GASTRO-RESISTANT ORAL AND CONTROLLED-RELEASE DOSAGE FORMS.

Abstract

This description relates to gastro-resistant controlled-release dosage forms comprising Compound (I): (see Formula) (I), or a pharmaceutically acceptable salt and / or solvate thereof, the pharmacokinetic properties of these dosage forms, and their preparation. The novel dosage forms described herein are useful for reducing the risk of QT prolongation in a subject and for treating a disorder in a subject in need, e.g., a subject diagnosed with schizophrenia, for example, in the treatment of negative symptoms in a subject diagnosed with schizophrenia who has the CYP2D6 EM genotype.

Description

ORAL AND CONTROLLED-RELEASE DOSAGE FORMS GASTRORESISTANT bRpznn / eznz / B / Yi RELATED APPLICATIONS This application claims priority and benefit from U.S. provisional application no. 62 / 523,204, filed on June 21, 2017. Its contents are incorporated herein in full by reference. FIELD OF DESCRIPTION This description generally refers to gastro-resistant (GR) controlled-release (CR) oral dosage forms that reduce the risk of QT prolongation in patients treated with the compound identified as 1 H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), and to the use of these dosage forms for treating schizophrenia and other diseases. BACKGROUND The QT interval is a measure of the duration of ventricular depolarization and repolarization. Prolongation of the QT interval, called QT prolongation, can increase the risk of ventricular arrhythmias, including torsades de pointes (TdP). Because several drugs have been shown to induce QT prolongation, the development of new drugs typically includes evaluating their QT prolongation potential. Minerva Neurosciences, Inc. (Waltham, MA) is developing an investigational drug, roluperidone hydrochloride, codenamed MIN-101, for the treatment of 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-isoindole-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2). Formula I below shows the structure of the free base (Compound (I)): As described in U.S. Patent No. 9,458,130, the contents of which are incorporated herein in their entirety, QT prolongation has been observed in patients treated with MIN-101 that appears to be related to plasma levels of Compound (I) and, more specifically, to a metabolite identified as BFB-520. Patent 130 describes that the QT prolongation induced by MIN-101 administration can be reduced by administering this agent in a modified-release (MR) formulation that provides a maximum plasma concentration (Cmax) of Compound (I) and BFB-520 below 80 ng / mL and 12 ng / mL, respectively. However, there is a need for a formulation that further reduces the potential for QT prolongation following oral administration of MIN-101 in the fasted or fed state, while simultaneously maintaining a therapeutically effective level of Compound (I) over a dosing interval. COMPENDIUM The present description is based, in part, on the finding that minimizing the release of Compound (I) during the first four hours after oral administration of a dosage form comprising Compound (I) is a key factor in maintaining low plasma levels of BFB-520. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 2 mg to about 200 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 2 mg to about 200 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 4 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from 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. bRpznn / eznz / B / Yi In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from 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; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 1 hour and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 1.5 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 2 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 2.5 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from 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; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 3 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 3.5 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. from about 4 mg to about 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 4 hours and about 22 hours. In one aspect, the present description provides a gastro-resistant controlled-release dosage form comprising Compound (I), wherein the amount of Compound (I) is from 4 mg to 8 mg, from 8 mg to 16 mg, from 16 mg to 32 mg, from 32 mg to 40 mg, from 40 mg to 64 mg, from 64 mg to 80 mg or from 80 mg to 100 mg. In one aspect, the present description provides a gastro-resistant 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 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, 93mg, 94mg, 95 mg,96 mg, 97 mg, 98 mg, 99 mg or 100 mg. bRpznn / eznz / B / Yi In one respect, the present description provides a gastro-resistant 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. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. about 32 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. about 32 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 4 hours and about 22 hours. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. about 64 of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: i. about 64 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof; and i. at least one controlled-release agent; where the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of between about 4 hours and about 22 hours. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the AUCcmh of Compound (I) is less than about 68 h*ng / mL. In one aspect, the present description provides gastro-resistant controlled-release dosage forms comprising the Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 16 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 17 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 18 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 19 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 20 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 21 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 22 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the Cmax of Compound (I) is less than about 23 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the 24h AUCo of Compound (I) is between about 50 h*ng / mL and about 400 h*ng / mL. In one aspect, the present description provides gastro-resistant controlled-release dosage forms bRpznn / eznz / B / Yi comprising the Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the 24h AUCo of Compound (I) is between about 75 h*ng / mL and about 350 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the 24h AUCo of Compound (I) is between about 75 h*ng / mL and about 300 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the 24h AUCo of Compound (I) is between about 100 h*ng / mL and about 300 h*ng / mL. In one aspect, the present description provides gastro-resistant controlled-release dosage forms comprising the Compound (I) described herein, wherein the amount of Compound (I) is about 32 mg and the plasma pharmacokinetic profile for the metabolite BFB-520 of Compound (I) comprises a Cmax 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. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the 4h AUCo of Compound (I) is less than about 50 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 60 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 70 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 80 h*ng / mL. In one aspect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 90 ng / ml. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 100 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCcmh of Compound (I) is less than about 110 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 120 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the AUCo-4h of Compound (I) is less than about 130 h*ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the Cmax of Compound (I) is less than about 36 ng / mL or less than about 25 ng / mL. In one respect, the present description provides gastro-resistant controlled-release dosage forms comprising Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the 24h AUCo of Compound (I) is between about 200 h*ng / ml_ and about 600 h*ng / ml_. In one aspect, the present description provides gastro-resistant controlled-release dosage forms comprising the Compound (I) described herein, wherein the amount of Compound (I) is about 64 mg and the plasma pharmacokinetic profile for the metabolite BFB-520 of Compound (I) comprises a Cmax 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. In one embodiment, the gastro-resistant controlled-release dosage forms described herein are in the form of a tablet comprising a tablet core and an enteric coating. In one embodiment, the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, and a controlled-release agent. In one embodiment, the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled-release agent, a filler, a gluing agent, and a lubricant. In one embodiment, the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled-release agent, a filler, a gluent, a lubricant, and a coating. In one embodiment, the controlled-release agent in the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises one or more hypromellose molecules. In one embodiment, the controlled-release agent in the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises one or more hypromellose compounds 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 equivalent grade. In one embodiment, the controlled-release agent in the tablet core of the gastro-resistant controlled-release dosage forms described herein comprises a mixture of (i) a low-viscosity hypromellose with a viscosity of between about 15 millipascal-seconds (mPa-s) and about 100 mPa-s and (ii) a high-viscosity hypromellose with a viscosity of about 100,000 mPa-s, wherein each of the low- and high-viscosity hypromelloses is of a controlled-release or sustained-release grade and is further characterized by a methoxy content of 19.0% to 24.0% and a hydroxypropoxy content of 4.0% to 12.0%. In one embodiment, the slider in the tablet core of the gastro-resistant controlled-release dosage forms described herein is anhydrous colloidal silica. In one embodiment, the lubricant in the tablet core of the gastro-resistant controlled-release dosage forms described herein is magnesium stearate. In one embodiment, the enteric coating of the gastro-resistant controlled-release dosage forms described herein comprises at least one polymeric controlled-release agent with a dissolving property with a pH of more than 5.5, 6.0 or 6.5, and an anti-adherent agent. In one embodiment, the enteric coating of the gastro-resistant controlled-release dosage forms described herein further comprises a plasticizer. bRpznn / eznz / B / Yi In one embodiment, the polymeric controlled-release agent of the enteric coating of the gastro-resistant controlled-release dosage forms described herein comprises Eudragit L30D55. In one embodiment, the anti-adherent agent of the enteric coating of the gastro-resistant controlled-release dosage forms described herein is Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: of about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; from about 4 to about 14% w / w hypromellose (Metolose® 90SH Κ15M 100 SR); of about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); of around 25 to around 35% w / w of microcrystalline cellulose; from around 13 to around 23% w / w of lactose monohydrate; from about 0.1 to about 4% w / w of anhydrous colloidal silica; from about 0.1 to about 4% magnesium stearate; of about 1 to about 10% w / w of Eudragit L30D55; and of about 0.5 to about 5% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: approximately 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 9% w / w hypromellose (Metolose® 90SH K15M 100 SR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; about 1% magnesium stearate; approximately 5% w / w of Eudragit L30D55; and approximately 1% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: of about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; of about 4 to about 14% w / w of hypromellose (Methocel™ Κ15M CR); of about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); bRpznn / eznz / B / Yi of around 25 to around 35% w / w of microcrystalline cellulose; from around 13 to around 23% w / w of lactose monohydrate; from about 0.1 to about 4% w / w of anhydrous colloidal silica; from about 0.1 to about 4% w / w of magnesium stearate; from about 1 to about 10% of Eudragit L30D55; of about 0.5 to about 5% w / w of Plasacryl HTP20; and of about 0.5 to about 5% w / w of Surelease E-7-19040. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: approximately 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; approximately 9% w / w of hypromellose (Methocel™ K15M CR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; approximately 1% w / w of magnesium stearate; approximately 5% w / w of Eudragit L30D55; about 1% w / w of Plasacryl HTP20; and about 1% w / w of Surelease E-7-19040. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: of about 7 to about 17% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; of about 4 to about 14% w / w of hypromellose (Methocel™ K100LV CR); of about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); of around 25 to around 35% w / w of microcrystalline cellulose; from around 13 to around 23% w / w of lactose monohydrate; from about 0.1 to about 4% w / w of anhydrous colloidal silica; from about 0.1 to about 4% magnesium stearate; of about 1 to about 10% w / w of Eudragit L30D55; and of about 0.5 to about 5% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: about 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate of bRpznn / eznz / B / Yi; about 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; approximately 0.5% w / w magnesium stearate; approximately 5% w / w of Eudragit L30D55; and approximately 1% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: approximately 12% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 30% w / w microcrystalline cellulose; approximately 19% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; approximately 1% w / w of magnesium stearate; approximately 5% w / w of Eudragit L30D55; and approximately 1% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: of about 19 to about 29% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; of about 4 to about 14% w / w of hypromellose (Methocel™ K100LV CR); of about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); of around 19 to around 29% w / w of microcrystalline cellulose; from around 8 to around 18% w / w of lactose monohydrate; from about 0.1 to about 4% w / w of anhydrous colloidal silica; from about 0.1 to about 4% magnesium stearate; of about 1 to about 10% w / w of Eudragit L30D55; and of about 0.5 to about 5% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: bRpznn / eznz / B / Yi around 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 24% w / w of microcrystalline cellulose; approximately 13% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; approximately 0.5% w / w magnesium stearate; approximately 5% w / w of Eudragit L30D55; and approximately 1% w / w of Plasacryl HTP20. In one respect, the present description provides a gastro-resistant controlled-release dosage form comprising: approximately 24% w / w of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof; about 9% w / w hypromellose (Methocel™ K100LV CR); approximately 23% w / w of hypromellose (Methocel™ K100M CR); approximately 24% w / w of microcrystalline cellulose; approximately 13% w / w of lactose monohydrate; approximately 0.5% w / w of anhydrous colloidal silica; approximately 1% w / w of magnesium stearate; approximately 5% w / w of Eudragit L30D55; and approximately 1% w / w of Plasacryl HTP20. In one aspect, the present description provides a method for reducing the risk of QT prolongation when treating a subject with Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the method comprises oral administration to the subject of a gastro-resistant controlled-release dosage form described herein. In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises 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. In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises 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. bRpznn / eznz / B / Yi In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has a diagnosis of, e.g., schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype. In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises once-daily oral administration to the subject of a gastro-resistant controlled-release dosage form described herein, wherein the subject has a diagnosis of, e.g., schizophrenia, and wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype. In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises oral administration to the subject of a gastro-resistant controlled-release dosage form described herein (e.g., including 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 a diagnosis of, e.g.schizophrenia, where the subject with a diagnosis of schizophrenia has a CYP2D6 IM or PM genotype. In one aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, wherein the method comprises once-daily oral administration to the subject of a gastro-resistant controlled-release dosage form described herein (e.g., including 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 a diagnosis of, e.g., schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 IM or PM genotype. In one respect, for any of the methods described herein, the subject has been fed prior to oral administration of the gastro-resistant controlled-release dosage form described herein. In one respect, for any of the methods described herein, the subject is fasting prior to oral administration of the gastro-resistant controlled-release dosage form described herein. In one respect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in reducing the risk of QT prolongation. In one respect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g. bRpznn / eznz / B / Yi e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in reducing the risk of QT prolongation, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the gastro-resistant controlled-release dosage form is administered once daily. bRpznn / eznz / B / Yi In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, where the subject has been fed prior to oral administration of the dosage form. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, wherein the subject is in a fasting state prior to oral administration of the dosage form. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, and wherein the subject has been fed prior to oral administration of the dosage form. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein the subject is in a fasting state prior to oral administration of the dosage form. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the subject has been fed prior to oral administration of the dosage form. In one aspect, the present description provides a gastro-resistant controlled-release dosage form described herein for use in the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the subject is in a fasted state prior to oral administration of the dosage form. In one respect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a drug to reduce a risk of QT prolongation. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a drug for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a drug for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a drug to reduce the risk of QT prolongation, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein for use in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the gastro-resistant controlled-release dosage form is administered once daily. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of the drug for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, where the subject is in a fasting state prior to oral administration of the dosage form. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, and wherein the subject is in a fasting state prior to oral administration of the dosage form. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the subject is in a fasting state prior to oral administration of the dosage form. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of the drug for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject who needs it, e.g., the subject has a diagnosis of schizophrenia, where the subject has been fed prior to oral administration of the dosage form. In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia has a CYP2D6 EM genotype, and wherein the subject has been fed prior to oral administration of the dosage form. bRpznn / eznz / B / Yi In one aspect, the present description provides for the use of a gastro-resistant controlled-release dosage form described herein in the manufacture of a medicament for the treatment of a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, e.g., the subject has a diagnosis of schizophrenia, wherein the subject with a diagnosis of schizophrenia 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, wherein the subject has been fed prior to oral administration of the dosage form. Therefore, in one aspect, the present description provides a gastro-resistant, 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 the dosage form, upon oral administration to a subject, produces a plasma pharmacokinetic (PK) profile for Compound (I) comprising a Tmax of between about 4 and about 11 hours. In one embodiment, the Tmax of Compound (I) in the plasma PK profile 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. In some formulations, the amount of Compound (I) in the oral dosage form 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, 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. 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 further comprises: (a) an AUCo-4h of less than about 68 h*ng / mL; (b) a Cmax 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; and (c) an AUCo-24 h of between about 75 h*ng / mL and about 350 h*ng / mL or between about 100 h*ng / mL and 300 h*ng / mL. In one embodiment, the plasma PK profile for the BFB-520 metabolite of Compound (I) comprises a Cmax below 3.0 ng / mL, below 2.5 ng / mL, below 2.0 ng / mL, below 1.5 ng / mL, or below 1.0 ng / mL. 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 further comprises: (a) an AUCo-4h of less than about 8 h*ng / mL; (b) a Cmax of Compound (I) of less than about 2.5 ng / mL; and (c) an AUCo-24 n of between about 12 h*ng / mL and 35 h*ng / mL. In one embodiment, the plasma PK profile for the metabolite BFB520 of Compound (I) comprises a Cmax below 2.0 ng / mL, below 1.5 ng / mL, below 1.0 ng / mL, or below 0.5 ng / mL. 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 further comprises: (a) an AUC0-4H of less than about 16 h*ng / mL; (b) a Cmax of Compound (I) of less than about 5 ng / mL; and (c) an AUC0-24 h of between about 25 h*ng / mL and 75 h*ng / mL. In one embodiment, the plasma PK profile for the metabolite BFB-520 of Compound (I) comprises a Cmax below 2.5 ng / mL, below 2.0 ng / mL, below 1.5 ng / mL, or below 1.0 ng / mL. 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 further comprises: (a) an AUC0-4H of less than about 32 h*ng / mL; (b) a Cmax of Compound (I) of less than about 10 ng / mL or less than about 6 ng / mL; and (c) an AUCo-24 h of between about 50 h*ng / mL and 150 ITng / mL. In one embodiment, the plasma PK profile for the metabolite BFB-520 of Compound (I) comprises a Cmax below 2.5 ng / mL, below 2.0 ng / mL, below 1.5 ng / mL, or below 1.0 ng / mL. 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 further comprises: (a) an AUCo-4h of less than about 80 h*ng / mL; (b) a Cmax of Compound (I) of less than about 24 ng / mL or less than about 20 ng / mL; and (c) an AUCo-24 h of between about 125 ITng / mL and 375 h*ng / mL. In one embodiment, the plasma PK profile for the metabolite BFB-520 of Compound (I) comprises a Cmax below 3.5 ng / mL, below 3.0 ng / mL, below 2.5 ng / mL, or below 2.0 ng / mL. In one embodiment, 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 further comprises: (a) an AUCo-4h of less than about 50, 60, 70, 80, 90, 100, 110, 120 or 130 Tng / mL; (b) a Cmax of Compound (I) of less than about 36 ng / mL or less than about 25 ng / mL; and (c) an AUCo-24 h of between about 200 ITng / mL and 600 ITng / mL. In one modality, the plasma PK profile for the BFB-520 metabolite of Compound (I) comprises a Cmax below 4.0 ng / mL, below 3.5 ng / mL, below 3.0 ng / mL, or below 2.5 ng / mL. In one embodiment, the dosage form comprises approximately 80 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile further comprises: (a) an AUC0-4H of less than approximately 160 ng / mL; (b) a Cmax of Compound (I) of less than approximately 48 ng / mL or less than approximately 40 ng / mL; and (c) an AUCo-24 h of between approximately 250 ng / mL and 750 ng / mL. In one embodiment, the profile of bRpznn / eznz / B / Yi Plasma PK for the metabolite BFB-520 of Compound (I) comprises a Cmax below 4.5 ng / mL, below 4.0 ng / mL, below 3.5 ng / mL or below 3.0 ng / mL. In one embodiment, the dosage form comprises approximately 100 mg of Compound (I), or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the plasma PK profile further comprises: (a) an AUC0-4H of less than approximately 220 h*ng / mL; (b) a Cmax of Compound (I) of less than approximately 72 ng / mL; and (c) an AUCo-24h of between approximately 325 h*ng / mL and 975 h*ng / mL. In one embodiment, the plasma PK profile for the metabolite BFB520 of Compound (I) comprises a Cmax below 5.0 ng / mL, below 4.5 ng / mL, below 4.0 ng / mL, or below 3.5 ng / mL. In some formulations of any of the above dosage forms, plasma PK parameters are determined after two daily administrations of a single unit of the dosage form. In one formulation, the PK parameter is determined after the 3rd or 4th administration. In one embodiment, the dosage form comprises about 32 mg of Compound (I) and, when administered to a subject, produces a plasma pharmacokinetic (PK) profile for Compound (I) that is similar to the target profile shown in Figure 1. In some modalities of any of the above dosage forms, the plasma PK profile for one or both of Compound (I) and metabolite BFB-520 occurs after the 1st, 2nd, 3rd, or 4th daily administration of a single unit of the dosage form. In some modalities, the plasma PK profile for one or both of Compound (I) and the metabolite BFB-520 is obtained when administered to a subject in a fasted state. In other modalities, the plasma PK profile for one or both of Compound (I) and the metabolite BFB-520 is obtained when administered to a fed subject. In one embodiment, a controlled-release dosage form of the description comprises from about 4 to about 100 mg of Compound (I) and produces a target in vitro dissolution profile by using a two-stage, 24-hour in vitro dissolution method comprising a 2-hour acid stage and a 22-hour buffer stage. The target in vitro dissolution profile comprises (a) no detectable release of Compound (I) during the first 2.0 hours of the dissolution method and (b) the release of at least 80% of the total amount of Compound (I) in the dosage form over a period of 16–19 hours. In one embodiment, the target in vitro dissolution profile comprises the release of at least 85%, 90%, or 95% of the amount of Compound (I) in the dosage form by hour 24 of the dissolution method. In one embodiment, the target in vitro dissolution profile further comprises the release of Compound (I) at a release rate that produces each of the following cumulative percentages bRpznn / eznz / B / Yi of the initial total amount: (i) less than 0.6% at 2.5 hours; (i) from 0.2 to 7.9% at 3.0 hours; (iii) from 2.5 to 19.2% at 4 hours; (iv) from 12.7 to 34.0% at 6 hours; (v) from 22.8 to 44.3% at 8 hours; (vi) from 35.5 to 75.7% at 1 p.m.; (vii) from 43.3 to 89.0% at 16 hours; and (viii) from 59.3 to 96.9% at 19 hours. In one embodiment, the target in vitro dissolution profile further comprises the release of Compound (I) at a release rate that produces each of the following cumulative percentages of the initial total amount: bRpznn / eznz / B / Yi (i) (i) (iii) (iv) (V) (vi) (vii) (viii) (X) (x) (xi) (xii) less than about 0.5% at 2.5 hours; from about 2.8 to about 3.1% at 3.0 hours; from about 9.0 to about 11.0% at 4 hours; from about 14.5 to about 18.0% at 5 hours; from about 19.5 to about 24.5% at 6 hours; from about 30.5 to about 38.0% at 8 hours; from about 41.5 to about 51.0% at 10 hours; from about 54.5 to about 67.0% at 13 hours; from about 58.5 to about 71.5% at 14 hours; from around 61.5 to around 75.5% at 3 pm; from around 70.0 to around 86.0% at 6 pm; and from around 77.5 to around 95.0% at 9 pm. In one embodiment, the CR dosage form comprises 32 mg of Compound (I) and generates in vitro cumulative dissolution and dissolution rate profiles that are substantially similar to the target profile shown in Figure 1 or the target profile shown in Tables 6 and 7 in the examples below. In one embodiment, the target in vitro dissolution profile further comprises the release of Compound (I) at a release rate that produces each of the following cumulative percentages of the initial total amount: (xiii) less than about 0.5% at 2 hours; (xiv) from about 19 to about 29% at 4 hours; (xv) from about 54 to about 64% at 8 hours; and (xvi) from about 83 to about 93% at 16 hours. In one embodiment, the target in vitro dissolution profile further comprises the release of Compound (I) at a release rate that produces each of the following cumulative percentages of the initial total amount: (xvii) less than about 0.5% at 2 hours; (xviii) around 24.1% at 4 hours; (xix) around 59.2% at 8 hours; and (xx) around 88.6% at 16 hours. In each of the above modalities, the dissolution method is preferably carried out in accordance with the dissolution method described in the Examples below. In one embodiment, the CR oral dosage form is a tablet comprising a tablet core and an enteric coating. The tablet core comprises a desired amount of Compound (I), a controlled-release agent, a filler, a gluing agent, and a lubricant, and the enteric coating comprises at least one polymeric controlled-release agent with a dissolving property at a pH greater than 5.5 and an anti-adherent. In one embodiment, the enteric coating is dissolving at a pH greater than 6.0 or 6.5. In one embodiment, the CR oral dosage form is a tablet comprising a tablet core and an enteric coating. The tablet core comprises a desired amount of Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., MIN-101), a controlled-release agent, a filler, a gluing agent, and a lubricant. The enteric coating comprises at least one polymeric controlled-release agent with dissolving properties at a pH greater than 5.5 and an anti-adherent. In one embodiment, the enteric coating is dissolving at a pH greater than 6.0 or 6.5. In some embodiments, the controlled-release agent in the tablet core comprises a mixture of (i) a low-viscosity hypromellose with a viscosity of from about 15 millipascal-seconds (mPa-s) to about 100 mPa-s and (ii) a high-viscosity hypromellose with a viscosity of about 100,000 mPa-s, wherein each of the low- and high-viscosity hypromellose is of a controlled-release or sustained-release grade and is further characterized by a methoxy content of 19.0% to 24.0% and a hydroxypropoxy content of 4.0% to 12.0%. In one embodiment, the high-viscosity hypromellose is characterized by a methoxy content of 22.0% to 24.0% and a hydroxypropoxy content of 9.5% to 11.5%. In one embodiment, low viscosity hypromellose comprises about 10% of the weight of the tablet core and high viscosity hypromellose comprises about 24% of the weight of the tablet core. In one embodiment, the tablet core comprises 38.4 mg of 1 H-isoindole-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-pyridine]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2) and the controlled-release agent in the tablet core consists essentially of (i) 9.45% w / w of a hypromellose having the chemical and physical characteristics of the hypromellose product marketed as METOLOSE® 90 SH 100 SR by Shin-Etsu Chemical Co., Ltd., or METHOCEL™ K100LV CR; and (i) 22.67% w / w of a hypromellose with the chemical and physical characteristics of the hypromellose product marketed as METHOCEL™ K100M CR by The Dow Chemical Company. In one embodiment, the dosage form further comprises a controlled-release coating located between the tablet core and the enteric coating. The controlled-release coating comprises at least one controlled-release agent. In one embodiment, the controlled-release coating comprises a semipermeable membrane comprising ethylcellulose as the controlled-release agent. In one embodiment of the dosage form comprising a controlled-release coating, the tablet core comprises 38.4 mg of 1 H-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 tablet core consists essentially of (i) 9.36% w / w of a hypromellose having the chemical and physical characteristics of the hypromellose product marketed as METHOCEL™ K15M CR by The Dow Chemical Company, or METHOCEL™ K100LV CR; and 22.46% of a hypromellose with the chemical and physical characteristics of the hypromellose product marketed as METHOCEL™ K100M CR by The Dow Chemical Company and the controlled release agent in the controlled release coating consists essentially of 0.94% w / w of an ethylcellulose with the chemical and physical characteristics of the ethylcellulose product marketed as Surelease® E-7-19040 by Colorcon. In some embodiments of any of the above dosage forms, the enteric coating essentially consists of a mixture of (i) 4.68% w / w of a methacrylic acid and ethyl acrylate copolymer with the same physical and chemical properties as the copolymer marketed as EUDRAGIT® L 30 D-55 by Evonik Industries AG and (ii) 0.80% w / w of a release agent with the chemical and physical characteristics of the release product marketed as PlasACRYL™ by Evonik Industries AG. In one embodiment, the gastro-resistant CR tablet of the description has a round, oval, capsule, or oblong shape. In one embodiment, the tablet is round, with a diameter of 10 mm and a radius of curvature (R) of 10. In other respects, the present description provides a batch composition and a process for manufacturing a gastro-resistant CR oral dosage form described herein. In yet another aspect, the present description provides a method for reducing the risk of QT prolongation when treating a subject with Compound (I), wherein the method comprises administering to the subject a gastro-resistant CR oral dosage form described herein. bRpznn / eznz / B / Yi In yet another aspect, the present description provides a method for treating a disorder (e.g., negative symptoms of schizophrenia) in a subject in need thereof, wherein the method comprises daily administration to the patient of a gastro-resistant CR oral dosage form described herein. In one embodiment, the subject, e.g., a patient, has a diagnosis of schizophrenia. In one embodiment, the patient has a diagnosis of schizophrenia, an extensive metabolizer (EM) genotype of CYP2D6, 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 poor metabolizer (PM) genotype of CYP2D6, and the gastro-resistant CR oral dosage form comprises 4 mg to 16 mg of Compound (I).In another modality, the patient has a diagnosis of schizophrenia, an intermediate metabolizer (IM) genotype of CYP2D6, and the gastro-resistant CR oral dosage form comprises 8 mg to 32 mg of Compound (I). In another aspect, this description provides a gastro-resistant oral CR dosage form described herein for use in the treatment of negative symptoms in a patient. In one modality, the patient has a diagnosis of schizophrenia. In another modality, the dosage form is intended for use in improving one or both negative symptoms and cognitive impairment in patients diagnosed with schizophrenia. In another aspect, this description provides the use of a gastro-resistant CR oral dosage form described herein for the preparation of a medication to treat negative symptoms in a patient. In one instance, the patient has a diagnosis of schizophrenia. In another aspect, the present description provides a kit for use in the treatment of negative symptoms in a patient, wherein the kit comprises an oral gastro-resistant CR dosage form described herein and instructions for the use of the dosage form. In one modality, the instructions include instructions for testing the patient to determine the patient's CYP2D6 genotype. In another modality, the instructions include instructions for administering the dosage form to the patient in a fed or fasted state. In all aspects and embodiments of the foregoing invention, Compound (I) can be provided in the gastro-resistant CR oral dosage form as 1H-isoindole-1-one, 2-[[1[2-(4-fluorophenyl)-2-oxoethyl]-4-pyridinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2). BRIEF DESCRIPTION OF THE FIGURES The patent application file contains at least one color drawing. Upon request, and after payment of the required fee, the Office will provide copies of this patent application or patent publication with the color drawing(s). The drawings show several graphs that include the plasma concentration profile over time of several compounds, including, for example, 1H-isoindole-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-pyridine]methyl]-2,3-dihydro-, i.e., Compound (I). In these drawings, the use of "MIN-101" or "MIN101" refers to the free base, i.e., Compound (I). The preceding summary, as well as the detailed description of the invention that follows, will be better understood when read together with the accompanying drawings. Figure 1 shows an example of a target plasma PK profile for Compound (I) produced by oral administration of a gastro-resistant, controlled-release dosage form comprising 32 mg of Compound (I) (“New Prediction Formulation”) compared to the plasma PK profile observed for Compound (I) produced by a prior 32 mg modified-release MIN-101 tablet (described in Example 1) (“MR 32 mg”). The time profile is 24 hours. Figure 2 compares the target in vitro dissolution profiles for Compound (I) (target, red curve) with the observed dissolution profiles for two examples of 32 mg gastro-resistant CR tablets from the present description, where the left graph shows the cumulative dissolution profiles and the right graph shows the dissolution rate profiles. The time profile is 24 hours. Figure 3 shows another example of a target plasma PK profile for Compound (I) produced by oral administration of a gastro-resistant, controlled-release dosage form comprising 32 mg of Compound (I) to a subject in a fed or fasted state (“Optimal Formulation”) compared to plasma PK profiles observed for Compound (I) produced by a previously described 32 mg MIN-101 modified-release tablet (described in Example 1) in subjects in a fed or fasted state. The time profile is 24 hours. Figure 4 is a graph of the plasma concentration profile over time of Compound (I) for subjects who received administration of a 32 mg MR tablet. The time profile is 36 hours. Figure 5 is a graph of the time profile of plasma concentrations of Compound (I) for subjects administered one GR-01 tablet. The time profile is 36 hours. Figure 6 is a graph of the plasma concentration profile over time of Compound (I) for subjects who received administration of one GR-02 tablet. The time profile is 36 hours. Figure 7 is a graph of the mean plasma concentration profile over time of Compound (I) for subjects who received administration of 32 mg MR tablets, GR-01 tablets, or GR-02 tablets. The time profile is 48 hours. Figure 8 is a graph of the rates of increase or decrease in the plasma concentration profile of bRpznn / eznz / B / Yi over time for Compound (I) for subjects who received administration of 32 mg MR tablets, GR-01 tablets, or GR-02 tablets. The time profile is 8 hours. Figure 9 is a graph of the plasma concentration profile over time of BFB-520 for subjects who received administration of a 32 mg MR tablet. The time profile is 36 hours. Figure 10 is a graph of the plasma concentration profile over time of BFB-520 for subjects who received administration of one GR-01 tablet. The time profile is 36 hours. Figure 11 is a graph of the plasma concentration profile over time of BFB-520 for subjects who received administration of one GR-02 tablet. The time profile is 36 hours. Figure 12 is a graph of the mean plasma concentration profile over time of BFB-520 for subjects who received administration of 32 mg MR tablets, GR-01 tablets, or GR-02 tablets. The time profile is 48 hours. Figure 13 is a graph of the rates of increase or decrease in the plasma concentration profile over time for BFB-520 for subjects who received administration of 32 mg MR tablets, GR-01 tablets, or GR-02 tablets. The time profile is 8 hours. Figure 14 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of Compound (I) for subjects who received administration of 4 daily doses of either a 32 mg MR tablet or a GR-01 (32 mg) tablet based on actual data observed after dosing on Day 1. The time profile is 96 hours. Figure 15 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of BFB-520 for subjects who received 4 daily doses of either a 32 mg MR tablet or a 32 mg GR-01 tablet based on actual data observed after dosing on Day 1. The time profile is 96 hours. Figure 16 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of Compound (I) for subjects who received administration of 4 target doses of 64 mg (2x32 mg) of either a 32 mg MR tablet or a GR-01 tablet. The time profile is 96 hours. Figure 17 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of BFB-520 for subjects who received 4 daily doses of 64 mg (2x32 mg) of either a 32 mg MR tablet or a GR-01 tablet. The time profile is 96 hours. bRpznn / eznz / B / Yi Figure 18 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of Compound (I) for subjects who received 4 daily doses of either a 32 mg MR tablet or a 32 mg GR-02 tablet based on actual data observed after dosing on Day 1. The time profile is 96 hours. Figure 19 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of BFB-520 for subjects who received 4 daily doses of either a 32 mg MR tablet or a 32 mg GR-02 tablet based on actual data observed after dosing on Day 1. The time profile is 96 hours. Figure 20 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of Compound (I) for subjects who received administration of 4 daily doses of either a 32 mg MR tablet or a GR-02 tablet based on actual data observed after dosing on Day 1. The time profile is 96 hours. Figure 21 is a pair of graphs of the predicted profile of steady-state plasma concentrations over time of BFB-520 for subjects who received 4 daily doses of 64 mg (2x32 mg) of either a 32 mg MR tablet or a GR-02 tablet. The time profile is 96 hours. Figure 22 is a graph of the plasma concentration profile over time of Compound (I) for subjects who received GR-01 tablets while fed. The time profile is 36 hours. Figure 23 is a graph of the plasma concentration profile over time of Compound (I) for subjects who received GR-01 tablets in a fasted state. The time profile is 36 hours. Figure 24 is a graph comparing the mean plasma concentration profile over time of Compound (I) for subjects who received GR-01 tablets while fed or fasted. The time profile is 48 hours. Figure 25 is a graph of the plasma concentration profile over time of BFB-520 for subjects who received GR-01 tablets while fed. The time profile is 48 hours. Figure 26 is a graph of the plasma concentration profile over time of BFB-520 for subjects who received GR-01 tablets in a fasted state. The time profile is 48 hours. Figure 27 is a graph comparing the mean plasma concentration profile of BFB-520 for subjects who received GR-01 tablets while fed or fasted. The time profile is 48 hours. Figure 28 is a pair of graphs of the steady-state plasma concentration profile over time for Compound (I) for subjects who received 4 daily doses of one GR-01 tablet (32 mg) based on actual data observed after Day 1 dosing in a fed or fasted state. The time profile is 96 hours. Figure 29 is a pair of graphs of the predicted time profile of steady-state plasma concentrations of BFB-520 for subjects who received 4 daily doses of one GR-01 tablet (32 mg) based on actual data observed after Day 1 dosing in a fed or fasted state. The time profile is 96 hours. Figure 30 is a pair of graphs of the predicted time profile of steady-state plasma concentrations of Compound (I) for subjects who received 4 daily doses of 64 mg (2 x 32 mg) of one GR-01 tablet in a fed or fasted state. The time profile is 96 hours. Figure 31 is a pair of graphs of the predicted time profile of steady-state plasma concentrations of BFB-520 for subjects who received four daily doses of 64 mg (2 x 32 mg) of one GR-01 tablet (64 mg) in a fed or fasted state. The time profile is 96 hours. DETAILED DESCRIPTION This description 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 manufacturing the dosage forms, and the use of the dosage forms for the therapeutic treatment of patients suffering from various disorders and conditions. In one embodiment, the present description relates to novel gastro-resistant CR oral dosage forms comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein, upon oral administration to a subject, the Cmax of Compound (I) and its metabolite, BFB-520, are reduced while the AUC(o-tau) is maintained compared to previously described formulations and / or dosage forms, e.g., those described in U.S. Patent No. 9,458,130. In one embodiment, the present description relates to novel gastro-resistant CR oral dosage forms comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein, following oral administration to a subject, an AUC-based exposure to Compound (I) is maintained similar to that in a prior study with previously described formulations and / or dosage forms, e.g., those described in U.S. Patent No. 9,458,130, which achieved its primary objective of improving negative symptoms in patients with bRpznn / eznz / B / Yi schizophrenia with both evaluated doses, 64 mg and 32 mg. In one embodiment, the present description relates to novel gastro-resistant CR oral dosage forms comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein, following oral administration to a subject, the ti / 2 of Compound (I) is prolonged compared to previously described formulations and / or dosage forms, e.g., those described in U.S. Patent No. 9,458,130. In one embodiment, the present description relates to novel gastro-resistant CR oral dosage forms comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein following oral administration to a subject, the Cmax of BFB-520 in the subject's plasma is reduced to promote drug safety. In one embodiment, the present description relates to novel gastro-resistant CR oral dosage forms comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein upon oral administration to a subject, the Cmax of BFB-520 is reduced by about 30% or more (e.g., 30%, 35%, or 40%) compared to previously described formulations and / or dosage forms, e.g., those described in U.S. Patent No. 9,458,130. In one instance, reducing the Cmax of BFB-520 in the subject leads to a reduction in the potential for transient QTc prolongations observed in a previous study with the highest dose but not with the lowest dose. For example, administration of the novel gastro-resistant oral CR dosage forms described herein comprising Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, does not produce observable QTc prolongations. In one embodiment, the present description refers to novel gastro-resistant CR oral dosage forms 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 can occur with or without food without changing its pharmacokinetic properties. In one embodiment, the present description refers 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) maintain previously established general tolerability and safety profiles. The novel gastro-resistant CR oral dosage forms described herein allow delivery of Compound (I) to a lower portion of the gastrointestinal tract, which unexpectedly reduced the highest concentration of BFB-520. This unexpected pharmacokinetic effect did not produce observable QTc prolongations in subjects receiving these novel gastro-resistant CR oral dosage forms. bRpznn / eznz / B / Yi Definitions and abbreviations The terms used herein have common meanings, and the meaning of these terms is independent in each instance. However, except where otherwise stated, the following definitions apply in the specification and claims. Chemical nomenclature, common names, and chemical structures can be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical nomenclature, and there is ambiguity between the structure and the name, the structure is understood to take precedence. All references to Compound (I) herein include all pharmaceutically acceptable salts (such as MIN-101) and / or all solvates (e.g., including hydrates) and alternative physical forms thereof unless otherwise stated. All dosages stated herein are based on the molecular weight of the freebase Compound (I), which is 366.43 g / mol, rather than the molecular weight of the pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof or of any excipient in the composition, unless otherwise stated. All quantities of a component of an oral dosage form described herein are stated as % w / w and refer to the total weight of the oral dosage form, unless otherwise stated. The expression "around" as part of a quantitative expression such as "around X" includes any value that is 10% greater or less than X, and also includes any numerical value that lies between X-10% and X+10%. Thus, for example, a weight of around 40 g includes a weight between 36 and 44 g. “Administration” refers to the introduction of an agent, such as a compound or dosage form described herein, into a subject. The related terms “administer” and “administration of” (and grammatical equivalents) refer to direct administration, which may be administration 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. "BFB-520" is a metabolite of Compound (I) and has the structure shown in Formula II below: OH bRpznn / eznz / B / YiAi (II) . "BFB-999" is a metabolite of Compound (I) and the structure of a maleate salt of BFB-999 is shown in Formula III below: (III) . A “similar PK profile” as used herein with respect to a plasma concentration-time profile produced by oral administration to a subject of a dosage form described herein 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 the similar plasma concentration-time profile produce a PK property, such as AUC, deemed bioequivalent by a regulatory authority. In one embodiment, the regulatory authority is the United States Food and Drug Administration. "BNSS" is the Brief Negative Symptoms Scale. “Comprising” or “comprising” as applied to a particular dosage form, composition, method, or process described or claimed herein means that the dosage form, composition, or method includes all the elements mentioned in a specific description or claim, but does not exclude other elements. “Consisting essentially of” and “consisting essentially of” means that the composition, dosage form, method, or process described or claimed does not exclude other materials or steps that do not materially affect the aforementioned physical, pharmacological, and pharmacokinetic properties or therapeutic effects of the composition, dosage form, method, or process. “Consisting of” and “consisting of” means the exclusion of more than trace elements of other substantial ingredients and process or method steps. "Controlled release" or "CR", as used herein with respect to an oral dosage form of the description, means that Compound (I) is released from the dosage form according to a predetermined profile that may include when and where release occurs after oral administration and / or a specified release rate over a specified period of time. “Controlled-release agent,” as used herein with respect to an oral dosage form of the description, 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 materials, of natural or synthetic origin, such as polymeric materials, triglycerides, triglyceride derivatives, fatty acids and fatty acid salts, talc, boric acid, and colloidal silica. The "CYP2D6 allele" refers to one of the more than 100 named versions of the CYP2D6 gene that are present in the general population, and which are typically classified into one of three categories: active (functional); decreased activity (partially active or decreased function); and inactive (non-functional). Active CYP2D6 alleles include: *1, *2, *2A, *33, *35, *39, *48, and *53. The CYP2D6 alleles with decreased activity include: *9, *10, *17, *29, *41, *49, *50, *54, *55, *59, *69 and *72. Inactive CYP2D6 alleles include: *3, *4, *5 (delete), *6, *7, *8, *11, *12, *13, *14A, *14B, *15, *18, *19, *20, *21, *38, *40, *42, *44, *56, *56A, *56B and *68. The term "CYP2D6 extensive metabolizer (EM) genotype" applied to a subject means that the subject has a CYP2D6 protein that produces CYP2D6 metabolic activity considered normal. CYP2D6 EM genotypes include combinations of: (a) two active CYP2D6 alleles, (b) one active and one reduced-activity CYP2D6 allele, and (c) one active and one inactive CYP2D6 allele. The term "CYP2D6 intermediate metabolizer (IM) genotype" 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 of reduced activity; and (c) two CYP2D6 alleles of reduced activity. The term "CYP2D6 PM genotype" applied to a subject means that the subject has a positive test result for a CYP2D6 poor metabolizer genotype and is therefore likely to have no CYP2D6 activity. A CYP2D6 PM genotype consists of 2 inactive alleles. "CYP2D6 UM genotype" applied to a subject means that the subject has a positive test result for a CYP2D6 ultrarapid metabolizer genotype and is therefore likely to have above-average CYP2D6 activity. A CYP2D6 UM genotype consists of 3 or more active alleles. The "enteric coating", as used herein with respect to a dosage form of the description, refers to a pH-dependent material surrounding a core comprising Compound (I) and which remains substantially intact in the acidic environment of the stomach, but dissolves in the pH environment of the intestines. bRpznn / eznz / B / Yi In one modality, in the dosage forms of the description, the filler is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose and sorbitol. "Fluid," as used herein, refers to a substance used to promote powder flow by reducing cohesion between particles. In one embodiment, in the dosage forms described, the flake is selected from the group consisting of anhydrous colloidal silica, starch, and talc. "Lubricant," as used herein, refers to a substance that prevents the ingredients from sticking together and / or clumping in the machinery used in the preparation of the dosage forms described herein. In one embodiment of the dosage forms described herein, the lubricant is selected from the group consisting of magnesium stearate, spherical acid, and vegetable stearin. "Fasting condition" or "fasting state," as used to describe a subject, means that the subject has not eaten for at least 4 hours prior to a time of interest, such as the time of administration of a dosage form described herein. In one modality, a subject in a fasting state has not eaten for at least 6, 8, 10, or 12 hours prior to administration of a dosage form described herein. "Feeding condition" or "feeding state," as used to describe a subject herein, means that the subject has eaten less than 4 hours before a time of interest, such as the time of administering a dosage form described herein. In one modality, a subject in a feeding state has not eaten for at least 3, 2, 1, or 0.5 hours before the administration of a dosage form described herein. “Gastro-resistant” or “GR,” as applied to an oral CR dosage form described herein, means that the release of Compound (I) in the stomach of a subject shall not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of Compound (I) in the dosage form. “MIN-101” is a code name for 1H-isoindole-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), with an alternative name of 2-{1[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindole-1-one dihydrate hydrochloride. "Oral dosage form", as used herein, refers to a pharmaceutical product containing a specified amount (dose) of Compound (I) as the active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and inactive components (excipients), formulated in a particular configuration suitable for oral administration, such as a tablet or capsule. “Pharmaceutically acceptable salt,” as used herein with respect to Compound (I), means a salt form of Compound (I) as well as hydrates of the salt form with one or more water molecules present. Such salts and hydrated forms maintain the biological activity of Compound (I) and are not biologically or otherwise undesirable, i.e., they have minimal, if any, toxicological effects. In one embodiment, the pharmaceutically acceptable salt of Compound (I) has a single molecule of HCl and two molecules of water, i.e., 1:1:2-Hisoindole-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-pyridine]methyl]-2,3-dihydro-, hydrochloride, hydrate. "PANSS" is the Positive and Negative Syndrome Scale. “Pharmacokinetic parameter” means a measure or characteristic that describes the pharmacokinetic properties of a compound of interest. The PK parameters used herein are defined below. “AUC” is the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest, and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng-H / mL (ng x H / mL). “AUC(0-4H)” means the AUC from 0 hours to 4 hours after administration of a single dose. “AUC(0-24H)” means the AUC from 0 hours to 24 hours after administration of a single dose. “AUC_uit” means the AUC from time 0 to the last quantifiable concentration (uit). "AUC(or tau)" means the AUC from 0 hours to the end of a dosing interval. "Cmax" means the maximum (peak) plasma concentration observed of a specified compound, such as Compound (I), following administration of one dose of a composition comprising the compound. In one modality, Cmax is measured after two or more doses of the composition. In another modality, Cmax is measured when the specified compound reaches steady state. "Cmin" means the minimum observed plasma concentration of a specified compound, such as Compound (I), following administration of one dose of a composition comprising the compound. In one embodiment, Cmax is measured after two or more doses of the composition. In one embodiment, Cmax is measured when the specified compound reaches steady state. "Cee" means concentration in the steady state. "Cprom" stands for the average concentration, which is the ratio of AUC over time. "Cp" means the plasma concentration of a specified compound, such as Compound (I), at any time T after administration of a dose of a composition comprising the compound. "Cp(úit)" means the last measured Cp, with respect to the time of collection of the last of a series of blood samples for the assay of the specified compound. "Cpcn" means the Cpen at the specified time; therefore, CP(4H> and Cp <i2H) son las Cpa las 4 y 24 bRpznn / eznz / B / Yi horas, respectivamente. "H" means hours. "PK" stands for pharmacokinetics. "Steady state" means that the absorption rate of a specified compound of interest such as Compound (I) is equal to the elimination rate of the compound. "Tau" means a dosing interval (H). For example, for a daily dose, tau is 24H. Tmax means the time to maximum (or peak) concentration in plasma or serum of a specified therapeutic compound after administration of a single dose of a composition comprising the compound and before administration of a second dose. Vmax means the maximum absorption rate (mg / H). "Subject" and "patient" may be used interchangeably herein, and refer to a human being of any age. "Therapeutically effective amount," as used herein with respect to the therapeutic uses of a dosage form comprising Compound (I) or a pharmaceutically acceptable salt and / or solvate thereof, means an amount of the free base (Compound (I)) that is sufficient to treat, ameliorate, or prevent a specified disease, symptom of disease, disorder, or condition, or to produce a detectable therapeutic or inhibitory effect. The effect may be detected by any assay method known in the art. The effective amount for a particular subject may depend on the subject's body weight, size, and health; the nature and extent of the condition; and whether additional therapies will be administered to the subject. Therapeutically effective amounts for a given situation may be determined by routine experimentation within the physician's skill and judgment. “Treat,” “treating,” “treatment,” and similar terms, as used herein with respect to one or more specific symptoms of the disease, shall include the management and care of a patient for the purpose of ameliorating one or more of the specified symptoms, and shall include the administration of an oral, controlled-release, gastro-resistant dosage form described herein at a dosing frequency and for a treatment period sufficient to prevent the occurrence of one or more of the symptoms, reduce the frequency, intensity, or severity of one or more of the symptoms, delay or prevent the development of additional symptoms, or any combination of these treatment objectives. In one modality, the effect of treatment with a dosage form described herein is assessed by comparing the severity of the subject’s symptoms at baseline (e.g.,(before treatment) and after at least one treatment period. In one modality, the treatment period is at least one week, at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least 10 weeks, or at least twelve weeks or more. In one modality, the symptoms to be treated are at least one negative symptom in a schizophrenic or non-schizophrenic patient, the dosage form comprises 32 mg of Compound (I), the dosage frequency is once daily, and the treatment period is at least eight weeks. Compendium of gastro-resistant controlled-release (CR) oral dosage forms In one embodiment, the present description refers to a gastro-resistant CR oral dosage form comprising from about 4 mg to about 100 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt and / or solvate of Compound (I), wherein the gastro-resistant CR oral dosage form is 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. bRpznn / eznz / B / Yi In one formulation, the CR GR-01 32 mg tablet has the following composition: Composition Tablet CR GR-01 Function % w / w mg / tablet MIN-1011 12.09 38.40 Active ingredient Hypromellose (Metolose® 90SH 100 SR) 9.45 30.00 Controlled release excipient Hypromellose (Methocel™ K100M CR) 22.67 72.00 Controlled release excipient Microcrystalline cellulose 29.95 95.10 Filler Lactose monohydrate 18.89 60.00 Filler Colloidal anhydrous silica 0.47 1.50 Glide Magnesium stearate 0.94 3.00 Lubricant Total (tablet core) 94.47 300.00 Eudragit L30D55 ​​4.72 15.00 Controlled release excipient Plasacryl HTP20 0.80 2.55 Anti-adherent agent Total 100.00 317.55 1 Salt correction factor of 1.2 applied NA: Not applicable bRpznn / eznz / B / Y In one formulation, the 32 mg CR GR-02 tablet has the following composition: Composition Tablet CR GR-02 Function % w / w mg / tablet MIN-1011 11.98 38.40 Active ingredient Hypromellose (Methocel™ K15M CR) 9.36 30.00 Controlled release excipient Hypromellose (Methocel™ K100M CR) 22.46 72.00 Controlled release excipient Microcrystalline cellulose 29.67 95.10 Filler Lactose monohydrate 18.72 60.00 Filler Colloidal anhydrous silica 0.47 1.50 Glide Magnesium stearate 0.94 3.00 Lubricant Total (tablet core) 93.59 300.00 Eudragit L30D55 ​​4.68 15.00 Controlled release excipient Plasacryl HTP20 0.80 2.55 Anti-adherent agent Surelease E-7-19040 0.94 3.00 Controlled-release excipient Total 100.00 320.55 1Salt correction factor of 1.2 applied NA:Not applicable bRpznn / eznz / B / Yi In one formulation, the 32 mg CR GR-01 / B tablet has the following composition: Component / ingredient GR-01 / B-32mg mg / tablet % (w / w) MIN-1011 38.40 12.11 Hypromellose (METHOCEL™ K100LVCR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 96.60 30.42 Lactose 60.00 18.89 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 bRRznn / eznz / B / Yi1Salt correction factor of 1.2 applied In one formulation, the CR GR-01 / C 32 mg tablet has the following composition: bRpznn / eznz / B / Yi Component / ingredient GR-01 / C-32 mg mg / tablet % (w / w) MIN-1011 38.40 12.11 Hypromellose (METHOCEL™ K100LVCR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 95.10 29.95 Lactose 60.00 18.89 Anhydrous colloidal silica 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 In one formulation, the 64 mg CR GR-01 / B tablet has the following composition: Component / ingredient GR-01 / B-64 mg mg / tablet % (w / w) MIN-1011 76.8 24.19 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 77.40 24.37 Lactose 40.80 12.85 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 1Salt correction factor of 1.2 applied bRpznn / eznz / B / Yi In one formulation, the 64 mg CR GR-01 / C tablet has the following composition: Component / ingredient GR-01 / C-64 mg mg / tablet % (w / w) MIN-1011 76.8 24.19 Hypromellose (METHOCEL™ K100LVCR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 75.90 23.91 Lactose 40.80 12.85 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 bRpznn / eznz / B / Yi Design and manufacture of controlled-release oral dosage forms resistant to acid. An object of the present description is to provide a gastro-resistant, controlled-release oral dosage form comprising from about 4 mg to 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 present, following oral administration to a subject, a desired specific release profile for Compound (I) that reduces peak plasma concentrations of BFB-520 while simultaneously providing a therapeutically effective amount of Compound (I) during one or more dosing intervals.This desired release profile is achieved in two ways: (a) delaying the release of Compound (I) until after gastric emptying pushes the dosage form into the small intestine and then (b) 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 provides a plasma PK profile comprising a Tmax for Compound (I) of between about 4 and about 22 hours. This in vivo release profile for Compound (I) is designed to reduce the subject's plasma levels of BFB-520 below a threshold that correlates with an increased risk of QT prolongation. In one modality, the threshold is a Cmax for BFB-520 below 5.0 ng / mL, below 4.5 ng / mL, below 4.0 ng / mL, below 3.5 ng / mL, below 3.0 ng / mL, below 2.5 ng / mL, below 2.0 ng / mL, below 1.5 ng / mL, below 1.0 ng / mL, or below 0.5 ng / mL. In some formulations, the plasma PK profile for Compound (I) is further characterized by one or more additional PK parameters, such as Cmax, AUC(o-tau), Cmin, and other PK parameters defined above. Those skilled in the art will understand 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. The values ​​for Tmax and other plasma PK parameters produced by a dosage form described herein may exhibit some inter-individual variation within a population of subjects. Therefore, in some modalities, certain plasma PK parameters are expressed as mean values ​​determined for a population of at least 2, 4, 8, 16, or more subjects. In one modality, the population consists of healthy volunteers. In one modality, each subject in the population tests positive for an EM genotype. In one modality, each subject in the population tests positive for either an EM or an IM genotype. In one modality, each subject in the population tests positive for either an IM or a PM genotype. In one modality, each subject in the population tests positive for a PM genotype. Compound (I) can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and transformations and manipulations of functional groups, including the use of protecting groups, as can be obtained from the relevant scientific literature or standard reference textbooks in the field. Although not limited to one or more sources, recognized reference textbooks in organic synthesis 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, 3rd ed.; John Wiley & Sons: New York, 1999. A method for preparing Compound (I) is described in U.S. Patent No. Q7,166,617, the contents of which are incorporated herein in their entirety. In one embodiment, the drug substance form of Compound (I) used in the dosage form is a dihydrate of a 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), having a molecular formula of C22H23FN2O2, HCl, 2H2O and a molecular weight of 438.92. Methods for preparing this drug substance of Compound (I) are described in U.S. Patent Nos. 7,166,617 and 9,458,130. An amount of this drug substance equivalent to a specified amount of free base can be calculated by multiplying the specified amount of Compound (I) by 1.2; therefore, 38.4 mg of this drug substance is equivalent to 32.0 mg of Compound (I). In one embodiment, the delayed and sustained release properties of the CR oral dosage form can be provided by surrounding a sustained-release composition comprising the desired amount of Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, within an enteric coating. Several physical and chemical approaches for designing sustained-release compositions are well known in the art. Any sustained-release composition capable of releasing Compound (I) to provide the in vivo plasma PK profile described herein may be used to prepare a dosage form of the described formulation. In one embodiment, 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, crosslinked polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, crosslinked sodium carboxymethylcellulose, carboxymethyl starch, starch and its derivatives, acrylic and methacrylic acid polymers and copolymers, polyesters, polyanhydrides, polymethyl vinyl ether / anhydride copolymers, potassium methacrylate-divinylbenzene copolymers, polyvinyl alcohols, glucan, scleroglucan, mannan, beta-cyclodextrins, and cyclodextrin derivatives containing linear and / or branched polymer chains. In one embodiment, the polymeric material is a hydroxypropyl methocellulose. In one embodiment, a mixture of low-viscosity and high-viscosity hypromellose is used as the controlled-release agent in the sustained-release composition. The viscosity properties of suitable hypromelloses can be determined in a 2 wt% solution in water at 20°C as described in the official USP Hypromellose Monograph, December 1, 2016, which is available at http: / / www.usp.org / usp-nf / official-text / stage6 / hypromellose-2015-11-20. The enteric coating, which typically comprises a pH-sensitive polymer, begins to dissolve in an aqueous solution with a pH greater than 5.5 and, in one embodiment, begins to dissolve in an aqueous solution with a pH greater than 6.0. In one embodiment, the pH-sensitive polymer begins to dissolve in an aqueous solution with a pH greater than 6.5. In one embodiment, the pH-sensitive polymer begins to dissolve in an aqueous solution with a pH of 6.7. In one embodiment, the amounts of Compound (I) released in the stomach from a gastro-resistant CR dosage form administered to subjects in a fed or fasted state are approximately equal (e.g., differing by less than 5%, less than 2%, or less than 1%). bRpznn / eznz / B / Yi The composition and thickness of the enteric coating are typically chosen to maintain substantially its integrity in the stomach, while also allowing substantially all of the enteric coating to dissolve after the dosage form leaves the stomach. In one modality, substantially all of the enteric coating dissolves 15 minutes, 30 minutes, 1 hour, or 2 hours after the dosage form leaves the stomach. The design and preparation of enteric-coated gastro-resistant coatings are well known in the formulation technique. Polyacids with an appropriate pKa range can be used to prepare enteric coatings.Non-exhaustive examples of suitable enteric coating materials include polymerized gelatin, shellac, methacrylic acid type C NF copolymer, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers, typically formed from methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters. For example, the enteric coating may comprise a methacrylic acid-based copolymer and ethyl acrylate marketed as EUDRAGIT® L 30 D-55 by Evonik Industries AG.In one embodiment, the coating comprises a mixture of (i) EUDRAGIT® L 30 D-55 at between 4.5% and 5.0%, w / w, or around 4.7% w / w and (ii) PlasACRYL™ HTP20 at 0.80% w / w. In another aspect, the description provides a batch composition and a process for manufacturing a gastro-resistant CR oral dosage form described herein. In one embodiment, a batch composition for manufacturing a 32 mg dosage form comprises the components listed in Table 4 in Example 4 below. In another embodiment, a batch composition for manufacturing a 32 mg dosage form comprises the components listed in Table 5 in Example 4 below or the Table in Example 4 below. Examples of processes suitable for manufacturing these 32 mg dosage forms are described in Flowcharts 1 and 2 of Example 4. Analytical methods A. In vitro dissolution evaluation To evaluate the potential of a proposed gastro-resistant CR oral dosage form comprising Compound (I) to produce the desired in vivo release profile and plasma PK provided for Compound (I), an in vitro dissolution evaluation such as bRpznn / eznz / B / Yi can be performed as will be described in the Examples below. In one embodiment, the dosage form comprises 32 mg and produces cumulative dissolution and dissolution rate profiles that are substantially similar to the target profile, CR-GR-01 or CR-GR-02, shown in Figure 1 and Tables 6 and 7 below. In one embodiment, the cumulative dissolution amount and dissolution rate at any time point in substantially similar profiles are within + / - 10% of the values ​​for the corresponding time point in the target dissolution profiles, CR-GR-01 or CR-GR-02, shown in Tables 6 and 7. B. Detection of Compound (I) and BFB-520 in human plasma To evaluate whether a gastro-resistant CR oral dosage form comprising Compound (I) produces the desired PK profile for one or both of Compound (I) and BFB-520, plasma concentrations of the compound(s) of interest may be determined at various time points following administration of the dosage form to a single subject, but are typically determined in a group of two or more subjects. In one modality, the PK profile is determined in a group of at least 8, 12, 16, or 20 subjects. In one modality, the group comprises healthy male and female subjects. In one modality, the number of subjects in the group is chosen to allow a statistically significant assessment of whether the PK profile produced by a test oral dosage form is a bioequivalent PK profile to the PK profile shown in Figure 1. An open-label, randomized, three-treatment, three-period study to evaluate the pharmacokinetic profile of Compound (I) and its metabolite BFB-520 following single oral administration of three MIN-101 formulations (two prototype gastro-resistant CR formulations (GR) (GR-01 and GR02) and one comparator MR formulation (MR32)) is summarized in Scheme 1 (MIN-101) and Scheme 2 (BFB-520). Full details of these experiments are provided in the Examples section. bRpznn / eznz / B / Yi Scheme 1. Summary of the PK study of MIN-101 for formulations MR32, GR-01 and GR-02. MR32 CMAX AUC MIN101 DATA AND PARAMETERS (from n=12 subjects with cross) 29.52 ng / ml 291.55 H.ng / ml TMax 2.4H GRO1 CMAX AUC MIN101 RELATIVE BIOAVAILABILITY COMPARED TO MR32 (from n=12 subjects with cross) 19.59 ng / ml F=69.9% 284.5 H.ng / ml F=101.3% TMax 6.0H GRO2 CMAX AUC MIN101 RELATIVE BIOAVAILABILITY COMPARED TO MR32 (from n=13 subjects with cross) 15.43 ng / ml F=54.33% 253.01 H.ng / ml F=86.9% TMax 15.2 H RATE OF INCREASE OF MIN101 CONCENTRATIONS IN PLASMA (VMax) MR32 GR01 GR02 VMax ng / ml / H 26.2 11.9 2.9 RATIO Test / MR32 REF 0.45 0.4 bRRznn / eznz / B / Yi Scheme 2. Summary of the PK study of BFB-520 for formulations MR32, GR-01 and GR-02. MR32 BFB-520 DATA AND PARAMETERS (from n=12 subjects with crossover) CMAX 1.91 ng / ml AUC 30.26 H.ng / ml TMax 6.9H GRO1 BFB-520 RELATIVE BIOAVAILABILITY COMPARED TO MR32 (from n=12 subjects with crossover) CMAX 1.43 ng / ml F=80.48% AUC 27.48 H.ng / ml F=96.1% TMax 12.5 H GRO2 BFB-520 RELATIVE BIOAVAILABILITY COMPARED TO MR32 (from n=12 subjects with crossover) CMAX 1.27 ng / ml F=69.48% AUC 27.53 H.ng / ml F=88.46% TMax 17.5 H RATE OF INCREASE OF BFB-520 CONCENTRATIONS IN PLASMA (VMax) MR32 GR01 GR02 VMax ng / ml / H 0.84 0.54 0.2 RATIO Test / MR32 REF 0.64 0.24 The pharmacokinetic (PK) profiles of MIN-101 and its metabolite BFB-520 were predicted for three MIN-101 formulations (two prototype gastro-resistant (GR) CR formulations (GR-01 and GR-02) and one comparator MR formulation (MR32)) at two dosages (32 mg and 64 mg), based on four daily doses. These studies are summarized in Scheme 3 (32 mg) and Scheme 4 (64 mg). Full details are provided in the Examples section. Scheme 3. Compendium of predicted plasma concentrations of MIN-101 and BFB-520 for formulations MR32, GR-01 and GR-02 (32 mg). bRpznn / eznz / B / Yi EXPECTED PLASMA CONCENTRATIONS OF 32 mg MR32 GR01 AND GR02 ON DAY 4 MR32 GR01 GR01 GR02 GR02 MIN101 CMaxSS 27.1 20.9 ng / ml F=76.9% 15.4 ng / ml F=56.7% AUCSS72-96 292.6 287.6 H.ng / ml F=98.3% 248.3 H.ng / ml F=84.9% CMinSS 3.32 6.46 ng / ml 7.17 ng / ml BFB-520 CMaxSS 1.89 1.46 ng / ml F=77.2% 1.23 ng / ml F=64.8% AUCSS72-96 29.1 26.3 H.ng / ml F=90.6% 23.6 H.ng / ml F=81.4% CMinSS 0.5 0.66 ng / ml 0.79 ng / ml Scheme 4. Compendium of predicted plasma concentrations of MIN-101 and BFB-520 for formulations MR32, GR-01 and GR-02 (64 mg). EXPECTED PLASMA CONCENTRATIONS OF 64 mg MR32 GR01 AND GR02 ON DAY 4 2xMR32 2xGR01 2xGR01 2xGR02 2xGR02 MIN101 CMaxSS 54.28 41.77 ng / ml F=76.9% 30.77 ng / ml F=56.7% AUCSS72-96 585.2 577.6 H.ng / ml F=98.7% 498.6 ng / ml F=85.2% CMinSS 6.64 12.93 ng / ml 14.35 ng / ml BFB-520 CMaxSS 3.79 2.92 ng / ml F=77.2% 2.45 ng / ml F=64.8% AUCSS72-96 58.1 52.8 H.ng / ml F=90.8% 47.4 H.ng / ml F=81.6% CMinSS 0.99 1.32 ng / ml 1.58 ng / ml The phosphokinase (PK) profiles of the GR-01 formulation in healthy CYP2D6 EM male and female subjects under fed and fasted conditions are summarized in Scheme 5 (MIN-101) and Scheme 6 (BFB520). Subjects who completed Part 1 of the study (evaluation of the PK profile of MIN-101 and its metabolite BFB-520 in formulations GR-01, GR-02, and MR32) returned and received an additional single oral dose of GR-01 under fed or fasted conditions to allow assessment of the feeding effect by comparing the PK properties with those obtained in Part 1 (Examples 9-12). There was a clearance period of 14 ± 2 days after Part 1. Full details of these experiments are provided in the Examples section. Scheme 5. Summary of the PK study of MIN-101 for the GR-01 formulation in the fed and fasted state. bRpznn / eznz / B / YiAi GRO1 ALIM. MIN101 (of n=12 subjects with crossover) CMAX AUC TMax 20.89 ng / ml F-108.97% in tablets with FASTING 269.19 H.ng / ml F=95.14% in tablets with FASTING 12.5H GRO1 CMAX AUC TMax FASTING MIN101 (from n=12 subjects with crossover) 19.59 ng / ml 284.52 H.ng / ml 6.0 H Scheme 6. Summary of the PK study of BFB-520 for the GR-01 formulation in the fed and fasted state. GRO1 ALIM.BFB-520 (^en=12 subjects with crossover) CMAX 1.69 ng / ml F= 121.32% in tablets with FASTING AUC 30.12 ng / ml F=111.58% in tablets with FASTING TMax 18.25 ng / ml GRO1 FASTING BFB-520 (from n=12 subjects with crossover) CMAX 1.43 ng / ml AUC 27.48 H.ng / ml TMax 12.5 H The pharmacokinetic (PK) profiles of MIN-101 and its metabolite BFB-520 were predicted in fed and fasted states for the gastro-resistant formulation GR-01 at two doses (32 mg and 64 mg), based on four target doses. These studies are summarized in Scheme 7 (32 mg) and Scheme 8 (64 mg), respectively. Full details are provided in the Examples section. Scheme 7. Compendium of predicted plasma concentrations of MIN-101 and BFB-520 for GR-01 (32 mg) in fed and fasted states. EXPECTED PLASMA CONCENTRATIONS OF 32 mg GR01 IN FEEDING AND FASTING STATEMENTS ON DAY 4 GR01 FEEDING GR01 FASTING MIN101 CMaxSS 16.7 F=80.0% 20.9 ng / ml AUCSS72-96 263.8 F=91.7% 287.6 H.ng / ml CMinSS 3.32 6.46 ng / ml BFB-520 CMaxSS 1.51 F=103.7% 1.46 ng / ml AUCSS72-96 29.5 F= 109.4% 26. 3 H.ng / ml CMinSS 1.03 0.66 ng / ml bRpznn / eznz / B / Yi Scheme 8. Compendium of predicted plasma concentrations of MIN-101 and BFB-520 for GR-01 (64 mg) in fed and fasted states. EXPECTED PLASMA CONCENTRATIONS OF 64mg GR01 IN FEEDING AND FASTING STATEMENTS ON DAY 4 GR01 FEEDING GR01 FASTING MIN101 CMaxSS 33.41 F=80.0% 41.77 ng / ml AUCSS72-96 527.5 F=91.3% 577.6 H.ng / ml CMinSS 16.17 12.93 ng / ml BFB-520 CMaxSS 3.01 F= 103.7% 2.91 ng / ml AUCSS72-96 59.0 F= 109.1% 54 4.ng / ml CMinSS 2.06 1.32 ng / ml BFB-520 is believed to be partially metabolized by CYP2D6. In clinical studies of MIN-101, CYP2D6 poor metabolizers exhibited elevated plasma levels of BFB-520. Therefore, in one modality, the Cmax for BFB-520 is assessed following oral administration of a trial dosage form comprising Compound (I) only to subjects assigned either an IM CYP2D6 or an EM CYP2D6 genotype using a commercially available genotype test. In another modality, all subjects were assigned an EM CYP2D6 genotype. The plasma levels of Compound (I) and the metabolite BFB-520 produced after oral administration of an oral dosage form of the description can be determined using the method described below. Variations and improvements to this method are also expected to be applicable. Blood samples from subjects are collected in sodium heparin tubes at various times of interest. A suitable sample collection schedule includes: • Day 1 (D1): pre-dose; 1 hr; 2 hours; 3 hours; 4 hours; 6h; 8am; 10am; 12pm and 4pm; • From Day 2 to Day 6 (D2-D6): before the dose • Day 7 (D7): before the dose; 1 h; 2 h; 3 h; 4 h; 6 h; 8 h; 10 h; 12 h; 16; 24 h (D8) and 48 h (D9). After blood centrifugation, the desired number of aliquots (typically 2) are prepared from each plasma sample in suitable storage containers (e.g., tightly capped polypropylene tubes to prevent leakage and drying during storage). The containers holding the plasma samples are stored at -80°C for up to one month prior to analysis. A GLP-validated method for detecting and quantifying Compound (I) and its metabolites BFB-520 and BFB-999 employs a liquid chromatography (LC) analysis coupled to mass spectrometry (MS / MS) detection after a liquid / liquid extraction step of Compound (I) and metabolites BFB-520 and BFB-999 from plasma samples. The analytical method uses two internal standards (a deuterated analogue of MIN-101 (designated herein [2H6]-MIN-101 or MIN-101-d6 or CYR-101-d6) and BFB-784 for BFB-520 and BFB-999), which were subjected to the same analytical procedure as MIN-101, BFB-520, and BFB-999 in plasma samples. MIN-101-d6 and BFB-784 have the structures shown in Formulas IV and V below: bRpznn / eznz / B / Yi Chromatograms are processed automatically by default. The chromatographic peaks of MIN-101, BFB-520, BFB-999, and internal standards (IS) are identified according to their retention times. The recorded response is expressed as the area ratio of MIN-101 to MIN-101-d6, and of BFB-520 or BFB-999 to BFB-784. The lower limit of quantification (LLOQ) of this analytical method in plasma is 0.25 ng / mL for MIN-101 and its metabolites BFB-520 and BFB-999. The details of the analytical method are described in Example 7 below. Variations and improvements to this analytical method are also expected to be applicable. Treatment methods The gastro-resistant CR oral dosage forms described herein may be useful for treating diseases or conditions treatable with Compound (I). By way of example only, Compound (I) is believed to be potentially useful for treating schizophrenic and non-schizophrenic patients with one or more of the following symptoms or conditions: negative symptoms, depressive symptoms, sleep disorders, and cognitive impairment. In a phase 2b study, 32 mg and 64 mg doses of MIN-101 showed 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 the 32 mg MR tablet described in Example 1 below and an essentially identical 64 mg MR tablet. Neither of these MR tablets had a GR coating, and each produced in vitro dissolution and plasma PK profiles that differ from those produced by the gastro-resistant CR oral dosage forms described herein. Negative symptoms generally refer to a reduction in normal functioning and include five main subdomains: blunted affect (affective flattening, dull expression), alogia (poverty of speech), demotivation (loss of volition), anhedonia (reduced ability to experience or anticipate pleasure), and asociality (social withdrawal).While negative symptoms are a well-documented and intensively studied aspect of schizophrenia, this class of symptoms has 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) (see, e.g., Boone et al., J. of Internat. Neuropsychol. Soc., 2003, Vol. 9, pp. 698–709; Bastiaansen, J. et al., J. Autism Dev. Disord. 2011, Vol. 41:1256-1266; Getz, K. et al., Am. J. Psychiatry 2002, Vol 159:644-651; WinogradGurvich, 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; Chaudhury, S., et al., Indian J. of Neurotrauma 2005, Vol 2:13-21; Ameen, S et al., German J. of Psychiatry 2007). In fact, as early as 2001, it was proposed that negative symptoms are common to mental illnesses in general (Herbener and Harrow, Schizophrenia Bulletin 2001, Vol. 27:527-537). Furthermore, reports from several population studies have concluded that between 20-22% of the general population has one or more negative symptoms, and that most 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). Therefore, it is an object of the present description to treat at least one negative symptom in a subject by administering to the subject a gastro-resistant CR dosage form described herein once daily (QD). In one modality, the subject has a diagnosis of schizophrenia. In another modality, the subject does not have a clinical diagnosis of schizophrenia, i.e., bRpznn / eznz / B / Yi is a non-schizophrenic patient. For the purposes of the description covered herein, it should be understood that the expressions "negative symptoms" include the primary negative symptoms typically associated with schizophrenia, the negative symptoms measured in the PANSS negative symptoms subscale score, the negative factor score based on the pentagonal structure model method, and the negative symptoms measured in the BNSS. In one modality, the negative symptom is one of five major subdomains of negative symptoms: blunted affect, alogia, demotivation, anhedonia, and asociality. The main characteristics of each subdomain will be described below. Blunted affect (affective flattening, blunted expression) is characterized by a reduced intensity and range of emotional expression that manifests itself through vocal and nonverbal modes of communication, including intonation (prosody), facial expression, hand gestures, and body movements. Alogia (poverty of speech) is characterized by a decrease in the amount of speech, a spontaneous reduction in speech, and a loss of fluency in conversation. Demotivation (loss of volition) is characterized by deficits in initiating and maintaining goal-directed behaviors such as work, study, sports, personal hygiene, and daily tasks, especially when they require significant effort (cognitive or physical) and organization, as well as deficits in the desire to undertake such activities. This subdomain is related to apathy and lack of energy. Anhedonia (reduced capacity to experience or anticipate pleasure) is characterized by an expectation of a reward, a recreational experience or other pleasurable experience ("wanting") that is affected more markedly and systematically (anticipatory anhedonia) than the appreciation ("enjoyment") of the experience itself (consummatory anhedonia). Asociality (social withdrawal) is characterized by decreased interest, motivation, and appreciation of social interactions with others, such as family and friends, loss of interest in intimate (sexual) relationships regardless of any somatic problems, and, in the case of a child, may include loss of interest in playing with other children. In some formulations, the dosage form is administered to the subject once daily for an initial treatment period long enough to achieve improvement in at least one negative symptom. In one formulation, the initial 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 one formulation, positive symptoms in a subject treated with the dosage form are stable throughout the treatment period, meaning they remain substantially at the same level as at baseline. In one formulation, the level of improvement in negative symptoms is a reduction of at least 3 points in the five-factor PANSS negative symptom factor scores (pentagonal structure model) after 12 weeks of treatment.In one modality, the subject's negative symptom score continues to improve from 12 weeks until at least around 24, 36, or 48 weeks of treatment. The PANSS pentagonal structure model is described in WHITE L, HARVEY PD, OPLER L, LINDENMAYER J. EMPIRICAL ASSESSMENT OF THE FACTORIAL STRUCTURE OF CLINICAL SYMPTOMS IN SCHIZOPHRENIA. PSYCHOPATHOLOGY. 1997;30(5):263-74. In some modalities, if a subject experiences improvement in at least one negative symptom during the first treatment period, administration of the therapeutically effective dose 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 have functional improvement following the improvement in negative symptoms. In one modality, the positive symptoms in a subject treated with the dosage form are stable for at least part of the second treatment period, meaning they remain substantially at the same level as at baseline. In some modalities, the subject has a diagnosis of schizophrenia. In one modality, a subject selected for treatment with an oral dosage form of the description has a baseline negative PANSS subscore greater than or equal to 20.In one modality, the selected subject also has baseline scores of less than 4 on the following PANSS items: excitation, hyperactivity, hostility, mistrust, uncooperativeness, and poor impulse control. In another modality, the selected schizophrenic subject has exhibited stable positive symptoms of schizophrenia for at least the preceding month, two months, or three months and has exhibited negative symptoms for at least the preceding month, two months, or three months. In some modalities, a schizophrenic subject treated with the gastro-resistant oral CR dosage form described herein has prominent negative symptoms. In one modality, a schizophrenic subject is defined as having prominent negative symptoms when the subject scores >4 (moderate) on at least three items of the PANSS negative symptom subscale but not on items of the PANSS positive character subscale. In another modality, the subject has both prominent positive and negative symptoms when the subject scores >4 on items for both positive and negative symptoms. Up to 75% of schizophrenic patients experience cognitive impairment, and the previously described phase 2b study of MIN-101 demonstrated an improvement in cognitive function. Thus, in one respect, administration of the gastro-resistant oral CR dosage form described herein to a patient diagnosed with schizophrenia is intended to improve cognitive function in the patient. In some cases, the subject has not been previously treated with an antipsychotic drug. In other cases, the subject has discontinued previous treatment with an antipsychotic drug because they are experiencing one or more of the following: satisfactory reduction of positive symptoms, an inadequate response to negative symptoms, or intolerable side effects. A secondary outcome of the phase 2b study of MIN-101 described above was the performance of patients on the Calgary Depression 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 between positive and negative symptoms and has become the recommended 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. A correlation analysis between the initial treatment effects on negative symptoms and depression symptoms in this patient cohort showed that there was only a small correlation between the effects of MIN-101 on these two symptom categories.Therefore, given that the effects of MIN-101 on negative symptoms and symptoms of depression in patients with schizophrenia were largely independent of each other, MIN-101 has the potential to alleviate one or more symptoms of depression in patients who are not schizophrenic. Therefore, another objective of this description is to treat at least one symptom of depression in a subject in need by means of a method of administering a gastro-resistant CR dosage form described herein. In one modality, the subject has a diagnosis of schizophrenia. In another modality, the improvement in the symptoms of depression in a schizophrenic patient is measured using the CDSS. Another objective of this description is to reduce the risk of QT prolongation in a subject treated with Compound (I) by administering Compound (I) to the subject as formulated in a gastro-resistant CR dosage form described herein. In one modality, the subject has been identified as having one or more risk factors for drug-induced QT prolongation. In one modality, the subject discontinued prior treatment with a compound other than Compound (I) because they experienced QT prolongation. In one modality, the subject discontinued prior treatment with a different dosage form comprising Compound (I) because they experienced QT prolongation.In one modality, the subject has a selected diagnosis within the group consisting of: prominent negative symptoms of schizophrenia, prominent positive and prominent negative symptoms of schizophrenia, major depressive disorder (MDD), a sleep disorder, and cognitive impairment. bRpznn / eznz / B / Yi In some forms of any of the above treatment methods, the gastro-resistant oral dosage form is administered in the morning or evening. In one form, the dosage form is administered at least two hours before eating. In some forms of any of the above treatment methods, the subject is 12 years of age or older. In some forms, the subject is at least 14, 16, 18, or 20 years of age. In some forms, the subject is under 50, 45, 40, 35, or 30 years of age. In one form, the subject is at least 16 years old and under 40, 35, or 30 years of age. In some modalities of any of the above treatment methods, the dosage form may be administered to the subject in combination with another therapeutic agent. In one modality, the other therapeutic agent does not inhibit CYP2D6 activity. In another modality, the subject is diagnosed with schizophrenia, and the other therapeutic agent is an antipsychotic drug. In some modalities of any of the above treatment methods, the subject may have been assigned an IM genotype and / or an EM genotype. In one modality, the subject has been assigned an EM genotype. In some forms of any of the above treatment methods, the oral dosage form may comprise 32 mg of Compound (I). In one form, the oral dosage form consists essentially of the components listed in Table 2 or Table 3 below. EXAMPLES Example 1: Description of a 32 mg MR tablet used in the MIN-101 Phase 2b Trial. The 32 mg MR tablets are supplied as round tablets (diameter: 10 mm and R=10) with a white coating free of visual defects. Each tablet contains 32 mg of Compound (I). The full description of the components and the quantitative composition of the 32 mg MR tablet are provided in Table 1 below. Table 1: Composition of the 32 mg MR tablet bRpznn / eznz / B / Yi Composition 32 mg MR Tablet Function % w / w mg / tablet MIN-1011 12.19 38.40 Active ingredient Hypromellose (Methocel™ K100LV CR) 9.52 30.00 Controlled-release excipient Hypromellose (Methocel™ K4M CR) 22.86 72.00 Controlled-release excipient Microcrystalline cellulose (Avicel PH102) 30.19 95.10 Filler Lactose monohydrate (Fast Fio J Λ Λ f- r—1 _ II _ _ bRpznn / eznz / B / Y Colloidal anhydrous silica (Aerosil 200 Pharma) 0.48 1.50 Glide Magnesium stearate (vegetable grade source Hyqual NF) 0.95 3.00 Lubricant Total (tablet cores) 95.23 300.00 Sepifilm (LP 770 Blanc) 4.76 15 Coating agent Total 100.00 315.00 1Salt correction factor of 1.2 applied NA: Not applicable Example 2: Description of an example of a 32 mg gastro-resistant CR tablet. CR GR-01 tablets are supplied as round tablets (diameter: 10 mm and R=10), free from visual defects. Each tablet contains 32 mg of Compound (I). The complete description of the components and the quantitative composition of the CR GR-01 tablet are provided in Table 2. Table 2: Composition of the CR GR-01 tablet Composition Tablet CR GR-01 Function % w / w mg / tablet MIN-1011 12.09 38.40 Active ingredient Hypromellose (Metolose® 90SH 100 SR) 9.45 30.00 Controlled release excipient Hypromellose (Methocel™ Κ1ΩΩM Excinerator of bRpznn / eznz / B / Y Eudragit L30D55 ​​4.72 15.00 Controlled-release excipient Plasacryl HTP20 0.80 2.55 Anti-adherent agent Total 100.00 317.55 1Salt correction factor of 1.2 applied NA: Not applicable Example 3: Description of another example of a 32 mg gastro-resistant CR tablet. CR GR-02 tablets are supplied as round tablets (diameter: 10 mm and R=10), free from visual defects. Each tablet contains 32 mg of Compound (I). The complete description of the components and the quantitative composition of the CR GR-02 tablet are provided in Table 3. Table 3: Composition of the CR GR-02 tablet Composition Tablet CR GR-02 Function % w / w mg / tablet MIN-1011 11.98 38.40 Active ingredient Hypromellose (Methocel™ K15M CR) 9.36 30.00 Controlled release excipient Hypromellose (Methocel™ K100M Excipient of bRpznn / eznz / B / Y Plasacryl HTP20 0.80 2.55 Anti-adherent agent Surelease E-7-19040 0.94 3.00 Controlled-release excipient Total 100.00 320.55 Salt correction factor of 1.2 applied NA: Not applicable Example 4: Batch formula for CR GR-01 and CR GR-02 tablets. A representative batch size for CR GR-01 and CR GR-02 tablets is 5400 tablets. Batch formulations are described in Tables 4 and 5 below. Table 4: Batch formula for the CR GR-01 tablet Composition kg / lot MIN-101 0.206 Hypromellose Metolose® 90SH 100SR 0.162 Hypromellose Methocel™ K100M CR 0.389 C.phiInQa minrnnriQtnlinn n 514 bRRznn / eznz / B / Y NA: Not applicable Table 5: Batch formula for the CR GR-02 tablet Composition kg / lot MIN-101 0.207 Hypromellose Methocel™ K15M CR 0.162 Hypromellose Methocel™ K100M CR 0.389 Microcrystalline cellulose 0.514 Lactose 0.324 Colloidal anhydrous silica 0.008 Magnesium stearate 0.016 Eudragit L30D55 ​​0.081 Plasacryl HTP 20 0.014 Surelease E-7-19040 0.016 Total 1.731 Table 5A: Batch formula for GR-01 / B tablets (representative formula size λ λ ** I λ+λ / » λΙλ ΕΣ ΛΛ ίΛΓΛΓΛ Composition kg / batch MIN-101 5.75 Hypromellose Methocel™ K100 LV CR 4.5 Hypromellose Methocel™ K100M CR 10.80 Microcrystalline cellulose 14.5 Lactose 9 Colloidal anhydrous silica 0.22 Magnesium stearate 0.22 Eudragit L30D55 ​​2.25 Plasacryl HTP 20 0.380 Total 47.63 Example 5: Development of an optimized in vitro dissolution method Based on the pharmacokinetic (PK) profiles of Compound (I) obtained from 32 mg MIN-101 MR tablets used in clinical studies, an in vitro / in vivo correlation (IVIVC) approach was proposed. The IVIVC approach is defined by the PDA as a predictive mathematical model that describes the relationship between an in vitro property of the dosage form and an in vivo response. In this context, the model refers to the relationship between the in vitro dissolution of the 32 mg MR tablet and its in vivo response, such as the plasma concentration of Compound (I). The main objectives of the IVIVC model were to validate the use of a predictive in vitro dissolution method and to select optimized target formulations. If clinical results confirm the validity of the IVIVC model, the in vitro dissolution method could be used as a surrogate method for clinical studies. First, after analyzing all the PK data for Compound (I) from the clinical studies, an in vitro dissolution profile of the 32 mg MR tablet described in Example 1 was defined. This target in vitro dissolution profile was then used to develop an optimized in vitro dissolution method. This method is described in the following example. Secondly, and when the in vitro dissolution method was considered to be sufficiently close to expectations, the target in vitro dissolution profile of a gastro-resistant CR oral dosage form was defined and used to design the gastro-resistant dosage forms described in Examples 2 and 3. The dissolution profiles for these two GR dosage forms (GR-01 and GR-02) and the 32 mg MR tablet from Example 1, which were generated using the optimized dissolution method, are shown in Tables 6 and 7 below. Table 6: In vitro cumulative dissolution profiles Time (hours) Cumulative Dissolution of Compound (1) (mg) Target Profile 32 mg MR Tablet GR-01 Tablet GR-02 Tablet 0 0 0 0 0 bRRznn / eznz / e / YiAi Table 7: In vitro dissolution rate profiles Time (hours) Compound dissolution rate (1) (mg / hour) Target profile 32 mg MR tablet GR-01 tablet GR-02 tablet 0 0 0 0 0 0.5 0 6.4 0 0 1 0 3.7 0 0 2 0 2.7 0 0 2.5 0.4 - 0 0 3 1.5 2.0 2.3 0.1 4 2.3 4.11 3.3 0.8 5 2.0 2.41 - 1.7 6 1.9 - 2.2 2 8 1.9 1.9 1.5 1.8 10 1.9 - - 1.5 11 - 1.3 1.8 - 13 1.6 0.8 1.9 1.4 14 1.3 - - - 15 1.2 - - - 16 0.5 1.3 1.1 18 1.0 - - 0.9 19 0.2 0.7 0.9 21 0.9 - 0.9 24 0.8 0.4 1 is not considered The CR GR-01 and CR GR-02 tablets and the 32 mg MR tablet, for comparative use, were evaluated in a clinical study (MIN-101-C06) to assess the plasma PK profile of each dosage form. bRpznn / eznz / B / Yi Example 6: Analytical method for the assay of 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 (throughout this document). The volumes are given as examples; different volumes can be prepared if 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: Buffer solution with pH 9 Transfer the contents of one ampoule of buffer concentrate with pH 9 (Merck, P / N 109889) to a 500 mL volumetric flask. Fill to 500.0 mL with water. Storage: 1 month at approx. +5°C. Shock absorber: Ammonium acetate shock absorber 1 M Dissolve 7.7 g of ammonium acetate with 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. Or dissolve 0.77 g of ammonium acetate in 1 L of water. Degas if necessary (by sonication or by magnetic stirring under vacuum). Storage: 5 days at room temperature. Reconstitution solvent: 80 / 20 (v / v) solution of 10 nm ammonium acetate buffer / acetonitrile Mix 400 mL of ammonium acetate buffer solution with 100 mL of acetonitrile. Or add 4 mL of 1 M ammonium acetate buffer solution to 396 mL of water and 100 mL of acetonitrile. Storage: 5 days at room temperature. bRpznn / eznz / B / Yi Solvent for rinsing needle: 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. Solvent for rinsing needle: 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. Solvent for rinsing column: 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 PROCEDURE Control plasma and plasma samples are thawed at room temperature and centrifuged at 1920 g for 5 minutes at +4SC. • Sample preparation Blank reagent sample In a 10 mL polypropylene tube: 1. Transfer 250 pL of water. Blank and zero samples In a 10 mL polypropylene tube: 1. Transfer 250 pL of control plasma. Calibration standards In a 1.5 mL conical polypropylene tube: 1. Transfer 900 pL of control plasma, 2. Add 100 pL of suitable WS, 3. Mix in a vortex for 30 seconds, 4. Transfer 250 pL of the preparation to a 10 mL polypropylene tube. QC samples bRpznn / eznz / B / Yi In a 1.5 mL conical polypropylene tube: 1. Transfer 900 μΙ_ of control plasma, 2. Add 100 μΙ_ of suitable QC-WS, 3. Mix in a vortex for 30 seconds, 4. Transfer 250 µL of the preparation to a 10 mL polypropylene tube. Specimens In a 10 mL polypropylene tube: 1. Transfer 250 pL of plasma sample. Samples diluted 20 times [2] In a 1.5 mL conical polypropylene tube: 1. Transfer 380 pL of control plasma, 2. Add 20 pL of control plasma for dilution, 3. Mix in a vortex for 30 seconds, 4. Transfer 250 pL of the preparation to a 10 mL polypropylene tube. • Extraction procedure 1. Add 25 pL of dilution solvent (blank reagent sample, blank sample) or 25 pL of IS-WS (other samples), 2. Add 1 mL of buffer solution with a pH of 9, 3. Mix in a vortex for 10 seconds, 4. Add 4 mL of diethyl ether, 5. Mix in an oscillating stirrer at low speed for 20 minutes, 6. Centrifuge at 1920 g for 10 minutes at +4SC, 7. Transfer the tubes to ca. -80°C for 15 minutes, 8. Transfer the organic phase (upper phase) to a 5 mL glass tube, 9. Evaporate to dry under a hydrogen flow at +30°C, 10. Reconstitute with 200 pL of reconstitution solvent, 11. Mix in a vortex for 30 seconds, 12. Centrifuge at 1920 g for 5 minutes at +4°C, 13. Transfer the final extract to a polypropylene vial, 14. Close the vial with a Teflon / silicone / Teflon septum cap, 15. Centrifuge at 2500 g for 7 minutes at +4SC, bRpznn / eznz / B / Yi 16. Place the vials in the automatic sample generator until analysis. O [4] 13. Transfer the final extract to a 2 mL polypropylene 96-well collection plate, 14. Seal the plate with a pre-perforated silicone lid, 15. Centrifuge at 2500 g for 7 minutes at +4eC, 16. Place the plate in the automatic sample generator until analysis. ANALYSIS CONDITIONS • Chromatographic conditions Column and oven Column: Gemini C18 100 x 4.6 mm, 3.0 pm (Phenomenex) Guard or filter column: C18 4 x 2 mm (Phenomenex) Column temperature: +40eC ±5SC Column rinse solvent: 90 / 10 (v / v) acetonitrile / water solution Column rinse conditions: 60 minutes at 0.6 mL / min Automatic sample generator Injection volume: 5 pL (to be adjusted according to the sensitivity of the MS) Automatic sample generator temperature: +5°C Bomb Mobile phase A: 10 mM ammonium acetate buffer solution Mobile phase B: Acetonitrile Socratic mode bRpznn / eznz / B / Yi Flow rate (mL / min) Mobile phase A (%) Mobile phase B (%) 0.6 35 65 Detection Detection type: MRM Ionization type and mode: ES1 in positive ionization mode Precursor ion: [M+H]+ MRM Transitions Analyte Transition MRM MIN-101 (CYR-101) 367>146 BFB-520 369 >146 BFB-999 383 > 232 CYR-101-Ó6 373 >152 BFB-784 387 >164 bRpznn / eznz / B / Yi • Team LC n.g1 Description Equipment Type Automatic Sample Generator Automatic Sample Generator G1367B and Thermostat G1330B (Agilent) LC Pump Quaternary Pump G1311A and Degasser G1322A (Agilent) Column Oven Column Compartment with Thermostat G1316A (Agilent) Detector EP10+HSID++ (Ionics) System care Solvent for rinsing needle: 80 / 20 (v / v) acetonitrile / water solution Needle rinse programming Step Description 1 Wash needle in rinse port for 15 seconds 2 Remove def amount of sample, 200 pUmin, 1 mm deviation 3 Wash needle in rinse port for 15 seconds 4 Inject 5 Remote start pulse, duration: 10x12.5 ms Conditions of analysis Injection volume: 5 μL Execution time: 6.0 min Retention times (Rt) Analyte Rt (min) MIN-101 (CYR-101) ca. 2.9 BFB-520 ca. 2.3 BFB-999 ca. 2.4 CYR-101-Ó6 ca. 2.9 BFB-784 ca. 2.4 bRpznn / eznz / B / Yi • LC Team No. 23 [51 Description Equipment Type Automatic Sample Generator Sample Manager Acquity UPLC FTN (Waters) LC Pump Acquity UPLC l-Class (Waters) Column Oven Column Heater Acquity UPLC (Waters) XevoTQ-S Detector (Waters) System care Solvent for rinsing needle External (Wash): 80 / 20 (v / v) acetonitrile / water solution Internal (Purge): 65 / 35 (v / v) acetonitrile / water solution Needle Rinse Schedule: Pre-injection wash: 0 seconds Post-injection wash: 6 seconds Assay Conditions Injection volume: 0.5 pL Run time: 6.0 min Retention Times (Rt) Analyte Rt (min) MIN-101 (CYR-101) ca. 3.0 BFB-520 ca. 2.4 BFB-999 ca. 2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.5 LC Team No. 22 [3] Description Equipment Type: Automatic Sample Generator (Acquity UPLC Waters) LC Pump Column Oven High-Temperature Column Heater (Acquity UPLC Waters) API 4000 Detector (AbSciex) bRpznn / eznz / B / Yi System care Solvent for rinsing needles Strong solvent: 80 / 20 (v / v) acetonitrile / water solution 2000 ml Weak solvent: 65 / 35 (v / v) acetonitrile / water solution 4000 ml Conditions of analysis Injection volume: 1 pL Injection mode: Partial cycle Run time: 6.0 min Retention times (Rt) Analyte Rt (min) MIN-101 (CYR-101) BFB-520 ca. 2.9 ca. 2.3 BFB-999 ca. 2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.4 DATA PROCESSING AND ACCEPTANCE CRITERIA bRpznn / eznz / B / Yi Data processing [2] MIN-101 (CYR-101) BFB-520 BFB-999 Calibration Interval LLOQ (ng / mL) 0.2500 0.2500 0.2500 ULOQ (ng / mL) 200.0 50.00 50.00 Response Peak Area of ​​MIN-101 / Peak Area of ​​CYR-101-d6 Peak Area of ​​BFB-520 / Peak Area of ​​BFB-784 Peak Area of ​​BFB-999 / Peak Area of ​​BFB-784 Regression Model 1 / X2 Weighted Simple Linear Regression 1 / X2 Weighted Simple Linear Regression 1 / X2 Weighted Simple Linear Regression Example 7: Synopsis of the MIN-101C06 protocol Sponsor / Company Name: Minerva Neurosciences, Inc. Product name under investigation: MIN-101____________________________________________________________________________ Study Name: Phase 1, open-label, randomized, 3-treatment, 3-period, single-dose crossover study in healthy subjects with extensive CYP2D6 metabolism to compare the pharmacokinetic properties of 2 gastro-resistant modified-release MIN-101 formulations and 1 comparator and their metabolites followed by assessment of the dietary effects of the selected gastro-resistant controlled-release formulation Goals: Primary: Part 1: PK Assessment • Evaluate the pharmacokinetic (PK) profiles of MIN-101 and its main metabolites (BFB520 and BFB-999) after administration of two gastro-resistant modified-release (MR) MIN-101 formulations and one comparator in healthy male and female subjects with healthy cytochrome P450 (CYP) 2D6 extensive metabolizers (EMs). • Select one gastro-resistant MR formulation for use in a fed state. Part 2: Food Effect • Evaluate the effect of food (provided as a high-fat, high-calorie meal) on the bioavailability of MIN-101 and its main metabolites when the selected gastro-resistant MR formulation is administered as a single 32 mg dose to healthy male and female subjects with healthy CYP2D6 EMs. Secondary: Part 1: PK Assessment • To provide additional information on the safety and tolerability of single doses of MIN-101 in healthy male and female subjects with CYP2D6 MS. • Evaluate the relationship between plasma levels of MIN-101 and its main metabolites on electrocardiogram (ECG) parameters, including QT / QTcF Part 2: Feeding Effect • Evaluate the safety and tolerability of the selected MR formulation in healthy male and female subjects with CYP2D6 EM in a fed state compared to a fasted state. bRpznn / eznz / B / Yi Methodology: This is a single-center, two-part, phase 1 study. Part 1: PK Assessment Part 1 is an open-label, randomized, three-treatment sequential study conducted over three periods to evaluate the pharmacokinetic profile of MIN-101 and its metabolites (BFB-520 and BFB-999) following single oral administration of three MIN-101 formulations (two prototype gastro-resistant CR formulations and one comparator MR formulation). Each subject will receive a single dose of each formulation during the three periods. There will be a clearance period of 14 ± 2 days between the three periods. In total, doses will be administered to 16 healthy male or female subjects with CYP2D6 EM (ideally an equal split between genders, but a minimum of 6 of each sex) to ensure data for 12 evaluable subjects. To be evaluable, subjects must have received all 3 formulations and have sufficient data for the primary endpoint of Part 1 of the study. Subjects must provide written informed consent to participate in the study before any assessments or laboratory samples are collected. Subjects will be assessed for study eligibility during the preliminary screening period. After obtaining written informed consent, a complete medical history will be documented. A complete physical examination will be performed, including measurement of vital signs, ECG (in triplicate), body weight, and height. Hematology, clinical chemistry, and urinalysis will be performed for all subjects.All subjects must be willing to use a dual-barrier contraceptive method acceptable with their partners from the preliminary examination until 90 days after the last dose. Part 2: Dietary Effect Subjects who completed Part 1 of the study will return and receive an additional single oral dose of one of the selected GR prototypes under feeding conditions to allow for assessment of the effect of the food by comparing the PK properties with those obtained in Part 1. Part 2 will commence after a review of the PK and safety data to determine which GR formulation will be used. There will be a washout period of 14 ± 2 days after the completion of Part 1. End-of-study or early withdrawal assessments will be performed 5-9 days after the last dose received. bRpznn / eznz / B / Yi Number of subjects (planned): In total, doses will be administered to 16 healthy male or female subjects with CYP2D6 EM (ideally an equal division by gender, but a minimum of 6 of each sex) to ensure data in 12 evaluable subjects. Subjects who withdraw due to adverse events (AEs) unrelated to IMP will be replaced as needed to ensure 12 evaluable subjects for both Part 1 and Part 2 at the end of the clinical study. Subjects who withdraw due to an IMP-related AE will not be replaced. Diagnosis and main criteria for inclusion / exclusion: Inclusion criteria Subjects must meet all of the following inclusion criteria during the preliminary screening to enroll in the study: 1. Confirmed CYP 2D6 extensive metabolizer genotype defined as a subject having at least one functional allele (*1 or *2) but no non-functional allele, meaning any combination of *1 and *2, and one decreased-function allele (*10, *17 or *41) is permitted by documented evidence 2. The subject has voluntarily given his informed written consent before performing any procedure related to the study. 3. Must be between 18 and 45 years of age, inclusive 4. The subject must be a healthy man or woman as indicated below: • Clinical chemistry, hematology, and urinalysis must be within acceptable normal limits (if outside the range, with the exception of potassium, magnesium, and calcium, they should be considered clinically significant and therefore exclusionary) and must be performed within 21 days of receiving the first dose of the study drug. • Body mass index between 18 and 30 kg / m², inclusive. • Normal vital signs after 5 minutes of rest in a supine position. or 95 mm Hg < systolic blood pressure < 140 mm Hg or 50 mm Hg < diastolic blood pressure < 90 mm Hg or 50 bpm < heart rate < 90 bpm A normal 12-lead ECG is defined as: P <120 ms, 120 ms < PR <210 ms, QRS < 120 ms, QTc (Fridericia) < 430 ms for men and < bRpznn / eznz / B / Yi 440 ms for women (incomplete right bundle branch block may be acceptable) 5. Agree to abstain from taking any medication (except for permitted contraceptives as defined in inclusion criteria 6), including prescription and non-prescription medications (including vitamins and natural or herbal remedies, e.g., St. John's wort) for 21 days before the first dose with IMP in period 1 until discharge from the study (end of post-study medical follow-up period 4) 6. The subject agrees to use the following contraceptive methods: Female subjects of childbearing age must be willing to use two contraceptive methods throughout and for up to 30 days after the study ends. One of these must be a highly effective method, defined as one that produces a low failure rate (i.e., less than 1% per year) when used consistently and correctly. The following highly effective contraceptive methods are acceptable for this study: • Surgical sterilization (i.e., bilateral tubal ligation / salpingectomy, hysterectomy for female subjects or their partners; vasectomy for male subjects or their partners) • Placement of an intrauterine device or intrauterine system • Hormonal contraception (implantable, patch, injectable) PLEASE NOTE: Oral hormonal contraceptives are not permitted in this study. • True sexual abstinence when this is in line with the subject's preferred and usual lifestyle, periodic abstinence (e.g., ovulation calendar methods, symptothermal, post-ovulation), declaration of abstinence for the duration of the trial, and coitus interruptus are NOT acceptable contraceptive methods. The following acceptable methods may be used as a second form of contraception during the study: • Barrier methods for women include the use of condoms by their partner or the use of an occlusive cap [diaphragm or cervical / vault caps] with spermicidal foam, gel, film, cream, or suppository bRpznn / eznz / B / Yi Female subjects in the postmenopausal stage (defined as spontaneous amenorrhea for at least 1 year or spontaneous amenorrhea for at least 6 months confirmed by a follicle-stimulating hormone [FSH] result of >40 IU / mL) are eligible for this study. Male subjects Male subjects who have been sterilized or who have infertile partners (including homosexual men) must use a barrier method of contraception. This is to prevent unintentional exposure of the partner to the study drug through seminal fluid (for male subjects, this should be a condom or the partner's use of an occlusive cap [diaphragm or cervical / vault caps]). Male subjects with fertile partners must be willing to use a barrier contraceptive method with their partners throughout the study (a condom or their partner's use of an occlusive cap [diaphragm or cervical / vault caps]). Their partners must also be using a highly effective contraceptive method, defined as one with 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 the study ends. Subjects must agree to inform the investigator if their partner becomes pregnant during this time. 7. You must be willing and able to communicate and participate throughout the study. 8. Willing to eat all the food provided throughout the study. bRpznn / eznz / B / Yi Exclusion criteria Subjects who meet any of the following exclusion criteria will not be eligible to enroll in the study: 1. History of clinically significant gastrointestinal disease (especially peptic ulcers, gastrointestinal bleeding, ulcerative colitis, Crohn's disease, or irritable bowel syndrome); renal, hepatic, neurological, hematological, endocrine, oncological, pulmonary, immunological, or psychiatric disease (especially those with a history of clinically significant depression, suicidal ideation, or suicide attempts); or cardiovascular disease; or any other condition that, in the opinion of the principal investigator, jeopardizes the subject's safety or affects the validity of the study results. 2. Acute diarrhea or constipation within 7 days prior to the first scheduled study day. If the preliminary examination occurs >7 days before the first study day, this criterion will be determined on the first study day. Diarrhea is defined as the passage of loose or watery stools and / or a bowel movement frequency of >3 times per day. Constipation is defined as the inability to have a bowel movement more frequently than every other day. 3. The subject has donated blood within 90 days or plasma within 30 days of the study dose administration. 4. Regular alcohol consumption in men > 21 units per week and in women > 14 units per week (1 unit = 1 / z pint of beer, 25 mL of 40% alcohol or a 125 mL glass of wine) 5. The subject has a borderline or long QTc interval, as defined by preliminary examination readings >430 ms for men and >440 ms for women, or a personal or family history of long QT syndrome. 6. The subject has participated in a clinical trial within 90 days prior to the start of the study. 7. Pregnant or breastfeeding women 8. The subject has used any prescription or nonprescription drug (PPD), including vitamin supplements, within the 21 days prior to day -1 9. The subject has been treated with any drug that alters P450 2D6 or 3A4 enzymes (e.g., beta-blockers, antidepressants, antipsychotics, certain antibiotics such as erythromycin, ketoconazole, rifampicin, trimethoprim or clathromycin, 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. The subject has smoked or used nicotine products within the 2 months prior to or during the study 11. The subject has consulted with or been referred to a general practitioner or counselor for abuse or misuse of alcohol, non-medical drugs, medicinal drugs, or other substances, e.g., solvents. 12. The subject has a positive blood test for HIV, hepatitis B surface antigen (HBsAg), and hepatitis C antibody 13. Any current or past use of drugs such as opiates, cocaine, ecstasy, or intravenous amphetamines and / or a positive urine test for alcohol or adjective drugs. Subjects who admit to occasional past cannabis use will not be excluded, provided they have a negative test for addictive drugs and have abstained from cannabis use for at least 3 months. 14. The subject has a current uncontrolled intercurrent illness (i.e., active infection) or has had a clinically significant illness in the 30 days prior to Day -1 15. The subject underwent major surgery within 28 days of entering the study, or 12 months prior to the study in the case of gastrointestinal surgery. 16. Failure to meet the fitness investigator's standards for participation for any other reason. Test product, dosage and route of administration: Part 1: After a 10-hour overnight fast, on the morning of dosing days, the study drug will be administered with 240 mL of non-carbonated water. Subjects will have their first meal at lunchtime. Subjects will receive a single oral administration of one of the following regimens in randomized order, separated by a clearance period of 14 ± 2 days: Regimen A: 32 mg of MIN-101 of the current modified-release formulation (comparative) identified as formulation MR-32 administered in a fasted state. Regimen B: 32 mg of MIN-101 of gastro-resistant CR formulation identified as GR-01: administered in a fasted state. bRpznn / eznz / B / Yi Regimen C: 32 mg of MIN-101 of gastro-resistant CR formulation identified as GR02: administered in a fasted state Part 2: In Part 2, subjects will receive 1 oral dose of the selected gastro-resistant CR formulation (GR-01 or GR-02) while feeding. After fasting for 10 hours overnight, on the morning of Day 1, subjects will receive a high-fat, high-calorie breakfast before administration of the study drug. Subjects will consume the meal within 25 minutes or less. The study drug will be administered 30 minutes after the meal is completed and the meal begins. All study drugs will be administered orally with 240 mL of non-carbonated water. Water may be consumed at will, except for 1 hour before and 1 hour after drug administration. Reference therapy, dosage and method of administration: Not applicable.32 mg of MIN-101 from the current modified-release formulation that will be used for comparison. Duration of subject participation / Duration of study / Duration of treatment: Selection: Up to 21 days before the first dosing period 1 Institutionalization: From the morning of Day -1 until Day 4 during 4 separate periods Purging period: 14±2 days from the dosing of the previous period End-of-study visit: (± 2 days) days after the last dose Total duration of study (including a preliminary examination period of 21 days): Up to 78 days. bRpznn / cznz / B / Yi EVALUATION CRITERIA Pharmacokinetics: Plasma will be stored at -80°C until analysis. Plasma samples will be 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 time 0 (before the 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 all periods. The following key plasma PK parameters will be measured using non-compartmental methods: Cmax, Tmax' ± delay, partial AUC (e.g., AUC12, AUC24), AUCur, AUC„, and t1 / 2. Additional PK parameters may be included if deemed appropriate. The ECG will be detailed as there will be a PK / PD assessment The effects on cardiovascular variables will be assessed using descriptive statistics and frequency tables. These tables will include observed values ​​and changes relative to baseline values ​​(the pre-dose ECG will be used as the baseline) to allow for the detection of clinically significant changes in individuals. The ECG variables to be analyzed are heart rate, PR interval, QRS interval, QT interval, and QTc interval, with heart rate corrected using QTcF. QTcF values ​​will be tabulated in their absolute values ​​and also compared to baseline measurements to detect individual QTcF changes. Descriptive statistics for QTcF intervals and changes from baseline will be summarized at each scheduled time point. The percentage of subjects with QTc intervals > 450 milliseconds, > 480 milliseconds, or > 500 milliseconds will be summarized, as will the percentage of subjects with QTcF interval increases from baseline of 30 to 59 milliseconds or > 60 milliseconds. Significant abnormalities in the ECG waveform that constitute changes from baseline readings (e.g., changes in T wave morphology or the appearance of U waves) will be reported. Safety and tolerability: The incidence of adverse events and clinically significant abnormal laboratory values, vital signs, and ECGs will be recorded based on the investigator's observation and the subjects' reports. bRpznn / eznz / B / Yi STATISTICAL CONSIDERATIONS Sample size: The sample size for this study is based on both quantitative and qualitative considerations. In previous single-dose experience with MS subjects, the between-subject coefficient of variance (CV) for plasma AUC and Cmax for the reference formulation of MIN-101 is estimated to be approximately 30% and 50%, respectively. Therefore, the selected sample size of 12 to 16 participants should be sufficient to address the objectives of this study and detect the occurrence of rare adverse events should such an event be likely due to MIN-101 treatment. Every effort will be made to enroll an equal number of men and women. Pharmacokinetics: Pharmacokinetic parameters will be summarized by mean, standard deviation, standard error of the mean, coefficient of variation, minimum, median, and maximum, as appropriate, for each formulation and among the selected MR formulation for each dietary condition. 90% confidence intervals for the partial plasma AUC ratio with logarithmic mean transformation, AUC1, and AUC2 and Cmax will be constructed using the least squares estimated means and between-subjects variance from a mixed-effects model. Further analysis will be performed if deemed necessary, including the relationship between plasma levels of MIN-101 and its main metabolites and changes in QTcF intervals. Safety: The safety and tolerability of MIN-117 will be assessed based on a review of individual values ​​and summary statistics. The incidence of treatment-emergent adverse events will be tabulated by counts and percentages. Abnormalities in clinical laboratory tests, vital signs, and ECG will be based on predefined normal ranges and tabulated by dose group, showing the counts and percentages for each subject. bRpznn / eznz / B / Yi Examples 8-11 detail an open-label, randomized, three-treatment, three-period study to evaluate the pharmacokinetic profile of MIN-101 and its metabolite BFB-520 following single oral administration of three MIN-101 formulations (two prototype gastro-resistant CR (GR) formulations (GR-01 and GR-02) and one comparator MR formulation (MR32)). Each subject received a single dose of 5 mg of each formulation during the three periods. There was a clearance of 14 ± 2 days between the three periods. The Examples show several tables that include the plasma concentration profile over time for 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” refers to the free base, i.e., Compound (I). Example 8: In vivo pharmacokinetic analysis of MIN-101 in CR GR-01 tablets, CR tablets GR-02 and MR 32 mg capsules (MR32) (tau = 72 h) MR32 - 12 subjects (crossover) Cmax mean geo: 28.34 ng / mL Median Tmax: 2.00 H AUC(otau): 291.55 ng H / mL bRRznn / eznz / B / Yi Table 8. Mean parameters and plasma concentrations of MIN-101 MR32 MR32 PLASMA CONCENTRATIONS OF MR32 MIN-101 and AUCo-t Hours MEAN Sd Sm cv% 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 6.56 7.42 6.46 113.08 1 19.68 7.24 5.44 36.77 1.5 23.96 7.68 6.33 32.04 2 24.16 7.89 5.97 32.64 2.5 24.68 6.47 5.19 26.24 3 22.06 5.41 4.71 24.54 3.5 20.34 5.38 4.21 26.46 4 19.45 5.61 4.92 28.83 5 21.54 10.08 7.17 46.80 6 15.19 6.89 4.91 45.33 7 11.89 5.89 3.82 49.52 8 10.36 4.69 3.39 45.27 10 12.46 5.94 4.95 47.65 12 12.66 5.64 4.41 44.58 14 10.33 4.86 3.96 47.05 16 7.74 3.14 2.64 40.56 20 4.12 2.26 1.85 54.83 24 3.11 1.62 1.48 52.21 28 2.39 2.24 1.38 93.57 32 1.45 1.42 0.96 97.56 36 0.96 1.15 0.65 119.73 48 0.20 0.35 0.27 176.68 60 0.03 0.12 0.06 346.41 72 0.04 0.13 0.07 346.41 CMax ng / ml 29.52 9.00 6.70 30.48 Tmax H 2.42 1.33 0.99 54.98 AUCO-t H.ng / ml 291.55 66.12 53.61 22.68 See Figure 4. GR-01 - 12 subjects (crossover) Cmax media geo: 18.82 ng / mL Median of Tmax^ 4.50 H AUC(o-tau): 284.52 ng-H / mL Relative bioavailability with respect to MR32: F% Cmax: 69.9%, F% AUC(o-tau): 101.3% Table 9. Parameters and plasma concentrations of individual MIN-101 GR-01 bRpznn / eznz / B / Y GR01 AVERAGE PLASMA CONCENTRATIONS OF GR01 MIN-101 (ng / ml) and AUCo-t íH.na / ml) Hours 1-MIN-101 2-MIN-101 3-MIN-101 5-MIN-101 6-MIN-101 7-MIN-101 8-MIN-101 9-MIN-101 10-MIN-101 11-MIN-101 12-MIN-101 13-MIN-101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4.22 0.00 0.00 0.00 1.5 0.00 0.00 6.26 0.00 0.00 0.00 0.00 0.38 0.00 0.42 0.00 0.00 7.98 2 3.83 5.42 10.68 2.50 0.00 0.00 13.23 0.00 8.71 16.03 0.48 8.14 2.5 15.95 13.82 11.87 12.14 0.00 3.45 12.42 3.00 12.78 24.17 23.30 7.62 3 17.85 17.61 11.10 13.88 0.39 12.78 11.08 24.02 12.98 26.68 28.00 10.13 3.5 15.56 21.53 10.97 12.31 6.52 10.89 10.94 28.19 13.60 25.78 24.01 12.18 4 20.60 19.03 8.23 ​​11.96 15.23 9.53 8.04 22.91 17.64 24.78 22.59 11.30 5 17.05 17.24 6.66 14.68 15.63 8.44 14.90 17.95 12.92 24.46 12.86 12.69 6 15.26 14.41 6.89 13.19 13.39 6.06 12.36 11.72 7.62 19.24 5.64 10.42 7 9.61 11.29 6.28 12.62 10.60 4.71 11.51 13.95 6.70 17.83 9.72 9.08 8 7.46 7.20 5.58 11.86 10.51 3.51 8.19 16.53 13.39 14.16 5.82 8.52 10 4.30 5.10 12.66 11.69 6.19 2.71 18.08 17.00 18.05 8.68 13.19 10.59 12 9.45 5.59 10.24 20.15 7.24 3.05 12.22 13.92 16.31 11.15 13.39 12.47 14 13.11 10.14 12.01 17.73 7.12 3.52 12.65 12.02 14.42 11.67 20.32 6.36 16 10.98 6.35 12.59 16.88 6.40 3.18 7.19 11.25 13.43 13.29 19.44 6.02 20 5.54 3.88 4.69 8.36 4.95 2.65 2.44 7.99 6.52 9.76 5.92 3.23 24 5.57 1.94 3.21 6.73 6.31 2.38 2.90 12.21 3.90 10.97 3.63 7.08 28 4.31 1.64 3.18 2.55 3.91 2.35 1.47 7.67 3.79 10.31 0.54 5.80 32 3.50 1.56 2.73 1.16 3.55 5.90 0.66 3.59 2.79 7.59 0.67 3.46 36 2.37 1.06 1.34 0.54 2.14 12.25 0.00 1.06 0.56 3.73 0.37 3.60 48 1.33 0.73 0.28 0.00 2.04 2.55 0.00 0.00 0.00 0.56 0.00 1.76 60 0.00 0.48 0.00 0.00 1.33 1.33 0.00 0.00 0.00 0.00 0.00 0.45 72 0.00 0.69 0.00 0.00 0.41 0.44 0.00 0.00 0.00 0.00 0.00 0.27 CMax ng / ml 20.6 21.5 12.7 20.2 15.6 12.8 18.1 28.2 18.1 26.7 28.0 12.7 Tmax H 4.0 3.5 10.0 12.0 5.0 3.0 10.0 3.5 10.0 3.0 3.0 5.0 AUCO-t H.ng / ml 281.6 219.3 230.1 309.7 262.8 257.0 213.8 357.2 289.7 430.4 279.0 283.6 F AUC 84.0 93.6 98.8 172.8 92.0 112.6 80.0 92.5 76.9 143.9 76.0 92.5 F Cmax 65.3 72.9 48.6 110.5 54.2 69.1 74.4 66.4 37.7 116.9 76.9 45.7. bRRznn / eznz / e / Y Table 10. Mean parameters and plasma concentrations of MIN-101 GR-01 GR01 PLASMA CONCENTRATIONS OF GR01 MIN-101 and AUCo-t Hours MEAN Sd Sm CV% 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 1 0.35 1.22 0.65 346.41 1.5 1.25 2.77 1.95 220.78 2 5.75 5.57 4.67 96.91 2.5 11.71 7.46 5.46 63.69 3 15.54 7.84 6.08 50.45 3.5 16.04 7.01 5.89 43.68 4 15.99 6.08 5.27 38.00 5 14.62 4.60 3.26 31.47 6 11.35 4.17 3.35 36.70 7 10.33 3.58 2.64 34.63 8 9.39 3.93 3.25 41.81 10 10.69 5.39 4.42 50.45 12 11.26 4.66 3.48 41.34 14 11.76 4.67 3.33 39.73 16 10.58 4.87 3.96 46.01 20 5.49 2.33 1.85 42.48 24 5.57 3.30 2.58 59.31 28 3.96 2.80 2.04 70.67 32 3.10 2.06 1.50 66.68 36 2.42 3.33 2.05 137.50 48 0.77 0.92 0.77 119.51 60 0.30 0.51 0.40 171.48 72 0.15 0.24 0.20 159.83 CMax ng / ml 19.59 5.74 4.61 29.30 Tmax H 6.00 3.43 3.00 57.19 AUCO-t H.ng / ml 284.52 60.83 41.49 21.38 FAUC 101.30 29.16 20.90 28.79 F Cmax 69.90 23.92 17.04 34.22 See Figure 5. GR-02 - 12 subjects (crossover) Cmax mean geo: 15.43 ng / mL Median Tmax: 14.00 H AUC(otau): 253.01 ng-H / mL Relative bioavailability with respect to MR32: F% Cmax: 54.33%, F% AUC(o-tau): 86.9% bRpznn / eznz / B / Y Table 11. Parameters and plasma concentrations of individual MIN-101 GR-02 GR02 MEAN PLASMA CONCENTRATIONS OF GR02 MIN-101 (ng / ml) and AUCo-t Hours 1 -MIN-101 2-MIN-101 3-MIN-101 4-MIN-101 5-MIN-101 7-MIN-101 8-MIN-101 9-MIN-101 10-MIN-101 11-MIN-101 12-MIN-101 13-MIN-101 14-MIN-101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.03 2 0.00 0.00 0.41 0.00 0.70 0.00 0.00 0.00 0.00 0.00 0.00 0.88 6.86 2.5 2.13 0.00 1.87 0.00 1.17 1.09 0.00 1.24 2.48 1.02 0.00 2.79 11.97 3 4.71 0.41 2.66 0.00 2.98 1.52 0.66 2.55 2.87 5.06 4.14 2.81 11.48 3.5 6.35 1.16 3.08 0.35 2.16 2.14 1.06 3.14 5.27 11.72 7.24 3.02 14.23 4 8.70 2.20 3.06 1.17 2.19 2.25 1.21 3.45 6.24 12.69 8.58 3.45 12.39 5 8.93 6.06 3.40 3.00 10.46 2.87 2.49 4.07 7.52 14.53 7.76 8.84 11.67 6 7.60 6.39 2.61 2.92 10.83 3.37 1.94 4.24 6.94 11.33 5.09 8.09 8.75 7 5.96 5.09 3.56 5.85 7.32 3.15 2.06 4.52 4.85 10.76 5.23 9.19 8.67 8 5.11 4.28 2.89 5.14 6.40 3.30 2.58 5.76 5.02 6.39 11.43 8.98 10.06 10 4.90 3.27 3.92 5.82 12.63 4.26 3.26 9.25 5.39 10.25 12.96 11.15 15.14 12 15.08 2.81 6.31 9.24 20.26 3.27 6.31 8.07 21.50 17.68 13.88 16.18 25.98 14 11.62 7.94 7.57 10.68 18.73 3.42 3.77 10.16 11.15 16.50 15.37 9.96 29 85 16 9.87 5.79 11.46 7.68 15.69 8.22 2.61 10.94 9.53 9.32 19.54 7.85 19.75 20 10.00 6.27 6.62 3.77 6.34 5.19 0.94 7.50 4.26 8.94 9.83 4.94 6.44 24 9.29 4.59 5.07 5.95 6.69 12.66 0.64 10.97 6.98 7.46 12.76 13.32 3.97 28 8.23 ​​3.21 4.04 4.43 1.64 13.20 0.48 10.56 10.72 6.28 10.99 7.05 3.54 32 8.21 4.06 2.61 3.35 0.44 6.48 0.00 7.92 9.55 3.03 4.75 4.90 1.38 36 4.24 2.75 1.59 2.12 0.00 2.87 0.00 4.57 4.94 1.66 2.00 3.42 0.40 48 1.72 0.93 0.58 0.58 0.00 0.43 0.00 0.91 0.00 0.55 0.29 0.54 0,00 60 0.00 1.34 0.41 0.00 0.00 0.00 0.00 0.65 0.00 0,00 0.00 0.31 0.00 72 0.00 0.28 0.00 0.00 0,00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 CMax ng / ml 15.1 7.9 11.5 10.7 20.3 13.2 6.3 11.0 21.5 17.7 19.5 16.2 29.9 Tmax H 12.0 14.0 16.0 14.0 12.0 28.0 12.0 24.0 12.0 12.0 16.0 12.0 14.0 AUCO-t H.ng / ml 319.8 190.9 183.2 182.0 247.4 233.2 53.0 308.3 275.7 300.5 357.4 298.6 338.9 F AUC 95.4 81.5 78.6 101.6 86.6 102.2 19.8 79.9 73.2 100.5 97.3 97.5 116.3 F Cmax 47.8 26.9 44.0 58.6 70.3 71.4 26.0 25.8 45.0 77.5 53.7 58.3 101.1. Table 12. Mean parameters and plasma concentrations of MIN-101 GR-02 GR02 PLASMA CONCENTRATIONS OF GR02 MIN-101 and AUCo-t Hours MEAN Sd Sm CV% 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 1.5 0.16 0.59 0.31 375.28 2 0.68 1.95 1.04 286.76 2.5 1.98 3.29 1.89 166.30 3 3.22 3.03 1.90 94.21 3.5 4.69 4.39 3.38 93.69 4 5.20 4.14 3.38 79.73 5 7.05 3.94 3.24 55.85 6 6.16 3.20 2.68 51.99 7 5.86 2.63 2.09 44.82 8 5.95 2.84 2.19 47.70 10 7.86 4.27 3.79 54.29 12 12.81 7.69 6.62 60.04 14 12.06 7.28 5.35 60.38 16 10.63 5.24 3.98 49.25 20 6.23 2.37 1.75 37.95 24 7.72 4.01 3.23 52.01 28 6.49 4.15 3.47 63.88 32 4.36 2.90 2.24 66.52 36 2.35 1.62 1.26 69.09 48 0.50 0.34 0.29 68.40 60 0.21 0.41 0.30 197.87 72 0.02 0.08 0.04 375.28 CMax ng / ml 15.43 6.70 5.37 43.38 Tmax H 15.23 5.20 3.67 34.12 AUCO-t H.ng / ml 253.01 85.28 65.81 33.71 F AUC 86.94 24.39 16.36 28.05 F Cmax 54.33 23.09 17.99 42.50 See Figure 6. bRpznn / eznz / B / Y Table 13. Comparison of plasma concentrations of MR32, GR-01 and GR-02 MIN-101 Mean plasma concentrations of MR 32, GR01 and GR02 MIN-101 (ng / ml) Hours MR32-Mean GR01-Mean GR02-Mean 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.5 6.56 0.00 0.00 1 19.68 0.35 0.00 1.5 23.96 1.25 0.16 2 24.16 5.75 0.68 2.5 24.68 11.71 1.98 3 22.06 15.54 3.22 3.5 20.34 16.04 4.69 4 19.45 15.99 5.20 5 21.54 14.62 7.05 6 15.19 11.35 6.16 7 11.89 10.33 5.86 8 10.36 9.39 5.95 10 12.46 10.69 7.86 12 12.66 11.26 12.81 14 10.33 11.76 12.06 16 7.74 10.58 10.63 20 4.12 5.49 6.23 24 3.11 5.57 7.72 28 2.39 3.96 6.49 32 1.45 3.10 4.36 36 0.96 2.42 2.35 48 0.20 0.77 0.50 60 0.03 0.30 0.21 72 0.04 0.15 0.02 Max ng / ml 29.5 19.6 15.4 Tmax H 2.4 6.0 15.2 AUCO-t H.ng / ml 291.6 284.5 253.01 FAUC REF 101.3 86.94 F Cmax REF 69.9 54.33 bRpznn / eznz / B / Y See Figure 7. Table 14. Comparison of plasma concentrations of MR32, GR-01 and GR-02 MIN-101 Rates of increase and decrease. Rates of increase and decrease of conc. in plasma mean MR32 and GR01 MIN101 (ng / mL) / H Hours MR32-SPEED. GR01-SPEED GR02-SPEED 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.5 26.25 0.00 0.00 1 26.24 0.70 0.00 1.5 8.56 1.80 0.31 2 0.39 9.00 1.05 2.5 1.03 11.92 2.60 3 0.00 7.66 2.48 3.5 0.00 1.00 2.94 4 0.00 0.00 1.02 5 2.09 0.00 1.85 6 0.00 0.00 0.00 7 0.00 0.00 0.00 8 0.00 0.00 0.09 10 1.05 0.65 0.96 12 0.10 0.29 2.48 14 0.00 0.25 0.00 16 0.00 0.00 0.00 20 0.00 0.00 0.00 24 0.00 0.02 0.37 28 0.00 0.00 0.00 32 0.00 0.00 0.00 36 0.00 0.00 0.00 VMax (ng / ml) / H 26.2 11.9 2.9 Time to VMax 0.50 2.50 3.50 TEST / MR32 REF 0.45 0.11 bRpznn / eznz / B / Yi During each time interval (dt), the plasma concentration (Cp) of MIN-101 increases or decreases. From t=0 to Tmax, the rate of increase Vmax = d(Cp) / dt. After Vmax, the rates decrease. See Figure 8. Example 9: In vivo pharmacokinetic analysis of BFB-520 in CR GR-01 tablets, CR GR-02 tablets and 32 mg MR capsules (MR32) (tau = 72 h) MR32 - 12 subjects (crossover) Cmax media geo: 1.77 ng / mL Median Tmax: 6.00 H AUC(otau): 30.26 ng-H / mL Table 15. Parameters and plasma concentrations of individual BFB-520 MR32 MR32 CONCENTRACIONES EN PLASMA DE MR32 BFB-520 (ng / mL) y AUCo-t (Η.ηα / m ) Horas 1-BFB-520 2-BFB-520 3-BFB-520 5-BFB-520 6-BFB-520 7-BFB-520 8-BFB-520 9-BFB-520 10-BFB-520 11-BFB-520 12-BFB-520 13-BFB-520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0,25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.56 0.54 0.00 0.30 0.53 0.32 0.28 1.01 0.00 0.70 0.56 0.26 1.5 1.20 0.85 0.58 0.36 0.72 0.61 0.76 1.29 0.43 1.28 1.10 0.50 2 1.24 0.65 0.89 0.62 0.92 0.89 0.59 2.42 0.80 1.41 1.23 0.80 2.5 1.41 0.75 0.97 0.89 1.18 0.88 0.84 2.16 1.19 1.69 1.76 0.79 3 1.37 0.94 0.99 1.18 1,56 1.12 1.10 3.33 1.58 1.93 1.63 0.74 3.5 1.72 1.03 0.81 1.25 1.44 1.20 1.28 2.91 1.57 1.91 1.94 0.84 4 2.03 0.99 0.98 1.38 1,65 1.21 1.38 2.30 1.65 1.77 2.27 0.95 5 1.91 1.10 1.09 0.90 1.64 1.10 1.07 2.55 2.97 2.09 1.61 1.03 6 1.81 1.09 0.83 0.88 1.76 0.96 1.09 2.23 3.13 1.94 1.73 1.10 7 1.91 0.95 0.90 0.90 1.40 0.94 0.89 2.25 2.91 2.10 1.16 1.01 8 1.69 0.92 0.71 0.79 1.60 1.01 1.19 2.63 3.13 1.93 1.42 1.08 10 1.27 1.00 1.09 0.63 1.69 0.73 1.73 1.97 2.76 2.46 1.44 1.01 12 0.73 1.20 0.56 0.84 1.39 0.56 1.42 1.07 2.12 2.63 1.26 0.71 14 0.88 1.06 0.62 1.07 1.30 0.75 1.46 2.63 2.35 2.74 1.37 0.55 16 0.99 0.86 0.54 0.65 0.85 0.58 1.23 1.76 1.53 1.65 1.03 0.51 20 1.43 0.68 0.48 0.58 0.61 0.86 0.70 1.20 0.87 1.40 0.95 0.41 24 0.69 0.39 0.35 0.00 0,35 0.77 0.47 0.67 0.70 0.58 0.63 0.36 28 0.89 0.00 0.31 0.00 0.30 0.44 0.00 0.45 0.46 0.37 0.33 0.61 32 0.40 0.00 0.00 0.00 0.00 0.35 0.00 0.00 0.28 0.00 0.00 0.81 36 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.61 48 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max ng / ml 2.0 1.2 1.1 1.4 1.8 1.2 1.7 3.3 3.1 2.7 2.3 1.1 Tmax H 4.0 12.0 10.0 4.0 6.0 4.0 10.0 3.0 6.0 14.0 4.0 6.0 AUCO-t H.ng / ml 34.7 20.1 16.7 15.3 27.2 22.6 24.8 44.9 47.2 46.7 34.5 28.5. bRpznn / eznz / B / Y Table 16. Plasma concentrations and mean parameters of MR32 BFB-520 MR32 PLASMA CONCENTRATIONS OF MR32 BFB-520 and AUCo-t Hours MEAN Sd Sm cv% 0 0.00 0.25 0.00 0.5 0.00 1 0.42 0.29 0.23 68.42 1.5 0.81 0.33 0.28 41.40 2 1.04 0.51 0.36 48.77 2.5 1.21 0.45 0.36 37.60 3 1.46 0.68 0.46 46.84 3.5 1.49 0.58 0.43 38.99 4 1.55 0.48 0.40 31.20 5 1.59 0.67 0.54 42.36 6 1.55 0.69 0.55 44.45 7 1.44 0.68 0.57 47.23 8 1.51 0.75 0.57 49.53 10 1.48 0.66 0.53 44.91 12 1.21 0.63 0.46 52.49 14 1.40 0.77 0.60 54.91 16 1.01 0.44 0.36 43.42 20 0.85 0.34 0.27 40.36 24 0.50 0.22 0.18 44.39 28 0.35 0.26 0.19 75.95 32 0.15 0.26 0.21 168.74 36 0.05 0.18 0.09 346.41 48 0.00 60 0.00 72 0.00 Max ng / ml 1.91 0.80 0.65 41.65 Tmax H 6.92 3.65 3.06 52.84 AUC0-t H.ng / ml 30.26 11.35 9.43 37.51 See Figure 9. GR-01 - 12 subjects (crossover) Cmax mean geo: 1.77 ng / mL Median Tmax: 6.00 h AUC(o-tau): 27.48 ng-H / mL Relative bioavailability with respect to MR32: F% Cmax: 80.48%, F% AUC(o-tau): 96.1% bRpznn / eznz / B / Y Table 17. Parameters and plasma concentrations of individual GR-01 BFB-520 GR01 PLASMA CONCENTRATIONS OF GR01 BFB-520 (ng / mL) and AUCo-t β-inHg (ng / mL) Hours 1-BFB-520 2-BFB-520 3-BFB-520 5-BFB-520 6-BFB-520 7-BFB-520 8-BFB-520 9-BFB-520 10-BFB-520 11-BFB-520 12-BFB-520 13-BFB-520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.26 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.00 0.00 2.5 0.00 0.56 0.43 0.00 0.00 0.00 0.30 0.00 0.46 0.60 0.28 0.00 3 0.42 0.71 0.45 0.44 0.00 0.26 0.60 0.60 0.63 0.88 0.53 0.38 3.5 0.54 1.00 0.50 0.47 0.00 0.38 0.57 1.28 0.74 1.00 0.86 0.43 4 0.84 1.04 0.49 0.63 0.35 0.39 0.45 1.41 1.08 1.29 0.72 0.51 5 1.01 0.98 0.39 0.72 0.62 0.51 0.75 1.56 1.13 1.45 0.99 0.61 6 1.07 1.07 0.43 0.78 0.83 0.54 0.85 1.47 0.85 1.19 0.72 0.64 7 1.20 1.28 0.37 0.92 0.93 0.51 0.88 1.47 0.71 1.47 0.74 0.80 8 1.17 1.07 0.44 1.10 1.03 0.68 0.76 1.80 1.37 1.63 1.06 0.74 10 0.68 0.96 0.68 1.23 0.77 0.33 1.28 1.72 1.84 1.32 1.37 0.99 12 0.65 0.77 0.55 1.30 0.66 0.32 0.91 1.40 1.74 0.78 2.26 1.08 14 1.00 0.87 0.72 1.73 0.74 0.43 1.24 1.54 1.82 1.11 1.11 1.05 16 1.00 0.71 0.83 1.80 0.51 0.43 1.09 1.49 1.80 1.24 1.11 0.95 20 0.69 0.70 0.63 1.58 0.67 0.40 0.71 1.73 1.13 1.44 1.17 0.68 24 0.57 0.31 0.43 0.85 0.50 0.00 0.39 1.31 0.57 1.05 0.99 0.58 28 0.72 0.26 0.50 0.58 0.59 0.00 0.28 1.15 0.92 1.27 0.65 0.58 32 0.33 0.00 0.28 0.30 0.46 0.44 0.00 0.67 0.62 0.68 0.28 0.43 36 0.29 0.00 0.00 0.00 0.38 1.10 0.00 0.28 0.00 0.51 0.00 0.42 48 0.00 0.00 0.00 0.00 0.00 0.00 0.33 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max ng / ml 1.2 1.3 0.8 1.8 1.0 1.1 1.3 1.8 1.8 1.6 2.3 1.1 Tmax H 7.0 7.0 16.0 16.0 8.0 36.0 10.0 8.0 10.0 8.0 12.0 12.0 AUCO-t H.ng / ml 23.5 18.6 16.1 31.3 19.7 19.0 19.6 43.8 36.1 40.6 33.7 27.9 F AUC 67.7 92.5 96.3 204.6 72.3 83.9 79.2 97.6 76.5 86.9 97.7 98.0 F Cmax 59.0 107.4 75.8 131.0 58.6 90.8 73.6 54.0 58.8 59.7 99.6 97.5. bRRznn / eznz / e / Y Table 18. Plasma concentrations and mean parameters of GR-01 BFB-520 GR01 PLASMA CONCENTRATIONS OF GR01 BFB-520 and AUCo-t Hours MEAN Sd Sm CV% 0 0.00 0.25 0.00 0.5 0.00 0.22 0.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.5 0.65 0.35 0.27 53.37 4 0.77 0.36 0.31 47.35 5 0.89 0.36 0.29 40.77 6. 0.87 0.29 0.22 33.50 7 0.94 0.35 0.28 37.58 8 1.07 0.39 0.29 36.81 10 1.10 0.45 0.36 40.79 12 1.04 0.55 0.43 53.43 14 1.11 0.42 0.31 37.58 16 1.08 0.45 0.34 41.52 20 0.96 0.43 0.38 45.29 24 0.63 0.36 0.28 57.32 28 0.63 0.36 0.26 57.90 32 0.37 0.23 0.18 60.48 36 0.25 0.33 0.25 133.52 48 0.03 0.09 0.05 346.41 60 0.00 72 0.00 Max ng / ml 1.43 0.43 0.37 30.06 Tmax H. 12.50 8.04 5.08 64.32 AUC0-t H.ng / ml 27.48 9.46 8.07 34.41 F AUC 96.10 35.77 18.95 37.22 F Cmax 80.48 24.60 20.65 30.56 See Figure 10. GR-02 - 12 subjects (crossover) Geo mean cmax: 1.13 ng / mL Median of Tmáx^ 16.00 H AUC(otau): 27.53 ng-H / mL Relative bioavailability with respect to MR32: F% Cmax: 69.48%, F% AUC(o-tau): 88.46% Table 19. Parameters and plasma concentrations of individual GR-02 BFB-520 bRpznn / eznz / B / Y GR02 CONCENTRACIONES EN PLASMA DE GR02 BFB-520 (ng / mL) y AUCo-t íH.na / ml) Horas 1-BFB-520 2-BFB-520 3-BFB-520 4-BFB-520 5-BFB-520 7-BFB-520 8-BFB-520 9-BFB-520 10-BFB-520 11-BFB-520 12-BFB-520 13-BFB-520 14-BFB-520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0,00 0.00 0.00 0.00 0.00 0.00 0,00 0.00 2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.5 0.00 0.00 0.00 0.00 0.00 0,00 0.00 0.00 0.00 0.00 0.00 0,00 0.44 3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.26 0.00 0.00 0.66 3.5 0.00 0.00 0.00 0.00 0.00 0,00 0.00 0.00 0.00 0.62 0.00 0.00 0.76 4 0.38 0.00 0.00 0.00 0.00 0,00 0.00 0.00 0.00 0.97 0.27 0,00 1.08 5 0.35 0.00 0.00 0.00 0.32 0.00 0.00 0.27 0.27 1.37 0.35 0.35 0.75 6 0.53 0.38 0.00 0.00 0.49 0.00 0.00 0.28 0.42 1.47 0.36 0.45 0.75 7 0.54 0.29 0.00 0.00 0.41 0.29 0.00 0.27 0.39 1.64 0.49 0.58 0.79 8 0.47 0.32 0.00 0.25 0.57 0.25 0.00 0.51 0.42 1.85 0.57 0.69 0.79 10 0.47 0.35 0.25 0.36 0.62 0.34 0.00 0.74 0.51 1.82 1.12 1.07 1.14 12 0.88 0.00 0.41 0.52 0.94 0.36 0.35 0.74 1.28 2.26 0.80 1.09 1.99 14 1.00 0.33 0.51 0.68 1.26 0.36 0.41 0.98 1.28 2.45 1.26 1.16 2.25 16 1.01 0.39 0.59 0.62 1.40 0.52 0.37 1.26 1.22 2.38 1.37 1.03 2.31 20 1.08 0.64 0.79 0.59 1.25 0,76 0.26 1.43 0.71 2.42 1.64 0.80 1.38 24 0.81 0.44 0.55 0.49 0.76 0.95 0.00 0.68 0.61 1.75 1.39 0.69 0.84 28 0.97 0.47 0.56 0.56 0.48 1.22 0.00 1.00 0.93 1.74 1.04 0.87 0.59 32 0.82 0.34 0.31 0.33 0.00 1,14 0.00 1.03 1.21 0.70 0.59 0,61 0.33 36 0.47 0.32 0.00 0.00 0.00 0.66 0.00 0.65 0.64 0.41 0.32 0.46 0.00 48 0.27 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max ng / ml 1.1 0.6 0.8 0.7 1.4 1.2 0.4 1.4 1.3 2.4 1.6 1.2 2.3 Tmax H 20.0 20.0 20.0 14.0 16.0 28.0 14.0 20.0 12.0 14.0 20.0 14.0 16.0 AUCO-t H.ng / ml 30.0 11.5 12.3 12.5 21.8 23.8 6.1 31.9 31.4 61.4 38.8 32.9 43.5 FAUC 86.6 57.0 73.3 81.9 80.3 105.2 24.8 71.1 66.6 131.5 112.6 115.5 143.7 F Cmax 53.1 53.3 72.2 49.2 79.9 100.6 23.9 42.9 41.0 89.3 72.3 104.8 120.8. bRRznn / eznz / e / Y Table 20. Plasma concentrations and mean parameters of GR-02 BFB-520 GR02 PLASMA CONCENTRATIONS OF GR01 BFB-520 and AUCo-t Hours MEAN Sd Sm cv% 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.00 2.5 0.03 0.13 0.07 375.28 3 0.07 0.20 0.13 280.02 3.5 0.11 0.27 0.19 254.72 4 0.21 0.40 0.29 191.24 5 0.31 0.40 0.27 130.19 6 0.39 0.42 0.28 106.04 7 0.44 0.45 0.30 102.76 8 0.52 0.49 0.31 94.19 10 0.68 0.51 0.41 75.52 12 0.90 0.68 0.51 75.73 14 1.07 0.70 0.53 65.30 16 1.11 0.69 0.54 61.68 20 1.06 0.59 0.47 55.93 24 0.77 0.45 0.31 59.06 28 0.80 0.45 0.34 55.61 32 0.57 0.41 0.33 71.69 36 0.30 0.28 0.24 92.16 48 0.02 0.00 60 0.00 72 0.00 Max ng / ml 1.27 0.63 0.47 49.77 Tmax H 17.54 4.46 3.56 25.42 AUCO-t H.ng / ml 27.53 15.99 12.65 58.08 FAUC 88.46 33.92 27.56 38.35 F Cmax 69.48 29.58 24.00 42.56 See Figure 11. bRpznn / eznz / B / Y Table 21. Comparison of plasma concentrations of MR32, GR-01 and GR-02 BFB-520. Mean plasma concentrations of MR32 GR01 and GR02 BFB-520 (ng / ml) Hours MR32 Mean GRO1-Mean GR02-Mean 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.5 0.00 0.00 0.00 1 0.42 0.00 0.00 1.5 0.81 0.00 0.00 2 1.04 0.04 0.00 2.5 1.21 0.22 0.03 3 1.46 0.49 0.07 3.5 1.49 0.65 0.11 4 1.55 0.77 0.21 5 1.59 0.89 0.31 6 1.55 0.87 0.39 7 1.44 0.94 0.44 8 1.51 1.07 0.52 10 1.48 1.10 0.68 12 1.21 1.04 0.90 14 1.40 1.11 1.07 16 1.01 1.08 1.11 20 0.85 0.96 1.06 24 0.50 0.63 0.77 28 0.35 0.63 0.80 32 0.15 0.37 0.57 36 0.05 0.25 0.30 48 0.00 0.03 0.02 60 0.00 0.00 0.00 72 0.00 0.00 0.00 CMax ng / ml 1.9 1.4 1.27 Tmax H 6.9 12.5 17.5 AUCO-8 H.ng / ml 9.7 4.5 1.66 AUCO-12 H.ng / ml 15.4 8.8 4.4 AUCO-t H.ng / ml 30.3 27.5 27.5 FAUC REF 96.1 88.5 F Cmax REF 80.5 69.5 bRpznn / eznz / B / Y See Figure 12. Table 22. Comparison of plasma concentrations of MR32, GR-01 and GR-02 BFB-520 Rates of increase and decrease. Rates of increase and decrease of conc. in plasma mean of MR32 GR01 and GR02 BFB-520 (ng / mL) / H Hours MR32-SPEED. GR01-SPEED GR02-SPEED 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.5 0.00 0.00 0.00 1 0.84 0.00 0.00 1.5 0.77 0.00 0.00 2 0.46 0.09 0.00 2.5 0.34 0.35 0.07 3 0.49 0.54 0.07 3.5 0.07 0.31 0.07 4 0.11 0.24 0.20 5 0.04 0.13 0.10 6 0.00 0.00 0.08 7 0.00 0.07 0.04 8 0.07 0.13 0.08 10 0.00 0.01 0.08 12 0.00 0.00 0.11 14 0.10 0.04 0.09 16 0.00 0.00 0.02 20 0.00 0.00 0.00 24 0.00 0.00 0.00 28 0.00 0.00 0.01 32 0.00 0.00 0.00 36 0.00 0.00 0.00 VMax (ng / ml) / H 0.84 0.54 0.20 Time to VMax 1.00 3.00 4.00 TEST / MR32 REF 0.64 0.24 bRpznn / eznz / B / Yi During each time interval (dt), the plasma concentration (Cp) of BFB-520 increases or decreases. From t=0 to Tmax, the rate of increase Vmax = d(Cp) / dt. After Vmax, the rates decrease. See Figure 13. Example 10: Expected steady-state plasma concentrations of MIN-101 and BFB-520 in MR32 and GR-01 tablets (32 and 64 mg) Table 23. Predicted steady-state plasma concentrations of MIN-101 in 32 mg tablets of MR32 and GR-01 Mean plasma concentrations at steady state MR32 » C.R01 MIN-101 in0'nlL: Hours MR32SS GR01 SS 72 3.32 6.45 72.5 9.68 6.20 73 22.62 6.30 73.5 26.74 6.96 74 26.78 11.23 74.5 27.14 16.97 75 24.39 20.59 75.5 22.54 20.89 76 21.96 20.58 77 23.38 18.91 78 16.83 15.30 79 13.34 13.96 80 11.89 12.95 82 13.49 13.53 84 13.66 14.02 86 10.97 13.80 88 8.24 12.32 92 4.44 6.75 96 3.32 6.46 CMaxSS ng mi 27.1 20.9 CMinSS 3.32 6.46 TmaxSS H 2.50 3.5 AUC72-96 H.ng nil 292.6 287.6 F AUC REF 98.3 F Cmax REF 76.9 See Figure 14. 100 Table 24. Predicted steady-state plasma concentrations of BFB-520 in mg tablets of MR32 and GR-01 Steady-state plasma concentrations of MR32 and GR01 BFB-520 {ng / ml| Hours MR32SS GR01 SS 72 0.50 0.66 72.5 0.44 0.63 73 0.81 0.60 73.5 1.15 0.57 74 1.35 0.58 74.5 1.48 0.72 75 1.70 0.97 75.5 1.71 1.10 76 1.89 1.42 77 1.74 1.27 73 1.66 1.21 79 1.54 1.24 80 1.66 1.46 82 1.53 1.31 84 1.26 1.29 86 1.41 1.25 88 1.03 1.19 92 0.85 1.03 96 0.50 0.66 CMaxSS ng mi 1.89 1.46 CMinSS 0.50 0.66 TmaxSS H 4.00 8.00 AUC72-96 H.ngml 29.1 26.3 F AUC REF 90.6 F Cmax REF 77.2 bRRznn / eznz / e / Y See Figure 15. 101 Table 25. Predicted steady-state plasma concentrations of MIN-101 in mg tablets of MR32 and GR-01 Steady-state plasma concentrations of MR32 and GR01 64 mg MIN101 Hours MR32SS GR01 SS 72 6.64 12.90 72.5 19.36 12.40 73 45.24 12.60 73.5 53.47 13.93 74 53.55 22.46 74.5 54.28 33.94 75 48.77 41.18 75.5 45.07 41.77 76 43.93 41.17 77 46.76 37.82 78 33.65 30.60 79 26.69 27.92 80 23.78 25.90 82 26.97 27.06 84 27.31 28.05 86 21.94 27.61 88 16.49 24.64 92 8.89 13.49 96 6.64 12.93 CMaxSS ng mi 54.28 41.77 CMinSS 6.64 12.93 TmaxSS H 2.50 3.50 AUC72-96 H.ngml 585.2 577.6 F AUC REF 98.7 F Cmax REF 76.9 bRRznn / eznz / e / Y See Figure 16. 102 Table 26. Expected steady-state plasma concentrations of BFB-520 in mg tablets of MR32 and GR-01 Steady-state plasma concentrations of MR32 and GR01 $4 mg BFB-52C<n9,rnl> Hours MR325S GR01 SS 72 0.99 1.32 72.5 0.88 1.27 73 1.63 1.20 73.5 2.31 1.13 74 2.69 1.16 74.5 2.96 1.45 75 3.40 1.93 75.5 3.41 2.19 76 3.79 2.84 77 3.48 2.54 7B 3.33 2.41 79 3.07 2.48 80 3.32 2.92 82 3.05 2.62 84 2.51 2.57 86 2.83 2.49 88 2.05 2.37 92 1.70 2.05 96 0.99 1.32 CMaxSS ng.'ml 3.79 2.92 CMinSS 0.99 1.32 TmaxSS H 4.00 8.00 AUC72-96 H.ng'ml 58.1 52.8 F AUC REF 90.8 F Cmax REF 77.2 bRRznn / eznz / e / Yi See Figure 17. Example 11: Expected steady-state plasma concentrations of MIN-101 and BFB-520 in MR32 and GR-02 tablets (32 and 64 mg) 103 Table 27. Predicted steady-state plasma concentrations of MIN-101 in mg tablets of MR32 and GR-02 bRRznn / eznz / e / Y Mean plasma concentrations in ECT entable MRn? v GRfl? ΜΙΝ-1Π1 Ind'mD Hours MR32SS GR02 SS 72 3.32 8.26 72.5 9.68 7.88 73 22.62 7.46 73.5 26.74 7.23 74 26.78 7.37 74.5 27.14 8.32 75 24.39 9.22 75.5 22.54 10.37 75 21.96 12.08 77 23.38 11.87 78 16.83 10.49 79 13.34 9.74 80 11.89 10.56 82 13.49 10.66 84 13.66 15.38 85 10.97 13.87 88 8.24 12.09 92 4.44 7.17 95 3.32 8.27 CMaxSS ngml 27.1 15.4 CMinSS 3.32 7.17 TmaxSS H 2.50 12 AUC72-96 H.ng mi 292.6 248.3 F AUC REF 84.9 F Cmax REF 56.7 See Figure 18. 104 Table 28. Expected steady-state plasma concentrations of BFB-520 in mg tablets of MR32 and GR-02 Plasma concentrations Pn est stable MR32 v fiROPRFA.^XiInn mn Hours MR32SS GR02 SS 72 0.50 0.79 72.5 0.44 0.76 73 0.81 0.72 73.5 1.15 0.67 74 1.35 0.63 74.5 1.48 0.63 75 1.70 0.63 75.5 1.71 0.63 76 1.89 1.04 77 1.74 0.75 78 1.66 0.78 79 1.54 0.78 80 1.66 1.10 82 1.53 0.92 84 1.26 1.20 86 1.41 1.22 88 1.03 1.23 92 0.85 1.13 96 0.50 0.79 CMaxSS ng ml 1.89 1.23 CMinSS 0.50 0.79 TmaxSS H 4.00 16.00 AUC72-96 H.ng'ml 29.1 23.6 F AUC REF 81.4 F Cmax REF 64.8 See Figure 19. bRRznn / eznz / e / Y 105 Table 29. Predicted steady-state plasma concentrations of MIN-101 in mg tablets of MR32 and GR-02 Steady-state plasma concentrations of MR32 and GR0264 mg MIN101 ln0'm|l HOURS MR32SS GR02 SS 72 6.64 16.53 72.5 19.36 15.77 73 45.24 14.93 73.5 53.47 14.45 74 53.55 14.75 74.5 54.28 16.64 75 48.77 18.44 75.5 45.07 20.74 76 43.93 24.16 77 46.76 23.75 78 33.65 20.98 79 26.69 19.49 80 23.78 21.12 82 26.97 21.32 84 27.31 30.77 86 21.94 27.73 88 16.49 24.18 92 8.89 14.35 96 6.64 16.53 CMaxSS ng mi 54.28 30.77 CMinSS 6.64 14.35 TmaxSS H 2.50 12.00 AUC72-96 H.ng ml 585.2 498.6 F AUC REF 85.2 F Cmax REF 56.7 See Figure 20. 106 Table 30. Predicted steady-state plasma concentrations of BFB-520 in mg tablets of MR32 and GR-02 Steady-state plasma concentrators of MR32 and GR0264 mg BFB-521? HOURS MR32SS GR02 SS 72 0.99 1.58 72.5 0.88 1.52 73 1.63 1.43 73.5 2.31 1.35 74 2.69 1.27 74.5 2.96 1.26 75 3.40 1.26 75.5 3.41 1.27 76 3.79 2.07 77 3.48 1.50 78 3.33 1.57 79 3.07 1.57 80 3.32 2.20 82 3.05 1.83 84 2.51 2.40 86 2.83 2.44 88 2.05 2.45 92 1.70 2.25 96 0.99 1.58 CMaxSS ng.'ml 3.79 2.45 CMinSS 0.99 1.58 TmaxSS H 4.00 16.00 AUC72-96 H.ng'ml 58.1 47.4 F AUC REF 81.6 F Cmax REF 64.8 bRpznn / eznz / B / This See Figure 21. Examples 12–15 detail an evaluation of the PK profile of the GR-01 formulation in healthy male and female subjects with healthy CYP2D6 EM under fed and fasted (or predicted) fasting states. Subjects who completed Part 1 of the study (evaluation of the PK profile of MIN-101 and its metabolite BFB-520 in the GR-01, GR-02, and MR32 formulations) returned and received an additional single oral dose of GR-01 under fed or fasted conditions to allow for assessment of the feeding effect by comparing the PK properties with those obtained in Part 1 (Examples 9–12). There was a clearance period of 14 ± 2 days after Part 1. Example 12: In vivo pharmacokinetic analysis of MIN-101 in CR GR-01 tablets in subjects in a fed state compared to a fasted state, (tau = 72 h) Nutritional status - 12 subjects (crossover) Cmax mean geo: 19.70 ng / mL Tmax: 12.00 H AUC(otau): 269.19 ng-H / mL 107 Table 31. Plasma concentrations and parameters of individual MIN-101 CR GR-01 (Feeding status) groi PLASMA CONCENTRATIONS IN FEEDING STATUS OF GR01 MIN-101 (ng / rnL) and AUCo-t (H.nq mil bRpznn / eznz / B / Y Hours 1 -MIN-101 2-MIN-101 3-MIN-101 5-MIN-101 6-MIN-101 7-MIN-101 8-MIN-101 9-MIN-101 10-MIN-101 ll-MIN-101 12-MIN-101 13-MIN-101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.5 0.00 0.00 6.78 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3 0.00 0.00 11.16 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 6.11 3.5 0.00 0.00 11.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 7.61 4 0.00 0.00 14.38 0.00 0.00 0.29 0.00 0.00 0.00 0.00 0.00 6.83 5 0.00 0.00 14.05 23.02 0.00 12.75 0.00 0.00 0.53 0.00 0.00 6.91 € 0.00 18.46 13.78 13.78 0.00 16.81 0.00 0.00 23.86 0.00 0.00 6.14 7 0.00 18.93 12.69 10.82 0.00 11.65 0.00 0.00 18.16 15.83 0.00 5.15 8 0.00 12.77 6.36 9.89 0.00 10.59 0.00 0.00 17.78 14.65 0.00 4.24 10 3.52 7.72 3.90 11.82 0.00 7.97 0.00 23.19 14.80 11.23 0.00 6.86 12 35.98 6.41 9.71 6.41 19.91 13.62 0.00 8.39 14.32 12.39 24.84 12.40 14 12.33 3.95 7.26 2.94 11.75 13.61 0.00 5.32 16,35 17.47 12.74 8.83 16 14.86 9.72 10.01 1.55 8.72 8.89 0.00 6.30 20.47 12.39 7.55 6.04 20 7.18 4.51 4.76 0.52 6.95 9.42 4.24 5.28 11.74 11.61 14.00 4.23 24 6.70 2.72 5.92 0.00 12.81 5.57 10.84 30.76 9.83 10.33 26.27 6.75 28 7.17 2.40 4.48 0.00 18.56 5.20 5.81 16.53 5.52 7.82 21.35 4.34 32 6.56 2.19 2.84 0.00 10.82 3.49 2.32 10.29 3.17 3,44 14.17 3.32 36 5.97 1.15 1.61 0.00 5.35 2.19 0.92 3.93 1.80 1.85 6.78 2.42 48 1.66 0.39 0.90 0.00 1.57 0.67 0.00 0.83 0.50 0.47 0.91 0.59 60 0.00 0.00 0.00 0.35 0.00 0.63 0.33 0.00 0.00 0.31 0.00 0.00 0.36 72 0,00 0.00 0.00 0.00 0.30 0.00 0,00 0.00 0.00 0.00 0.00 0.00 CMax of mi 36.0 18.9 14.4 23.0 19.9 16.8 10.8 30.8 23.9 17.5 26.3 12.4 Tmax H 12.0 7.0 4.0 5.0 12.0 6.0 24.0 24.0 6.0 14.0 24.0 12.0 AUCO-t H.of mi 305.0 177.2 241.3 108.5 347.8 272.9 92.2 367.3 359.7 303.5 444.8 210.2 F AUC 108.3 80.8 104.8 35.0 132.3 106.2 43.1 102.8 124.2 70.5 159.4 74.1 F Cmax 174.7 87.9 113.6 114.2 127.4 131.5 60.0 109.1 132.2 65.5 93.8 97.7. 108 Table 32. Plasma concentrations and parameters of MIN-101 media CR GR-01 (feeding status) bRRznn / eznz / e / Y GR01 PLASMA CONCENTRATIONS IN EST. THE ALIM. OF GR01 MIN-101 V AUCO-t Hours MEAN Sd Sm CV'o 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.00 2.5 0.57 1.96 1.04 346.41 3 1.44 3.53 2.40 245.26 3.5 1.55 3.69 2.59 238.14 4 1.79 4.42 2.94 246.80 5 4.77 7.77 6.27 162.90 6 7.74 9.01 8.00 116.41 7 7.77 7.71 6.91 99.30 8 6.36 6.59 5.65 103.62 10 7.58 6.94 5.20 91.54 12 13.70 9.54 6.71 69.63 14 9.38 5.54 4.66 59.09 16 8.88 5.51 3.85 62.03 20 7.04 3.93 3.13 55.89 24 10.71 9.09 6.31 84.89 28 8.26 6.76 5.27 81.78 32 5.22 4.30 3.50 82.42 36 2.83 2.17 1.79 76.52 48 0.71 0.52 0.39 73.23 60 0.16 0.22 0.19 133.11 72 0.03 0.09 0.05 346.41 CMax ng mi 20.89 7.48 5.91 35.83 Tmax H 12.50 7.65 6.00 61.16 AUCOs H.ng mi 269.19 107.53 86.11 39.95 F AUC 95.14 36.15 28.68 38.00 F Cmax 108.97 31.40 23.32 28.81 See Figure 22 Fasting state - 12 subjects (cross-over) Geo mean cmax: 18.82 ng / mL Median of Tmáx: 4.50 H AUC(o-tau): 284.52 ng-H / mL 109 Table 33. Plasma concentrations and parameters of individual MIN-101 CR GR-01 (fasting state) bRpznn / eznz / B / YiAi GRoi__PLASMA CONCENTRATIONS IN FASTING STATE OF GR01 MIN-101 (ng / mL) and AUCo-t (H.na mi) Hours 1-MIN-101 2-MIN-101 3-MIN-101 5-MIN-101 6-MIN-101 7-MIN-101 8-MIN-101 9-MIH-101 10-MIN-101 11 -MIN-101 12-MIN-101 13-MIN-101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4.22 0.00 0.00 0.00 1.5 0.00 0.00 6.26 0.00 0.00 0.00 0.00 0.38 0.00 0.42 0.00 0.00 7.98 2 3.83 5.42 10.68 2.50 0.00 0.00 13.23 0.00 8.71 16.03 0.48 8.14 2.5 15.95 13.82 11.87 12.14 0.00 3.45 12.42 3.00 12.78 24.17 23.30 7.62 3 17.85 17.61 11.10 13.88 0.39 12.78 11.08 24.02 12.98 26.68 28.00 10.13 3.5 15.56 21.53 10.97 12.31 6.52 10.89 10.94 28.19 13.60 25.78 24.01 12.18 4 20.60 19.03 8.23 ​​11.96 15.23 9.53 8.04 22.91 17.64 24.78 22.59 11.30 5 17.05 17.24 6.66 14.68 15.63 8.44 14.90 17.95 12.92 24.46 12.86 12.69 6 15.26 14.41 6.89 13.19 13.39 6.06 12.36 11.72 7.62 19.24 5.64 10.42 7 9.61 11.29 6.28 12.62 10.60 4.71 11.51 13.95 6.70 17.83 9.72 9.08 8 7.46 7.20 5.58 11.86 10.51 3.51 8.19 16.53 13.39 14.16 5.82 8.52 10 4.30 5.10 12.66 11.69 6.19 2.71 18.08 17.00 18.05 8.68 13.19 10.59 12 9.45 5.59 10.24 20.15 7.24 3.05 12.22 13.92 16.31 11.15 13.39 12.47 14 13.11 10.14 12.01 17.73 7.12 3.52 12.65 12.02 14.42 11.67 20.32 6.36 16 10.98 6.35 12.59 16.88 6.40 3.18 7.19 11.25 13.43 13.29 19.44 6.02 20 5.54 3.88 4.69 8.36 4.95 2.65 2.44 7.99 6.52 9.76 5.92 3.23 24 5.57 1.94 3.21 6.73 6.31 2,38 2.90 12.21 3,90 10.97 3.63 7,08 28 4.31 1.64 3.18 2.55 3.91 2.35 1.47 7.67 3.79 10.31 0.54 5.80 32 3.50 1.56 2.73 1.16 3.55 5.90 0.66 3.59 2.79 7.59 0.67 3.46 36 2.37 1.06 1.34 0.54 2.14 12.25 0.00 1.06 0,56 3.73 0.37 3.60 48 1.33 0.73 0.28 0.00 2.04 2.55 0.00 0.00 0.00 0.56 0.00 1.76 60 0.00 0.48 0.00 0.00 1.33 1.33 0.00 0.00 0.00 0.00 0.00 0.45 72 0.00 0.69 0.00 0.00 0.41 0.44 0.00 0.00 0.00 0.00 0.00 0.00 0.27 CMax of mi 20.6 21.5 12.7 20.2 15.6 12.8 18.1 28.2 18.1 26.7 28.0 12.7 Tmax H 4.0 3.5 10.0 12.0 5.0 3.0 10.0 3.5 10.0 3.0 3.0 5.0 AUCO-t H.ng ml 281.6 219.3 230.1 309.7 262.8 257.0 213.8 357.2 289.7 430.4 279.0 283.6. 110 Table 34. Plasma concentrations and parameters of MIN-101 mean CR GR-01 (fasting state) bRpznn / eznz / B / YiAi GR01 CONC IN PLASMA IN FASTING STATE OF GR01 MIN-101 and AUCO-t Average Hours Sd CV°« 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 1 0.35 1.22 0.65 346.41 1.5 1.25 2.77 1.95 220.78 2 5.75 5.57 4.67 96.91 2.5 11.71 7.46 5.46 63.69 3 15.54 7.84 6.08 50.45 3.5 16.04 7.01 5.89 43.68 4 15.99 6.08 5.27 38.00 5 14.62 4.60 3.26 31.47 6 11.35 4.17 3.35 36.70 7 10.33 3.58 2.64 34.63 6 9.39 3.93 3.25 41.81 10 10.69 5.39 4.42 50.45 12 11.26 4.66 3.48 41.34 14 11.76 4.67 3.33 39.73 16 10.58 4.87 3.96 46.01 20 5.49 2.33 1.85 42.48 24 5.57 3.30 2.58 59.31 28 3.96 2.80 2.04 70.67 32 3.10 2.06 1.50 66.68 36 2.42 3.33 2.05 137.50 48 0.77 0.92 0.77 119.51 60 0.30 0.51 0.40 171.48 72 0.15 0.24 0.20 159.83 CMax ng mi 19.59 5.74 4.61 29.30 Tmax H 6.00 3.43 3.00 57.19 AUCO-t H.ng mi 284.52 60.83 41.49 21.38 See Figure 23. 111 Table 35. Plasma concentrations and parameters of MIN-101 mean CR GR-01 (fed state with respect to fasting state) Mean plasma concentrations of MIN-101 with GR01 and feeding effect |nfl''ml| Hours GR01 FEEDING. GR01 FASTING 0 0.00 0.00 0.25 0.00 0.00 0.5 0.00 0.00 1 0.00 0.35 1.5 0.00 1.25 2 0.00 5.75 2.5 0.57 11.71 3 1.44 15.54 3.5 1.55 16.04 4 1.79 15.99 5 4.77 14.62 6 7.74 11.35 7 7.77 10.33 8 6.36 9.39 10 7.58 10.69 12 13.70 11.26 14 9.38 11.76 16 8.88 10.58 20 7.04 5.49 24 10.71 5.57 28 8.26 3.96 32 5.22 3.10 36 2.83 2.42 48 0.71 0.77 60 0.16 0.30 72 0.03 0.15 Max ng mi 20.9 19.6 Tmax H 12.5 6.0 AUCO-t H.ngml 269.2 284.5 F AUC 95.14 REF F Cmax 108.97 REF bRpznn / eznz / B / Yi Relative bioavailability of MIN-101 in the GR-01 formulation under fed conditions compared to fasted conditions: F% Cmax: 108.97% F% AUC(o-tau): 95.14% See Figure 24 Example 13: In vivo pharmacokinetic analysis of BFB-520 in CR GR-01 tablets in subjects in a fed state compared to a fasted state, (tau = 72 h) Nutritional status - 12 subjects (crossover) Cmax mean geo: 1.54 ng / mL Median Tmax: 18.00 H AUC(or tau): 30.12 ng-H / mL 112 Table 36. Plasma concentrations and parameters of individual BFB-520 CR GR-01 (feeding status) bRpznn / eznz / B / Y GR01 CONCENTRACIONES EN PLASMA DE GR01 BFB-520 EN EST. ALIM. (ng / mL) y AUCO-t (H.ngmL) Horas 1-BFB-520 2-BFB-520 3-BFB-520 5-BFB-520 6-BFB-520 7-BFB-520 8-BFB-520 9-BFB-520 10-BFB-520 11-BFB-520 12-BFB-520 13-BFB-520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0,25 0,00 0,00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3.5 0.00 0.00 0.33 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 0.00 0.00 0.48 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.27 5 0.00 0.00 0.64 0.46 0.00 0.82 0.00 0.00 0.00 0.00 0.00 0.32 6 0.00 0.46 0.76 0.61 0.00 1.19 0.00 0.00 0.90 0.00 0.00 0.34 7 0.00 0.90 1.09 0.64 0.00 1.28 0.00 0.00 1.19 1.00 0.00 0.38 8 0.00 1.06 0.83 0.90 0.00 1.53 0.00 0.00 1.54 1.77 0.00 0.42 10 0.00 1.08 0.70 1.07 0.00 1.44 0.00 0.51 1.57 1.74 0.00 0.67 12 1.48 0.52 0.69 0.79 0.79 1.82 0.00 1.14 1.50 1.64 1.08 0.67 14 1.56 0.46 0.62 0.52 0.97 2.20 0.00 1.51 2.06 2.53 1.38 0.83 16 1.03 0.79 0.76 0.39 0.87 1.69 0.00 1.26 2.13 2.28 0.95 0.85 20 0.87 0.85 0.64 0.00 1.15 2.15 0.00 1.43 2.36 2.66 0.83 0.72 24 0.65 0.58 0.46 0.00 1.02 1.15 0.69 2.95 1.08 1.88 1.25 0.41 28 1.14 0.48 0.63 0.00 1.75 1.13 0.81 2.46 1.42 1.93 1.86 0.56 32 0.89 0.30 0.32 0.00 1.31 0.90 0.43 2,35 0.74 0.95 1.36 0.43 36 0.60 0,00 0.00 0.00 0.90 0.58 0.00 0.95 0.36 0.60 0.78 0.34 48 0.00 0.00 0.00 0.00 0.26 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max ng'ml 1.6 1.1 1.1 1.1 1.8 2.2 0.8 2.9 2.4 2.7 1.9 0.9 Tmax H 14.0 10.0 7.0 10.0 28.0 14.0 28,0 24.0 20.0 20.0 28.0 16.0 AUCO-t H.ngml 24.4 17.5 18.0 8.2 34.9 43.7 6.8 49.2 45.6 55.8 34.4 22.9 F AUC 104.2 94.2 112.0 26.1 177.5 230.2 34.5 112.5 126.5 137.5 102.1 82.0 F Cmax 130.3 84.3 132.0 59.3 170.1 199.6 63.4 163.9 128.4 162.9 82.5 79.1. 113 Table 37. Plasma concentrations and parameters of BFB-520 media CR GR-01 (feeding status) GR01 CONC IN PLASMA OF GR01 BFB-520 IN EST. SUPPLY and AUCO-t Hours AVERAGE Sd Sm CV'O 0 0.00 0.25 0.00 0.5 0.00 1 0.00 0.00 0.00 sOIV 0! 1.5 0.00 0.00 0.00 =DIV 0! 2 0.00 0.00 0.00 sDIV 0! 2.5 0.00 0.00 0.00 =DIV 0! 3 0.00 0.00 0.00 =DIV 0! 3.5 0.03 0.09 0.05 346.41 4 0.06 0.15 0.10 244.57 5 0.19 0.30 0.25 159.98 6 0.35 0.43 0.36 120.06 7 0.54 0.53 0.48 98.36 8 0.67 0.69 0.60 102.84 10 0.73 0.65 0.54 88.88 12 1.01 0.53 0.43 52.69 14 1.22 0.78 0.65 64.14 16 1.08 0.67 0.50 61.50 20 1.14 0.86 0.68 75.79 24 1.01 0.78 0.54 77.24 28 1.18 0.72 0.59 61.16 32 0.83 0.63 0.46 75.80 36 0.42 0.36 0.31 85.11 48 0.02 60 0.00 72 0.00 Max ng mi 1.69 0.73 0.61 43.32 Tmax H 18.25 7.56 6.42 41.41 AUCO-t H.ng mi 30.12 16.26 13.82 53.98 F AUC 111.58 55.50 37.75 49.74 F Cmax 121.32 46.86 39.66 38.63 bRRznn / eznz / e / Y See Figure 25 Fasting status - 12 subjects (crossover) Cmax mean geo: 1.32 ng / mL Median Tmax: 12.5 H AUC(o-tau): 27.48 ng-H / mL 114 Table 38. Plasma concentrations and parameters of individual BFB-520 CR GR-01 (fasting state) bRpznn / eznz / B / Y GR01 PLASMA CONCENTRATIONS OF GR01 BFB-520 IN EST. FASTING (ng / mL) and AUCO-t (H.nginL) Hours 1-BFB-520 2-BFB-520 3-BFB-520 5-BFB-520 6-BFB-520 7-BFB-520 8-BFB-520 9-BFB-520 10-BFB-520 11-BFB-520 12-BFB-520 13-BFB-520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.26 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.00 0.00 2.5 0.00 0.56 0.43 0.00 0.00 0.00 0.30 0.00 0.46 0.60 0.28 0.00 3 0.42 0.71 0.45 0.44 0.00 0.26 0.60 0.60 0.63 0.88 0.53 0.38 3.5 0.54 1.00 0.50 0.47 0.00 0.38 0.57 1.28 0.74 1.00 0.86 0.43 4 0.84 1.04 0.49 0.63 0.35 0.39 0.45 1.41 1.08 1.29 0.72 0.51 5 1.01 0.98 0.39 0.72 0.62 0.51 0.75 1.56 1.13 1.45 0.99 0.61 6 1.07 1.07 0.43 0.78 0.83 0.54 0.85 1.47 0.85 1.19 0.72 0.64 7 1.20 1.28 0.37 0.92 0.93 0.51 0.88 1.47 0.71 1.47 0.74 0.80 8 1.17 1.07 0.44 1.10 1.03 0.68 0.76 1.80 1.37 1.63 1.06 0.74 10 0.68 0.96 0.68 1.23 0.77 0.33 1.28 1.72 1.84 1.32 1.37 0.99 12 0.65 0.77 0.55 1.30 0.66 0.32 0.91 1.40 1.74 0.78 2.26 1.08 14 1.00 0.87 0.72 1.73 0.74 0.43 1.24 1.54 1.82 1.11 1.11 1.05 16 1.00 0.71 0.83 1.80 0.51 0.43 1.09 1.49 1.80 1.24 1.11 0.95 20 0.69 0.70 0.63 1.58 0.67 0.40 0.71 1.73 1.13 1.44 1.17 0.68 24 0.57 0.31 0.43 0.85 0.50 0.00 0.39 1.31 0.57 1.05 0.99 0.58 28 0.72 0.26 0.50 0.58 0.59 0.00 0.28 1.15 0.92 1.27 0.65 0.58 32 0.33 0.00 0.28 0.30 0.46 0.44 0.00 0.67 0.62 0.68 0.28 0.43 36 0.29 0.00 0.00 0.00 0.38 1.10 0.00 0.28 0.00 0.51 0.00 0.42 48 0.00 0.00 0.00 0.00 0.00 0.00 0.33 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0,00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max ng ml 1.2 1.3 0.8 1.8 1.0 1,1 1.3 1.8 1.8 1.6 2.3 1.1 Tmax H 7.0 7.0 16.0 16.0 8.0 36.0 10.0 8.0 10.0 8.0 12.0 12.0 AUCO-t H.ng mi 23.5 18.6 16.1 31.3 19.7 19.0 19.6 43.8 36.1 40.6 33.7 27.9. 115 Table 39. Plasma concentrations and parameters of BFB-520 mean CR GR-01 (fasting state) GR01 CONC IN PLASMA OF GR01 BFB-520y AUCO-t Hours AVERAGE Sd Sm CVS 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.04 0.10 0.07 233.68 2.5 0.22 0.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.5 0.65 0.35 0.27 53.37 4 0.77 0.36 0.31 47.35 5 0.89 0.36 0.29 40.77 6 0.87 0.29 0.22 33.50 7 0.94 0.35 0.28 37.58 8 1.07 0.39 0.29 36.81 10 1.10 0.45 0.36 40.79 12 1.04 0.55 0.43 53.43 14 1.11 0.42 0.31 37.58 16 1.08 0.45 0.34 41.52 20 0.96 0.43 0.38 45.29 24 0.63 0.36 0.28 57.32 28 0.63 0.36 0.26 57.90 32 0.37 0.23 0.18 60.48 36 0.25 0.33 0.25 133.52 48 0.03 0.09 0.05 346.41 60 0.00 72 0.00 Max ng mi 1.43 0.43 0.37 30.06 Tmax H 12.50 8.04 5.08 64.32 AUCO-t H.ng'ml 27.48 9.46 8.07 34.41 F AUC 96.10 35.77 18.95 37.22 F Cmax 80.48 24.60 20.65 30.56 bRpznn / eznz / B / Y See Figure 26 116 Table 40. Plasma concentrations and parameters of BFB-520 mean CR GR-01 (fed state versus fasting state) bRpznn / eznz / B / Yi GR01 CONC IN PLASMA OF GR01 BFB-520y AUCO-t Hours AVERAGE Sd Sm CVS 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.04 0.10 0.07 233.68 2.5 0.22 0.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.5 0.65 0.35 0.27 53.37 4 0.77 0.36 0.31 47.35 5 0.89 0.36 0.29 40.77 6 0.87 0.29 0.22 33.50 7 0.94 0.35 0.28 37.58 8 1.07 0.39 0.29 36.81 10 1.10 0.45 0.36 40.79 12 1.04 0.55 0.43 53.43 14 1.11 0.42 0.31 37.58 16 1.08 0.45 0.34 41.52 20 0.96 0.43 0.38 45.29 24 0.63 0.36 0.28 57.32 28 0.63 0.36 0.26 57.90 32 0.37 0.23 0.18 60.48 36 0.25 0.33 0.25 133.52 48 0.03 0.09 0.05 346.41 60 0.00 72 0.00 Max ng mi 1.43 0.43 0.37 30.06 Tmax H 12.50 8.04 5.08 64.32 AUCO-t H.ng mi 27.48 9.46 8.07 34.41 F AUC 96.10 35.77 18.95 37.22 F Cmax 80.48 24.60 20.65 30.56 Relative bioavailability of BFB-520 in formulation GR-01 in the fed state compared to the fasted state: F% Cmax: 121.32% F% AUC(o-tau):111.58% See Figure 27 Example 14: Expected dietary effect on steady-state plasma concentrations of MIN-101 and BFB-520 in GR-01 (32 mg) tablets Determination of elimination slopes from plasma concentration curves over time averaged before numerical calculations. MIN-101 Feeding state: Ke= 0.119 / H Fasting state: Ke= 0.082 / H BFB-520: 117 Feeding state: from 14 H to 28 H during the bistable phase Ke= 0.014 / H; post-absorption Ke= 0.233 / H Fasting state: from 14 H to 28 H during the bistable phase Ke= 0.005545 / H; post absorption Ke= 0.1586 / H bRRznn / eznz / B / Yi 118 Table 41. Expected steady-state plasma concentrations of MIN-101 in tablet form GR-01 of 32 mg (fed and fasting states) Plasma concentrations of MIN101 in steady state GR01 32 mg FOOD AND FASTING MIN-101 (ngmL) HOURS GR01 FOOD. SS GR01 FASTING SS 72 11.45 6.45 72.5 10.70 6.20 73 10.09 6.30 73.5 9.50 6.96 74 8.95 11.23 74.5 9.00 16.97 75 9.39 20.59 75.5 9.04 20.89 76 10.46 20.58 77 11.04 18.91 78 13.30 15.30 79 12.71 13.96 80 11.83 12.95 82 11.04 13.53 84 16.70 14.02 86 11.53 13.80 88 10.57 12.32 92 8.09 6.75 96 11.45 6.46 CMaxSS ng / ml 16.7 20.9 CMinSS 8.09 6.46 TmaxSS H 12.00 3.5 AUC72-96 H.ng / ml 263.8 287.6 F AUC 91.7 REF F Cmax 80.0 REF bRpznn / eznz / B / Y See Figure 28. 119 Table 42. Expected steady-state plasma concentrations of BFB-520 in tablet form GR-01 of 32 mg (fed and fasting states) Plasma concentrations of BFB-520 in steady state GR01 32 mg FASTING BFB-520 (ng mL) HOURS GR01 FASTING SS GR01 FASTING SS 72 72.5 73 73.5 74 74.5 75 75.5 76 77 78 79 80 82 84 86 88 92 96 1.03 1.02 1.01 1.00 0.99 0.99 0.98 1.00 1.25 1.13 1.29 1.46 1.51 1.26 1.43 1.43 1.21 1.19 1.03 0.66 0.64 0.62 0.60 0.63 0.79 1.04 1.18 1.41 1.38 1.33 1.38 1.45 1.37 1.29 1.26 1.19 1.02 0.66 CMaxSS ng / ml CMinSS TmaxSS H AUC72-96 H.ng / ml F AUC F Cmax 1.51 1.03 8.00 29.5 109.4 103.7 1.45 0.66 8.00 27.0 REF REF See Figure 29. bRpznn / eznz / B / Yi Example 15: Expected dietary effect on steady-state plasma concentrations of MIN-101 and BFB-520 in GR-01 tablets (64 mg) Determination of elimination slopes from plasma concentration curves over time averaged before numerical calculations. MIN-101 Power supply state: Ke= 0.119 / H Fasting state: Ke= 0.082 / H BFB-520: Feeding state: from 14 H to 28 H during the bistable phase Ke= 0.014 / H; post-absorption Ke= 0.233 / H Fasting state: from 14 H to 28 H during the bistable phase Ke= 0.005545 / H; post-absorption Ke= 0.1586 / H 120 Table 43. Predicted steady-state plasma concentrations of MIN-101 in 64 mg GR01 tablets (fed and fasting states) Plasma concentrations of MIN-101 in steady state GR01 64mg FOOD AND FASTING MIN-101 (ng-mL) HOURS GR01 FOOD SS GR01 FASTING SS 72 22.91 12.90 72.5 21.41 12.40 73 20.17 12.60 73.5 19.01 13.93 74 17.91 22.46 74.5 18.00 33.94 75 18.78 41.18 75.5 18.08 41.77 76 20.92 41.17 77 22.08 37.82 78 26.60 30.60 79 25.42 27.92 80 23.65 25.90 82 22.08 27.06 84 33.41 28.05 86 23.05 27.61 88 21.14 24.64 92 16.17 13.49 96 22.91 12.93 CMaxSS ng / ml 33.41 41.77 CMinSS 16.17 12.93 TmaxSS H 12.00 3.50 AUC72-96 H.ng / ml 527.5 577.6 F AUC 91.3 REF F Cmax 80.0 REF bRpznn / eznz / B / Y See Figure 30. 121 Table 44. Expected steady-state plasma concentrations of BFB-520 in tablets GR-01 of 64 mg (fed and fasting states) Plasma concentrations of BFB-520 in steady state GR01 64mg FOOD AND FASTING BFB-520 (ngmL) HOURS GR01 FOOD SS GR01 FASTING SS 72 2.06 1.32 72.5 2.04 1.28 73 2.02 1.24 73.5 2.00 1.21 74 1.99 1.26 74.5 1.97 1.58 75 1.95 2.09 75.5 1.99 2.37 76 2.50 2.82 77 2.27 2.77 78 2.57 2.66 79 2.92 2.76 80 3.01 2.91 82 2.51 2.75 84 2.87 2.57 86 2.86 2.52 88 2.42 2.37 92 2.38 2.03 96 2.06 1.32 CMaxSS ng / ml 3.01 2.91 CMinSS 2.06 1.32 TmaxSS H 8.00 8.00 AUC72-96 H.ng / ml 59.0 54.1 F AUC 109.1 REF F Cmax 103.7 REF bRpznn / eznz / B / Yi See Figure 31. Example 16: Description of 32 mg gastro-resistant CR tablet (GR01 / B-32 mg) CR GR-01 / B tablets are supplied as round tablets (10 mm diameter, R=10), free from visual defects. Each tablet contains 32 mg of Compound (I). A full description of the components and the quantitative composition of the CR GR-01 / B tablet is provided in Table 45. Table 45: Composition of the CR GR-01 / B 32 mg tablet Component / ingredient GR-01 / B-32mg mg / tablet % (w / w) MIN-1011 38.40 12.09 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 122 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 96.67 30.42 Lactose 60.00 18.89 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.62 100.00 bRpznn / eznz / B / Yi Salt correction factor of 1.2 applied Example 17: Description of 64 mg gastro-resistant CR tablet (GR-01 / B-64 mg) CR GR-01 / B tablets are supplied as round tablets (10 mm diameter, R=10), free from visual defects. Each tablet contains 64 mg of Compound (I). A full description of the components and the quantitative composition of the CR GR-01 / B tablet is provided in Table 46. Table 46: Composition of the CR GR-01 / B 64 mg tablet Component / ingredient GR-01 / B-64 mg mg / tablet %(w / w) MIN-1011 76.8 24.14 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 77.40 24.37 Lactose 40.80 12.85 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 1231Salt correction factor of 1.2 applied bRpznn / eznz / B / Yi Example 18: Comparison of the 32 mg GR-01 tablet, the 32 mg GR-01 / B tablet, and the 64 mg GR-01 / B tablet Table 47: Composition of the compression: GR01 vs GR01 / B Component / ingredient GR01-32 mg GR01 / B-32 mg GR01 / B-64 mg mg / comprimido % (w / w) mg / comprimido % (w / w) mg / comprimido % (w / w) MIN-1011 38.40 12.09 38.40 12.09 76.8 24.14 Hipromelosa (Metolose® 90SH 100 SR) 30.00 9.45 Hipromelosa (METHOCEL™ K100LV CR) 30.00 9.45 30.00 9.45 Hipromelosa (Methocel™ K100M CR) 72.00 22.67 72.00 22.67 72.00 22.67 Microcrystalline cellulose 95.10 29.95 96.60 30.42 77.40 24.37 Lactose 60.00 18.89 60.00 18.89 40.80 12.85 Silica colloidal anhidra 1.50 0.47 1.50 0.47 1.50 0.47 Magnesium stearate 3.00 0.94 1.50 0.47 1.50 0.47 Eudragit L30D55 ​​15.0 4.72 15.0 4.72 15.0 4.72 Plasacryl HTP20 2.55 0.80 2.55 0.80 2.55 0.80 Total 317.55 5.53 317.55 100.00 317.55 100.00 Salt correction factor of 1.2 applied 124 Example 19: Stability Data Experiments: Comparison of GR-01 and GR01 / B 32 mg tablets “Impurity A”, “2-isomer” and “PMIC” refer to manufacturing process impurities for MIN-101. Table 48: Stability data at 25 -C / 60 % RH bRpznn / eznz / B / Yi Product Name: Strength: Storage Condition: MIN-101 32 mg 25 EC / 60% RH Product Manufacturer: Amatsi Aquitaine API Manufacturer: PCAS Packaging Closure: TEKNIFLEX® VPOA 10200 and aluminum blister packs Analysis Stability Range (months) Initial 1 3 6 9 12 Tablets GR01 Related Substance (%) Impurity A 2-isomer PMIC Unspecified Impurity Total Impurities <loq <loq 0,08 <0,1 % cada uno 0,15 0,02 0,13 0,29 0,03 0,18 rrt0,67 : 0,11 0,46 0,04 0,20 0,12 0,51 0,24 rrt 0,67 0,52 0,26 0,59 comprimidos gr01 b sub. relacionado (%) impureza a 2-¡sómero pmic imp. sin especificar total de impurezas nd 0,07 0,09 0,37 0,16 0,38125 Table 49: Stability data at 40SC / 75% RH Product Name: Strength: Storage Condition: MIN-101 32 mg 40 9C / 75 % RH Product Manufacturer: Amats! Aquitaine Manufacturer APLPCAS Packaging Closure: TEKNIFLEX® VPOA 10200 and aluminum blister packs Analysis Stability Range (months) Initial 1 3 6 Tablets GR01 Related Sub. (%) Impurity A 2-isomer PMIC Unspecified Imp. Total Impurities <loq <loq 0,08 <0,1 % cada uno 0,15 0,04 0,27 rrt0,67 0,57 0,06 0,44 : 0,18 0,94 0,77 0,24 1,46 comprimidos gr01 b sub. relacionado(%) impureza a 2-¡sómero pmic imp. sin especificar total de impurezas nd 0,07 0,09 0,26 0,23 0,51 0,34 rrt 0,67 0,11 0,71 0,52 1,00bRpznn / eznz / B / Yi 126 Example 20: In vitro dissolution specifications for GR-01 / B tablets Table 50: Specifications for GR-01 / B tablets Analysis Method Acceptance Criteria HPLC Dissolution Report Results (%) (±10%) 2 hours 0.0% 4 hours 24.1% 8 hours 59.2% d Q QQ GO / bRpznn / eznz / B / Yi Example 21: Description of 32 mg gastro-resistant CR tablet (GR-01 / C-32 mg) CR GR-01 / C tablets are supplied as round tablets (10 mm diameter, R=10), free from visual defects. Each tablet contains 32 mg of Compound (I). A full description of the components and the quantitative composition of the CR GR-01 / C tablet is provided in Table 51. Table 51: Composition of the CR GR-01 / C 32 mg tablet Component / ingredient GR-01 / C-32 mg mg / tablet % (w / w) MIN-1011 38.40 12.11 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 95.10 29.95 Lactose 60.00 18.89 Anhydrous colloidal silica 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 127 Example 22: Description of 64 mg gastro-resistant CR tablet (GR-01 / C-64 mg) CR GR-01 / C tablets are supplied as round tablets (10 mm diameter, R=10), free from visual defects. Each tablet contains 64 mg of Compound (I). A full description of the components and the quantitative composition of the CR GR-01 / C tablet is provided in Table 53. Table 53: Composition of the CR GR-01 / C 64 mg tablet bARznn / eznz / e / Yi Component / ingredient GR-01 / C-64 mg mg / tablet % (P / P) MIN-1011 76.8 24.19 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 Microcrystalline cellulose 75.90 23.91 Lactose 40.80 12.85 Colloidal anhydrous silica 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 ​​15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 EQUIVALENTS AND INCORPORATION BY REFERENCE The dosage forms, compositions, and methods described herein are based on certain preferred forms. However, since particular variations in these will be evident to those skilled in the art, the description provided herein should not be considered limited to them. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by a person skilled in the art to which this description pertains. In the descriptive text and claims, singular forms also include the plural, unless the context clearly dictates otherwise. 128 It should be understood that at least some of the descriptions have been simplified to focus on elements relevant to a clear understanding of the description, while other elements, beyond those that those skilled in the art would appreciate, have been omitted for clarity. However, since these five elements are well known in the art, and since they do not necessarily facilitate a better understanding of the description, a description of these elements is not provided herein. Furthermore, to the extent that a method is not based on the particular order of the steps stated herein, the particular order of the steps listed in a claim should not be construed as limiting that claim. All patents, patent applications, references, and publications cited herein are incorporated herein in their entirety and by reference as if fully stated. Such documents are not admitted as prior art to this description.< / loq> < / loq>

Claims

1. A gastro-resistant controlled-release dosage form comprising: i. from 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.

2. The gastro-resistant controlled-release dosage form of claim 1, wherein the dosage form produces, after oral administration to the subject, a plasma pharmacokinetic profile for Compound (I) comprising a Tmax of around 1, 1.5, 2, 2.5, 3, 3.5 or 4 hours and around 22 hours.

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

4. La forma de dosificación de liberación controlada gastrorresistente de la reivindicación 1, donde la cantidad del Compuesto (I) es de 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 o 100 mg.

5. The gastro-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 gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUCcmh of Compound (I) is less than about 68 h*ng / mL.

7. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the Cmax of Compound (I) 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 gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 32 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC0-24 h of Compound (I) is from about 75 h*ng / mL to about 350 h*ng / mL or from about 100 h*ng / mL to about 300 h*ng / mL.

9. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein 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 for the metabolite BFB-520 of Compound (I) comprises a Cmax below 3.0 ng / mL, below 2.5 ng / mL, below 2.0 ng / mL, below 1.5 ng / mL or below 1.0 ng / mL.

10. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUCo-4h of Compound (I) is less than about 50, 60, 70, 80, 90, 100, 110, 120 or 130 h*ng / mL.

11. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the Cmax of Compound (I) is less than about 36 ng / mL or less than about 25 ng / mL.

12. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein the amount of Compound (I) is about 64 mg, or an equivalent amount of a pharmaceutically acceptable salt and / or solvate thereof, and the AUC0-24 h of Compound (I) is between about 200 h*ng / mL and about 600 h*ng / mL.

13. The gastro-resistant controlled-release dosage form of any of claims 1-5, wherein 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 for the metabolite BFB-520 of Compound (I) comprises a Cmax below 4.0 ng / mL, below 3.5 ng / mL, below 3.0 ng / mL, or below 2.5 ng / mL.

14. The gastro-resistant controlled-release dosage form of any of the preceding claims, wherein the dosage form is a tablet comprising a tablet core and an enteric coating.

15. The gastro-resistant controlled-release dosage form of claim 14, wherein the tablet core of the dosage form comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof and a controlled-release agent.

16. The gastro-resistant controlled-release dosage form of claim 15, wherein the tablet core further comprises a filler, a gluing agent, and a lubricant. bRpznn / eznz / B / Yi 131 17. The gastro-resistant controlled-release dosage form of claim 14, wherein the tablet core of the dosage form comprises Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, a controlled-release agent, a gluing agent, and a lubricant.

18. The gastro-resistant controlled-release dosage form of any of claims 15-17, wherein the controlled-release agent in the tablet core comprises one or more hypromellose tablets.

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

20. The gastro-resistant controlled-release dosage form of claim 16 or 17, wherein the glide in the tablet core is anhydrous colloidal silica.

21. The gastro-resistant controlled-release dosage form of claim 16 or 17, wherein the lubricant in the tablet core is magnesium stearate.

22. The gastro-resistant controlled-release dosage form of claim 14, wherein the enteric coating of the dosage form comprises at least one polymeric controlled-release agent having a dissolving property with a pH of more than 5.5, 6.0 or 6.5, and an anti-adherent agent.

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

24. The gastro-resistant controlled-release dosage form of claim 22 or 23, wherein the polymeric controlled-release agent comprises Eudragit L30D55.

25. The gastro-resistant controlled-release dosage form of claim 22 or 23, wherein the anti-adherent agent is Plasacryl HTP20.

26. A gastro-resistant controlled-release dosage form 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 of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w of microcrystalline cellulose; about 13 to about 23% w / w of lactose monohydrate; about 0.1 to about 4% w / w of colloidal anhydrous silica; about 0.1 to about 4% of magnesium stearate; of about 1 to about 10% w / w of Eudragit L30D55; and of about 0.5 to about 5% w / w of Plasacryl HTP20.

27. The gastro-resistant controlled-release dosage form of claim 26, comprising: 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); about 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w of microcrystalline cellulose; about 19% w / w of lactose monohydrate; about 0.5% w / w of colloidal anhydrous silica; about 1% of magnesium stearate; about 5% w / w of Eudragit L30D55; and about 1% w / w of Plasacryl HTP20.

28. A gastro-resistant controlled-release dosage form 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 (Methocel™ K15M CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w of microcrystalline cellulose; about 13 to about 23% w / w of lactose monohydrate; about 0.1 to about 4% w / w of anhydrous colloidal silica; about 0.1 to about 4% w / w of magnesium stearate; about 1 to about 10% of Eudragit L30D55; of about 0.5 to about 5% w / w of Plasacryl HTP20; and of about 0.5 to about 5% w / w of Surelease E-7-19040.

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

30. A gastro-resistant controlled-release dosage form 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 (Methocel™ K100LV CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 25 to about 35% w / w of microcrystalline cellulose; about 13 to about 23% w / w of lactose monohydrate; about 0.1 to about 4% w / w of colloidal anhydrous silica; about 0.1 to about 4% of magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and from around 0.5 to around 5% w / w of Plasacryl HTP20.

31. The gastro-resistant controlled-release dosage form of claim 30, comprising: 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); about 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w of microcrystalline cellulose; about 19% w / w of lactose monohydrate; about 0.5% w / w of colloidal anhydrous silica; about 0.5% w / w of magnesium stearate; about 5% w / w of Eudragit L30D55; and about 1% w / w of Plasacryl HTP20.

32. The gastro-resistant controlled-release dosage form of claim 30, comprising: 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); about 23% w / w of hypromellose (Methocel™ K100M CR); about 30% w / w of microcrystalline cellulose; about 19% w / w of lactose monohydrate; about 0.5% w / w of colloidal anhydrous silica; about 1% w / w of magnesium stearate; about 5% w / w of Eudragit L30D55; and about 1% w / w of Plasacryl HTP20.

33. A gastro-resistant controlled-release dosage form 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 of hypromellose (Methocel™ K100LV CR); about 17 to about 27% w / w of hypromellose (Methocel™ K100M CR); about 19 to about 29% w / w of microcrystalline cellulose; about 8 to about 18% w / w of lactose monohydrate; about 0.1 to about 4% w / w of colloidal anhydrous silica; about 0.1 to about 4% of magnesium stearate; about 1 to about 10% w / w of Eudragit L30D55; and from around 0.5 to around 5% w / w of Plasacryl HTP20.

34. The gastro-resistant controlled-release dosage form of claim 33, comprising: 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); about 23% w / w of hypromellose (Methocel™ K100M CR); about 24% w / w of microcrystalline cellulose; about 13% w / w of lactose monohydrate; about 0.5% w / w of colloidal anhydrous silica; about 0.5% w / w of magnesium stearate; about 5% w / w of Eudragit L30D55; and about 1% w / w of Plasacryl HTP20.

35. The gastro-resistant controlled-release dosage form of claim 33, comprising: 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); about 23% w / w of hypromellose (Methocel™ K100M CR); about 24% w / w of microcrystalline cellulose; about 13% w / w of lactose monohydrate; about 0.5% w / w of colloidal anhydrous silica; about 1% w / w of magnesium stearate; about 5% w / w of Eudragit L30D55; and about 1% w / w of Plasacryl HTP20.

36. A method for reducing the risk of QT prolongation when treating a subject with Compound (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the method comprises oral administration to the subject of a gastro-resistant controlled-release dosage form of any of claims 1-35.

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

38. The method according to claim 36 or 37, wherein the gastro-resistant controlled-release dosage form is administered once daily.

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

40. The method of any of claims 36-39, wherein the subject has been fed prior to oral administration of the dosage form.

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

42. A gastro-resistant controlled-release dosage form of any of claims 1-35 for use in reducing the risk of QT prolongation.

43. A gastro-resistant controlled-release dosage form of any of claims 1-35 for use in the treatment of negative symptoms in a subject, wherein the subject has a diagnosis of schizophrenia.

44. A gastro-resistant controlled-release dosage form for use according to claim 42 or 43, wherein the gastro-resistant controlled-release dosage form is administered once daily.

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

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

47. A gastro-resistant controlled-release dosage form for use according to claim 42-45, wherein the subject is in a fasting state prior to oral administration of the dosage form.

48. The use of a gastro-resistant controlled-release dosage form of any of claims 1-35 in the manufacture of medicinal products to reduce the risk of QT prolongation.

49. The use of a gastro-resistant controlled-release dosage form of any of claims 1-35 in the manufacture of medicaments for the treatment of negative symptoms in a subject, wherein the subject has a diagnosis of schizophrenia.

50. The use of claim 48 or 49, wherein the gastro-resistant controlled-release dosage form is administered once daily.

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

52. The use of any of claims 48-51, wherein the subject has been fed prior to oral administration of the dosage form.

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