Controlled-Release PDE10A Formulations

Description

1 / 34 Controlled-Release PDE10A Formulations CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims the benefit of priority under U.S. Provisional Application No. 63 / 455,403, filed March 29, 2023, the disclosure of which is incorporated in the present invention in its entirety. BACKGROUND OF THE INVENTION

[002] The present disclosure relates generally 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 wide variety of conditions or disorders that would benefit from increased cAMP and / or cGMP levels in neurons, including a variety of neurological, psychotic, anxiety, and / or movement disorders.

[003] Therapeutic compounds with short elimination half-lives that are rapidly distributed in the gastrointestinal tract are often characterized by sharp initial increases in plasma concentrations, followed by a sharp decline as they are eliminated. The peak-to-trough plasma concentration ratio (PTR), defined as the ratio of the maximum / peak plasma concentration (Cmax) and the trough / minimum plasma concentration (Cmin) over a dosing interval (e.g., once daily), is useful for representing how quickly a patient's drug concentrations can fall from their maximum concentration to predose levels. Compounds exhibiting a high PTR may not provide the necessary sustained target occupancy over the preferred dosing interval and may require administration of a higher daily dose and / or increased frequency of administration. Petition 870250087591, dated 09 / 26 / 2025, pp. 217 / 254 2 / 34

[004] Controlled-release (CR) formulations have been prepared in a number of ways, generally to delay or retard the release of the active ingredient to the absorption site. The compositions of the present invention solve the difficult problem of providing a therapeutically effective sustained plasma concentration of a PDE10A inhibitor by controlling the release of the inhibitor using formulations with zero-order release profiles that extend for more than 12 hours after ingestion.

[005] Several potent PDE10A inhibitors have been described, see, for example, US9,062,059 (incorporated in the present invention in its entirety), US8957077, US8975261, 9,359,348, US9,376,450 and EP2,776,418. However, clinical trials have shown that, without optimization of pharmacokinetic profiles and dose, the benefit of PDE10A inhibitors in the treatment of schizophrenia is confounded by insufficient target engagement and side effects. Understanding the requirements for PDE10A inhibitors constitutes a challenging, but promising, field of invention and drug development.

[006] There is still a need for CR formulations of PDE10A inhibitors with an improved tolerability profile (reduction of adverse events / side effects, e.g., dystonia, akathisia) and patient adherence. SUMMARY OF THE INVENTION

[007] U.S. Patent 9,062,059 discloses potent PDE10A inhibitors, including 2-methyl-N-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-(((15,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine (Compound A), an ester derivative, geometric isomer, stereoisomer, or optical isomer thereof, as a therapeutic for neurological and psychiatric disorders. This disclosure provides CR formulations of Compound A and its use in the treatment Petition 870250087591, dated 09 / 26 / 2025, pages 218 / 254 3 / 34 of schizophrenia and other psychiatric disorders that improve the tolerability profile. One aspect of this disclosure provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders that allow high peak concentrations (Cmax) with minimal or no incidence of dystonia. Another aspect of this disclosure provides CR formulations of Compound A in which the formulation excipients are not dose-dependent. Another aspect of this disclosure provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders that can be dosed at high concentrations without titration. Another aspect of this disclosure provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders that can be administered at doses that provide high peak concentrations (Cmax) with minimal or no incidence of dystonia.Another aspect of this discovery provides controlled-release formulations of Compound A that deliver high peak concentrations (Cmax) and their use in the treatment of schizophrenia and other psychiatric disorders.

[008] This disclosure further provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders where the incidence of dystonia is reduced or eliminated. This disclosure further provides CR formulations of Compound A and their use in the treatment of schizophrenia and other psychiatric disorders where the incidence of dystonia is reduced or eliminated by administering extended doses (16 mg or higher) to ensure that effective concentrations can be maintained throughout the dosing interval. The disclosure further provides CR formulations of Compound A having zero-order or near-zero release profiles, with pharmacokinetic profiles exhibiting minimal fluctuation between peak and trough concentrations, which improves the profile of Petition 870250087591, dated 09 / 26 / 2025, pp. 219 / 254 4 / 34 Tolerability. One aspect of this embodiment is CR formulations of Compound A with PTR starting around 1.0 to around 3.5. One aspect of this revelation is realized when the PTR is from around 1.0 to around 2.0. Another aspect of this revelation is realized when the ratio between the peak concentration and the trough concentration is from around 1.0 to around 1.5. Yet another aspect of this revelation is realized when the ratio between the peak concentration and the trough concentration is from around 1.0 to around 1.3.

[009] Another aspect of the revelation is performed whereby patients are dosed with approximately 20 mg to approximately 80 mg, approximately 17 mg to approximately 47 mg, 20 mg to approximately 36 mg, or approximately 17 mg to approximately 24 mg of CR formulations of Compound A with minimal or no dystonia. One embodiment of this aspect is performed when the CR formulation of Compound A is compared to an immediate-release (IR) formulation of Compound A having the same dose.

[010] Another aspect of the disclosure is realized in that dystonia in healthy participants and / or patients suffering from schizophrenia or other psychiatric disorders are dosed with CR formulations described in the present invention 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 realized when the CR formulation of Compound A is compared to an IR formulation of Compound A having the same dose.

[011] Another aspect of the disclosure is realized in which healthy participants and patients suffering from schizophrenia or other psychiatric disorders are dosed with CR formulations described in the present invention of about 20 mg to about 36 mg, about 20 mg to about 24 mg, or 24 mg of the Compound A CR formulations without titration, whereby the patients experience minimal or no observed dystonia. One embodiment of this aspect is realized when the Compound A CR formulation Petition 870250087591, dated 09 / 26 / 2025, pp. 220 / 254 5 / 34 A is compared to an IR formulation of Compound A having the same dose.

[012] One aspect of the disclosure is CR formulations comprising about 2 mg to about 80 mg of Compound A dosed once daily. Another aspect of the disclosure is CR formulations comprising from 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 a period of about 12-24 hours. Following repeated administration of the composition in an in vivo setting, steady-state plasma Cmax concentrations are achieved in ~10 to 24 hours and are generally sustained throughout the dosing interval. Another aspect of this modality is achieved when Compound A is dosed once daily at doses of approximately 17 mg to approximately 47 mg, approximately 20 mg to approximately 36 mg, or approximately 20 mg to approximately 24 mg, in which the incidence of dystonia is mitigated.Another aspect of this modality is realized when the CR formulation of Compound A is administered once daily without the occurrence of dystonia. Another aspect of this modality is realized when the CR formulation of Compound A is administered at approximately 20 mg to approximately 47 mg once daily, without the occurrence of dystonia.

[013] Another aspect of the revelation is the CR formulations in which the amount of Compound A present in said formulation is estimated to produce generally sustained / constant enzyme occupancy (EO) levels at both the peak and trough of the 24-hour dosing interval (Table 6-9), in contrast to the IR formulation (Table 5). A submodality of this aspect of the revelation is realized when high levels of estimated EO are sustained at both the peak and trough at doses ranging from about 17 mg to about 47 mg, about 20 mg to about 36 mg, or about 20 mg to 24 mg. An aspect of this submodality is realized when Petition 870250087591, dated 09 / 26 / 2025, pp. 221 / 254 6 / 34 Estimated EO levels, both at peak and trough, are sustained above 75% at steady state. Another aspect of this submodality is realized when estimated EO levels, both at peak and trough, are sustained from approximately 65%-99%, 67%-99%, 70%-99%, 80%-99%, 85%-99% at steady state. Another aspect of this submodality is realized when estimated EO levels, both at peak and trough, are sustained from approximately 70% to 99% at doses ranging from approximately 17 mg to 47 mg, or approximately 20 mg to 36 mg, in both the healthy population and the population suffering from schizophrenia without reported dystonia events. Another aspect of this submodality is performed when estimated EO levels, both at peak and trough, are sustained from about 70% to 99% at doses ranging from about 17 mg to 47 mg or 20 mg to 36 mg in patients suffering from schizophrenia without reported dystonia events.Another aspect of this submodality is performed when estimated EO levels are sustained from approximately 70% to 99% at doses ranging from approximately 17 mg to 47 mg or approximately 20 mg to 36 mg in a healthy population without reported dystonia events.

[014] Other aspects of the invention can be realized by reviewing the descriptive report as a whole. BRIEF DESCRIPTION OF THE DRAWINGS

[015] FIG. 1 illustrates the Enzymatic Occupation of PDE10A versus Plasma Concentrations of Compound A after Administration of a Single Oral Dose of the Compound to Healthy Individuals.

[016] FIG. 2 illustrates that the Tmax for the IR formulation of Compound A ranged from 0.5 to 2 he PTR of about 12-17.

[017] FIG. 3 illustrates the in vitro dissolution profiles of CR formulations of Compound A designed to achieve 80% release over periods of 12, 16 Petition 870250087591, dated 09 / 26 / 2025, pp. 222 / 254 7 / 34 and 20 hours, respectively.

[018] FIG. 4 illustrates the pharmacokinetic profiles of CR formulations exhibiting 80% release over periods of 12, 16 and 20 hours.

[019] Several aspects described in the present invention are described in further detail in the following subsections. DETAILED DESCRIPTION OF THE INVENTION

[020] Studies with Compound A and other PDE10A inhibitors have shown activity in assays that support clinical efficacy in the treatment of schizophrenia in enzyme occupancies (EO) >30% (Smith et al., Biological Psychiatry 2022, Volume 91, Issue 9, S309 - S310 and Li, YW, et al., Neuropharmacology. 2016 Mar;102:121-35. doi: 10,1016 / j.neuropharm.2015.10.037. Epub October 30, 2015. PMID: 26522433). Data from a single-dose escalation study and a PET study with an IR formulation of Compound A were used to construct an EO-concentration relationship (Figure 1). These studies in healthy participants demonstrated that administration of IR Compound A (3 mg and 6 mg) achieved estimated EO values ​​at Cmax of ~64% and ~78%, respectively (Table 5), and was rapidly dissipated from the brain within a few hours (estimated EO values ​​at C24 of ~8.9% and ~21%). However, dystonia was reported and appeared to be related to the time to maximum concentration (Tmax).

[021] This disclosure provides compound A CR tablet formulations in which general limitations of psychiatric tolerability, such as dystonia, akathisia, anxiety, depression, nausea, etc., are mitigated and / or eliminated. In particular, compound A CR formulations can be administered once daily at high clinical doses (e.g., 20 mg, 24 mg, 36 mg, etc.) without dystonia. Specifically, the present disclosure provides a CR tablet formulation comprising a Petition 870250087591, dated 09 / 26 / 2025, pp. 223 / 254 8 / 34 1) First layer containing approximately 1%-25% by weight of Compound A: A or a pharmaceutically acceptable salt, derived from an ester, geometric isomer, stereoisomer or optical isomer thereof and about 60-90% by weight of low viscosity polyethylene oxide (PEO) polymer; 2) second layer comprising approximately 50%-70% by weight of high viscosity polyethylene oxide polymer, approximately 10%-40% by weight of metal halide and approximately 5%-30% by weight of tablet-forming agent; 3) a semi-permeable coating wherein the coating comprises approximately 1%-15% by weight of the tablet, said tablet having a hole in the first layer.

[022] One embodiment of this disclosure is carried out in which the percentage of Compound A and low viscosity PEO is relative to the total weight of the first layer, and the percentage of high viscosity PEO, metal halide and tablet-forming agent is relative to the total weight of the second layer.

[023] In one embodiment, Compound A, or its ester derivatives, geometric isomers, stereoisomers or optical isomers thereof, are present in about 4%-25% by weight of the total weight of the first layer, preferably about 5%-15% by weight.

[024] In another embodiment, low viscosity polyethylene oxide (PEO) is any low viscosity PEO with a molecular weight range (g / mol) of about 100,000 to 300,000; preferably 200,000 Petition 870250087591, dated 09 / 26 / 2025, pp. 224 / 254 9 / 34 g / mol. A sub-emphasis of this aspect is realized when low viscosity PEO is present at about 65%-88% by weight of the total weight of the first layer, preferably about 70%-88% by weight.

[025] In another embodiment, high viscosity polyethylene oxide (PEO) is any high viscosity PEO with 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 subemphasis of this aspect is carried out when the high viscosity PEO is present in about 50%-70% by weight of the total weight of the second layer, preferably about 60%-68% by weight.

[026] Tablet-forming agent is any agent known in the state of the art used for long-term drug stabilization, volume increase of solid dose formulations, and intensification of the therapeutic effects of drugs. In one embodiment, a tablet-forming agent selected from lactose, spray-dried lactose, microcrystalline cellulose (e.g., Avicel PH101 and PH102), mannitol (e.g., Perlitol SD200), sorbitol, dehydrated dibasic calcium phosphate, dehydrated calcium sulfate, and the like, preferably microcrystalline cellulose, is optionally present in the second layer. A sub-embodiment of this aspect is realized when the tablet-forming agent is present in about 0%-25% by weight of the total weight of the second layer, preferably about 10%-20% by weight.

[027] 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, wherein the sodium chloride is present as a powder. A subemphasis of this aspect is carried out when the metal halide is present in about 10%-40% by weight of the total weight of the second layer, preferably about 15%-25% in Petition 870250087591, dated 09 / 26 / 2025, pages 225 / 254 10 / 34 weight.

[028] Typical semipermeable polymers, known in the state of the art as osmosis and reverse osmosis membranes, are cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, acetaldehyde dimethyl acetate, ethyl carbamate-cellulose acetate, polyamides, polyurethanes, sulfonated polystyrenes, cellulose phthalate-cellulose acetate, cellulose methyl carbamate-cellulose acetate, cellulose succinate-cellulose acetate, cellulose acetate, dimethylaminoacetate, ethyl carbamate-cellulose acetate, cellulose chloroacetate-cellulose acetate, cellulose dipalmatate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanoate, cellulose valerate-acetate, cellulose succinate-acetate, cellulose succinate-propionate, methylcellulose, p-toluene sulfonate-cellulose acetate, cellulose butyrate-acetate,Selectively semipermeable crosslinked polymers formed by the coprecipitation of a polyanion and a polycation, as 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, semipermeable polymers, as disclosed by Loeb and Sourirajan in U.S. Patent No. 3,133,132, lightly crosslinked polystyrene derivatives, crosslinked poly(styrene sulfonate sodium), poly(vinylbenzyltrimethyl ammonium 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 to 2 and an acetyl content of 21 to 35%, cellulose triacetate 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.

[029] In one embodiment, the semipermeable coating is selected from the group comprising cellulose acetate, ethylcellulose, or a combination thereof. A subemphasis is carried out when the Petition 870250087591, dated 09 / 26 / 2025, pages 226 / 254 11 / 34 The semipermeable coating comprises a blend of cellulose acetate, ethylcellulose, or a blend thereof, and low molecular weight polyethylene glycol. In one aspect of this sub-embodiment, 1%-15%, preferably 5%-15%, by weight of the semipermeable coating tablet core comprises cellulose acetate, ethylcellulose, or a blend thereof, with about 5%-20%, preferably 5%-10%, by weight of the low molecular weight polyethylene glycol coating. In one aspect of this embodiment, the polyethylene glycol has a molecular weight range from about 600-10,000 g / mol, preferably about 3,000 to about 4,000 g / mol, more preferably about 3,350 g / mol.

[030] In another form, the hole is about 0.1 to 1 mm in diameter.

[031] In one embodiment of the CR tablet formulation, Compound A, or a pharmaceutically acceptable salt derived from an ester, geometric isomer, stereoisomer, or optical isomer thereof, is present at about 4%–25% by weight of the total weight of the first layer; low-viscosity polyethylene oxide (PEO) has a molecular weight range (g / mol) of about 100,000 to 300,000 and is present at about 65%–88% by weight of the total weight of the first layer; 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 at 60%–68% by weight of the total weight of the second layer. A subemphasis of this aspect is carried out when the tablet-forming agent is not present. A sub-modality of this aspect is realized when the tablet-forming agent is present at up to about 25% by weight of the total weight of the second layer, preferably about 10%-20% by weight.Another sub-modality of this aspect is performed when the metal halide is present in approximately 15%. Petition 870250087591, dated 09 / 26 / 2025, pages 227 / 254 12 / 34 25% by weight of the total weight of the second layer, preferably 15%-20% by weight. Another sub-embodiment of this aspect is realized when 5%-15% by weight of the semi-permeable coating tablet core is present and comprises cellulose acetate, ethylcellulose or a blend thereof, containing about 5%-20%, preferably 5%-10%, by weight of the low molecular weight polyethylene glycol coating. It should be noted that the tablet composition percentages are based on the total weight of each layer separately, where the total weight of each layer is 200 mg in Example 2 and 100 mg in Example 3.

[032] In one embodiment of the CR tablet formulation, compositions containing a ratio of low viscosity PEO to high viscosity PEO of 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, are disclosed. In another embodiment of the CR tablet formulation, compositions containing a ratio of high viscosity PEO to metal halide of about 10:1 to about 1:0, respectively, are disclosed, preferably a ratio selected from about 5:1, 4:1, 3:1, 2:1 and 1:0, respectively. In another embodiment of the CR tablet formulation, compositions containing a cellulose to metal halide ratio of about 0:1 to about 1:1.6, respectively, are disclosed, preferably about 1:1.1, 1:1.2, 1:1.3 or 1:1.4, respectively.In one aspect of this embodiment, approximately 5%-15% of the total coating weight (relative to the total tablet weight) of the cellulose acetate + polyethylene glycol blend is present.

[033] Another embodiment of the CR formulation is carried out when an alcohol sugar is optionally present in the formulation. A sub-embodiment of this aspect of the invention is carried out when the alcohol sugar Petition 870250087591, dated 09 / 26 / 2025, pages 228 / 254 13 / 34 present is selected from mannitol, sucrose, lactose. Another sub-embodiment of this aspect of the invention is carried out when the sugar alcohol is mannitol. Another sub-embodiment of this aspect of the invention is carried out when the controlled-release formulation in the presence of mannitol in the first layer distributes Compound A in a resistance of up to 12 mg for a period from about 12 to 24 hours after placing the composition in an in vivo environment.

[034] Another embodiment of CR formulation is carried out when it comprises additional excipients, as needed, to ensure manufacturability, stability or in vivo performance of the final dosage form. In one embodiment, 0%-2% of lubricating agents are present, such as magnesium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium stearyl fumarate, preferably magnesium stearate.

[035] When preparing the tablet, the second layer may contain a lacquer or dye to enable visual differentiation between the tablet layers as a means of ensuring that the hole is punched on the correct face of the coated tablet. Examples of useful dyes are Red Iron Oxide, Yellow Iron Oxide, Black Iron Oxide and / or FD&C Blue No. 2 lake.

[036] The CR coated tablet formulation described above may be further coated with a film coating for the purpose of modifying the appearance or color of the formulation, but without further modifying the release rate of the active ingredient from the formulation. The film coating may be composed of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and / or polyvinyl alcohol-polyethylene glycol copolymer, together with plasticizers, opacifiers and / or colorants.

[037] One aspect of this CR formulation is realized when it is Petition 870250087591, dated 09 / 26 / 2025, pages 229 / 254 14 / 34 dosed at high doses, including initial doses up to 48 mg, up to approximately 80 mg with moderate titration. Another aspect of this CR formulation is realized when it is dosed at high doses up to approximately 80 mg without titration. Another submodality of this aspect of the development are Compound A CR formulations that can be administered once daily in a clinical dose range of approximately 17 mg to approximately 47 mg, preferably approximately 20 mg to approximately 36 mg, approximately 20 mg to approximately 24 mg, and most preferably 24 mg without dystonia. DEFINITIONS

[038] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by a person skilled in the art. Generally, the nomenclature used in the present invention and the laboratory procedures in polymer chemistry, pharmaceutical science, drug delivery, pharmaceutical process technology and pharmacokinetics are those well known and commonly employed in the state of the art.

[039] As used in the present invention, the articles “a” and “an” refer to one or more of (i.e., at least one) of the grammatical object of the article. By way of example, an element means one or more elements. Furthermore, the use of the term including, as well as other forms such as include, includes and included, is not limiting.

[040] All ranges disclosed in the present invention include the recited endpoint and are combinable independently (for example, the range from 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 in the present invention are not limited to the precise range or value; they are sufficiently imprecise to include values ​​that approximate those ranges. Petition 870250087591, dated 09 / 26 / 2025, pages 230 / 254 15 / 34 and / or values.

[041] As used in the present invention, the term comprising may include embodiments consisting of and consisting essentially of. The terms comprise(s), include(s), having, has, may, contains and variants thereof, as used in the present invention, are intended to be open phrases, terms or transitional words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such a description should also be interpreted as describing compositions or processes as consisting of and consisting essentially of enumerated components, which permits the presence only of the named components or compounds, together with any acceptable carriers or fluids, and excludes other components or compounds.

[042] By “pharmaceutically active agent”, “active ingredient”, “medicine” or “beneficial agent” is meant Compound A and pharmaceutically acceptable salts thereof, and derivatives that produce a similar localized or systemic effect or effects in animals. Derivatives of the active ingredient, such as esters, ethers and amides, regardless of their ionization and solubility characteristics, may be used alone or blended with other compounds. Also, prodrugs of the active agent may be used in a form that, after release from the tablet, is converted by enzymes, hydrolyzed by body pH or converted by other metabolic processes, into the original form or into a biologically active form. That is, prodrugs are specifically included within the definition of pharmaceutically active ingredients. Compositions such as those having separate racemic blends and enantiomers of the active ingredient are included within the scope of the present invention.Additionally, carbohydrates, like that. Petition 870250087591, dated 09 / 26 / 2025, pp. 231 / 254 16 / 34 as anhydrous compositions and polymorphs of the active ingredient, may be included in the compositions of the present invention.

[043] The term “pharmaceutically acceptable salts” means non-toxic salts of the active ingredients that are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, esylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, valerate.

[044] As used throughout the descriptive report and attached claims, the following definitions and abbreviations apply: Approximately: As used in the present invention, the term "approximately," when used in the present invention in reference to a value, refers to a value that is the same as, or in the context is more or less than, 10% of the referenced value, for example, "approximately 5" means "4.5-5.5." In general, those skilled in the art, familiar with the context, will appreciate the absolute amount and / or the relative degree of difference encompassed by approximately in that context.

[045] Administration: As used in the present invention, the term "administration" refers to the act of providing an active agent, composition, or formulation to an individual. Examples of routes of administration to the human body may be through the eyes (ophthalmic), mouth (oral), skin (transdermal), nose. Petition 870250087591, dated 09 / 26 / 2025, pages 232 / 254 17 / 34 (nasal), lungs (inhalants), rectal, vaginal, oral mucosa (buccal), ear, by injection (e.g., intravenously (IV), subcutaneously, intratumorally, intraperitoneally, intramuscularly (IM), intradermally (ID), etc.) and similar methods.

[046] Agent: As used in the present invention, the term agent refers to a particle, compound, molecule or entity of any chemical class, including, for example, a small molecule or a combination or complex thereof. In some embodiments, the term agent may refer to a compound, molecule or entity that includes a polymer or a plurality thereof.

[047] API: As used in the present invention, the term API refers to an active pharmaceutical ingredient, for example, a PDE10 inhibitor, which is a component of the compositions or formulations disclosed in the present invention that is biologically active and confers a therapeutic or prophylactic benefit to a person or animal in need thereof. As used in the present invention, an API is Compound A as the active ingredient.

[048] Biocompatible: As used in the present invention, the term biocompatible refers to a material that is not toxic to the body, is pharmaceutically acceptable and is not carcinogenic.

[049] Controlled Release (CR): As used in the present invention, controlled release refers to a dosage form that is manipulated to deliver an active agent or other type of substance into the body at a particular rate over time. The release rate of the pharmaceutically active ingredient from the device (capsule, pill, tablet, etc.) to the environment of use is not immediate, but follows a predetermined pattern. Thus, relatively constant or predictably variable amounts of the beneficial agent can be released by a Petition 870250087591, dated 09 / 26 / 2025, pages 233 / 254 18 / 34 specified time period.

[050] Dose: As used in the present invention, the term dose means an amount of an agent, API, formulation or pharmaceutical composition administered or recommended to be administered at a particular time.

[051] Mitigate: As used in the present invention, the term mitigate or mitigated means to make less severe or to reduce.

[052] Patient: As used in the present invention, the term patient refers to any human being who will receive the pharmaceutical compositions described in the present invention.

[053] Pharmaceutically acceptable: As used in the present invention, the term pharmaceutically acceptable refers to excipients (vehicles, additives) and compositions that can reasonably be administered to an individual to provide an effective dose of the active ingredient employed and that are generally considered safe, for example, that are physiologically tolerable and typically do not produce an allergic or similar unforeseen reaction, such as gastric discomfort and the like, when administered to a human being. In another embodiment, this term refers to molecular entities and compositions approved by a federal or state government regulatory agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans.

[054] Pharmaceutical composition: As used in the present invention, the term pharmaceutical composition refers to a composition containing an active pharmaceutical or biological ingredient, together with one or more additional components, for example, a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. Petition 870250087591, dated 09 / 26 / 2025, pages 234 / 254 19 / 34 As used in the present invention, 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 appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a 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, bulking agents, osmotic agents, stabilizers, lipoprotectors, solubilizers, emulsifiers, salts, adjuvants, tonicity-enhancing agents, delivery vehicles, and antimicrobial preservatives. The pharmaceutical compositions or formulations are not toxic to receptors at the dosages and concentrations employed.

[055] Steady State: the time at which the rate of drug uptake equals the rate of drug elimination (i.e., in a state of equilibrium).

[056] Individual: As used in the present invention, the term “individual,” also referred to as “participant” or “patient,” refers to an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, an individual suffering from a relevant disease, disorder, or condition. In some embodiments, an individual is susceptible to a disease, disorder, or condition. In some embodiments, an individual exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, an individual does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, an individual is someone with one or more characteristic attributes of susceptibility or risk of Petition 870250087591, dated 09 / 26 / 2025, pages 235 / 254 20 / 34 a disease, disorder, or condition. In some modalities, an individual is a patient. In some modalities, an individual is an individual to whom the diagnosis and / or therapy is and / or has been administered.

[057] Therapeutically Effective Amount: As used in the present invention, the term “therapeutically effective amount” refers to an amount of the active ingredient (e.g., small molecule) sufficient to produce the desired therapeutic effect in a human or animal, for example, the amount necessary to elicit treatment, cure, prevent or inhibit the development and progression of a disease or its symptoms and / or the amount necessary to alleviate 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 contemplated mode of administration. A person skilled in the art can readily determine a therapeutically effective amount of a given molecule.

[058] Viscosity: As used in the present invention, viscosity refers to the 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 shear rate or shear rates that are appropriately selected by those skilled in the art to be relevant to the viscosity range of the sample of interest.

[059] Volume % or % by volume: As used in the present invention, the terms “volume %” or “% by volume” refer to parts by volume per hundred parts of the total volume of the polymer carrier, for example, microparticle, microsphere or minitab. Unless otherwise indicated, the percentages (%) reported in the present invention are by volume.

[060] % by weight or % by weight: As used in the present invention, the terms “% by weight” or “% by weight” refer to parts by weight per hundred parts. Petition 870250087591, dated 09 / 26 / 2025, pages 236 / 254 21 / 34 of the total weight of the carrier volume, for example, mixture, carrier, powder, particle, granulation. For example, 10% by weight of active agent would mean 10 parts of active agent by weight and 90 parts of carrier by weight.

[061] The following examples illustrate the preparation of the drug in the delivery device (e.g., tablet, capsule, etc.) of this invention and the controlled release of the active ingredient Compound A in a use environment and should not be considered as limiting the invention set forth in the appended claims.

[062] The dosage regimen using the compositions of the present invention is selected according to a variety of factors, including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular active ingredient or salt thereof employed. A physician or veterinary expert in the field can readily determine and prescribe the effective amount of the drug required to prevent, combat or halt the progression of the condition.

[063] Another aspect of the disclosure is the CR formulations of Compound A which can be administered in doses up to 80 mg with good tolerability, whereas the immediate-release formulation of Compound A was not expanded above 6 mg (Study 6) due to dystonia and neuropsychiatric adverse events. On the other hand, safety and tolerability data after administration of Compound A at 80 mg in the CR formulation of the present disclosure did not result in adverse events that would preclude further dose escalation. EXAMPLES

[064] In the following examples, Compound A is the active ingredient. The compositions were prepared using the ingredients, quantities and Petition 870250087591, dated 09 / 26 / 2025, pages 237 / 254 22 / 34 formulation procedures to follow. EXAMPLE 1 - Immediate-Release Formulation Table 1 Ingredients: Anhydrous Microcrystalline Cellulose, Dibasic Calcium Phosphate, Croscarmellose Sodium, Magnesium Stearate. Hard Gelatin Capsule, Size 3. TOTAL: Formula Unit (mg) 1.000 57.27 114.5 5.400 1.800 180.0

[065] The immediate-release formulation in Example 1 was prepared as follows: Compound A was triturated with a portion of dibasic calcium phosphate. This triturate was sequentially mixed with a portion of microcrystalline cellulose, and then with the remaining dibasic calcium phosphate, microcrystalline cellulose, and croscarmellose sodium; this mixture was further lubricated with magnesium stearate. The lubricated mixture was then placed in capsules. EXAMPLE 2 - Controlled-Release Formulation: Table 2 %(weight) Tablet Core Ingredients Formula % (weight) Example 2 Unit (mg) Layer 1 Compound A 12.00 6 Polyethylene Oxide, WSR N80 LEO 145.5 72.5 Mannitol 200 SD 41.50 21 Magnesium Stearate 1.000 0.5 Total Weight of Layer 1 200.0 100 Layer 2 Polyethylene Oxide, Coagulant WSR 129.6 65 LEO Dye, FD&C Blue No. 2 (Indigo Carmine, E132) 0.600 0.3 Aluminum Lake Cellulose, microcrystalline, PH-200 28.80 14.2 Sodium Chloride 40.00 20 Magnesium Stearate 1.000 0.5 Petition 870250087591, dated 09 / 26 / 2025, pages 238 / 254 23 / 34% (weight) Tablet Core Ingredients Formula % (weight) Example 2 Unit (mg) Total Weight of 2s Layer 200.0 100 Total Weight of Tablet Core 400.0 Coating - (mg) Polyethylene glycol 3350 4.900 10 Cellulose acetate CA-398-10 44.10 90 Coating Weight 49.00 100 Total 449.0 EXAMPLE 3 - Controlled-release formulation (lower tablet core weight (100 mg per layer)) Table 3 %(weight) Tablet Core Ingredients Unit Formula % (weight) Example 3 (mg) Layer 1 Compound A 2.00 2 Polyethylene Oxide, WSR N80 LEO 76 76 Mannitol 200 SD 21.50 21.5 Magnesium Stearate 0.5 0.5 Total Weight of Layer 1 100.0 100 Layer 2 Polyethylene Oxide, Coagulant WSR LEO 64.8 64.8 Dye, FD&C Blue No. 2 (Indigo Carmine, E132) 0.300 0.3 Aluminum Lake Microcrystalline Cellulose, PH-200 14.40 14.4 Sodium Chloride 20.00 20 Magnesium Stearate 0.500 0.5 Total Weight of 2s Layer 100.0 100 Total Tablet Core Weight 200.0 Coating (mg) Polyethylene Glycol 3350 4.400 10 Cellulose Acetate CA-398-10 39.60 90 Coating Weight 44.00 100 Total 244.0

[066] The CR tablet formulations in Examples 2 and 3 below were prepared as follows: Petition 870250087591, dated 09 / 26 / 2025, pages 239 / 254 24 / 34 Layer 1, Compound A, low molecular weight PEO and mannitol were premixed, further mixed with a portion of magnesium stearate, roller-compacted, milled, and mixed with the remaining magnesium stearate. In Layer 2, high molecular weight PEO, microcrystalline cellulose, sodium chloride, dye, and magnesium stearate were mixed. The Layer 1 and Layer 2 mixtures were compressed to form bilayer tablets. Cellulose acetate and polyethylene glycol were dissolved in an acetone:water solvent system (31:1 ratio) and coated onto the cores of bilayer tablets using a perforated pan tablet coater until the target coating weight was achieved. The coated tablets were perforated with a single hole in the Layer 1 face of each tablet using a laser drill. The tablets were dried at 40 °C to remove residual acetone.Bilayer tablets may consist of two layers of equal weight, or the weights of the layers may be up to 2 times different, for example, from 100:200 mg to 200:100 mg. The total tablet weight may vary from 200 to 600 mg. The total coating weight may be from 25 to 75 mg by weight per tablet, depending on the size and surface area of ​​the tablet core and the permeability of the coating, which may be modulated by the amount of PEG included in the coating.

[067] The controlled-release formulations given by Example 2 and Example 3 exhibited an increase in unit ejection force (values ​​exceeding approximately 1.0-1.5 N / mm2) during compression of the bilayer tablet where the level of Compound A in the Layer 1 granulation exceeded 6%. Such higher unit ejection forces are undesirable in tablet compression. Unexpectedly, the removal of mannitol from Layer 1 and its replacement with low molecular weight PEO, as shown in Example 3, Petition 870250087591, dated 09 / 26 / 2025, pages 240 / 254 25 / 34 below, mitigated this effect, resulting in unit ejection forces consistently below 1 N / mm2, even at Compound A levels of up to approximately 25% in the Layer 1 granulation. EXAMPLE 4 Table 4 Tablet Core Ingredients Formula %(weight) Example 4 Unit (mg) Layer 1 Compound A 24.00 12 Polyethylene Oxide, WSR N80 LEO 175 87.5 Magnesium Stearate 1.000 0.5 Total Weight of Layer 1 200.0 100 Layer 2 Polyethylene Oxide, Coagulant WSR LEO 129.6 65 Dye, FD&C Blue No. 2 (Indigo Carmine, 0.6000 0.3 E132) Aluminum Lake Microcrystalline Cellulose, PH-200 28.80 14.2 Sodium Chloride Powder 40.0 20 Magnesium Stearate 1.00 0.5 Total Weight of Layer 2 200.0 100% Total global 400.0 Coating (mg) Polyethylene glycol 3350 4.900 10 Cellulose acetate CA-398-10 44.10 90 Coating weight 49.00 100 Total 449.0

[068] The controlled-release formulation of Example 4 was prepared as follows: Compound A was passed through a #20 mesh screen to disaggregate it, the low molecular weight PEO was passed through a sieving mill (e.g., U20 Comil) fitted with a suitably sized screen (e.g., 7C075R) operating at approximately 1000 rpm. The Layer 1 ingredients were then mixed in a 3 cubic foot blender for 195 revolutions. Half of the magnesium stearate charge from Layer 1 was sieved through a #60 mesh screen to disaggregate it and added to Petition 870250087591, dated 09 / 26 / 2025, pp. 241 / 254 26 / 34 blender with the other ingredients of Layer 1 and mixed for 90 revolutions to lubricate. The Layer 1 mixture was granulated using a roller compactor (e.g., Gerteis TG87) equipped with serrated rollers and a 1 mm square mesh granulator and operated at a roller speed of approximately 2-4 rpm, a roller force of approximately 4-5 kN / cm and a gap of 2 mm. The remaining magnesium stearate from Layer 1 was sieved through a No. 60 mesh screen to disaggregate and loaded into the 3 cubic foot blender with the Layer 1 granulation and mixed for 90 revolutions to lubricate. The excipients of Layer 2, except for the magnesium stearate, were sieved through a No. 30 mesh screen to disaggregate. The excipients from layer 2 were mixed in a 3 cubic foot blender at 65 rotations.The mixture was passed through a sieve mill (e.g., U20 Comil) fitted with a suitably sized screen (e.g., 7C075R) and operated at approximately 1000 rpm. The materials were further mixed in a 3 cubic foot blender at 130 rpm. Magnesium stearate was passed through a No. 60 mesh screen to disaggregate, added to the blender with the other Layer 2 excipients, and mixed at 90 rpm to lubricate. The lubricated Layer 1 and Layer 2 mixtures were compressed using a suitable multilayer tablet press fitted with standard 3 / 8 in. round convex compression tools, directing layer weights of 200 mg each and a tablet thickness of approximately 5.7 mm.An excess of coating solution containing cellulose acetate:PEG 3350 in a 9:1 ratio in an acetone:water solvent system at a 31:1 ratio and with a solids loading of approximately 5% w / w was prepared by dispersing the PEG 3350 in water, combining it with acetone, and slowly adding the cellulose acetate. Petition 870250087591, dated 09 / 26 / 2025, pages 242 / 254 27 / 34 stirring to dissolve. Tablet cores were coated with cellulose acetate:PEG 3350 to a target weight gain of 49 mg / tablet using a suitable pan coater operating at an air inlet temperature of approximately 40 °C, an outlet temperature of approximately 25 °C, a solution spray rate of approximately 45–60 g / minute per spray gun, and a gun-to-bed distance of approximately 4 in. A 1 mm diameter and 0.25 mm deep hole was drilled in the center of the Layer 1 face of each tablet using a suitable laser drill (e.g., CMS TT15). The drilled tablets were tray-dried for approximately 36 hours at 40 °C using a suitable drying oven to remove excess acetone.

[069] CR formulations of Compound A were developed and evaluated to determine if sufficient EO could be maintained using once-daily dosing with a slower-rising and more sustained pharmacokinetic profile. Compared to the IR formulation in Study 6 (Table 5), in Study 4, a single-dose study that evaluated the pharmacokinetics and tolerability of Compound A, the CR formulation exhibited a delayed Tmax (10-24h), a shallower PTR (~1.3), and consequently, a sustained EO between peak and trough (Table 6).

[070] The CR formulations of Compound A were further evaluated in three multiple-dose studies with treatment durations of 7 to 18 days in adult participants with schizophrenia, and in two of these 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 7) and participants with schizophrenia (n=14 - Table 8)) were titrated from doses of 2 mg to Petition 870250087591, dated 09 / 26 / 2025, pages 243 / 254 28 / 34 mg as monotherapy or from 2 or 4 mg up to 16 mg (n=19) as adjunctive therapy (only participants with schizophrenia) to prescribed antipsychotic therapy.

[071] Study 2 was designed similarly to Study 1; participants were administered CR-release formulations of Compound A / placebo as monotherapy in participants with schizophrenia (n=16) and healthy participants (n=16), or as adjunctive therapy (n=17) (only participants with schizophrenia) and titrated from 4 mg to 24 mg (see Table 7 for an illustration of pharmacokinetics at the 24 mg dose level as monotherapy in healthy adults). In Study 2, an additional panel of participants with schizophrenia received CR-release formulations of Compound A / placebo as monotherapy and titrated from 8 mg to 48 mg (n=26) (see Table 8 for an illustration of pharmacokinetics at the 48 mg dose level).

[072] In Study 3, a panel of participants [(n=8) - monotherapy in adult participants with schizophrenia] was titrated from 16 mg to 24 mg or placebo, while in another panel, participants (n=18) received 24 mg / placebo without titration (Table 9) to determine if titration was required for tolerability.

[073] Overall, Compound A CR formulations were generally well tolerated in participants with schizophrenia as monotherapy and as adjunctive therapy throughout Studies 1 to 3 and dose titrations. In Study 1 (Table 8), dystonia was reported in 5 of 33 (15%) participants with schizophrenia who received Compound A CR formulations (3 after monotherapy [1 after 2 mg, 4 mg, and 12 mg] and 2 after adjunctive therapy [8 mg, 16 mg]). All events responded promptly to benzotropine.

[074] In Study 2, when doses were titrated from 4 mg to 24 mg and from 8 mg to 48 mg, no Compound-related dystonia Petition 870250087591, dated 09 / 26 / 2025, pp. 244 / 254 29 / 34 A was observed. Cmax values ​​of ~1800 nM and C24 of ~1200 nM were achieved at the highest dose level in Study 2 (Table 8), substantially higher than the 376 nM Cmax associated with dystonia in healthy participants in Study 6 (IR formulation - Table 5).

[075] In Study 3, Compound A was generally well tolerated when dosing was initiated at 16 mg (data not shown in Table 9) or 24 mg without titration, with pharmacokinetic estimates similar to those previously observed for the CR formulation (see Table 9 for pharmacokinetics of the 24 mg dose without titration). There were 2 transient dystonia events after the first 16 mg dose, but both events responded to treatment, and participants continued dosing without recurrence. No dystonia events were reported when dosing was initiated at 24 mg without titration (Table 9). Other adverse events (i.e., depression, anxiety, and stress) across the three studies were mostly of mild or moderate intensity, and there was no clear dose-related increase in specific events (Table 10).

[076] Unexpectedly, throughout Study 1 and Study 2, in healthy participants, tolerability improved at doses up to approximately 47 mg. Furthermore, in Study 2, participants with schizophrenia did not experience dystonia at doses from approximately 4 mg to 48 mg, although the maximum and minimum concentration values ​​(Cmax and C24) and the EO calculated at Cmax and C24 (Table 8) were similar to or higher than those associated with dystonia in the study with the IR formulation (Table 5). Similar trends in sustained exposures and occupancy estimates were also observed in participants with schizophrenia who received Compound A as monotherapy in Study 1 and Study 2 (Table 8). Exposures of the CR formulation of Compound A and sustained EO estimates Petition 870250087591, dated 09 / 26 / 2025, pp. 245 / 254 Results in participants with schizophrenia who received adjunctive therapy were similar to those in participants who received monotherapy.

[077] Overall, studies 1 to 3 also showed that, in both healthy participants and participants with schizophrenia, tolerability was improved, as doses from about 17 mg to about 47 mg did not result in dystonia. Additionally, there were no reports of dystonia after administration of the CR formulation up to 12 mg (n=9) and 24 mg (n=12) in healthy participants.

[078] In another study, Study 4 (a single-dose study evaluating the slower and faster intermediate CR formulations), all subjects received a single 2 mg dose of Compound A four times (4 treatment periods) under fasting conditions, where treatment was provided after an 8-hour overnight fast and fasting continued until 4 hours after dosing. The observed Tmax range was 6-16 hours, 10-24 hours, and 20-24 hours for the faster, intermediate, and slow-release CR formulations, respectively, administered in the fasting state. The PTR for the intermediate CR formulation was ~1.3 (Table 6).

[079] In another study, Study 5 (no table illustration), with approximately 54 participants who received the 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 Day 1 and Day 2 and 80 mg on Day 3, only 2 participants reported dystonia after 48 mg of compound A. Overall, with the CR formulation over a dose range of 20 mg to 80 mg, 2 of ~82 (2.4%) participants reported compound A-related dystonia, which is significantly less than that seen with the IR formulation (Note: preliminary study results).

[080] In a study of an IR formulation of Compound A (Study 6), Petition 870250087591, dated 09 / 26 / 2025, pages 246 / 254 31 / 34 where pharmacokinetics and tolerability were evaluated (Table 5), although no healthy participants reported dystonia after the 1 mg dose, after 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 1 hour and 10 minutes, 1 hour and 27 minutes, and 1 hour and 31 minutes after the dose. After the 6 mg dose, dystonia began 3 hours and 50 minutes after the dose. This participant also reported depressive feelings and nightmares. Another individual also reported depressive feelings, anxiety, and stress. Due to these adverse events, it was decided not to further increase the dose.

[081] Based on the EO-concentration relationship, CR doses of Compound A of 24 mg or higher are expected to produce sustained EO of approximately 65%, 77%, or 80% or higher at steady state, which is superior to the EO associated with the IR formulation. Surprisingly, the high levels of sustained EO achieved by the CR formulation were not associated with an increase in dystonia. No dystonia events were reported in healthy participants in Study 1 and Study 2, and in participants with schizophrenia (across Studies 1, 2, 3, and 5), dystonia was observed with a much lower incidence—approximately 2% (2 participants out of approximately ~82) at doses ranging from 20 mg to 80 mg. Even more surprising is that no dystonia events were reported with the high levels of sustained EO achieved by the CR formulation at doses ranging from 17 mg to 47 mg in both healthy participants and participants with schizophrenia.These findings suggest that a sustained high EO can be achieved by the CR formulation of Compound A, with an unexpectedly favorable tolerability profile with respect to dystonia.

[082] In another study with healthy individuals, Study 7 (without Petition 870250087591, dated 09 / 26 / 2025, pages 247 / 254 32 / 34 illustration in table), healthy individuals were dosed from 8 mg / placebo to 72 mg / placebo (n = 12), with no reports of dystonia up to and including doses of 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 5: Summary Statistics of Pharmacokinetics and Calculated %EO of IR Formulation in Healthy Adults (Study 6) Dose (mg) AUC0-inf a (nM*hr) Cmax (nM)a Tmax (h)b C24 (nM)a PTR Cmax EO (%) C24 EO (%) 1 1020 (46) 141 (30) 1.50 8.06 (120) 17.5 40 3.6 3 2800 (27) 376 (17) 0.875 21.3 (91) 17.6 64 8.9 6 6490 (33) 759 (18) 1.13 59.8 (74) 12.7 78 21 The values ​​a represent the geometric mean (%CV) The values b represent the average time PTR: Peak-to-Trough Concentration Ratio EO: Enzyme Occupation Table 6: Summary Statistics of Pharmacokinetics and Calculated %EO of CR Formulation in Healthy Adults (Study 4) Dose (mg) AUC0-inf a (nM*hr) Cmax (nM)a Tmax (h)b C24 (nM)a PTR Cmax EO (%) C24 EO (%) 2 1280 (32) 56.7 (33) 20.00 43.7 (38) 1.3 21 17 The a values ​​represent the geometric mean (%CV) The b values ​​represent the time-averaged PTR: Peak-to-Trough Concentration Ratio EO: Enzyme Occupation Table 7: Summary Statistics of Pharmacokinetics and Calculated %EO of CR Formulation in Healthy Adults Study Dose (mg) Day AUC0-24a (nM*h) Cmax (nM)a Tmax (h)b C24 (nM)a PTR Cmax EO (%) C24 EO (%) 1 12 14 9820 (21.9) 519 (14.2) 11.00 375 (28.0) 1.38 71 63 2 24 16 15600 (36.1) 807 (34.0) 13.99 625 (39.7) 1.29 79 74 18 13600 (59.6) 741 (48.0) 11.99 433 (111.3) 1.71 77 62 Petition 870250087591, dated 09 / 26 / 2025, pp. 248 / 254 33 / 34 Table 8: Summary Statistics of Pharmacokinetics and Calculated %EO of CR Formulation as Monotherapy in Adult Participants with Schizophrenia Study Dose (mg) Day AUC024a (nM*h) Cmax (nM)a Tmax (h)b C24 (nM)a PTR Cmax EO (%) C24 EO (%) 1 12 14 12300 (27.0) 628 (28.5) 16 459 (33.4) 1.37 74 68 2 24 (Panel B) 16 24600 (36.6) 1250 (37.7) 10.09 949 (45.7) 1.32 85 82 18 26600 (38.3) 1300 (36.8) 12.05 1010 (47.5) 1.29 86 83 48 (Panel D) 13 31800 (54.5) 1670 (51.9) 16.02 1370 (47.5) 1.22 88 86 15 34400 (66.5) 1890 (52.9) 16.02 1160 (97.8) 1.63 89 81 The values ​​a represent the geometric mean (%CV) The values ​​b represent the mean time PTR: Peak-Trough Concentration Ratio EO: Enzyme Occupation Table 9: Summary Statistics of Pharmacokinetics and Calculated %EO of CR Formulation as Monotherapy without Titration in Adult Participants with Schizophrenia (Study 3) Dose (mg) Day AUC0-24a (nM*h) Cmax (nM)a Tmax (h)b C24 (nM)a PTR Cmax EO (%) C24 EO (%) 24 7 19500 (48.1) 1110 (46.7) 11.03 677 (52.2) 1.63 83 75 The values ​​a represent the geometric mean (%CV) The values ​​b represent the time-averaged PTR: Peak-to-Trough Concentration Ratio EO: Enzyme Occupation Table 10 Participants with Non-Serious Related Adverse Events (Part 1) Panel B: Participants with Schizophrenia - Young Adults) (Incidence > 0% in One or More Treatment Groups Screening Compound A 24mg Placebo Total n (%) n (%) n (%) n (%) Participants in the population with one or more Adverse Events 18 14 4 18 Related Adverse Events not Serious 0 (0.0) 5 (35.7) 0 (0.0) 5 (27.8) without Related Adverse Events not Serious 18 (100.0) 9 (64.3) 4 (100.0) 13 (72.2) Petition 870250087591, dated 09 / 26 / 2025, pp. 249 / 254 34 / 34 Screening Compound A 24mg Placebo Total n (%) n (%) n (%) n (%) Investigations 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Increased alanine aminotransferase 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Metabolism and nutrition disorders 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Decreased appetite Musculoskeletal and connective tissue disorders 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Musculoskeletal stiffness 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Nervous system disorders 0 (0.0) 3 (21.4) 0 (0.0) 3 (16.7) Hypertonia 0 (0.0) 1 (7.1) 0 (0.0) 1 (5.6) Drowsiness 0 (0.0) 2 (14.3) 0 (0.0) 2 (11.1) Post-experimentation n (%) Participants in the population 18 with one or more Non-Serious Related Adverse Events 0 (0.0) without Non-Serious Related Adverse Events 18 (100.0) Investigations 0 (0.0) Increased alanine aminotransferase 0 (0.0) Metabolism and nutrition disorders 0 (0.0) Decreased appetite 0 (0.0) Musculoskeletal and connective tissue disorders 0 (0.0) Musculoskeletal stiffness 0 (0.0) Nervous system disorders 0 (0.0) Hypertonia 0 (0.0) Sleepiness 0 (0.0) Each participant is counted only once for each applicable row and column. The adverse events listed under Post-trial refer to adverse events reported after a 14-day follow-up period following the last dose received. The total does not include screening or post-trial testing. Panel B: Titration with 24 mg or placebo (Days 1 to 7). One participant discontinued before the 24 mg dose on Day 2. One participant discontinued after the 24 mg dose on Day 4. One participant discontinued after the 24 mg dose on Day 3. One participant discontinued before the 24 mg dose on Day 5. The adverse event terms are from MedDRA Version 25. Dystonia was not observed in any patient receiving the 24 mg dose in the study. Petition 870250087591, dated 09 / 26 / 2025, pages 250 / 254

Claims

1 / 4 CLAIMS 1. Controlled-release tablet formulation, characterized in that it comprises: 1) a first layer having about 1%-25% by weight of the pharmaceutically acceptable Compound A, represented by structural formula I: or a pharmaceutically acceptable salt, derived from an ester, geometric isomer, stereoisomer or optical isomer thereof and about 60-90% by weight of low viscosity polyethylene oxide (PEO) polymer; 2) second layer comprising approximately 50%-70% by weight of high-viscosity polyethylene oxide polymer, approximately 10%-40% by weight of metal halide and approximately 5%-30% by weight of tablet-forming agent; and 3) Semi-permeable coating wherein the coating comprises about 1%-15% by weight of the tablet, said tablet having a hole in the first layer, wherein said formulation does not induce dystonia after administration.

2. Formulation according to claim 1, characterized in that 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%-88% by weight.

3. Formulation according to claim 1 or 2, characterized in that the high viscosity polyethylene oxide has a molecular weight range. Petition 870250087591, dated 09 / 26 / 2025, p. 251 / 254 2 / 4 molecular (g / mol) of about 4,000,000 to 7,000,000 and is present in the second layer at about 50%-70% by weight. 4.Formulation according to claim 1, characterized in that the tablet-forming agent is selected from lactose, spray-dried lactose, microcrystalline cellulose, mannitol, sorbitol, dehydrated dibasic calcium phosphate and dehydrated calcium sulfate.

5. Formulation according to claim 4, characterized in that the tablet-forming agent is microcrystalline cellulose, present in about 10%-20% by weight.

6. Formulation according to claim 1, characterized in that the metal halide is selected from sodium chloride, potassium chloride, calcium chloride and potassium iodide, or a mixture thereof, and is present in about 15%-25% by weight.

7. Formulation according to claim 1, characterized in that the semipermeable coating comprises cellulose acetate, ethylcellulose or a combination thereof and low molecular weight polyethylene glycol. 8.Formulation according to claim 1, characterized in that Compound A, or a pharmaceutically acceptable salt derived from an ester, geometric isomer, stereoisomer or optical isomer thereof, is present in about 4%-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 about 65%-88% by weight of the total weight of the first layer.

9. Formulation according to claim 1 or 3, characterized in that: a) the high viscosity polyethylene oxide has a molecular weight range Petition 870250087591, dated 09 / 26 / 2025, p. 252 / 254 3 / 4 molecular (g / mol) of about 4,000,000 to 7,000,000 and is present in about 60%-68% by weight, b) the tablet-forming agent is present up to 10%-20% by weight and c) the metal halide is present in about 15%-25% by weight of the total weight of the second layer. 10.Formulation according to claim 1 or 7, characterized in that 5%-15% of the semipermeable coating comprises cellulose acetate, ethylcellulose or a blend thereof, wherein the cellulose acetate, ethylcellulose or a blend thereof contains about 5%-20% by weight of low molecular weight polyethylene glycol.

11. Formulation according to any one of claims 1, 8 or 9, characterized in that it further comprises a sugar alcohol selected from mannitol, sucrose and lactose.

12. Formulation according to any one of claims 1, 8 or 9, characterized in that it exhibits peak-to-trough concentration levels of Compound A from about 1.0 to about 3.

5.

13. Formulation, according to any one of claims 1, 8, 9 or 12, characterized in that it comprises from about 17 mg to about 47 mg of Compound A, which can be administered once daily without causing dystonia. 14.Formulation, according to any one of claims 1, 8, 9, 12 or 13, characterized in that it comprises Compound A at doses of 16 mg or higher, which exhibits sustained muscarinic enzyme occupancy at peak and trough of about 65% or higher.

15. Formulation, according to claim 14, characterized in that, when administered to a population of patients suffering from schizophrenia, no incidents of dystonia have been reported.

16. Use of Compound A defined in any of claims 1, 8, 9 and 12 to 14, characterized in that it is for the manufacture of a controlled-release formulation to treat schizophrenia or other psychiatric disorders in a patient requiring the same, wherein said formulation comprises said Compound A in doses of 16 mg or higher without inducing dystonia in the patient. 17.Product, process, system, kit, means or use, characterized in that it comprises one or more elements described in the descriptive report, claims, drawings, sequence listing, or summary of this application, when applicable. Petition 870250087591, dated 09 / 26 / 2025, pp. 254 / 254.

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