Gastro-resistant, controlled release oral dosage form

Abstract

To provide gastro-resistant, controlled release dosage forms and methods for preparing the same, the dosage forms being useful in reducing the risk of QT prolongation in a subject, in treating a disorder in a subject in need thereof such as a subject diagnosed with schizophrenia, and in treating negative symptoms in a subject diagnosed with schizophrenia having the CYP2D6 EM genotype.SOLUTION: A gastro-resistant, controlled release dosage form is provided comprising: i. about 4 mg to about 100 mg of a compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent. Compound (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 523,204, filed June 21, 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] Field of the Disclosure The present disclosure generally relates to oral gastro-resistant (GR) controlled-release (CR) dosage forms that reduce the risk of QT prolongation in patients treated with a compound identified as 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride salt, hydrate (1:1:2), and the use of these dosage forms to treat schizophrenia and other diseases. [Background technology]

[0003] The QT interval is a measure of the duration from depolarization to repolarization of the ventricles. A prolongation of the QT interval, termed QT prolongation, can lead to an increase in ventricular arrhythmias, including polymorphic ventricular tachycardia (TdP). Several drugs have been shown to induce QT prolongation, and new drug development typically includes evaluation of their potential for QT prolongation.

[0004] Lorperidone hydrochloride, code-named MIN-101, an investigational drug, is being developed by Minerva Neurosciences, Inc. (Waltham, MA) to treat negative symptoms in patients with schizophrenia. The active ingredient in MIN-101 (formerly known as CYR-101 and MT-210) has the chemical name 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2). Formula I:

[0005] [ka] (I) represents the structure of the free base [Compound (I)].

[0006] As disclosed in U.S. Patent No. 9,458,130, the contents of which are incorporated herein in their entirety, QT prolongation in patients treated with MIN-101 was observed and appeared to be related to plasma levels of Compound (I), and more specifically, a metabolite identified as BFB-520. The '130 patent discloses that QT prolongation induced by administration of MIN-101 was associated with a peak plasma concentration (C) of Compound (I) and BFB-520. max This paper discloses that QT prolongation can be reduced by administering the drug in a modified release (MR) formulation, which provides QT prolongation of less than 80 ng / mL and less than 12 ng / mL, respectively. However, a need exists for a formulation that further reduces the potential for QT prolongation following oral administration of MIN-101, while maintaining therapeutically effective levels of Compound (I) throughout the dosing interval, in either the fasted or fed state. Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure is based, in part, on the discovery that minimizing the release of Compound (I) during the first four hours following oral administration of a dosage form containing Compound (I) is an important factor for maintaining low plasma levels of BFB-520. [Means for solving the problem]

[0008] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 2 mg to about 200 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent The present invention provides a gastroresistant controlled release dosage form comprising:

[0009] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 2 mg to about 200 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0010] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent The present invention provides a gastroresistant controlled release dosage form comprising:

[0011] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0012] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0013] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0014] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0015] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0016] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T maxThe present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0017] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon oral administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0018] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I), wherein the amount of Compound (I) is 4 mg to 8 mg, 8 mg to 16 mg, 16 mg to 32 mg, 32 mg to 40 mg, 40 mg to 64 mg, 64 mg to 80 mg, or 80 mg to 100 mg.

[0019] In one aspect, the present disclosure provides a gastroresistant controlled release dosage form comprising Compound (I), wherein the amount of Compound (I) is 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, In some embodiments, the dosage form is 0 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg.

[0020] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I), wherein the amount of Compound (I) is 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, 64 mg, 80 mg, 96 mg, or 100 mg.

[0021] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 32 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent The present invention provides a gastroresistant controlled release dosage form comprising:

[0022] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 32 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0023] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 64 of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent The present invention provides a gastroresistant controlled release dosage form comprising:

[0024] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: i. about 64 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent A gastroresistant controlled release dosage form comprising: Upon administration to a subject, T max The present invention provides a dosage form that produces a plasma pharmacokinetic profile for Compound (I) comprising:

[0025] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg and the AUC 0~4H About 68 hours * The dosage form has a saturation of less than 100 ng / mL.

[0026] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 16 ng / mL.

[0027] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. maxis less than about 17 ng / mL.

[0028] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 18 ng / mL.

[0029] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 19 ng / mL.

[0030] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 20 ng / mL.

[0031] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 21 ng / mL.

[0032] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 22 ng / mL.

[0033] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the C of Compound (I) is about 100 mg. max is less than about 23 ng / mL.

[0034] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg and the AUC 0~24hr About 50 hours * ng / mL to approximately 400 hours * ng / mL.

[0035] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg and the AUC 0~24hr About 75 hours * ng / mL to approximately 350 hours * ng / mL.

[0036] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg and the AUC 0~24hr About 75 hours * ng / mL to approximately 300 hours * ng / mL.

[0037] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 32 mg and the AUC 0~24hr About 100 hours * ng / mL to approximately 300 hours * ng / mL.

[0038] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form comprising Compound (I) as disclosed herein, wherein the amount of Compound (I) is about 32 mg, and the plasma pharmacokinetic profile for the BFB-520 metabolite of Compound (I) is less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. max The present invention provides a dosage form comprising:

[0039] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 50 hours * The dosage form has a saturation of less than 100 ng / mL.

[0040] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 60 hours * The dosage form has a saturation of less than 100 ng / mL.

[0041] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 70 hours * The dosage form has a saturation of less than 100 ng / mL.

[0042] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 80 hours * The dosage form has a saturation of less than 100 ng / mL.

[0043] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 90 hours * The dosage form has a saturation of less than 100 ng / mL.

[0044] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 100 hours * The dosage form has a saturation of less than 100 ng / mL.

[0045] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 110 hours * The dosage form has a saturation of less than 100 ng / mL.

[0046] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 120 hours * The dosage form has a saturation of less than 100 ng / mL.

[0047] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~4H About 130 hours * The dosage form has a saturation of less than 100 ng / mL.

[0048] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg, and the C of Compound (I) is about 100 mg. max is less than about 36 ng / mL or less than about 25 ng / mL.

[0049] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form comprising Compound (I) disclosed herein, wherein the amount of Compound (I) is about 64 mg and the AUC 0~24hr About 200 hours * ng / mL to approximately 600 hours * ng / mL.

[0050] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form comprising Compound (I) as disclosed herein, wherein the amount of Compound (I) is about 64 mg, and the plasma pharmacokinetic profile for the BFB-520 metabolite of Compound (I) is less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, or less than 2.5 ng / mL. maxThe present invention provides a dosage form comprising:

[0051] In one embodiment, the gastroresistant controlled-release dosage form disclosed herein is in the form of a tablet comprising a core tablet and an enteric coating.

[0052] In one embodiment, the core tablet of the gastroresistant controlled-release dosage form disclosed herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, and a controlled-release agent.

[0053] In one embodiment, the core tablet of the gastroresistant controlled-release dosage form disclosed herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled-release agent, a filler, a glidant, and a lubricant.

[0054] In one embodiment, the core tablet of the gastroresistant controlled-release dosage form disclosed herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled-release agent, a filler, a glidant, a lubricant and a coating.

[0055] In one embodiment, the controlled release agent in the core tablet of the gastroresistant controlled release dosage form disclosed herein comprises one or more hypromelloses.

[0056] In one embodiment, the controlled release agent in the core tablet of the gastroresistant controlled release dosage form disclosed herein comprises one or more hypromellose selected from the group consisting of Metolose® 90SH K15M 100 SR, Metolose® 90SH 100 SR, Methocel™ K100M CR, Methocel™ K15M CR, Methocel™ K4M CR, and Methocel™ K100LV CR, or grades thereof.

[0057] In one embodiment, the controlled release agent in the core tablet of the gastroresistant controlled release dosage form disclosed herein comprises a mixture of (i) low-viscosity hypromellose having a viscosity between about 15 millipaque seconds (mPa·sec) and about 100 mPa·sec and (ii) high-viscosity hypromellose having a viscosity of about 100,000 mPa·sec, wherein each of the low-viscosity hypromellose and the high-viscosity hypromellose is of controlled-release or sustained-release grade and further characterized by a methoxy content of 19.0% to 24.0% and a hydroxypropyl content of 4.0% to 12.0%.

[0058] In one embodiment, the lubricant in the core tablet of the gastroresistant controlled-release dosage form disclosed herein is anhydrous colloidal silica.

[0059] In one embodiment, the lubricant in the core tablet of the gastroresistant controlled-release dosage form disclosed herein is magnesium stearate.

[0060] In one embodiment, the enteric coating of the gastroresistant controlled-release dosage form disclosed herein comprises at least one polymeric controlled-release agent having dissolution properties above pH 5.5, 6.0 or 6.5, and an anti-adherent agent.

[0061] In one embodiment, the enteric coating of the gastroresistant controlled-release dosage form disclosed herein further comprises a plasticizer.

[0062] In one embodiment, the polymeric controlled-release agent of the enteric coating of the gastroresistant controlled-release dosage form disclosed herein comprises Eudragit L30D55.

[0063] In one embodiment, the anti-adherent agent of the enteric coating of the gastroresistant controlled-release dosage form disclosed herein is Plasacryl HTP20.

[0064] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w of hypromellose (Metolose® 90SH K15M 100 SR); about 17 to about 27% w / w hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and about 0.5 to about 5% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0065] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w of hypromellose (Metolose® 90SH K15M 100 SR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; Approximately 19% w / w lactose monohydrate about 0.5% w / w anhydrous colloidal silica; approximately 1% magnesium stearate; Approximately 5% w / w Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0066] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w hypromellose (Methocel™ K15M CR); about 17 to about 27% w / w hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate; about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% w / w magnesium stearate; about 1 to about 10% Eudragit L30D55; about 0.5 to about 5% w / w of Plasacryl HTP20; and about 0.5 to about 5% w / w of Surelease E-7-19040 The present invention provides a gastroresistant controlled release dosage form comprising:

[0067] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w hypromellose (Methocel™ K15M CR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w lactose monohydrate; about 0.5% w / w anhydrous colloidal silica; approximately 1% w / w magnesium stearate; approximately 5% w / w Eudragit L30D55; Approximately 1% w / w Plasacryl HTP20; and Approximately 1% w / w of Surelease E-7-19040 The present invention provides a gastroresistant controlled release dosage form comprising:

[0068] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w hypromellose (Methocel™ K100LV CR); about 17 to about 27% w / w hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and about 0.5 to about 5% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0069] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w lactose monohydrate; about 0.5% w / w anhydrous colloidal silica; about 0.5% w / w magnesium stearate; Approximately 5% w / w Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0070] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w lactose monohydrate; about 0.5% w / w anhydrous colloidal silica; approximately 1% w / w magnesium stearate; Approximately 5% w / w Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0071] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 19 to about 29% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w hypromellose (Methocel™ K100LV CR); about 17 to about 27% w / w hypromellose (Methocel™ K100M CR); about 19 to about 29% w / w microcrystalline cellulose; about 8 to about 18% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and about 0.5 to about 5% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0072] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 24% w / w microcrystalline cellulose; approximately 13% w / w lactose monohydrate; about 0.5% w / w anhydrous colloidal silica; about 0.5% w / w magnesium stearate; Approximately 5% w / w Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0073] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w hypromellose (Methocel™ K100M CR); approximately 24% w / w microcrystalline cellulose; approximately 13% w / w lactose monohydrate; about 0.5% w / w anhydrous colloidal silica; approximately 1% w / w magnesium stearate; Approximately 5% w / w Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 The present invention provides a gastroresistant controlled release dosage form comprising:

[0074] In one aspect, the present disclosure provides a method of reducing the risk of QT prolongation when treating a subject with Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, comprising oral administration to the subject of a gastro-resistant controlled-release dosage form described herein.

[0075] In one aspect, the present disclosure provides a method of treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof, the method comprising oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has a diagnosis of the disorder, e.g., schizophrenia.

[0076] In one aspect, the present disclosure provides a method of treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof, comprising once-daily oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has a diagnosis of the disorder, e.g., schizophrenia.

[0077] In one aspect, the disclosure provides a method of treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, comprising oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has, for example, a diagnosis of schizophrenia, and the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype.

[0078] In one aspect, the disclosure provides a method of treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, comprising once-daily oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has, for example, a diagnosis of schizophrenia, and the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype.

[0079] In one aspect, the disclosure provides a method of treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, comprising oral administration to the subject of a gastro-resistant controlled-release dosage form described herein (e.g., comprising a low dose of Compound (I), such as about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg), wherein the subject has, for example, a diagnosis of schizophrenia, and wherein the subject with a diagnosis of schizophrenia has a CYP2D6 IM or PM genotype.

[0080] In one aspect, the disclosure provides a method of treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, comprising once-daily administration to the subject of a gastro-resistant controlled-release dosage form described herein (e.g., comprising a low dose of Compound (I), such as about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg), wherein the subject has, for example, a diagnosis of schizophrenia, and wherein the subject with a diagnosis of schizophrenia has a CYP2D6 IM or PM genotype.

[0081] In one aspect, for any of the methods disclosed herein, the subject is in a fed state prior to oral administration of a gastroresistant controlled release dosage form described herein.

[0082] In one aspect, for any of the methods disclosed herein, the subject is in a fasted state prior to oral administration of a gastroresistant controlled release dosage form described herein.

[0083] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form disclosed herein for use in reducing the risk of QT prolongation.

[0084] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia).

[0085] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype.

[0086] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype and the dosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg.

[0087] In one aspect, the present disclosure provides a gastroresistant controlled-release dosage form as disclosed herein for use in reducing the risk of QT prolongation, wherein the dosage form is administered once daily.

[0088] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the dosage form is administered once daily.

[0089] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the dosage form is administered once daily.

[0090] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype and has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, administered once daily.

[0091] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject is in a fed state prior to oral administration of the dosage form.

[0092] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject is in a fasted state prior to oral administration of the dosage form.

[0093] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the subject is in a fed state prior to oral administration of the dosage form.

[0094] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the subject is in a fasted state prior to oral administration of the dosage form.

[0095] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype and has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, and wherein the subject is in a fed state prior to oral administration of the dosage form.

[0096] In one aspect, the present disclosure provides a gastro-resistant controlled-release dosage form as disclosed herein for use in treating a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype and has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, and wherein the subject is in a fasted state prior to oral administration of the dosage form.

[0097] In one aspect, the present disclosure provides the use of a gastroresistant controlled-release dosage form disclosed herein in the manufacture of a medicament for reducing the risk of QT prolongation.

[0098] In one aspect, the present disclosure provides use of a gastroresistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia).

[0099] In one aspect, the present disclosure provides the use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype.

[0100] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype, and the dosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, or about 8 mg.

[0101] In one aspect, the present disclosure provides the use of a gastroresistant controlled-release dosage form disclosed herein in the manufacture of a medicament for reducing the risk of QT prolongation, wherein the gastroresistant controlled-release dosage form is administered once daily.

[0102] In one aspect, the present disclosure provides use of a gastroresistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the gastroresistant controlled-release dosage form is administered once daily.

[0103] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the gastro-resistant controlled-release dosage form is administered once daily.

[0104] In one aspect, the disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype, and the dosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, or about 8 mg, and wherein the gastro-resistant controlled-release dosage form is administered once daily.

[0105] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject is in a fasted state prior to oral administration of the dosage form.

[0106] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the subject is in a fasted state prior to oral administration of the dosage form.

[0107] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype, the dosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, or about 8 mg, and the subject is in a fasted state prior to oral administration of the dosage form.

[0108] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject is in a fed state prior to oral administration of the dosage form.

[0109] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 EM genotype and the subject is in a fed state prior to oral administration of the dosage form.

[0110] In one aspect, the present disclosure provides use of a gastro-resistant controlled-release dosage form disclosed herein in the manufacture of a medicament for the treatment of a disorder (e.g., a negative symptom of schizophrenia) in a subject in need thereof (e.g., the subject has a diagnosis of schizophrenia), wherein the subject has a CYP2D6 IM or PM genotype, the dosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6 mg, 7 mg, or about 8 mg, and the subject is in a fed state prior to oral administration of the dosage form.

[0111] Thus, in one aspect, the present disclosure provides a gastroresistant controlled release oral dosage form comprising: (i) about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and (ii) at least one controlled-release agent, wherein, upon oral administration to a subject, the T max In one embodiment, the oral dosage form provides a plasma pharmacokinetic (PK) profile for Compound (I) comprising: max is between about 5 and about 10 hours, between about 6 and about 9 hours, between about 7 and about 9 hours, or between about 6 and about 8 hours.

[0112] In some embodiments, the amount of Compound (I) in the oral dosage form is 4 mg to 8 mg, 8 to 16 mg, 16 mg to 32 mg, 32 mg to 40 mg, 40 mg to 64 mg, 64 mg to 80 mg, 80 mg to 100 mg, or is about any of 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, 64 mg, 80 mg, 96 mg, or 100 mg.

[0113] In one embodiment, the dosage form comprises about 32 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 68 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 16 ng / mL, 17 ng / mL, 18 ng / mL, 19 ng / mL, 20 ng / mL, 21 ng / mL, 22 ng / mL, or 23 ng / mL; max and (c) approximately 75 hours * ng / mL to approximately 350 hours * ng / mL or approximately 100 hours * ng / mL to 300 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. maxIncludes.

[0114] In one embodiment, the dosage form comprises about 4 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 8 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 2.5 ng / mL; max and (c) approximately 12 hours * ng / mL to 35 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 2.0 ng / mL, less than 1.5 ng / mL, less than 1.0 ng / mL, or less than 0.5 ng / mL. max Includes.

[0115] In one embodiment, the dosage form comprises about 8 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 16 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 5 ng / mL; max and (c) approximately 25 hours * ng / mL to 75 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. max Includes.

[0116] In one embodiment, the dosage form comprises about 16 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 32 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 10 ng / mL or less than about 6 ng / mL max and (c) approximately 50 hours *ng / mL to 150 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. max Includes.

[0117] In one embodiment, the dosage form comprises about 40 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 80 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 24 ng / mL or less than about 20 ng / mL max and (c) approximately 125 hours * ng / mL to 375 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, or less than 2.0 ng / mL. max Includes.

[0118] In certain embodiments, the dosage form comprises about 64 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 50, 60, 70, 80, 90, 100, 110, 120, or 130 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 36 ng / mL or less than about 25 ng / mL max and (c) approximately 200 hours * ng / mL to 600 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, or less than 2.5 ng / mL. max Includes.

[0119] In one embodiment, the dosage form comprises about 80 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 160 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 48 ng / mL or less than about 40 ng / mL max and (c) approximately 250 hours * ng / mL to 750 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, or less than 3.0 ng / mL. max Includes.

[0120] In one embodiment, the dosage form comprises about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile is: (a) at about 220 hours * AUC below ng / mL 0~4H (b) a C of Compound (I) of less than about 72 ng / mL max and (c) approximately 325 hours * ng / mL to 975 hours * AUC between ng / mL 0~24hr In certain embodiments, the plasma PK profile for the BFB-520 metabolite of Compound (I) has a C of less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, or less than 3.5 ng / mL. max Includes.

[0121] In some embodiments of any of the above dosage forms, the plasma PK parameters are determined after the second once-daily administration of the single unit dosage form, hi certain embodiments, the PK parameters are determined after the third or fourth administration.

[0122] In one embodiment, the dosage form contains about 32 mg of Compound (I) and, when administered to a subject, produces a plasma pharmacokinetic (PK) profile for Compound (I) similar to the target profile shown in Figure 1.

[0123] In some embodiments of any of the above dosage forms, the plasma PK profiles for one or both of Compound (I) and metabolite BFB-520 occur after the first, second, third, or fourth once-daily administration of the single unit dosage form.

[0124] In some embodiments, the plasma PK profiles for Compound (I) and / or metabolite BFB-520 occur when administered to a subject in a fasted state. In other embodiments, the plasma PK profiles for Compound (I) and / or metabolite BFB-520 occur when administered to a subject in a fed state.

[0125] In some embodiments, the controlled-release dosage forms of the present disclosure contain about 4 to about 100 mg of Compound (I) and generate a target in vitro dissolution profile using a 24-hour, two-phase in vitro dissolution method comprising a 2-hour acid phase and a 22-hour buffer phase. The target in vitro dissolution profile comprises (a) no detectable release of Compound (I) in the first 2.0 hours of the dissolution method, and (b) at least 80% of the total amount of Compound (I) in the dosage form is released over a 16-19 hour period. In some embodiments, the target in vitro dissolution profile comprises at least 85%, 90%, or 95% of the amount of Compound (I) in the dosage form is released by the 24-hour dissolution method.

[0126] In certain embodiments, the target in vitro dissolution profile further comprises releasing Compound (I) at release rates that each result in the following cumulative percentages of the total starting amount: (i) less than 0.6% by 2.5 hours; (ii) from 0.2 to 7.9% by 3.0 hours; (iii) 2.5 to 19.2% by 4 hours; (iv) 12.7 to 34.0% by 6 hours; (v) 22.8 to 44.3% by 8 hours; (vi) 35.5 to 75.7% by 13 hours; (vii) 43.3 to 89.0% by 16 hours; and (viii) from 59.3 to 96.9% by 19 hours.

[0127] In certain embodiments, the target in vitro dissolution profile further comprises releasing Compound (I) at release rates that each result in the following cumulative percentages of the total starting amount: (i) less than about 0.5% by 2.5 hours; (ii) from about 2.8 to about 3.1% by 3.0 hours; (iii) from about 9.0 to about 11.0% by 4 hours; (iv) from about 14.5 to about 18.0% by 5 hours; (v) from about 19.5 to about 24.5% by 6 hours; (vi) from about 30.5 to about 38.0% by 8 hours; (vii) from about 41.5 to about 51.0% by 10 hours; (viii) from about 54.5 to about 67.0% by 13 hours; (ix) from about 58.5 to about 71.5% by 14 hours; (x) from about 61.5 to about 75.5% by 15 hours; (xi) from about 70.0 to about 86.0% by 18 hours; and (xii) from about 77.5 to about 95.0% by 21 hours.

[0128] In one embodiment, the CR dosage form contains 32 mg of Compound (I) and produces an in vitro cumulative dissolution profile and dissolution rate profile substantially similar to the target profiles shown in Figure 1 or to the target profiles shown in Tables 6 and 7 in the Examples below.

[0129] In certain embodiments, the target in vitro dissolution profile further comprises releasing Compound (I) at release rates that each result in the following cumulative percentages of the total starting amount: (xiii) less than about 0.5% by 2 hours; (xiv) from about 19 to about 29% by 4 hours; (xv) from about 54 to about 64% by 8 hours; and (xvi) from about 83 to about 93% by 16 hours.

[0130] In certain embodiments, the target in vitro dissolution profile further comprises releasing Compound (I) at release rates that each result in the following cumulative percentages of the total starting amount: (xvii) less than about 0.5% by 2 hours; (xviii) approximately 24.1% by 4 hours; (xix) approximately 59.2% by 8 hours; and (xx) Approximately 88.6% by 16 hours.

[0131] In each of the above embodiments, the lysis method is preferably carried out according to the lysis method described in the Examples below.

[0132] In some embodiments, the CR oral dosage form is a tablet comprising a core tablet and an enteric coating. The core tablet comprises a desired amount of Compound (I), a controlled-release agent, a filler, a glidant and a lubricant, and the enteric coating comprises at least one polymeric controlled-release agent having a dissolution property above pH 5.5 and an anti-adherent agent. In some embodiments, the enteric coating dissolves at a pH above 6.0 or 6.5.

[0133] In some embodiments, the CR oral dosage form is a tablet comprising a core tablet and an enteric coating. The core tablet comprises a desired amount of Compound (I) or its pharmaceutically acceptable salt and / or solvate (e.g., MIN-101), a controlled-release agent, a filler, a glidant, and a lubricant, and the enteric coating comprises at least one polymeric controlled-release agent having a dissolution property above pH 5.5 and an anti-adherent agent. In some embodiments, the enteric coating dissolves at a pH above 6.0 or 6.5.

[0134] In some embodiments, the controlled-release agent in the core tablet comprises a mixture of (i) low-viscosity hypromellose having a viscosity of about 15 milliPascal-seconds (mPa·sec) to about 100 mPa·sec and (ii) high-viscosity hypromellose having a viscosity of about 100,000 mPa·sec, each of which is of controlled-release or sustained-release grade and further characterized by a methoxy content of 19.0% to 24.0% and a hydroxypropyl content of 4.0% to 12.0%. In some embodiments, the high-viscosity hypromellose is characterized by a methoxy content of 22.0% to 24.0% and a hydroxypropyl content of 9.5% to 11.5%. In some embodiments, the low-viscosity hypromellose comprises about 10% by weight of the core tablet, and the high-viscosity hypromellose comprises about 24% by weight of the core tablet.

[0135] In one embodiment, the core tablet comprises 38.4 mg of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), and the controlled-release agent in the core tablet consists essentially of: (i) 9.45% w / w hypromellose having the chemical and physical characteristics of the hypromellose product commercially available as METOLOSE® 90 SH 100 SR, or METHOCEL™ K100LV CR by Shin-Etsu Chemical Co., Ltd.; and (ii) 22.67% w / w hypromellose having the chemical and physical characteristics of the hypromellose product commercially available as METHOCEL™ K100M CR by Dow Chemical Company.

[0136] In some embodiments, the dosage form further comprises a controlled-release coating located between the core tablet and the enteric coating. The controlled-release coating comprises at least one controlled-release agent. In some embodiments, the controlled-release coating comprises a semipermeable membrane comprising ethylcellulose as a controlled-release agent.

[0137] In one embodiment of the dosage form including a controlled-release coating, the core tablet comprises 38.4 mg of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), the controlled-release agent in the core tablet consists essentially of 9.36% w / w hypromellose having the chemical and physical characteristics of the hypromellose product commercially available as METHOCEL™ K15M CR, or METHOCEL™ K100LV CR by The Dow Chemical Company; and 22.46% hypromellose having the chemical and physical characteristics of the hypromellose product commercially available as METHOCEL™ K100M CR by The Dow Chemical Company, and the controlled-release agent in the controlled-release coating is Surelease® by Colorcon. Consists essentially of 0.94% w / w ethylcellulose having the chemical and physical characteristics of the ethylcellulose product commercially available as E-7-19040.

[0138] In some embodiments of any of the above dosage forms, the enteric coating consists essentially of a mixture of (i) 4.68% w / w of a copolymer of methacrylic acid and ethyl acrylate, having the same physical and chemical properties as the copolymer commercially available as EUDRAGIT® L30D-55 by Evonik Industries AG, and (ii) 0.80% w / w of an anti-adherent agent, having the chemical and physical characteristics of the anti-adherent agent commercially available as PlasACRYL™ by Evonik Industries AG.

[0139] In some embodiments, the gastro-resistant CR tablets of the present disclosure have a round, oval, capsule, or rectangular shape. In some embodiments, the tablets are round with a diameter of 10 mm and a radius of curvature (R) of 10.

[0140] In other aspects, the present disclosure provides batch compositions and processes for producing the gastro-resistant CR oral dosage forms described herein.

[0141] In yet another aspect, the disclosure provides a method of reducing the risk of QT prolongation when treating a subject with Compound (I), comprising administering to the subject a gastro-resistant CR oral dosage form described herein.

[0142] In yet a further aspect, the present disclosure provides a method of treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, comprising once-daily administration to the patient of a gastro-resistant CR oral dosage form described herein. In one embodiment, the subject, e.g., the patient, has a diagnosis of schizophrenia. In certain embodiments, the patient has a diagnosis of schizophrenia, a CYP2D6 extensive metabolizer (EM) genotype, and the oral dosage form comprises 32 mg to 64 mg of Compound (I). In another embodiment, the patient has a diagnosis of schizophrenia, a CYP2D6 poor metabolizer (PM) genotype, and the gastro-resistant CR oral dosage form comprises 4 mg to 16 mg of Compound (I). In another embodiment, the patient has a diagnosis of schizophrenia, a CYP2D6 intermediate metabolizer (IM) genotype, and the gastro-resistant CR oral dosage form comprises 8 mg to 32 mg of Compound (I).

[0143] In another aspect, the present disclosure provides a gastro-resistant CR oral dosage form as described herein for use in treating negative symptoms in a patient. In some embodiments, the patient has a diagnosis of schizophrenia. In some embodiments, the dosage form is intended for use in improving one or both of negative symptoms and cognitive impairment in a patient with a diagnosis of schizophrenia.

[0144] In another aspect, the present disclosure provides a use of a gastro-resistant CR oral dosage form described herein for the preparation of a medicament for treating negative symptoms in a patient. In some embodiments, the patient has a diagnosis of schizophrenia.

[0145] In another aspect, the present disclosure provides a kit for use in treating negative symptoms in a patient, the kit comprising a gastro-resistant CR oral dosage form described herein and instructions for use of the dosage form. In some embodiments, the instructions include instructions for testing the patient to determine the patient's CYP2D6 genotype. In some embodiments, the instructions include instructions for administering the dosage form to the patient in a fed or fasted state.

[0146] In all of the above aspects and embodiments of the invention, Compound (I) is provided in the gastro-resistant CR oral dosage form as 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride salt, hydrate (1:1:2).

[0147] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0148] In the figures, various graphs are shown containing the plasma concentration time profiles of various compounds, including, for example, 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, i.e., Compound (I). In these figures, the use of "MIN-101" or "MIN101" is intended to refer to the free base, i.e., Compound (I).

[0149] The foregoing summary, as well as the following detailed description of the present disclosure, will be better understood when read in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0150] [Figure 1]1 shows exemplary target plasma PK profiles for Compound (I) produced by oral administration of a gastroresistant controlled-release dosage form comprising 32 mg of Compound (I) (the "prospective new formulation") compared to the plasma PK profile observed for Compound (I) produced by a conventional 32 mg modified-release MIN-101 tablet (described in Example 1) ("MR 32 mg"). The time profile is over a 24-hour period. [Figure 2] Figure 2 compares the target in vitro dissolution profile for Compound (I) (target, red curve) with the observed dissolution profiles for two exemplary gastro-resistant CR 32 mg tablets of the present disclosure, with the left graph showing the cumulative dissolution profile and the right graph showing the dissolution rate profile. The time profile is over 24 hours. [Figure 3] 3 shows another exemplary target plasma PK profile for Compound (I) resulting from oral administration of a gastro-resistant controlled-release dosage form ("optimal formulation") containing 32 mg of Compound (I) to subjects in either a fed or fasted state, compared to the plasma PK profile observed for Compound (I) resulting from a conventional 32 mg modified-release MIN-101 tablet (described in Example 1) in patients in a fasted or fed state. The time profile is over a 24-hour period. [Figure 4] 4 is a graph of the plasma concentration time profile of Compound (I) for subjects administered MR 32 mg tablets. The time profile spans 36 hours. [Figure 5] 5 is a graph of the plasma concentration time profile of Compound (I) for subjects administered GR-01 tablets. The time profile spans 36 hours. [Figure 6] 6 is a graph of the plasma concentration time profile of Compound (I) for subjects administered GR-02 tablets. The time profile spans 36 hours. [Figure 7]7 is a graph of the mean plasma concentration time profile of Compound (I) for subjects administered MR 32 mg tablets, GR-01 tablets, or GR-02 tablets. The time profiles extend over a 48 hour period. [Figure 8] 8 is a graph of the rate of increase or decrease in the plasma concentration time profile of Compound (I) for subjects administered MR 32 mg tablets, GR-01 tablets, or GR-02 tablets. The time profile spans an 8 hour period. [Figure 9] 9 is a graph of the plasma concentration time profile of BFB-520 for subjects administered MR 32 mg tablets. The time profile spans 36 hours. [Figure 10] 10 is a graph of the plasma concentration time profile of BFB-520 for subjects administered GR-01 tablets. The time profile spans 36 hours. [Figure 11] 11 is a graph of the plasma concentration time profile of BFB-520 for subjects administered GR-02 tablets. The time profile spans 36 hours. [Figure 12] 12 is a graph of the mean plasma concentration time profile of BFB-520 for subjects administered MR 32 mg tablets, GR-01 tablets, or GR-02 tablets. The time profile spans 48 hours. [Figure 13] 13 is a graph of the rate of increase or decrease of the plasma concentration time profile of BFB-520 for subjects administered MR 32 mg tablets, GR-01 tablets, or GR-02 tablets. The time profile spans an 8 hour period. [Figure 14] 14 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses of MR 32 mg tablets or GR-01 tablets (32 mg), based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 15]15 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects administered four daily doses of MR 32 mg tablets or GR-01 tablets (32 mg), based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 16] 16 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses of 64 mg (2 x 32 mg) of MR 32 mg or GR-01 tablets. The time profiles span 96 hours. [Figure 17] 17 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects receiving four daily doses of 64 mg (2 x 32 mg) of either MR 32 mg or GR-01 tablets. The time profiles span 96 hours. [Figure 18] 18 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses of MR 32 mg tablets or GR-02 tablets (32 mg), based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 19] 19 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects administered four daily doses of MR 32 mg tablets or GR-02 tablets (32 mg), based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 20] 20 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses of MR 32 mg tablets or GR-02 tablets, based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 21]21 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects receiving four daily doses of 64 mg (2 x 32 mg) of either MR 32 mg tablets or GR-02 tablets. The time profiles span 96 hours. [Figure 22] 22 is a graph of the plasma concentration time profile of Compound (I) for subjects administered GR-01 tablets in the fed state. The time profile spans 36 hours. [Figure 23] 23 is a graph of the plasma concentration time profile of Compound (I) for subjects administered GR-01 tablets in the fasted state. The time profile spans 36 hours. [Figure 24] 24 is a graph comparing the mean plasma concentration time profiles of Compound (I) for subjects administered GR-01 tablets in the fed or fasted state. The time profiles are over a 48 hour period. [Figure 25] 25 is a graph of the plasma concentration time profile of BFB-520 for subjects administered GR-01 tablets in the fed state. The time profile spans 48 hours. [Figure 26] 26 is a graph of the plasma concentration time profile of BFB-520 for subjects administered GR-01 tablets in the fasted state. The time profile spans 48 hours. [Figure 27] 27 is a graph comparing the mean plasma concentration time profiles of BFB-520 for subjects administered GR-01 tablets in the fed or fasted state. The time profiles are over a 48 hour period. [Figure 28] 28 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses (32 mg) of GR-01 tablets in the fed or fasted state, based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 29]29 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects administered four daily doses (32 mg) of GR-01 tablets in the fed or fasted state, based on actual data observed after dosing on Day 1. The time profiles span 96 hours. [Figure 30] 30 is a pair of graphs of predicted steady-state plasma concentration time profiles of Compound (I) for subjects administered four daily doses of 64 mg (2 x 32 mg) of GR-01 tablets in the fed or fasted state. The time profiles span 96 hours. [Figure 31] 31 is a pair of graphs of predicted steady-state plasma concentration time profiles of BFB-520 for subjects receiving four daily doses of 64 mg (2 x 32 mg) of GR-01 tablets in the fed or fasted state. The time profiles span 96 hours. DETAILED DESCRIPTION OF THE INVENTION

[0151] The present disclosure relates to novel gastro-resistant CR oral dosage forms comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, bulk compositions and processes for making the dosage forms, and uses of the dosage forms for the therapeutic treatment of patients suffering from various disorders and conditions.

[0152] In one embodiment, the present disclosure provides a novel gastro-resistant CR oral dosage form comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, which, upon oral administration to a subject, exhibits a decrease in AUC (0~tau) While the C of compound (I) and its metabolite BFB-520 was maintained, max The present invention relates to an oral dosage form in which

[0153] In one embodiment, the present disclosure relates to a novel gastro-resistant CR oral dosage form comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, which, upon oral administration to a subject, maintains a similar AUC-based exposure of Compound (I) compared to previous studies using previously disclosed formulations and / or dosage forms, such as those disclosed in U.S. Pat. No. 9,458,130, which achieved the primary endpoint of improving negative symptoms in patients with schizophrenia at both the 64 mg and 32 mg doses tested.

[0154] In one embodiment, the present disclosure provides a novel gastro-resistant CR oral dosage form comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, which upon oral administration to a subject, provides a reduced t of Compound (I) compared to previously disclosed formulations and / or dosage forms, e.g., those disclosed in U.S. Pat. No. 9,458,130. 1 / 2 The present invention relates to an oral dosage form in which the time to release is extended.

[0155] In one embodiment, the present disclosure provides a novel gastro-resistant CR oral dosage form comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein upon oral administration to a subject, the C of BFB-520 in the plasma of the subject is reduced to promote drug safety. max The present invention relates to an oral dosage form in which

[0156] In one embodiment, the present disclosure provides a novel gastro-resistant CR oral dosage form comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, which upon oral administration to a subject, exhibits a reduced C of BFB-520 compared to previously disclosed formulations and / or dosage forms, e.g., those disclosed in U.S. Pat. No. 9,458,130. max is reduced by about 30% or more (e.g., 30%, 35%, or 40%).

[0157] In one embodiment, the C of BFB-520 in a subject maxThis reduction in QTc leads to a reduction in the likelihood of a transient QTc increase that was observed in previous studies at higher doses but not at lower doses. In one example, administration of the novel gastro-resistant CR oral dosage forms described herein comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, does not result in observable QTc prolongation.

[0158] In one embodiment, the present disclosure relates to a novel gastro-resistant CR oral dosage form comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein administration of the dosage form does not produce an observable food effect, i.e., administration of the dosage form may occur with or without food and does not alter its pharmacokinetic properties.

[0159] In one embodiment, the present disclosure relates to novel gastro-resistant CR oral dosage forms comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the dosage forms comprising Compound (I) retain the overall safety and tolerability profile previously established.

[0160] The novel gastroresistant CR oral dosage forms disclosed herein enable delivery of Compound (I) to the lower gastrointestinal tract, unexpectedly reducing the maximum concentration of BFB-520. This unexpected pharmacokinetic effect did not result in observable QT prolongation in subjects administered these novel gastroresistant CR oral dosage forms.

[0161] Abbreviations Terms used herein have their ordinary meaning, and the meaning of such terms is independent at each occurrence. Notwithstanding the foregoing, the following definitions apply throughout the specification and claims, except where otherwise stated.

[0162] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure is understood to control.

[0163] All references herein to Compound (I) include all of its pharmaceutically acceptable salts (such as MIN-101) and / or solvates (including, e.g., hydrates), as well as alternative physical forms, unless otherwise specified. All dosages described herein are based on the molecular weight of the free base of Compound (I), which is 366.43 g / mole, and not the molecular weight of its pharmaceutically acceptable salts or solvates (e.g., hydrates) or any excipients in the compositions, unless otherwise specified.

[0164] All amounts of components of the oral dosage forms described herein, given on a % w / w basis, refer to the total weight of the oral dosage form, unless otherwise specified.

[0165] The term "about" as part of a quantitative expression, e.g., "about X," includes any value 10% above or below X, and also includes any number between X-10% and X+10%. Thus, for example, a weight of about 40 g includes weights between 36 and 44 g.

[0166] "Administration" refers to the introduction of a pharmaceutical agent, e.g., a compound or dosage form described herein, into a subject. The related terms "administering" and "administration of" (and grammatical equivalents) refer to both direct administration, which may be administered to a subject by a medical professional or by self-administration by the subject, and / or indirect administration, which may be the act of prescribing a drug, such as a dosage form described herein. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient.

[0167] "BFB-520" is a metabolite of compound (I) and has the structure shown in Formula II below:

[0168] [ka] (II) It has.

[0169] "BFB-999" is a metabolite of compound (I), and the structure of the maleate salt of BFB-999 is shown in Formula III below:

[0170] [ka] (III) It has.

[0171] "Similar PK profile," as used herein with reference to plasma concentration time profiles resulting from oral administration of a dosage form of the present disclosure to a subject, is a plasma concentration time profile that is substantially similar to the target profile shown in Figure 1, such that a first dosage form comprising Compound (I) that produces the target plasma concentration time profile in Figure 1 and a second dosage form comprising Compound (I) that produces a similar plasma concentration time profile, produce PK profiles, such as AUC, that are considered bioequivalent by a regulatory agency. In an embodiment, the regulatory agency is the US Food and Drug Administration.

[0172] "BNSS" stands for Brief Negative Symptom Scale.

[0173] "Comprising" or "comprises," when applied to a particular dosage form, composition, method, or process described or claimed herein, means that the dosage form, composition, or method includes all of the elements recited in the particular specification or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, or process does not exclude other materials or steps that do not materially affect the described physical, pharmacological, pharmacokinetic profile, or therapeutic efficacy of the composition, dosage form, method, or process. "Consists of" and "consisting of" mean the exclusion of more than trace amounts of other ingredients and substantial method or process steps.

[0174] "Controlled release" or "CR," as used herein with respect to oral dosage forms of the present disclosure, means that Compound (I) is released from the dosage form according to a predetermined profile, which may include the time and place at which release occurs after oral administration and / or a particular rate of release over a particular period of time.

[0175] "Controlled-release agent," as used herein with respect to oral dosage forms of the present disclosure, refers to one or more substances or materials that modulate the release of Compound (I) from the dosage form. Controlled-release agents may be organic or inorganic, naturally occurring or synthetic materials, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, and colloidal silica.

[0176] "CYP2D6 allele" refers to one of over 100 named versions of the CYP2D6 gene present in the population, typically classified into one of three categories: active (functional), reduced activity (partially active or reduced function), and inactive (non-functional).

[0177] Active CYP2D6 alleles are * 1. * 2. * 2A, * 33. * 35, * 39, * 48, and * Including 53.

[0178] CYP2D6 alleles with reduced activity are * 9. * 10. * 17. * 29, * 41, * 49, * 50, * 54, * 55, * 59, * 69, and * Including 72.

[0179] Inactive CYP2D6 alleles are * 3. * 4. * 5 (deletion), * 6. * 7. * 8. * 11. * 12. * 13. * 14A, * 14B, * 15. * 18, * 19. * 20, * twenty one, * 38, * 40, * 42, * 44, * 56, * 56A, * 56B, and * Including 68.

[0180] The term "CYP2D6 extensive metabolizer (EM) genotype," as applied to a subject, means that the subject has a CYP2D6 that results in CYP2D6 metabolic activity that is considered normal. The CYP2D6 EM genotype includes combinations of (a) two active CYP2D6 alleles, (b) one active CYP2D6 allele and one CYP2D6 allele with reduced activity, and (c) one active CYP2D6 allele and one inactive CYP2D6 allele.

[0181] "CYP2D6 intermediate metabolizer (IM) genotype," as applied to a subject, means that the subject has a CYP2D6 genotype that results in reduced CYP2D6 metabolic activity. CYP2D6 IM genotypes include combinations of (a) one inactive CYP2D6 allele and one reduced-activity CYP2D6 allele, and (c) two reduced-activity CYP2D6 alleles.

[0182] "CYP2D6 PM genotype," as applied to a subject, means that the subject has a positive test result for the CYP2D6 poor metabolizer genotype and is therefore predisposed to not have CYP2D6 activity. The CYP2D6 PM genotype is two inactive alleles.

[0183] "CYP2D6 UM genotype," as applied to a subject, means that the subject has a positive test result for the CYP2D6 extremely extensive metabolizer genotype and is therefore prone to higher than average CYP2D6 activity. A CYP2D6 UM genotype is three or more active alleles.

[0184] "Enteric coating," as used herein with respect to dosage forms of the present disclosure, refers to a pH-dependent material that is present around a core comprising Compound (I) and that remains substantially intact in the acidic environment of the stomach but dissolves in the pH environment of the intestine.

[0185] In one embodiment, in the dosage form of the present disclosure, the filler is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0186] "Lubricant," as used herein, refers to a substance used to promote powder flow by reducing cohesion between particles. In one embodiment, in the dosage form of the present disclosure, the lubricant is selected from the group consisting of anhydrous colloidal silica, starch, and talc.

[0187] "Lubricant," as used herein, refers to a substance that prevents ingredients from sticking and / or clumping in machinery used in preparing the dosage forms of the present disclosure. In one embodiment, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of magnesium stearate, steric acid, and vegetable stearin.

[0188] "Fasting conditions" or "fasting state," when used to describe a subject, means that the subject has not eaten for at least 4 hours prior to the time of interest, e.g., the time of administration of a dosage form described herein. In some embodiments, a subject in a fasting state has not eaten for at least any of 6, 8, 10, or 12 hours prior to administration of a dosage form described herein.

[0189] "Fed condition" or "fed state," as used herein to describe a subject, means that the subject has eaten less than 4 hours prior to the time of interest, e.g., the time of administration of a dosage form described herein. In some embodiments, a subject in a fed state has not eaten for at least any of 3, 2, 1, or 0.5 hours prior to administration of a dosage form described herein.

[0190] "Gastro-resistant" or "GR," as applied to the CR oral dosage forms described herein, means that the release of Compound (I) in the stomach of a subject does not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of Compound (I) in the dosage form.

[0191] "MIN-101" is the code name for 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), with the alternative name 2-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one hydrochloride dihydrate.

[0192] "Oral dosage form," as used herein, refers to a pharmaceutical product containing a specific amount (dose) of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, as the active ingredient, and inactive ingredients (excipients), formulated into a particular structure, e.g., a tablet or capsule, that is suitable for oral administration.

[0193] "Pharmaceutically acceptable salts," as used herein with respect to Compound (I), refer to salt forms of Compound (I) and hydrate forms of salts having one or more water molecules present. Such salt and hydrate forms retain the biological activity of Compound (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. In one embodiment, a pharmaceutically acceptable salt of Compound (I) has a single HCl molecule and two water molecules, i.e., 1H-isoindol-1-one,2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2).

[0194] "PANSS" is a scale for assessing positive and negative symptoms.

[0195] "Pharmacokinetic parameter" means a measure or characteristic that describes the pharmacokinetic properties of a compound of interest. As used herein, PK parameters are defined below.

[0196] "AUC" is a measure of exposure to a compound of interest and is the total area under the plasma concentration-time curve, which is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng·hr / mL (ng × hr / mL).

[0197] "AUC (0~4H) " means the AUC from 0 to 4 hours after administration of a single dose.

[0198] "AUC (0~24H) " means the AUC from 0 to 24 hours after administration of a single dose.

[0199] "AUC last ” is the time from time 0 to the last quantifiable concentration (C last ) means the AUC up to

[0200] "AUC (0~tau) " means the AUC from time 0 to the end of the dosing interval.

[0201] "C max " refers to the maximum (peak) plasma concentration of a particular compound, e.g., Compound (I), observed after administration of a dose of a composition comprising that compound. In one embodiment, C max is measured after two or more doses of the composition. max is measured when a particular compound reaches steady state.

[0202] "C min " refers to the minimum plasma concentration of a particular compound, e.g., Compound (I), observed after administration of a dose of a composition comprising that compound. In one embodiment, C max is measured after two or more doses of the composition. max is measured when a particular compound reaches steady state.

[0203] "C ss " means steady state concentration.

[0204] "C ave" means the mean concentration, which is the ratio of AUC over time.

[0205] "C p " means the plasma concentration of a particular compound, e.g., Compound (I), at any time T after administration of a dose of a composition comprising that compound.

[0206] "C p(last) ” is the last measured C relative to the last blood sample drawn in a series for assaying a particular compound. p means.

[0207] "C p(T) " is the C at a particular time p Therefore, C p(4H) and C p(12H) are the C at 4 hours, respectively. p and C at 24 hours p means.

[0208] "H" stands for time.

[0209] "PK" is pharmacokinetics.

[0210] "Steady state" means that the rate of absorption of a particular compound of interest, eg, Compound (I), equals the rate of excretion of the compound.

[0211] "Tau" means the dosing interval (H). For example, for once-daily dosing, tau is 24H.

[0212] T max means the time to maximum (or peak) plasma or serum concentration of a particular therapeutic compound after administration of a composition containing a single dose of that compound and before administration of a second dose.

[0213] V max means the maximum absorption rate (mg / hr).

[0214] "Subject" and "patient" are used interchangeably herein and refer to humans of any age.

[0215] "Therapeutically effective amount," as used herein with respect to therapeutic use of a dosage form containing Compound (I) or its pharmaceutically acceptable salts and / or solvates, means an amount of the free base [Compound (I)] sufficient to treat, ameliorate, or prevent a particular disease, disease symptom, disorder, or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount for a particular subject will vary depending on the subject's weight, size, and health; the nature and extent of the condition; and whether additional therapeutic agents are to be administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0216] The terms "treat," "treating," "treatment," and similar terms, as used herein in reference to one or more specific disease symptoms, include the management and care of a patient to ameliorate one or more of the specific symptoms, and include administration of a gastric resistant controlled-release oral dosage form described herein at a dosing frequency and treatment duration sufficient to prevent the onset of one or more of the symptoms, reduce the frequency, intensity, or severity of one or more of the symptoms, delay or avoid the onset of further symptoms, or any combination of these therapeutic purposes. In certain embodiments, the efficacy of treatment with a dosage form of the present disclosure is assessed by comparing the severity of the subject's symptoms at baseline (e.g., before treatment) with the subject's symptoms after at least one treatment period. In certain embodiments, the treatment period is at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks or more. In one embodiment, the symptom being treated is at least one negative symptom in a schizophrenic or non-schizophrenic patient, the dosage form contains 32 mg of Compound (I), the dosing frequency is once daily, and the treatment duration is at least 8 weeks.

[0217] Overview of gastroresistant controlled-release (CR) oral dosage forms In one embodiment, the disclosure provides a gastro-resistant CR oral dosage form comprising between about 4 mg and about 100 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt and / or solvate of Compound (I), selected from the group consisting of a 32 mg CR GR-01 tablet, a 32 mg CR GR-02 tablet, a 32 mg CR GR-01 / B tablet, a 64 mg CR GR-01 / B tablet, a 32 mg CR GR-01 / C tablet, and a 64 mg CR GR-01 / C tablet.

[0218] In one embodiment, a 32 mg CR GR-01 tablet has the following composition: [Table 1] 1 Applied salt correction factor 1.2 NA: Not applicable

[0219] In one embodiment, a 32 mg tablet of CR GR-02 has the following composition: [Table 2] 1 Applied salt correction factor 1.2 NA: Not applicable

[0220] In one embodiment, a 32 mg CR GR-01 / B tablet has the following composition: [Table 3] 1 Applied salt correction factor 1.2

[0221] In one embodiment, a 32 mg CR GR-01 / C tablet has the following composition: [Table 4]

[0222] In one embodiment, a 64 mg CR GR-01 / B tablet has the following composition: [Table 5] 1 Applied salt correction factor 1.2

[0223] In one embodiment, a 64 mg CR GR-01 / C tablet has the following composition: [Table 6]

[0224] Design and manufacture of gastroresistant controlled release oral dosage forms The object of the present disclosure is to provide a gastro-resistant controlled-release oral dosage form comprising between about 4 mg and about 100 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt and / or solvate of Compound (I). The dosage form is formulated to exhibit a specific, desired release profile for Compound (I) upon oral administration to a subject, which provides a therapeutically effective amount of Compound (I) during one or more dosing intervals, while reducing the maximum plasma concentration of BFB-520. This desired release profile is achieved in two ways: (a) delaying the release of Compound (I) after gastric emptying until the dosage form is pushed into the small intestine, and then (b) providing a T for Compound (I) between about 4 and about 22 hours. max and providing a sustained release of at least about 90%, 95%, or 100% of the amount of Compound (I) in the dosage form at a rate that results in a plasma PK profile comprising:

[0225] The in vivo release profile of Compound (I) is designed to reduce the subject's plasma levels of BFB-520 below a threshold value that correlates with a higher risk of QT prolongation. In one embodiment, the threshold value is the C maxwhich is less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, less than 1.0 ng / mL, or less than 0.5 ng / mL.

[0226] In some embodiments, the plasma PK profile for Compound (I) may be determined by one or more additional PK parameters, such as the C as defined above. max , AUC (0~tau) , C min and other PK parameters. It will be understood by those skilled in the art that the values ​​for some of these additional PK parameters will depend, at least in part, on the amount of Compound (I) in the dosage form.

[0227] T produced by the dosage forms described herein max and other plasma PK parameters may exhibit some inter-individual variability within a subject population. Thus, in some embodiments, a particular plasma PK parameter is expressed as a mean value determined for a population of at least 2, 4, 8, 16, or more subjects. In some embodiments, the population consists of healthy volunteers. In some embodiments, each subject in the population has a positive test for the EM genotype. In some embodiments, each subject in the population has a positive test for the EM genotype or the IM genotype. In some embodiments, each subject in the population has a positive test for the IM genotype or the PM genotype. In some embodiments, each subject in the population has a positive test for the PM genotype.

[0228] Compound (I) may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, as may be obtained from the relevant scientific literature or from standard reference textbooks in the field. Recognized reference textbooks for organic synthesis, without limitation, include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3 rd John Wiley & Sons: New York, 1999. Methods for preparing compound (I) are described in U.S. Pat. No. 7,166,617, the contents of which are incorporated herein in their entirety.

[0229] In one embodiment, the drug substance form of Compound (I) used in the dosage form has the molecular formula C 22 H 23 The dihydrate of the hydrochloride salt of Compound (I), having the chemical name 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), with FN2O2, HCl, 2H2O and a molecular weight of 438.92. Methods for preparing this Compound (I) drug substance are described in U.S. Patent Nos. 7,166,617 and 9,458,130. The amount of this drug substance equivalent to a specific amount of free base can be calculated by multiplying the specific amount of Compound (I) by 1.2; thus, 38.4 mg of this drug substance is equivalent to 32 mg of Compound (I).

[0230] In certain embodiments, the delayed and sustained release properties of the CR oral dosage form may be provided by enclosing a sustained release composition comprising a desired amount of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, within an enteric coating.

[0231] Various physical and chemical methods for designing sustained-release compositions are well known in the art. The dosage forms of the present disclosure may be prepared using any sustained-release composition capable of releasing Compound (I) and producing the in vivo plasma PK profile described herein. In some embodiments, the sustained-release composition comprises at least one polymeric material that modulates the release of Compound (I). Suitable polymeric materials include, but are not limited to, cross-linked polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, starch and its derivatives, acrylic acid and methacrylic acid polymers and copolymers, polyesters, polyanhydrides, polymethylvinyl ether / anhydride copolymers, potassium methacrylate-divinylbenzene copolymers, polyvinyl alcohol, glucan, scleroglucan, mannan, beta-cyclodextrin, and cyclodextrin derivatives containing linear and / or branched polymer chains. In one embodiment, the polymeric material is hydroxypropyl methocellulose.

[0232] In some embodiments, a mixture of low-viscosity hypromellose and high-viscosity hypromellose is used as a controlled-release agent in a sustained-release composition. The viscosity characteristics of suitable hypromellose can be determined in a 2 wt% solution in water at 20°C as described in the USP Hypromellose Monograph, Official December 1, 2016, available at http: / / www.usp.org / usp-nf / official-text / stage-6 / hypromellose-2015-11-20.

[0233] Typically, the enteric coating comprising a pH-sensitive polymer begins to dissolve in an aqueous solution at a pH above 5.5, and in one embodiment, begins to dissolve in an aqueous solution at a pH above 6.0. In one embodiment, the pH-sensitive polymer begins to dissolve in an aqueous solution at a pH above 6.5. In one embodiment, the pH-sensitive polymer begins to dissolve in an aqueous solution at a pH of 6.7. In some embodiments, the amount of Compound (I) released into the stomach from a gastroresistant CR dosage form administered to a subject in a fed or fasted state is approximately the same (e.g., less than 5%, less than 2%, or less than 1% difference).

[0234] The composition and thickness of the enteric coating are typically selected to substantially maintain its integrity in the stomach while allowing substantially all of the enteric coating to dissolve after the dosage form leaves the stomach, hi certain embodiments, substantially all of the enteric coating dissolves within 15 minutes, 30 minutes, 1 hour, or 2 hours after the dosage form leaves the stomach.

[0235] The design and preparation of gastro-resistant enteric coatings is well known in the art of formulation. Polyacids with an appropriate pKa range may be used to prepare the enteric coating. Non-limiting examples of suitable enteric coating materials are polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers (typically formed from methyl acrylate, ethyl acrylate, methyl methacrylate and / or copolymers of acrylic and methacrylic acid esters). For example, the enteric coating may comprise a copolymer based on methacrylic acid and ethyl acrylate commercially available as EUDRAGIT® L 30 D-55 by Evonik Industries AG. In one embodiment, the coating comprises a mixture of (i) 4.5% to 5.0% w / w, or about 4.7% w / w, EUDRAGIT® L 30 D-55 and (ii) 0.80% w / w PlasACRYL™.

[0236] In another aspect, the present disclosure provides batch compositions and processes for producing the gastro-resistant CR oral dosage forms described herein. In one embodiment, a batch composition for producing a 32 mg dosage form includes the components listed in Table 4 in Example 4 below. In another embodiment, a batch composition for producing a 32 mg dosage form includes the components listed in Table 5 in Example 4 below, or in a table in Example 4 below. Examples of processes suitable for producing these 32 mg dosage forms are described in Flowcharts 1 and 2 in Example 4.

[0237] Analysis method A. In vitro dissolution test To assess the potential of proposed gastro-resistant CR oral dosage forms containing Compound (I) to produce desirable in vivo release and plasma PK profiles for Compound (I), in vitro dissolution studies can be performed as described in the Examples below.

[0238] In one embodiment, the dosage form contains 32 mg and produces a cumulative dissolution profile and dissolution rate profile substantially similar to the target profile, the CR-GR-01 profile or the CR-GR-02 profile shown in Figure 1 and below in Tables 6 and 7. In one embodiment, the cumulative amount dissolved and dissolution rate at each time point in the substantially similar profile is within + / - 10% of the value for the corresponding time point in the target, CR-GR-01 or CR-GR-02 dissolution profile shown in Tables 6 and 7.

[0239] B. Detection of Compound (I) and BFB-520 in Human Plasma To evaluate whether a gastroresistant CR oral dosage form containing Compound (I) produces the desired PK profile for one or both of Compound (I) and BFB-520, the plasma concentration of the compound of interest can be determined at various time points after administration of the dosage form to a single subject, but is typically determined in a group of two or more subjects. In some embodiments, the PK profile is determined in a group of at least 8, 12, 16, or 20 subjects. In some embodiments, the group includes healthy male and female subjects. In some embodiments, the number of subjects in the group is selected to allow a statistically significant assessment of whether the PK profile produced by the test oral dosage form is a bioequivalent PK profile with respect to the PK profile shown in Figure 1.

[0240] Open-label, randomized, three-treatment sequence, three-period studies to evaluate the PK profiles of Compound (I) and its metabolite BFB-520 after single oral administration of three formulations of MIN-101: two prototype CR gastro-resistant (GR) formulations (GR-01 and GR-02) and one comparator MR formulation (MR32) are summarized in Scheme 1 (MIN-101) and Scheme 2 (BFB-520). Full details of these experiments can be found in the Examples section.

[0241] Scheme 1. Overview of PK studies of MIN-101 for MR32, GR-01, and GR-02 formulations. [Table 7]

[0242] Scheme 2. Overview of PK studies of BFB-520 for MR32, GR-01, and GR-02 formulations. [Table 8]

[0243] The PK profiles of MIN-101 and its metabolite BFB-520 were predicted for three formulations of MIN-101: two prototype CR gastro-resistant (GR) formulations (GR-01 and GR-02) and one comparator MR formulation (MR32), at two doses (32 mg and 64 mg) based on four once-daily administrations. These studies are summarized in Scheme 3 (32 mg) and Scheme 4 (64 mg). Full details can be found in the Examples section.

[0244] Scheme 3. Summary of predicted plasma concentrations of MIN-101 and BFB-520 for MR32, GR-01, and GR-02 formulations (32 mg). [Table 9]

[0245] Scheme 4. Summary of predicted plasma concentrations of MIN-101 and BFB-520 for MR32, GR-01, and GR-02 formulations (64 mg). [Table 10]

[0246] The PK profiles of GR-01 formulations in healthy male and female subjects with CYP2D6 EM under fed and fasted conditions are summarized in Scheme 5 (MIN-101) and Scheme 6 (BFB-520). Subjects who completed Part 1 of the study (evaluation of the PK profiles of MIN-101 and its metabolite BFB-520 in GR-01, GR-02, and MR32 formulations) were returned and further administered a single oral dose of GR-01 under fed or fasted conditions, and the PK profiles were compared to those obtained in Part 1, allowing for evaluation of the effect of food (Examples 9-12). Part 1 was followed by a 14 ± 2 day washout period. Full details of these experiments can be found in the Examples section.

[0247] Scheme 5. Overview of PK studies of MIN-101 for the GR-01 formulation in fed and fasted states. [Table 11]

[0248] Scheme 6. Overview of PK studies of BFB-520 on the GR-01 formulation in fed and fasted states. [Table 12]

[0249] The PK profiles of MIN-101 and its metabolite BFB-520 were predicted for the gastroresistant formulation GR-01 at two doses (32 mg and 64 mg) based on four once-daily administrations in the fed and fasted states. These studies are summarized in Scheme 7 (32 mg) and Scheme 8 (64 mg), respectively. Full details can be found in the Examples section.

[0250] Scheme 7. Summary of predicted plasma concentrations of MIN-101 and BFB-520 for GR-01 (32 mg) in fed and fasted states. [Table 13]

[0251] Scheme 8. Summary of predicted plasma concentrations of MIN-101 and BFB-520 for GR-01 (64 mg) in fed and fasted states. [Table 14]

[0252] BFB-520 is believed to be partially metabolized by CYP2D6. In clinical studies of MIN-101, poor CYP2D6 metabolizers exhibited elevated plasma levels of BFB-520. Thus, in one embodiment, only subjects assigned to the IM CYP2D6 genotype or the EM CYP2D6 genotype using commercially available genotyping tests were assessed for C ... maxis assessed. In one embodiment, all of the subjects were assigned an EM CYP2D6 genotype.

[0253] Following oral administration of an oral dosage form of the present disclosure, the levels of Compound (I) and metabolite BFB-520 produced in plasma can be determined by the method described below. It is expected that variations and improvements to this method can be used as well.

[0254] Blood samples from the subject are collected into sodium heparin tubes at various time points of interest. Suitable sampling schedules include the following: Day 1 (D1): Pre-dose; 1 hour; 2 hours; 3 hours; 4 hours; 6 hours; 8 hours; 10 hours; 12 hours and 16 hours; Days 2 to 6 (D2~D6): Before administration Day 7 (D7): Pre-dose; 1 hour; 1 hour; 2 hours; 3 hours; 4 hours; 6 hours; 8 hours; 10 hours; 12 hours; 16 hours; 24 hours (D8) and 48 hours (D9).

[0255] After centrifugation of the blood, the desired number of aliquots (typically 2) of each plasma sample are prepared in suitable storage containers (e.g., tightly capped polypropylene tubes to prevent leakage and drying during storage). The containers containing the plasma samples are stored at -80°C for up to 1 month before analysis.

[0256] The GLP validated method for the detection and quantification of Compound (I) and its metabolites BFB-520 and BFB-999 uses a liquid / liquid extraction step of Compound (I) and its metabolites BFB-520 and BFB-999 from plasma samples, followed by liquid chromatography (LC) analysis coupled to mass spectrometry detection (MS / MS).

[0257] The analytical method was performed using two internal standards [both BFB-520 and BFB-999], a deuterated analog of MIN-101 (referred to herein as [2 H6]-MIN-101 or MIN-101-d6 or CYR-101-d6) and BFB-784] are used. MIN-101-d6 and BFB-784 are represented by the following formulas IV and V:

[0258] [ka] (IV) [ka] (V) It has the structure shown in

[0259] Chromatograms were processed by default in automatic mode. Chromatographic peaks of MIN-101, BFB-520, BFB-999, and internal standards (IS) were identified by their retention times. Responses were reported as the area ratio of MIN-101 to MIN-101-d6, and the area ratio of BFB-520 or BFB-999 to BFB-784.

[0260] The lower limit of quantitation (LLOQ) of this analytical method in plasma is 0.25 ng / mL for MIN-101 and its metabolites BFB-520 and BFB-999.

[0261] Details of the analytical method are provided below in Example 7. It is expected that variations of this analytical method and improvements thereon can be used as well.

[0262] Treatment method The gastro-resistant CR oral dosage forms of the present disclosure may be useful for treating diseases or conditions amenable to treatment with Compound (I). By way of non-limiting example, it is believed that Compound (I) may be effectively used to treat schizophrenic and non-schizophrenic patients with one or more of the following symptoms or conditions: negative symptoms, depressive symptoms, sleep disorders, and cognitive impairment.

[0263] In a Phase 2b study, MIN-101 at doses of 32 mg and 64 mg demonstrated rapid, statistically significant, and clinically meaningful reductions in negative symptoms in patients with schizophrenia. The oral dosage forms used in this Phase 2b study were 64 mg MR tablets essentially identical to the 32 mg MR tablets described in Example 1 below. Neither of these MR tablets had a GR coating, and each produced an in vitro dissolution profile and plasma PK profile that differed from those produced by the gastro-resistant CR oral dosage form of the present disclosure.

[0264] Negative symptoms generally refer to a reduction in normal functioning and include five major subdomains: blunted affect (flattened emotions, reduced emotional expression), allotropy (poverty of speech), apathy (loss of motivation), anhedonia (reduced ability to experience or expect pleasure), and asociality (social withdrawal). Negative symptoms are a well-documented and intensively studied aspect of schizophrenia, but this class of symptoms has also been identified in patients with other psychiatric and neurological disorders, including, for example, Alzheimer's disease and other dementias, particularly frontotemporal dementia (FTD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (e.g., Boone et al., J. of Internat. Neuropsycol. Soc., 2003, Vol 9, pages 698-709; Bastiaansen, J. et al., J. Autism Dev. Disord. 2011, Vol 41:1256-1266; Getz, K. et al., Am. J. Psychiatry 2002, Vol 10, pages 1256-1266). 159:644-651;Winograd-Gurvich, C. et al., Brain Res. Bulletin, 2006, Vol. 70:312-321;Galynker et al., Neuropsychiatry Neuropsychol Behav Neurol 2000, Vol 13:171-176;Galynker I, et al., J. Nerv. Ment. Dis 1997, Vol 185:616-621; see Chaudhury, S., et al., Indian J. of Neurotrauma 2005, Vol 2:13-21; Ameen, S et al., German J. of Psychiatry 2007). Indeed, as early as 2001, it was proposed that negative symptoms are common across psychiatric disorders (Herbener and Harrow, Schizophrenia Bulletin 2001, Vol. 27:527-537).Furthermore, several population studies have reported that 20-22% of the general population have one or more negative symptoms, and that the majority of subjects with negative symptoms do not have a clinically diagnosed psychiatric disorder (Werbeloff, N. et al., PLoS ONE 2015, Vol 10:e0119852; Barrantes-Vidal, N., et al., Schizophr. Res. 2010, Vol 122:219-225).

[0265] Therefore, it is an object of the present disclosure to treat at least one negative symptom in a subject by administering the gastro-resistant CR dosage form described herein to the subject once a day (QD).In one embodiment, the subject is diagnosed with schizophrenia.In another embodiment, the subject does not have a clinical diagnosis of schizophrenia, that is, is a non-schizophrenic patient.

[0266] For purposes of the disclosure contained herein, the term "negative symptoms" should be understood to include the core negative symptoms typically associated with schizophrenia, negative symptoms as measured in the PANSS negative symptom subscale score, negative factor scores based on the pentagonal structural model methodology, and negative symptoms as measured in the BNSS.

[0267] In one embodiment, the negative symptoms are one of five major subdomains of negative symptoms: blunted affect, alogia, apathy, anhedonia, and antisociality. Core features of each subdomain are described below.

[0268] Affective flattening (flattened affect, blunted emotional expression) is characterized by a reduction in the intensity and range of emotional expression manifested through vocal or nonverbal modes of communication, including intonation, facial expressions, hand gestures, and body language.

[0269] Alogia (poverty of speech) is characterized by reduced speech volume, reduced spontaneous speech, and loss of conversational ability.

[0270] Apathy (loss of motivation) is characterized by deficits in initiating and maintaining purposeful activities, such as work, study, sports, personal hygiene, and daily tasks, especially when necessary, as well as effort (cognitive or physical) and significant organization, and a lack of desire to engage in such activities. This subdomain is related to apathy and lack of energy.

[0271] Anhedonia (reduced ability to experience or anticipate pleasure) is characterized by a significant and consistent impairment in the prospect of ("desire") for reward, recreation, or other enjoyable experiences (motivational anhedonia) compared with the perception of the experience itself ("satisfaction") (consummatory anhedonia).

[0272] Antisociality (social withdrawal) is characterized by loss of interest, motivation, and awareness of social interactions with others, such as family and friends; loss of interest in intimate (sexual) relationships unrelated to any physical problems; and in children, may include loss of interest in playing with other children.

[0273] In some embodiments, the dosage form is administered to the subject once a day for a first treatment period that is long enough to achieve improvement in at least one negative symptom.In some embodiments, the first treatment period is at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.In some embodiments, the positive symptoms of the subject treated with the dosage form remain stable during the treatment period, i.e., remain at substantially the same level as baseline.In some embodiments, the level of improvement in negative symptoms is a decrease of at least 3 points in the negative symptom factor score of the five-factor PANSS (pentagonal structure model) after 12 weeks of treatment.In some embodiments, the negative symptom score of the subject continues to improve from 12 weeks to at least about 24, 36, or 48 weeks of treatment. The PANSS pentagonal structure model is described in White L, Harvey PD, Oppler L, Lindenmayer J. EMPIRICAL ASSESSMENT OF THE FACTORIAL STRUCTURE OF CLINICAL SYMPTOMS IN SCHIZOPHRENIA. PSYCHOPATHOLOGY. 1997;30(5):263-74.

[0274] In some embodiments, if the subject experiences an improvement in at least one negative symptom during the first treatment period, then administering a therapeutically effective amount of Compound (I) continues for a second treatment period of at least 12 weeks, at least 24 weeks, at least 48 weeks, or until the subject is determined to show functional improvement following the improvement in negative symptoms.In some embodiments, the positive symptoms in the subject treated with the dosage form remain stable, i.e., remain at substantially the same level as baseline, during at least a portion of the second treatment period.

[0275] In some embodiments, the subject has a diagnosis of schizophrenia. In some embodiments, the subject selected for treatment with the oral dosage form of the present disclosure has a baseline PANSS negative subscore of 20 or greater. In some embodiments, the selected subject also has a baseline score of less than 4 on the following PANSS items: agitation, hyperactivity, hostility, suspiciousness, uncooperativeness, and poor impulse control. In some embodiments, the selected schizophrenic subject has had stable positive symptoms of schizophrenia for at least the previous 1, 2, or 3 months and has had negative symptoms for at least the previous 1, 2, or 3 months.

[0276] In some embodiments, the schizophrenic subject treated with the gastro-resistant CR oral dosage form of the present disclosure has predominant negative symptoms.In some embodiments, a schizophrenic subject is defined as having predominant negative symptoms if the subject has a score of 4 or higher (moderate) in at least three subscale items of the PANSS negative symptoms subscale, but none of the PANSS positive symptoms subscale items.In some embodiments, a subject has both predominant positive symptoms and predominant negative symptoms if the subject has a score of 4 or higher in both the positive and negative symptom items.

[0277] Up to 75% of patients with schizophrenia suffer from cognitive impairment, and the Phase 2b study of MIN-101 discussed above showed improvements in cognitive function. Thus, in some embodiments, administration of the gastro-resistant CR oral dosage form of the present disclosure to a patient with a diagnosis of schizophrenia is intended to improve the patient's cognitive function.

[0278] In some embodiments, the subject has not previously been treated with an antipsychotic drug. In other embodiments, the subject has discontinued previous treatment with an antipsychotic drug due to experiencing one or more of the following: unsatisfactory reduction in positive symptoms, inadequate response to negative symptoms, or intolerable side effects.

[0279] A secondary outcome of the Phase 2b study of MIN-101 discussed above was patient performance on the Calgary Depression Rating Scale for Schizophrenia (CDSS). Addington D, Addington J, Maticka-Tyndale E. Assessing Depression in Schizophrenia: The Calgary Depression Scale. British Journal of Psychiatry Supplement 1993;(22):39-44. The CDSS has little overlap with positive and negative symptoms, making it the recommended rating scale for assessing the severity of depression in patients with schizophrenia. In the Phase 2b study, symptom severity as measured by the CDSS was reduced after treatment with 32 or 64 mg of MIN-101 compared with placebo. Analysis of the correlation between baseline treatment effects on negative symptoms and depressive symptoms in this patient cohort demonstrated that there was only a small correlation between the effects of MIN-101 on these two symptom categories. Thus, the effects of MIN-101 on negative and depressive symptoms in patients with schizophrenia are largely independent of each other, and MIN-101 has efficacy in alleviating one or more depressive symptoms in patients without schizophrenia.

[0280] Therefore, another object of the present disclosure is to treat at least one symptom of depression in a subject in need thereof by administering a gastro-resistant CR dosage form described herein. In some embodiments, the subject has a diagnosis of schizophrenia. In some embodiments, the improvement of depressive symptoms in schizophrenic patients is measured using CDSS.

[0281] It is another object of the present disclosure to reduce the risk of QT prolongation in a subject treated with Compound (I) by administering Compound (I) formulated in a gastro-resistant CR dosage form described herein to the subject. In some embodiments, the subject has been identified as having one or more risk factors for drug-induced QT prolongation. In some embodiments, the subject has discontinued previous treatment with a compound other than Compound (I) due to experiencing QT prolongation. In some embodiments, the subject has discontinued previous treatment with a different dosage form containing Compound (I) due to experiencing QT prolongation. In some embodiments, the subject has a diagnosis selected from the group consisting of predominant negative symptoms of schizophrenia, predominant positive symptoms and predominant negative symptoms of schizophrenia, major depressive disorder (MDD), sleep disorder, and cognitive impairment.

[0282] In some embodiments of any of the above methods of treatment, the gastro-resistant oral dosage form is administered in the morning or evening. In certain embodiments, the dosage form is administered at least 2 hours before a meal.

[0283] In some embodiments of any of the above treatment methods, the subject is 12 years of age or older. In some embodiments, the subject is at least 14, 16, 18, or 20 years of age. In some embodiments, the subject is under 50, 45, 40, 35, or 30 years of age. In certain embodiments, the subject is at least 16 years of age and under 40, 35, or 30 years of age.

[0284] In some embodiments of any of the above treatment methods, the dosage form may be administered to a subject in combination with another therapeutic agent. In some embodiments, the other therapeutic agent does not inhibit the activity of CYP2D6. In some embodiments, the subject is diagnosed with schizophrenia, and the other therapeutic agent is an antipsychotic drug.

[0285] In some embodiments of any of the above methods of treatment, the subject may be assigned to an IM genotype or and an EM genotype. In certain embodiments, the subject is assigned to an EM genotype.

[0286] In some embodiments of any of the above methods of treatment, the oral dosage form may comprise 32 mg of Compound (I). In certain embodiments, the oral dosage form consists essentially of the components listed in Table 2 or Table 3 below.

[0287] Example [Example]

[0288] Description of the 32mg MR tablet used in the Phase 2b clinical trial of MIN-101 MR 32 mg tablets are provided as round (10 mm diameter, R=10), white coated tablets with a good appearance. Each tablet contains 32 mg of Compound (I). A complete description of the ingredients and quantitative composition of MR 32 mg tablets is set forth in Table 1 below. Table 1: Composition of MR 32 mg tablets [Table 15] 1 Applied salt correction factor 1.2 NA: Not applicable [Example]

[0289] Description of an exemplary 32 mg gastroresistant CR tablet CR GR-01 tablets are provided as round (10 mm diameter, R=10) tablets with no visible defects. Each tablet contains 32 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-01 tablets is set forth in Table 2 below. Table 2: Composition of CR GR-01 tablets [Table 16] 1 Applied salt correction factor 1.2 NA: Not applicable [Example]

[0290] Description of another exemplary 32 mg gastroresistant CR tablet CR GR-02 tablets are provided as round (10 mm diameter, R=10) tablets with no visible defects. Each tablet contains 32 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-02 tablets is set forth in Table 3 below. Table 3: Composition of CR GR-02 tablets [Table 17] 1 Applied salt correction factor 1.2 NA: Not applicable [Example]

[0291] Batch formulation for CR GR-01 and CR GR-02 tablets A typical batch size for CR GR-01 and CR GR-02 tablets is 5,400 tablets. The batch formulations are set forth in Tables 4 and 5 below.

[0292] Table 4: Batch formulation for CR GR-01 tablets [Table 18] NA: Not applicable

[0293] Table 5: Batch formulation for CR GR-02 tablets [Table 19]

[0294] Table 5A: Batch formulation for GR-01 / B tablets (typical batch formulation size is 150,000 tablets) [Table 20] [Example]

[0295] Development of an optimized in vitro dissolution method Based on the pharmacokinetic profile of Compound (I) obtained using the MIN-101 MR 32 mg tablet used in clinical studies, we proposed an in vitro / in vivo correlation (IVIVC) method. The IVIVC method is defined by the FDA as a predictive mathematical model that describes the relationship between a dosage form's in vitro properties and its in vivo response. In this context, the model refers to the relationship between the in vitro dissolution of the MR 32 mg tablet and its in vivo response, such as the plasma concentration of Compound (I). The primary objective of the IVIVC model was to validate the use of predictive in vitro dissolution methods and to select target-optimized formulations. Once the validity of the IVIVC model is confirmed by clinical results, the in vitro dissolution method can be used as a surrogate method for clinical studies.

[0296] First, after analyzing all PK data for Compound (I) from clinical studies, the in vitro dissolution profile of the MR 32 mg tablet was defined as described in Example 1. This target in vitro dissolution profile was then used to develop an optimized in vitro dissolution method, which is described in the following example.

[0297] Second, and if the in vitro dissolution method is deemed sufficiently close to expectations, a target in vitro dissolution profile for the gastroresistant CR oral dosage form is defined and used to design the gastroresistant dosage form as described in Examples 2 and 3. The dissolution profiles for these two GR dosage forms (GR-01 and GR-02) and the MR 32 mg tablet of Example 1 were generated using the optimized dissolution method and are shown in Tables 6 and 7 below.

[0298] Table 6: Cumulative in vitro dissolution profile [Table 21]

[0299] Table 7: In vitro dissolution rate profile [Table 22] 1 Not considered

[0300] CR GR-01 and CR GR-02 tablets and MR 32 mg tablets, used as comparators, were tested in a clinical study (MIN-101-C06) to evaluate the plasma PK profile of each dosage form. [Example]

[0301] Analytical methods for assaying MIN-101, BFB-520, and BFB-999 in human plasma Preparation of solvents and reagents All solvents and reagents listed below are recognized as analytical grade or higher (pertaining to the entire document) The volumes are given as an example and different volumes may be prepared provided that the proportions are maintained. Dilution solvent: 50 / 50 (v / v) acetonitrile / water solution Mix 500 mL of acetonitrile with 500 mL of water. Storage: 1 month at room temperature Buffer solution: a buffer solution with a pH of 9 Transfer the contents of one ampoule of pH buffer concentrate (Merck, P / N 109889) to a 500 mL volumetric flask. Fill to 500 mL with water. Storage: 1 month at approximately +5°C. Buffer: 1M ammonium acetate buffer Dissolve 7.7 g of ammonium acetate in 100 mL of water. Storage: 3 months at approximately +5°C. Mobile phase: 10 mM ammonium acetate buffer solution Add 10 mL of 1 M ammonium acetate buffer to 990 mL of water. Alternatively, dissolve 0.77 g of ammonium acetate in 1 L of water. Degas if necessary (by sonication or by magnetic stirring under vacuum). Storage: At room temperature for 5 days. Reconstitution solvent: 80 / 20 (v / v) 10 mM ammonium acetate buffer / acetonitrile solution Mix 400 mL of 10 mM ammonium acetate buffer solution with 100 mL of acetonitrile. Alternatively, add 4 mL of 1 M ammonium acetate buffer to 396 mL of water and 100 mL of acetonitrile. Storage: At room temperature for 5 days. Needle rinsing solution: 80 / 20 (v / v) acetonitrile / water solution Mix 800 mL of acetonitrile with 200 mL of water. Degas if necessary (by sonication or by magnetic stirring under vacuum). Storage: 1 month at room temperature. Needle rinsing solution: 65 / 35 (v / v) acetonitrile / water solution Mix 650 mL of acetonitrile with 350 mL of water. Degas if necessary (by sonication or by magnetic stirring under vacuum). Storage: 1 month at room temperature. Column rinsing solution: 90 / 10 (v / v) acetonitrile / water solution Mix 900 mL of acetonitrile with 100 mL of water. Degas if necessary (by sonication or by magnetic stirring under vacuum). Storage: 1 month at room temperature. Sample preparation and extraction procedures Control plasma and plasma samples are thawed at room temperature and centrifuged at 1920 g for 5 minutes at +4°C. Sample preparation Blank reagent sample In a 10 mL polypropylene tube: 1. Transfer 250 μL of water. Blank and zero samples In a 10 mL polypropylene tube: 1. Transfer 250 μL of control plasma. Calibration Standards In a 1.5 mL conical polypropylene tube: 1. Transfer 900 μL of subject plasma. 2. Add 100 μL of the appropriate WS, 3. Mix on a vortex for 30 seconds. 4. Transfer 250 μL of the preparation to a 10 mL polypropylene tube. QC samples In a 1.5 mL conical polypropylene tube: 1. Transfer 900 μL of subject plasma. 2. Add 100 μL of the appropriate QC-WS, 3. Mix on a vortex for 30 seconds. 4. Transfer 250 μL of the preparation to a 10 mL polypropylene tube. specimen In a 10 mL polypropylene tube: 1. Transfer 250 μL of plasma sample. 20x diluted sample [2] In a 1.5 mL conical polypropylene tube: 1. Transfer 380 μL of control plasma, 2. Add 20 μL of the plasma sample to be diluted; 3. Mix on a vortex for 30 seconds. 4. Transfer 250 μL of the preparation to a 10 mL polypropylene tube. Extraction procedure 1. Add 25 μL of dilution solvent (blank reagent sample, blank sample) or 25 μL of IS-WS (other samples), 2. Add 1 mL of pH 9 buffer solution. 3. Mix on a vortex for 10 seconds. 4. Add 4 mL of diethyl ether 5. Mix on a reciprocating shaker at low speed for 20 minutes; 6. Centrifuge at 1920 g for 10 minutes at +4°C. 7. Transfer to a tube at approximately -80°C for 15 minutes. 8. Transfer the organic phase (upper layer) into a 5 mL glass tube. 9. Evaporate to dryness under a nitrogen stream at +30°C. 10. Reconstitute with 200 μL of reconstitution solvent. 11. Mix on a vortex for 30 seconds 12. Centrifuge at 1920g for 5 minutes at +4°C. 13. Transfer the final extract to a polypropylene vial. 14. Seal the vial using a cap with a Teflon / silicone / Teflon septum; 15. Centrifuge at 2500g for 7 minutes at +4°C. 16. Place the vial in the autosampler until analysis. or [4] 13. Transfer the final extract into a 2 mL polypropylene 96-well collection plate; 14. Seal the plate using a pre-perforated silicone cap mat. 15. Centrifuge at 2500g for 7 minutes at +4°C. 16. Place plate in autosampler until analysis.

[0302] [Table 23]

[0303] [Table 24]

[0304] [Table 25]

[0305] [Table 26]

[0306] [Table 27] [Example]

[0307] List of Protocol MIN-101 C06 Name of sponsor / company: Minerva Neurosciences, Inc. Name of the test drug: MIN-101 Study Title: A Phase 1, Open-Label, Randomized, 3-Treatment Sequence, 3-Period, Single-Dose, Crossover Study in Healthy CYP2D6 Extensive Metabolizers to Compare the Pharmacokinetic Properties of Two Gastro-Resistant and One Comparator Modified-Release Formulations of MIN-101 and Its Metabolites, with a Subsequent Food Effect Test of Selected Gastro-Resistant Controlled-Release Formulations the purpose: Primary: Part 1: Penalty rating To evaluate the pharmacokinetic (PK) profiles of MIN-101 and its major metabolites (BFB-520 and BFB-999) following administration of two gastrotolerance and one comparator modified-release (MR) formulations of MIN-101 in healthy male and female cytochrome P450 (CYP) 2D6 extensive metabolizer (EM) subjects. Select one gastroresistant MR formulation for use in the fed state. Part 2: The effects of diet To evaluate the effect of food (given as a high-fat, high-calorie meal) on the bioavailability of MIN-101 and its major metabolites when selected gastro-resistant MR formulations are administered as a single 32 mg dose to healthy CYP2D6 EM male and female subjects. secondary Part 1: Penalty rating · To provide additional information regarding the safety and tolerability of a single dose of MIN-101 in healthy male and female subjects with CYP2D6 EM. To evaluate the relationship between plasma levels of MIN-101 and its main metabolites on electrocardiogram (ECG) parameters, including QT / QTcF. Part 2: The effects of diet To evaluate the safety and tolerability of selected MR formulations in healthy male and female subjects with CYP2D6 EM in the fed state compared with the fasted state. Methodology: This is a single-center, two-part, phase 1 study. Part 1: Penalty rating Part 1 is an open-label, randomized, 3-treatment sequence, 3-period study to evaluate the PK profiles of MIN-101 and its major metabolites (BFB-520 and BFB-999) following single oral administration of three formulations of MIN-101: two prototype CR gastric resistant (GR) formulations and one comparator MR formulation. Each subject will receive a single dose of each formulation over three periods, with a 14±2 day washout between the three periods. A total of 16 healthy CYP2D6 EM male or female subjects (ideally with an equal gender split but a minimum of six subjects of each gender) will be dosed, with data available in 12 evaluable subjects. To be evaluable, subjects must receive all three formulations and have sufficient data for the primary objectives of this part of the study. Before any assessments are performed or any laboratory samples are collected, subjects must provide written informed consent to participate in the study. Subjects will be evaluated for study eligibility during a screening period. After written informed consent is obtained, a complete medical history will be documented. A complete physical examination will be performed, including vital signs, ECG (triplicate), weight, and height measurements. Hematology, clinical chemistry, and urinalysis will be performed on all subjects. All subjects must be willing to use an acceptable dual-barrier method of birth control with their partner from screening until 90 days after the final dose. Part 2: The effects of diet Subjects who complete Part 1 of the study will be returned to receive an additional single oral dose of one of the selected GR prototypes under fed conditions, allowing for evaluation of the effect of food by comparison of the PK characteristics to those obtained in Part 1. Part 2 will begin after review of PK and safety data to determine which GR formulation will be used. There will be a washout period of 14 ± 2 days after completion of Part 1. End-of-study or early withdrawal assessments will be performed 5-9 days after the last dose received. Number of targets (planned): In total, 16 healthy CYP2D6 EM male or female subjects (ideally with an equal gender split but a minimum of 6 of each gender) will be dosed, with data available in 12 evaluable subjects. Subjects who discontinue due to adverse events (AEs) not related to the IMP will be replaced as needed to ensure 12 evaluable subjects for Parts 1 and 2 at the end of the clinical study. Subjects who discontinue due to an AE related to the IMP will not be replaced. Key diagnostic and inclusion / exclusion criteria: Selection Criteria Subjects must meet all of the following inclusion criteria during screening to participate in the study: 1. At least one functional allele ( * 1, or * 2) but without a non-functional allele [ * 1 and * 2, as well as reduced-function alleles ( * 10. * 17 or * 41) means any combination of the following: Subjects defined as confirmed CYP2D6 extensive metabolizer genotypes are permitted by documented testing. 2. Subjects will provide voluntary, written, informed consent prior to any study-related procedures. 3. Must be between 18 and 45 years old (inclusive) 4. Subjects must be healthy males or females as indicated below: Clinical chemistry, hematology, and urinalysis tests must be within normal, acceptable limits (with the exception of potassium, magnesium, and calcium, which must be considered clinically significant for exclusion) and must be performed within 21 days of receiving the first dose of study drug. Body mass index between 18 and 30 kg / m 2Between (including both ends) · Normal vital signs after a 5-minute rest in the supine position: 〇 95 mmHg < Systolic blood pressure < 140 mmHg 〇 50 mmHg < Diastolic blood pressure < 90 mmHg 〇 50 bpm < Heart rate < 90 bpm 〇 A normal 12-lead ECG is defined as follows: P ≦ 120 ms, 120 ms < PR < 210 ms, QRS < 120 ms, QTc (Fridericia) ≦ 430 msec (male) and ≦ 440 msec (female) (incomplete right bundle branch block may be tolerated) 5. From 21 days before the first administration using IMP until release from the study (end of the 4th post-study medical follow-up period), agree to refrain from all pharmaceuticals, including over-the-counter and prescription medications (including vitamins and natural or herbal therapies, e.g., St. John’s Wort), except for those with permitted fetal restrictions as defined in Selection Criterion 6 6. The subject agrees to use the following methods of fetal restriction Female subjects of childbearing potential must intend to use two methods of contraception throughout the study and up to 30 days after study completion. One of these must be a very effective method defined as having a low failure rate (i.e., less than 1% per year) when used consistently and correctly The following very effective methods of contraception are permitted for this study: · Contraceptive surgery (i.e., tubal ligation / salpingectomy, hysterectomy for female subjects or partners; vasectomy for male subjects or partners) · Placement of an intrauterine contraceptive device or system · Hormonal contraception (implants, patches, injections) Note: Oral hormonal contraception is not approved for this study True sexual abstinence, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation), and commitments of sexual abstinence during investigational and drug-free periods are not acceptable methods of contraception when consistent with the subject's preferred normal lifestyle. The following acceptable methods can be used as a second form of contraception under study: Barrier methods for female subjects include spermicidal foams, gels, films, creams, or vaginal suppositories, along with the partner's use of condoms or the subject's use of an occlusive cap (diaphragm or cervical / fornix cap). Female subjects who were postmenopausal (defined as at least 1 year of spontaneous amenorrhea or at least 6 months of spontaneous amenorrhea confirmed by a follicle-stimulating hormone [FSH] result of 40 IU / mL or greater) were eligible for the study. Male target Male subjects who have contraceptives or partners of non-childbearing potential (including homosexuals) are required to use one method of contraception that prevents the partner's unintentional exposure to the study drug via semen (for male subjects, this must be a condom or the use of a partner's occlusive cap [diaphragm or cervical / fornix cap]). Male subjects with a partner of childbearing potential must be willing to use one barrier method of birth control (condoms or partner's use of an occlusive cap [diaphragm or cervical / fornix cap]) with their partner throughout the study. Their partner must also use a highly effective method of birth control, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as sterilization, implants, injectables, combined oral contraceptives, and intrauterine devices, for up to 90 days after completion of the study. Subjects must agree to inform the investigator if their partner becomes pregnant during this period. 7. Must be willing and able to communicate and participate throughout the study. 8. Willingness to consume all meals provided throughout the study Exclusion criteria Subjects who meet any of the following exclusion criteria should not participate in this study: 1. History of clinically significant gastrointestinal disease (especially peptic ulcer, gastrointestinal bleeding, ulcerative colitis, Crohn's disease or irritable bowel syndrome), renal, hepatic, neurological, hematological, endocrine, oncological, pulmonary, immune or psychiatric disease (especially those with a history of clinically significant depression, suicidal ideation or suicide attempt), or cardiovascular disease, or any other condition that, in the investigator's opinion, jeopardizes the subject's safety or affects the validity of the study results. 2. Acute diarrhea or constipation within 7 days prior to the expected first study date. If screening occurs more than 7 days prior to the first study date, this criterion will be determined on the first study date. Diarrhea is defined as passage of liquid stool and / or greater than 3 bowel movements per day. Constipation is defined as failure to have a bowel movement more frequently than every other day. 3. Subject has donated blood within 90 days or plasma within 30 days of study administration 4. Usual alcohol consumption for men is more than 21 units per week, and for women is more than 14 units per week (1 unit = 1 / 2 pint of beer, 25ml of 40% spirits, or 125ml of glass of wine). 5. Subject has a borderline or prolonged QTc Fridericia interval as defined by a screening reading of greater than 430 msec in men and greater than 440 in women or a personal or family history of long QT syndrome 6. Subject has participated in a clinical trial within 90 days prior to the start of the study. 7. Pregnant or breastfeeding women 8. Subject has used any prescription medication or over-the-counter (OTC) medication, including vitamin supplements, within 21 days prior to Day -1. 9. Subjects have been treated with any known P450 2D6 or 3A4 enzyme replacement medication (e.g., beta-blockers, antidepressants, antipsychotics, certain antibiotics, e.g., erythromycin, ketoconazole, rifampicin, trimethoprim, or clarithromycin, benzodiazepines such as alprazolam or midazolam, antihistamines such as chlorpheniramine, calcium channel blockers such as amlodipine or diltiazem, or PDE5 inhibitors) within 30 days prior to the study. 10. Subject smoked or used nicotine products within 2 months prior to or during the study. 11. Subject has received advice or been referred by a GP or counsellor about alcohol abuse or misuse, or misuse of non-medicinal, medicinal or other substances (e.g., solvents). 12. Subject has positive blood screening for HIV, Hepatitis B surface antigen (HBsAg), and Hepatitis C antibody 13. A positive urine screen for any current or previous use of drugs such as opiates, cocaine, ecstasy, or intravenous amphetamines and / or alcohol or drug abuse. Subjects who admit to past occasional use of cannabis are not excluded as long as they have a negative drug abuse screen and have abstained from cannabis use for at least three months. 14. Subject has currently uncontrolled intervening illness (i.e., active infection) or has had clinically significant illness within the last 30 days prior to Day -1 15. Subject has undergone major surgical procedures within 28 days of study entry or within 12 months prior to the study for gastrointestinal procedures. 16. Unable to satisfy the Investigator as to his or her fitness to participate for any other reason. Test product, dosage, and route of administration: Part 1: After a 10-hour overnight fast, the study drug will be administered with 240 mL of still water on the morning of dosing. Subjects will have their first meal at lunchtime. Subjects will receive a single oral dose of each of the following regimens in a randomized fashion, separated by a washout period of 14±2 days: Regimen A: 32 mg of MIN-101, the current modified-release formulation (comparator) specified as the MR formulation administered in the fasted state Regimen B: 32 mg of MIN-101 in a gastroresistant CR formulation identified as GR-01: administered in the fasted state Regimen C: 32 mg of MIN-101 in a gastroresistant CR formulation identified as GR-02: administered in the fasted state Part 2: In part 2, subjects receive a single oral dose of the selected gastro-resistant CR formulation (GR-01 or GR-02) in the fed state. After an overnight 10-hour fast, on the morning of Day 1, subjects will be given a high-fat, high-calorie breakfast before receiving study medication. Subjects will have 25 minutes or less to consume the meal. After completing the meal and 30 minutes after the start of the meal, study medication will be administered. All study medications will be administered orally with 240 mL of non-carbonated water. Water will be allowed as desired, except 1 hour before and 1 hour after drug administration. Reference therapy, dosage and mode of administration: Not applicable. 32 mg of the current modified-release formulation of MIN-101 used as the comparator. Subject participation period / study period / treatment period: choice: Up to 21 days before first dosing period 1 Institutional Treatment: - From the morning of Day 1 through Day 4 of four separate periods Washout period: 14±2 days from the previous administration period End-of-Study Visit: 7 (±2 days) after the last administration Overall study length (including 21-day screening period): Maximum 78 days. Evaluation criteria Pharmacokinetics: Plasma is stored at -80°C until analysis. Plasma samples are analyzed for MIN-101 and its metabolites BFB-520 and BFB-999 using a validated LC-MS / MS method. Blood samples for MIN-101 will be collected at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 48, 60, and 72 hours post-dose on Day 1 of the entire period. The following key plasma PK parameters will be calculated using non-compartmental methods: C max , T max , T lag , partial AUC (e.g., AUC 12 , AUC 24 ), AUC last , AUC ∞ , and t 1 / 2 Additional PK parameters may be included if deemed appropriate. ECG detailed when PK / PD evaluation exists Effects on cardiovascular variables will be assessed by tabulation of descriptive statistics and frequencies. These tabulations will include observed values ​​and changes from baseline (pre-dose ECG will be used as baseline), allowing for the detection of clinically relevant changes in individuals. The ECG variables analyzed are heart rate, PR interval, QRS interval, QT interval, and QTc interval corrected for heart rate using QTcF. QTcF values ​​are tabulated relative to their absolute values ​​and also relative to baseline measurements to detect individual QTcF changes. Descriptive statistics for QTcF interval and change from baseline will be summarized at each scheduled time point. The percentage of subjects with a QTc interval of greater than 450 ms, greater than 480 ms, or ≥500 ms will be summarized, as will the percentage of subjects with an increase in QTcF interval from baseline of 30 to 59 ms or ≥60 ms. Any significant abnormalities in the ECG waveform that are a change from the baseline reading will be reported (eg, changes in T wave morphology or the appearance of U waves). Safety and Tolerability: The incidence of adverse events and clinically significant abnormal laboratory, vital sign, and ECG values ​​will be recorded based on investigator observation and subject report. Statistical considerations Sample Size: The sample size for this study was based on both quantitative and qualitative considerations. In a previous single-dose study in EM subjects, plasma AUC and C were measured against the MIN-101 reference formulation. max The inter-subject coefficients of variation (CV) for MIN-101 and MIN-101 are estimated to be approximately 30% and 50%, respectively. Therefore, the selected sample size of 12 to 16 completers should be sufficient to address the objectives of this study and detect the occurrence of rare adverse events (such events tend to be attributable to treatment with MIN-101). Every effort will be made to have equal numbers of males and females participating. Pharmacokinetics: Pharmacokinetic parameters are summarized by the mean, standard deviation, standard error of the mean, coefficient of variation, minimum, median, and maximum values, as appropriate, for each formulation and among the MRs selected for each fed condition. Log-transformed partial AUC values ​​for plasma, AUC last , and AUC ∞ and C max 90% confidence intervals for the mean ratios of will be constructed using estimated least squares means and between-subject variability from the mixed effects model. Additional analyses, including the relationship between plasma levels of MIN-101 and its main metabolites and changes in QTcF interval, will be performed if deemed necessary. Safety: The safety and tolerability of MIN-117 will be based on review of individual values ​​and simple statistics. The incidence of treatment-emergent adverse events will be tabulated as numbers and percentages. Clinical laboratory, vital sign, and ECG abnormalities will be tabulated by dose group showing number of subjects and percentages based on predefined normal ranges.

[0308] Examples 8-11 detail an open-label, randomized, three-treatment sequence, three-period study to evaluate the PK profiles of MIN-101 and its metabolite BFB-520 after single oral administration of three formulations of MIN-101: two prototype CR gastric-resistant (GR) formulations (GR-01 and GR-02) and one comparator MR formulation (MR32). Each subject received a single dose of each formulation over three periods. There was a 14±2 day washout between the three periods.

[0309] The Examples provide various tables containing the plasma concentration time profiles of various compounds, including, for example, 1H-isoindol-1-one,2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, i.e., Compound (I). In these tables, the use of "MIN-101" or "MIN101" is intended to refer to the free base, i.e., Compound (I). [Example]

[0310] In vitro pharmacokinetic analysis of MIN-101 in CR GR-01 tablets, CR GR-02 tablets, and MR32 mg capsules (MR32) (tau = 72 hours) MR32 -12 subjects (crossover) Geometric mean C max :28.34ng / mL Median T max :2.00H AUC (0~tau) :291.55ng·H / mL Table 8. MR32 Mean MIN-101 Plasma Concentrations and Parameters [Table 28] See Figure 4.

[0311] GR-01 -12 subjects (crossover) Geometric mean C max :18.82ng / mL Median T max :4.50H AUC (0-tau) :284.52ng·H / mL Relative bioavailability vs. MR32:F% C max :69.9%, F% AUC (0-tau) :101.3% Table 9. GR-01 Individual MIN-101 Plasma Concentrations and Parameters [Table 29] Table 10. GR-01 Mean MIN-101 Plasma Concentrations and Parameters [Table 30] See Figure 5.

[0312] GR-02 -12 subjects (crossover) Geometric mean C max :15.43ng / mL Median T max :14.00H AUC (0-tau) :253.01ng·H / mL Relative bioavailability vs. MR32:F% C max :54.33%, F% AUC (0-tau) :86.9% Table 11. GR-02 Individual MIN-101 Plasma Concentrations and Parameters [Table 31] Table 12. GR-02 Mean MIN-101 Plasma Concentrations and Parameters [Table 32] See Figure 6.

[0313] Table 13. Comparison of MIN-101 plasma concentrations in MR32, GR-01, and GR-02 [Table 33] See Figure 7.

[0314] Table 14. Comparison of MIN-101 plasma concentrations in MR32, GR-01, and GR-02 - Percent increase or decrease [Table 34] During each time interval (dt), the plasma concentration (Cp) of MIN-101 increases or decreases. max Up to the rate of increase V max =d(Cp) / dt. V max After this, the rate of increase decreases. See Figure 8. [Example]

[0315] In vivo pharmacokinetic analysis (tau=72 hours) of BFB-520 in CR GR-01 tablets, CR GR-02 tablets, and MR 32 mg capsules (MR32) MR32 -12 subjects (crossover) Geometric mean C max :1.77ng / mL Median T max :6.00H AUC (0-tau) :30.26ng·H / mL Table 15. MR32 Individual BFB-520 Plasma Concentrations and Parameters [Table 35]

[0316] Table 16. MR32 Mean BFB-520 Plasma Concentrations and Parameters [Table 36] See Figure 9.

[0317] GR-01 -12 subjects (crossover) Geometric mean C max :1.77ng / mL Median T max :6.00H AUC (0-tau) :27.48ng·H / mL Relative bioavailability vs. MR32:F% C max :80.48%, F% AUC (0-tau) :96.1% Table 17. GR-01 Individual BFB-520 Plasma Concentrations and Parameters [Table 37]

[0318] Table 18. GR-01 Mean BFB-520 Plasma Concentrations and Parameters [Table 38] See Figure 10.

[0319] GR-02 -12 subjects (crossover) Geometric mean C max :1.13ng / mL Median T max :16.00H AUC (0-tau) :27.53ng·H / mL Relative bioavailability vs. MR32:F% C max :69.48%, F% AUC (0-tau) :88.46% Table 19. GR-02 Individual BFB-520 Plasma Concentrations and Parameters [Table 39]

[0320] Table 20. GR-02 Mean BFB-520 Plasma Concentrations and Parameters [Table 40] See Figure 11.

[0321] Table 21. Comparison of BFB-520 plasma concentrations in MR32, GR-01, and GR-02 [Table 41] See Figure 12.

[0322] Table 22. Comparison of BFB-520 plasma concentrations in MR32, GR-01, and GR-02 - Percent increase or decrease [Table 42] During each time interval (dt), the plasma concentration (Cp) of BFB-520 increases or decreases. max Up to the rate of increase V max =d(Cp) / dt. V max After this, the rate of increase decreases. See Figure 13. [Example]

[0323] Predicted plasma concentrations of MIN-101 and BFB-520 at steady state for MR32 and GR-01 tablets (32 and 64 mg)

[0324] Table 23. Predicted Plasma Concentrations of MIN-101 at Steady State for MR32 and GR-01, 32 mg Tablets [Table 43] See Figure 14.

[0325] Table 24. Predicted Plasma Concentrations of BFB-520 at Steady State for MR32 and GR-01, 32 mg Tablets [Table 44] See Figure 15.

[0326] Table 25. Predicted Plasma Concentrations of MIN-101 at Steady State for MR32 and GR-01, 64 mg Tablets [Table 45] See Figure 16.

[0327] Table 26. Predicted Plasma Concentrations of BFB-520 at Steady State for MR32 and GR-01, 64 mg Tablets [Table 46] See Figure 17. [Example]

[0328] Predicted plasma concentrations of MIN-101 and BFB-520 at steady state for MR32 and GR-02 tablets (32 and 64 mg)

[0329] Table 27. Predicted Plasma Concentrations of MIN-101 at Steady State for MR32 and GR-02, 32 mg Tablets [Table 47] See Figure 18.

[0330] Table 28. Predicted Plasma Concentrations of BFB-520 at Steady State for MR32 and GR-02, 32 mg Tablets [Table 48] See Figure 19.

[0331] Table 29. Predicted Plasma Concentrations of MIN-101 at Steady State for MR32 and GR-02, 64 mg Tablets [Table 49] See Figure 20.

[0332] Table 30. Predicted Plasma Concentrations of BFB-520 at Steady State for MR32 and GR-02, 64 mg Tablets

[0333] [Table 50] See Figure 21.

[0334] Examples 12-15 detail the evaluation (or prediction) of the PK profile of GR-01 formulations in healthy CYP2D6 EM male and female subjects in the fed and fasted states. Subjects who completed Part 1 of the study (evaluation of the PK profiles of MIN-101 and its metabolite BFB-520 in GR-01, GR-02, and MR32 formulations) returned and further received a single oral dose of GR-01 under fed or fasted conditions to allow for evaluation of the food effect by comparing the PK profiles with those obtained in Part 1 (Examples 9-12). Part 1 was followed by a washout period of 14 ± 2 days. [Example]

[0335] In vivo pharmacokinetic analysis of MIN-101 in CR GR-01 tablets in subjects in fed vs. fasted states (tau=72 hours) Feeding condition - 12 subjects (crossover) Geometric mean C max :19.70ng / mL T max :12.00H AUC (0-tau) :269.19ng·H / mL

[0336] Table 31. CR GR-01 Individual MIN-101 Plasma Concentrations and Parameters (Fed State) [Table 51]

[0337] Table 32. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fed State) [Table 52] See Figure 22.

[0338] Fasting condition - 12 subjects (crossover) Geometric mean C max :18.82ng / mL Median T max :4.50H AUC (0-tau) :284.52ng·H / mL Table 33. CR GR-01 Individual MIN-101 Plasma Concentrations and Parameters (Fasting State) [Table 53]

[0339] Table 34. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fasting State) [Table 54] See Figure 23.

[0340] Table 35. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fed vs. Fasted State) [Table 55]

[0341] Relative bioavailability of MIN-101 in the GR-01 formulation in fed vs. fasted states: F% C max :108.97% F% AUC (0-tau) :95.14% See Figure 24. [Example]

[0342] In vivo pharmacokinetic analysis of BFB-520 in CR GR-01 tablets in subjects in fed vs. fasted states (tau=72 hours) Fasting condition - 12 subjects (crossover) Geometric mean C max :1.54ng / mL Median T max :18.00H AUC (0-tau) :30.12ng·H / mL

[0343] Table 36. CR GR-01 Individual BFB-520 Plasma Concentrations and Parameters (Fed State) [Table 56]

[0344] Table 37. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fed State) [Table 57] See Figure 25.

[0345] Fasting condition - 12 subjects (crossover) Geometric mean C max :1.32ng / mL Median T max :12.5H AUC (0-tau) :27.48ng·H / mL Table 38. CR GR-01 Individual BFB-520 Plasma Concentrations and Parameters (Fasting State) [Table 58]

[0346] Table 39. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fasting State) [Table 59] See Figure 26.

[0347] Table 40. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fed vs. Fasted State) [Table 60]

[0348] Relative bioavailability of BFB-520 in the GR-01 formulation in fed vs. fasted states: F% C max :121.32% F% AUC (0-tau) :111.58% See Figure 27. [Example]

[0349] Predicted food effect on steady-state plasma concentrations of MIN-101 and BFB-520 in GR-01 tablets (32 mg) Determination of the elimination slope from the mean plasma concentration-time curve before numerical calculation MIN-101 Feeding status: K e =0.119 / hour Fasting state: K e =0.082 / hour BFB-520: Feeding status: 14-28 hours during the flip-flop period K e = 0.014 / hr; Post-absorption K e =0.233 / hour Fasting state: 14 to 28 hours during the flip-flop period K e = 0.005545 / hour; Post-absorption K e =0.1586 / hour

[0350] Table 41. Predicted Plasma Concentrations of MIN-101 at Steady State (Fed and Fasted States) for GR-01, 32 mg Tablets [Table 61] See Figure 28.

[0351] Table 42. Predicted Plasma Concentrations of BFB-520 at Steady State (Fed and Fasted States) for GR-01, 32 mg Tablets [Table 62] See Figure 29. [Example]

[0352] Predicted food effect on steady-state plasma concentrations of MIN-101 and BFB-520 in GR-01 tablets (64 mg) Determination of the elimination slope from the mean plasma concentration-time curve before numerical calculation MIN-101 Fasting state: K e =0.119 / hour Fasting state: K e =0.082 / hour BFB-520: Feeding status: 14-28 hours during the flip-flop period K e = 0.014 / hr; Post-absorption K e =0.233 / hour Fasting state: 14 to 28 hours during the flip-flop period K e = 0.005545 / hour; Post-absorption K e =0.1586 / hour

[0353] Table 43. Predicted Plasma Concentrations of MIN-101 at Steady State (Fed and Fasted Conditions) for GR-01, 64 mg Tablets [Table 63] See Figure 30.

[0354] Table 44. Predicted Plasma Concentrations of BFB-520 at Steady State (Fed and Fasted States) for GR-01, 64 mg Tablets [Table 64] See Figure 31. [Example]

[0355] Description of 32mg gastro-resistant CR tablets (GR 01 / B-32mg) CR GR-01 / B tablets are supplied as round (10 mm diameter and R=10) tablets with no visible defects. Each tablet contains 32 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-01 tablets is set forth below in Table 45.

[0356] Table 45: Composition of CR GR-01 / B 32 mg tablets [Table 65] 1 Applied salt correction factor 1.2 [Example]

[0357] Description of 64mg gastro-resistant CR tablets (GR 01 / B-64mg) CR GR-01 / B tablets are supplied as round (10 mm diameter and R=10) tablets with no visible defects. Each tablet contains 64 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-01 / B tablets is set forth below in Table 46.

[0358] Table 46: Composition of CR GR-01 / B 64 mg tablets [Table 66] 1 Applied salt correction factor 1.2 [Example]

[0359] Comparison of GR-01 32mg tablets, GR-01 / B 32mg tablets, and GR-01 / B 64mg tablets

[0360] Table 47: Tablet composition: GR01 vs. GR01 / B [Table 67] 1 Applied salt correction factor 1.2 [Example]

[0361] Stability Data Study: Comparison of GR-01 and GR-01 / B 32mg Tablets "Impurity A," "2-isomer," and "PMIC" refer to impurities from the manufacturing process of MIN-101.

[0362] Table 48: Stability data at 25°C / 60%RH [Table 68]

[0363] Table 49: Stability data at 40°C / 75%RH [Table 69] [Example]

[0364] In vitro dissolution characteristics of GR-01 / B tablets

[0365] Table 50: Dissolution characteristics of GR-01 / B tablets [Table 70] [Example]

[0366] Description of 32mg gastro-resistant CR tablets (GR-01 / C-32mg) CR GR-01 / C tablets are supplied as round (10 mm diameter, R=10) tablets with no visible defects. Each tablet contains 32 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-01 / C tablets is set forth below in Table 51.

[0367] Table 51: Composition of CR GR-01 / C 32 mg tablets [Table 71] [Example]

[0368] Description of 64mg gastro-resistant CR tablets (GR-01 / C-64mg) CR GR-01 / C tablets are supplied as round (10 mm diameter, R=10) tablets with no visible defects. Each tablet contains 64 mg of Compound (I). A complete description of the ingredients and quantitative composition of CR GR-01 / C tablets is set forth below in Table 53.

[0369] Table 53: Composition of CR GR-01 / C 64 mg tablets [Table 72]

[0370] Equivalents and Incorporation by Reference The dosage forms, compositions, and methods of the present disclosure have been described herein with reference to certain preferred embodiments, however, the present disclosure should not be construed as limited thereto, as certain variations thereon will be apparent to those of ordinary skill in the art based on the disclosure set forth herein.

[0371] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and claims, the singular forms "a," "an," and "the" also include the plural unless the context clearly dictates otherwise.

[0372] It should be understood that at least some of the descriptions of the present disclosure have been simplified to focus on elements relevant to a clear understanding of the present disclosure, while other elements that one skilled in the art would recognize may also form part of the present disclosure have been excluded for clarity. However, because such elements are well known in the art and because they do not necessarily facilitate a fuller understanding of the present disclosure, descriptions of such elements are not provided herein.

[0373] Furthermore, to the extent that the method does not rely on the particular order of steps set forth herein, the particular order of steps recited in a claim should not be construed as a limitation on that claim.

[0374] All patents, patent applications, references, and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure.

Claims

1. i. about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and ii. at least one controlled release agent 1. A gastroresistant controlled release dosage form comprising:

2. Upon oral administration to a subject, the T ｍａｘ 2. The gastroresistant controlled release dosage form of claim 1, which produces a plasma pharmacokinetic profile for compound (I) comprising:

3. 2. The gastric resistant controlled release dosage form of claim 1, wherein the amount of compound (I) is 4 mg to 8 mg, 8 mg to 16 mg, 16 mg to 32 mg, 32 mg to 40 mg, 40 mg to 64 mg, 64 mg to 80 mg, or 80 mg to 100 mg.

4. When the amount of compound (I) is 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg 2. The gastric resistant controlled release dosage form of claim 1, wherein the active ingredient is 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg.

5. 2. The gastric resistant controlled release dosage form of claim 1, wherein the amount of compound (I) is 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, 64 mg, 80 mg, 96 mg, or 100 mg.

6. The amount of compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC of compound (I) is ０～４Ｈ About 68 hours ＊ 6. The gastric resistant controlled release dosage form according to claim 1, wherein the saturation of the gastric acid in the gastrointestinal tract is less than 100 ng / mL.

7. The amount of compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the C of compound (I) ｍａｘ 6. The gastric resistant controlled release dosage form of claim 1, wherein the NADH is less than about 16 ng / mL, 17 ng / mL, 18 ng / mL, 19 ng / mL, 20 ng / mL, 21 ng / mL, 22 ng / mL, or 23 ng / mL.

8. The amount of compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC of compound (I) is ０～２４ｈｒ But about 75 hours ＊ ng / mL to approximately 350 hours ＊ ng / mL or about 100 hours ＊ ng / mL to approximately 300 hours ＊ 6. The gastric resistant controlled release dosage form according to claim 1, wherein the saturation of the gastric acid in the gastrointestinal tract is between 1000 and 1500 ng / mL.

9. The amount of compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma pharmacokinetic profile of the BFB-520 metabolite of compound (I) is less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. ｍａｘ 6. The gastroresistant controlled release dosage form according to claim 1, comprising:

10. The amount of compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC of compound (I) is ０～４Ｈ but about 50, 60, 70, 80, 90, 100, 110, 120, or 130 hours ＊ 6. The gastric resistant controlled release dosage form according to claim 1, wherein the saturation of the gastric acid in the gastrointestinal tract is less than 100 ng / mL.

11. The amount of compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the C of compound (I) ｍａｘ 6. The gastric resistant controlled release dosage form according to claim 1, wherein the saturation level is less than about 36 ng / mL or less than about 25 ng / mL.

12. The amount of compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC of compound (I) is ０～２４ｈｒ About 200 hours ＊ ng / mL to approximately 600 hours ＊ 6. The gastric resistant controlled release dosage form according to claim 1, wherein the saturation of the gastric acid in the gastrointestinal tract is between 1000 and 1500 ng / mL.

13. The amount of compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma pharmacokinetic profile of the BFB-520 metabolite of compound (I) is less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, or less than 2.5 ng / mL. ｍａｘ 6. The gastroresistant controlled release dosage form according to claim 1, comprising:

14. 14. A gastroresistant controlled release dosage form according to any one of claims 1 to 13, which is a tablet comprising a core tablet and an enteric coating.

15. 15. A gastroresistant controlled release dosage form according to claim 14, wherein the core tablet of the dosage form comprises compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, and a controlled release agent.

16. 16. The gastroresistant controlled release dosage form according to claim 15, wherein the core tablet further comprises a filler, a glidant, and a lubricant.

17. 15. The gastroresistant controlled release dosage form of claim 14, wherein the core tablet of the dosage form comprises compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled release agent, a filler, a glidant, and a lubricant.

18. 18. A gastroresistant controlled release dosage form according to any one of claims 15 to 17, wherein the controlled release agent in the core tablet comprises one or more hypromelloses.

19. 19. The gastric resistant controlled release dosage form of any one of claims 15 to 18, wherein the controlled release agent in the core tablet comprises a mixture of (i) low-viscosity hypromellose having a viscosity of between about 15 millipaque seconds (mPa-sec) and about 100 mPa-sec and (ii) high-viscosity hypromellose having a viscosity of about 100,000 mPa-sec, each of the low-viscosity hypromellose and high-viscosity hypromellose being controlled-release or sustained-release grade and further characterized by a methoxy content of 19.0% to 24.0% and a hydroxypropoxy content of 4.0% to 12.0%.

20. 18. The gastroresistant controlled release dosage form according to claim 16 or 17, wherein the lubricant in the core tablet is anhydrous colloidal silica.

21. 18. A gastroresistant controlled release dosage form according to claim 16 or 17, wherein the lubricant in the core tablet is magnesium stearate.

22. 15. A gastroresistant controlled release dosage form according to claim 14, wherein the enteric coating of the dosage form comprises at least one polymeric controlled release agent having dissolution properties above pH 5.5, 6.0 or 6.5, and an anti-adherent agent.

23. 23. The gastroresistant controlled-release dosage form according to claim 22, wherein the enteric coating of the dosage form further comprises a plasticizer.

24. 24. The gastroresistant controlled release dosage form according to claim 22 or 23, wherein the polymeric controlled release agent comprises Eudragit L30D55.

25. 24. The gastroresistant controlled release dosage form according to claim 22 or 23, wherein the anti-adherent agent is Plasacryl HTP20.

26. about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w of hypromellose (Metolose® 90SH K15M 100 SR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and About 0.5 to about 5% w / w of Plasacryl HTP20 1. A gastroresistant controlled release dosage form comprising:

27. about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Metolose® 90SH K15M 100 SR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w microcrystalline cellulose; Approximately 19% w / w lactose monohydrate about 0.5% w / w of anhydrous colloidal silica; Approximately 1% magnesium stearate; about 5% w / w of Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 27. The gastroresistant controlled release dosage form of claim 26, comprising:

28. about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w of hypromellose (Methocel™ K15M CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate; about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% w / w magnesium stearate; about 1 to about 10% Eudragit L30D55; about 0.5 to about 5% w / w of Plasacryl HTP20; and about 0.5 to about 5% w / w of Surelease E-7-19040 1. A gastroresistant controlled release dosage form comprising:

29. about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Methocel™ K15M CR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w microcrystalline cellulose; About 19% w / w lactose monohydrate; about 0.5% w / w of anhydrous colloidal silica; about 1% w / w magnesium stearate; about 5% w / w Eudragit L30D55; about 1% w / w of Plasacryl HTP20; and Approximately 1% w / w of Surelease E-7-19040 29. The gastroresistant controlled release dosage form of claim 28, comprising:

30. about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w of hypromellose (Methocel™ K100LV CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w microcrystalline cellulose; about 13 to about 23% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and About 0.5 to about 5% w / w of Plasacryl HTP20 1. A gastroresistant controlled release dosage form comprising:

31. about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Methocel™ K100LV CR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w microcrystalline cellulose; About 19% w / w lactose monohydrate; about 0.5% w / w of anhydrous colloidal silica; about 0.5% w / w magnesium stearate; about 5% w / w of Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 31. The gastroresistant controlled release dosage form of claim 30, comprising:

32. about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Methocel™ K100LV CR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w microcrystalline cellulose; About 19% w / w lactose monohydrate; about 0.5% w / w of anhydrous colloidal silica; about 1% w / w magnesium stearate; about 5% w / w of Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 31. The gastroresistant controlled release dosage form of claim 30, comprising:

33. about 19 to about 29% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 4 to about 14% w / w of hypromellose (Methocel™ K100LV CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 19 to about 29% w / w microcrystalline cellulose; about 8 to about 18% w / w lactose monohydrate about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and About 0.5 to about 5% w / w of Plasacryl HTP20 1. A gastroresistant controlled release dosage form comprising:

34. about 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Methocel™ K100LV CR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); About 24% w / w microcrystalline cellulose; About 13% w / w lactose monohydrate; about 0.5% w / w of anhydrous colloidal silica; about 0.5% w / w magnesium stearate; about 5% w / w of Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 34. The gastroresistant controlled release dosage form of claim 33, comprising:

35. about 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; About 9% w / w of hypromellose (Methocel™ K100LV CR); Approximately 23% w / w of hypromellose (Methocel™ K100M CR); About 24% w / w microcrystalline cellulose; About 13% w / w lactose monohydrate; about 0.5% w / w of anhydrous colloidal silica; about 1% w / w magnesium stearate; about 5% w / w of Eudragit L30D55; and Approximately 1% w / w of Plasacryl HTP20 34. The gastroresistant controlled release dosage form of claim 33, comprising:

36. 40. A method of reducing the risk of QT prolongation when treating a subject with compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, comprising oral administration to the subject of a gastroresistant controlled-release dosage form of any one of claims 1 to 35.

37. 36. A method of treating negative symptoms in a subject, comprising oral administration of a gastro-resistant controlled release dosage form according to any one of claims 1 to 35 to the subject, wherein the subject has a diagnosis of schizophrenia.

38. 38. The method of claim 36 or 37, wherein the gastroresistant controlled release dosage form is administered once daily.

39. 39. The method of claim 37 or 38, wherein the subject with a diagnosis of schizophrenia has the CYP2D6 EM genotype.

40. 40. The method of any one of claims 36 to 39, wherein the subject is in a fed state prior to oral administration of the dosage form.

41. 40. The method of any one of claims 36 to 39, wherein the subject is in a fasted state prior to oral administration of the dosage form.

42. 36. A gastroresistant controlled release dosage form according to any one of claims 1 to 35 for use in reducing the risk of QT prolongation.

43. 36. A gastroresistant controlled release dosage form according to any one of claims 1 to 35 for use in treating negative symptoms in a subject with a diagnosis of schizophrenia.

44. 44. A gastroresistant controlled release dosage form for use according to claim 42 or 43, to be administered once daily.

45. 45. A gastro-resistant controlled release dosage form for use according to claim 43 or 44, wherein the subject with a diagnosis of schizophrenia has the CYP2D6 EM genotype.

46. 46. ​​A gastro-resistant controlled release dosage form for use according to any one of claims 42 to 45, wherein the subject is in a fed state prior to oral administration of the dosage form.

47. 46. ​​A gastroresistant controlled release dosage form for use according to claims 42 to 45, wherein the subject is in a fasted state prior to oral administration of the dosage form.

48. 40. Use of a gastroresistant controlled release dosage form according to any one of claims 1 to 35 in the manufacture of a medicament for reducing the risk of QT prolongation.

49. 40. Use of a gastroresistant controlled release dosage form according to any one of claims 1 to 35 in the manufacture of a medicament for the treatment of negative symptoms in a subject with a diagnosis of schizophrenia.

50. 50. The use according to claim 48 or 49, wherein the gastroresistant controlled release dosage form is administered once daily.

51. 51. The use of claim 49 or 50, wherein the subject with a diagnosis of schizophrenia has the CYP2D6 EM genotype.

52. 52. The use of any one of claims 48 to 51, wherein the subject is in a fed state prior to oral administration of the dosage form.

53. 52. The use of any one of claims 48 to 51, wherein the subject is in a fasted state prior to oral administration of the dosage form.

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