for four months, six months, eight months, ten months, one year, two years, three years, four years, or five years.