Controlled release PDE10A formulations

Abstract

The present disclosure relates generally to the treatment of central nervous system disorders associated with phosphodiesterase 10A (PDE10A), such as schizophrenia, bipolar affective disorder, and Alzheimer's disease, as therapies for neurological and psychiatric disorders. The present disclosure provides controlled release formulations of 2-methyl-N-((5-methyl-1, 3, 4-thiadiazol-2-yl) methyl)-6-(((1S, 2S)-2-(5-methylpyridin-2-yl) cyclopropyl) methoxy) pyrimidin-4-amine (Compound A) and their use in the treatment of schizophrenia and other psychiatric disorders that improve tolerance characteristics.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 455,403, filed March 29, 2023, the entire disclosure of which is incorporated herein by reference. Background Technology

[0002] This disclosure generally relates to the treatment of central nervous system disorders associated with phosphodiesterase 10A (PDE10A), such as schizophrenia, bipolar disorder, and neuropsychiatric symptoms associated with Alzheimer's disease. Inhibition of PDE10A is believed to be useful in the treatment of schizophrenia and a variety of conditions or disorders that benefit from increased intraneuronal cAMP and / or cGMP levels, including various neurological, psychotic, anxiety, and / or motor disorders.

[0003] Therapeutic compounds with short elimination half-lives are rapidly released from the gastrointestinal tract, typically characterized by a sharp initial increase in plasma concentration followed by a sharp decline as they undergo elimination. The "peak-to-trough" plasma concentration ratio (PTR), defined as the ratio of the maximum / peak plasma concentration (Cmax) to the minimum / trough plasma concentration (Cmin) within a dosing interval (e.g., once daily), can be used to indicate how quickly a patient's drug concentration can decrease from its maximum concentration to pre-dose levels. Compounds exhibiting high PTRs may not provide the required sustained target occupancy within preferred dosing intervals and may necessitate higher daily doses and / or increased dosing frequency.

[0004] Controlled-release (CR) formulations have been prepared using various methods, typically slowing or delaying the delivery of the active ingredient to the absorption site. The compositions of this invention address the challenge of achieving therapeutically effective sustained plasma concentrations of PDE10A inhibitors by controlling the release of an inhibitor with a zero-order release profile that extends post-ingestion for more than 12 hours.

[0005] Several potent PDE10A inhibitors have been described, for example, see US9,062,059 (incorporated herein in its entirety), US8957077, US8975261, 9,359,348, US9,376,450, and EP2,776,418. However, clinical trials have shown that the benefits of PDE10A inhibitors in treating schizophrenia, without optimized pharmacokinetic characteristics and dosage, are perplexing due to insufficient target engagement and side effects. Understanding the requirements of PDE10A inhibitors constitutes a challenging yet promising area of ​​drug discovery and development.

[0006] There is still a need for CR formulations of PDE10A inhibitors with improved tolerability (reduced adverse events / side effects, such as dystonia and akathisia) and patient compliance. Summary of the Invention

[0007] US Patent 9,062,059 discloses a potent PDE10A inhibitor, which includes 2-methyl- N -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-(((1 S ,2 S This disclosure discloses 2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine (compound A), its ester derivatives, geometric isomers, stereoisomers, or optical isomers as therapeutic agents for neurological and psychiatric disorders. One aspect of this disclosure provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders with improved tolerability characteristics. Another aspect of this disclosure provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders where high peak concentrations (Cmax) are permitted and the incidence of dystonia is extremely low or absent. A third aspect of this disclosure provides a CR formulation of compound A, wherein the excipients of the formulation are not dose-dependent. A fourth aspect of this disclosure provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders where administration at high concentrations without titration is permitted. A fifth aspect of this disclosure provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders where administration at doses providing high peak concentrations (Cmax) and the incidence of dystonia is extremely low or absent. Another aspect of this disclosure provides a controlled-release formulation of compound A that can provide a high peak concentration (Cmax) and its use in the treatment of schizophrenia and other mental disorders.

[0008] This disclosure further provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders, wherein the incidence of dystonia is reduced or eliminated. This disclosure further provides a CR formulation of compound A and its use in the treatment of schizophrenia and other mental disorders, wherein the incidence of dystonia is reduced or eliminated when an elevated dose (16 mg or higher) is administered to ensure that an effective concentration is maintained over the duration of the dosing interval. This disclosure further provides a CR formulation of compound A having a release profile of or near zero order, whose pharmacokinetic characteristics exhibit minimal fluctuations between peak and trough concentrations, improving tolerability characteristics. One aspect of this embodiment is a CR formulation of compound A with a PTR of about 1.0 to about 3.5. One aspect of this disclosure is achieved when the PTR is about 1.0 to about 2.0. Another aspect of this disclosure is achieved when the peak concentration to trough concentration ratio is about 1.0 to about 1.5. Another aspect of this disclosure is achieved when the peak concentration to trough concentration ratio is about 1.0 to about 1.3.

[0009] Another aspect of this disclosure is achieved in which a CR formulation of compound A, administered to a patient at a dose of about 20 mg to about 80 mg, about 17 mg to about 47 mg, 20 mg to about 36 mg, or about 17 mg to about 24 mg, results in mild or no dystonia. One embodiment of this aspect is achieved when the CR formulation of compound A is compared with an immediate-release (IR) formulation of compound A having the same dose.

[0010] Another aspect of this disclosure is achieved in which the CR formulation described herein is administered to healthy participants and / or patients with schizophrenia or other mental disorders at doses of about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to about 24 mg. One embodiment of this aspect is achieved when the CR formulation of compound A is compared with an IR formulation of compound A having the same dose.

[0011] Another aspect of this disclosure is achieved in which healthy participants and patients with schizophrenia or other mental disorders are administered about 20 mg to about 36 mg, about 20 mg to about 24 mg, or 24 mg of the CR formulation of compound A described herein without titration, wherein the patients experienced mild dystonia or no dystonia was observed. One embodiment of this aspect is achieved when the CR formulation of compound A is compared with an IR formulation of compound A having the same dose.

[0012] One aspect of this disclosure is a CR formulation comprising about 2 mg to about 80 mg of compound A, administered once daily. Another aspect of this disclosure is a CR formulation comprising about 16 mg to about 36 mg, about 20 mg to about 24 mg, or 24 mg of compound A without titration. One aspect of this embodiment is achieved when the release of compound A is controlled and occurs over a period of about 12-24 hours. After repeated administration of the composition to the in vivo environment, a steady-state Cmax plasma concentration is reached in ~10 to 24 hours and is generally maintained within the dosing interval. This other aspect of the embodiment is achieved when compound A is administered once daily at a dose of about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to about 24 mg, wherein the incidence of dystonia is reduced. Another aspect of the embodiment is achieved when a CR formulation of compound A is administered once daily without causing dystonia. Another aspect of the embodiment is achieved when a CR formulation of compound A is administered once daily at a dose of about 20 mg to about 47 mg without causing dystonia.

[0013] Another aspect of this disclosure is a CR formulation in which, compared to an IR formulation (Table 1), the amount of compound A present in said formulation is expected to produce an overall sustained / constant enzyme occupancy (EO) level at both peak and trough values ​​over a 24-hour dosing interval (Tables 2-5). A sub-implementation of this aspect of the disclosure is achieved when a high level of the expected EO is maintained at both peak and trough values ​​at doses ranging from about 17 mg to about 47 mg, from about 20 mg to about 36 mg, or from about 20 mg to 24 mg. Another aspect of this sub-implementation is achieved when the expected EO levels at both peak and trough values ​​are maintained at more than 75% in steady state. Another aspect of this sub-implementation is achieved when the expected EO levels at both peak and trough values ​​are maintained at about 65%-99%, 67%-99%, 70%-99%, 80%-99%, or 85%-99% in steady state. Another aspect of this sub-implementation was achieved when, in both healthy individuals and individuals with schizophrenia, at doses ranging from approximately 17 mg to 47 mg, or approximately 20 mg to 36 mg, the estimated EO levels at both peak and trough were maintained at approximately 70% to 99% and no dystonia events were reported. Another aspect of this sub-implementation was achieved when, in patients with schizophrenia, at doses ranging from approximately 17 mg to 47 mg, or approximately 20 mg to 36 mg, the estimated EO levels at both peak and trough were maintained at approximately 70% to 99% and no dystonia events were reported. Another aspect of this sub-implementation was achieved when, in healthy individuals, at doses ranging from approximately 17 mg to 47 mg, or approximately 20 mg to 36 mg, the estimated EO levels were maintained at approximately 70% to 99% and no dystonia events were reported.

[0014] Other aspects of the invention can be realized after reading the entire specification.

[0015] Brief description of the attached figures Figure 1 The relationship between PDE10A enzyme occupancy and plasma concentration of compound A after a single oral dose of the compound was shown.

[0016] Figure 2 The Tmax of the IR formulation of compound A was shown to be in the range of 0.5 to 2 h and the PTR was approximately 12–17 h.

[0017] Figure 3 The in vitro dissolution profiles of the CR formulation of compound A are shown, which were designed to achieve 80% release over time periods of 12, 16, and 20 hours, respectively.

[0018] Figure 4The pharmacokinetic curves of the CR formulation, which exhibited 80% release over time periods of 12, 16, and 20 hours, are shown.

[0019] The various aspects described herein are further described in detail in the following sections. Detailed Implementation

[0020] Studies using compound A and other PDE10A inhibitors have shown activity in multiple assays, supporting clinical efficacy in treating schizophrenia at enzyme occupancy (EO) >30% (Smith et al., Biological Psychiatry, 2022, Vol. 91, No. 9, S309-S310 and Li, YW et al., Neuropharmacology, 2016, Mar; 102: 121-35. doi: 10.1016 / j.neuropharm.2015.10.037. Epub 2015 Oct 30. PMID: 26522433). EO-concentration relationships were established using data from escalating single-dose studies and PET studies of IR formulations of compound A. Figure 1 These studies in healthy participants showed that the IR (internal response) of compound A (3 mg and 6 mg) reached ~64% and ~78% of the estimated EO values ​​at Cmax, respectively (Table 1), and was rapidly cleared from the brain several hours later (~8.9% and ~21% of the estimated EO values ​​at C24). However, dystonia was reported and appeared to be related to the time to reach maximum concentration (Tmax).

[0021] This disclosure provides a CR tablet formulation of compound A, wherein overall psychological tolerability limitations such as dystonia, akathisia, anxiety, depression, nausea, etc., are reduced and / or eliminated. Specifically, the CR formulation of compound A can be administered once daily at high clinical doses (e.g., 20 mg, 24 mg, 36 mg, etc.) without dystonia. More specifically, this disclosure provides a CR tablet formulation comprising: 1) The first layer, which has about 1% to 25% by weight of compound A: A Or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer or optical isomer thereof, and about 60-90% by weight of a low-viscosity polyethylene oxide (PEO) polymer; 2) A second layer comprising approximately 50%-70% by weight of a high-viscosity polyethylene oxide polymer, approximately 10%-40% by weight of a metal halide, and approximately 5%-30% by weight of a tableting compound; and 3) A semi-permeable coating, wherein the coating accounts for about 1% to 15% of the tablet by weight, and the tablet has pores in the first layer.

[0022] One embodiment of this disclosure is implemented in which the percentages of compound A and low-viscosity PEO are relative to the total weight of the first layer and the percentages of high-viscosity PEO, metal halide and tablet are relative to the total weight of the second layer.

[0023] In one embodiment, compound A or its ester derivatives, geometric isomers, stereoisomers or optical isomers are present at about 4% to 25% by weight of the total weight of the first layer, preferably about 5% to 15% by weight.

[0024] In another embodiment, the low-viscosity polyethylene oxide (PEO) is any low-viscosity PEO having a molecular weight range of about 100,000 to 300,000 (g / mol); preferably 200,000 g / mol. A sub-implementation of this aspect is achieved when the low-viscosity PEO is present at about 65 wt% to 88 wt%, preferably about 70 wt% to 88 wt%, of the total weight of the first layer.

[0025] In another embodiment, the high-viscosity polyethylene oxide (PEO) is any high-viscosity PEO having a molecular weight range (g / mol) of about 4,000,000 to 7,000,000 g / mol, preferably about 5,000,000 g / mol. A sub-implementation of this aspect is achieved when the high-viscosity PEO is present at about 50%-70% by weight, preferably about 60%-68% by weight, of the total weight of the second layer.

[0026] Compressed tablets are any pharmaceutical agents known in the art for long-term stabilization of drugs, expansion of solid dosage forms, and enhancement of the therapeutic effect of drugs. In one embodiment, the compressed tablet is selected from lactose, spray-dried lactose, microcrystalline cellulose (e.g., Avicel PH101 and PH102), mannitol (e.g., Pearlitol SD200), sorbitol, dehydrated dicalcium phosphate, dehydrated calcium sulfate, etc., preferably with microcrystalline cellulose optionally present in the second layer. A sub-implementation of this aspect is achieved when the compressed tablet is present at about 0%-25% by weight, preferably about 10%-20% by weight, of the total weight of the second layer.

[0027] In another embodiment, the metal halide is a penetrant selected from sodium chloride, potassium chloride, calcium chloride, potassium iodide, etc., preferably sodium chloride, wherein the sodium chloride exists in powder form. A sub-implementation of this aspect is achieved when the metal halide is present at about 10%-40% by weight, preferably about 15%-25% by weight, of the total weight of the second layer.

[0028] Typical semi-permeable polymers (known in the art as osmosis and reverse osmosis membranes) include cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetates, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, β-glucan acetate, dimethyl acetaldehyde acetate, cellulose acetate urethane, polyamides, polyurethanes, sulfonated polystyrene, cellulose acetate phthalates, cellulose acetate methyl urethane, cellulose acetate succinate, cellulose acetate, dimethyl aminoacetate, cellulose acetate ethyl urethane, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, and cellulose dioctanoate. Dicaprylate, cellulose divalerate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, methylcellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, selectively semi-permeable polymers crosslinked by co-precipitation of polyanionic and polycationic compounds, such as those disclosed in U.S. Patent Nos. 4,327,725, 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142, semi-permeable polymers. Materials such as those disclosed by Loeb and Sourirajan in U.S. Patent No. 3,133,132, including lightly cross-linked polystyrene derivatives, cross-linked poly(sodium styrene sulfonate), poly(vinylbenzyltrimethylammonium chloride), cellulose acetates having a degree of substitution of up to 1 and an acetyl content of up to 21%, cellulose diacetates having a degree of substitution of 1 to 2 and an acetyl content of 21 to 35%, and cellulose triacetates having a degree of substitution of 2 to 3 and an acetyl content of 35 to 44%, as disclosed in U.S. Patent No. 4,160,020.

[0029] In one embodiment, the semi-permeable coating is selected from the group consisting of cellulose acetate, ethyl cellulose, or combinations thereof. A sub-embodiment is achieved when the semi-permeable coating comprises a mixture of cellulose acetate, ethyl cellulose, or a mixture thereof, and low molecular weight polyethylene glycol. In one aspect of this sub-embodiment, 1%-15% by weight, preferably 5%-15% by weight, of the semi-permeable coating of the core comprises cellulose acetate, ethyl cellulose, or a mixture thereof, having about 5%-20% by weight, preferably 5%-10% by weight, of the coating low molecular weight polyethylene glycol. In one aspect of this embodiment, the polyethylene glycol has a molecular weight in the range of about 600-10,000 g / mol, preferably about 3,000 to about 4,000 g / mol, more preferably about 3,350 g / mol.

[0030] In another embodiment, the orifice has a diameter of about 0.1 to 1 mm.

[0031] In one embodiment of the CR tablet formulation, compound A or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer, or optical isomer thereof is present at about 4% to 25% by weight of the total weight of the first layer, and low-viscosity polyethylene oxide (PEO) having a molecular weight range of about 100,000 to 300,000 g / mol; and high-viscosity polyethylene oxide (PEO) having a molecular weight range of about 4,000,000 to 7,000,000 g / mol and being present at about 65% to 88% by weight of the total weight of the first layer, and at 60% to 68% by weight of the total weight of the second layer. One sub-implementation of this aspect is implemented when the tablet is not present. Another sub-implementation of this aspect is implemented when the tablet is present at up to about 25% by weight of the total weight of the second layer, preferably about 10% to 20% by weight. Another sub-implementation of this aspect is achieved when the metal halide is present at about 15%-25% by weight, preferably 15%-20% by weight, of the total weight of the second layer. Another sub-implementation of this aspect is achieved when 5%-15% by weight of a semi-permeable coating of the tablet core is present and comprises cellulose acetate, ethyl cellulose, or mixtures thereof, containing about 5%-20% by weight, preferably 5%-10% by weight, of low molecular weight polyethylene glycol of the coating. It should be noted that the tablet composition percentages are each based on the total weight of each layer, wherein the total weight of each layer is 200 mg in Example 2 and 100 mg in Example 3.

[0032] In one embodiment of the CR tablet formulation, a composition is disclosed comprising a low-viscosity PEO to high-viscosity PEO ratio of approximately 1:0.5, approximately 1:0.7, approximately 1:0.8, approximately 1:0.9, approximately 1:1, approximately 1:1.2, approximately 1:1.4, 1:1.6, 1:1.8, or approximately 1:2. In another embodiment of the CR tablet formulation, a composition comprising a high-viscosity PEO to metal halide ratio of approximately 10:1 to approximately 1:0, preferably selected from ratios of approximately 5:1, 4:1, 3:1, 2:1, and 1:0. In yet another embodiment of the CR tablet formulation, a composition comprising a cellulose to metal halide ratio of approximately 0:1 to approximately 1:1.6, preferably approximately 1:1.1, 1:1.2, 1:1.3, or 1:1.4. In one aspect of this embodiment, a cellulose acetate + polyethylene glycol mixture is present at approximately 5%-15% (relative to the total weight of the tablets) of the total coating weight.

[0033] Another embodiment of the CR formulation is achieved when the sugar alcohol is optionally present in the formulation. A sub-embodiment of this aspect of the invention is achieved when the present sugar alcohol is selected from mannitol, sucrose, and lactose. Another sub-embodiment of this aspect of the invention is achieved when the sugar alcohol is mannitol. Another sub-embodiment of this aspect of the invention is achieved when a controlled-release formulation containing mannitol in the first layer releases compound A in an amount up to 12 mg over a period of approximately 12-24 hours after the composition is placed in the in vivo environment.

[0034] Another embodiment of the CR formulation is achieved when it contains additional excipients required to ensure the manufacturability, stability, or in vivo performance of the finished dosage form. In one embodiment, 0%-2% of a lubricant is present, such as magnesium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, or sodium stearate fumarate, preferably magnesium stearate.

[0035] When preparing tablets, the second layer may contain a lake or dye to visually distinguish the tablet layers, serving as a method to ensure proper drilling on the correct surface of the coated tablet. Examples of available colorants include red iron oxide, yellow iron oxide, black iron oxide, and / or FD&C Blue No. 2 lake.

[0036] The aforementioned CR-coated tablet formulations can be further coated with a film to modify the appearance or color of the formulation, but will not further modify the release rate of the active ingredient from the formulation. The film coating may consist of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and / or polyvinyl alcohol-polyethylene glycol copolymer, as well as plasticizers, opacifiers and / or colorants.

[0037] One aspect of the CR formulation is achieved when it is administered at a high dose, including up to 48 mg, with a starting dose of up to about 80 mg after moderate titration. Another aspect of the CR formulation is achieved when it is administered at a high dose of up to about 80 mg without titration. Another sub-implementation of this aspect of the present disclosure is a CR formulation of compound A, which can be administered once daily at a clinical dose range of about 17 mg to about 47 mg, preferably about 20 mg to about 36 mg, about 20 mg to about 24 mg, and more preferably 24 mg without dystonia.

[0038] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein, as well as laboratory procedures in polymer chemistry, pharmaceutical science, drug delivery, pharmaceutical process technology, and pharmacokinetics, are well-known and commonly used in the art.

[0039] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” refers to one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0040] All ranges disclosed herein include the stated endpoints and can be combined independently (e.g., a range “from 50 mg to 500 mg” includes the endpoints (50 mg and 500 mg) as well as all intermediate values). The endpoints and any values ​​of the ranges disclosed herein are not limited to precise ranges or values; they are sufficiently imprecise to include values ​​that approximate these ranges and / or values.

[0041] As used herein, the term "comprising" may include embodiments that are "consisting of" and "consisting essentially of". The terms "comprise(s)", "include(s)", "having", "has", "may", "contain(s)", and variations thereof, as used herein, are intended as open-ended transitional phrases, terms, or words that require the presence of a specified component / step and allow for the presence of other components / steps. However, such descriptions should be interpreted as also describing a composition or method as "consisting of the listed components" and "essentially consisting of the listed components", which allows for the presence of only the named components or compounds and any acceptable carrier or fluid, and excludes other components or compounds.

[0042] "Pharmaceutical active agent," "active ingredient," "drug," or "beneficial agent" refers to compound A and its pharmaceutically acceptable salts, as well as derivatives that produce similar local or systemic effects or multiple effects in animals. Derivatives of the active ingredient, such as esters, ethers, and amides, can be used alone or in combination with other compounds, regardless of their ionization and solubility characteristics. Furthermore, prodrugs of the active agent can be used in a form that, after release from the tablet, is converted to its original or biologically active form by enzymatic conversion, hydrolysis by body pH, or other metabolic processes. That is, prodrugs are specifically included within the definition of a pharmaceutical active ingredient. Compositions included within the scope of this invention are those having racemic mixtures of the active ingredient and isolated enantiomers. Furthermore, hydrates of the active ingredient, as well as anhydrous compositions and polymorphs, can be included in the compositions of this invention.

[0043] The term "pharmaceutically acceptable salt" refers to a non-toxic salt of an active ingredient, typically prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts include: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, calcium ethylenediaminetetraacetate, camphorsulfonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonate, propionate, dodecyl sulfate, ethanesulfonate, fumarate, gluconate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, and hyaluronic acid. Hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, iodide, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, oleate, oxalate, pamoate, palmitate, pantothenate, phosphate / bisphosphonate, polygalacturonic acid salt, salicylate, stearate, acetite, succinate, tannic acid salt, tartrate, theochloroate, toluenesulfonate, triethyl iodide, valerate.

[0044] As used throughout the specification and appended claims, the following definitions and abbreviations shall apply: about: As used herein, the term “about” refers to the same numerical value as that referred to, or a value plus or minus 10% of that numerical value in the context; for example, “about 5” means “4.5-5.5”. Generally, those skilled in the art will understand the absolute amount and / or relative degree of difference covered by “about” in that context.

[0045] Application: As used herein, the term “administration” refers to the act of providing an active agent, composition, or formulation to a subject. Exemplary routes of administration to the human body may include the eye (ophthalmic), mouth (oral), skin (transdermal), nose (nasal cavity), lungs (inhalation), rectum, vagina, oral mucosa (buccal), ear, and via injection (e.g., intravenous (IV), subcutaneous, intratumoral, intraperitoneal, intramuscular (IM), intradermal (ID), etc.).

[0046] Agent: As used herein, the term "pharmaceutical" refers to any chemical class of particles, compounds, molecules, or entities, including, for example, small molecules or combinations or complexes thereof. In some embodiments, the term "pharmaceutical" may refer to a compound, molecule, or entity comprising one or more polymers.

[0047] API:As used herein, the term "API" refers to an active pharmaceutical ingredient, such as a PDE10 inhibitor, which is a component of the compositions or formulations disclosed herein that has biological activity and provides therapeutic or preventative benefit to humans or animals in need. As used herein, API is compound A as an active ingredient.

[0048] Biocompatible: As used herein, the term "biocompatible" refers to materials that are non-toxic to the body, pharmaceutically acceptable, and non-carcinogenic.

[0049] Controlled release (CR): As used herein, “controlled release” refers to a dosage form designed to release an active agent or other type of substance into the body at a specific rate that varies over time. The rate at which the active pharmaceutical ingredient is released from the device (capsule, pill, tablet, etc.) into the environment of use is not instantaneous but follows a predetermined pattern. Thus, a relatively constant or predictably varying amount of a beneficial agent can be delivered over a specified period of time.

[0050] dose: As used herein, the term “dosage” refers to the quantity of a drug, API, formulation, or pharmaceutical composition administered or recommended for administration at a particular time.

[0051] Relieve: As used in this article, the terms “mitigation” or “reduced” refer to a reduction or decrease in severity.

[0052] patient: As used herein, the term “patient” means any person who is about to receive the pharmaceutical composition described herein.

[0053] Pharmaceutically acceptable: As used herein, the term "pharmaceuticalally acceptable" means an excipient (carrier, additive) and composition that can be reasonably administered to a subject to provide an effective dose of the active ingredient used and is "generally considered safe," for example, that is physiologically tolerable when administered to humans and generally does not cause allergic reactions or similar adverse reactions, such as gastrointestinal upset. In another embodiment, the term refers to molecular entities and compositions approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0054] Pharmaceutical composition:As used herein, the term "pharmaceutical composition" refers to a composition containing an active pharmaceutical ingredient or biological component and one or more additional components, such as a composition in which the active agent is formulated with one or more pharmaceutically acceptable carriers. As used herein, the terms "pharmaceutical formulation" and "formulation" are used interchangeably with "pharmaceutical composition." In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that demonstrates a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. Additional components that may be included, as appropriate, include pharmaceutically acceptable excipients, additives, diluents, buffers, sugars, amino acids, chelating agents, surfactants, polyols, polymers, fillers, penetrants, stabilizers, lyophilization protectants, solubilizers, emulsifiers, salts, adjuvants, tonicotinic agents, delivery carriers, and antimicrobial preservatives. The pharmaceutical composition or formulation is non-toxic to the receptor at the doses and concentrations employed.

[0055] Steady state: The moment when the drug infusion rate equals the drug elimination rate (i.e., when the drug is in equilibrium).

[0056] Subjects: As used herein, the term "subject," also referred to as "participant" or "patient," refers to an organism, typically a mammal (e.g., a human, including, in some embodiments, a fetal human form). In some embodiments, the subject suffers from a relevant disease, symptom, or condition. In some embodiments, the subject is susceptible to a disease, symptom, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, symptom, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, symptom, or condition. In some embodiments, the subject is a subject who has one or more characteristics of being susceptible to or at risk of developing a disease, symptom, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom a diagnosis and / or treatment has been administered.

[0057] Effective therapeutic dose: As used herein, the term "therapeutic effective amount" refers to an amount of an active ingredient (such as a small molecule) sufficient to produce the desired therapeutic effect in a human or animal, for example, the amount required to induce treatment, cure, prevention, or inhibition of the development and progression of a disease or its symptoms, and / or the amount required to alleviate symptoms or cause disease remission. Therapeutic effective amounts can vary depending on the structure and potency of the active ingredient and the intended mode of administration. Those skilled in the art can readily determine the therapeutic effective amount of a given molecule.

[0058] Viscosity:As used herein, viscosity is a measure of a substance’s resistance to deformation or flow at a given rate. Viscosity can be measured, for example, using a viscometer at a given one or more shear rates, which are appropriately selected by those skilled in the art to relate to the viscosity range of the target sample.

[0059] Volume % or Volume by volume: As used herein, the terms “volume%” or “% by volume” refer to the number of parts by volume of the total volume of a polymer carrier, such as microparticles, microspheres, or minitabs. Unless otherwise stated, all percentages (%) reported herein are volume percentages.

[0060] Weight% or weight% (% by weight): As used herein, the term "weight%" or "% by weight" refers to the number of parts by weight of the total weight of one hundred parts of carrier volume, such as mixtures, carriers, powders, granules, and pellets. For example, 10% by weight of surfactant means 10 parts by weight of surfactant and 90 parts by weight of carrier.

[0061] The following examples illustrate the preparation of a drug and the controlled release of active ingredient compound A into the environment of use in the delivery device of the present invention (e.g., tablets, capsules, etc.), and should not be construed as limiting the invention described in the appended claims.

[0062] The dosage regimen for using the compositions of the present invention is selected based on a variety of factors, including: patient type, species, age, weight, sex, and health status; severity of the condition to be treated; route of administration; patient's renal and hepatic function; and the specific active ingredient or its salt used. Physicians or veterinarians with ordinary skills can easily determine and prescribe the effective amount of medicine required to prevent, counteract, or halt the progression of the condition.

[0063] Another aspect of this disclosure is a CR formulation of compound A, which can be administered at doses up to 80 mg and is well tolerated; however, due to adverse events of dystonia and neuropsychiatric adverse events, the immediate-release formulation of compound A has not been increased to above 6 mg (Study 6). Conversely, safety and tolerability data following administration of compound A at 80 mg in the CR formulation of this disclosure did not result in adverse events, thus ruling out further dose increases.

[0064] Example In the following examples, compound A is the active ingredient. The composition was prepared using the following ingredients, amounts, and formulation procedures.

[0065] Example 1 - Immediate-release formulation

[0066]

[01] The immediate-release formulation in Example 1 was prepared according to the following method: Compound A was ground with a portion of dicalcium phosphate. This ground material was then mixed sequentially with a portion of microcrystalline cellulose, followed by the remaining dicalcium phosphate, microcrystalline cellulose, and croscarmellose sodium; the mixture was further mixed with magnesium stearate for lubrication. The lubricated mixture was then filled into capsules.

[0067] Example 2 - Controlled-release formulation:

[0068] Example 3 - Controlled-release formulation (low core weight (100 mg per layer))

[0069]

[02] The controlled-release tablet formulations in Examples 2 and 3 below were prepared by the following method:

[03] Layer 1: Compound A, low molecular weight PEO, and mannitol are premixed, further mixed with a portion of magnesium stearate, rolled, ground, and mixed with the remaining magnesium stearate. In Layer 2, high molecular weight PEO, microcrystalline cellulose, sodium chloride, colorant, and magnesium stearate are mixed. The mixture of Layer 1 and Layer 2 is compressed to form a bilayer tablet. Cellulose acetate and polyethylene glycol are dissolved in an acetone:water (31:1 ratio) solvent system and coated onto the bilayer tablet core using a perforated disc tablet coating machine until the target coating weight is achieved. A single hole is drilled on the surface of Layer 1 of each tablet using a laser drill. The tablets are dried at 40°C to remove residual acetone. The bilayer tablet may consist of two equal-weight layers, or the layer weights may be up to twice different (e.g., from 100:200 mg to 200:100 mg). The total tablet weight may vary between 200 and 600 mg. The total coating weight can be 25-75 mg per tablet, depending on the size and surface area of ​​the tablet core and the permeability of the coating, which can be adjusted by the amount of PEG contained in the coating.

[0070] The controlled-release formulations given in Examples 2 and 3 exhibited an increase in unit ejection force during bilayer tablet compression (the value exceeded approximately 1.0-1.5 N / mm). 2 In this granulation process, the content of compound A in layer 1 exceeds 6%. Such a high unit ejection force is undesirable in tablet compression. Unexpectedly, as shown in Example 4 below, removing mannitol from layer 1 and replacing it with low molecular weight PEO mitigated this effect, resulting in a unit ejection force consistently below 1 N / mm. 2 This is also true even in layer 1 granulation when the content of compound A is as high as about 25%.

[0071] Example 4

[0072] The controlled-release formulation of Example 4 was prepared by the following method: Compound A is passed through a 20-mesh sieve to remove agglomerates. Low molecular weight PEO is passed through a sieve (e.g., U20 Comil) equipped with a suitable sieve (e.g., 7C075R) at approximately 1000 rpm. Layer 1 components are then mixed in a 3 cubic foot bin mixer for 195 rpm. Half of Layer 1, containing magnesium stearate, is passed through a 60-mesh sieve to remove agglomerates and added to the mixer along with the other Layer 1 components. The mixture is stirred for 90 rpm for lubrication. The Layer 1 mixture is granulated using a roller press (e.g., Gerteis TG87) equipped with knurled rollers and a 1 mm square-hole pellet mill, operating at a roller speed of approximately 2–4 rpm, a roller force of approximately 4–5 kN / cm, and a 2 mm gap. The remaining Layer 1 magnesium stearate is passed through a 60-mesh sieve to remove agglomerates and added to the granulated Layer 1 mixture in a 3 cubic foot bin mixer. The mixture is stirred for 90 rpm for lubrication. Layer 2 excipients, except for magnesium stearate, are sieved through a 30-mesh sieve to remove lumps. The layer 2 excipients are stirred for 65 rpm in a 3 cubic foot bin mixer. The mixture is then passed through a sieve (e.g., U20 Comil) equipped with a suitable sieve (e.g., 7C075R) at approximately 1000 rpm. The material is further mixed in a 3 cubic foot bin mixer for 130 rpm. Magnesium stearate is passed through a 60-mesh sieve to remove lumps and added to the mixer along with the other layer 2 excipients, and stirred for 90 rpm for lubrication. The lubricated mixture of layers 1 and 2 is compressed using a suitable multilayer tableting machine equipped with a 3 / 8-inch round standard convex compression tool, targeting a layer weight of 200 mg per layer and a tablet thickness of approximately 5.7 mm. A coating solution containing cellulose acetate:PEG 3350 in a 9:1 ratio and an excess of approximately 5% w / w solids loading was prepared by dispersing PEG 3350 in water, combining it with acetone, and slowly adding cellulose acetate while stirring to dissolve. The solution was then applied to tablet cores with cellulose acetate:PEG 3350 to a target weight gain of 49 mg / tablet using a suitable disc coater operated at an inlet air temperature of approximately 40°C, an outlet temperature of approximately 25°C, a solution spray rate of approximately 45–60 g / min per spray gun, and a gun-to-bed distance of approximately 4 inches. Holes of 1 mm diameter and 0.25 mm depth were drilled at the center of the surface of each tablet layer 1 using a suitable laser drill (e.g., CMS TT15). The drilled tablet trays were dried in a suitable drying oven at 40°C for approximately 36 hours to remove excess acetone.

[0073] Develop and evaluate CR formulations of compound A to determine whether once-daily dosing can maintain an effective EO with a slow-rising, more sustained pharmacokinetic profile. Compared to the IR formulation in Study 6 (Table 1), in Study 4, a single-dose study evaluating the PK and tolerability of compound A, the CR formulation exhibited a delayed Tmax (10–24 h), a smaller PTR (~1.3), and therefore a sustained EO between peak and trough (Table 2).

[0074] The CR formulation of compound A was further evaluated in three multi-dose studies with treatment durations of 7–18 days in adult participants with schizophrenia, and in two of the three studies, healthy non-elderly participants were also evaluated. Study 1 was a randomized, placebo-controlled titration study in which participants (healthy participants (n=10–Table 3) and participants with schizophrenia (n=14–Table 4)) were titrated from 2 mg to 12 mg as monotherapy or from 2 or 4 mg to 16 mg (n=19) as adjunctive therapy to prescription antipsychotic therapy (participants with schizophrenia only).

[0075] Study 2 was designed similarly to Study 1; participants with schizophrenia (n=16) and healthy participants (n=16) were administered a CR-release formulation / placebo of compound A as monotherapy or as adjunctive therapy (n=17) (schizophrenia participants only) and titrated from 4 mg to 24 mg (see Table 3 for pharmacokinetic analysis at the 24 mg dose level as monotherapy in healthy adults). In Study 2, an additional group of participants with schizophrenia were administered a CR-release formulation / placebo of compound A as monotherapy and titrated from 8 mg to 48 mg (n=26) (see Table 4 for pharmacokinetic analysis at the 48 mg dose level).

[0076] In Study 3, one group of participants [(n=8) - monotherapy in adult participants with schizophrenia] were titrated from 16 mg to 24 mg or placebo, while another group of participants (n=18) received 24 mg / placebo without titration (Table 5) to determine whether titration was necessary for tolerability.

[0077] Overall, in studies 1 through 3 and in dose titration, the CR formulation of compound A was generally well tolerated as monotherapy and as adjunctive therapy in participants with schizophrenia. In study 1 (Table 4), dystonia was reported in 5 (15%) of the 33 participants with schizophrenia who received the CR formulation of compound A (3 monotherapy participants [1 each of 2 mg, 4 mg, and 12 mg] and 2 adjunctive therapy participants [8 mg and 16 mg]). All events resulted in an immediate response to benzalkonium chloride.

[0078] In Study 2, no dystonia associated with compound A was observed when the dose was titrated from 4 mg to 24 mg and from 8 mg to 48 mg. In Study 2, the Cmax value of ~1800 nM and the C24 value of ~1200 nM at the highest dose level (Table 4) were significantly higher than the 376 nM Cmax associated with dystonia in healthy participants in Study 6 (IR formulation - Table 1).

[0079] In Study 3, compound A was generally well tolerated when administered at 16 mg (data not shown in Table 5) or 24 mg without titration, with p-values ​​similar to those previously observed for the CR formulation (p-values ​​for the 24 mg dose without titration, see Table 5). Two transient dystonia events occurred after the first dose of 16 mg, but both events were responsive to treatment and did not recur with continued dosing. No dystonia events were reported when administered at 24 mg without titration (Table 5). Other adverse events (i.e., depression, anxiety, and stress) in all three studies were mostly mild to moderate in intensity, and there was no clear dose-related increase in any particular event (Table 6).

[0080] Surprisingly, in Studies 1 and 2, tolerability improved at doses up to approximately 47 mg in healthy participants. Furthermore, in Study 2, participants with schizophrenia did not experience dystonia at doses ranging from approximately 4 mg to 48 mg, although the maximum and trough concentrations (Cmax and C24) and the estimated EOs calculated at Cmax and C24 (Table 4) were similar to, or greater than, those associated with dystonia in studies using the IR formulation (Table 1). Similar trends in sustained exposure and occupancy estimates were also observed in participants with schizophrenia receiving compound A as monotherapy in Studies 1 and 2 (Table 4). Exposure to and sustained EO estimates for the CR formulation of compound A in participants with schizophrenia receiving it as adjunctive therapy were similar to those in participants receiving monotherapy.

[0081] Overall, studies 1–3 also showed that tolerability was improved in both healthy and schizophrenic participants, as doses from approximately 17 mg to approximately 47 mg did not cause dystonia. Furthermore, in healthy participants, no dystonia was reported after administration of CR formulations up to 12 mg (n=9) and 24 mg (n=12).

[0082] In another study, Study 4 (a single-dose study evaluating the slowest, intermediate, and fastest release CR formulations), all subjects received four single doses of 2 mg compound A under fasting conditions (four treatment cycles), with treatment administered after an 8-hour overnight fast and fasting continuing for up to four hours post-dose. The observed Tmax ranges for the fastest, intermediate, and slowest release CR formulations administered under fasting conditions were 6–16 hours, 10–24 hours, and 20–24 hours, respectively. The PTR for the intermediate release CR formulation was ~1.3 (Table 2).

[0083] In another study, Study 5 (no table description), among approximately 54 participants who received a CR formulation of compound A (48 mg / placebo on day 1 and 60 mg / placebo on day 2, or 48 mg / placebo on day 1 and 80 mg / placebo on day 2, or 48 mg / placebo on days 1 and 2 and 80 mg on day 3), only 2 participants reported dystonia after 48 mg of compound A. Overall, with CR formulations used in the dose range of 20 mg to 80 mg, 2 out of ~82 participants (2.4%) reported dystonia related to compound A, which was significantly less than that seen with IR formulations (Note: Preliminary study results).

[0084] In a study evaluating the PK and tolerability of an IR formulation of compound A (Study 6) (Table 1), while no healthy participants reported dystonia after the 1 mg dose, the 3 mg dose (n=12), and the 6 mg dose (n=6), 3 participants (25%) and 1 participant (17%) reported dystonia, respectively. After the 3 mg dose, dystonia began to occur at 1 hour 10 minutes, 1 hour 27 minutes, and 1 hour 31 minutes post-dose. After the 6 mg dose, dystonia began to occur at 3 hours 50 minutes post-dose. This participant also reported depressive mood and nightmares. Another participant also reported depressive mood, anxiety, and stress. Given these adverse events, it was decided not to increase the dose further.

[0085] Based on the EO-concentration relationship, CR doses of compound A at 24 mg and higher were expected to produce approximately 65%, 77%, or 80% or higher sustained EO at steady state, which is greater than the EO associated with the IR formulation. Surprisingly, the high levels of sustained EO achieved with the CR formulation were not associated with an increase in dystonia. In Studies 1 and 2, no dystonia events were reported in healthy participants, and in participants with schizophrenia (Studies 1, 2, 3, and 5), a significantly reduced incidence of dystonia was observed at doses ranging from 20 mg to 80 mg – approximately 2% (2 out of ~82 participants). Even more surprisingly, in both healthy and schizophrenic participants, no dystonia events were reported with high levels of sustained EO achieved with the CR formulation at doses ranging from 17 mg to 47 mg. These findings suggest that CR formulations of compound A can achieve high levels of sustained EO with unexpectedly good tolerability for dystonia.

[0086] In another study of healthy subjects, Study 7 (no table description), no dystonia was reported in healthy subjects who were administered doses ranging from 8 mg / placebo to 72 mg / placebo (n=12), with a maximum dose of 48 mg. Plasma exposure in this study was generally similar to that observed in other multi-dose studies reported in this paper (data not shown).

[0087] Table 6 Participants with non-serious related adverse events (Part 1, Group B: Participants with schizophrenia - young adults) (Incidence >0% in one or more treatment groups)

Claims

1. A controlled-release tablet formulation comprising: 1) A first layer, comprising about 1% to 25% by weight of a pharmaceutically acceptable compound A, represented by structural formula I: I Or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer or optical isomer thereof, and about 60-90% by weight of a low-viscosity polyethylene oxide (PEO) polymer; 2) A second layer comprising approximately 50%-70% by weight of a high-viscosity polyethylene oxide polymer, approximately 10%-40% by weight of a metal halide, and approximately 5%-30% by weight of a tableting compound; and 3) A semi-permeable coating, wherein the coating comprises about 1% to 15% by weight of the tablet, and the tablet has pores in the first layer.

2. The formulation according to claim 1, wherein the low-viscosity polyethylene oxide has a molecular weight range of about 100,000 to 300,000 (g / mol) and is present in the first layer at about 65% to 88% by weight.

3. The formulation according to any one of claims 1 to 2, wherein the high-viscosity polyethylene oxide has a molecular weight range of about 4,000,000 to 7,000,000 (g / mol) and is present in the second layer at about 50% to 70% by weight.

4. The formulation according to any one of claims 1 to 3, wherein the compressed tablet is selected from lactose, spray-dried lactose, microcrystalline cellulose, mannitol, sorbitol, dehydrated dicalcium phosphate, and dehydrated calcium sulfate.

5. The formulation according to claim 4, wherein the compressed tablet is microcrystalline cellulose, present in about 10% to 20% by weight.

6. The formulation according to any one of claims 1 to 5, wherein the metal halide is selected from sodium chloride, potassium chloride, calcium chloride, potassium iodide, mixtures thereof, and is present in an amount of about 15% to 25% by weight.

7. The formulation according to any one of claims 1 to 6, wherein the semi-permeable coating comprises cellulose acetate, ethyl cellulose, or a combination thereof and low molecular weight polyethylene glycol.

8. The formulation according to any one of claims 1 to 7, wherein compound A or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer or optical isomer thereof is present in about 4% to 25% by weight, and the low-viscosity polyethylene oxide has a molecular weight range of about 100,000 to 300,000 (g / mol) and is present in about 65% to 88% by weight of the total weight of the first layer.

9. The formulation according to any one of claims 1 to 8, wherein: a) The high-viscosity polyethylene oxide has a molecular weight range of about 4,000,000 to 7,000,000 (g / mol) and is present in an amount of about 60% to 68% by weight. b) The compressed tablets contain at most 10%-20% by weight, and c) The metal halide is present at approximately 15%-25% by weight of the total weight of the second layer.

10. The formulation according to any one of claims 1 to 9, wherein 5%-15% of the semi-permeable coating comprises cellulose acetate, ethyl cellulose, or a mixture thereof, wherein the cellulose acetate, ethyl cellulose, or the mixture thereof contains about 5%-20% by weight of low molecular weight polyethylene glycol.

11. The formulation according to any one of claims 1 to 10, wherein a sugar alcohol is optionally present, said sugar alcohol being selected from mannitol, sucrose and lactose.

12. The formulation according to any one of claims 1 to 11, exhibiting a peak-to-trough concentration level of about 1.0 to about 3.5 for compound A.

13. The formulation according to any one of claims 1 to 12, comprising about 17 mg to about 47 mg of compound A, which can be administered once daily without causing dystonia.

14. The formulation according to any one of claims 1 to 13, comprising 16 mg or higher doses of compound A, exhibiting a sustained muscarinic enzyme occupancy rate of about 65% or higher at both peak and trough values.

15. The formulation according to any one of claims 1 to 14, comprising about 17 mg to about 47 mg of compound A.

16. The formulation of claim 15, wherein no dystonia was reported when administered to a population of patients with schizophrenia.

17. A method for treating schizophrenia or other mental disorders in patients in need, the method comprising administering to the patient a controlled-release formulation of compound A according to any one of claims 1 to 16 at a dose of 16 mg or higher without inducing dystonia in the patient.

18. The method of claim 17, wherein compound A is administered to the patient at a dose of about 17 mg to about 47 mg without inducing dystonia in the patient.

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