EA040638B1 - PHARMACEUTICAL COMPOSITION CONTAINING 2-((1-(2-(4-FLUOROPHENYL)-2-OXOETHYL)PIPERIDIN-4-YL)METHYL)ISOINDOLINE-1-ONE FOR TREATMENT OF PSYCHONEUROLOGICAL DISEASE OR SLEEP DISORDER, METHOD FOR TREATMENT OF PSYCHONEUROLOGICAL DISEASE OR SLEEP DISORDER SLEEP, TABLET AND SET - Google Patents

Description

The technical field to which the invention belongs

The present invention in some embodiments relates to pharmaceutical compositions and methods for the treatment of a neuropsychiatric disease or sleep disorder or disorder, in particular schizophrenia in a patient.

State of the art

Schizophrenia is a complex, non-standard and heterogeneous mental disorder affecting up to 0.7% of the world population according to the World Health Organization (WHO, 2006). Patients with schizophrenia experience a range of symptoms, including positive symptoms such as delusions, hallucinations, thought disturbances, and agitation; negative symptoms, such as mood swings and an inability to enjoy daily life; cognitive symptoms such as reduced ability to process information and make decisions, difficulty concentrating and reduced short-term memory function and sleep disturbances.

The etiology of schizophrenia has not been fully established. The main explanatory hypothesis for the pathophysiology of schizophrenia is the dopamine (DA) hypothesis, which proposes that overactivity of DA transmission is responsible for the pronounced symptoms of the disorder. This hypothesis is based on the observation that drugs effective in the treatment of schizophrenia share the common feature of blocking DA D2 receptors. However, these so-called typical antipsychotics are associated with a very high incidence of extrapyramidal symptoms (EPS). In addition, negative symptoms and cognitive impairment are believed to be relatively insensitive to typical antipsychotics.

Currently, the most approved treatments for schizophrenia generally show efficacy in treating positive symptoms. An estimated 4.2 million people suffered from schizophrenia in 2012 in the United States and the five major markets of the European Union. Among them, an estimated 48% experienced mostly negative symptoms and 80% suffered from cognitive impairment. In addition, approximately 50% of patients with schizophrenia experience sleep disturbances, which can further exacerbate both positive and negative symptoms.

The introduction of so-called atypical antipsychotics in the last decade has represented a significant advance in the treatment of schizophrenia. Although these atypical antipsychotics differ widely in chemical structure and receptor binding profiles, they have the characteristic of potent serotonin (5-hydroxytryptamine) type 2 (5-HT2A) receptor antagonism. The high 5-HT2A:D2 affinity ratio is believed to substantially reduce the propensity to induce EPS compared to typical antipsychotics.

However, many patients remain non-adherent despite the tolerability benefits of atypical antipsychotics. Although the risk of EPS appears to be lower with atypical antipsychotics, the high doses required for some atypical antipsychotics are likely to increase the incidence of EPS and require concomitant medications such as drugs for the treatment of Parkinson's disease.

In addition to EPS, antipsychotics cause a wide range of side effects, including sedation, anticholinergic effects, increased prolactin levels, orthostatic hypotension, weight gain, altered glucose metabolism, and prolongation of the QT complex. These side effects may affect patient compliance with their treatment regimen. It should be noted that non-compliance with the treatment regimen is the main reason for the recurrence of the disease.

Although atypical antipsychotics offer advantages over typical antipsychotics in terms of symptom relief and side effect profile, these differences are usually minor. A small number of patients still remain refractory to all currently available antipsychotics. They continue to look for new agents to solve these problems.

The disclosure provides compositions, methods, and kits for addressing this urgent and unmet need for the treatment of schizophrenia that are effective in all subjects, especially those that have not been observed to be effectively treated with currently available therapies. Compositions, methods, and kits of disclosure result in patient compliance with the treatment regimen and regimen.

The essence of the invention

The disclosure provides pharmaceutical formulations for the treatment of a neuropsychiatric disease or sleep disorder or disorder, containing from 1 to 100 mg of Compound (I)

or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable diluent, excipient or carrier, provided that when administered to a human, the maximum concentration in

- 1 040638 plasma (C _max ) compound (I), determined in humans by HPLC, below 50 ng/ml.

The disclosure provides a tablet for the treatment of a neuropsychiatric disease or a sleep disorder or disorder comprising hypromellose, an excipient, a glidant, a lubricant, and approximately 64 mg of compound (I), or a pharmaceutically acceptable salt or solvate thereof, provided that when administered to a human, the maximum plasma concentration ( C _max ) of compound (I) determined in humans by HPLC below 50 ng/ml.

The disclosure provides a method for treating a neuropsychiatric disease or disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition containing Compound (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need of such treatment.

The disclosure provides a method for treating schizophrenia, comprising administering a pharmaceutical formulation to a subject in need of such treatment.

The disclosure provides a kit for the treatment of a neuropsychiatric disease or disorder or sleep disorder, containing a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt and solvate thereof, and instructions for use.

The disclosure provides a kit for the treatment of a neuropsychiatric disease or disorder or sleep disorder, containing a tablet containing compound (I) or a pharmaceutically acceptable salt and solvate thereof, and instructions for use.

Unless otherwise indicated, all technical and scientific terms used in the present description have the same meaning as generally understood by a person skilled in the art to which this invention pertains. In the description of the singular form, the plural is also included, unless the context clearly indicates otherwise. While methods and materials similar or equivalent to those described herein may be used in the practice or study of the disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in the present description are incorporated by reference. The references cited in the present description do not establish the state of the art of the claimed invention. In the event of a conflict, the present description, including definitions, will govern. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

Brief description of the drawings

The foregoing summary of the invention, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings.

In FIG. 1 is a graph illustrating the plasma concentration-time profiles of MIN-101.

In FIG. 2 is a graph illustrating the plasma concentration-time profiles of BFB-520.

In FIG. 3 is a graph illustrating the plasma concentration-time profiles of BFB-999.

In FIG. 4 is a graph illustrating the plasma concentrations of MIN 101, BFB-520 and BFB999 by period.

In FIG. 5 is a series of graphs illustrating changes in the QTcF interval with BFB-520, BFB-999 and CYR-101 concentrations.

In FIG. 6 is a diagram illustrating the sleep monitoring scheme using PSG and V-Watch.

In FIG. 7 is a diagram illustrating Part 1 of the study design.

In FIG. 8 is a diagram illustrating Part 2 of the study design.

In FIG. 9 is a diagram illustrating the study period layout.

In FIG. 10 is a diagram illustrating the global study design for phase IIB in patients with schizophrenia.

Detailed description of the invention

The disclosure provides pharmaceutical compositions, methods, and kits for the treatment of a neuropsychiatric disease or condition. Preferably, the neuropsychiatric disease or condition is schizophrenia. Compositions and disclosure kits include pharmaceutical compositions. Pharmaceutical formulations contain compounds (I).

The disclosure relates to pharmaceutical compositions for the treatment of a neuropsychiatric disease or disorder or sleep disorder, where said composition contains hypromellose, a filler, a glidant, a lubricant, and from 1 to 100 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, provided that that when administered to a human, the maximum plasma concentration (Cmax) of Compound (I) as determined in humans by HPLC is below 50 ng/mL.

The disclosure also relates to a tablet for the treatment of a neuropsychiatric disease or disorder or sleep disorder, comprising hypromellose, an excipient, a glidant, a lubricant, and approximately 32 mg of compound (I), or a pharmaceutically acceptable salt or solvate thereof, when administered to a human, which has a maximum concentration in plasma (C _max ) of compound (I), determined in humans by HPLC, below 50 ng/ml.

The disclosure also relates to a method for treating a neuropsychiatric disease or disorder, comprising administering a therapeutically effective amount of a therapeutically effective amount of the claimed pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need of such treatment.

In one embodiment, the neuropsychiatric disorder is schizophrenia.

The disclosure also relates to a kit for the treatment of a neuropsychiatric disease or disorder or sleep disorder, containing a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt or solvate thereof and instructions for use.

The disclosure also relates to a kit for the treatment of a neuropsychiatric disease or disorder or sleep disorder, containing a tablet containing compound (I) or a pharmaceutically acceptable salt or solvate thereof and instructions for use.

As used herein, the term amorphous form refers to the non-crystalline solid form of a substance.

As used herein, the compound is stable where no significant amounts of degradation products are observed under constant humidity conditions (e.g., 10, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, and 95% RH , exposure to light and temperatures (for example, higher than 0°C, for example 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70°C) for a certain period (for example, one week, two weeks, three weeks and four weeks).The compound is not considered to be stable under a certain condition when degradation impurities appear or the area percentage (e.g. AUC as characterized by HPLC) of existing impurities begins to rise. important role in determining the stability of the compound.

As used herein, the term mixing means combining, blending, stirring, shaking, rotating or oscillating. The term agitation means mixing, shaking, oscillating or rotating. The term oscillation means mixing, shaking, agitation or rotation.

Unless explicitly stated otherwise, the terms approximately and approximately are synonymous. In one embodiment, approximately and approximately refer to the listed amount, amount, or range of ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1% or ±0.5%. In another embodiment, approximately and approximately refer to the listed amount, value, or range of ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In yet another embodiment, approximately and approximately refer to the listed amount, value, or range of ±5%.

When the terms approximately and roughly are used when listing XRPD peaks, those terms refer to the listed X-ray powder diffraction peak ±0.5°2θ, ±0.4°2θ, ±0.3°2θ, ±0.2°2θ, or ±0 ,1°2θ. In another embodiment, the terms approximately and approximately refer to the listed X-ray powder diffraction peak ±0.2°2θ. In another embodiment, the terms approximately and approximately refer to the listed X-ray powder diffraction peak ±0.1°2θ.

When the terms approximately and approximately are used when listing a temperature or temperature range, these terms refer to the listed temperature or temperature range of ±5°C, ±2°C, or ±1°C. In another embodiment, the terms about and approximately refer to the listed temperature or temperature range of ±2°C.

Compound (I):

The disclosure provides pharmaceutical formulations of Compound (I)

or a pharmaceutically acceptable salt thereof.

In one embodiment, the formulations of disclosure provide the maximum plasma concentration (Cmax) and area under the curve (AUC) of compound (I) and its two active metabolites (BFB-520 and BFB-999) at doses associated with improved therapeutic response and fewer side effects. reactions (eg, prolongation of QT intervals).

In one embodiment, the opening formulations increase the maximum plasma concentration (Cmax) and area under the curve (AUC) of BFB-999 and at the same time decrease the maximum plasma concentration ( _Cmax ) and area under the curve (AUC) of BFB-520.

In one embodiment, the formulations of disclosure provide a maximum plasma concentration (C _max ) of compound (I) below 50, below 45, below 40, below 35, below 30, below 25, below 20, below 15, or below 10 ng/mL. In one embodiment, the formulations of the disclosure provide an AUC value of compound (I) below 400 h*ng/ml, below 350 h*ng/ml, below 300 h*ng/ml, below 250 h*ng/ml, below 200 h * ng / ml, below 150 h * ng / ml or below 100 h * ng / ml.

In one embodiment, the disclosure formulations provide a maximum plasma concentration (C _max ) of 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, or below 1.0 ng/ml. In one embodiment, the disclosure formulations provide a BFB-520 AUC value below 40 h*ng/mL, below 35 h*ng/mL, below 30 h*ng/mL, below 25 h*ng/mL, below 20 h*ng/mL. ml, below 15 h*ng/ml or below 10 h*ng/ml. In one embodiment, BFB-520 is associated with prolongation of QT intervals at supertherapeutic doses.

In one embodiment, to avoid prolongation of the QT interval, the maximum plasma concentration (C _max ) of compound (I) and BFB-520 should not exceed 80 and 12 ng/ml, respectively. In one embodiment, the disclosure formulations provide a C _max of BFB-520 below 10 ng/ml, below 9.0 ng/ml, below 8.0 ng/ml, below 7.0 ng/ml, below 6.0 ng/ml, 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 or below 1.0 ng/ml. In one embodiment, the disclosure formulations provide a Cmax of BFB-999 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, or below 1.0 ng/ml. In one embodiment, the disclosure formulations provide an AUC value of BFB999 below 40 h*ng/ml, below 35 h*ng/ml, below 30 h*ng/ml, below 25 h*ng/ml, below 20 h*ng/ml, below 15 h*ng/ml or below 10 h*ng/ml.

In one embodiment, the disclosure formulations contain about 1-100 mg of compound (I), about 1-75 mg of compound (I), about 2-75 mg of compound (I), about 5-75 mg of compound (I), about 10- 75 mg of compound (I), approximately 15-75 mg of compound (I), approximately 15-70 mg of compound (I), approximately 15-65 mg of compound (I). In one embodiment, the formulations of the disclosure contain about 16 mg of compound (I), about 32 mg of compound (I), about 40 mg of compound (I), or about 64 mg of compound (I).

In one embodiment, the formulations of the disclosure are suitable for long term use (e.g., one week, two weeks, three weeks, four weeks, two months, four months, six months, eight months, ten months, one year, two years, three years, four years and five years).

In one embodiment, the opening formulations are administered once a day.

In one embodiment, the disclosure formulations are administered to the patient on an empty stomach. In one embodiment, the opening formulations are administered to the patient at least 4 hours after the patient has eaten, at least 6 hours after the patient has eaten, at least 8 hours after the patient has eaten, at least 10 hours after the patient has taken food, at least 12 hours after the patient has taken food. In one embodiment, the disclosure formulations are administered to the patient after a meal. In one embodiment, the disclosure formulations are administered to the patient 4 hours after the patient has taken food, 3 hours after the patient has taken food, 2 hours after the patient has taken food, 1 hour after the patient has taken food, or 0.5 hours after the patient has taken food.

By food is meant any amount of food that includes any source of carbohydrates, proteins, amino acids, etc.

In one embodiment, the formulations of the disclosure are suitable for oral administration, intravenous administration, intramuscular administration, or subcutaneous administration. In one embodiment, the formulations of the disclosure are suitable for oral administration. In one embodiment, the formulations of the disclosure are in the form of a tablet or capsule.

In one embodiment, the tablet formulation contains compound (I), a release modifier, a filler, a glidant, and a lubricant. In one embodiment, the release modifier is hypromellose (eg, hypromellose K100LV CR, hypromellose K4M CR, hypromellose E50, or a combination thereof). In one embodiment, the filler is microcrystalline cellulose, lactose, or a combination thereof. In one embodiment, the glidant is colloidal anhydrous silica. In one embodiment, the lubricant is magnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or a combination thereof.

In a further embodiment, the tablet formulation may further comprise a binder such as hydroxypropyl cellulose. In a further embodiment, the tablet formulation may further comprise a disintegrant such as crospovidone. In a further embodiment, the tablet formulation may further comprise an anti-adhesive such as talc. In a further embodiment, the tablet formulation may further comprise a pH adjuster such as an organic or inorganic acid or an organic or inorganic base. In a further embodiment, the tablet formulation may further comprise a sweetener, such as a sugar (eg, mannitol).

In one embodiment, the release profile of the tablet formulation is controlled by changing the amount of release modifier in the formulation. In one embodiment, the rate of release of compound (I) from the tablet formulation is reduced by increasing the amount of release modifier.

In one embodiment, the formulations of the disclosure are in immediate release form. In one embodiment, the formulations of the disclosure are in modified release form. In one embodiment, modified release formulations are in the form of slow (release rate 16 to 24 hours), medium (release rate 10 to 12 hours), or fast (release rate 5 to 7 hours) release.

In one embodiment, the formulations of the disclosure are in controlled release form.

In one embodiment, the formulations of the disclosure are in sustained release form (eg, release occurs over at least 4, 6, 8, 10, 12, 18, or 24 hours). In one embodiment, the formulations of disclosure are in the form of a slow form with a sustained release.

The disclosure also relates to methods for treating neuropsychiatric diseases and disorders, in particular schizophrenia, comprising administering a therapeutically effective amount of a composition of the invention to a patient in need of such treatment.

In one embodiment, a method is provided for treating or alleviating at least one symptom of neuropsychiatric diseases and disorders, in particular schizophrenia, comprising administering a therapeutically effective amount of a composition of the invention to an object in need of such treatment.

In one embodiment, a method for treating or alleviating at least one symptom of schizophrenia is provided, comprising administering a therapeutically effective amount of a composition of the invention to an entity in need of such treatment.

In one embodiment, a method is provided for treating or alleviating at least one symptom of schizophrenia, comprising administering a composition of the invention to an object in need of such treatment, in which the amount of compound (I) is in the range of about 1-100 mg, about 1-75 mg, about 2-75 mg, about 5-75 mg, about 10-75 mg, about 15-75 mg, about 15-70 mg, or about 15-65 mg.

In one embodiment, a method is provided for treating or alleviating at least one symptom of schizophrenia, comprising administering a composition of the invention to a subject in need of such treatment wherein the amount of compound (I) is about 16 mg, about 32 mg, about 40 mg, or about 64 mg .

In one embodiment, the formulations of the disclosure are administered to treat or alleviate at least one symptom of schizophrenia associated with negative and/or positive symptoms of schizophrenia, cognition, sleep architecture and continuity, and social functioning.

In another embodiment, the disclosure compounds are administered to improve symptoms of depression.

In one embodiment, a method for treating or alleviating at least one condition or disorder associated with depression is provided, comprising administering a composition of the invention to a patient in need of such treatment.

In another embodiment, a method for improving sleep, such as sleep architecture and continuity, is provided, comprising administering a composition of the invention to a patient in need of such treatment.

In one embodiment, a method is provided for treating or alleviating at least one aspect of a sleep disorder in a patient suffering from neuropsychiatric diseases and disorders, in particular schizophrenia, comprising administering the composition of the invention to an object. In one embodiment, at least one aspect of the sleep disorder is being treated. In another embodiment, at least one aspect of the sleep disorder is improved. In one aspect, disruption of at least one aspect of sleep is associated with schizophrenia.

Various aspects of sleep may be treated, including, but not limited to, sleep latency, persistent sleep latency, distribution of slow wave sleep during a sleep period or one or more time segments of a sleep period, overall sleep continuity, and sleep architecture.

A cognitive impairment is a reduced ability to think, concentrate, formulate ideas, reason logically, and remember. In one embodiment, a method is provided for treating or alleviating a cognitive impairment or improving cognitive functions, comprising administering a composition of the invention to a patient in need of such treatment. In one embodiment, a method for treating schizophrenia without causing cognitive impairment is provided.

In one embodiment, a method is provided for treating schizophrenia and restoring, enhancing and improving cognitive function in a patient after cessation of treatment with another active pharmaceutical ingredient, such as an antidepressant.

In one embodiment, a method of treating schizophrenia is provided in combination with an active pharmaceutical ingredient for cognitive impairment (eg, an antidepressant agent for cognitive impairment) without causing or increasing cognitive impairment, or to improve, enhance, or restore cognitive function in a patient.

In another embodiment, the cognitive impairment seen in a patient suffering from schizophrenia is treated or alleviated by administering a composition of the invention to the patient. As will be appreciated based on the disclosure herein, altering sleep parameters can improve cognitive function. By way of non-limiting example, improving and/or increasing slow wave sleep (SWS) improves cognitive function. In one aspect, in general, cognitive functions are improved. In another aspect, one or more aspects of cognitive function are improved, including memory improvement, executive function, verbal memory, and fluency of speech, among others. In one embodiment, the patient's cognitive function is improved to a level where the patient's normal cognitive function is restored. In another embodiment, the patient's cognition is improved beyond the patient's level of normal cognition such that the patient's levels of cognition are increased.

In one embodiment, cognitive function is improved in a patient suffering from schizophrenia.

The active ingredient is compound (I) (also known as CYR-101 and MT-210). US Pat. No. 7,166,617, incorporated herein by reference in its entirety, discloses cyclic amide derivatives including Compound (I), 2-{1-[2-(4-fluorophenyl)-2oxoethyl]piperidin-4-ylmethyl}-2, 3-dihydroisoindol-1-one monohydrochloride dihydrate. The derivatives disclosed in US Pat. No. 7,166,617 were found to have high affinity for the sigma ligand binding site and low Ki constant inhibition for sigma 1 and/or sigma 2. It was also found that these compounds had selective binding profiles that were completely different from the profiles of conventional known compounds, and were suitable for the treatment of diseases that can be subject to therapeutic and/or prophylactic treatment through the control of neural functions of sigma ligands.

The formulations of Compound (I) as described herein represent an important milestone in the development of customized formulations of neuropsychiatric therapies based on optimal efficacy, safety, tolerability and pharmacokinetic profiles. The formulations as described herein are capable of addressing significant areas of unmet need in the treatment of negative symptoms, cognitive impairment and sleep disorders while providing a very favorable safety profile.

The formulations of the disclosure are capable of maintaining Compound (I) plasma levels for one day while simultaneously reducing BFB-520 levels and increasing BFB-999 levels associated with improved sleep due to affinity for 5-HT2A and H1 histaminergic receptors. Opening formulations have been shown to reduce BFB-520 levels, which are associated with prolongation of QT intervals at supertherapeutic doses. The QT interval represents the duration of ventricular depolarization and subsequent repolarization and is measured from the start of the QRS complex to the end of the T wave. Delay in cardiac repolarization creates electrophysiological conditions that contribute to the development of cardiac arrhythmias, most obviously bidirectional ventricular tachycardia (TdP), but other ventricular tachyarrhythmias are also possible . TdP is a polymorphic ventricular tachyarrhythmia that appears on the ECG as a continuous curvature of the QRS complex vector around an isoelectric baseline. The feature of TdP is determined in the prolongation of the QT interval in the supraventricular extrasystole, preceding the arrhythmia. TdP can develop into ventricular fibrillation, leading to sudden death. In accordance with the ICH-B14 Clinical Evaluation of QT/QTc Prolongation and Proarrhythmic Possibility for Antiarrhythmics, Discontinuation of a clinical trial for a patient should be considered if there is a marked prolongation of the QT/QTc interval during treatment with an investigational medicinal product, especially if the measurement is derived from more than one ECG.

The disclosure provides an optimal formulation that reduces the risk of QT/QTc prolongation and achieves a once daily dosing strategy to facilitate patient compliance with the regimen and treatment regimen.

Definitions

In other embodiments, as set forth in more detail elsewhere herein, the dosage and dosing regimen for Compound (I) and/or Form A of Compound (I) may be optimized based on the health and condition of the subject being treated, as well as desired treatment outcome.

As used herein, the term receptor means a molecule with which one or more kinds of signaling molecules can specifically interact. For example, the 5-HT1A receptor is a subtype of the 5-HT receptor that binds to the neurotransmitter serotonin (5hydroxytryptamine).

The term subject refers to any animal, including mammals such as, but not limited to, humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates.

The term treatment (and related terms treat and cure) includes palliative, restorative, and preventive (prophylactic) treatment of the subject. The term palliative care refers to treatment that alleviates or reduces the effect or severity of a condition in a subject without recovery. The term preventive treatment (and the corresponding term prophylactic treatment) refers to treatment that prevents a condition from occurring in a subject. The term restorative treatment (curative) refers to treatment that stops progression, reduces pathological manifestations, or completely eliminates the condition in the subject. Treatment may be with a therapeutically effective amount of a compound, salt, or composition that elicits a biological or medical response in a tissue, system, or subject that is expected by the subject, such as a researcher, physician, veterinarian, or medical practitioner. It should also be understood that the term treatment includes not only complete remission of all symptoms experienced by the subject of treatment, but also partial relief of one or more present symptoms, as well as prevention of the onset of symptoms by proactive administration of a compound of formula I to a subject subject to or liable to develop any of symptoms such as in patients with a chronic or relapsing neuropsychiatric disease or disorder.

As used herein, the term modified release can be understood as the release of a drug from a tablet that has been modified in some way. This usually slows down the release of the drug so that the drug does not need to be taken too frequently and therefore improves compliance. Another advantage of modified release is that drug release is controlled and less rise and fall in blood concentrations are observed, thus reducing the likelihood of peak effects and increasing the likelihood of therapeutic efficacy over longer periods of time.

The release pattern of a drug from modified release (MR) dosage forms is deliberately varied from releasing a standard (immediate release) dosage formulation to achieve the desired therapeutic goal or better patient compliance with the regimen and treatment regimen. Types of MR drugs may include delayed release (eg, enteric-coated), sustained release (ER) and orally disintegrating tablets (ODT).

The term modified release formulation can be used to describe a formulation that alters the timing and/or rate of release of a drug. A modified release dosage form is a formulation in which the drug release characteristics of the period of action and/or site are chosen to achieve therapeutic or suitable targets not provided by standard dosage forms such as solutions, ointments or immediate dissolving dosage forms. Several types of modified release drugs for oral administration have been established, including:

A sustained release formulation refers to a formulation that provides at least a 2-fold reduction in dosing frequency compared to an immediate release (standard) dosage form. Examples of sustained release dosage forms include controlled release, sustained release, and long acting drugs.

A delayed release formulation refers to a formulation that releases a discrete portion or portions of the drug at a given time rather than immediately after administration. The initial part can be released immediately after administration. Enteric-coated dosage forms are common delayed release products (eg, enteric-coated aspirin and other NSAID products).

The term "compound of disclosure" or "compound of disclosure" refers to compound (I), Form A of compound (I), or a pharmaceutically acceptable salt thereof, as described herein.

As used herein, the term pharmaceutically acceptable with respect to a compound or composition refers to a form of a compound or composition that can increase or increase the solubility or availability of the compound in a subject in order to provide or increase the bioavailability of the compound or composition.

The term pharmaceutically acceptable salt is intended to describe the salt form of one or more of the compositions of the present invention, which are provided to increase the solubility of the compound, for example, in the gastric juice of the gastrointestinal tract of a patient, to promote the dissolution and bioavailability of the compounds and/or compositions. In one embodiment, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. sodium salts and

- 7 040638 potassium are the most preferred salts of neutralization compositions containing carboxylic acids and free acid phosphate, covered by this disclosure. The term salt will mean any salt in accordance with the use of the compounds covered by this disclosure. Where the compounds are used in pharmaceutical indications, including the treatment of depression, the term salt will mean a pharmaceutically acceptable salt in accordance with the use of the compounds as pharmaceutical agents.

As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the parent compound and exhibit minimal, if any, undesirable toxicological effects. Non-limiting examples of such salts are (a) acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acids, naphthalenesulfonic acids, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium and the like, or with an organic cation formed from N ,N-dibenzylethylenediamine, ammonium or ethylenediamine; or (c) combinations of (a) and (b); for example, a zinc tannate salt or the like.

In one embodiment, the compositions contain base addition salts of the present compound. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of the present compounds that are acidic in nature are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from such pharmacologically acceptable cations such as alkali metal (e.g., potassium and sodium) and alkaline earth (e.g., calcium and magnesium) cations, ammonium, or water-soluble amine addition salts. such as N-methylglucamine (meglumine) and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines, among others.

A formulation or pharmaceutically acceptable formulation is a formulation containing a compound of the invention, or a salt, solvate, ester, or amino acid conjugate thereof. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. A unit dosage form is any of various forms including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (eg, formulation of the compound of the invention or salts thereof) in a unit dose of the composition is an effective amount and will vary according to the specific treatment being considered. One of skill in the art will appreciate that it is sometimes necessary to make standard dosage adjustments depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, ocular, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In another embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that are necessary.

In some embodiments, the implementation of the pharmaceutical compositions of the present invention may additionally contain other auxiliary components that are routinely present in pharmaceutical compositions established for use in the art. Thus, for example, the compositions may contain additional materials used in physically formulated various dosage forms of the compositions of the present invention, such as colorants, flavors, preservatives, antioxidants, opacifiers, thickeners, and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and optionally mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, dyes, fragrances and/or flavoring agents and the like, which do not adversely interact with the oligonucleotide(s) of the composition.

In some embodiments, the implementation of the pharmaceutical compositions of the present invention contain one or more excipients. In some such embodiments, the excipients are selected from water, saline solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrole.

- 8 040638 don.

In some embodiments, the pharmaceutical composition of the present invention is prepared using known techniques, including, but not limited to, mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, incorporating, or tableting processes.

Modifications to the compound can affect the solubility, bioavailability, and metabolic rate of the active species, thus providing control over the delivery of the active species. In addition, modifications can affect the desired activity of the compound, in some cases increasing the activity compared to the parent compound. This can be easily assessed by obtaining a derivative and testing its antidepressant activity in accordance with the methods covered in the present description, or by other methods known to a person skilled in the art.

The compositions covered in the present description, can be administered orally. In other embodiments, formulations may be administered parenterally by inhalation, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term parenteral includes subcutaneous, transdermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. As will be apparent to one of skill in the art in light of the embodiments covered herein, the routes of administration and dosage of the active ingredient or ingredients (e.g., a compound of formula I) may be adjusted more or less depending on the chosen route of administration. In addition, it will be apparent that optimization of the dosage of the active ingredient for any chosen dosage form may be desirable and can be achieved using the methods described in this application or known in the art for evaluating the effectiveness of antipsychotic compounds.

The pharmaceutical compositions embodied herein may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and cornstarch. In one embodiment, lubricants such as magnesium stearate are also added. For oral administration in capsule form, suitable diluents include lactose and/or dried cornstarch as two non-limiting examples. When aqueous oral suspensions are required, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added if desired.

In one embodiment, the compositions of the present invention may be administered in combination with one or more other drugs. Such other drugs may be administered or co-administered in forms and dosages as known in the art.

The term co-administration or combination therapy is used to describe a therapy in which at least two compounds are used to treat schizophrenia or other neuropsychiatric disease or condition, as described herein, simultaneously. In one embodiment, at least two compounds in effective amounts are used to treat schizophrenia or other neuropsychiatric disease or condition at the same time. In another embodiment, at least two compounds, the combination of which contains an effective amount, are used to treat schizophrenia or other neuropsychiatric disease or condition, as described in this application, simultaneously. In one embodiment, the result of treatment with at least two compounds may be additive from the results of treatment obtained using each compound separately, or directly additive, or additive, to a lesser extent than the results obtained with two compounds separately. In one embodiment, the outcome of treatment with at least two compounds may be synergistic to varying degrees. In one embodiment, the result of treatment with at least two compounds may be less than the results of treatment obtained using each compound separately. In one aspect, the result of treatment with a composition encompassed herein is such that, for one compound, the result of treatment is less than that obtained with the compound alone, while the results of treatment relative to the other compounds in the composition are approximately the same as those obtained. treatments received separately.

Although the term co-administration includes the administration of two active compounds to a patient at the same time, the compounds should not be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time.

In one embodiment, the compound described in this application may be administered together with one or more atypical antipsychotics. Examples of atypical antipsychotics include, but are not limited to, fluphenazine, risperidone, olanzapine, clozapine, quetiapine, ziprasidone, aripiprazole, sertindole, zotepine, and perospirone. Examples of antidepressants useful in combination therapy as covered herein include, but are not limited to, fluoxetine, citalopram, escitalopram, venlafaxine, duloxetine, bupropion.

Synthesis of compound (I)

Standard synthetic methods and techniques for obtaining transformations and transformations of organic molecules and functional groups, including the use of protective groups, can be obtained from the relevant scientific literature or from standard reference books in the art. Although not limited to them, any one or more sources recognized as guides to organic synthesis include Smith, M. B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, ^3rd ; John Wiley & Sons: New York, 1999.

The method of obtaining compound (I) is described in US patent 7166617, the entire content of which is incorporated into this description by reference.

As used herein, the phrase pharmaceutically acceptable refers to those compounds, materials, compositions, carriers, and/or dosage forms that are medically suitable for use in interaction with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problem, or complications in accordance with a reasonable benefit/risk ratio.

Pharmaceutically acceptable excipient means an excipient that is useful in the manufacture of a pharmaceutical composition that is generally harmless, non-toxic and not biologically or otherwise undesirable, and includes an excipient that is acceptable both in veterinary medicine and in pharmaceutical use. A pharmaceutically acceptable excipient as used in the specification and in the claims includes one or more of such excipients.

The pharmaceutical composition of the disclosure is formulated to be in accordance with its intended route of administration. Examples of routes of administration include parenteral, eg intravenous, intradermal, subcutaneous, oral (eg inhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tonicity adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat, ameliorate, or prevent an established disease or condition, or to exert a measurable therapeutic or inhibitory effect. The effect can be detected using any test method known in the art. The exact effective amount for a subject will depend on the subject's body weight, size, and health status; the nature and extent of the condition and the therapeutic agent or combination of therapeutic agents selected for administration. Therapeutically effective amounts for a given situation can be determined by standard studies, ie within the skill and judgment of the practitioner. In one aspect, the disease or disorder being treated is a neuropsychiatric disease or disorder. In another aspect, the disease or condition being treated is schizophrenia.

For any compound, a therapeutically effective amount can be assessed initially either in cell culture assays or in animal models, typically rats, mice, rabbits, dogs or pigs. An animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine appropriate doses and routes of administration for humans. Therapeutic/prophylactic efficacy and toxicity can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, for example, ED ₅₀ (therapeutically effective dose for 50% of the population) and LD ₅₀ (lethal dose for 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD ₅₀ /ED ₅₀ . Pharmaceutical compositions that exhibit high therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form used, the sensitivity of the patient and the route of administration.

Dosage and administration is adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors that may be taken into account include disease severity, subject's general health, subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), response susceptibility, and tolerance. response to therapy. Long acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or every other week, depending on the half-life and rate of elimination of the particular formulation.

Pharmaceutical formulations containing Compound (I) can be prepared in a manner which is generally known, for example, by standard mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, incorporating or lyophilizing processes. Pharmaceutical formulations may be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and/or adjuvants that facilitate the processing of the active ingredient in formulations that can be used pharmaceutically. Of course, the appropriate composition depends on the chosen route of administration.

Pharmaceutical formulations suitable for injectable use include sterile aqueous solutions (when soluble in water) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that it can be easily drawn into a syringe. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the desired particle size in the case of a dispersion, and using surfactants. Prevention of the action of microorganisms can be achieved with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases it will be preferable to include isotonic agents, eg sugars, polyalcohols such as mannitol, sorbitol, sodium chloride, in the composition. Sustained absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating Compound (I) in the required amount in an appropriate solvent as required with one or a combination of the ingredients listed above, followed by filtered sterilization. Generally, dispersions are prepared by incorporating Compound (I) into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying, which provides a powder of compound (I) plus any additional desired ingredient from its previously filter-sterilized solution.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, Compound (I) may be incorporated with excipients and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, wherein the compound (I) in the liquid carrier is taken orally and rinsed and spit out or swallowed. Pharmaceutically compatible binding agents and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a leavening agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterote; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

For administration by inhalation, Compound (I) is supplied as an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, for example a gas such as carbon dioxide or a nebulizer.

Systemic administration may also be via transmucosal or transdermal administration. For transmucosal or transdermal administration, the composition uses substances that facilitate penetration through the appropriate barrier to be penetrated. Such penetration agents are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts and derivatives.

- 11 040638 fusidic acid. Transmucosal administration can be carried out through the use of nasal sprays or suppositories. For transdermal administration, Compound (I) is formulated in ointments, balms, gels or creams, as is generally known in the art.

Compound (I) may be formulated with pharmaceutically acceptable carriers that will protect the compound from rapid removal from the body, eg in a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials may also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes that target infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. They can be obtained in accordance with methods known to the person skilled in the art, for example, as described in US patent 4522811 (the contents of which are included in this description in full).

It is most preferred to formulate oral or parenteral compositions in unit dosage form for ease of administration and dosage uniformity. Used in the present description of the standard dosage form refers to physically discrete units suitable as unit doses for the object to be treated; each unit containing a predetermined amount of the active ingredient, calculated to provide the desired therapeutic effect in combination with the required pharmaceutical carrier. The specification for unit dosage forms of the disclosure is due to and depends directly on the characteristics of the compound (I) and the specific therapeutic effect to be achieved.

When used for therapeutic purposes, the dosage of the pharmaceutical compositions used in accordance with the application varies depending on the agent, age, weight, and clinical condition of the recipient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors influencing the selected dosage. Dosages may range from about 0.01 to about 5000 mg/kg per day. In one aspect, dosages may range from about 1 to about 1000 mg/kg per day. In one aspect, the dose will be in the range of about 0.1 to about 50 g/day; from about 0.1 to about 25 g/day; about 0.1 to about 10 g/day; from about 0.1 to about 3 g/day or from about 0.1 to about 1 g/day in single, divided or continuous doses (the dose of which may be adjusted for patient weight in kg, body surface area in m ² and age in years). In other aspects, dosages may range from about 16 mg of Compound (I) per day to about 64 mg of Compound (I) per day, administered as a single dose. In another aspect, dosages may range from about 30 mg of Compound (I) per day to about 50 mg of Compound (I) per day, administered as a single dose. In one aspect, the dosage of compound (I) in the pharmaceutical composition is 30 mg per day, 31 mg per day, 32 mg per day, 33 mg per day, 34 mg per day, 35 mg per day, 36 mg per day 37 mg per day , 38 mg daily, 39 mg daily, 40 mg daily, 41 mg daily, 42 mg daily, 43 mg daily, 44 mg daily, 45 mg daily, 46 mg daily 47 mg daily, 48 mg per day, 49 mg per day and 50 mg per day given as a single dose. In one embodiment, the dosage of Compound (I) in the pharmaceutical composition is 40 mg per day administered as a single dose.

An effective amount of a pharmaceutical agent is an amount that provides an improvement objectively detectable by a clinician or other qualified observer. Used in the present description, the term effective dosage refers to the amount of compound (I) to obtain the desired effect in the subject.

Pharmaceutical compositions may be included in a container, sachet or dispenser along with instructions for use.

The pharmaceutical composition of the disclosure is administered orally, intranasally, transdermally, pulmonary, inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, compound (I) is administered orally. One of ordinary skill in the art will recognize the advantages of certain routes of administration.

The dosage regimen using Compound (I) is selected according to various factors including the type, species, age, weight, sex and health of the patient; the severity of the condition to be treated; route of administration; the patient's kidney and liver function; and the specific compound or salt used. Usually, an experienced physician or veterinarian can easily determine and prescribe the effective amount of drug needed to prevent, counter or stop the progression of the condition.

Methods for preparing and administering the disclosed compounds of the application can be found in Reming- 12 040638ton: the Science and Practice of Pharmacy, ^19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, Compound (I) is used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid excipients or diluents and sterile aqueous or organic solutions. compound (I) will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage size in the range described in this application.

All percentages and ratios used in the present description, unless otherwise indicated, are by weight.

Methods of treatment

The disclosure also provides methods for treating a neuropsychiatric disease or disorder in a subject in need of such treatment by administering to the subject in need of such treatment a therapeutically effective amount of Compound (I) or a pharmaceutical formulation thereof. The neuropsychiatric disease or disorder may be schizophrenia.

The term subject refers to any animal, including mammals such as, but not limited to, humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates. Subjects may or may not be diagnosed with schizophrenia. Subjects may exhibit one or more of the signs or symptoms of schizophrenia.

In some embodiments, the subjects of the disclosure may be treated for schizophrenia with one or more typical or atypical antipsychotics before, in combination with, or after treatment with a pharmaceutical formulation containing Compound (I). In some embodiments, subjects may be treated for schizophrenia with one or more typical or atypical antipsychotics prior to initiation of treatment with a pharmaceutical formulation containing Compound (I), and one or more typical or atypical antipsychotics may not be effective in treating the sign or symptom. schizophrenia in the subject.

Other features and advantages of the disclosure are apparent from various examples. The following examples illustrate various components and techniques useful in the practice of the disclosure.

The examples do not limit the claimed compositions, methods and kits of the disclosure. Based on the present disclosure, a person skilled in the art can identify and use other components and techniques suitable for the practical implementation of the disclosure.

Examples

Example 1

A prolongation of the QTc interval was observed and was found to be related to exposure to compound (I) and its metabolite BFB-520. QT prolongation was most evident in a patient who had slow CYP2D6 metabolizers and who showed high plasma levels of BFB-520. Conducted further analysis of the relationship between QT/QTc and concentrations of compound (I) BFB-520. It was determined that in order to prevent QT elongation, the C _max of compound (I) and BFB-520 should not exceed 80 and 12 ng/ml, respectively.

To further evaluate the incidence of QT/QTc changes from baseline greater than 30 and 60 ms and the incidence of QTc values greater than 450, 480 and 500 ms, the following study was performed.

Part 1 of this study was designed to characterize and compare the pharmacokinetic (PK) profile of Compound (I) when administered as MR formulations and nutritional effects after single dose administration in 6 directions in a subject, a crossover study.

Part 2 of the study was designed to evaluate the effect of multiple doses of the selected MR formulation on safety, tolerability and cardiovascular parameters. The effects of Compound (I) on sleep parameters will also be evaluated. In the CYR-1O1CO1 study, compound (I) had an effect on the distribution of slow wave sleep (SWS): compound (I) significantly increased SWS in the first third of the night and decreased it in the last third of the night. The results also suggested that Compound (I) may have sleep stimulatory effects as it improved parameters of sleep initiation (sleep latency, persistent sleep latency). In the current study, sleep will be used as a biomarker that can help determine the minimum active dose that should be evaluated in the patient's next study. Sleep parameters will be analyzed using the VWatch methodology.

The formulations used in Part 1 of the study were selected from the active treatment design field, compound (I) and HPMC release controlling agent as the 2 main formulation variables. On the release rate axis of the design space, MR formulations will be described as slow (release rate 16-19 h), medium (release rate 10-12 h), or fast (release rate 5-7 h). The 2-dimensional composition design field is shown in Scheme 1, where F1-F4 represent boundary compositions. Part 2 of the study was designed to evaluate multiple dose administration of the selected formulation from Part 1 at low and high dose levels versus placebo in a larger cohort of previously unexperimented subjects.

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Pharmacological profile (Preclinical studies):

In in vitro receptor binding studies, Compound (I) showed a unique binding profile. Compound (I) is associated with high affinity only for 5-HT2A, α1adrenergic and sigma2 receptors (K _i =7.53, 14.43, 8.19 nmol/l, respectively). Affinity for DA receptors was rather weak (IC ₅₀ >1000 nmol/l). Both major metabolites BFB-520 and BFB-999 showed a similar profile as Compound (I), with lower affinity for σ2 receptors and lower and equal affinity for Compound (I) for 5-HT2A receptors, respectively.

In in vivo functional tests, compound (I) acted as an antagonist at sigma2 and 5HT2A receptors. Following oral administration, Compound (I) slightly increased dopamine turnover in the nucleus accumbens and striatum and increased the release of DA metabolites such as DOPAC and HVA in the prefrontal cortex at high dose levels. At effective dose levels in animal models of antipsychotic activity, Compound (I) did not affect monoamine levels, while other antipsychotics markedly increased DA turnover and DOPAC and HVA output, reflecting their significant D2 antagonistic effects.

Compound (I) was investigated in male Wistar rats in several behavioral models designed to evaluate the potential for antipsychotic drug activity in humans. Compound (I) inhibited methamphetamine-, apomorphine- and phencyclidine-induced hyperlocomotion similarly to other antipsychotics. Similarly, BFB-520 and BFB-999 also inhibited methamphetamine-induced hyperlocomotion with an ED50 higher than compound (I). In addition, compound (I) significantly alleviated the impairment of PCP-induced social interaction after repeated administration, while other atypical antipsychotics did not alleviate this impairment and increased the impairment of spontaneous behavior change induced by MK-801.

Pharmacological safety studies

A series of safety pharmacology studies investigated the effects of Compound (I) on general activity and behavior, CNS, respiratory function, gastrointestinal tract, and water and electrolyte excretion in rats at oral doses ranging from 1 to 30 mg/kg of Compound (I), induced various changes in general activity and behavior. These clinical signs were observed 0.25 to 4 hours post-dose and disappeared 6 hours post-dose. Compound (I) inhibited CNS function and lowered thresholds for electroshock-induced convulsions. High doses (>10 mg/kg) of Compound (I) affected respiratory function, inhibited gastric emptying, damaged gastrointestinal membranes, reduced urine volume, and increased urinary potassium excretion.

The effects of compound (I) on the cardiovascular system have been investigated in vitro and in vivo. In in vitro electrophysiological studies using guinea-pig papillary muscle, Compound (I) at 1 μM or more prolonged action potential duration (APD) to the same extent as risperidone and haloperidol. Similarly, BFB-520 at 0.1 µm or more and BFB999 at 0.1 µm or more extended PPD in isolated guinea pig papillary muscles to the same or greater extent than Compound (I). In in vitro electrophysiological studies using cultured cells expressing cloned cardiac ion channels, Compound (I) inhibited IKr current with an IC50 of 0.325 μM compared to risperidone (0.319 μM). For BFB-520, it blocked the IKr current with an IC50 of 0.181 µm lower than that of the parent compound, but higher than that of haloperidol (0.026 µM), thioridazine (0145 µm), or ziprasidone (0134 µm).

Pharmacokinetic profile

Pharmacokinetic (PK) studies of compound (I) were carried out in particular in rats and monkeys. Compound (I) was rapidly absorbed after a single oral administration. Plasma radioactivity peaked at 0.63 to 2.75 hours in male rats and 3 to 3.5 hours in male monkeys. Oral absorption rates ranged from 90.3 to 94.7% in rats and from 70.0 to 99.9% in monkeys. The plasma half-lives of radioactivity ranged from 45.13 to 51.52 hours in rats and from 174.74 to 184.78 hours in monkeys. The half-lives of unchanged compound (I) ranged from 1.68 to 2.06 hours in rats and from 1.68 to 2.57 hours in monkeys. The absolute oral bioavailability of Compound (I) ranged from 52.4 to 64.5% in rats and 90% or higher in monkeys.

Upon repeated administration of 1 mg/kg/day for 14 days to male rats, plasma radioactivity increased with the number of doses, reaching a steady state after the 7th administration. Food and gender effects were also evaluated in rats.

When compound (I) was orally administered to non-fasted rats at 1 mg/kg, plasma radioactivity had a delayed T _max of approximately 1 hour and reduced C _max to about 72% of the value in fasted male rats, although AUCs were similar in the two groups. In addition, pharmacokinetic parameters for total radioactivity in female rats were comparable to those in male rats. When ¹⁴ C-Compound (I) was orally administered to lactating rats, it was believed that compound (I) and/or its metabolites were rapidly transferred into milk and slowly excreted.

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Compound (I) absorption was also studied in single and multiple dose toxicity studies in rats and monkeys for toxicokinetics and in genotoxicity and embryofetal development studies for plasma evidence. After single and repeated administration, the levels of compound (I) and its main metabolites BFB-520 and BFB-999 increased in a dose-dependent manner in both rats and monkeys, with only rats having a gender difference.

After a single dose of BFB-520 to monkeys, levels of BFB-520, Compound (I) and BFB-999 increased with dose increments greater than proportional to one. BFB-520 reached its maximum concentration 4 hours post-dose and T _max for Compound (I) and BFB-999 were comparable to those of BFB-520. In conclusion, the brain transfer of compound (I) was studied in male rats after oral administration (10 mg/kg). Plasma and brain _Cmax concentrations were 3164.62 and 4946.62 ng/g, respectively. The Kp value (brain/plasma concentration ratio) was 1.38 ml/g.

Several metabolites (ie BFB-999, BFB-520 and BFB-885) were found in the plasma and urine of male and female rats and male monkeys following oral administration of ¹⁴ C-Compound (I). The metabolic rate in female rats was slower than in male rats, but the metabolic profiles were similar in male and female rats. Even if Compound (I) has been shown to be metabolized to BFB-520 and BFB-999 by the P450 cytochromes CYP1A2, CYP2C19, CYP2D6 and CYP3A4, additional studies using human liver microsomes suggest that Compound (I) is primarily metabolized by using an enzymatic reaction, in addition to CYP isoforms. In turn, BFB-520 was metabolized by CYP2D6 and CYP3A4. No significant inhibitory effects were observed on the human P450 isoforms (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2E1 and 3A4), while a weak inhibitory effect was shown on CYP2D6. In the study of drug-drug interactions of compound (I) in in vitro metabolism, an IC ₅₀ value of more than 50 μm was determined for the following concomitant drugs: ketoconazole, fluvoxamine, paroxetine and lorazepam.

The main route of elimination of radioactivity in rats and monkeys after a single oral or intravenous administration was through the feces. Bile excretion was 44.2% 48 hours after a single oral dose in cannulated bile duct rats. Urinary excretion rates of radioactivity were approximately 35% in rats and monkeys. The overall elimination of this radioactivity was 101.1% (including carcasses) in rats and 92.6% in monkeys at 168 hours after a single oral dose. After repeated administration to rats for 14 days, the total elimination of this radioactivity was 96.6% in urine and feces and 0.7% in the carcass 168 hours after the last injection. It was determined that the enterohepatic circulation rate was approximately 27% after intraduodenal administration of bile samples in rats treated with ¹⁴ C Compound (I).

In one embodiment, the compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled release formulations.

Example 2

Part 1 of the study is an open-label, non-randomised, 6-period, single-dose, cross-over study in 12 healthy CYP 2D6 EM male subjects. For Part 1, subjects will receive the following treatment regimens in a non-randomized manner:

Treatment regimen A: Prototype composition MR 1: 32 mg of the compound (I) sustained release administered on an empty stomach

Treatment regimen B: Prototype fasting formulation MR 2

Treatment regimen C: Prototype MR Formulation 3 administered on an empty stomach or Prototype Formulation 1 or 2 administered after a meal

Treatment regimen D: Prototype MR Formulation 4 administered on an empty stomach or Prototype Formulation 1, 2 or 3 administered after a meal

Treatment regimen E: Prototype formulation MR 5 administered on an empty stomach, or prototype formulation 1, 2, 3 or 4 administered after a meal

Treatment regimen F: Prototype formulation MR 1, 2, 3, 4 or 5 administered after a meal.

Formulation selection within Part 1 is made after a full review of all data from the previous treatment regimen, and composition, doses, and need for optional retreatment for Part 2 are made after a full review of all data from Part 1.

Part 2 of the study is a double-blind, randomized, placebo-controlled, 6-sequence, 3-period crossover study in 24 healthy CYP2D6 EAT male and female subjects. For Part 2, in each of the 3 study periods, subjects receive the following treatment regimens in a randomized manner:

Treatment regimen G: Placebo QD for 7 days

Treatment regimen H: High dose of MR QD prototype formulation for 7 days

Treatment regimen I: Low dose MR QD prototype formulation for 7 days

- 15 040638

Based on the design field concept above, the IMP formulations used in Part 1 of the study are selected from a design field with compound (I) active treatment and hypromellose (HPMC) as the release controlling agent (HPMC viscosity controlled release based on the ratio of 2 HPMC polymers) in as two main compositional variables. The two-dimensional design field of the composite composition is shown in Table. 1, where F1-F4 represent boundary compositions. Part 2 of the study is designed to evaluate multiple dose administration of the selected formulation from Part 1 at low and high dose levels versus placebo in a larger cohort of previously naive subjects.

Table 1. Quantitative range of excipient composition for the design field

Component 16 mg Slow formulation 1% wt./May s. 64 mg Slow formulation 2%wt/May s. 16 mg Rapid formulation 3% wt./May s. 64 mg Rapid formulation 4% wt./May s. Compound (I)* 6.40 25.60 6.40 25.60 Hypromellose K100LV CR 12.00 6.00 36.00 30.00 Hypromellose K4M CR 24.00 24.00 - - Microcrystalline cellulose РН102** 36, 10 22.90 36, 10 22.90 Lactose Fastflo 316 20.00 20.00 20.00 20.00 silicon dioxide colloidal anhydrous, Aerosil 200 Pharma 0.50 0.50 0.50 0.50 magnesium stearate 1.00 1.00 1.00 1.00 Total 100.00 100.00 100.00 100.00

* Applied salt correction factor 1.2.

** The amount of microcrystalline cellulose PH102 will be adjusted accordingly to maintain the same tablet weight.

In accordance with the details of the composition, the inventors therefore present the extreme positions of the dosage range of 16-64 mg of compound (I) and the ranges for the levels of hypromellose K100LV CR and hypromellose IgM CR in the MR tablet, with the understanding that any intermediate composition within these ranges can be manufactured and dosed as an IMP during a clinical trial. All other components of the formulations remain unchanged with the exception of microcrystalline cellulose PH102, the content of which can be adjusted to maintain tablet weight depending on the effectiveness and purity of the medicinal substance and the weight of hypromellose K10 0LV CR and hypromellose K4M CR. The final composition of the selected formulations is recorded in the protocol for the batch produced for the production of clinical trials.

MR Tablet Composition of Prototype Compound (I) (Formulations 1, 2, 3 and 4)

A complete summary of the components and quantitative composition of the compositions of the MR tablet of the prototype compound (I) 1, 2, 3 and 4 is given in table. 2. Consistent with the formulation design field approach described in Section 2.1.P.1, this formulation represents the 16-64 mg dose endpoint range of compound (I) and the concentration ranges of hypromellose K100LV CR and hypromellose K4M CR that can be used in research.

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Table 2. MR Tablet Composition of Prototype Compound (I) (Formulations 1, 2, 3 and 4)

Component 16 mg Slow formulation 1 mg/tablet 64 mg Slow Composition 2 mg/tablet 16 mg Quick Formulation 3 mg/tablet 64 mg Fast composition 4 mg/tablet Functions Binding to standard At Compound (I) ¹ 19.20 76.80 19.20 76, 80 Active Substance Chapter DS or other as appropriate Hypromellose K100LV CR 36.00 18.00 108.00 90.00 Release Modifier USP Ph. Eur., JP Hypromellose K4M CR 72.00 72.00 Release Modifier USP Ph. Eur., JP Microcrystalline cellulose РН102 ² 108.30 68.70 108.30 68.70 Filler Ph. EUR. , NF, JP Lactose Fastflo 316 60.00 60.00 60.00 60.00 Filler NF/ USP, Ph. Eur., JP Silica colloidal anhydrous, Aerosil 200 Pharma 1.50 1.50 1.50 1.50 Glidan t USP Ph. Eur., JP Stearate magnesium 3.00 3.00 3.00 3.00 Sliding agent Ph. EUR. , NF, JP total weight 300.00 300.00 300.00 300.00

applied salt correction factor 1.2.

2tl

The amount of microcrystalline cellulose PH102 will be adjusted accordingly to maintain the same tablet weight.

In table. 3 shows the series formulations for MR tablet formulations of prototype compound (I) 1, 2, 3, and 4. These formulations represent the range of compound (I) dose extremes and concentrations of hypromellose K100LV CR and hypromellose K4M CR that can be used in the study. The composition ratio of colloidal anhydrous silica, Fastflo 316 lactose and magnesium stearate will remain constant. The composition ratio of microcrystalline cellulose PH102 can be adjusted depending on the potency and purity of the drug substance and the weights of hypromellose K100LV CR and hypromellose K4M CR to maintain a tablet weight of 300 mg.

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Table 3. Design field of batch formulations for the MR tablet of the prototype compound (I)

Component 16 mg Slow formulation 1% wt./May s. 64 mg Slow formulation 2%wt/May s. 16 mg Rapid formulation 3% wt./May s. 64 mg Rapid formulation 4% wt./May s. Compound (I) ¹ 6, 40 25.60 6.40 25.60 Hypromellose K100LV CR 12.00 6.00 36.00 30.00 Hypromellose K4M CR 24.00 24.00 — - Microcrystalline cellulose PH102 ² 36.10 22.90 36, 10 22.90 Lactose Fastflo 316 20.00 20.00 20.00 20.00 Silica colloidal anhydrous, Aerosil 200 Pharma 0.50 0.50 0.50 0.50 magnesium stearate 100 1.00 1.00 100 Total 100.00 100.00 100.00 100.00

applied salt correction factor 1.2.

² The amount of microcrystalline cellulose PH 102 will be adjusted accordingly to maintain the same tablet weight.

Scheme 2. Production of an MR tablet of the prototype compound (I)

Component Way Control Compound (I) Hypromellose K100LV CR Hypromellose K4M CR (when necessary) Microcrystalline Weigh the required amount of Compound (I), hypromellose K100LV CR, hypromellose K4M CR (if necessary), microcrystalline cellulose PH102, lactose Quantity Compounds (I) Quantity hypromellose K100LV CR Quantity Hypromellose K4M CR

-18040638

Soft cellulose PH102 Lactose Fastflo 316 Silica colloidal anhydrous, Aerosil 200 Pharma Fastflo 316 and colloidal silica anhydrous and sieved through a sieve of suitable size. Transfer to a suitable container size and mix. Sift the entire mixture through a sieve of suitable size. Transferred to original container appropriate size and mix. F (if necessary) Quantity microcrystalline cellulose PH102 Lactose quantity Fastflo 316 Amount of colloidal anhydrous silica, Aerosil 200 Pharma Sieve mesh size of sieve mesh Mixing time and speed magnesium stearate The required amount of magnesium stearate is weighed and sieved through a sieve of suitable size. Transfer to the above container and mix. This is a mixture of the MR tablet of the prototype Compound (I) F Amount of magnesium stearate Sieve mesh size of sieve mesh Mixing time and speed Pill mix MR prototype Compounds (I) Compress the mixture of the MR tablet of the prototype Compound (I) into tablets This is an MR tablet of the prototype Compound (I) g Amount of tablet mix MR prototype Compounds (I) ¹ Tablet appearance ² Pressing force ³ Tablet hardness ⁴ Tablet weight

The MR tablet of Compound (I) prototype is packaged in a sealed container.

¹ The appearance of the tablet will be assessed as in the process control during batch production, the details of which will be recorded in the batch protocol ² The pressing force will be used throughout the production process, and it can be adjusted to ensure that the appropriate tablet hardness is achieved.

³ Tablet hardness will be measured periodically throughout batch production as defined in the batch protocol.

⁴ Tablet weight will be measured as a process control during batch production, the details of which will be recorded in the batch protocol.

The amount of compound (I) and each excipient is controlled by weight using suitably calibrated weights to confirm that the appropriate composition of the formulation is being achieved. The second operator controls the mass. The homogeneity of the mixture is controlled by the predefined mixing conditions detailed in Scheme 2. These parameters have been designed to ensure the homogeneity of all possible mixtures of compositions within the volume

- 19 040638 of the proposed design field. The execution of these technological instructions will be controlled and documented in the protocol of mass production. In order to ensure that content uniformity is uniform throughout the design field, a set series at points in the design field described in Scheme 1 was made and examined. The content uniformity of the final tablet is assessed by analysis.

The tablet hardness is controlled by applying constant pressure with regular testing (destructive) throughout the series using the tablet compression hardness test.

The tablets are squeezed by hand; each tablet is weighed separately using an appropriately calibrated scale and a second operator controls the weight.

All excipients used in formulations comply with current Ph. Eur., the USP/NF or JP as below. All excipients are purchased from approved suppliers. The Manufacturer's Certificate of Analysis will be accepted and all excipients submitted to Quotient Clinical Ltd will be tested for identification, if necessary, in accordance with Quotient Clinical Ltd's receipt requirements.

Table 4. Specification for the MR tablet of the prototype compound (I)

Study Way Acceptance Criteria Appearance Visual control White with a yellowish or grayish tint, tablets with colored beige spots, not containing visible defects Analysis HPLC 90.0%-110.0% allowable Identification HPLC The retention time of the test sample corresponds to the retention time of the standard sample ±3% Related impurities HPLC Overview > 0.1% Impurity A < 1.0% 2-isomer < 1.0% Unidentified impurities NMT 0.5% Total impurity content NMT 3.0% Uniformity of the composition HPLC AV < 15.0 Dissolution HPLC Review results

Dissolution test

The dissolution test is a compendial method conducted in accordance with USP monograph <711> device 2. The dissolution medium is 450 ml of 0.01 M hydrochloric acid with a pH switch with artificial intestinal juice of double strength on an empty stomach (option 2), providing a total volume 900 ml and stirring at 75 rpm.

Samples were analyzed for compound (I) by reverse phase isocratic HPLC using a 5 µm Intersil ODS-3V column (4.6 mm x 150 mm) or an appropriately validated alternative with UV detection at 248 nm. The mobile phase consists of a mixture of acetonitrile: water: trifluoroacetic acid.

Description of HPLC Analysis, Identification and Uniformity Method for MR Tablets of Prototype Compound (I)

The method for analyzing the active ingredient content of the MR tablet of the prototype Compound (I) is an isocratic reverse phase HPLC method using a 5 µm Intersil ODS-3V (4.6 mm x 150 mm) column or an appropriately validated alternative with UV detection at 248 nm. The mobile phase consists of a mixture of acetonitrile: water: trifluoroacetic acid.

Description of the test for related impurities

The method for determining related impurities in the MR tablet of the prototype Compound (I) is a reverse phase gradient HPLC method using a 5 µm Intersil ODS-3V (4.6 mm x 150 mm) column or an appropriately validated alternative with UV detection at 248 nm. Mobile phase A is 0.1% TFA in water, mobile phase B is 0.1% TFA in acetonitrile.

Compound (I) CO2: Formulation once a day

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A two-part study designed to evaluate the pharmacokinetic profile of Compound (I) and its major metabolites following single and multiple dose administration of a prototype modified release formulation to healthy CYP2D6 in fast metabolizing male and female subjects and to evaluate the relationship between the pharmacokinetic profile of the compound ( I) and its main metabolites and parameters of the cardiovascular system. The study designs for Part 1 and Part 2 are shown in FIG. 7 and 8, respectively, and in FIG. 9 shows a diagram of the dosing period.

Table 5. Summary Analysis of Selected PK Parameters - Period 1 (32 mg sustained release, fasted)

MIN-101 Tmax (h) Stax(ng/ml) Tag (h) tl/2(h) AiPosl (h * ng / ml) N 10 10 10 9 10 Average n. d . 22.52 n. d. 6, 257 211.9 Median 2.25 23.74 0 5, 353 220.4 CV% n. d . 28.3 n. d. 38.1 18.6 BFB-520 Tmax (h) Stax(ng/ml) Tag (h) tl/2(h) AiPosl (h * ng / ml) N 10 10 10 4 10 Average n. d . 1.321 n. d. 6,540 18, 60 Median 4 1.294 0.5 6,458 18.04 CV% n. d . 27.7 n. d. 21.1 24.7 BFB-999 Tmax (h) Stax(ng/ml) Tag (h) tl/2(h) AiPosl (h * ng / ml) N 10 10 10 5 10 Average N.D. 1.510 n. d. 6.202 16, 02 Median 3 1.436 0.25 5.486 15, 22 CV% Η. D . 19.5 n. d. 27.3 22.3

In addition, the plasma concentration-time profiles for Compound (I), BFB-520 and BFB-999 are shown in FIG. 1-3. C _max for Compound (I), BFB-520 and BFB-999 is shown in FIG. 4. The effect on QTcF with compound (I), BFB-520 and BFB-999 is shown in FIG. 5.

Composition of MR under fasting conditions:

Short latency period indicates rapid bioavailability

Exposure variability is usually low

Low to non-quantifiable values for most after 24 hours

PK is generally dose proportional for Compound (I) and BFB-999 and to a lesser extent for BFB-520

Inversion of BFB-520 and BFB-999, usually occurring with reduced levels of BFB-520 and a higher ratio of BFB-999 to BFB-520

The resulting MR formulation data suggest that a shorter time in the small intestine is beneficial while lowering BFB-520 levels.

The half-life of compound (I) and 2 metabolites in the range of 3-8 hours is longer for 40 mg sustained release, most likely due to inversion (uptake and elimination balanced during the final phase)

Simulation results show steady state within 10 to 14 days and no accumulation for all three test substances.

Power action:

Positive pronounced effect of nutrition - higher impact

The MR formulation behaved similarly to the IR formulation with rapid release and absorption mainly prior to reaching the colon

This explains the additional increase in BFB-520 levels

Due to rapid uptake, the increase in C _max of compound (I) was ∼2x, the increase in Cmax of BFB-520 was ∼3x, and the increase _{in Cmax} of BFB-999 was ∼0.5x

The half-life was substantially shortened: the postprandial/fasted ratios were 0.5 for Compound (I); 0.8 for BFB-520; 0.6 for BFB-999.

Therefore, accumulation is not expected

The increase in AUC was minimal (compared to C _max ): from 1.3 to 1.8-fold with the largest increase for BFB-520

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Compound (I) C03 Phase IIb in patients with schizophrenia

Phase IIb, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, tolerability, and safety of Compound (I) in patients with negative symptoms of schizophrenia, followed by a 24-week, open-label, extension study. The study design is shown in Fig. 10.

Research objectives:

Primary: To evaluate the efficacy of Compound (I) versus placebo in improving negative symptoms of schizophrenia as measured by change from baseline in the Negative Disorder Subscale of the Positive and Negative Symptoms of Schizophrenia Scale (PANSS) pentagonal model after 12 weeks of treatment.

Main secondary:

To evaluate the efficacy of Compound (I) versus placebo in improving other symptoms of schizophrenia as measured by change from baseline in total PANSS scores and pentagon subscores and three factor analysis after 12 weeks of double-blind treatment.

To evaluate the efficacy of Compound (I) versus placebo in improving the negative symptoms of schizophrenia as measured by the change from baseline in the total scores of the Brief Negative Symptom Schizophrenia Scale (BNSS) score after 12 weeks of double-blind treatment.

To evaluate the effect versus placebo of Compound (I) on cognitive function as measured by the Brief Assessment of Cognitive Function in Patients with Schizophrenia (BACS) during 12 weeks of double-blind treatment.

To evaluate the retention of efficacy, and safety, and tolerability of compound (I) during the 24-week phase of an open-label extension study. Other purposes:

To evaluate the effect versus placebo of Compound (I) on depressive symptoms as measured by the Calgary Depression Rating Scale for Schizophrenia (CDSS) after 12 weeks of double-blind treatment.

Assess the effect versus placebo of Compound (I) on social functioning by means of the Personal and Social Functioning Scale (PSP) after 12 weeks of double-blind treatment.

To evaluate the effect versus placebo of Compound (I) on sleep architecture and continuity as measured by the V-Watch methodology after 12 weeks of double-blind treatment.

Key Inclusion Criteria

The patient is male or female, aged 18 to 60 inclusive.

The patient meets the diagnostic criteria for schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-V)

The patient has been stable in terms of positive symptoms for the past three months according to their treating psychiatrist

The patient has had negative symptoms for the past three months according to his treating psychiatrist

Patient with a negative PANSS subscore of at least 20.

Patient with a PANSS score <4: P4 Agitation, hyperactivity, P7 Hostility, P6 Suspiciousness, G8 Lack of contact, G14 Weakened control of impulsivity

No change in psychotropic drug within the last month

The patient must be a rapid metabolizer for CYP2D6 P450 as determined by genotyping analysis prior to the first dose of drug.

Main Exclusion Criteria

Current bipolar disorder, panic disorder, obsessive-compulsive disorder, or evidence of mental retardation.

The patient's condition due to the direct physiological effect of a substance (eg, drug of abuse or drug) or general health.

Significant risk of suicide or suicide attempt or danger to self or others.

A patient who cannot be discontinued from psychotropic medication except for those who are approved for psychotropic medication.

A patient who received clozapine during the 6 month screening visit.

A patient receiving long-term treatment with an antipsychotic drug may be enrolled in the study four weeks after the last injection.

Patient with a history of significant other underlying or non-sustainable neurological, neurosurgical (eg, head trauma), metabolic, hepatic, renal, haematological, pulmonary, cardiovascular, metabolic, gastrointestinal, or urological disorder.

A patient with a clinically significant electrocardiogram (ECG) abnormality that could be a dangerous study abnormality, including a QT interval adjusted for heart rate using the Friedrichia formula (QTcF) > 430 ms for men and > 450 ms for women .

Key Performance Estimates

Positive and Negative Syndromes Rating Scale (PANSS)

The Brief Negative Symptom Scale (BNSS) is a semi-structured interview designed to measure the present level of negative symptom severity in schizophrenia and schizoaffective disorder (Kirkpatrick et al.).

Anhedonia

Distress

Asociality

lack of will

Blunted affect

alogia

Brief Assessment of Cognitive Function in Patients with Schizophrenia (BACS)

Scale of Personal and Social Functioning (PSP):

social functioning assessment assessed by the clinician, socially useful activities, personal and social relationships, self-care, anxious and aggressive behavior, sleep architecture and continuity.

Sleep assessment

Sleep and circadian rhythm disturbances are present in 30 to 80% of patients with schizophrenia.

Patients with documented insomnia Poor quality of life Increased symptom severity Poor compliance/adherence

Sleep disturbances have also been associated with increased psychosis

Sleep is important for memory consolidation, so disturbances in sleep architecture or desynchronization of circadian cycles may also be one of the causes of the observed cognitive impairment in schizophrenia.

Compound (I) showed an effect on sleep architecture in a previous Phase 2a study that could likely be related to the observed improvements in negative symptoms and cognitive function, so these will be further explored in the present study.

In the subgroup of patients (20) who underwent sleep recording (PSG), sleep was assessed at baseline and after 14 days. Compound (I) had an effect on the distribution of slow wave sleep (SWS): it shifted SWS from the end to the beginning of the night: Compound (I) significantly increased SWS in the first third of the night and decreased in the last third of the night.

Sleep initiation parameters (latent period of falling asleep, latent period of constant sleep).

Subjective sleep quality, as measured by PSQI, improved, and this improvement was greater with compound (I) than with placebo, although not statistically significant.

V-Watch: sleep biomarker and related diagnostic tools

Overview-1 of the VWatch methodology (FIG. 6): Compared to standard polysomnography (PSG), which is based on brain wave measurements, the V-Watch methodology uses physiological measures to assess sleep.

Physiological systems and their positions depend on the physiological state (wake or sleep)

The process of sleep affects the whole body, not just the brain

The changes observed in cortical waves during sleep are only reflections of the transitions between sleep stages, and they are not the only way to assess these transitions.

These transitions can also be detected from other physiological systems.

Characteristics of heart rate (level, regularity, instability, and sudden changes) and bodily movement can be used to distinguish between wakefulness and sleep and distinguish between sleep stages.

Example 3 Various Tablet Formulations of Compound (I)

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Table 6-1. Compositions for MR MIN-101 16 and 64 mg tablet formulations

composition 117055-01-1 (16 Slow) mg 117055-01- (64 Slow) 2 mg 117055-01(16 Fast) 3 mg 117055-01-4 (64 mg Fast) %mm mg/tablet label g/n a 50 G ser AI %mm mg/tab years g/n a 50 G ser AI %mm mg/tab years g/n a 50 G ser AI %mm mg/tab years g/n a 50 G ser AI MIN- 101* 5.3 3 16.0 2.6 7 21, 33 64.0 Yu, 67 5, 3 3 16.0 2.6 7 21, 33 64.0 10, 67 Giprom losa K4M CR 30.00 90.0 15.00 30.00 90.0 15.00 Giprom losa K100LV CR 30.00 90.0 15.00 30.00 90.0 15.00 Microcr 62, 188, 31, 46, 140 23, 62, 188 31, 46, 140 23, istallic cellulo for PH102 Silica colloidal anhydrous, Aerosil 200 Pharma 67 1.0 0 0 3.0 34 0.5 0 67 1.0 0 , O 3.0 34 0.5 0 67 1, oh 0 , O 3.0 34 0.5 0 67 1.0 0 , O 3.0 34 0.5 0 Stearate magnesium 1.0 0 3.0 0.5 0 1.0 0 3.0 0.5 0 1, oh 0 3.0 0.5 0 1.0 0 3.0 0.5 0 Total 100 .00 300.0 50, 01 100 .00 300.0 50, 01 100 .00 300.0 50.0 100 .00 300.0 50, 01

* Erroneously omitted salt correction factor

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Table 6-2. Compositions for MR MIN-101 16 and 64 mg tablet formulations

composition 117055-08-1 16 mg Slow 117055-08-2 64 mg Slow 117055-08-3 16 mg Fast 117055-08-4 64 mg Fast %m/ m mg/tablet label g/n a 50 g ser AI %m/ m mg/tab years ka g/n A 50 G ser AI %mm mg/tab years ka g/n a 50 g ser AI %mm mg/tab years ka g/n A 50 G ser AI MIN- 101* 5.3 3 16.0 2.6 7 21, 33 64, 0 Yu, 67 5.3 3 16.0 2.6 7 21, 33 64, 0 Yu, 67 Giprom loza K100LV CR 35.00 105.0 17, 50 35.00 105 , O 17, 50 Hypromellose E50 20.00 60.0 Yu, 00 20.0 60.0 Yu, 00 Microcr 57, 173, 28, 41, 125 20, 72, 218 36, 56, 170 28, istallic cellulo for PH102 Silica colloidal anhydrous, Aerosil 200 Pharma 67 1.0 0 0 3.0 84 0.5 0 67 1.0 0 , O 3.0 84 0.5 0 67 1, oh 0 , O 3.0 34 0.5 0 67 1.0 0 , O 3.0 34 0.5 0 Stearate magnesium 1.0 0 3.0 0.5 0 1.0 0 3.0 0.5 0 1, oh 0 3.0 0.5 0 1.0 0 3.0 0.5 0 Total 100 .00 300.0 50, 01 100 .00 300 .0 50, 01 100 .00 300 .0 50.0 100 .00 300 .0 50, 01

* Erroneously omitted salt correction factor

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Table 7 Compositions for MR MIN-101 16 and 64 mg tablet formulations

CompoZy tion 117055-11-1 16 mg Slow 117055-11-2 64 mg Slow 117055-11-3 16 mg Fast 117055-11-4 64 mg Fast %m/ m mg/tablet label g/n a 50 g ser AI %m/ m mg/tab years ka g/n A 50 G ser AI %m/ m mg/tab years ka g/n A 50 G ser AI %m/ m mg/tab years ka g/n A 50 G ser AI MIN- 101* 6, 4 19.2 3.2 25, 6 76, 8 12, 8 6, 4 19, 2 3.2 25, 6 76, 8 12, 8 Giprom loza K100LV CR 35.00 105.0 17, 5 35.0 105 , O 17, 5 Giprom losa E50 20.0 60.0 Yu, 0 20.0 60.0 Yu, 0 Mannitol M200 56, 6 169 8 28, 3 37, 4 112 .2 18, 7 71, 6 214 , θ 35, 8 52, 4 157 .2 26, 2 Silica colloidal anhydrous, Aerosil 200 Pharma 1.0 3.0 0.5 1.0 3.0 0.5 1, oh 3.0 0.5 1.0 3.0 0.5 Stearate magnesium 1.0 3.0 0.5 1.0 3.0 0.5 1, oh 3.0 0.5 1.0 3.0 0.5 Total 100 .0 300.0 50.0 100 .0 300 .0 50.0 100 .0 300 .0 50.0 100 .0 300 .0 50.0

* Applied salt correction factor 1.2.

-26040638

Table 8. Compositions for MR MIN-101 16 and 64 mg tablet formulations

Composition 117055-13-1 16 mg Slow 117055-13-2 64 mg Slow 117055-13-3 64 mg Slow 117055-13-4 64 mg Slow 117055-13-5 16 mg Fast 117055-13-6 64 mg Fast % mm mg/tab l etc A g/n a 50 G ser AI % mm mg/tab l etc A g/n a 50 G ser AI % mm mg/tab l etc A g/n a 50 G ser AI % mm mg/tab l etc A g/n a 50 G ser AI % mm mg/tab l etc A g/n a 50 G ser AI % mm mg/tab l etc A g/n A 50 G ser AI MIN-101* 6.4 19, 2 3.2 0 25, 8 76.8 12, 80 25, 6 76.8 12, 8 25, 6 76.8 12, 8 6.4 19, 2 3.2 25 .6 76.8 12, 8 Hypromellose K100LV CR 35.0 105 , O 17, 50 35.0 105 , O 17, 50 50.0 150 , O 25.0 - - - 20.0 60.0 yu, 0 20 , O 60.0 yu, 0 Hypromellose K4M CR - - - - - - - - - 30.0 90.0 15.0 - - - - - - Mannitol M2 0 0 25, 3 84, 9 14, 15 18, 7 56.1 9.3 5 22, 4 67, 2 eleven, 2 42, 4 127 .2 21, 2 71.6 214 , θ 35, 8 52 ,4 157 .2 26, 2 Microcrystals chesky cellulose PH102 28, 3 84, 9 14, 15 18, 7 56.1 9.3 5 Dioxide silicon colloidal anhydrous, Aerosil 200 Pharma 1, oh 3.0 0.5 0 1.0 3.0 0.5 0 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1, 0 3.0 0.5 magnesium stearate 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1, oh 3.0 0.5 1, 3.0 0.5 0 0 0 Total 100 .0 300 .0 50.00 100 .0 300 .0 50.00 100 .0 300 .0 50.0 100 .0 300 .0 50.0 100 .0 300 .0 50.0 10 oh 0 300 .0 50.0

* Applied salt correction factor 1.2.

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Table 9 Compositions for MR MIN-101 64 mg tablet formulations

Compovitz AND I 117055-17-1 64 mg Slow 117055-17-2 64 mg Slow 117055-17-3 64 mg Fast 117055-17-4 64 mg Fast %mm mg/tablet label g/n a 50 g Ser II %m/ m mg/tab years ka g/n a 50 G ser AI %m/ m mg/tab years ka g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 G ser AI MIN-101* 25.6 0 76.8 0 12, 80 25, 6 76.8 12, 80 25, 60 76, 80 12, 80 25, 60 76, 80 12, 80 Hypromel vine K100LV CR 50.0 0 150.00 25.00 50.0 150 , O 25.00 20.00 60.00 10.00 20.00 60.00 10.00 Mannitol M2 0 0 13.4 4 40.3 2 6, 7 2 15, 68 47, 04 7.8 4 31, 44 94, 32 15, 72 36, 68 110 04 18, 34 Microcrystalline cellulose PH102 8.96 26, 8 8 4.4 8 6, 7 2 20, 16 3.3 6 20, 96 62, 88 Yu, 48 15, 72 47, 16 7.8 6 Silica colloidal anhydrous, Aerosil 200 Pharma 1.00 3.00 0.5 0 1.0 3.0 0.5 0 1.0 0 3.0 0 0.5 0 1, oh 0 thirty 0 0.5 0 Stearate magnesium 1.00 3.00 0.5 0 1.0 3.0 0.5 0 1.0 0 3.0 0 0.5 0 1, oh 0 thirty 0 0.5 0 Total 100.0 300.00 50.00 100 .00 300 .00 50.00 100 .00 300 .00 50.00 100 .00 300 .00 50.00

* Applied salt correction factor 1.2.

Table 10 Compositions for MR MIN-101 16 and 64 mg tablet formulations

compo position 117055-21-1 64 mg Fast 117055-21-2 64 mg Fast 117055-21-3 16 mg Fast 117055-24-1 16 mg Slow 117055-24-2 16 mg Slow 117055-24-3 16 mg Slow % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/n A 50 G ser AI MIN- 101* 25.6 0 76.8 0 12.8 0 25.6 0 76.80 12.8 0 6.40 19.2 0 3.20 6.40 19.2 0 3.20 6.40 19.2 0 3.20 6.40 19.2 0 3.2 0 Hypro mello for K100L VCR 25.0 0 75.0 0 12.5 0 25.0 0 75.0 0 12.5 0 25.0 0 75.0 0 12.5 0 50.0 0 150.00 25.0 0 50.0 0 150.00 25.0 0 55.0 0 165.00 27, 50 Manni t М2 0 0 28.4 85.3 2 14.2 2 33.1 8 99.5 16.5 46.6 2 139, 86 23.3 1 24.9 74.8 8 12.4 8 29.1 2 87.3 14.5 25.6 2 76.8 12, 81 Microcrystalline cellulose PH102 18.9 6 56, 8 8 9.48 14.2 2 42.6 6 7.11 19.9 8 59.9 4 9.99 16, 6 4 2 8.32 12.4 8 37.4 4 6.24 10.9 8 32.9 4 5.4 9 diox id flint 1.00 3.00 0.50 100 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.5 0

- 28 040638

AND I colloidal anhydrous, Aeros il 200 Pharm a Stear at magnesium 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.5 0 Total 100.00 300.00 50.0 0 100.00 300.00 50.0 0 100.00 300.00 50.0 0 100.0 300.00 50.0 0 100.00 300.00 50.0 0 100.00 300.00 50.00

Table 11 Compositions for MR MIN-101 16 and 64 mg tablet formulations

Compovitz AND I 117055-26-1 16 mg Slow 117055-26-2 64 mg Slow 117055-26-3 16 mg Fast 117055-26-3 64 mg Fast %mm mg/tablet label g/n a 50 g ser AI %mm mg/tab years ka g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 ser AI MIN-101* 6.40 19.2 0 3.2 0 25, 6 76, 80 12, 80 6, 4 0 19, 20 3.2 0 25, 60 76, 80 12, 80 Hypromel vine K100LV CR 55.0 0 165.00 27, 50 50.0 150 , O 25.00 27.00 81.00 13, 50 22.00 66.00 eleven, 00 Mannitol M2 0 0 25.6 2 76.6 6 12, 81 15, 68 47, 04 7.8 4 45, 22 135 .66 22, 61 35, 28 105 .84 17, 64 Microcrystalline cellulose a РН102 10.9 8 32.9 4 5.4 9 6, 7 2 20, 16 3.3 6 19, 38 58, 04 9.6 9 15, 12 45, 36 7.5 6 Silica colloidal anhydrous, Aerosil 200 Pharma 1.00 3.00 0.5 0 1.0 0 3.0 0 0.5 0 10 0 3.0 0 0.5 0 1.0 0 3.0 0 0.5 0 Stearate magnesium 1.00 3.00 0.5 0 1.0 0 3.0 0 0.5 0 10 0 3.0 0 0.5 0 1.0 0 3.0 0 0.5 0 Total 100.00 300.00 50.00 100 .00 300 .00 50.00 100 .00 300 .00 50.00 100 .00 300 .00 50.00

* Applied salt correction factor 1.2.

-29040638

Table 12 Compositions for MR MIN-101 16 and 64 mg tablet formulations

Composition 117055-30-1 64 mg Fast 117055-30-2 64 mg Fast 117055-30-3 16 mg Fast 117055-33-1 16 mg Slow 117055-33-2 16 mg Slow 117055-33-3 16 mg Slow % mm mg/tablet label g/n a 50 g Ser II % mm mg/tablet label g/n a 50 g Ser II % mm mg/tablet label g/n A 50 G ser AI % mm mg/tablet label g/n a 50 g Ser II % mm mg/tablet label g/n a 50 g Ser II % mm mg/tablet label g/n A 50 G ser AI MIN-101* 6.40 19.2 3.2 25.6 76.8 12, 6.40 19.2 3.2 6.4 19.2 3.2 25.6 76.5 12, 6.40 19.2 3.2 0 0 0 0 80 0 0 0 0 0 0 80 0 0 Hypromellose 27.00 81.0 13, 22.0 66.0 eleven, 30.0 90.0 15, 55, 165, 27, 50.0 150, 25, 58.0 174, 29, a K100LV CR 0 50 0 0 00 0 0 00 00 00 50 00 00 0 00 00 Mannitol M2 00 45.22 135, 22, 35.2 105, 17, 43.1 129 21, 25, 76.8 12, 15.8 47.0 7.8 23.5 70.5 eleven, 66 61 8 84 64 2 36 56 62 6 81 8 4 4 2 6 76 microcrysta 19.38 58.1 9.6 15.1 45.3 7.5 18.4 55.4 9.2 Yu, 32.9 5.4 6, 72 20.1 3.3 10.0 30.2 5.0 llic 4 9 2 6 6 8 4 4 98 4 9 6 6 8 4 4 cellulose PH102 Dioxide 1.00 3.00 0.5 1.00 3.00 0.5 1.00 3.00 0.5 1.0 3.00 0.5 1.00 3.00 0.5 1.00 3.00 0.5 silicon 0 0 0 0 0 0 0 colloidal anhydrous, Aerosil 200 Pharma Stearate 1.00 3.00 0.5 1.00 3.00 0.5 1.00 3.00 0.5 1.0 3.00 0.5 1.00 3.00 0.5 1.00 3.00 0.5 magnesium 0 0 0 0 0 0 0 General 100.00 300, 50, 100, 300, 50, 100, 300, 50, 100 300, 50, 100, 300, 50, 100, 300, 50, quantity 00 00 00 00 00 00 00 00 .0 00 00 00 00 00 00 00 00

* Applied salt correction factor 1.2.

Table 13 Compositions for MR MIN-101 16 and 64 mg tablet formulations

composition AND I 117055-38-1 16 mg Slow 117055-38-2 64 mg Slow 117055-38-3 16 mg Fast 117055-38-4 64 mg Fast %mm mg/tablet label g/n a 50 g Ser II %mm mg/tab years ka g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 G ser AI MIN-101* 6.40 19.2 0 3.2 0 25, 6 76, 80 12, 80 6.4 0 19, 20 3.2 0 25, 60 76, 80 12, 80 Hypromel vine K100LV CR 40.0 0 120 00 20.00 45, 00 135 00 22, 50 25.00 75, 00 12, 50 20.00 60.00 yu, 00 Mannitol M2 0 0 36.4 7 109, 41 18, 24 19, 53 58, 59 9.7 7 46, 97 140 .91 23, 49 37, 03 111 09 18, 52 Microcrystalline cellulose PH102 15, 6 3 46.8 9 7.8 2 8.3 7 25, eleven 4.1 9 20, 13 60, 39 yu, 07 15, 87 47, 61 7.9 4 Silica colloidal anhydrous, Aerosil 200 Pharma 0.50 1.50 0.2 5 0.5 0 1.5 0 0.2 5 0.5 0 1.5 0 0.2 5 0.5 0 1.5 0 0.2 5 magnesium stearate 100 3.00 0.5 0 1, oh 0 3.0 0 0.5 0 1.0 0 thirty 0 0.5 0 1.0 0 thirty 0 0.5 0 Total 100.00 300.00 50, 01 100 .00 300 .00 50, 01 100 .00 300 .00 50, 01 100 .00 300 .00 50, 01

* Applied salt correction factor 1.2.

- 30 040638

Table 14 Analytical Study for MR MIN-101 64mg Tablet Formulations (64mg slow from Experiment 9)

Experiment Average percentage of claimed content (%) 2-hour automatic operation time (passing through a 10 µm down-current filter) 30.3% 2 hour filter time manual work without 30.9% 19-hour automatic operation time (passing through a 10 µm down-current filter) 82.0% 19 o'clock time filtering manual work without 82.6% 19 hour centrifugation time manual work with 82.2% 19 hour filtering time through PTFE filter handmade with 0.4 5 µm syringe 82.8%

Table 15 Compositions for MR MIN-101 64 mg tablet formulations

Composition 117055-46-1; 64 mg Slow %mm mg/tablet g/per 50g series MIN-101* 25.6 76, 80 12.80 Hypromellose K100LV CR 45.00 135.00 22.50 Mannitol M2 0 0 19.53 58.59 9, 77 Microcrystalline cellulose RN102 8.37 25.11 4.19 Silica colloidal anhydrous, Aerosil 200 Pharma 0.50 1.50 0.25 magnesium stearate 1.00 3.00 0.50 Total 100.00 300.00 50.01

* Applied salt correction factor 1.2.

- 31 040638

Table 16 Compositions for MR MIN-101 16 and 64 mg tablet formulations

composition AND I 117055-48-1 16 mg Slow 117055-48-2 64 mg Slow 117055-48-3 16 mg Fast 117055-48-4 6 4 mg Fast %mm mg/tablet label g/n A 50 G ser AI %mm mg/tab years g/n a 50 G ser AI %mm mg/tab years ka g/n a 50 G ser AI %mm mg/tab years g/n a 50 G ser AI MIN-101* 6.40 19.2 0 3.2 0 25, 60 76, 80 12, 80 6, 4 0 19, 20 3.2 0 25, 60 76, 80 12, 80 Hypromel vine K100LV CR 55.0 0 165.00 27, 50 50.00 150 00 25, 000 25.00 75.00 12, 50 20.00 60.00 Yu, 00 Mannitol M2 00 25.9 7 77.9 1 12, 99 16, 03 48, 09 8.0 2 46, 97 140 .91 23, 49 37, 03 111 09 18, 52 Microcrystalline cellulose PH102 11.1 3 33.3 9 5.5 7 6, 8 7 20, 61 3.4 4 20, 13 60, 39 10, 07 15, 87 47, 61 7.9 4 Silica colloidal anhydrous, Aerosil 200 Pharma 0.50 1.50 0.2 5 0.5 0 1.5 0 0.2 5 0.5 0 1.5 0 0.2 5 0.5 0 1.5 0 0.2 5 Stearate magnesium 1.00 3.00 0.5 0 1.0 0 3.0 0 0.5 0 1.0 0 3.0 0 0.5 0 1.0 0 3.0 0 0.5 0 Total 100.00 300.00 50, 01 100 .00 300 .00 50, 01 100 .00 300 .00 50, 01 100 .00 300 .00 50, 01

* Applied salt correction factor 1.2.

Table 17 Compositions for MR MIN-101 16 and 64 mg tablet formulations

Composition 117055-52-1 16 mg Slow 117055-52-2 64 mg Slow %mm mg/tablet g/at 50 %mm mg/tablet g/at 50 weaving g series weaving g series MIN-101* 6.40 19.20 3.20 25.60 76.80 12.80 Hypromellose K4M CR 36.00 108.00 18.00 30.00 90.00 15.00 Microcrystalline cellulose PH102 36, 10 108.30 18.05 22.90 68.70 11.45 Lactose Fastflo 316 20.00 60.00 10.00 20.00 60.00 10.00 Silica colloidal anhydrous, Aerosil 200 Pharma 0.50 1.50 0.25 0.50 1.50 0.25 magnesium stearate 1.00 3.00 0.50 1.00 3.00 0.50 Total 100.0 0 300.00 50.00 100.0 0 300.00 50.01

* Applied salt correction factor 1.2.

Table 18 Compositions for MR MIN-101 16 and 64 mg tablet formulations

magnesium stearate 100 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 General 100, 300.00 50.0 100, 300.00 50.0 100, 300.00 50.0 quantity 00 0 00 0 00 0

* Applied salt correction factor 1.2.

- 32 040638

Table 19 Compositions for MR MIN-101 16 and 64 mg tablet formulations

composition 117055-55-1 6 4 mg Fast 117055-55-2 16 mg Fast 117055-55-3 6 4 mg Fast 117055-55-4 16 mg Slow 117055-58-1 40 mg Average 117055-58-2 32 mg Slow % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and % mm mg/tablet label g/per 50 g series and MIN- 101* 25.8 0 76.8 0 12.8 0 6.40 19.2 0 3.20 25.6 0 76.80 12.8 0 6.40 19.2 0 3.20 16.00 48.0 0 8.00 12.8 0 38.4 0 6.40 Hyprom cellose K100LV CR 30.0 0 90.0 0 15.0 0 36.00 108.00 18.0 0 6.00 18.0 0 3.00 12.0 0 36.00 6.00 21.0 0 63.0 0 10.5 0 10.00 30.0 0 5.00 Giprom elloza K4M CR - - - - - 24.0 0 72.0 0 12.0 0 24.0 0 72.0 0 12.0 0 12.0 0 36.00 6.00 24.0 0 72.0 0 12.0 0 Microcrystalline personal cellulose РН102 22.9 0 68.7 0 11.4 5 36.10 108.3 18.0 5 22.9 0 68.7 0 11.4 5 36.10 108.3 18.0 5 29.5 0 88.5 0 14.7 5 31.7 0 95.1 0 15.8 5 lactose a Fastfl about 316 20.0 0 60.0 0 10.0 0 20.0 0 60.0 0 10.0 0 20.0 0 60.0 0 10.0 0 20.0 0 60.0 0 10.0 0 20.0 0 60.0 0 10.0 0 20.00 60.0 0 10.0 0 Dioxy 0.50 1.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 d flints i COLLOY anhydrous, Aerosi 1 200 Pharma Steara t magnesium 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 Total 100.00 300.00 50.0 0 100.00 300.00 50.0 0 100.00 300.00 50.0 0 100.0 300.00 50.0 0 100.00 300.00 50.0 0 100, 00 300.00 50.0 0

* Applied salt correction factor 1.2.

- 33 040638

Table 20. Composition per Lot for SR MIN-101 Standard Tablets

Component Function %mm mg/tablet g/per 200 g series (up to 1333 tablets) Intragranular Blend MIN-101 drug substance ¹ medicinal substance 6.40 9.60 12.80 Kolliwax NSO sliding substance 20.00 30.00 40.00 Lactose (Pharmatose 200) Filler 58.93 88.40 117.86 Microcrystalline cellulose (Vivapur 101) Filler 10.00 15.00 20.00 Hydroxypropylcellulose (HPC-L) Binder 2.80 4.20 5.60 Silica colloidal anhydrous (Aerosil 200) Glidant 0.13 0.20 0.26 citric acid monohydrate pH regulator 0.67 1.00 1.34 Sterile irrigation water ² Auxiliary substance process IN enough Intermediate quantity - 98.93 148.40 197.86 Extragranular Blend ³ Magnesium stearate (Hyqual) sliding substance 1.07 1.60 2.14 Tablet core weight - 100.00 150.00 200.00

¹ Salt conversion factor 1.2, i.e. 9.60 mg MIN-101 hydrochloride formulation equivalent to 8.0 mg MIN-101 free base

Sterile irrigation water was used for wet granulation and removed during drying step ³ The final extragranular tableting mix was calculated based on the yield of available intragranular mix

Claims (21)

Table 21 Compositions for MR MIN-101 16 and 64 mg Tablet Formulations (Process Development) Composition 117055-60 6 4 mg Fast 117055-61 16 mg Fast 117055-62 64 mg Slow 117055-63 16 mg Slow 117055-64 40 mg Mean % m/m mg/tablet label g/per 100 g series and % mm mg/tablet label g/per 100 g series and % mm mg/tablet label g/per 100 g series and % mm mg/tablet label g/per 100 g series and % mm mg/tablet label g/per 100 g series MIN-101* 25.6 0 76.8 0 25.6 0 6.40 19.2 0 6.40 25.6 0 76.8 0 25.6 0 6.40 19.20 6.40 16.0 0 48.00 16.00 Hypromellose K100LV CR 30.0 0 90.0 0 30.0 0 36.0 0 108.00 36.0 0 6.00 18.0 0 6.00 12.00 36.00 12.0 0 21.0 0 63.00 21.00 Hypromellose K4M CR - - - - - 24.0 0 72.0 0 24.0 0 24.00 72.00 24.0 0 12.0 0 36.00 12.00 Microcrystalline cellulose PH102 22.9 0 68.7 0 22.9 0 36, 1 0 108 3 36, 1 0 22.9 0 68.7 0 22.9 0 36, 10 108.3 36, 1 0 29.5 0 88.50 29.50 Lactose Fastflo 316 20.0 0 60.0 0 20.0 0 20.0 0 60.0 0 20.0 0 20.0 0 60.0 0 20.0 0 20.00 60.00 20.0 0 20.0 0 60.00 20.00 Dioxide silicon colloidal anhydrous, Aerosil 200 Pharma 0.50 1.50 0.50 0.50 1.50 0.50 0.50 1.50 0.50 0.50 1.50 0.50 0.50 1.50 0.50 magnesium stearate 1.00 3.00 1.00 1.00 3.00 1.00 1.00 3.00 1.00 1.00 3.00 1.00 1.00 3.00 1.00 General 100, 300, 100, 100, 300, 100, 100, 300, 100, 100.0 300.0 100, 100, 300.0 100.0 quantity 00 00 00 00 00 00 00 00 00 0 00 00 0 0 * Applied salt correction factor 1.2. Inclusion of features by reference The full disclosure of each of the patent documents and scientific articles mentioned in the present description is incorporated by reference in all respects. Equivalents The disclosure of the application can be carried out in other specific forms without departing from the essence or its essential features. Therefore, the above embodiments should be considered in all respects to be illustrative and not restrictive of the disclosure of the application described herein. The scope of the disclosure of the application is thus defined by the appended claims and not by the preceding description, and all changes that fall within the meaning and range of equivalence of the claims are to be considered to be covered by its scope. CLAIM 1. Pharmaceutical composition for the treatment of a neuropsychiatric disease or disorder or sleep disorder, where the specified composition contains hypromellose, filler, glidant, lubricant and from 1 to 100 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, provided that, when administered to a human, the maximum plasma concentration (Cmax) of Compound (I) as determined in humans by HPLC is below 50 ng/mL. 2. The pharmaceutical composition according to claim 1, when administered to a human, the area under the AUC curve of the compound (I), determined by HPLC in humans, is below 400 h * ng / ml. 3. Pharmaceutical composition for the treatment of a neuropsychiatric disease or disorder or sleep disorder, where the specified composition contains hypromellose, filler, glidant, lubricant and from 1 to 100 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, provided that when administered to a human, the maximum plasma concentration (Cmax) of BFB-520 as determined by HPLC in humans is below 10 ng/mL, where - 35 040638 BFB-520 is the active metabolite of compound (I). 4. Pharmaceutical composition according to claim 3, provided that when administered to a human, the maximum plasma concentration (Cmax) of BFB-520 determined by HPLC in humans is below 5 ng/ml, where BFB-520 is the active metabolite of compound (I). 5. A pharmaceutical formulation according to claim 3, wherein, when administered to a human, the area under the curve (AUC) of BFB-520 as determined by HPLC in humans is below 40 h*ng/mL. 6. A pharmaceutical composition for the treatment of a neuropsychiatric disease or sleep disorder or disorder, wherein said composition contains hypromellose, a filler, a glidant, a lubricant, and from 1 to 100 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, provided that under administration to humans, the maximum plasma concentration (Cmax) of BFB-999 as determined by HPLC in humans is below 5 ng/ml, where BFB-999 is the active metabolite of compound (I). 7. A pharmaceutical formulation according to claim 6, wherein, when administered to a human, the area under the curve (AUC) of BFB-999 as determined by HPLC in humans is below 40 h*ng/mL. 8. Pharmaceutical composition according to any one of claims 1 to 7, which is suitable for long-term use. 9. A pharmaceutical composition according to any one of claims 1 to 8 which is in an immediate release form. 10. Pharmaceutical composition according to any one of claims 1 to 8, which is in a controlled release form. 11. Pharmaceutical composition according to any one of claims 1-10, wherein the entire administered dose of compound (I) is released from the pharmaceutical composition within 16-24 hours. 12. Pharmaceutical composition according to any one of claims 1 to 11, containing 10-75 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof. 13. Pharmaceutical composition according to any one of claims 1 to 12, containing 15-65 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof. 14. A pharmaceutical composition according to any one of claims 1 to 13, containing about 16 mg, about 32 mg, about 40 mg, about 64 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof. 15. A pharmaceutical composition according to any one of claims 1-14, wherein the filler is microcrystalline cellulose, lactose, or a combination thereof. 16. A pharmaceutical formulation according to any one of claims 1 to 15, wherein the glidant is anhydrous colloidal silica. 17. A pharmaceutical composition according to any one of claims 1-16, wherein the lubricant is magnesium stearate, Kolliwax® HCO - hydrogenated castor oil, sodium stearyl fumarate, or a combination thereof. 18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the compound (I) is monohydrochloride dihydrate. 19. Pharmaceutical composition according to any one of claims 1 to 18, which is in the form of a tablet. 20. A tablet for the treatment of a neuropsychiatric disease or sleep disorder or disorder, comprising hypromellose, an excipient, a glidant, a lubricant, and approximately 64 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, provided that when administered to a human, the maximum plasma concentration ( Cmax) of compound (I) determined in humans by HPLC is below 50 ng/ml. 21. A tablet for the treatment of a neuropsychiatric disease or disorder or sleep disorder, comprising hypromellose, an excipient, a glidant, a lubricant, and approximately 32 mg of compound (I) or a pharmaceutically acceptable salt or solvate thereof, when administered to a human, the maximum plasma concentration (Cmax) compound (I), determined in humans by HPLC, below 50 ng/ml. -