Formulations of T-type calcium channel modulators and methods of use thereof

Abstract

Described herein, in part, are dosage forms and compositions useful for the prevention and / or treatment of diseases or conditions associated with aberrant T-type calcium channel function, such as epilepsy and epileptic syndromes (e.g., absent seizures, teenager myospastic epilepsy or genetic epilepsy), tremor (e.g., epilepsy seizures, spasmodic epilepsy, or hereditary epilepsy), or tremor (e.g., epilepsy seizures). Idiopathic tremor (e.g., idiopathic tremor) and psychiatric disorders (e.g., mood disorders (e.g., severe depressive disorder)). The invention also includes methods for modulating the function of T-type calcium channels.

Description

Formulations and administration of T-type calcium channel modulators

[0001] This application is a divisional application of Chinese invention patent application No. 202080061862.9, entitled "Formulation of T-type calcium channel modulator and method of use thereof," filed on July 10, 2020 (PCT application No. PCT / US2020 / 041530). Cross-reference to related applications.

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 62 / 873,022, filed July 11, 2019; U.S. Provisional Patent Application No. 62 / 934,820, filed November 13, 2019; and U.S. Provisional Patent Application No. 62 / 958,923, filed January 9, 2020, each of which is incorporated herein by reference in its entirety. Background Technology

[0003] T-type calcium channels are low-pressure activated ion channels that mediate calcium influx into cells. Abnormal function of these ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders, such as major depressive disorder), pain, tremors (e.g., essential tremor), and epilepsy or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, compounds that selectively modulate T-type calcium channels in mammals could be used to treat such disease states. Summary of the Invention

[0004] This document describes compositions and dosage forms that can be used to prevent and / or treat diseases or conditions associated with abnormal function of T-type calcium channels, such as epilepsy and epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) and mood disorders (e.g., severe depressive disorder). The invention also includes methods for modulating the function of T-type calcium channels.

[0005] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient functions to alter the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006] In one aspect, the present invention provides an oral dosage form comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a release polymer (e.g., a controlled-release polymer, a hydrophilic matrix polymer, such as an HPMC polymer as a hydrophilic matrix polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel)), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)). In some embodiments, the dosage form comprises about 0.9% by weight to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the dosage form comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0007] The dosage forms disclosed herein may contain about 10% to about 70% by weight of a modulated polymer. The dosage forms disclosed herein may contain a diluent (e.g., microcrystalline cellulose).

[0008] In another aspect, the present invention discloses an oral dosage form comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC polymer.

[0009] In another aspect, the present invention provides an oral dosage form comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0010] This article also provides an oral dosage form comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC polymer.

[0011] In one aspect, this article provides an oral dosage form comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0012] The present invention provides, in part, an oral (e.g., microparticle) composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and a release polymer (e.g., a controlled-release polymer, a hydrophilic matrix polymer, such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel)), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)).

[0013] In some embodiments, the composition comprises about 0.9% to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0014] This article also provides an oral (e.g., microparticle) composition comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC.

[0015] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0016] This document provides, in part, an oral (e.g., microparticle) composition comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC.

[0017] The present invention partially discloses an oral (e.g., microparticle, swellable core) composition comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0018] In one aspect, the present invention provides crystal forms of compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II)) wherein the crystal forms exhibit X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2.

[0019] In another aspect, the present invention provides crystal forms of compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II)) wherein the crystal forms exhibit X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2 and 17.8±0.2.

[0020] This invention partially provides a method of treating a neurological disorder in a subject with this need, wherein the method includes administering to the subject an oral dose, composition, or crystal form disclosed herein. In some embodiments, the neurological disorder is epilepsy. In other embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is hereditary epilepsy (e.g., CACNA1G-related hereditary generalized epilepsy). In some embodiments, the neurological disorder is absence seizures. In other embodiments, the neurological disorder is absence epilepsy (e.g., CACNA1H-related absence epilepsy). In some embodiments, the neurological disorder is epilepsy associated with CACNA1G, H, or I. In some embodiments, the epilepsy is childhood absence epilepsy (CAE). In other embodiments, the epilepsy is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy is Lenox-Gastaut syndrome. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). In other embodiments, the neurological disorder is tremor (e.g., essential tremor, Parkinson's disease tremor, or cerebellar tremor, CACNA1G-related tremor). In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with CACNA1G mutation). In other embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is insomnia.

[0021] In another aspect, this document provides methods for treating psychiatric disorders in subjects with such needs, wherein the methods include administering to the subject an oral dose, composition, or crystalline form disclosed herein. In some embodiments, the psychiatric disorder is a mood disorder. In other embodiments, the mood disorder is a major depressive disorder.

[0022] In some embodiments of the methods described herein, the dosage form is administered to the subject once daily. The dosage form may be administered to the subject twice daily. The dosage form may be administered to the subject every other day.

[0023] In some embodiments of the methods described herein, a subject may be given about 15 mg to 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) daily, or a subject may be given about 30 mg to 50 mg (e.g., about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) daily.

[0024] In some embodiments of the methods described herein, the dosage form may have a lower Cg after administration to a subject compared to a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max Value. In other embodiments of the methods disclosed herein, the dosage form may have a larger t after administration to a subject than a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile, a dosage form without a modulated release rate profile, or a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0025] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition or crystal form disclosed herein) that results in a reduction in the number of seizures.

[0026] In one aspect, this article provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition or crystal form disclosed herein) that results in a reduction in seizure density as measured by electroencephalography (EEG).

[0027] This document partially provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystal form disclosed herein) that results in a reduction in the mean seizure duration as measured by EEG.

[0028] In another aspect, this document discloses a method for treating generalized epilepsy syndrome with absence seizures in patients with such need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystal form disclosed herein) that results in a reduction in the cumulative duration of seizures as measured by EEG.

[0029] This article partially provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., the oral dose, composition, or crystal form described herein) that results in a reduction in the total duration of spike discharges of 2.5–4 Hz after hyperventilation and light stimulation challenges, as measured by EEG.

[0030] In another aspect, this article provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystal form) that results in a decrease in overall severity as measured by a Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score.

[0031] This document also provides a method for treating essential tremor in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystal form disclosed herein) that results in a reduction of essential tremor as assessed by a Essential Tremor Rating Assessment Scale (TETRAS) score. In some embodiments, the reduction of essential tremor is assessed by an upper limb score on the Essential Tremor Rating Assessment Scale (TETRAS). In other embodiments, the reduction of essential tremor is assessed by TETRAS-ADL (Activities of Daily Living). The reduction of essential tremor is assessed by a TETRAS performance subscale score or by individual TETRAS performance items.

[0032] This article also provides a method for treating essential tremor in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dose, composition, or crystal form disclosed herein) that results in a reduction of essential tremor as assessed by an accelerometer-based upper limb score.

[0033] In another aspect, this document provides a method for treating essential tremor in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystal form disclosed herein) that results in a reduction of the σ band. In some embodiments, the essential tremor is an upper limb tremor.

[0034] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following brief description, detailed description, embodiments, and claims. Attached Figure Description

[0035] Figure 1 is a powder X-ray diffraction pattern of form C of compound (II).

[0036] Figure 2 is a differential scanning calorimetry (DSC) thermal analysis diagram of form C of compound (II).

[0037] Figure 3 is a thermogravimetric analysis (TGA) thermal analysis diagram of form C of compound (II).

[0038] Figure 4 is a hot-stage micrograph (HSM) of compound C of formula (II).

[0039] Figure 5 shows the average concentration-time curves of the compound of formula (I) after a single 20 mg oral dose of modulated-release tablets and immediate-release capsules of the compound of formula (II).

[0040] Figure 6 shows the reduction in tremors during the Archimedes spiral mission when the compound of formula (II) is applied.

[0041] Figure 7 is a powder X-ray diffraction pattern of compound B of formula (II).

[0042] Figure 8 is a differential scanning calorimetry (DSC) thermal analysis diagram of compound (II) of type B.

[0043] Figure 9 is a thermogravimetric analysis (TGA) thermal analysis diagram of compound (II) of type B.

[0044] Figure 10 is a hot stage micrograph (HSM) of compound B of formula (II).

[0045] Figure 11 shows the mean (±SD) concentrations after a single oral dose of the 5 mg tablet formulation 4.

[0046] Figure 12 shows the stage 1 sleep EEG (NREMσ) in healthy volunteers. Detailed Implementation

[0047] As generally described herein, the present invention provides compositions or dosage forms (e.g., compounds comprising formula (I) or pharmaceutically acceptable salts thereof) that can be used to prevent and / or treat diseases or conditions related to the function of T-type calcium channels, such as epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy). Methods are also provided for treating mood disorders (e.g., depression, major depressive disorder, dysphoric disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)). Methods are also provided for modulating the function of T-type calcium channels. Methods are also provided for treating pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). Methods are also provided for treating tremor (e.g., essential tremor, Parkinson's disease tremor, or cerebellar tremor). Methods are also provided for treating ataxia (e.g., spinocerebellar ataxia, cerebellar ataxia, or spinocerebellar ataxia with CACNA1G mutations). Methods are also provided for treating tinnitus. Methods are also provided for treating insomnia.

[0048] definition

[0049] Generally, the “effective amount” of a compound refers to the amount sufficient to elicit the desired biological response. Those skilled in the art will understand that the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. Effective amounts include both therapeutic and prophylactic treatments.

[0050] As used herein, and unless otherwise indicated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" can also include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effect of another therapeutic agent.

[0051] As used herein, the term "refractory" refers to a disease, disorder, or condition that is not readily responsive to or controlled by a therapy or treatment. In some embodiments, the disease, disorder, or condition described herein is refractory (e.g., refractory epilepsy or refractory absence seizures) and does not respond to standard therapy or treatment.

[0052] As used herein, the term "subject" contemplated for administration includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0053] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0054] As used herein, and unless otherwise indicated, the terms “treatment” and “management” cover actions that occur while a subject is suffering from a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow its progression (“therapeutic management”), and also cover actions that occur before a subject begins to suffer from a particular disease, disorder, or condition (“preventive management”).

[0055] As used herein, the term "pharmaceutically acceptable salt" means a salt that, within reasonable medical judgment, is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include: adipic acid salts, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate. Laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and their stereoisomers (e.g., enantiomers, diastereomers), etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed from counterions such as halide ions, hydroxide ions, carboxyl ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonates, and aryl sulfonates.

[0056] The term "modified release polymer" refers to a polymer used in formulations (e.g., tablets and capsules) that alters the release rate of a drug after administration to a subject. For example, a modulated release polymer is used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, a modulated release polymer is a controlled-release polymer. For example, a modulated release polymer or controlled-release polymer is an HPMC polymer. In some embodiments, the modulated release polymer may include a hydrophilic matrix polymer (e.g., hydroxypropyl methylcellulose, HPMC), a hydrophobic matrix polymer (e.g., ethylcellulose, ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100).

[0057] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0058] As used herein, the term "flow aid" refers to an excipient used to promote powder flow by reducing interparticle friction and binding forces. Examples of flow aids include fumigated silica (e.g., colloidal silica), talc, and magnesium carbonate.

[0059] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping and sticking to tablet punches or capsule filling machines. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (such as vegetable stearin).

[0060] As used herein, the term "coating agent" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and makes large or unpleasant-tasting tablets easier to swallow. These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way to the foregoing list of exemplary substituents.

[0061] Dosage Forms and Compositions

[0062] In one aspect, the present invention characterizes dosage forms or compositions for regulating T-type calcium channels and diseases, disorders or conditions associated with their function (e.g., mood disorders (e.g., severe depressive disorder), epilepsy or epilepsy syndromes, such as absence seizures, juvenile myoclonic epilepsy, status epilepticus or hereditary epilepsy).

[0063] In another aspect, the present invention provides a dosage form comprising a compound of formula (I):

[0064] Or its pharmaceutically acceptable salt (e.g., eutectic) or solvate.

[0065] In another aspect, the present invention provides dosage forms comprising compounds of formula (II):

[0066] .

[0067] Modified-release formulations and compositions

[0068] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient functions to alter the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0069] In one aspect, this disclosure provides an oral dosage form comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and a release polymer (e.g., a controlled-release polymer, a hydrophilic matrix polymer, such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)).

[0070] In one aspect, the present invention provides a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) and a release modulator (e.g., a controlled-release polymer, a hydrophilic matrix polymer, such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)), for example, in an amount sufficient to alter the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) after administration to a subject.

[0071] In some embodiments, the dosage form comprises about 0.9% to about 40% by weight (e.g., about 0.9% to about 30%, about 1% to about 25% by weight, about 2% to about 25% by weight, about 3% to about 20% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 40% by weight) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 30% to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0072] In some embodiments, the dosage form comprises about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 19% to about 20% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 21% to about 22% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 4% to about 15% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 4% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 4% to about 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 5% to about 6% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 9% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0073] In another aspect, the present invention provides a dosage form or composition comprising about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) and a release modulating polymer (e.g., a controlled-release polymer, a hydrophilic matrix polymer, such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel)), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)), for example, in an amount sufficient to alter the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) after administration to a subject.

[0074] In other embodiments, the dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 5 mg to about 15 mg (e.g., about 10 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the dosage form comprises about 25 mg to about 35 mg (e.g., about 30 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 35 mg to about 45 mg (e.g., about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0075] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a release-modifying polymer (e.g., HPMC polymer). In some embodiments, the dosage form comprises about 10% to about 70% by weight of a release-modifying polymer (e.g., HPMC polymer). In some embodiments, the dosage form comprises about 50% to about 60% by weight of a release-modifying polymer (e.g., HPMC polymer).

[0076] In some embodiments, the dosage form further comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the dosage form comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15% to about 35% by weight (e.g., about 15% to about 20%, about 20% to about 25%, 25% to about 30%, 30% to about 35% by weight) of microcrystalline cellulose.

[0077] In some embodiments, the dosage form further comprises a flow aid. In some embodiments, the flow aid comprises colloidal silica. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the dosage form further comprises a coating agent.

[0078] In some embodiments, approximately 80% of the compound of formula (I) is released within 7 hours after administration to the subject. In some embodiments, approximately 80% of the compound of formula (I) is released within 7 hours using a USP device type-I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0079] In some embodiments, after administration to a subject, the dosage form has a reduced Cg compared to a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max Value. In some embodiments, after administration to a subject, the dosage form has a larger t value than a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile, a dosage form without a modulated release rate profile, or a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0080] In other embodiments, the dosage form is administered to the patient once daily. In some embodiments, the dosage form is administered to the patient twice daily. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In some embodiments, the dosage form is a suspension.

[0081] In another aspect, the present invention provides an oral dosage form comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC polymer.

[0082] In another aspect, the present invention provides an oral dosage form comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0083] In another aspect, the present invention provides an oral dosage form comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC polymer.

[0084] In another aspect, the present invention provides an oral dosage form comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0085] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and a modulated-release polymer (e.g., a controlled-release polymer, such as an HPMC polymer as a hydrophilic matrix polymer).

[0086] In some embodiments, the composition comprises about 0.9 wt% to about 40 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 14 wt% to about 25 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 19 wt% to about 20 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 21 wt% to about 22 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 4 wt% to about 15 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 4 wt% to about 10 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 4% to about 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 5% to about 6% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 9% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0087] In some embodiments, the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the composition comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the composition comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0088] In some embodiments, the composition comprises about 55 mg to 65 mg of a modulating polymer. In some embodiments, the composition comprises about 10 wt% to about 70 wt% of a modulating polymer. In some embodiments, the composition comprises about 50 wt% to about 60 wt% of a modulating polymer.

[0089] In some embodiments, the composition comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In other embodiments, the composition comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) of microcrystalline cellulose. In some embodiments, the composition comprises about 15% to about 35% by weight (e.g., about 15% to about 20%, about 20% to about 25%, 25% to about 30%, 30% to about 35% by weight) of microcrystalline cellulose.

[0090] In some embodiments, the composition comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the composition comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the composition further comprises a flow aid. In some embodiments, the flow aid comprises colloidal silica. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition further comprises a coating agent. In some embodiments, the compound of formula (I) or (II) is stable in the formulation at about 25°C and 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 36 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 60 months. In some embodiments, the compound is stable at about 40°C and 75% relative humidity for at least 6 months.

[0091] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC.

[0092] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0093] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 55 mg to 65 mg of HPMC.

[0094] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0095] In some embodiments of the oral dosage forms or compositions described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is a crystalline form. In some embodiments, the crystalline form is as described herein.

[0096] Crystal form of the compound of formula (II)

[0097] This document also provides crystal forms of the compound of formula (II), wherein the crystal form exhibits X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2 and 26.6±0.2.

[0098] In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2. In other embodiments, the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2. In some embodiments, the crystal form has a substantially identical X-ray powder diffraction pattern to that shown in Figure 1. In some embodiments, Cu Kα radiation is used to obtain the powder X-ray diffraction pattern. In some embodiments, the crystal form has a melting point starting at approximately 226.6 °C, as determined by differential scanning calorimetry. In some embodiments, the crystal form has a differential scanning calorimetry profile that is substantially the same as that shown in Figure 2.

[0099] In another aspect, this document provides crystal forms of compounds of formula (II) that exhibit X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, and 17.8±0.2.

[0100] In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, and 20.5±0.2. In other embodiments, the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2, and 21.2±0.2. In some embodiments, the crystal form has a substantially identical X-ray powder diffraction pattern to that shown in Figure 7. In some embodiments, Cu Kα radiation is used to obtain the powder X-ray diffraction pattern. In some embodiments, the crystal form has an initial melting point of about 97.9, 131.6, 223.7, 83.8, 128.9, 168.9, or 224.4 °C, as determined by differential scanning calorimetry. In some embodiments, the crystal form has a differential scanning calorimetry profile that is substantially the same as that shown in Figure 8.

[0101] Immediate-release formulation

[0102] In another aspect, the present invention provides a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is released immediately upon administration to a subject.

[0103] This article also provides an oral capsule for immediate release comprising: about 15 mg to about 20 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II); and about 75 mg to 85 mg of a diluent; about 2 mg to 10 mg of a binder; about 1% to about 5% of a disintegrant; and about 0.1 mg to 5 mg of a lubricant.

[0104] application

[0105] In some implementations, the dosage form is administered to the subject more than once a day (e.g., twice a day, three times a day, or four times a day).

[0106] In some embodiments, the dosage form is administered to the subject once daily (e.g., one 20 mg tablet daily, two 20 mg tablets daily, or three 20 mg tablets daily). In some embodiments, the dosage form is administered to the subject twice daily. In some embodiments, the dosage form is administered to the subject every other day. In some embodiments, about 1 mg to 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject daily. In other embodiments, about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject daily. In some embodiments, about 30 mg to 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject daily.

[0107] In some embodiments, after administration to a subject, the dosage form has a reduced Cg compared to a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max Value. In some embodiments, after administration to a subject, the dosage form has a larger tmax value than a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modulated release rate profile, a dosage form without a modulated release rate profile, or a dosage form without a modulated release polymer, such as an HPMC polymer).

[0108] Treatment

[0109] This article describes compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II)) and their use in treating diseases, disorders, or conditions related to the function of T-type calcium channels.

[0110] In one aspect, this document provides a method for treating a neurological disorder in a subject with this need, wherein the method comprises administering to the subject an oral dosage form or oral composition disclosed herein. In some embodiments, the subject has a mutation in one or both of the T-type calcium channel genes CACNA1H and CACNA1G. In some embodiments, the neurological disorder is epilepsy. In some embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is hereditary epilepsy. In some embodiments, the neurological disorder is absence seizures. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). In some embodiments, the neurological disorder is tremor (e.g., essential tremor, Parkinson's disease tremor, or cerebellar tremor). In other embodiments, the neurological disorder is characterized by tremor, but Parkinson's disease is not tremor itself. In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with a CACNA1G mutation). In some embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is insomnia.

[0111] In some embodiments, the compositions provided by the present invention effectively treat tremor (e.g., essential tremor). In some embodiments, the compositions provided by the present invention effectively treat epilepsy or epilepsy syndromes, such as absence seizures, juvenile myoclonic epilepsy, status epilepticus, or hereditary epilepsy. The compositions of the present invention can also modulate all T-type calcium channels, such as Cav3.1, Cav3.2, and / or Cav3.3. In some embodiments, the compositions provided by the present invention effectively treat psychiatric disorders, such as mood disorders, for example, major depressive disorder.

[0112] In another aspect, this document provides methods for treating psychiatric disorders in subjects with such needs, wherein the methods include administering to the subject an oral dosage form disclosed herein. In some embodiments, the psychiatric disorder is a mood disorder. In some embodiments, the mood disorder is a major depressive disorder.

[0113] Epilepsy and Epilepsy Syndromes

[0114] The compositions described herein can be used to treat epilepsy and epilepsy syndromes. Epilepsy is a central nervous system disorder in which the activity of nerve cells in the brain is disrupted, resulting in seizures that can manifest as abnormal movements, staged abnormal behaviors, sensory disturbances, and sometimes loss of consciousness. The symptoms of epileptic seizures vary widely, ranging from a simple blank stare for a few seconds to repetitive twitching of the arms or legs during a seizure.

[0115] Epilepsy can involve generalized seizures or partial or focal seizures. Generalized seizures involve all areas of the brain. A person experiencing a generalized seizure may cry or make some noise, freeze for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are usually open, and the person may appear not to be breathing and actually turn blue. Recovery of consciousness is gradual, and the person may be confused for several minutes to several hours. The main types of generalized seizures are: tonic-clonic, tonic, clonic, myoclonic, myoclonic-tonic-clonic, myoclonic-non-tonic, non-tonic, and absence seizures (typical, atypical, myoclonic, eyelid myoclonic), and epileptic spasms. In partial or focal seizures, only a part of the brain is involved, and therefore only a part of the body is affected. Symptoms may vary depending on the part of the brain with abnormal electrical activity.

[0116] As described in this article, epilepsy includes generalized, partial, complex partial (e.g., seizures involving only a part of the brain but with impaired consciousness), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0117] The compositions described herein can also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction, caused at least in part by certain aspects of epilepsy, are also known as epileptic encephalopathy. These are associated with treatment-resistant, frequent seizures and severe cognitive impairment (e.g., West syndrome).

[0118] In some embodiments, the epilepsy syndrome includes epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for hereditary generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)). Am J Hum Genet. 2019 Aug 1;105(2):267-28. In some embodiments, the epileptic syndrome is Doose syndrome or myoclonic unstable epilepsy. In some embodiments, the epileptic syndrome is epileptic encephalopathy with continuous peaks and waves (CSWS) during sleep. In some embodiments, the epileptic syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epileptic syndrome is Jeavons syndrome.

[0119] Absence seizures

[0120] Absence seizures are one of the most common types of seizures in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures are relatively brief, nonconvulsive seizures characterized by a sudden loss of consciousness and responsiveness, typically lasting 10–30 seconds, with rapid recovery of normal consciousness without postictal confusion. On accompanying EEG recordings, the seizures are characterized by the sudden onset and shift of widespread 1–6 Hz (e.g., 3 Hz) peaks and wave discharges. Absence seizures often occur multiple times daily, disrupting learning and psychosocial function, and posing a risk of injury due to the frequent occurrence of loss of consciousness. Typically, absence seizures begin in early childhood and remit during adolescence. However, in a minority of patients, they persist into adulthood, and they often develop drug resistance and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are often highly disabling, particularly by disqualifying patients from obtaining a motor vehicle license or from engaging in occupations and hobbies in which the loss of consciousness associated with the seizure poses a safety risk, and are associated with severe psychosocial dysfunction (Wirrell et al., 1997).

[0121] Although absence seizures are generally considered relatively “easy” to treat, randomized controlled trials in patients with childhood absence epilepsy have shown that even the most effective antiepileptic drugs, ethosuximide and valproate, only achieved complete seizure control in 53% and 58% of patients, respectively, at 16 weeks (as assessed by video-EEG recordings) (Glauser et al., 2010), and 45% and 44%, respectively, at 12 months (Glauser et al., 2013). Lamotrigine, another commonly used AED for absence seizures, achieved seizure control in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproate are often associated with intolerable side effects (occurring in 24% of patients treated with either drug) (Glauser et al., 2010), and the latter is now generally considered contraindicated in girls and women of childbearing potential. Other treatment options for absence seizures are limited, with only benzodiazepines (benzodiazepines) having definite efficacy—and these are often poorly tolerated due to sedative and cognitive side effects. Absence seizures persisting into adulthood are particularly difficult to treat, and patients often receive multiple medications, leading to severe side effects and an inability to achieve seizure control.

[0122] Extensive evidence suggests that low-threshold (T-type) calcium channels play a crucial role in the generation and maintenance of absence seizures, and are a key component of the oscillatory bursts of discharge occurring in thalamic cortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the present invention characterizes a method of treating absence seizures with the compositions described herein. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0123] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizure is atypical absence seizure. In some embodiments, the absence seizure includes adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0124] In some embodiments, the method described herein further includes identifying a subject with absence seizures.

[0125] In another aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the number of seizures.

[0126] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the average or total duration of seizures.

[0127] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the frequency, duration, or both of seizures as measured by electroencephalography (EEG).

[0128] The methods covered include methods for treating generalized epilepsy syndrome with absence seizures in patients with this need, which include administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the average duration of seizures as measured by EEG.

[0129] This article partially provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the cumulative duration of seizures as measured by EEG.

[0130] In one aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the total duration of spike discharges of 2.5–4 Hz after hyperventilation and light stimulation challenge, as measured by EEG.

[0131] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) that results in a decrease in overall severity, as measured by a Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-I (CGI-I) score. The CGI-S is a 7-point scale test used to rate the severity of a patient's disease at the time of assessment relative to a clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test used to evaluate improvement in a patient's disease relative to baseline.

[0132] In another aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the number of seizures.

[0133] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in seizure density as measured by electroencephalography (EEG).

[0134] The methods covered include methods for treating generalized epilepsy syndrome with absence seizures in patients with this need, which include administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the average duration of seizures as measured by EEG.

[0135] This article partially provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the cumulative duration of seizures as measured by EEG.

[0136] In one aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the total duration of spike discharges of 2.5–4 Hz after hyperventilation and light stimulation challenge, as measured by EEG.

[0137] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) that results in a decrease in overall severity, as measured by a Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-I (CGI-I) score. The CGI-S is a 7-point scale test used to rate the severity of a patient's disease at the time of assessment relative to a clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test used to evaluate improvement in a patient's disease relative to baseline.

[0138] In another aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the number of seizures.

[0139] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) that results in a reduction in the density of seizures as measured by electroencephalography (EEG).

[0140] The methods covered include methods for treating generalized epilepsy syndrome with absence seizures in patients with this need, which include administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the average duration of seizures as measured by EEG.

[0141] This article partially provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the cumulative duration of seizures as measured by EEG.

[0142] In one aspect, this disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a patient in need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the total duration of spike discharges of 2.5–4 Hz after hyperventilation and light stimulation challenge, as measured by EEG.

[0143] This article also provides a method for treating generalized epilepsy syndrome with absence seizures in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a decrease in overall severity as measured by a Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score. CGI-S is a 7-point scale test used to rate the severity of a patient’s disease at the time of assessment relative to a clinician’s past experience with patients with the same diagnosis. CGI-I is a 7-point scale test used to evaluate improvement in a patient’s disease relative to baseline.

[0144] Hereditary epilepsy

[0145] In some embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or a hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is hereditary generalized epilepsy. In some implementations, epilepsy or epilepsy syndrome includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-childhood epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial epilepsy in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0146] In some embodiments, the method described herein further includes, prior to administering the composition described herein, identifying a subject with epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-childhood epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial epilepsy in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy).

[0147] In one aspect, the present invention characterizes a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) comprising administering the composition described herein to a subject in need of such treatment.

[0148] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has antibodies against ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, and KCN. Mutations in one or more of the following: T1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0149] In some embodiments, the method described herein further includes identifying, prior to application of the composition described herein, the presence of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, L Subjects with mutations in one or more of the following: GI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0150] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has antibodies against ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, and DO. CK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCT D7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, serine protease Inhibitory protein I1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3 GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15,Mutations in one or more of the following: ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0151] In some embodiments, the method described herein further includes identifying those having ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2 (TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM 2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A , GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3 , KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, P ACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, serine protease inhibitor I1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12 SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX , SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2,Subjects with mutations in one or more of the following: CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0152] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has antibodies against ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, and DNAJC5. (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7 (CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8 (CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3. Mutations in one or more of the following: NR2F1, NRXN1, PACS1, PCDH19, PIGA PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1 (CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0153] In some embodiments, the method described herein further includes identifying substances having ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, and DNAJC5. (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7 (CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8 (CLN7), NALCN, NGLY1, NHLRC1 Subjects with mutations in one or more of the following: (EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0154] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has antibodies against ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRB2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, K CNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PL CB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC Mutations in one or more of the following: 13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0155] In some embodiments, the method described herein further includes identifying individuals possessing ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRB2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, and KCNQ2. , KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5 Subjects with mutations in one or more of the following: SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0156] Mood Disorders

[0157] This document also provides methods for treating psychiatric disorders such as mood disorders, including clinical depression, postnatal or birth depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, dysphoric mood, bipolar disorder, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-resistant depression, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine disorders and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or health disorders or conditions in women).

[0158] Clinical depression, also known as major depressive disorder, severe depressive disorder (MDD), unipolar depression, unipolar disorder, and recurrent depression, is a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience difficulty sleeping, weight loss, and generally feel anxious and irritable. Clinical depression affects how an individual feels, thinks, and acts, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may find it difficult to perform daily activities and may feel as if life is not worth living.

[0159] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, feeling restless, difficulty sleeping, extreme exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of separation from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0160] Postnatal depression (PND), also known as postpartum depression (PPD), refers to a class of clinical depression affecting women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0161] In some implementations, subjects with perinatal depression also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In one implementation, subjects experiencing perinatal depression are at increased risk of experiencing perinatal depression.

[0162] Atypical depression (AD) is characterized by mood responsiveness (e.g., anomalous anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also have excessive sleep or somnolence (hypersomnia), heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0163] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), no response to pleasurable stimuli, more pronounced depressive mood than sadness or loss, excessive weight loss, or excessive guilt.

[0164] Major psychotic depression (PMD) or psychotic depression refers to a severe depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0165] Catatonic depression is a major depressive disorder characterized by disordered motor behavior and other symptoms. Individuals may become silent and catatonic, and be immobile or exhibit meaningless or strange movements.

[0166] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which individuals experience a seasonal pattern of depressive episodes during the fall or winter.

[0167] Dysphoria is a condition associated with unipolar depression in which the same physical and cognitive problems are present. They are less severe and tend to be more persistent (e.g., at least 2 years).

[0168] Dual depression is defined as persistent, severe depression (dysthymia) lasting at least two years and characterized by stages of major depressive disorder.

[0169] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive features.

[0170] Recurrent transient depression (RBD) refers to a condition in which an individual experiences a depressive episode approximately once a month, each episode lasting 2 weeks or less and typically less than 2-3 days.

[0171] Mild depressive disorder or mild depression means that at least two symptoms of depression have been present for two weeks.

[0172] Bipolar disorder, or manic-depressive disorder, causes extreme mood instability, including elevated mood (mania or hypomania) and depressed mood (depression). During a manic episode, an individual may abnormally feel or exhibit happiness, energy, or irritability. They often make ill-considered decisions with little regard for consequences. Sleep needs are typically reduced. During a depressive episode, there may be crying, poor eye contact with others, and a negative outlook on life. People with this disorder have a high 20-year suicide risk, exceeding 6%, while the incidence of self-harm is 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.

[0173] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, and chronic stress.

[0174] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but whose symptoms have not improved. For example, antidepressants or psychotherapy (psychotherapy) do not alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, individuals with treatment-resistant depression experience symptom improvement but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics) and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0175] Postoperative depression refers to depressive feelings following surgery (e.g., due to the need to confront death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in previously enjoyed hobbies and activities, or a persistent sense of worthlessness or despair.

[0176] Mood disorders related to a condition or disorder of women's health refer to mood disorders (e.g., depression) that are related to (e.g., caused by) a condition or disorder of women's health (e.g., as described herein).

[0177] Suicidal ideation, suicidal thought, and suicidal behavior indicate an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual focus on suicide. The range of suicidal ideation varies greatly, from, for example, fleeting thoughts to broad ideas, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, acquiring means of suicide, withdrawing from social contact, focusing on death, feeling trapped or hopeless, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to others as if they would never see them again.

[0178] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenge, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, somnolence, overeating, decreased appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from person to person. Symptoms of depression and their remission can be determined by a physician or psychologist (e.g., through a mental status examination).

[0179] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysphoric disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0180] In some embodiments, the method includes monitoring subjects with known depression scales, such as the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impression-Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, treatment efficacy can be determined by a decrease in the total Hamilton Depression Rating Scale (HAM-D) score exhibited by the subject. Treatment efficacy can be assessed over a specified treatment period. For example, treatment efficacy can be determined by a decrease in the total HAM-D score from baseline after administration of the composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or lifetime).

[0181] In some embodiments, the subject has mild depressive disorder, e.g., mild severe depressive disorder. In some embodiments, the subject has moderate depressive disorder, e.g., moderate severe depressive disorder. In some embodiments, the subject has major depressive disorder, e.g., major severe depressive disorder. In some embodiments, the subject has extremely severe depressive disorder, e.g., extremely severe depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., prior to treatment with the composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18 and includes the extreme values. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 and includes the extreme values. In some embodiments, the subject's HAM-D total score prior to treatment with the composition described herein is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the total HAM-D score of a subject after treatment with the composition described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the total HAM-D score after treatment with the composition described herein is less than 10, 7, 5, or 3. In some embodiments, the decrease in the total HAM-D score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with the composition described herein. In some embodiments, the decrease in baseline HAM-D total score to HAM-D total score after treatment with the composition described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50%. In some embodiments, the percentage decrease in baseline HAM-D total score to HAM-D total score after treatment with the composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the treatment effect is measured as the decrease in HAM-D total score relative to baseline HAM-D total score after treatment with the composition described herein.

[0182] In some embodiments, the method of treating a depressive disorder (e.g., severe depressive disorder) provides a therapeutic effect within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less (e.g., as measured by a reduction in the Hamilton Depression Rating Scale (HAM-D)). In some embodiments, the method of treating a depressive disorder (e.g., severe depressive disorder) provides a therapeutic effect within the first or second day of treatment with the composition described herein (e.g., as determined by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., severe depressive disorder) provides a therapeutic effect within 14 days or less after the start of treatment with the composition described herein (e.g., as determined by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., severe depressive disorder) provides a therapeutic effect within 21 days or less after the start of treatment with the composition described herein (e.g., as determined by a statistically significant reduction in the total HAM-D score). In some embodiments, the method for treating depressive disorders (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the total HAM-D score) within 28 days or less after the initiation of treatment with the composition described herein. In some embodiments, the therapeutic effect is a decrease in the total HAM-D score from baseline after treatment with the composition described herein. In some embodiments, the subject's total HAM-D score prior to treatment with the composition described herein is at least 24. In some embodiments, the subject's total HAM-D score prior to treatment with the composition described herein is at least 18. In some embodiments, the subject's total HAM-D score prior to treatment with the composition described herein is between 14 and 18, including the extreme values. In some embodiments, the decrease in the total HAM-D score relative to baseline after treatment with the composition described herein is at least 10. In some embodiments, the decrease in the total HAM-D score relative to baseline after treatment with the composition described herein is at least 15. In some embodiments, the total HAM-D score associated with treatment of a subject using the compositions described herein does not exceed a number in the range of 6 to 8. In some embodiments, the total HAM-D score associated with treatment of a subject using the compositions described herein does not exceed 7.

[0183] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0184] In some embodiments, the CNS disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method of treating the depressive disorder (e.g., major depressive disorder) provides therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0185] The effectiveness of treatment for major depressive disorder can be determined by a decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) score observed in the participants. For example, MADRS scores can decrease within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding overt sadness, reported sadness, anxiety, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0186] pain

[0187] The dosage forms and compositions described herein can be used to treat pain. In some embodiments, the pain includes acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain includes acute pain or chronic pain. In some embodiments, the pain includes neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain includes central pain (e.g., thalamic pain). In some embodiments, the pain includes migraine.

[0188] In some embodiments, the method described herein further includes identifying a subject with pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain) or migraine) prior to administration of the dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0189] Tremor

[0190] The methods described herein can be used to treat tremors, for example, the dosages or compositions disclosed herein can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, or red nucleus tremor. Tremors include hereditary, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders; peripheral neuropathy (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes, and complex regional pain syndromes); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (tricyclic neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychological disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndromes (including classic essential tremor, essential orthostatic tremor, and task- and position-specific tremors), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmesian tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. The tremor may be familial.

[0191] Tremor is an involuntary, rhythmic contraction and relaxation of muscles that can involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0192] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, which may originate from, for example, tumors, strokes, or other focal diseases (e.g., multiple sclerosis) or neurodegenerative diseases.

[0193] Dystonic tremor occurs in individuals affected by dystonia (a movement disorder in which persistent, involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions). Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest or certain sensory manipulations.

[0194] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild, and some are non-progressive, and can progress slowly, starting on one side of the body but usually affecting both sides. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of the tremor may decrease with age, but its severity may increase. Worsening emotions, stress, fever, physical fatigue, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms typically progress over time and can be noticeable and persistent once they occur.

[0195] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur immediately after standing up in the legs and trunk. Spasms are felt in the thighs and legs, and the patient may uncontrollably sway when asked to stand in one place. Orthostatic tremor can also occur in patients with essential tremor.

[0196] Parkinson's tremor is caused by damage to the structures in the brain that control movement. It is often described as a "rolling" motion of the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor typically begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0197] The characteristic feature of red nucleus tremor is a coarse, slow tremor that can be present at rest, in a postural state, and intentionally. The tremor is associated with conditions affecting the red nucleus in the midbrain, such as stroke.

[0198] In some implementations, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor.

[0199] In another aspect, this article provides a method for treating essential tremor in patients with this need, comprising administering to the patient an adequate amount of a compound of formula (I) that results in a reduction of essential tremor as assessed by the Essential Tremor Rating Scale (TETRAS) score. The term “Essential Tremor Rating Scale (TETRAS)” as used herein refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities. It has an Activities of Daily Living (ADL) section and a Performance section. The ADL section has 12 items rated from 0 to 4, and the Performance section has 9 items rated from 0 to 4.

[0200] In some implementations, the reduction of essential tremor is assessed using the Essential Tremor Rating Scale (TETRAS) upper limb score.

[0201] In some implementations, the reduction of essential tremor is assessed by TETRAS performance subscale scores or individual TETRAS performance items.

[0202] In another aspect, this article provides a method for treating essential tremor in patients with this need, which includes administering a sufficient amount of a compound of formula (I) to the patient, resulting in a reduction of essential tremor as assessed by an accelerometer-based score (e.g., an accelerometer-based upper limb score).

[0203] In some implementations, the idiopathic tremor is an upper limb tremor.

[0204] In another aspect, this article provides a method for treating essential tremor in patients with this need, which includes administering to the patient an adequate amount of a compound of formula (I) that results in a reduction of essential tremor as assessed by a CGI score.

[0205] The efficacy of the compounds or compositions described herein for the treatment of essential tremor can be measured using the methods described in the following references: Ferreira, JJ et al., “MDS Evidence-Based Review of Treatments for Essential Tremor.” Mov. Disord. July 2019; 34(7):950-958; Elble, R. et al., “Task Force Report: Scales for Screening and Evaluating Tremor.” Mov. Disord. November 2013; 28(13):1793-800; Deuschl G. et al., “Treatment of patients with essential tremor.” Lancet Neurol. 2011; 10: 148-61; Reich SG et al., “Essential Tremor.” Med. Clin. N. Am. 103 (2019) 351-356. The public information of the references is incorporated herein by reference in its entirety.

[0206] Ataxia

[0207] Ataxia, including cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), typically involves a loss or failure of coordination. Patients exhibiting ataxia may have difficulty regulating the force, range, direction, speed, and rhythm involved in posture, balance, and limb movement. For example, truncal ataxia can lead to increased postural swaying and an inability to maintain the center of gravity above the base of support. Primary or secondary symptoms of ataxia, along with ataxic gait and limb tremors, may be accompanied by speech disturbances, dysphagia, ventilatory and speech abnormalities, as well as involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, severely interfering with daily activities.

[0208] As noted above, ataxia can be caused by a variety of underlying diseases and conditions in patients, including cerebellar and neurodegenerative disorders, as well as conditions resulting from chronic or long-term exposure to toxins. Symptoms of ataxia can be caused by a variety of diseases, disorders, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and conditions resulting from long-term or long-term or chronic exposure to toxins (including drugs and alcohol); in one implementation, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or a condition resulting from long-term or long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may lead to ataxia symptoms treatable according to the methods described herein include, but are not limited to: amyotrophic lateral sclerosis (ALS), benign paroxysmal positional vertigo (BPPV), cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant homotypic), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endostomy), cerebellar hypoplasia (retinal blanket degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar hypoplasia (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal disorders, autonomic dysfunction, balance disorders, dysethesis, endocrine disorders, and diseases caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptics). Fragile X syndrome / tremor ataxia syndrome, Friedreich ataxia, frontal lobe dysfunction, hereditary diseases, granulomatous vasculitis of the central nervous system, Has-Schwarz disease, hereditary motor and sensory neuropathy, hydrocephalus (e.g., hypobaric or normobaric), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem responses, episodic spinocerebellar ataxia in early childhood, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus-ataxia, neurodegenerative diseases, oligopontine atrophy, paraneoplastic disorders, Parkinson's disease (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-poliomyelitis syndrome. Severe brain damage (e.g., caused by head injury, neurosurgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infection, or brain tumor), spastic hemiparesis, spastic paraplegia, spastic paraplegia with glaucoma, precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-deafness).Spinocerebellar ataxia (malformation), Spinocerebellar ataxia 11, Spinocerebellar ataxia 17, Spinocerebellar ataxia 20, Spinocerebellar ataxia 25, Spinocerebellar ataxia 29, Spinocerebellar ataxia 42, Spinocerebellar ataxia 3, Spinocerebellar ataxia (autosomal recessive 1), Spinocerebellar ataxia (autosomal recessive 3), Spinocerebellar ataxia (autosomal recessive 4), Spinocerebellar ataxia (autosomal recessive 5), Spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), Spinocerebellar ataxia (Machado-Joseph type II), Spinocerebellar ataxia (X-linked, 2). Spinocerebellar ataxia (X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (book type), stroke (e.g., acute or hemorrhagic), vertebral artery anatomy, vertebral basement artery circulatory insufficiency, and diseases caused by vitamin deficiency, etc. In one embodiment, the ataxia is a result of a disease selected from spinocerebellar ataxia, Friedriech's ataxia, and fragile X-chromosome / tremor ataxia syndrome. In another specific embodiment, the ataxia is a result of spinocerebellar ataxia or fragile X-chromosome / tremor ataxia syndrome.

[0209] tinnitus

[0210] Methods for treating tinnitus in subjects with this need are provided using the disclosed dosage forms or compositions. Tinnitus is a condition in which an affected person perceives sound in one or both ears or in the head when no external sound is present. Often referred to as “ringing” in the ears, tinnitus can occur intermittently or continuously, and the perceived volume ranges from low to distressingly high. However, the perceived volume of tinnitus can vary from patient to patient; what is objectively considered distressing in one patient may be considered subtle in another.

[0211] Sleep disorders

[0212] This document provides methods for treating or preventing sleep disorders (e.g., narcolepsy) using the dosages or compositions disclosed herein. For example, sleep disorders can be central nervous system disorders of narcolepsy, type I narcolepsy, type II narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to drugs or substances, hypersomnia associated with a psychiatric disorder, sleep deprivation syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake disorder, late sleep-wake disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, and no-specification (NOS) circadian rhythm sleep-wake disorder.

[0213] combination therapy

[0214] The dosage forms or compositions described herein (e.g., for modulating T-type calcium channels) may be administered in combination with another agent or therapy. Subjects to receive the compounds disclosed herein may have a disease, disorder, or condition or symptoms thereof that would benefit from treatment with another agent or therapy. These diseases or conditions may be associated with epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) or tremor (e.g., essential tremor).

[0215] Antiepileptic drugs

[0216] Antiepileptic drugs include brivaceran, carbamazepine, clonazepam, clonazepam, diazepam, sodium valproate, escrispazepine, ethosuximide, ezogababine, felbapentin, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufenamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0217] Painkillers

[0218] Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine-like substances such as fentanyl and morphine; acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors. Given the ability of the compounds of the present invention to treat pain by inhibiting T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combinations with analgesics are particularly envisioned.

[0219] Tremor drugs

[0220] Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topiramate, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0221] Example

[0222] To provide a fuller understanding of the invention described herein, the following embodiments are illustrated. The synthetic and biological embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting their scope.

[0223] Example 1: Crystallinity of the compound of formula (II) analyzed by X-ray powder diffraction

[0224] Polymorphs of the compound of formula (II) were screened, and a stable solid form (referred to as form C) was identified. The crystallinity of form C was analyzed by X-ray powder diffraction (XRPD).

[0225] XRPD analysis was performed using Bruker D8 ADVANCE and the following conditions.

[0226] Bragg Brentano geometry.

[0227] 2θ range: 3° to 40°.

[0228] Step size: 0.02°.

[0229] Step time: 0.25 sec.

[0230] Slit: 0.3.

[0231] Sample rotation speed: 15 rpm.

[0232] Copper K α radiation.

[0233] Sample holder filled with Zero background silicon.

[0234] The powder X-ray diffraction pattern of form C of compound (II) is shown in Figure 1. The positions and relative intensities of the 10 largest peaks in the XRPD pattern of form C are shown in Table 1. The sample is highly crystalline and shows no evidence of any baseline shift indicating significant amorphicity.

[0235] Table 1. List of XRPD peak values ​​for form C (10 strongest reflections)

[0236]

[0237] Preparation of Form C

[0238] The free alkaline solution of the compound of formula (I) was cooled to 0°C to 10°C over 1 hour. Ethyl acetate / HCl (10-12%, 53.5 L, prepared internally from ethyl acetate and anhydrous HCl gas) was slowly added to the batch over 30 minutes while maintaining the temperature between 0°C and 10°C. The batch was warmed to 25°C to 30°C over 1.25 hours and held at this temperature for 4 hours. A vacuum (600-700 mmHg) was applied and the batch was distilled below 33°C for 6.25 hours, at which point the volume of the distillate was 115 L. The batch was cooled to 25°C to 30°C and diisopropyl ether (53.5 L, 5 volumes) was added. The batch was held at 25°C to 30°C with stirring for 2 hours, then filtered through a Nutsche NF202 filter under a nitrogen atmosphere and dried for 30 minutes. The filter cake was slurried / washed twice with diisopropyl ether (10.7 L, 1 volume) and blotted dry for 30 minutes to 1 hour. The substance was dried in a vacuum dryer VD201 at 65°C to 70°C under vacuum (600-650 mmHg) for 12 hours until the water content of the filter cake did not exceed 2.0% by weight, to give the compound of formula (II) in form C (10.01 kg, 90% yield, 0.45% water, based on KF).

[0239] Another stable solid form (referred to as type B) was identified through polymorph screening. The crystallinity of type B was analyzed by X-ray powder diffraction (XRPD).

[0240] XRPD analysis was performed using Bruker D8 ADVANCE and the same conditions as described above.

[0241] The powder X-ray diffraction pattern of form B of compound (II) is shown in Figure 7. The positions and relative intensities of the 10 largest peaks in the XRPD pattern of form C are shown in Table 2. The sample is highly crystalline and shows no evidence of any baseline shift indicating significant amorphicity.

[0242] Table 2. List of XRPD peak values ​​for Form B (10 strongest reflections)

[0243]

[0244] Preparation of Form B

[0245] The substance exhibiting diffraction pattern B was prepared from ethyl acetate by controlled solvent evaporation.

[0246] Place approximately 200 mg of the compound of formula (II) in a 30 to 50 mL glass vial / beaker. Add 20 mL of ethyl acetate and vortex / sonicate the sample for approximately one minute until a clear solution is obtained. Filter the solution through a syringe filter (Durapore PVDF 0.22 μm centrifugal filter from Millipore) to remove potential seeds in solid form. Then, leave the solution open to the environment with stirring for 48 hours.

[0247] Example 2: Thermal properties of compounds of formula (II) in form C and form B

[0248] The compound of formula (II) was further analyzed in form C by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM). The compound has a high melting point and does not undergo any physical or chemical changes below 180°C.

[0249] DSC

[0250] DSC of the compound in form C using Perkin Elmer Diamond DSC and the following conditional analysis (II).

[0251] An aluminum disc under nitrogen purification gas.

[0252] Sample size: 1 to 5 mg.

[0253] Temperature range: 25℃ to 250℃.

[0254] Heating rates: 2℃ / min, 5℃ / min, 10℃ / min.

[0255] The DSC thermal analysis plot of form C of compound (II) is shown in Figure 2. A summary of the obtained data is shown in Table 3. The obtained thermal analysis plot shows a single, sharp endothermic reaction due to the melting of form C, with an initial temperature of 226.6 °C.

[0256] Table 3. DSC data obtained for the form C of compounds of formula (II)

[0257]

[0258] TGA

[0259] TGA analysis was performed using Perkin Elmer Pyris1 and the following conditions.

[0260] Platinum disk under nitrogen purification gas.

[0261] Sample size: 2 to 4 mg.

[0262] Temperature range: Ambient temperature to 300℃.

[0263] Heating rate: 10℃ / min.

[0264] The TGA thermal analysis plot (Figure 3) shows a weight loss of approximately 0.8% w / w when heated from ambient temperature to 150°C, indicating that form C of compound (II) is neither a hydrate nor a solvate (the theoretical weight loss for a monohydrate is 4.1% w / w).

[0265] Table 4. TGA data for form C of compounds of formula (II)

[0266]

[0267] HSM

[0268] HSM of compound (II) in form C was performed at heating rates of 10 °C / min or 20 °C / min from ambient temperature to 300 °C (without sample equilibration). Figure 4 shows an HSM micrograph of compound (II) in form C. Experiments confirmed that the substance remained constant until approximately 180 °C. Melting began at approximately 201 °C, and the final melting of the particles ended at approximately 215 °C. The endothermic event observed in the DSC thermal analysis plot with an onset temperature of 227 °C corresponds to melting. Form B of compound (II) was further analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot-stage microscopy (HSM).

[0269] The DSC thermal analysis plots of substance B at heating rates of 10 °C / min and 2 °C / min are shown in Figure 8. A summary of the obtained data is shown in Table 4. The DSC thermal analysis plot with a heating rate of 10 °C / min shows three endothermic events. The first endothermic event, with an onset temperature of approximately 98 °C, can be attributed to the weight loss event observed in the TGA experiments (75 °C to 125 °C), possibly due to water or solvent loss. The slower heating rate of 2 °C / min was used to investigate the thermal events observed at higher temperatures. The DSC thermal analysis plot recorded at the obtained heating rate of 2 °C / min shows four main events: three endothermic events and one exothermic event. The first endothermic event (onset temperature 84 °C) is likely due to water or solvent loss. The second event (onset temperature 129 °C) is due to melting of the compound in a dehydrated or desolvated form. An exothermic event (onset temperature 169 °C) was observed after this melting, corresponding to the crystallization observed in the HSM (possibly producing substance C). The final endothermic event (initial temperature 224°C) was confirmed by HSM to be melting and corresponds to the melting of substance of type C.

[0270] Table 4. DSC data obtained for type B of compounds of formula (II)

[0271] Heating rate of 10℃ / min

[0272]

[0273] Heating rate 2℃ / min

[0274]

[0275] The TGA thermal analysis plot of substance B is shown in Figure 9. A summary of the obtained data is shown in Table 5. The TGA thermal analysis plot shows a typical stepwise weight loss of approximately 4.0% w / w for the hydrate in the temperature range of 75°C to 125°C. The theoretical weight of the monohydrate is 4.1%; indicating that type B is a possible hydrate. It is unlikely to be a solvate because it originates from a different solvent, and different solvates are unlikely to produce the same diffraction pattern. This weight loss event corresponds to the first endothermic event observed in the DSC thermal analysis plot. A significant weight loss of approximately 17% w / w was observed in the temperature range of 195°C to 300°C. Examination of the experimental residue revealed it to be a brown substance, indicating that degradation had occurred. Hot-stage microscopy confirmed melting at approximately 200°C followed by decomposition.

[0276] Table 5. TGA data for type B of compounds of formula (II)

[0277]

[0278] The HSM of the type B substance showed that the appearance of the substance remained unchanged up to 128 °C. The substance began to melt at 128 °C, and the melting of the final particles ended at a temperature of approximately 135 °C (see Figure 10). This confirms that the event observed in the DSC with an initial temperature of 227 °C was due to melting.

[0279] Recrystallization from the melt was observed between 161°C and 175°C, while the color change of the melt observed between 189°C and 195°C occurred simultaneously with the melting of the recrystallized solid.

[0280] The degradation of compounds during HSM may differ from that during DSC. HSM is performed in an air atmosphere; DSC is performed in an inert nitrogen atmosphere. Therefore, oxidation processes may occur during HSM, but not during DSC.

[0281] Example 3: Modified-release tablet formulation of compound (II)

[0282] preparation

[0283] In Phase 1, single-dose escalation studies of immediately released (“IR”) capsules showed that central nervous system (CNS)-related and psychiatric-related adverse events were the most frequently reported adverse events, typically occurring near the time to peak plasma concentration (Tmax). In subsequent cohorts of the same study, administration of 40 mg IR capsules as four 10-mg doses at 2-hour intervals reduced the mean Cmax value by approximately 50% compared to the value observed after a single oral 40-mg dose of the compound of formula (II), and mild headache and mild drowsiness were the only adverse events reported after escalation. In light of these findings, modified-release (“MR”) tablet formulations of the compound of formula (II) were developed to attempt to reduce the Cmax at a given dose while maintaining the total AUC.

[0284] The composition of the immediate-release capsules of the compounds of formula (II) is provided in Table 6 below.

[0285] Table 6. Formulations of compounds of formula (II) for immediate-release capsules

[0286]

[0287] Three initial tablet formulations of the compound of formula (II) (form C) with different release rate profiles were prepared: formulation 1 (approximately 80% of the compound of formula (I) is released within 2 hours after administration to the subject), formulation 2 (80% release rate at 5 hours), and formulation 3 (80% release rate at 7 hours). The composition of the formulations is shown in Table 7. Each tablet contains 20 mg of the compound of formula (II).

[0288] Table 7. Formulations of compounds of formula (II) used in dispensing tablets

[0289]

[0290] Preparation method

[0291] The method for preparing modulated-release tablets consists of six consecutive steps: 1) screening all components (compounds of formula (I) or pharmaceutically acceptable salts thereof, such as formula (II) and excipients), 2) blending compounds of formula (I) or pharmaceutically acceptable salts thereof, such as compounds of formula (II) with excipients (including intragranule lubrication), 3) rolling (including grinding), 4) external granule lubrication, 5) tableting, and 6) tablet coating.

[0292] Example 4: Pharmacokinetic Study of Modified-Release Tablets

[0293] Modulated-release tablets of the compound of formula (II) were developed in an attempt to mitigate some of the adverse effects observed with the immediate-release capsule formulation of the compound of formula (II). In a phase 1 study in fasting healthy volunteers, the C1 ratio of three modified-release tablet formulations of the compound of formula (II) was evaluated relative to the immediate-release capsule formulation. max Decrease and t max Delay.

[0294] The Phase 1 study was a randomized, open-label, 4-way crossover study. Eligible participants were randomized to one of four treatment sequences and received a single 20-mg dose of an immediate-release capsule formulation of compound (II) (compound of formula (II)) and a single 20-mg dose of one of three modulated-release tablet formulations of compound (II) while fasting: formulation 1 (80% release rate over 2 hours), formulation 2 (80% release rate over 5 hours), and formulation 3 (80% release rate over 7 hours). Study treatment was administered in four separate study visits, with a minimum clearance period of 1 week between each visit.

[0295] Figure 5 shows the average concentration-time curves of the compound of formula (I) after a single 20-mg oral dose of modulated-release tablets and immediate-release capsules of the compound of formula (II).

[0296] Following administration of 20 mg of compound (II) under fasting conditions, the plasma concentrations of compound (I) were quantifiable 0.75 hours prior to administration of each modulated-release tablet formulation of compound (II) under fasting conditions and after administration of the immediate-release capsule formulation (Figure 5). Upon reaching C... max Subsequently, the plasma concentrations of the compound of formula (I) decreased in a biphasic manner after administration of the immediate-release capsules and formulation 1 tablets under fasting conditions. Plasma concentrations reached C... max The levels then plateaued and then decreased in a monophasic manner after administration of formulations 2 and 3 tablets while fasting. The compounds of formula (I) remained quantifiable for at least 36 hours after administration of the immediate-release capsules and formulation 1 tablets, and for the duration of the 48-hour sampling phase after administration of formulations 2 and 3 tablets.

[0297] The formulation, consisting of 3 tablets in a feeding state, reaches C max The plasma concentration subsequently decreased in a biphasic manner. The compound of formula (I) remained quantifiable during the 48-hour sampling period following administration of 3 tablets of the formulation in an oral state (Figure 5).

[0298] Table 8 summarizes the median t for immediate-release capsules, formulation 1 tablets (release rate at 2 hours), formulation 2 tablets (release rate at 5 hours), and formulation 3 tablets (release rate at 7 hours). max Observed geometric mean C max Observed geometric mean AUC 最后 and AUC inf Compared to immediately released capsules, modulated-release formulations with longer release rates provide delayed t-release. max Value and decrease of C max Concentration, while maintaining AUC 最后 Overall exposure was assessed. The t-exposure was observed at approximately 8 to 10 hours for all formulations. ½ They are similar. There is no evidence that the absorption rate affects t. ½ In the three modulated-release tablet formulations, the AUC was... 最后 The relevant intra-subject variability is similar.

[0299] Table 8. Geometric mean (CV%) of pharmacokinetic parameters of compounds of formula (II) after a single oral dose of 20 mg in modulated-release tablets and immediate-release capsules (Study Phase 1)

[0300]

[0301] Abbreviation: AUC 外推The percentage of area extrapolated after the last quantifiable plasma concentration; AUC inf The area under the plasma concentration-time curve from the time of administration to infinity; AUC 最后 The area under the plasma concentration-time curve from the time of administration to the last measurable concentration; C max Peak plasma drug concentration; Cl / F, apparent plasma clearance after oral administration; CV%, expressed as a percentage coefficient of variation; t½, terminal elimination half-life; MR-release, t lag The time preceding the first measurable (non-zero) concentration; t max The time to reach the maximum (peak) plasma drug concentration; V z / F Apparent volume of distribution after oral administration. 1 Median (range).

[0302] Of the 18 subjects (see Example 4) who received a single oral dose of 20-mg of one of the three modulated-release tablet formulations (formulations 1-3) or IR capsules while fasting, 17 subjects (94.4%) experienced at least one adverse event after administration of any of the formulations (Table 9). At least one drug-related adverse event was reported in 15 of the 18 subjects (83.3%). No serious or severe adverse events were reported, and no subject discontinued treatment with the study drug due to adverse events.

[0303] Consistent with the expected lower Cmax exposure of the MR tablets compared to the IR capsules of formula (I), the percentage of subjects experiencing at least one adverse event and the percentage of subjects experiencing at least one drug-related adverse event were lower after administration of each MR tablet than after administration of the IR capsules (Table 9). The percentage of subjects experiencing any adverse event and the percentage of subjects experiencing any drug-related adverse event were lowest for formulation 3 in the MR tablets.

[0304] • At least one adverse event was reported in 33.3% of subjects after administration of formulation 3 tablets, in 44.4% of subjects after administration of formulation 2, in 61.1% of subjects after administration of formulation 1 tablets, and in 72.2% of subjects after administration of IR capsules.

[0305] • At least one drug-related adverse event was reported in 16.7% of subjects after administration of formulation 3, in 44.4% of subjects after administration of formulation 2, in 44.4% of subjects after administration of formulation 1, and in 72.2% of subjects after administration of IR capsules.

[0306] The increase in the percentage of subjects experiencing any adverse events and any drug-related adverse events was concentration-dependent and generally correlated with the order of Cmax (formulation 3 < formulation 2 < formulation 1 < IR capsule).

[0307] Table 9. Overall Summary of Emergency Adverse Events Following a Single Oral Dose of 20-mg in Tablets (Formulations 1-3) and Immediate-Release Capsules During Fasting (Safe Population)

[0308]

[0309] Abbreviations: IR = Immediate Release, MR = Modified Release, SAE = Serious Adverse Event, TEAE = Treatment-Emergency Adverse Event

[0310] Drug-related adverse events are those that researchers assess, as far as possible, in any way possible, in relation to the investigational drug. (Source)

[0311] Example 5: Pharmacokinetic Study of Modified-Release Tablets

[0312] A two-part, phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, pharmacokinetic (PK) and PD (including KSS, KDT, SQSQ, and 24-hour EEG readouts) of single-increment (part A: 20, 40, and 60 mg) and multiple-increment (part B: 20 ​​and 40 mg, for a total of 8 days) doses of 20 mg tablets (formulation 3) in healthy participants. Based on the results of this trial, exposure to compounds of formula (I) increased with dose following a single oral dose of 20 mg tablets (formulation 3) across a dose range from 20 mg to 60 mg. The variability of Cmax and AUC increased with dose following a single oral dose of 20 mg tablets (formulation 3).

[0313] In this study, single and multiple doses of 20 and 40 mg (daily for 8 days) were well tolerated. A single 60 mg dose administered to 6 healthy volunteers was not tolerated. Nausea occurred in 5 of the 6 participants, and vomiting occurred in 3 of the 6 participants.

[0314] Table 10. Geometric mean (geometric CV%) after a single oral dose for 20 mg tablet formulation 3 (Part A)

[0315]

[0316] AUC 24 =AUC (Area under the plasma concentration-time curve from administration to 24 hours post-administration) inf=AUC (Area under the plasma concentration-time curve from application to infinity) 最后 =The area under the plasma concentration-time curve from the time of administration to the last measurable concentration, C max = Peak plasma drug concentration, CL / F = Apparent total clearance of drug from plasma after oral administration, CV% = Coefficient of variation percentage, %AUC 外推 = The area under the plasma concentration-time curve extrapolated from time t to infinity, as a percentage of the total area under the curve, MR = release, t½ = elimination half-life, t lag = Delay time, t max = Time to peak plasma drug concentration, V z / F = Apparent volume of distribution at the end of the period following oral administration. 1 Median (range). 2 n=5.

[0317] Pharmacokinetic properties of the 20 mg tablets (formulation 3) at multiple 20 and 40 mg doses were determined on days 1 and 8 of administration (Table 11). Based on the results of this study, after 8 days of once-daily administration of the 20 mg tablet formulation, exposure to the compound of formula (II) increased with increasing dose within the 20 to 40 mg dose range. Variability of Cmax and AUC increased within the studied dose range. Steady state was reached before day 5 of repeated daily administration within the 20 to 40 mg dose range. An approximately two-fold increase in Cmax was observed within 8 days of administration.

[0318] Table 11: Geometric mean (geometric CV%) plasma pharmacokinetic parameters of 20 mg tablet formulation (formulation 3) after single and multiple oral doses (partial B)

[0319]

[0320] Abbreviation: AUC 24 =AUC (Area under the plasma concentration-time curve from administration to 24 hours post-administration) τ = The area under the plasma concentration-time curve during the administration interval, C avg = Average drug concentration during multiple dose administration, C max = Peak plasma drug concentration, C min = Minimum plasma drug concentration, CL / F = Apparent total clearance of drug from plasma after oral administration, CV% = Percentage of variation coefficient, MR = Adjusted release, NA = Not applicable, NC = Not calculated, Rac AUC = From AUC τ,ss and AUCτ The calculated cumulative ratio, Rac C max = From C max,ss The calculated cumulative ratio, ss = steady state, t½ = elimination half-life, t lag = Delay time, t max = Time to peak plasma drug concentration, V z / F = Apparent volume of distribution at the end of the period following oral administration. 1 Median (range). 2 Labeled as AUC on day 1 24

[0321] T-type calcium channels expressed in the thalamus are closely associated with the generation and regulation of sleep fusiform waves, which are significant thalamic cortical vibrations during NREM sleep. Sleep fusiform waves were detected in the σ band (11–15 Hz) on EEG (Figure 12). Therefore, in this experiment, the compound of formula (I), which indicates power reduction in the σ band, mediated the blockade of T-type calcium channels in the thalamic cortical circuit.

[0322] Example 6: Modulated-release tablet formulations of the compound of formula (I) 4 and 5

[0323] Formulations 4 and 5, provided as matrix-coated modulated-release (MR) tablets, are designed to release approximately 80% of the drug substance within 7 hours. The composition of the clinical batches of the products (formulations 4 and 5) is shown in Table 12. Each active tablet will contain the drug substance equivalent to 5 or 20 mg of the compound of formula (I), corresponding to approximately 5.475 mg or 21.90 mg of the compound of formula (II), respectively.

[0324] Table 12. Formulations of compounds of formula (I) containing 5 mg or 20 mg of release tablets.

[0325]

[0326] a Regarding the amount of free base adjustment formula (I)

[0327] b The amount of microcrystalline cellulose (Avicel PH101) is compensated according to formula (I).

[0328] The dissolution method used to assess the release was a chromatographic detection method using USP device type-I. The dissolution parameters and high-performance liquid chromatography (HPLC) conditions used to assess the release are shown below.

[0329] Table 13. Dissolution parameters

[0330]

[0331] Table 14. Chromatographic conditions

[0332]

[0333] Table 15. Gradient Procedure

[0334]

[0335] Preparation method

[0336] MR tablets are prepared by screening and blending excipients (including lubricants). The blend is granulated by rolling and grinding a strip of dense material. The granules are lubricated and then compressed into tablets. The tablets are then coated with a film.

[0337] During the process, during release testing, and in terms of stability, numerous quality attributes are monitored. These include hardness, friability, appearance, assays, related substances, content uniformity, moisture content, and dissolution.

[0338] Other formulations (formulations 6-9) are provided in Table 16.

[0339] Table 16. Formulations of compounds of formula (I) containing 10, 15, 30, and 40 mg of the compound (I).

[0340]

[0341] a Regarding the amount of free base adjustment formula (I)

[0342] b The amount of microcrystalline cellulose (Avicel PH101) is compensated according to formula (I).

[0343] Following a single 5 mg dose of compound (formulation 4) of formula (II) administered to healthy volunteers, the plasma concentration of the free base of compound (I) (i.e., compound (II)) was quantifiable up to 0.50 hours after administration of the adjusted-release tablet formulation of compound (II). Plasma concentrations plateaued after reaching Cmax and then decreased up to 24 hours after administration of formulation 4. The free base of compound (I) (i.e., compound (II)) remained quantifiable during the 24-hour sampling period following administration of the 5 mg dose of formulation 4. Figure 11 shows the mean (±SD) concentrations following a single oral dose of the 5 mg tablet formulation 4.

[0344] Table 17. Geometric mean (geometric CV%) after a single oral dose of the 5 mg tablet formulation 4

[0345]

[0346] AUC 24 =The area under the plasma concentration-time curve from the time of administration to 24 hours after administration, C max = Peak plasma drug concentration, CV% = coefficient of variation percentage, MR = release modulation, t lag = Delay time, t max = Time to reach peak plasma drug concentration. 1 Median (range).

[0347] Example 7: Long-term stability of the compound of formula (II) in formulation

[0348] The drug products are chemically and physically stable for up to 48 months at 25°C / 60%RH (Table 11), or chemically and physically stable for up to 6 months under accelerated conditions (40°C / 75%RH) (Table 19). Based on currently available stability data, the 20 mg drug product (formulation 3) packaged in 40 cc high-density polyethylene (HDPE) bottles has a shelf life of 60 months when stored between 20°C and 25°C according to the United States Pharmacopeia (USP) definition of controlled room temperature. Based on the excellent stability of the 20 mg drug product for at least 48 months and its substantially identical composition to the 5 mg drug product, the 5 mg drug product (formulation 4) packaged in 40 cc high-density polyethylene (HDPE) bottles has a shelf life of 24 months when stored between 20°C and 25°C.

[0349] Stability studies of MR tablets containing the compound of formula II were conducted at 25°C / 60%RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of formula II. Tablets were packaged in 40cc HDPE bottles containing 30 tablets each, with a CRC cap (Table 19).

[0350] Table 19. Stability study data of MR tablet formulation 3 (containing 20 mg of compound of formula (II)) at 25°C / 60% for 48 months.

[0351]

[0352] NMT - Not exceeding; RH - Relative humidity

[0353] Stability studies of MR tablets containing the compound of formula II were conducted at 40°C / 75%RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of formula II. Tablets were packaged in 40cc HDPE bottles containing 30 tablets each, with a CRC cap (Table 20).

[0354] Table 20. Stability study data of MR tablet formulation 3 (containing 20 mg of compound (II)) under accelerated conditions.

[0355]

[0356] NMT - Not exceeding; RH - Relative humidity

[0357] Stability studies of formulation 4 of the compound containing formula (II) were conducted at 25°C / 60%RH. The batch size was 30,000 tablets. The tablets were packaged in 40 cc HDPE vials containing 30 tablets each, with a CRC cap (Table 21).

[0358] Table 21. Stability study data of tablets (formulation 4) at 25°C / 60%RH for 3 months.

[0359]

[0360] Example 8: Evaluation of the safety, tolerability, pharmacokinetics, and efficacy of escalating multiple oral doses in adults with generalized epilepsy syndrome and absence seizures.

[0361] This label-disclosed MAD trial will primarily evaluate the safety and tolerability of 20 mg tablets (formulation 3) at doses of 20 mg daily and twice daily as adjunct to standard of care. Secondary objectives include characterizing PK, PD (sigma frequency power during NREM sleep), and the effect of the tablets (formulation 3) on seizure frequency.

[0362] Subjects

[0363] The participants in this study were men or women aged 18 to 60 years. Participants had a clinical diagnosis of an epilepsy syndrome (including, but not limited to, childhood absence seizures, juvenile absence seizures, juvenile myoclonic epilepsy, or Jeavons syndrome), wherein the absence seizures met the revised seizure classification of the International League Against Epilepsy (2017), the absence seizures persisted despite a documented trial with at least one standard antiepileptic treatment, and there was a history of absence epilepsy and electrocardiographic evidence.

[0364] Methodology:

[0365] Each participant will complete three phases of the study: screening, treatment (up to two dose levels, then gradually reduced), and safety follow-up.

[0366] All participants will receive the compound of formula (II) for two weeks, followed by a gradual reduction:

[0367] • Dosage level 1: 20 mg once daily (formulation 3) for 7 days and up to 14 days if 20 mg twice daily is not tolerated.

[0368] • Dosage level 2: 20 mg twice daily (formulation 3) for 7 days.

[0369] • Gradual reduction: If the participant tolerates 20 mg twice daily for the full 7 days, the gradual reduction will be 20 mg daily for 2 days (days 15 and 16), followed by 20 mg every other day for 5 days (days 17, 19, and 21). If the participant tolerates only 20 mg once daily, the gradual reduction will be 20 mg every other day for 7 days (days 15 through 21).

[0370] Safety and tolerability

[0371] Safety variables included clinical laboratory evaluations, physical examinations, vital signs, 12-lead ECG, C-SSRS, and AE assessments, including event type, frequency, severity, timing, and relationship to IP.

[0372] Pharmacokinetics

[0373] Pharmacokinetic parameters will include: maximum observed concentration (Cmax) and at steady state (Cmax, SS), time to Cmax (Tmax) and Cmax, SS (Tmax, SS), area under the concentration-time curve within the dosing interval (AUCtau or AUCSS), and total clearance at steady state (CLSS). If feasible, other parameters such as half-life, accumulation, and volume of distribution at steady state (VSS) will be calculated.

[0374] efficacy

[0375] The following were used to evaluate efficacy: a) the number of seizures reported by participants in their seizure diaries, including absence seizures, generalized tonic-clonic seizures, and myoclonic seizures; b) EEG measurements of the seizure activity and pharmacodynamic effects of the compound of formula (I), including: seizure density (the number of bilateral synchronous symmetrical spike discharges of approximately 2.5–5 Hz > 3 seconds over an approximately 24-hour period, including seizures induced by light stimulation and hyperventilation); mean seizure duration (the average duration of 2.5–5 Hz discharges greater than 3 seconds over a 24-hour period); cumulative seizure duration (the product of seizure density and mean seizure duration); total time with 2.5–4 Hz spike discharges after the hyperventilation and light stimulation challenge; and c) overall severity as measured by CGI-S and CGI-I scores.

[0376] Example 9: Evaluation of the potency, safety, tolerability and pharmacokinetics of compounds of formula (I) or pharmaceutically acceptable salts thereof in essential tremor.

[0377] A randomized controlled trial was conducted to investigate the potency, safety, and tolerability of the compound of formula (I) in essential tremor. Each patient completed three study phases: screening, treatment (21 or 28 days), and safety follow-up.

[0378] Patients were men and women aged 18 to 75 years who had been diagnosed with essential tremor for at least 3 years. Throughout the clinical trial, patients received a stable dose of one tremor medication. Patients with clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that may explain or cause the tremor, previous MRI-guided focused ultrasound or surgical interventions for essential tremor, or who had received botulinum toxin injections for essential tremor within 6 months prior to screening were excluded from the study.

[0379] Patients may orally receive 20 mg of compound of formula (I) (formulation 3) once daily for 14 days and twice daily for 7 days (part A) or orally receive 20 mg of compound of formula (I) (formulation 3) once daily for 14 days and twice daily for 14 days or placebo (part B).

[0380] On day 21 (part A) and day 28 (part B), the efficacy of the compound against upper limb tremor was assessed at baseline using the Essential Tremor Rating Scale (TETRAS) upper limb score (I).

[0381] On day 21 (part A) and day 28 (part B), the potency of the compound for other measures of tremor severity was assessed at baseline by TETRAS performance subscale scores and TETRAS performance individual item assessment formula (I).

[0382] The safety and tolerability of the compound of formula (I) were assessed by a comprehensive analysis of the following endpoints: adverse events reported by patients and clinicians, vital signs, clinical laboratory results, electrocardiogram (ECG), and the Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, on days 1, 7, 14, 21, and 28 (part B only).

[0383] Example 10: Evaluation of the potency, safety, tolerability and pharmacokinetics of the compound of formula (I) in essential tremor.

[0384] A clinical study was conducted to investigate the efficacy, safety, and tolerability of compound (I) in essential tremor. One patient diagnosed with essential tremor completed three study phases: screening, treatment (14 days), and safety follow-up. Throughout the clinical trial, the patient received a stable dose of one tremor medication. The patient received 20 mg of compound (I) once daily orally (one tablet of formulation 5) for 7 days and 40 mg of compound (I) once daily orally (two 20 mg tablets of formulation 5) for 7 days (for a total of 14 consecutive days).

[0385] The efficacy of the compound against upper limb tremor was assessed at baseline, day 7, and day 14 using the Essential Tremor Rating Scale (TETRAS) upper limb score (Formula I).

[0386] The efficacy of the compound for other measures of tremor severity was assessed at baseline, day 7, and day 14 by TETRAS performance subscale scores, TETRAS performance individual items, and accelerometer assessment formula (I).

[0387] The safety and tolerability of the compound of formula (I) were assessed by a comprehensive analysis of the following endpoints: adverse events reported by patients and clinicians (e.g., dizziness or headache), vital signs, clinical laboratory results, electrocardiogram (ECG), and the Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, on days 1, 7, 14, and 21.

[0388] Compared to baseline, upper limb tremor scores on TETRAS decreased after 7 days of continuous administration of 20 mg (formulation 5) (day 7), and a further decrease was observed after an additional 7 days of administration of 40 mg (two 20 mg tablets of formulation 5) (day 14). On day 14, the upper limb tremor score was reduced by at least 25% compared to baseline. Notably, the upper limb score increased after 7 days of clearance compared to the upper limb score on day 14 above, indicating a gradual recovery to baseline functional impairment.

[0389] Compared to baseline, TETRAS performance scores decreased after 7 days of continuous administration of 20 mg (formulation 5) (day 7), and a further decrease was observed after an additional 7 days of administration of 40 mg (two 20 mg tablets of formulation 5) (day 14). On day 14, the TETRAS performance score was at least 25% lower than baseline. Notably, after 7 days of clearance, the performance score increased compared to the performance score on day 14, indicating a gradual recovery to baseline functional impairment.

[0390] Figure 6 confirms the reduction in tremors during the Archimedes spiral task when compound of formula (I) (formulation 5) is administered.

[0391] Following 7 days of continuous administration of 20 mg (day 7), Kinesia ONE (accelerometer and gyroscope assessment of upper limb tremor) decreased compared to baseline, and a further decrease was observed after an additional 7 days of administration of 40 mg (day 14). On day 14, the tremor amplitude measured by accelerometer was reduced by at least 25% compared to baseline. Notably, after 7 days of clearance, the tremor amplitude measured by accelerometer increased compared to the tremor amplitude on day 14, indicating a gradual recovery to baseline functional impairment.

[0392] Emerging data indicate that the compound of formula (I) is well tolerated and can reduce upper limb tremor amplitude and improve ADL, such as writing skills. Physician rating scales, accelerometer-based tremor assessment tools, and patient symptom rating scales have consistently demonstrated the symptom relief provided by administration of the compound of formula (I) (formulation 5). Furthermore, anecdotal reports from participants suggest that previously lost abilities, such as carrying a tray with food or beverages, can be restored after taking the compound of formula (I) (formulation 5).

[0393] A non-randomized, uncontrolled, and labeled open-label trial was conducted to investigate the potency, safety, and tolerability of the compound of formula (I) in essential tremor. Each patient completed three study periods: screening, treatment (14 days), and safety follow-up. Video recordings of the TETRAS performance subscale were completed during screening.

[0394] Patients were men and women aged 18 to 75 years who had been diagnosed with essential tremor. Throughout the clinical trial, patients received a stable dose of one tremor medication. Patients with clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that may explain or cause the tremor, previous MRI-guided focused ultrasound or surgical interventions for essential tremor, or who had received botulinum toxin injections for essential tremor within 6 months prior to screening were excluded from the study.

[0395] The patient received 20 mg of compound (formula 5) orally once daily for 7 days and 40 mg of compound (formula 5) orally once daily for 7 days (two 20 mg tablets of formulation 5) for a total of 14 consecutive days.

[0396] The efficacy of the compound against upper limb tremor was assessed at baseline, day 7, and day 14 using the Essential Tremor Rating Scale (TETRAS) upper limb score (Formula I).

[0397] The efficacy of the compound for other measures of tremor severity was assessed at baseline, day 7, and day 14 by TETRAS performance subscale scores, TETRAS performance individual items, and accelerometer assessment formula (I).

[0398] The potency of the compound in formula (I) can also be assessed using Clinical Global Impression (CGI), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression of Change (PGI-C).

[0399] The potency of compounds of formula (I) can also be evaluated by any of the methods described herein.

[0400] The safety and tolerability of the compound of formula (I) were assessed by a comprehensive analysis of the following endpoints: adverse events reported by patients and clinicians (e.g., dizziness or headache), vital signs, clinical laboratory results, electrocardiogram (ECG), and the Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, on days 1, 7, 14, and 21.

[0401] In summary, the present invention relates to the following aspects:

[0402] 1. An oral dosage form comprising:

[0403] Compounds of formula (I) or pharmaceutically acceptable salts thereof; and

[0404] Modulated release polymers (e.g., controlled release polymers, hydrophilic matrix polymers, such as HPMC polymers, hydrophobic matrix polymers (e.g., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100)).

[0405] 2. The dosage form according to claim 1, wherein the dosage form comprises about 0.9% to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0406] 3. The dosage form according to item 1 or 2, wherein the dosage form comprises about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0407] 4. A dosage form according to any one of items 1-3, wherein the dosage form comprises about 19% to about 20% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0408] 5. A dosage form according to any one of items 1-3, wherein the dosage form comprises about 21% to about 22% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0409] 6. The dosage form according to item 1 or 2, wherein the dosage form comprises about 4% to about 15% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0410] 7. A dosage form according to any one of items 1, 2 or 6, wherein the dosage form comprises about 4% by weight to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0411] 8. A dosage form according to any one of items 1, 2, 6 or 7, wherein the dosage form comprises about 4% to about 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0412] 9. A dosage form according to any one of items 1, 2, 6 or 7, wherein the dosage form comprises about 5% to about 6% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0413] 10. A dosage form according to any one of items 1, 2, 6 or 7, wherein the dosage form comprises about 9% by weight to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0414] 11. A dosage form according to any one of items 1-10, wherein the dosage form comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0415] 12. A dosage form according to any one of items 1-11, wherein the dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0416] 13. A dosage form according to any one of items 1-11, wherein the dosage form comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0417] 14. The dosage form according to any one of items 1-13, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is crystalline.

[0418] 15. The dosage form according to item 14, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2 and 26.6±0.2.

[0419] 16. The dosage form according to item 14 or 15, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2 and 26.6±0.2.

[0420] 17. The dosage form according to any one of items 14-16, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2.

[0421] 18. The dosage form according to any one of items 14-17, wherein the crystal form has an X-ray powder diffraction pattern substantially the same as that shown in FIG1.

[0422] 19. The dosage form according to any one of items 14-18, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

[0423] 20. The dosage form according to any one of claims 14-19, wherein the crystal form has a melting point starting at about 226.6°C as determined by differential scanning calorimetry.

[0424] 21. The dosage form according to any one of claims 1-20, wherein the dosage form comprises about 55 mg to 65 mg of the modulated polymer.

[0425] 22. The dosage form according to any one of claims 1-21, wherein the dosage form comprises about 10% by weight to about 70% by weight of a modulating polymer.

[0426] 23. The dosage form according to any one of claims 1-22, wherein the dosage form comprises about 50% to about 60% by weight of a modulating polymer.

[0427] 24. The dosage form according to any one of items 1-23, wherein the dosage form further comprises a diluent.

[0428] 25. The dosage form according to item 24, wherein the diluent comprises microcrystalline cellulose.

[0429] 26. The dosage form according to claim 25, wherein the dosage form comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) microcrystalline cellulose.

[0430] 27. The dosage form according to claim 25, wherein the dosage form comprises about 15% to about 35% by weight (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, 30% to about 35% by weight) microcrystalline cellulose.

[0431] 28. The dosage form according to any one of items 1-27, wherein the dosage form further comprises a gliding agent.

[0432] 29. The dosage form according to claim 28, wherein the flow aid comprises colloidal silica.

[0433] 30. The dosage form according to any one of items 1-29, wherein the dosage form further comprises a lubricant.

[0434] 31. The formulation according to claim 30, wherein the lubricant comprises magnesium stearate.

[0435] 32. The dosage form according to any one of items 1-31, wherein the dosage form further comprises a coating agent.

[0436] 33. The dosage form according to any one of items 1-32, wherein about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is released within 7 hours after administration to the subject.

[0437] 34. The dosage form according to item 33, wherein approximately 80% of the compound of formula (I) is released over 7 hours using a USP device type-I, a medium containing 900 mL of 0.1 M HCl and a paddle speed of 100 rpm.

[0438] 35. A dosage form according to any one of claims 1-34, wherein the dosage form, after administration to a subject, has a reduced Cg compared to a reference oral dosage form (e.g., a dosage form having any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0439] 36. A dosage form according to any one of claims 1-35, wherein the dosage form, after administration to a subject, has a greater t0 than a reference oral dosage form (e.g., a dosage form having any expected release rate profile, such as a modulated release rate profile; a dosage form not having a modulated release rate profile; a dosage form not having a modulated release polymer, such as an HPMC polymer). max value.

[0440] 37. The dosage form according to any one of items 1-36, wherein the dosage form is administered to the patient once daily.

[0441] 38. The dosage form according to any one of items 1-36, wherein the dosage form is administered to the patient twice daily.

[0442] 39. An oral dosage form comprising:

[0443] About 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0444] Approximately 55 mg to 65 mg of HPMC polymer.

[0445] 40. An oral dosage form comprising:

[0446] About 14% by weight to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0447] Approximately 53% to approximately 64% by weight of HPMC polymer.

[0448] 41. An oral dosage form comprising:

[0449] About 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0450] Approximately 55 mg to 65 mg of HPMC polymer.

[0451] 42. An oral dosage form comprising:

[0452] About 3% by weight to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0453] HPMC polymers comprise approximately 53% to approximately 64% by weight.

[0454] 43. The dosage form according to any one of items 1-42, wherein the dosage form is a tablet.

[0455] 44. The dosage form according to any one of items 1-42, wherein the dosage form is a capsule.

[0456] 45. The dosage form according to any one of items 1-42, wherein the dosage form is a suspension.

[0457] 46. ​​An oral (e.g., microparticle) composition comprising:

[0458] Compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II)); and

[0459] Modulated release polymers (e.g., controlled release polymers, hydrophilic matrix polymers, such as HPMC polymers, hydrophobic matrix polymers (e.g., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100)).

[0460] 47. The composition according to claim 46, wherein the composition comprises about 0.9% to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0461] 48. The composition according to item 46 or 47, wherein the composition comprises about 14% by weight to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0462] 49. The composition according to any one of items 46-48, wherein the composition comprises about 19% to about 20% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0463] 50. The composition according to any one of items 46-48, wherein the composition comprises about 21% to about 22% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0464] 51. The composition according to item 46 or 47, wherein the composition comprises about 4% by weight to about 15% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0465] 52. The composition according to any one of items 46, 47 or 51, wherein the composition comprises about 4% by weight to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0466] 53. The composition according to any one of items 46, 47, 51 or 52, wherein the composition comprises about 4% to about 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0467] 54. The composition according to any one of items 46, 47, 51 or 52, wherein the composition comprises about 5% to about 6% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0468] 55. The composition according to any one of items 46, 47, 51 or 52, wherein the composition comprises about 9% by weight to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0469] 56. The composition according to any one of claims 46-55, wherein the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0470] 57. The composition according to any one of items 46-55, wherein the composition comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0471] 58. The composition according to any one of items 46-55, wherein the composition comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0472] 59. The composition according to any one of items 46-55, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is in a crystalline form.

[0473] 60. The composition according to claim 59, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2.

[0474] 61. The composition according to item 59 or 60, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2.

[0475] 62. The composition according to any one of claims 59-61, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2.

[0476] 63. The composition according to any one of items 59-62, wherein the crystal form has an X-ray powder diffraction pattern substantially the same as that shown in FIG1.

[0477] 64. The composition according to any one of items 59-63, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

[0478] 65. The composition according to any one of claims 59-64, wherein the crystal form has a melting point starting at about 226.6°C as determined by differential scanning calorimetry.

[0479] 66. The composition according to any one of items 59-65, wherein the crystal form has a differential scanning calorimetry curve that is substantially the same as that shown in FIG2.

[0480] 67. The composition according to any one of items 46-66, wherein the composition comprises about 55 mg to 65 mg of modulated polymer.

[0481] 68. The composition according to any one of claims 42-62, wherein the composition comprises about 10% by weight to about 70% by weight of a modulating polymer.

[0482] 69. The composition according to any one of claims 42-63, wherein the composition comprises about 50% to about 60% by weight of a modulating polymer.

[0483] 70. The composition according to any one of claims 42-64, wherein the dosage form comprises a diluent.

[0484] 71. The composition according to claim 65, wherein the diluent comprises microcrystalline cellulose.

[0485] 72. The composition according to claim 66, wherein the composition comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) microcrystalline cellulose.

[0486] 73. The composition according to claim 66, wherein the composition comprises about 15% to about 35% by weight (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, 30% to about 35% by weight) microcrystalline cellulose.

[0487] 74. The composition according to any one of items 42-68, wherein the composition further comprises a flow aid.

[0488] 75. The composition according to claim 69, wherein the flow aid comprises colloidal silica.

[0489] 76. The composition according to any one of items 42-70, wherein the composition further comprises a lubricant.

[0490] 77. The composition according to claim 71, wherein the lubricant comprises magnesium stearate.

[0491] 78. The composition according to any one of items 42-72, wherein the composition further comprises a coating agent.

[0492] 79. The composition according to any one of items 42-73, wherein the compound is stable at about 25°C and 60% relative humidity for at least 24 months.

[0493] 80. The composition according to any one of items 42-74, wherein the compound is stable at about 25°C and 60% relative humidity for at least 36 months.

[0494] 81. The composition according to any one of items 42-75, wherein the compound is stable at about 25°C and 60% relative humidity for at least 48 months.

[0495] 82. The composition according to any one of items 42-76, wherein the compound is stable at about 25°C and 60% relative humidity for at least 60 months.

[0496] 83. The composition according to any one of items 42-77, wherein the compound is stable at about 40°C and 75% relative humidity for at least 6 months.

[0497] 84. An oral (e.g., microparticle) composition comprising:

[0498] About 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0499] Approximately 55 mg to 65 mg HPMC.

[0500] 85. An oral (e.g., microparticle) composition comprising:

[0501] About 14% by weight to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0502] HPMC polymers comprise approximately 53% to approximately 64% by weight.

[0503] 86. An oral (e.g., microparticle) composition comprising:

[0504] About 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0505] Approximately 55 mg to 65 mg HPMC.

[0506] 87. An oral (e.g., microparticles, swellable core) composition comprising:

[0507] About 3% by weight to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and

[0508] HPMC polymers comprise approximately 53% to approximately 64% by weight.

[0509] 88. A crystal form of the compound of formula (II), wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2 and 26.6±0.2.

[0510] 89. The crystal form according to item 88, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2 and 26.6±0.2.

[0511] 90. The crystal form according to item 88 or 89, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2.

[0512] 91. The crystal form according to any one of items 88-90, wherein the crystal form has an X-ray powder diffraction pattern substantially the same as that shown in FIG1.

[0513] 92. The crystal form according to any one of items 88-91, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

[0514] 93. The crystal form according to any one of claims 88-92, wherein the crystal form has a melting point starting at about 226.6°C as determined by differential scanning calorimetry.

[0515] 94. A crystal form of the compound of formula (II), wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2 and 17.8±0.2.

[0516] 95. The crystal form according to claim 94, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2 and 20.5±0.2.

[0517] 96. The crystal form according to item 94 or 95, wherein the crystal form exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2, and 21.2±0.2.

[0518] 97. The crystal form according to any one of items 94-96, wherein the crystal form has an X-ray powder diffraction pattern substantially the same as that shown in FIG7.

[0519] 98. The crystal form according to any one of items 94-97, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

[0520] 99. The crystal form according to any one of claims 94-98, wherein the crystal form has a melting point starting at about 97.9, 131.6, 223.7, 83.8, 128.9, 168.9 or 224.4 °C as determined by differential scanning calorimetry.

[0521] 100. A method of treating a neurological disorder in a subject with such need, wherein the method comprises administering to the subject an oral dosage form according to any one of claims 1-45, a composition according to any one of claims 46-87, or a crystalline form according to any one of claims 88-99.

[0522] 101. The method according to item 100, wherein the neurological disorder is epilepsy.

[0523] 102. The method according to item 101, wherein the epilepsy is juvenile epilepsy.

[0524] 103. The method according to claim 101, wherein the epilepsy is hereditary epilepsy (e.g., CACNA1G-related hereditary generalized epilepsy).

[0525] 104. The method according to item 100, wherein the neurological disorder is absence seizures.

[0526] 105. The method according to claim 100, wherein the neurological disorder is absence epilepsy (e.g., CACNA1H-associated absence epilepsy).

[0527] 106. The method according to claim 100, wherein the neurological disorder is epilepsy related to CACNA1G, H or I.

[0528] 107. The method according to claim 101, wherein the epilepsy is childhood absence epilepsy (CAE).

[0529] 108. The method according to item 101, wherein the epilepsy is juvenile absence epilepsy (JAE).

[0530] 109. The method according to item 101, wherein the epilepsy is Lenox-Gastaut syndrome.

[0531] 110. The method according to claim 100, wherein the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine).

[0532] 111. The method according to item 100, wherein the neurological disorder is tremor (e.g., essential tremor, Parkinson's disease tremor, or cerebellar tremor, CACNA1G-related tremor).

[0533] 112. The method according to item 100, wherein the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with CACNA1G mutation).

[0534] 113. The method according to item 100, wherein the neurological disorder is tinnitus.

[0535] 114. The method according to item 100, wherein the neurological disorder is insomnia disorder.

[0536] 115. A method for treating a psychiatric disorder in a subject with such need, wherein the method comprises administering to the subject an oral dosage form according to any one of claims 1-45, a composition according to any one of claims 46-87, or a crystalline form according to any one of claims 88-99.

[0537] 116. The method according to item 115, wherein the psychiatric disorder is a mood disorder.

[0538] 117. The method according to item 116, wherein the mood disorder is a severe depressive disorder.

[0539] 118. The method according to any one of items 115-117, wherein the dosage form is administered to the subject once daily.

[0540] 119. The method according to any one of items 115-118, wherein the dosage form is administered to the subject twice daily.

[0541] 120. The method according to any one of items 115-119, wherein the dosage form is administered to the subject every other day.

[0542] 121. The method according to any one of items 100-120, wherein a subject is given about 15 mg to 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) daily.

[0543] 122. The method according to any one of items 100-120, wherein a subject is given about 30 mg to 50 mg (e.g., about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) daily.

[0544] 123. The method according to any one of claims 100-122, wherein, after administration to a subject, the dosage form has a reduced Cg compared to a reference oral dosage form (e.g., a dosage form having any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0545] 124. The method according to any one of claims 100-123, wherein, after administration to a subject, the dosage form has a larger t than a reference oral dosage form (e.g., a dosage form having any expected release rate profile, such as a modulated release rate profile; a dosage form without a modulated release rate profile; a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0546] 125. A method for treating a generalized epilepsy syndrome with absence seizures in a patient with such need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction in the number of seizures.

[0547] 126. A method of treating a generalized epilepsy syndrome with absence seizures in a patient with such need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction in seizure density as measured by electroencephalography (EEG).

[0548] 127. A method of treating a generalized epilepsy syndrome with absence seizures in a patient with such need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction in the average duration of seizures as measured by EEG.

[0549] 128. A method of treating a generalized epilepsy syndrome with absence seizures in a patient with such need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction in the cumulative duration of seizures as measured by EEG.

[0550] 129. A method for treating a generalized epilepsy syndrome with absence seizures in a patient with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99), resulting in a reduction in the total duration of spike discharges of 2.5-4 Hz after hyperventilation and light stimulation challenge, as measured by EEG.

[0551] 130. A method of treating a generalized epilepsy syndrome with absence seizures in a patient with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a decrease in overall severity as measured by a Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score.

[0552] 131. A method of treating essential tremor in a patient with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction of essential tremor as assessed by a Tetralogy of Traumatic Tremor Rating Scale (TETRAS) score.

[0553] 132. The method according to item 131, wherein the reduction of essential tremor is assessed by upper limb scoring using the Essential Tremor Rating Scale (TETRAS).

[0554] 133. The method according to item 131, wherein the reduction of essential tremor is assessed by TETRAS-ADL (Activities of Daily Living).

[0555] 134. The method according to item 131 or 132, wherein the reduction of essential tremor is assessed by TETRAS performance subscale scoring or TETRAS performance individual items.

[0556] 135. A method of treating essential tremor in a patient with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99) resulting in a reduction of essential tremor as assessed by an accelerometer-based upper limb score.

[0557] 136. A method of treating essential tremor in a patient with this need, comprising administering to the patient an adequate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form according to any one of items 1-45, a composition according to any one of items 46-87, or a crystalline form according to any one of items 88-99), which results in a reduction of the σ band.

[0558] 137. The method according to any one of items 131-136, wherein the idiopathic tremor is an upper limb tremor.

[0559] Equivalent schemes and scope

[0560] In the claims, articles such as “a,” “an,” and “the” can refer to one or more species unless the contrary is indicated or otherwise apparent from the context. A claim or description including “or” among one or more members of a group is considered to satisfy the requirement that one or more members of the group are present in, used in, or otherwise associated with the specified product or process, unless the contrary is indicated or otherwise apparent from the context. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or method. The invention includes embodiments in which more than one or all members of the group are present in, used in, or otherwise associated with a given product or method.

[0561] Furthermore, this invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, where an aspect of the invention is referred to as comprising a particular element and / or feature, certain embodiments of the invention or aspects of the invention consist of, or are substantially composed of, such elements and / or features. For simplicity, those embodiments are not specifically described herein in such language. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges may be assumed in different embodiments of the invention to be any specific value or subrange within the range, accurate to one-tenth of the lower limit unit of the range, unless the context clearly indicates otherwise.

[0562] This application relates to various granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, the specification shall prevail. Furthermore, any particular embodiment of the invention falling within the prior art may be expressly excluded from any one or more claims. Because such embodiments are considered known to those skilled in the art, they may be excluded even if not expressly stated herein. For any reason, whether or not related to the existence of prior art, any particular embodiment of the invention may be excluded from any claim.

[0563] Those skilled in the art will recognize or be able to determine many equivalent embodiments of the specific implementation described herein using no more than routine experiments. The scope of the embodiments described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. An oral dosage form comprising: a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof; and a modulating polymer thereof; wherein the oral dosage form comprises about 0.9% to about 40% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof and about 10% to about 70% by weight of a modulating polymer.

2. The oral dosage form of claim 1, wherein the oral dosage form comprises about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

3. The oral dosage form of claim 2, wherein the oral dosage form comprises about 2% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

4. The oral dosage form of claim 2, wherein the oral dosage form comprises about 3% to about 20% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

5. The oral dosage form of claim 1, wherein the oral dosage form comprises about 4% to about 15% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

6. The oral dosage form of claim 1, wherein the oral dosage form comprises about 4% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

7. The oral dosage form of claim 6, wherein the oral dosage form comprises about 4% to about 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

8. The oral dosage form of claim 6, wherein the oral dosage form comprises about 5% to about 15% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

9. The oral dosage form of claim 6, wherein the oral dosage form comprises about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

10. The oral dosage form according to any one of claims 1-9, wherein the oral dosage form comprises about 1 mg to about 40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

11. The oral dosage form of claim 10, wherein the oral dosage form comprises about 10 mg to about 30 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

12. The oral dosage form of claim 10, wherein the oral dosage form comprises about 15 mg to about 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

13. The oral dosage form according to any one of claims 1-12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II): (II)。 14. The oral dosage form of claim 13, wherein the compound of formula (II) is in crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at the following diffraction angles of 2θ: 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.

2.

15. The oral dosage form of claim 14, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG1.

16. The oral dosage form of claim 14 or 15, wherein the crystalline form has a melting point starting at about 226.6°C as determined by differential scanning calorimetry (DSC).

17. The oral dosage form as described in claim 15, wherein, The crystalline form has a DSC curve that is essentially the same as the DSC curve shown in Figure 2.

18. The oral dosage form of any one of claims 1-17, wherein the oral dosage form comprises about 55 mg to 65 mg of the modulated polymer.

19. The oral dosage form of any one of claims 1-18, wherein the oral dosage form comprises about 50% to about 60% by weight of a modulating polymer.

20. The oral dosage form according to any one of claims 1-19, wherein the oral dosage form further comprises a diluent.

21. The oral dosage form of claim 20, wherein the diluent is microcrystalline cellulose.

22. The oral dosage form of claim 21, wherein the oral dosage form comprises about 15 mg to about 40 mg of microcrystalline cellulose.

23. The oral dosage form of claim 21, wherein the oral dosage form comprises about 15% to about 35% by weight of microcrystalline cellulose.

24. The oral dosage form according to any one of claims 1-23, wherein the oral dosage form further comprises a gliding agent.

25. The oral dosage form of claim 24, wherein the gliding agent is colloidal silica.

26. The oral dosage form according to any one of claims 1-25, wherein the oral dosage form further comprises a lubricant.

27. The oral dosage form of claim 26, wherein the lubricant is magnesium stearate.

28. The oral dosage form according to any one of claims 1-27, wherein the oral dosage form further comprises a coating agent.

29. The oral dosage form according to any one of claims 1-28, wherein, Approximately 80% of the compounds of formula (I) or their pharmaceutically acceptable salts are released within 7 hours after administration to the subject.

30. The oral dosage form as described in claim 29, wherein, Measured using a USP device type-I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm, approximately 80% of the compound of formula (I) or its pharmaceutically acceptable salt was released within 7 hours.

31. The oral dosage form according to any one of claims 1-30, wherein the oral dosage form is for administration to a subject once daily.

32. The oral dosage form according to any one of claims 1-30, wherein the oral dosage form is for administration to a subject twice daily.

33. The oral dosage form of claim 1, comprising: about 15 mg to about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and about 55 mg to 65 mg of HPMC polymer.

34. The oral dosage form of claim 1, comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and about 53% to about 64% by weight of an HPMC polymer.

35. The oral dosage form of claim 1, comprising: about 3 mg to about 8 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and about 55 mg to 65 mg of HPMC polymer.

36. The oral dosage form of claim 1, comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and about 53% to about 64% by weight of an HPMC polymer.

37. The oral dosage form according to any one of claims 1-36, wherein the oral dosage form is a tablet.

38. The oral dosage form according to any one of claims 1-36, wherein the oral dosage form is a capsule.

39. The oral dosage form according to any one of claims 1-36, wherein the dosage form is a suspension.

40. The oral dosage form according to any one of claims 1-39, wherein the release-modifying polymer is selected from hydrophilic matrix polymers, hydrophobic matrix polymers, and polyacrylate polymers.

41. The oral dosage form of claim 40, wherein the sustained-release polymer is a hydrophilic matrix polymer.

42. The oral dosage form of claim 41, wherein the hydrophilic matrix polymer is hydroxypropyl methylcellulose.

43. The oral dosage form according to any one of claims 1-42, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is stable for at least 24 months at about 25°C and 60% relative humidity.

44. The oral dosage form according to any one of claims 1-43, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is stable at about 25°C and 60% relative humidity for at least 36 months.

45. The oral dosage form according to any one of claims 1-44, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is stable for at least 48 months at about 25°C and 60% relative humidity.

46. ​​The oral dosage form according to any one of claims 1-45, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is stable for at least 60 months at about 25°C and 60% relative humidity.

47. The oral dosage form according to any one of claims 1-42, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is stable at about 40°C and 75% relative humidity for at least 6 months.

48. Use of an oral dosage form of any one of claims 1-47 in the preparation of a medicament for treating a neurological disorder related to abnormal function of T-type calcium channels in a subject of need, wherein the neurological disorder is essential tremor.

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