Controlled-release PDE10A formulation

Abstract

The present disclosure relates generally to the treatment of central nervous system disorders associated with phosphodiesterase 10A (PDE10A), such as schizophrenia, bipolar disorder, and Alzheimer's disease, as a therapeutic agent 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 with improved tolerability profiles.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 455,403, filed March 29, 2023, the disclosure of which is incorporated herein in its entirety. [Background technology]

[0002] The present disclosure relates generally to the treatment of central nervous system disorders associated with phosphodiesterase 10A (PDE10A), such as neuropsychiatric conditions associated with schizophrenia, bipolar disorder, and Alzheimer's disease. Inhibition of PDE10A is believed to be effective in treating a variety of conditions and disorders that benefit from increasing intraneuronal cAMP and / or cGMP levels, including schizophrenia and neurological, psychiatric, anxiety, and / or movement disorders.

[0003] Therapeutic compounds with short elimination half-lives and rapid release in the gastrointestinal tract are often characterized by an initial rapid rise in plasma concentration followed by a rapid decline as the compound is excreted. The "peak-to-trough" plasma concentration ratio (PTR), defined as the ratio of the maximum / peak plasma concentration (Cmax) to the trough / minimum plasma concentration (Cmin) over a dosing interval (e.g., once daily), is useful for describing the time it will take for a patient's drug concentration to decline from the maximum concentration to pre-dose levels. Compounds that exhibit a high PTR may not provide the sustained target occupancy required over the recommended dosing interval, necessitating either a higher daily dose and / or more frequent administration.

[0004] Controlled-release (CR) formulations have generally been prepared in a variety of ways to slow or delay delivery of the active ingredient to the absorption site. The compositions of the present invention solve the difficult problem of providing therapeutically effective sustained plasma concentrations of PDE10A inhibitors by controlling the release of the inhibitor using a formulation with a zero-order release profile that lasts for 12 hours or more after ingestion.

[0005] Several potent PDE10A inhibitors have been described, for example, see U.S. Patent No. 6,269,629 (incorporated herein in its entirety), U.S. Patent No. 6,269,629, ...

[0006] There remains a need for CR formulations of PDE10A inhibitors with improved tolerability profiles (reduced adverse events / side effects such as dystonia, akathisia) and patient compliance. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 9,062,059 [Patent Document 2] U.S. Patent No. 8,957,077 [Patent Document 3] U.S. Patent No. 8,975,261 [Patent Document 4] U.S. Patent No. 9,376,450 [Patent Document 5] European Patent No. 2,776,418 Summary of the Invention

[0008] U.S. Patent No. 9,062,059 discloses potent PDE10A inhibitors, including 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), its ester derivatives, geometric isomers, stereoisomers, or optical isomers, as drugs for treating neurological and psychiatric disorders. The present disclosure provides a CR formulation of Compound A and its use in the treatment of schizophrenia and other psychiatric disorders that improves tolerability profiles. One aspect of the present disclosure provides a CR formulation of Compound A and its use in the treatment of schizophrenia and other psychiatric disorders that allows for a high peak concentration (Cmax) with minimal or no occurrence of dystonia. Another aspect of the present disclosure provides a CR formulation of Compound A in which the excipients of the formulation are not dose-dependent. Another aspect of the disclosure provides a CR formulation of Compound A and its use in the treatment of schizophrenia and other psychiatric disorders that can be administered at high concentrations without titration. Another aspect of the disclosure provides a CR formulation of Compound A and its use in the treatment of schizophrenia and other psychiatric disorders that can be administered at doses that provide a high peak concentration (Cmax) that minimizes or does not cause dystonia. Another aspect of the disclosure provides a controlled-release formulation of Compound A that provides a high peak concentration (Cmax) and its use in the treatment of schizophrenia and other psychiatric disorders.

[0009] The present disclosure further provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders, in which the incidence of dystonia is reduced or eliminated. The present disclosure further provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders, in which the incidence of dystonia is reduced or eliminated when administered at increasing doses (16 mg or greater) to ensure effective concentrations are maintained over the duration of the dosing interval. The present disclosure also provides CR formulations of Compound A having a zero-order or near-zero-order release profile, a pharmacokinetic profile that minimizes fluctuations between peak and trough concentrations, and an improved tolerability profile. One aspect of this embodiment is a CR formulation of Compound A having a PTR of about 1.0 to about 3.5. One aspect of the present disclosure is realized when the PTR is about 1.0 to about 2.0. Another aspect of the present disclosure is realized when the ratio of peak concentration to trough concentration is about 1.0 to about 1.5. Another aspect of the present disclosure is realized when the ratio of peak concentration to trough concentration is about 1.0 to about 1.3.

[0010] Another aspect of the present disclosure is realized by administering to a patient with minimal or no dystonia 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 of a CR formulation of Compound A. This embodiment is realized when comparing the CR formulation of Compound A to an immediate release (IR) formulation of Compound A at the same dose.

[0011] Another aspect of the disclosure is realized by administering about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to about 24 mg of a CR formulation described herein to healthy participants with dystonia and / or patients suffering from schizophrenia or other psychiatric disorders. This embodiment is realized when comparing a CR formulation of Compound A with an IR formulation of Compound A having the same dose.

[0012] Another aspect of the present disclosure is that healthy participants and patients suffering from schizophrenia or other psychiatric disorders are administered about 20 mg to about 36 mg, about 20 mg to about 24 mg, or 24 mg of a CR formulation of Compound A described herein without titration, and the patients experience minimal or no dystonia. This embodiment is realized when comparing a CR formulation of Compound A with an IR formulation of Compound A at the same dose.

[0013] One aspect of the present disclosure is a CR formulation containing about 2 mg to about 80 mg of Compound A administered once daily. Another aspect of the present disclosure is a CR formulation containing 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 realized when the release of Compound A is controlled and occurs over about 12 to 24 hours. After repeated administration of the composition to an in vivo environment, a steady-state Cmax plasma concentration is achieved in about 10 to 24 hours and is typically sustained throughout the dosing interval. Another aspect of this embodiment is realized when about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to about 24 mg of Compound A is administered once daily, resulting in a reduction in the occurrence of dystonia. Another aspect of this embodiment is realized when the CR formulation of Compound A is administered once daily without the occurrence of dystonia. Another aspect of this embodiment is realized when a CR formulation of Compound A is administered at about 20 mg to about 47 mg once daily without the occurrence of dystonia.

[0014] Another aspect of the present invention is a CR formulation, in which the amount of Compound A present in the formulation, as opposed to an IR formulation (Table 1), is estimated to produce generally sustained / constant enzyme occupancy (EO) levels at both peak and trough over a 24-hour dosing interval (Tables 2-5). Subembodiments of this aspect of the present disclosure are realized when high estimated EO levels are maintained at both peak and trough levels at doses ranging from about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to about 24 mg. One aspect of this subembodiment is realized when estimated EO levels at both peak and trough are maintained at greater than 75% at steady state. Another aspect of this subembodiment is realized when estimated EO levels at both peak and trough are maintained at about 65%-99%, 67%-99%, 70%-99%, 80%-99%, or 85%-99% at steady state. Another aspect of this subembodiment is realized when, in both a healthy population and a population suffering from schizophrenia without reports of dystonia, estimated EO levels, both peak and trough, are maintained at about 70%-99% at a dose range of about 17 mg-47 mg, or about 20 mg-36 mg. Another aspect of this subembodiment is realized when, in patients with schizophrenia without reports of dystonia, estimated EO levels, both peak and trough, are maintained at about 70%-99% at a dose range of about 17 mg-47 mg, or about 20 mg-36 mg. Another aspect of this subembodiment is realized when, in a healthy population without reports of dystonia events, estimated EO levels are maintained at about 70%-99% at a dose range of about 17 mg-47 mg, or about 20 mg-36 mg.

[0015] Other aspects of the present invention can be understood by reviewing the specification as a whole. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 shows PDE10A enzyme occupancy and plasma concentrations of Compound A after a single oral dose of the compound in healthy subjects. [Figure 2]FIG. 1 shows that the Tmax of the IR formulation of Compound A ranges from 0.5 to 2 hours, and the PTR is approximately 12 to 17. [Figure 3] FIG. 1 shows in vitro dissolution profiles of CR formulations of Compound A designed to achieve 80% release over 12, 16, and 20 hours, respectively. [Figure 4] FIG. 1 shows the pharmacokinetic profile of the CR formulation showing 80% release over 12, 16, and 20 hours. DETAILED DESCRIPTION OF THE INVENTION

[0017] Various aspects described herein are described in further detail in the following subsections.

[0018] Studies with Compound A and other PDE10A inhibitors have demonstrated quantitative measures of enzyme occupancy (EO) greater than 30% that support clinical efficacy in the treatment of schizophrenia. Compound A has demonstrated activity (Smith et al., Biological Psychiatry 2022, Volume 91, Issue 9, S309-S310 and Li, YW et al., Neuropharmacology. 2016 March;102:121-35. doi:10.1016 / j.neuropharm.2015.10.037. Epub 2015 October 30, PMID: 26522433). Data from single-dose and PET studies using IR formulations of Compound A were used to construct EO versus concentration relationships (Figure 1). These studies in healthy participants demonstrated that IR administration of Compound A (3 mg and 6 mg) resulted in estimated EO values ​​at Cmax of approximately 64% and 78%, respectively (Table 1), and demonstrated rapid clearance from the brain over several hours (estimated EO values ​​at Cmax of approximately 8.9% and 21%, respectively). However, dystonia has been reported and appears to be related to the time of maximum concentration (Tmax).

[0019] The present disclosure provides CR tablet formulations of Compound A that reduce and / or eliminate overall psychiatric tolerability limitations such as dystonia, akathisia, anxiety, depression, and nausea. In particular, CR formulations of Compound A can be administered once daily at high clinical doses (e.g., 20 mg, 24 mg, 36 mg, etc.) without causing dystonia. Specifically, the present disclosure provides: 1) about 1% to 25% by weight of Compound A [ka] or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer, or optical isomer thereof, and about 60% to 90% by weight of a low viscosity polyethylene oxide (PEO) polymer; 2) a second layer comprising about 50% to 70% by weight of a high viscosity polyethylene oxide polymer, about 10% to 40% by weight of a metal halide, and about 5% to 30% by weight of a tableting agent; 3) A semipermeable coating, wherein the coating comprises about 1% to 15% by weight of the tablet, and the tablet has holes in the first layer. The present invention provides a CR tablet formulation comprising:

[0020] An embodiment of the present disclosure is realized when the proportions of Compound A and low-viscosity PEO are based on the total weight of the first layer, and the proportions of high-viscosity PEO, metal halide, and tableting agent are based on the total weight of the second layer.

[0021] In one embodiment, Compound A or its ester derivative, geometric isomer, stereoisomer, or optical isomer is present in an amount of about 4% to 25%, preferably about 5% to 15%, of the total weight of the first layer.

[0022] In another embodiment, the low viscosity polyethylene oxide (PEO) is any low viscosity PEO having a molecular weight range (g / mol) of about 100,000 to 300,000, preferably 200,000 g / mol. A subembodiment of this aspect is realized when the low viscosity PEO is present in an amount of about 65% to 88%, preferably about 70% to 88%, by weight of the total weight of the first layer.

[0023] 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 g / mol to 7,000,000 g / mol, preferably about 5,000,000 g / mol. A subembodiment of this aspect is realized when the high viscosity PEO is present in an amount of about 50% to 70% by weight, preferably about 60% to 68% by weight, of the total weight of the second layer.

[0024] Tableting agents are any agent known in the art used for long-term stabilization of drugs, bulking up solid dosage formulations, and enhancing the therapeutic effect of drugs. In one embodiment, a tableting agent, preferably microcrystalline cellulose, selected from lactose, spray-dried lactose, microcrystalline cellulose (e.g., Avicel PH101 and PH102), mannitol (e.g., Pearlitol SD200), sorbitol, dibasic calcium phosphate dehydrate, calcium sulfate dehydrate, and the like, may be present in the second layer. A subembodiment of this aspect is realized when the tableting agent is present in an amount of about 0% to 25% by weight, preferably about 10% to 20% by weight, of the total weight of the second layer.

[0025] In another embodiment, the metal halide is an osmotic agent selected from sodium chloride, potassium chloride, calcium chloride, potassium iodide, and the like, preferably sodium chloride, and the sodium chloride is present as a powder. A subembodiment of this aspect is realized when the metal halide is present in an amount of about 10% to 40% by weight, preferably about 15% to 25% by weight, of the total weight of the second layer.

[0026] Typical semipermeable polymers known in the art as osmosis and reverse osmosis membranes include cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, polyurethanes, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmatate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, methylcellulose, cellulose acetate p -toluene sulfonic acid, cellulose acetate butyrate, cross-linked selectively semipermeable polymers formed by coprecipitation of polyanions and polycations such as those disclosed in U.S. Pat. Nos. 4,327,725, 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142, semipermeable polymers such as those disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132, U.S. Pat. Lightly crosslinked polystyrene derivatives such as those disclosed in US Pat. No. 4,160,020, crosslinked poly(sodium styrene sulfonate), poly(vinylbenzyltrimethylammonium chloride), cellulose acetate having a degree of substitution of up to 1 and an acetyl content of up to 21%, cellulose diacetate having a degree of substitution of 1-2 and an acetyl content of 21%-35%, and cellulose triacetate having a degree of substitution of 2-3 and an acetyl content of 35%-44%.

[0027] In one embodiment, the semipermeable coating is selected from the group consisting of cellulose acetate, ethyl cellulose, or a combination thereof. A subembodiment is realized when the semipermeable coating comprises a mixture of cellulose acetate, ethyl cellulose, or a mixture thereof with a low molecular weight polyethylene glycol. In one aspect of this subembodiment, 1% to 15%, preferably 5% to 15%, by weight of the core tablet of the semipermeable coating is composed of cellulose acetate, ethyl cellulose, or a mixture thereof, and about 5% to 20%, preferably 5% to 10%, by weight of the coating is composed of a low molecular weight polyethylene glycol. In one aspect of this embodiment, the molecular weight range of the polyethylene glycol is about 600 g / mol to 10,000 g / mol, preferably about 3000 g / mol to about 4000 g / mol, and more preferably about 3350 g / mol.

[0028] In another embodiment, the holes have a diameter of about 0.1 mm to 1 mm.

[0029] 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 in an amount of about 4% to 25% by weight of the total weight of the first layer; the low-viscosity polyethylene oxide (PEO) has a molecular weight range (g / mol) of about 100,000 to 300,000 and is present in an amount of about 65% to 88% by weight of the total weight of the first layer; and the high-viscosity polyethylene oxide (PEO) has a molecular weight range (g / mol) of about 4,000,000 to 7,000,000 g / mol and is present in an amount of 60% to 68% by weight of the total weight of the second layer. A subembodiment of this aspect is realized when no tableting agent is present. A subembodiment of this aspect is realized when a tableting agent is present in an amount of up to about 25% by weight, preferably about 10% to 20% by weight, of the total weight of the second layer. Another subembodiment of this aspect is realized when the metal halide is present in about 15% to 25% by weight, preferably 15% to 20% by weight, of the total weight of the second layer. Another subembodiment of this aspect is realized when 5% to 15% by weight of the tablet core is a semipermeable coating comprised of cellulose acetate, ethyl cellulose, or a mixture thereof, and about 5% to 20% by weight, preferably 5% to 10% by weight, of the coating weight, of low molecular weight polyethylene glycol. Note that the tablet composition percentages are based on the total weight of each layer, which is 200 mg in Example 2 and 100 mg in Example 3.

[0030] In one embodiment of a CR tablet formulation, a composition is disclosed in which the ratio of low-viscosity PEO to high-viscosity PEO is about 1:0.5, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.2, about 1:1.4, 1:1.6, 1:1.8, or about 1:2, respectively. In another embodiment of a CR tablet formulation, a composition is disclosed in which the ratio of high-viscosity PEO to metal halide is about 10:1 to about 1:0, respectively, preferably about 5:1, 4:1, 3:1, 2:1, and 1:0, respectively. In another embodiment of a CR tablet formulation, a composition is disclosed in which the ratio of cellulose to metal halide is about 0:1 to about 1:1.6, respectively, preferably about 1:1.1, 1:1.2, 1:1.3, or 1:1.4, respectively. In one aspect of this embodiment, the cellulose acetate + polyethylene glycol mixture is present at about 5% to 15% by weight of the total coating weight (based on the total tablet weight).

[0031] Another embodiment of the CR formulation is realized when an alcohol sugar is optionally present in the formulation. A subembodiment of this aspect of the invention is realized when the alcohol sugar present is selected from mannitol, sucrose, and lactose. Another subembodiment of this aspect of the invention is realized when the alcohol sugar is mannitol. Another subembodiment of this aspect of the invention is realized when the controlled-release formulation, when mannitol is present in the first layer, releases Compound A at a concentration of up to 12 mg over a period of about 12 to 24 hours after the composition is placed in an in vivo environment.

[0032] Another embodiment of the CR formulation is realized when it contains additional excipients as needed to ensure the manufacturability, stability, or in vivo performance of the finished dosage form. In one embodiment, a lubricant such as magnesium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium stearyl fumarate, preferably magnesium stearate, is present at 0%-2%.

[0033] When preparing tablets, the second layer may contain a lake or dye to allow visual differentiation between the tablet layers as a means of verifying that the coated tablet is perforated on the correct side. Examples of useful colorants include red iron oxide, yellow iron oxide, black iron oxide, and / or FD&C Blue No. 2 Lake.

[0034] The CR-coated tablet formulations described above can be further coated with a film coating to modify the appearance or color of the formulation, but without further altering the release rate of the active ingredient from the formulation. The film coating can be composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and / or polyvinyl alcohol-polyethylene glycol copolymer, as well as plasticizers, opacifiers and / or colorants.

[0035] One aspect of this CR formulation is achieved when administered at a high dose, including a high starting dose of 48 mg, followed by moderate titration to about 80 mg. Another aspect of this CR formulation is achieved when administered at a high dose up to about 80 mg without titration. Another subembodiment of this aspect of the disclosure is a CR formulation of Compound A that can be administered once daily without dystonia in 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. [Definition]

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Generally, the nomenclature and laboratory procedures used herein in polymer chemistry, pharmacology, drug delivery, pharmaceutical process technology and pharmacokinetics are those well known and commonly employed in the art.

[0037] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0038] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., the range "50 mg to 500 mg" includes the endpoints 50 mg and 500 mg, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact range or value; they are sufficiently imprecise to include values ​​that approximate those ranges and / or values.

[0039] As used herein, the term "comprising" can include the embodiments "consisting of" and "consisting essentially of." As used herein, the terms "comprise(s)," "include(s)," "having," "has," "may," and "contain(s)," and variations thereof, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified ingredients / steps and allow for the presence of others. However, such descriptions should also be construed as describing compositions or processes as "consisting of" and "consisting essentially of" the listed ingredients, which allows for the presence of only the specified ingredients or compounds, along with any acceptable carriers or fluids, and excludes other ingredients or compounds.

[0040] "Pharmaceutically active agent," "active ingredient," "medicine," or "beneficial agent" refers to Compound A and its pharmaceutically acceptable salts and derivatives that produce similar local or systemic effects in animals. Derivatives of active ingredients, such as esters, ethers, and amides, can be used alone or in mixtures with other compounds, regardless of their ionization and solubility characteristics. Prodrugs of active ingredients can also be used in forms that, upon release from the tablet, are converted by enzymes, hydrolyzed by the body's pH, or converted to their original or biologically active form by other metabolic processes. Thus, prodrugs are specifically included within the definition of a pharmaceutically active ingredient. Compositions within the scope of the present invention include racemic mixtures and compositions containing resolved enantiomers of the active ingredient. Additionally, hydrates, anhydrous compositions, and polymorphs of the active ingredient can be included in the compositions of the present invention.

[0041] The term "pharmaceutically acceptable salt" refers to a non-toxic salt of an active ingredient, typically prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolic acid arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, and the like. Contains: isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaate, palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, tannate, tartrate, thioclate, tosylate, trithiodide, valerate.

[0042] As used throughout this specification and the appended claims, the following definitions and abbreviations apply.

[0043] About: As used herein, the term "about," when used herein in reference to a value, refers to a value that is the same as a reference value or, in context, is ±10% of the reference value; for example, "about 5" means "4.5 to 5.5." Generally, a person skilled in the art familiar with the context will understand the absolute amount and / or relative degree of difference encompassed by "about" in that context.

[0044] Administration: 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 can be by eye (ophthalmic), mouth (oral), skin (transdermal), nose (nasal), lung (inhalation), rectum, vagina, oral mucosa (buccal), ear, injection (e.g., intravenous (IV), subcutaneous, intratumoral, intraperitoneal, intramuscular (IM), intradermal (ID)), etc.

[0045] Drug: As used herein, the term "drug" refers to any medicinal particle, compound, molecule, or entity, including, for example, a small molecule, or a combination or complex thereof. In some embodiments, the term "drug" can refer to a compound, molecule, or entity, including a polymer or a plurality thereof.

[0046] API: As used herein, the term "API" refers to an active pharmaceutical ingredient, such as a PDE10 inhibitor, that is biologically active and provides therapeutic or prophylactic benefit to humans or animals in need thereof in the compositions or formulations disclosed herein.As used herein, API refers to Compound A as the active ingredient.

[0047] Biocompatible: As used herein, the term "biocompatible" refers to a material that is not toxic to the body, is pharmaceutically acceptable, and is not carcinogenic.

[0048] Controlled Release (CR): As used herein, "controlled release" refers to a dosage form that has been engineered to release an active agent or other type of substance into the body at a specific rate as a function of time. The rate of release of the pharmaceutically active ingredient from the device (capsule, pill, tablet, etc.) into the environment of use is not immediate, but rather follows a predetermined pattern. Thus, a relatively constant or predictably varying amount of beneficial agent can be delivered over a specified period of time.

[0049] Dose: As used herein, the term “dose” means the amount of a drug, API, formulation, or pharmaceutical composition that is administered or recommended to be administered at a particular time.

[0050] Alleviate: As used herein, the term "alleviate" or "alleviated" means to make less severe or less severe.

[0051] Patient: As used herein, the term "patient" refers to any human receiving the pharmaceutical compositions described herein.

[0052] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to excipients (vehicles, additives) and compositions that are "generally regarded as safe," e.g., that can be reasonably administered to a subject to provide an effective amount of the active ingredient used, that are physiologically tolerated, and that typically do not cause allergic reactions or similar untoward reactions, such as stomach upset, when administered to humans. In another embodiment, the term refers to molecular entities and compositions approved by federal or state government regulatory agencies, or listed in the United States Pharmacopoeia or another generally recognized pharmacopoeia, for use in animals, more specifically in humans.

[0053] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition containing an active pharmaceutical or biological component along with one or more additional ingredients, e.g., 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 amount suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. Additional components that can be optionally included include pharmaceutically acceptable excipients, additives, diluents, buffers, sugars, amino acids, chelating agents, surfactants, polyols, polymers, bulking agents, osmotic agents, stabilizers, cryoprotectants, solubilizers, emulsifiers, salts, adjuvants, tonicity agents, delivery vehicles, and antimicrobial preservatives. The pharmaceutical composition or formulation is non-toxic to the recipient at the dosages and concentrations employed.

[0054] Steady state: The time when the rate of drug input equals the rate of drug elimination (i.e., at equilibrium).

[0055] Subject: 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, prenatal human forms). In some embodiments, the subject is afflicted with the relevant disease, disorder, or condition. In some embodiments, the subject is predisposed to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is a person with one or more characteristics characteristic of susceptibility to or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or who has been administered and / or who has been administered a diagnosis and / or treatment.

[0056] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a small molecule) sufficient to produce a desired therapeutic effect in a human or animal, for example, the amount necessary to treat, cure, prevent, or inhibit the onset and progression of a disease or its symptoms, and / or the amount necessary to improve symptoms or cause regression of a disease. The therapeutically effective amount may vary depending on the structure and potency of the active ingredient and the intended mode of administration. Those skilled in the art can easily determine the therapeutically effective amount of a given molecule.

[0057] Viscosity: As used herein, viscosity refers to a measure of a material's resistance to deformation or flow at a given rate. Viscosity can be measured, for example, by using a viscometer at one or more given shear rates appropriately selected by a person skilled in the art to relate to the viscosity range of the sample of interest.

[0058] Volume %: As used herein, the term "volume %" refers to the portion of volume per 100 parts of the total volume of the polymeric carrier, e.g., microparticles, microspheres, or minitabs. Unless otherwise specified, percentages (%) reported herein are by volume.

[0059] % by weight: As used herein, the term "% by weight" refers to the portion of weight per 100 parts of the total weight of the carrier, e.g., blend, carrier, powder, particle, granulation, volume. For example, 10% by weight of active agent means 10 parts by weight of active agent and 90 parts by weight of carrier.

[0060] The following examples illustrate the preparation of drugs in delivery devices (e.g., tablets, capsules, etc.) of the present invention and the controlled release of the active ingredient Compound A into a use environment, and should not be construed as limiting the invention as defined in the appended claims.

[0061] Dosage regimens using the compositions of the present invention are selected depending on a variety of factors, including the type, species, age, weight, sex, and condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the particular active ingredient or salt thereof employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of drug required to prevent, counter, or arrest the progression of the condition.

[0062] Another aspect of the present disclosure is a CR formulation of Compound A that can be administered at doses as high as 80 mg with good tolerability, whereas an immediate release formulation of Compound A was not titrated above 6 mg (Study 6) due to dystonic and neuropsychiatric adverse events. Conversely, safety and tolerability data following administration of 80 mg of Compound A in the CR formulation of the present disclosure did not result in adverse events that prevented further dose escalation.

[0063] [Example] In the following examples, Compound A is the active ingredient. The following ingredients and amounts and formulation procedures were used to prepare the compositions.

[0064] [Example 1] Immediate release formulation Ingredients Composition unit (mg) Compound A 1.000 Cellulose, microcrystalline 57.27 Anhydrous dibasic calcium phosphate 114.5 Croscarmellose sodium 5.400 Magnesium stearate 1.800 Size 3 hard gelatin capsules Total: 180.0 The immediate release formulation of Example 1 was prepared as follows.

[0065] Compound A was milled with a portion of dibasic calcium phosphate. This milled mixture was mixed with a portion of microcrystalline cellulose, and then mixed with the remaining dibasic calcium phosphate, microcrystalline cellulose, and croscarmellose sodium. This mixture was further mixed with magnesium stearate for lubrication. The lubricated mixture was filled into capsules.

[0066] [Example 2] Controlled-release formulation [Table 1] [Example 3] Controlled-release formulation (low core tablet weight (100 mg / layer)) [Table 2] The CR tablet formulations of Examples 2 and 3 below were prepared as follows.

[0067] For the first layer, Compound A, low molecular weight PEO, and mannitol were premixed, further mixed with a portion of the magnesium stearate, roller-compacted, pulverized, and mixed with the remaining magnesium stearate. For the second layer, high molecular weight PEO, microcrystalline cellulose, sodium chloride, colorant, and magnesium stearate were mixed. The blend of the first and second layers was compressed to form bilayer tablets. Cellulose acetate and polyethylene glycol were dissolved in an acetone:water (31:1) solvent system and coated onto bilayer tablet cores using a perforated pan tablet coater until the target coating weight was reached. For the coated tablets, a laser drill was used to drill one hole in the first layer of each tablet. The tablets were dried at 40°C to remove residual acetone. Bilayer tablets can consist of two layers of equal weight, or the layer weights can differ by up to two-fold (e.g., 100:200 mg to 200:100 mg). The total tablet weight can vary from 200 mg to 600 mg. The total coating weight may range from 25 mg to 75 mg per tablet, depending on the size and surface area of ​​the core tablet and the permeability of the coating (which can be adjusted by the amount of PEG included in the coating).

[0068] The controlled-release formulations shown in Examples 2 and 3 exhibited a unit ejection force (approximately 1.0 N / mm) during compression of bilayer tablets when the level of Compound A in the first layer granules exceeded 6%. 2 ~1.5N / mm 2 This increased unit ejection force is undesirable for tablet compression. Surprisingly, as shown in Example 4 below, removing mannitol from the first layer and replacing it with low molecular weight PEO mitigated this effect, resulting in a consistent unit ejection force of 1 N / mm even at levels of Compound A in the first layer granules up to about 25%. 2 It became less than.

[0069] [Example 4] [Table 3] The controlled-release formulation of Example 4 was prepared as follows.

[0070] Compound A was passed through a #20 mesh screen to separate lumps, and the low molecular weight PEO was passed through a screening mill (e.g., a U20 Comil) fitted with an appropriate size screen (e.g., a 7C075R) at approximately 1000 rpm. The first layer ingredients were then mixed in a 3 cubic foot bin blender for 195 revolutions. Half of the first layer magnesium stearate was passed through a #60 mesh screen to separate lumps and added to the blender with the other first layer ingredients, then mixed and lubricated for 90 revolutions. The first layer blend was granulated using a roller compactor (e.g., a Gerteis TG87) equipped with a knurled roll and a 1 mm square mesh granulator, operated at a roll speed of approximately 2 rpm to 4 rpm, a roll force of approximately 4 kN / cm to 5 kN / cm, and a gap of 2 mm. The remaining first layer magnesium stearate was sieved through a #60 mesh screen to de-lump and added to a 3 cubic foot bin blender with the first layer granulation for 90 revolutions to blend and lubricate. The second layer excipients, except for magnesium stearate, were sieved through a #30 mesh screen to de-lump. The second layer excipients were blended for 65 revolutions in the 3 cubic foot bin blender. The blend was passed through a screening mill (e.g., U20 Comil) fitted with an appropriate size screen (e.g., 7C075R) and operated at approximately 1000 rpm. The material was further blended for 130 revolutions in the 3 cubic foot bin blender. The magnesium stearate was sieved through a #60 mesh screen to de-lump and added to the blender with the other second layer excipients for 90 revolutions to blend and lubricate. The lubricated blend of the first and second layers was compressed using a suitable multilayer tablet press equipped with 3 / 8 inch round standard convex compression tooling, targeting a layer weight of 200 mg and a tablet thickness of approximately 5.7 mm. An excess coating solution containing cellulose acetate:PEG 3350 at a ratio of 9:1 in a 31:1 acetone:water solvent system, with a solids loading of approximately 5% w / w, was prepared by dispersing the PEG 3350 in water, combining with acetone, and slowly adding and dissolving the cellulose acetate with stirring.The tablet cores were coated with cellulose acetate:PEG 3350 using a suitable pan coater, operating at an inlet air temperature of approximately 40°C, an outlet temperature of approximately 25°C, a solution spray rate of approximately 45g / min to 60g / min per spray gun, and a gun-to-bed distance of approximately 4 inches, to achieve a target weight gain of 49mg / tablet. A suitable laser drill (e.g., CMS TT15) was used to drill a 1mm diameter, 0.25mm deep hole in the center of the first layer surface of each tablet. The drilled tablets were tray-dried at 40°C for approximately 36 hours in a suitable drying oven to remove excess acetone.

[0071] A CR formulation of Compound A was developed and evaluated to determine whether a slower-rising, more sustained pharmacokinetic profile could maintain adequate EO with once-daily dosing. In Study 4, a single-dose study evaluating the PK and tolerability of Compound A, the CR formulation had a later Tmax (10–24 hours) and a shallower PTR (approximately 1.3), resulting in a sustained EO between peak and trough (Table 2), compared with the IR formulation in Study 6 (Table 1).

[0072] The CR formulation of Compound A was further evaluated in three multiple-dose studies with treatment periods ranging from 7 to 18 days in adult participants with schizophrenia; two of these studies also evaluated non-elderly healthy participants. Study 1 was a randomized, placebo-controlled, dose-titrated study in which participants (healthy participants (n = 10; Table 3) and participants with schizophrenia (n = 14; Table 4)) were administered doses ranging from 2 mg to 12 mg as monotherapy or 2 mg or 4 mg to 16 mg as adjunctive therapy to prescribed antipsychotic medication (schizophrenia participants only) (n = 19).

[0073] Study 2 was designed similarly to Study 1, with participants receiving a CR-release formulation of Compound A / placebo titrated from 4 mg to 24 mg as monotherapy (patients with schizophrenia (n=16) and healthy participants (n=16)) or as adjunctive therapy (n=17) (patients with schizophrenia only) (see Table 3 for PK description at the 24 mg dose level as monotherapy in healthy adults). In Study 2, an additional panel of participants with schizophrenia received a CR-release formulation of Compound A / placebo titrated from 8 mg to 48 mg as monotherapy (n=26) (see Table 4 for PK description at the 48 mg dose level).

[0074] In Study 3, one panel of participants ((n=8) - monotherapy in adult participants with schizophrenia) received a titrated dose from 16 mg to 24 mg or placebo, while another panel of participants (n=18) received 24 mg / placebo without titration to determine if titration was necessary for tolerability (Table 5).

[0075] Overall, Compound A CR formulation was generally well tolerated in patients with schizophrenia as monotherapy and adjunctive therapy across Study 1-3 and dose titration. In Study 1 (Table 4), dystonia was reported in 5 of 33 (15%) patients with schizophrenia receiving Compound A CR formulation (3 patients after monotherapy [1 patient each after 2 mg, 4 mg, and 12 mg], and 2 patients after adjunctive therapy [8 mg and 16 mg]). All events responded promptly to benztropine.

[0076] In Study 2, doses were titrated from 4 mg to 24 mg and from 8 mg to 48 mg, and no Compound A-related dystonia was observed. At the highest dose level in Study 2, Cmax values ​​of approximately 1800 nM and C24 values ​​of approximately 1200 nM were achieved (Table 4), which was significantly higher than the dystonia-associated Cmax value of 376 nM in healthy participants in Study 6 (IR formulation - Table 1).

[0077] In Study 3, Compound A was generally well tolerated when initiated at 16 mg (data not shown in Table 5) or 24 mg without titration, and PK estimates were similar to those previously observed with the CR formulation (see Table 5 for PK at 24 mg without titration). There were two transient dystonic events after the first dose of 16 mg; both events responded to treatment, and participants continued treatment without recurrence. No dystonic events were reported when initiated at 24 mg without titration (Table 5). Other adverse events (e.g., depression, anxiety, stress) across all three studies were mostly mild or moderate, with no apparent dose-related increase in any specific event (Table 6).

[0078] Unexpectedly, across Studies 1 and 2, healthy participants demonstrated improved tolerability at doses up to approximately 47 mg. Furthermore, in Study 2, participants with schizophrenia did not experience dystonia at doses between approximately 4 mg and 48 mg, yet the maximum and trough concentration (Cmax and C24) values ​​and calculated EOs at Cmax and C24 (Table 4) were comparable to or greater than the values ​​associated with dystonia in the IR formulation (Table 1). Similar trends in sustained exposure and occupancy estimates were observed in participants with schizophrenia who received Compound A as monotherapy in Studies 1 and 2 (Table 4). Exposure and sustained EO estimates for the CR formulation of Compound A in participants with schizophrenia administered as adjunctive therapy were similar to those in participants receiving monotherapy.

[0079] Overall, Studies 1-3 demonstrated improved tolerability in both healthy and schizophrenic subjects, with no dystonia occurring at doses between approximately 17 mg and approximately 47 mg. Furthermore, no dystonia was reported after administration of CR formulations up to 12 mg (n=9) and 24 mg (n=12) in healthy participants.

[0080] In another study, Study 4 (a single-dose study evaluating the slowest, intermediate, and fastest CR formulations), all subjects received four single 2 mg doses (four treatment periods) of Compound A under fasting conditions, with treatment following an 8-hour overnight fast and continued fasting for 4 hours after dosing. The Tmax ranges observed for the fastest, intermediate, and slowest CR formulations administered in the fasted state were 6-16 hours, 10-24 hours, and 20-24 hours, respectively. The PTR for the intermediate CR formulation was approximately 1.3 (Table 2).

[0081] In another study, Study 5 (not shown in the table), of approximately 54 participants receiving the CR formulation of Compound A at 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 two reported dystonia after the 48 mg dose of Compound A. Overall, in the CR formulation in the 20 mg to 80 mg dose range, two of approximately 82 participants (2.4%) reported Compound A-related dystonia, which was significantly less than that seen with the IR formulation (note: preliminary study results).

[0082] In a study of the IR formulation of Compound A (Study 6), PK and tolerability were evaluated (Table 1). No healthy participants reported dystonia after a 1 mg dose, but 3 participants (25%) and 1 participant (17%) reported dystonia after a 3 mg dose (n=12) and a 6 mg dose (n=6), respectively. After a 3 mg dose, dystonia began at 1 hour 10 minutes, 1 hour 27 minutes, and 1 hour 31 minutes post-dose. After a 6 mg dose, dystonia began at 3 hours 50 minutes post-dose. This participant also reported feelings of depression and nightmares. Another subject reported feelings of depression, anxiety, and stress. Due to these adverse events, it was decided not to further increase the dose.

[0083] Based on the EO-concentration relationship, CR doses of Compound A 24 mg or higher are expected to provide sustained EO of approximately 65%, 77%, or 80% or more 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 increased dystonia. While no dystonic symptoms were reported in healthy participants in Studies 1 and 2, dystonia was observed at a very low incidence of approximately 2% (2 of 82 participants) at doses between 20 mg and 80 mg in schizophrenic participants (Studies 1, 2, 3, and 5). Even more surprising is that no dystonic events were reported at the high levels of sustained EO achieved with the CR formulation at doses ranging from 17 mg to 47 mg in both healthy and schizophrenic subjects. These findings suggest that the CR formulation of Compound A achieves high sustained EO and offers an unexpectedly favorable tolerability profile with respect to dystonia.

[0084] In another healthy subject study, Study 7 (not shown), healthy subjects received doses ranging from 8 mg / placebo to 72 mg / placebo (n=12), with no reported dystonia at doses up to 48 mg. Plasma exposures in this study were generally similar to those observed in the other multiple-dose studies reported here (data not shown). [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] TIFF2025539974000012.tif18155

Claims

1. 1. A controlled-release tablet formulation comprising: 1) about 1% to 25% by weight of a pharmaceutically acceptable salt of formula I Compound A 【Chemistry 1】 or a pharmaceutically acceptable salt, ester derivative, geometric isomer, stereoisomer, or optical isomer thereof, and about 60% to 90% by weight of a low viscosity polyethylene oxide (PEO) polymer; 2) a second layer comprising about 50% to about 70% by weight of a high viscosity polyethylene oxide polymer, about 10% to about 40% by weight of a metal halide, and about 5% to about 30% by weight of a tableting agent; 3) a semipermeable coating, said coating comprising about 1% to 15% by weight of said tablet, said tablet having holes in said first layer; 1. A controlled-release tablet formulation comprising:

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

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

4. 4. The formulation of any one of claims 1 to 3, wherein the tableting agent is selected from lactose, spray-dried lactose, microcrystalline cellulose, mannitol, sorbitol, dibasic calcium phosphate dehydrate, and calcium sulfate dehydrate.

5. 5. The formulation of claim 4, wherein the tableting agent is microcrystalline cellulose and is present at about 10% to 20% by weight.

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

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

8. 8. The formulation of 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 an amount of about 4% to 25% by weight, and the low-viscosity polyethylene oxide has a molecular weight range (g / mol) of about 100,000 to 300,000 and is present in an amount of about 65% to 88% by weight, based on the total weight of the first layer.

9. a) the high viscosity polyethylene oxide has a molecular weight range (g / mol) of about 4,000,000 to 7,000,000 and is present at about 60% to 68% by weight; b) the tableting agent is present in an amount of 10% to 20% by weight; c) the metal halide is Present at about 15% to 25% by weight The formulation according to any one of claims 1 to 8.

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

11. A formulation according to any preceding claim, wherein a sugar alcohol selected from mannitol, sucrose and lactose may be present.

12. 12. The formulation of any one of claims 1 to 11, which exhibits peak to trough concentration levels of Compound A of about 1.0 to about 3.

5.

13. The formulation according to any one of claims 1 to 12, which does not cause dystonia and contains about 17 mg to about 47 mg of compound A that can be administered once a day.

14. The formulation of any one of claims 1 to 13, comprising Compound A at a dose of 16 mg or more, which exhibits a sustained muscarinic enzyme occupancy of about 65% or more at both peak and trough.

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

16. 16. The formulation of claim 15, which when administered to a patient population suffering from schizophrenia, does not report the occurrence of dystonia.

17. 17. A method for treating schizophrenia or other psychiatric disorders in a patient in need thereof, comprising administering to said patient a controlled release formulation of Compound A according to any one of claims 1 to 16 at a dose of 16 mg or more, without inducing dystonia in said patient.

18. 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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