High strength single unit dose formulations and methods of use thereof

Abstract

Described herein, in part, are single unit dosage forms comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) wherein the composition is bioequivalent to a reference composition of the same dose intensity administered as a plurality of small round tablets. The invention further comprises methods useful for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor (e.g., idiopathic tremor).

Description

Related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 449,529, filed March 2, 2023, the entire contents of which are hereby incorporated by reference. Background Technology

[0002] Essential tremor (ET) is the most common movement disorder in adults, affecting up to 2% of the U.S. population (approximately 7 million Americans). ET is characterized by postural and kinetic tremors (i.e., tremors during voluntary movement) of 5 Hz to 12 Hz in the upper limbs. The most characteristic clinical feature is kinetic tremor in the arms and hands, but tremors can also occur in the head and voice, and are less common in the face, legs, and trunk. Diagnosis of ET is based on medical history and neurological examination, as described in the International Parkinson's and Movement Disorders Society Consensus Statement on the Classification of Tremors.

[0003] The severity of ET varies; some patients do not require treatment, while others suffer from severe disability and impairment in activities of daily living (such as dressing and eating). By definition, ET is usually unrelated to other neurological signs, although there is growing recognition that ET can also be associated with other motor features such as postural instability, dystonia, mild to moderate gait ataxia, and oculomotor abnormalities. ET is also associated with an increased prevalence of comorbid mental disorders, including anxiety and depression. ET typically worsens over time, with more severe tremors and corresponding disability progressing over years to decades.

[0004] ET can be sporadic, but a family history of autosomal dominant inheritance is common, and importantly, the calcium voltage-gated channel subunit α1G (CACNA1G) gene (which encodes T-type calcium) is involved. 2+ Variants in the channel isotype Cav3.1 have been identified as causes of ET in at least three families. The importance of the CACNA1G gene for cerebellar development and function is further highlighted by the following observations: variants in this gene may also cause childhood cerebellar atrophy and spinocerebellar ataxia type 42. The functional consequences of these genetic variants are related to T-type Ca in the cerebellum and distal cerebellar-thalamic-cortical (CTC) circuits. 2+The expression of the channel is consistent with its physiological contribution to oscillatory bursts of discharge in the thalamus, which are synchronized with and may drive clinically observable tremors.

[0005] Propranolol is the only FDA-approved oral treatment for the treatment of acute exacerbation (ET). Originally developed for hypertension, propranolol has shown limited efficacy in the treatment of ET, with side effects (e.g., bradycardia) often leading to discontinuation. The unmet medical need for ET has resulted in the off-label use of drugs across multiple classes, including anticonvulsants, barbiturates, benzodiazepines, and antipsychotics, with limited and significant therapeutic benefits for patients with ET. A recent evidence-based review concluded that, among 28 drugs studied for ET, only propranolol, primidone, and topiramate had sufficient evidence to support efficacy. Surgical interventions that interrupt the bursts of cerebellar-thalamic-cortical (CTC) activity (such as deep brain stimulation or focused ultrasound) are effective treatments for ET, but they carry risks such as sensory disturbances, mild hemiparesis, dysarthria, ataxia, gait disturbances, delirium, cognitive decline, tissue damage, venous thrombotic events, and intracerebral hemorrhage.

[0006] Voltage-gated ion channels play a crucial role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks. 2+ The channel changes have involved ET. It includes three isotypes (CaV3.1, CaV3.2, and CaV3.3), and T-type Ca... 2+ These calcium channels are widely expressed throughout the brain, particularly in the central nervous system (CTC) circuit. They have been shown to play a crucial role in regulating neuronal firing patterns by controlling the switching between a rigid, steady-state firing pattern and a pattern consisting of brief bursts of high-frequency activity in wild-type rodents and tremor rodent models. Importantly, the aberrant bursts in the CTC circuit occur at the same frequency as upper limb tremors in ET, suggesting that a reduction in T-type calcium channel-mediated burst firing may have a therapeutic benefit in reducing tremor-related burst firing in the CTC circuit.

[0007] PRAX-944 ( N -((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride) is a T-type calcium channel blocker being developed for the treatment of ET. 2+ High affinity, state-dependent, and selective inhibitory effect of the channel. In vitro electrophysiological studies have shown that PRAX-944 is an inhibitor of T-type Ca2+. 2+The channels (CaV3.1 and CaV3.3) are specific and have nanomolar efficiency.

[0008] By blocking T-type Ca 2+ PRAX-944 reduces burst activity in the CTC circuit, thereby reducing tremor and related disability. PRAX-944 has demonstrated robust activity in animal models of ET. To date, PRAX-944 programs have been completed in five Phase 1 studies in healthy participants using dose levels ranging from 2.5 mg to 120 mg. Recent clinical trials using PRAX-944 have utilized the MR7 formulation and introduced titration protocols for achieving higher dose levels. In summary, these developments contribute to improved safety and tolerability, as well as a wider therapeutic window, compared to immediate-release (IR) formulations. In the two trials Z944-103 and Z944-104, the MR7 formulation was designed to delay tmax and reduce Cmax with minimal impact on AUC compared to the IR formulation, and was associated with reduced frequency of CNS, psychiatric, and overall adverse events. Furthermore, the PRAX-944-105 trial demonstrated that doses above 40 mg were well tolerated when administered using a 28-day titration regimen. For the MR7 formulation administered in this manner, no maximum tolerated dose has been observed, and doses up to 120 mg have been well tolerated. Preliminary efficacy data were also collected in an early phase 2 trial in participants with ET.

[0009] With the modulated-release (MR) formulation demonstrating robust pharmacodynamic effects when administered once daily (QD) within 24 times the well-tolerated dose range, combined with preliminary efficacy data, there is a clear clinical basis to support further investigation of the safety and efficacy of PRAX-944 in addressing unmet needs in ET.

[0010] However, certain challenges associated with using currently available PRAX-944 MR formulations (i.e., placebo, 5 mg, and 20 mg tablets) have been identified during clinical trials. For example, PRAX-944 is delivered in different dose strengths in the form of multiple tablet combinations packaged in blister packs (e.g., including one or more of placebo, 5 mg, and 20 mg tablets) for clinical blinding purposes. It has been found that opening the blister pack, handling the small, round tablets, and taking many pills is particularly challenging for patients with movement disorders such as essential tremor (ET). Therefore, there is a need to develop new single-unit dose tablets with appropriate strengths to improve patient availability, reduce the total number of dose units (e.g., tablets) required to deliver a specific dose strength to a patient, and reduce or eliminate the risk of dosing errors. Summary of the Invention

[0011] This disclosure provides compositions and pharmaceutical compositions comprising single-unit dosage forms, said pharmaceutical compositions comprising (I) compounds or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II), such as PRAX-944 HCl). In some embodiments, the compositions described herein are bioequivalent to currently available oral dosage forms, such as the current PRAX-944 dosage form, which is a modulated-release (MR) formulation obtained in the form of spherical and small-sized (e.g., about 6 mm in diameter) 5 mg and 20 mg tablets. The invention further comprises methods for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor (e.g., essential tremor). This disclosure further comprises methods for preventing and / or treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor, such as essential tremor.

[0012] On one hand, this disclosure provides a single-unit dosage form comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl), wherein the single-unit dosage form is bioequivalent to a reference composition having the same dose strength when administered as one or more dosage forms (such as multiple small round 20 mg PRAX-944 tablets).

[0013] In some embodiments, the single-unit dosage form and the reference composition have: (i) different sizes; (ii) different shapes; (iii) both different sizes and different shapes; (iv) the same shape but different sizes; or (v) the same size but different shapes. In some embodiments, the single-unit dosage form is larger than the reference composition. In some embodiments, the reference composition comprises smaller, round 20 mg PRAX-944 tablets.

[0014] In some embodiments, the single-unit dosage form is a larger tablet that, when administered to subjects in an eating and / or fasting state, demonstrates bioequivalence compared to a reference composition having the same dose strength as one or more smaller dosage forms, optionally one or more small round 20 mg PRAX-944 tablets, in a feeding and / or fasting state; wherein bioequivalence is determined by: (a) a 90% confidence interval for the AUC being between about 80% and about 125% (e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%). %, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119% (a) approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, or approximately 125%), and (b) the 90% confidence interval for Cmax is between approximately 80% and approximately 125% (e.g., approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately...). (98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, or approximately 125%). In some embodiments, the 90% confidence interval of the AUC and / or the Cmax may be included within more stringent confidence limits, for example, approximately 90% to approximately 120%, approximately 90% to approximately 115%, approximately 90% to approximately 110%, or approximately 90% to approximately 100%.

[0015] In some embodiments, the single-unit dosage form (i) reduces the total number of dose units (e.g., tablets) required to deliver a specific dose intensity to a subject; (ii) is characterized by a physical size and shape (e.g., tablet size and shape) that makes it easier and more convenient for a subject with a movement disorder (such as essential tremor (ET)) to grasp; (iii) can be dispensed into single-unit dose intensities of 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg; and / or (iv) does not require titration to achieve a dose >40 mg. In some embodiments, titration may reduce and / or eliminate adverse events. In some embodiments, titration may comprise administration of one or more single-unit dosage forms described herein. In some embodiments, at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within a predetermined time period upon administration to a subject. In some embodiments, the predetermined time period may be in the range of about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours).

[0016] In some embodiments, at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours) when administered to a subject.

[0017] In some embodiments, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours) when administered to a subject.

[0018] In some embodiments, about 5% to about 25% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released over about 1 hour to about 2 hours upon administration to a subject.

[0019] In some embodiments, about 25% to about 50% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released over about 2 hours to about 4 hours upon administration to a subject.

[0020] In some embodiments, about 50% to about 75% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released over about 3 hours to about 7 hours upon administration to a subject.

[0021] In some embodiments, about 75% to about 100% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released over about 6 hours to about 10 hours upon administration to a subject.

[0022] In some embodiments, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 7 hours when administered to a subject.

[0023] In some embodiments, about 90% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 9 hours to about 12 hours when administered to a subject.

[0024] In some embodiments, at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released over a predetermined time period using a USP device type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm. In some embodiments, the predetermined time period may be in the range of about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours).

[0025] In some embodiments, at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), e.g., PRAX-944 HCl) is released using a USP device type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm over a period of about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours). In some embodiments, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), e.g., PRAX-944 HCl) is released using a USP device type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm over a period of about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours).

[0026] In some embodiments, the single-unit dosage form comprises about 1 mg to about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl). In some embodiments, the single-unit dosage form comprises about 1% by weight to about 70% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0027] In some embodiments, the single-unit dosage form further comprises a release modulating polymer. In some embodiments, the release modulating polymer comprises a matrix polymer optionally selected from the group consisting of hydrophilic matrix polymers, hydrophobic matrix polymers, polyacrylate polymers, and combinations thereof. In some embodiments, the release modulating polymer comprises (i) a hydrophilic matrix polymer optionally selected from the group consisting of hydroxypropyl methylcellulose, HPMC (hydroxypropyl methylcellulose), and combinations thereof, wherein the HPMC (hydroxypropyl methylcellulose) is optionally selected from the group consisting of Methocel K4M, Methocel K100LV, Methocel E50LV, and combinations thereof; (ii) a hydrophobic matrix polymer optionally selected from the group consisting of ethylcellulose, ethocel, and combinations thereof; and / or (iii) a polyacrylate polymer optionally selected from the group consisting of Eudragit RL100, Eudragit RS100, and combinations thereof. In some embodiments, the single-unit dosage form comprises about 5 mg to 300 mg of the release modulating polymer. In some embodiments, the single-unit dosage form comprises about 10% to about 70% by weight of the modulating polymer. In some embodiments, the modulating polymer is hydroxypropyl methylcellulose.

[0028] In some embodiments, the single-unit dosage form further comprises a diluent, optionally a soluble diluent. In some embodiments, the diluent comprises: (i) a cellulose derivative, optionally microcrystalline cellulose, optionally silanized microcrystalline cellulose; (ii) starch, optionally selected from the group consisting of hydrolyzed starch, pregelatinized starch, and combinations thereof; (iii) anhydrous lactose; (iv) lactose monohydrate; (v) dicalcium phosphate (DCP); and / or (vi) a sugar alcohol, optionally selected from the group consisting of sorbitol, xylitol, mannitol, and combinations thereof. In some embodiments, the single-unit dosage form comprises about 5 mg to about 300 mg of diluent. In some embodiments, the single-unit dosage form comprises about 5% by weight to about 50% by weight of diluent. In some embodiments, the diluent is microcrystalline cellulose, optionally silanized microcrystalline cellulose. In some embodiments, the diluent is a sugar alcohol, optionally mannitol.

[0029] In some embodiments, the single-unit dosage form further comprises a flow aid. In some embodiments, the flow aid is selected from the group consisting of fumed silica, optionally colloidal silica, talc, magnesium carbonate, and combinations thereof. In some embodiments, the single-unit dosage form comprises about 1 mg to about 10 mg of the flow aid. In some embodiments, the single-unit dosage form comprises about 1% by weight to about 10% by weight of the flow aid. In some embodiments, the flow aid is fumed silica, optionally colloidal silica.

[0030] In some embodiments, the single-unit dosage form further comprises a lubricant. In some embodiments, the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, talc, silica, fats, optionally vegetable stearins and combinations thereof. In some embodiments, the single-unit dosage form comprises about 1 mg to about 10 mg of lubricant. In some embodiments, the single-unit dosage form comprises about 1% by weight to about 10% by weight of lubricant. In some embodiments, the lubricant comprises magnesium stearate.

[0031] In some embodiments, the single-unit dosage form further comprises a coating. In some embodiments, the coating comprises a film-coating agent. In some embodiments, the coating comprises pharmacopoeia-grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and / or talc. In some embodiments, the single-unit dosage form comprises about 1 mg to about 20 mg of coating. In some embodiments, the single-unit dosage form comprises about 1% to about 10% by weight of coating. In some embodiments, the coating comprises Opadry® II White 85F18422.

[0032] In some embodiments, the single-unit dosage form comprises tablets, optionally formulated for oral administration. In some embodiments, the single-unit dosage form comprises rectangular tablets, oval tablets, or capsule-shaped tablets, optionally wherein the tablets are not round tablets. In some embodiments, for example, opening the blister pack of rectangular, oval, or capsule-shaped tablets, handling rectangular, oval, or capsule-shaped tablets, and taking one or more rectangular, oval, or capsule-shaped tablets are less challenging and more convenient for patients with movement disorders such as essential tremor (ET).

[0033] In some embodiments, the total weight of the single-unit dosage form is about 200 mg to about 600 mg per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 1% to about 100% by weight of PRAX-944HCl, optionally wherein the total weight of the dosage units (e.g., each tablet) is about 200 mg to about 600 mg (e.g., about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 35 ...0 mg, about 355 mg, about 350 mg, about 350 mg, about 350 mg, about 350 mg, about 350 mg, approximately 360 mg, approximately 365 mg, approximately 370 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, approximately 505 mg, approximately 510 mg, approximately 515 mg, approximately 520 mg, approximately 525 mg, approximately 530 mg, approximately 535 mg, approximately 540 mg, approximately 545 mg, approximately 550 mg, approximately 555 mg, approximately 560 mg mg, approximately 565 mg, approximately 570 mg, approximately 575 mg, approximately 580 mg, approximately 585 mg, approximately 590 mg, approximately 595 mg, or approximately 600 mg).

[0034] In some embodiments, the length of the single-unit dosage form is from about 1 mm to about 30 mm (e.g., lengths of about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, about 15 mm, about 15.5 mm, about 16 mm, about 16.5 mm, about 17 mm, about 17.5 mm, about 18 mm, about 18.5 mm, about 19 mm, about 19.5 mm, about 20 mm, about 20.5 mm, about 21 mm, about 21 mm, about 20 ... mm, approximately 21.5 mm, approximately 22 mm, approximately 22.5 mm, approximately 23 mm, approximately 23.5 mm, approximately 24 mm, approximately 24.5 mm, approximately 25 mm, approximately 25.5 mm, approximately 26 mm, approximately 26.5 mm, approximately 27 mm, approximately 27.5 mm, approximately 28 mm, approximately 28.5 mm, approximately 29 mm, approximately 29.5 mm, or approximately 30 mm).

[0035] In some embodiments, the width of the single-unit dosage form is from about 1 mm to about 30 mm (e.g., widths of about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, about 15 mm, about 15.5 mm, about 16 mm, about 16.5 mm, about 17 mm, about 17.5 mm, about 18 mm, about 18.5 mm, about 19 mm, about 19.5 mm, about 20 mm, about 20.5 mm). mm, approximately 21 mm, approximately 21.5 mm, approximately 22 mm, approximately 22.5 mm, approximately 23 mm, approximately 23.5 mm, approximately 24 mm, approximately 24.5 mm, approximately 25 mm, approximately 25.5 mm, approximately 26 mm, approximately 26.5 mm, approximately 27 mm, approximately 27.5 mm, approximately 28 mm, approximately 28.5 mm, approximately 29 mm, approximately 29.5 mm, or approximately 30 mm).

[0036] In some embodiments, the width of the single-unit dosage form is from about 1 mm to about 10 mm (e.g., widths of about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3 mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm). mm, approximately 4.9 mm, approximately 5 mm, approximately 5.1 mm, approximately 5.2 mm, approximately 5.3 mm, approximately 5.4 mm, approximately 5.5 mm, approximately 5.6 mm, approximately 5.7 mm, approximately 5.8 mm, approximately 5.9 mm, approximately 6 mm, approximately 6.1 mm, approximately 6.2 mm, approximately 6.3 mm, approximately 6.4 mm, approximately 6.5 mm, approximately 6.6 mm, approximately 6.7 mm, approximately 6.8 mm, approximately 6.9 mm, approximately 7 mm, approximately 7.1 mm, approximately 7.2 mm, approximately 7.3 mm, approximately 7.4 mm, approximately 7.5 mm, approximately 7.6 mm, approximately 7.7 mm, approximately 7.8 mm, approximately 7.9 mm, approximately 8 mm, approximately 8.1 mm, approximately 8.2 mm, approximately 8.3 mm, approximately 8.4 mm, approximately 8.5 mm, approximately 8.6 mm, approximately 8.7 mm, approximately 8.8 mm, approximately 8.9 mm, approximately 9 mm, approximately 9.1 mm, approximately 9.2 mm, approximately 9.3 mm, approximately 9.4 mm, approximately 9.5 mm, approximately 9.6 mm, approximately 9.7 mm, approximately 9.8 mm, approximately 9.9 mm, or approximately 10 mm).

[0037] In some embodiments, the length of the single-unit dosage form is from about 14 mm to about 16 mm (e.g., lengths of about 14 mm, about 14.1 mm, about 14.2 mm, about 14.3 mm, about 14.4 mm, about 14.5 mm, about 14.6 mm, about 14.7 mm, about 14.8 mm, about 14.9 mm, about 15 mm, about 15.1 mm, about 15.2 mm, about 15.3 mm, about 15.4 mm, about 15.5 mm, about 15.6 mm, about 15.7 mm, about 15.8 mm, about 15.9 mm, or about 16 mm), and the width is from about 5 mm to about 7 mm (e.g., widths of about 5 mm, about 5.1 mm, about 5.2 mm, about 5.3 mm, about 5.4 mm, about 5.5 mm, about 5.6 mm, about 5.7 mm, about 5.8 mm, about 5.9 mm, about 6 mm, or about 6.1 mm). mm, approximately 6.2 mm, approximately 6.3 mm, approximately 6.4 mm, approximately 6.5 mm, approximately 6.6 mm, approximately 6.7 mm, approximately 6.8 mm, approximately 6.9 mm, or approximately 7 mm).

[0038] In some embodiments, the single-unit dosage form contains an amount equivalent to about 5 mg of PRAX-944 free base per dose unit (e.g., per tablet), optionally about 1 mg to about 10 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0039] In some embodiments, the single-unit dosage form contains an amount equivalent to about 10 mg of PRAX-944 free base per dose unit (e.g., per tablet), optionally about 5 mg to about 15 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0040] In some embodiments, the single-unit dosage form contains an amount equivalent to about 15 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 10 mg to about 20 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0041] In some embodiments, the single-unit dosage form contains an amount equivalent to about 20 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 15 mg to about 25 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0042] In some embodiments, the single-unit dosage form contains an amount equivalent to about 25 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 20 mg to about 30 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0043] In some embodiments, the single-unit dosage form contains an amount equivalent to about 30 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 25 mg to about 35 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0044] In some embodiments, the single-unit dosage form contains an amount equivalent to about 35 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 30 mg to about 40 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0045] In some embodiments, the single-unit dosage form contains an amount equivalent to about 40 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 35 mg to about 45 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0046] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl) equivalent to about 45 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 40 mg to about 50 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0047] In some embodiments, the single-unit dosage form contains an amount equivalent to about 50 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 45 mg to about 55 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0048] In some embodiments, the single-unit dosage form contains an amount equivalent to about 55 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 50 mg to about 60 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0049] In some embodiments, the single-unit dosage form contains an amount equivalent to about 60 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 55 mg to about 65 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0050] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944HCl) equivalent to about 65 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 60 mg to about 70 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0051] In some embodiments, the single-unit dosage form contains an amount equivalent to about 70 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 65 mg to about 75 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0052] In some embodiments, the single-unit dosage form contains an amount equivalent to about 75 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 70 mg to about 80 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0053] In some embodiments, the single-unit dosage form contains an amount equivalent to about 80 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 75 mg to about 85 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944HCl).

[0054] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 85 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 80 mg to about 90 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0055] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) equivalent to about 90 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 85 mg to about 95 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0056] In some embodiments, the single-unit dosage form contains an amount equivalent to about 95 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 90 mg to about 100 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0057] In some embodiments, the single-unit dosage form contains an amount equivalent to about 100 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 95 mg to about 105 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0058] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 105 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 100 mg to about 110 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0059] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 110 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 105 mg to about 115 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0060] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 115 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 110 mg to about 120 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0061] In some embodiments, the single-unit dosage form contains an amount equivalent to about 120 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 115 mg to about 125 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0062] In some embodiments, the single-unit dosage form contains an amount equivalent to about 125 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 120 mg to about 130 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0063] In some embodiments, the single-unit dosage form contains an amount equivalent to about 130 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 125 mg to about 135 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0064] In some embodiments, the single-unit dosage form contains an amount equivalent to about 135 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 130 mg to about 140 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0065] In some embodiments, the single-unit dosage form contains an amount equivalent to about 140 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 135 mg to about 145 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0066] In some embodiments, the single-unit dosage form contains an amount equivalent to about 145 mg of PRAX-944 free base per dose unit (e.g., per tablet), and optionally about 140 mg to about 150 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0067] In some embodiments, the single-unit dosage form contains an amount equivalent to about 150 mg of PRAX-944 free base / dose unit (e.g., per tablet), optionally about 145 mg to about 155 mg of PRAX-944 HCl / dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0068] In some embodiments, the single-unit dosage form contains an amount equivalent to about 155 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 150 mg to about 160 mg of PRAX-944 HCl per dose unit (e.g., per tablet) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl).

[0069] In some embodiments, the single-unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 160 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 155 mg to about 165 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0070] In some embodiments, the single-unit dosage form contains an amount equivalent to about 1.0 mg to about 200 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg). mg) PRAX-944 free base / dose unit (e.g., per tablet) of the compound of formula (I) or its pharmaceutically acceptable salt (e.g., the compound of formula (II), such as PRAX-944HCl). In some embodiments, the single-unit dosage form comprises about 1% to about 50% by weight (e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight) of PRAX-944 HCl, optionally wherein the total dose unit (e.g., tablet) weight is about 50 mg to about 500 mg (e.g., about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 28 ... (mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, or approximately 500 mg).

[0071] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 5.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 1% to about 5% by weight of PRAX-944 HCl, optionally about 1 mg to about 10 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0072] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 10.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 1% to about 10% by weight of PRAX-944 HCl, optionally about 5 mg to about 15 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0073] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 20.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 1% to about 10% by weight of PRAX-944 HCl, optionally about 15 mg to about 25 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0074] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 40.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 5% to about 15% by weight of PRAX-944 HCl, optionally about 25 mg to about 50 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0075] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) equivalent to about 60.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 5% to about 20% by weight of PRAX-944 HCl, optionally about 50 mg to about 75 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0076] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 80.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 15% to about 25% by weight of PRAX-944 HCl, optionally about 75 mg to about 100 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0077] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 100.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 20% to about 25% by weight of PRAX-944 HCl, optionally about 75 mg to about 125 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0078] In some embodiments, the single-unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) in an amount equivalent to about 120.0 mg of PRAX-944 free base per dose unit (e.g., per tablet). In some embodiments, the single-unit dosage form comprises about 25% to about 35% by weight of PRAX-944 HCl, optionally about 110 mg to about 135 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0079] In some embodiments, the single-unit dosage form further comprises one or more of the following: (i) a release polymer, optionally about 35% to about 45% by weight, optionally about 175 mg to about 185 mg of release polymer per dose unit (e.g., per tablet); (ii) a soluble diluent, optionally about 6% to about 10% by weight, optionally about 34 mg to about 38 mg of soluble diluent per dose unit (e.g., per tablet); (iii) a flow aid, optionally about 1% to about 3% by weight, optionally about 6 mg to about 8 mg of flow aid per dose unit (e.g., per tablet); (iv) a lubricant, optionally about 0.5% to about 2% by weight, optionally about 3 mg to about 6 mg of lubricant per dose unit (e.g., per tablet); and (v) a coating, optionally about 12% to about 15% by weight, optionally about 1 mg to about 5 mg of coating per dose unit (e.g., per tablet).

[0080] In some embodiments, the single-unit dosage form comprises: (i) Prototype 01 (58% K4M round tablets) (DC); (ii) Prototype 01 (58% K4M capsules) (DC); (iii) Prototype 04 (58% K4M) (DG); (iv) Prototype 23 (50% K4M); (v) Prototype 28 (58% K100LV); (vi) Prototype 34 (50% K100LV, 8% mannitol EG); (vii) Prototype 36 (50% K100LV, 8% mannitol IG); (viii) Prototype 52 (28% K100LV, 30% E50LV); (ix) Prototype 53 (40% K100LV, 8% mannitol IG); or (x) Prototype 54 (46% K100LV, 12% mannitol IG). In some embodiments, the single-unit dosage form comprises: (i) large tablet prototype 04 (58% K4M) (DG); (ii) large tablet prototype 28 (58% K100LV); or (x) large tablet prototype 53 (40% K100LV, 8% mannitol IG).

[0081] On the one hand, this disclosure provides a pharmaceutical composition comprising a single-unit dosage form according to any one of the preceding claims, and at least one pharmaceutically acceptable carrier or excipient.

[0082] On one hand, this disclosure provides a method for treating a disease or condition related to abnormal function or activity of T-type calcium channels in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the single-unit dosage form or pharmaceutical composition described herein.

[0083] On one hand, this disclosure provides a method for treating tremor in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a single-unit dose or pharmaceutical composition described herein.

[0084] On one hand, this disclosure provides a method for treating essential tremor in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a single-unit dose or pharmaceutical composition described herein.

[0085] In some embodiments, the method reduces the essential tremor, as assessed by a Essential Tremor Assessment Scale (TETRAS) score. In some embodiments, the reduction in the essential tremor is assessed by an upper limb score on the Essential Tremor Assessment Scale (TETRAS). In some embodiments, the reduction in the essential tremor is assessed by TETRAS-ADL (Activities of Daily Living). In some embodiments, the reduction in the essential tremor is assessed by TETRAS performance subscale scores or TETRAS performance individual items. In some embodiments, the method reduces the essential tremor, as assessed by an accelerometer-based upper limb score. In some embodiments, the method reduces the Σ band. In some embodiments, the essential tremor is an upper limb tremor.

[0086] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following description of the drawings, detailed embodiments, examples and claims. Attached Figure Description

[0087] Figure 1 The composition and properties of the active pharmaceutical ingredient PRAX-944 (also referred to herein as PRAX-944 HCl) are described.

[0088] Figure 2A It depicts tablets of various shapes and sizes.

[0089] Figure 2B A comparison is drawn between currently available PRAX-944 dosage forms (which are modulated-release (MR) formulations obtained in the form of small (6 mm in diameter) 5 mg and 20 mg round tablets) and the exemplary bioequivalent single-unit dosage forms described herein.

[0090] Figure 3AThe study design for PRAX-944-107 is described. N = the number of participants planned for the total population; n = the number of participants planned for each subgroup. Fasting: Each dose of the study drug will be taken with 240 mL of water after an overnight fast. No food or drink, except water, is permitted for at least 10 hours prior to administration. Participants must remain fasted for 4 hours after administration. Participants are not permitted to drink water for 2 hours before and 1 hour after each administration. Eating: The study drug is administered concurrently with a high-fat, high-calorie diet.

[0091] Figure 3B The study drug administered in PRAX-944-107 was described.

[0092] Figure 3C An exemplary high-dose-strength PRAX-944 tablet formulation tested in study 944-107 is depicted.

[0093] Figure 3D A schematic diagram of an exemplary phase 3 clinical trial design is depicted to evaluate the efficacy of large single-unit doses of PRAX-944 tablets (20 mg, 40 mg, 80 mg, and 120 mg) compared to the same dose level delivered with small, round 20 mg PRAX-944 tablets (1, 2, 4, and 6 tablets, respectively).

[0094] Figures 4A-4B The in vitro performance of 20 mg strength PRAX-944 modulated-release (MR) tablets and immediate-release (IR) capsules was described. Figure 4A ) and in the body ( Figure 4B Release curve. To improve tolerability, PRAX-944 was formulated as modulated-release (MR) tablets to prolong drug release and absorption, and therefore reduced C40 compared to immediate-release (IR) formulations. max And prolong the plasma concentration-time curve. For example... Figure 4A As shown, for the immediate-release (IR) formulation, approximately 100% of PRAX-944 is released in about 1 hour; and for the moderate-release (MR) formulation, approximately 80% of PRAX-944 is released in about 7 hours.

[0095] like Figure 4B As shown, the IR formulation achieved a C131 (25.6) C2. max (ng / mL) (CV%) and AUC 1090 (24.4) ∞ (ng.hr / mL) (CV%); and the MR formulation achieved a CV of 47.1 (34.3). max (ng / mL) (CV%) and AUC of 1010 (34.2) ∞ (ng.hr / mL) (CV%).

[0096] Figure 5A In vitro release profiles of the PRAX-944 large-tablet prototypes (i.e., large-tablet prototype 01 (58% K4M round) (DC), large-tablet prototype 01 (58% K4M capsule) (DC), large-tablet prototype 04 (58% K4M) (DG), large-tablet prototype 23 (50% K4M), large-tablet prototype 28 (58% K100LV), large-tablet prototype 34 (50% K100LV, 8% mannitol EG), large-tablet prototype 36 (50% K100LV, 8% mannitol IG), large-tablet prototype 52 (28% K100LV, 30% E50LV), large-tablet prototype 53 (40% K100LV, 8% mannitol IG), and large-tablet prototype 54 (46% K100LV, 12% mannitol IG)) were plotted compared to the reference tablet (i.e., the small 20 mg clinical tablet). DC and DG specify direct compression and dry granulation, respectively.

[0097] Figure 5B In vitro release profiles of the PRAX-944 large tablet prototypes (i.e., large tablet prototype 04, large tablet prototype 28, and large tablet prototype 53) were depicted compared to the reference tablet (i.e., the small 20 mg clinical tablet).

[0098] Figure 5C In vitro release profiles of PRAX-944 MR tablets (i.e., 20 mg large tablets, 40 mg large tablets, 80 mg large tablets, and 120 mg large tablets) were plotted compared to the reference tablet (i.e., the small 20 mg round clinical tablet).

[0099] Figures 6A-6B Cross-analysis was used to depict the relative bioavailability of the 120 mg large tablet (test) compared to the small round tablet (reference). Cross-analysis showed that both the 120 mg large tablet and the small round tablet met the AUC. last and C max Bioequivalence criteria (90% CI, within 80-125%) Figure 6B Outlier subjects were excluded from the analysis.

[0100] Figure 7 The dose-proportionality with small round tablets or large tablets was depicted. Outlier subjects were excluded from the analysis.

[0101] Figures 8A-8B The study described the food-deficient effect of 120 mg PRAX-944. Co-administration of the 120 mg large tablet with a high-fat, high-calorie diet resulted in a decrease in the food-dependent effect. max The delay was 3 hours, and the AUC and C... maxSlightly increased, but within the invalidity margin (90% CI, within 80-125%). Outlier subjects were excluded from the analysis.

[0102] Figures 9A-9C Relative bioavailability was depicted through parallel analyses using small round tablets or large tablets. While large tablets appeared to have increased exposure relative to small round tablets, this could be an artifact of the parallel study design. Bioequivalence (BE) criteria were met when the relative bioavailability of the 120 mg tablets was assessed via cross-analysis, while large tablets showed higher exposure than small round tablets when assessed via parallel analysis, with magnitudes similar to those of the lower-strength tablets. Outlier subjects were excluded from the analysis.

[0103] Figure 10A An exemplary schematic diagram depicts a cross-bioequivalence study. Detailed Implementation

[0104] This disclosure provides compositions designed to provide a larger and more convenient PRAX-944 dosage form compared to currently available PRAX-944 dosage forms, which are obtained in the form of small, round 5 mg and 20 mg tablets (6 mm in diameter). For example, the pharmaceutical compositions of this disclosure are designed to minimize the number of tablets required to deliver a specific dose level of PRAX-944. Figure 1 They also increased the physical size of the tablets and shaped them into capsules to make them easier to grip and more convenient, including for patients, especially those with essential tremor (ET). Figure 2A Tablets of various shapes and sizes are shown, and Figure 2B A comparison is shown between currently available PRAX-944 dosage forms (which are modified-release (MR) formulations obtained in the form of small, round (6 mm in diameter) 5 mg and 20 mg tablets) and the exemplary bioequivalent single-unit dosage forms described herein. Furthermore, the pharmaceutical compositions of this disclosure comprising larger capsule-shaped tablets have substantially the same bioavailability, for example, with respect to the rate of absorption (maximum plasma drug concentration; Cmax) and extent (area under the plasma concentration-time curve; AUC) of PRAX-944, compared to multiple small, round 20 mg tablets.

[0105] definition Generally, the “effective amount” of a compound refers to the amount sufficient to elicit the desired biological response. As those skilled in the art will understand, the effective amount of a compound 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.

[0106] As used herein, and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, condition, or symptom, or to delay, reduce, or eliminate one or more symptoms associated with the disease, condition, or symptom. 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, condition, or symptom. The term "therapeuticly effective amount" may encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or symptom, or enhance the therapeutic efficacy of another therapeutic agent.

[0107] As used herein, the term “refractory” means a disease, condition, or symptom that is not readily responsive to or controlled by a therapy or treatment. In some embodiments, the disease, condition, or symptom described herein is refractory (e.g., refractory epilepsy, refractory absence seizures, or refractory essential tremor) and does not respond to standard therapies or treatments.

[0108] As used herein, the term "subject" to which it is considered 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 older adults)) and / or non-human animals, such as mammals like 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. In some embodiments, the terms "patient" and "subject" are used interchangeably herein. In some embodiments, the subject is selected for treatment with the compound of formula (I) due to a clinical diagnosis of essential tremor. In some embodiments, the subject selected for treatment with the compound of formula (I) has essential tremor but not intention tremor.

[0109] The terms “disease,” “symptom,” and “symptom” are used interchangeably in this article.

[0110] 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”).

[0111] 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 proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art; for example, Berge et al. in the *Journal of Pharmaceutical Sciences* (… J. Pharmaceutical Sciences Pharmaceutically acceptable salts are described in detail in (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 salts formed by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include acetates, adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzenesulfonate, benzoates, besylates, hydrogen sulfates, borates, butyrates, camphorates, camphor sulfonates, citrates, cyclopentanepropionate, cyclohexylaminosulfonate, digluconate, dodecyl sulfate, ethanedisulfonate, ethanesulfonate, esylate, formate, fumarate, gentianate, glucono-p-ethyl, glycerol phosphates, gluconate, glucuronate, glutamate, glutamate, glycolate, hemisulfate, heptaate, hexanoate, hippurate, hydroiodide, and 2-hydroxy-ethanesulfonate. Hydroxyethyl sulfonate, ketoglutarate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, napadylate, napsylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, orotate, palmitate, pyrate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, sebate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and their stereoisomers (e.g., enantiomers, diastereomers), etc.

[0112] 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. In some embodiments, the compound of formula (I) is a hydrochloride salt.

[0113] The terms "release modulating polymer" or "matrix polymer" refer to polymers used in formulations (e.g., tablets and capsules) that alter the release rate of a drug when administered to a subject. For example, release modulating polymers are used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, a release modulating polymer is a controlled-release polymer. For example, a release modulating polymer or controlled-release polymer is an HPMC polymer. In some embodiments, the release modulating 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).

[0114] As used herein, the terms “diluent” or “filler” refer to excipients 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).

[0115] As used herein, the term "flow aid" refers to an excipient used to promote powder flow by reducing interparticle friction and binding forces. Flow aids include, for example, fumed silica (e.g., colloidal silica), talc, and magnesium carbonate.

[0116] 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 (e.g., vegetable fats).

[0117] As used herein, the term "coating" refers to an excipient that protects the tablet ingredients from deterioration due to moisture in the air and makes large or unpleasant-tasting tablets easier to swallow. For example, a coating may include Opadry® II White 85F18422, which contains pharmacopoeia-grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and talc.

[0118] The term "bioavailability" refers to the extent to which the active portion (e.g., a drug and / or metabolites) is absorbed into the systemic circulation and becomes available at the site of drug action in the body.

[0119] The terms "bioequivalence" or "bioequivalent" mean that when two products are administered at the same dose under similar conditions, there is no significant difference between the two pharmaceutical products. A product (e.g., a single-unit dosage form or a pharmaceutical composition as described herein) can be considered bioequivalent to a second product (e.g., a reference composition) if, in a suitably designed study, the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action are not significantly different when the product is administered at the same molar dose as the second product under similar conditions. Two products with different absorption rates can be considered equivalent if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and reflected in the proposed labeling, is not necessary for achieving effective in vivo drug concentrations with prolonged use, and is considered medically insignificant to the pharmaceuticals. In some embodiments, bioequivalence can be based on a difference of no more than about 20% between the AUC and Cmax of the product relative to the second product. In some embodiments, bioequivalence may be based on a difference of no more than about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, or about 20% between the AUC and Cmax of the product and the second product.

[0120] In some embodiments, when, for example, the target parameter (e.g., C) maxThe 90% confidence interval for (and AUC) is between approximately 80% and approximately 125% (e.g., approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%). Bioequivalence can be assumed when the percentages are approximately 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, or 125%. In some embodiments, the 90% confidence intervals of the AUC and / or Cmax can be included within more stringent confidence limits, for example, approximately 90% to approximately 120%, approximately 90% to approximately 115%, approximately 90% to approximately 110%, or approximately 90% to approximately 100%. In some embodiments, bioequivalence can be determined based on steady-state studies and / or single-dose studies. In some embodiments, bioequivalence studies can be conducted under fasting and / or feeding conditions.

[0121] In some embodiments, the compositions described herein are bioequivalent to currently available oral dosage forms, such as the current PRAX-944 dosage form, which is a modulated-release (MR) formulation obtained in the form of round and small-sized (e.g., about 6 mm in diameter) 5 mg and 20 mg tablets.

[0122] Therefore, if the 90% confidence interval of the average area under the curve (AUC) (AUCt or AUCinf) of the plasma level of the test composition is within about 80% to about 125% of the corresponding average of the reference composition (e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about...), the test composition is considered to be of high quality. (99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, or approximately 125%), and if the plasma level of the composition is tested. The 90% confidence interval for the average maximum concentration (Cmax) is within about 80% to about 125% of the corresponding average value of the reference composition (e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about...). If the percentages are approximately 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, or 125%, then the test composition (as described herein in a single-unit dosage form or pharmaceutical composition) may be considered bioequivalent to the reference composition. In some embodiments, the reference composition comprises the PRAX-944 pharmaceutical product supplied in 5 mg and 20 mg MR, white, round, film-coated tablets. Each reference tablet may contain the equivalent of 5 mg or 20 mg of PRAX-944 free base and optionally contain PRAX-944 HCl DS of the following inactive ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silica, magnesium stearate, triacetin, titanium dioxide and talc.

[0123] The terms “dose intensity” and “dose level” are used interchangeably herein and may refer to the amount of active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944HCl)) measured in units of concentration. In some embodiments, the terms “dose intensity” and “dose level” may refer to the amount of active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl)) as a free base, and not to the amount of salt or derivative of the active agent included in the compositions, formulations, and dosage forms described herein.

[0124] The terms “dosage form” and “dosage unit” are used interchangeably herein and can refer to the physical form of a dose of an active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944HCl)) intended to be administered or consumed. In some embodiments, a dosage form comprises physically discrete units suitable for administration to a subject, e.g., each unit containing a predetermined amount and / or dose strength of an active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl)) calculated to produce the desired therapeutic effect, alone or in combination with one or more additional dosage units. The route of administration (ROA) for delivering the active agent may depend, for example, on the dosage form of the active agent. In some embodiments, the compositions, formulations, and dosage forms described herein may be formulated and intended for oral administration to a subject. In some embodiments, when formulated and intended for oral administration to a subject, the compositions, formulations, and dosage forms described herein may include capsules, tablets, pills, powders, lozenges, aqueous or oily suspensions, granules, emulsions, syrups, elixirs, etc. In such dosage forms, the active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl)) may be mixed with a pharmaceutically acceptable excipient or carrier.

[0125] The terms “single-unit dose” and “single-unit dosage form” are used interchangeably herein and can refer to compositions and formulations comprising an active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl)) comprising a discrete dose unit, e.g., a tablet. In some embodiments, the dosage forms described herein (e.g., single-unit dosage forms) are bioequivalent to currently available PRAX-944 dosage forms, e.g., comprising modulated-release (MR) formulations obtained in the form of 5 mg and 20 mg round tablets having a small size (about 6 mm in diameter).

[0126] The terms “multiple unit doses” and “multiple unit dosage forms” are used interchangeably herein and can refer to compositions and formulations comprising an active agent (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944HCl)) comprising multiple dose units, e.g., multiple tablets. In some embodiments, currently available PRAX-944 dosage forms comprise multiple unit dosage forms, e.g., comprising modulated-release (MR) formulations obtained in the form of 5 mg and 20 mg round tablets having a small size (about 6 mm in diameter).

[0127] Table 1. Abbreviations Modified PRAX-944 dosage forms and compositions PRAX-944 ( Figure 1PRAX-944 is an orally active, high-affinity, state-dependent, selective inhibitor of T-type calcium (Ca2+) channels. The T-type Ca2+ channel family comprises three distinct isoforms, CaV3.1, CaV3.2, and CaV3.3, which are widely but differentially expressed in the thalamic cortex and cerebellar circuits, including key pathways involved in the development of, for example, essential tremor (ET). PRAX-944 is being developed for the treatment of various diseases or conditions associated with abnormal function or activity of T-type calcium channels, including, for example, essential tremor (ET). For evaluation in clinical trials, PRAX-944 is currently manufactured as modulated-release (MR) tablets in 5 mg and 20 mg forms, film-coated tablets, and matched oral placebos (PO), administered once daily (QD). The MR mechanism is achieved by incorporating a hydrophilic polymer that hydrates and gels in an aqueous medium to form a matrix that controls the release of the drug substance (DS) from the tablet. Each active tablet contains, for example, the equivalent of 5 mg or 20 mg of PRAX-944 free base and PRAX-944 hydrochloride (HCl) DS containing the following inactive ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silica, magnesium stearate, triacetin, titanium dioxide, and talc. PRAX-944 was previously manufactured as an immediate-release (IR) tablet, as described, for example, in the first clinical trial Z944-B01. The current 5 mg and 20 mg MR formulations were developed based on observations from the first clinical trial Z944-B01, namely that dividing the administration over several hours into multiple doses reduced the central nervous system (CNS) and psychiatric adverse events (AEs) observed with single-day IR formulations, as described, for example, in the clinical trial Z944-104 (evaluating the safety and tolerability of the PRAX-944 MR7 formulation).

[0128] The PRAX-944 MR7 formulation currently used in clinical trials is designed to release 80% of the active drug into solution after 7 hours in vitro. This formulation was selected for further development after comparison with other MR formulations that have faster dissolution. Generally, compared to IR formulations, previously studied MR formulations, produced as 5 mg and 20 mg MR, film-coated tablets, reduce Cmax and delay tmax, but have the least impact on AUC. Additionally, the use of the MR formulation reduced the frequency of CNS, psychiatric, and overall adverse events (AEs), with a greater reduction in AE frequency corresponding to a greater reduction in Cmax, thus making the MR7 formulation the choice for the ongoing clinical trials. Furthermore, titration has demonstrated improved tolerability profiles for PRAX-944 MR7. However, during clinical trials, certain challenges associated with using currently available PRAX-944 MR formulations (i.e., placebo, 5 mg, and 20 mg MR tablets) have been identified. For example, PRAX-944 may be offered in different dose strengths in the form of multiple tablet combinations packaged in blister packs (e.g., including placebo, 5 mg, and 20 mg tablets) for clinical blinding purposes. It has been found that handling small, round tablets, blister packs, and multiple pills is particularly challenging for patients with movement disorders such as essential tremor (ET). Therefore, there is a need to develop new single-dose units with appropriate shapes, larger sizes, and higher dose strengths to improve patient comfort and convenience, and to reduce or eliminate the chance of dosing errors.

[0129] Therefore, in one aspect, this disclosure provides compositions comprising a single-unit dosage form, said single-unit dosage form comprising a compound of formula (I): (I) Or its pharmaceutically acceptable salt.

[0130] In some embodiments, the compound is an HCl salt of the compound of formula (I), as described in formula (II): (II).

[0131] In some embodiments, the compound is an acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, citrate, cyclohexylaminosulfonate, ethanedisulfonate, ethanesulfonate, hydroxyethylsulfonate, fumarate, gentianate, gluconate, glucuronate, glutamate, glutarate, ketoglutarate, glycolate, hippurate, lactobionate, maleate, malate, malonate, methanesulfonate, naphthalenedisulfonate, naphthalenesulfonate, oleate, orotate, oxalate, dihydroxynaphthalate, phosphate, sebate, succinate, or tartrate of the compound of formula (I).

[0132] Compounds of formula (I) are described, for example, in PCT Publication WO2009 / 146540, which is incorporated herein by reference. Crystalline salts of compounds of formula (I) are described, for example, in PCT Publication WO2021 / 007487, which is incorporated herein by reference. Deuterated analogs of compounds of formula (I) are described, for example, in PCT Publication WO2022 / 099207, which is incorporated herein by reference. The safety, efficacy, tolerability, and pharmacokinetics of compounds of formula (I) in modulated-release formulations, with and without titration, have been evaluated as described in PCT Publication WO2021 / 222342, which is incorporated herein by reference.

[0133] In some embodiments, the compound of formula (I) is in crystalline form. In some embodiments, the crystalline form is the previously or concurrently described crystalline form, such as crystalline pattern B, crystalline pattern C, or crystalline pattern D. Crystalline patterns B and C are described, for example, in WO 2021 / 007487, the entire contents of which are hereby incorporated herein by reference. Crystalline pattern D is characterized by an X-ray powder diffraction (XRPD) pattern containing at least one peak at a diffraction angle (º2θ), said at least one peak being selected from the group consisting of: The peak is at approximately 12.0º; The peak is at approximately 15.6º; The peak is at approximately 16.7º; The peak is at approximately 19.8º; The peak is at approximately 21.2º; The peak is at approximately 24.1º; The peak is at approximately 25.2º; The peak is at approximately 27.3º; and The peak is at approximately 30.2º.

[0134] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is PRAX-944 HCl ( N -((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride).

[0135] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) may be in dosage form, such as a single-unit dosage form, or in a pharmaceutical composition.

[0136] On one hand, the present invention provides compositions comprising a single-unit dosage form comprising (I) compound or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl).

[0137] On the one hand, the present invention provides a modulated-release dosage form comprising a single-unit dosage form containing a (I) compound or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl).

[0138] On one hand, the present invention provides compositions comprising a single-unit dosage form comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl), wherein the composition is bioequivalent to a reference composition having the same dose strength as a plurality of small, round 20 mg PRAX-944 tablets. In some embodiments, the composition exhibits bioequivalence when administered to human subjects, for example, in a fed and / or fasted state, compared to a reference composition having the same dose strength as a plurality of small, round 20 mg PRAX-944 tablets administered to subjects in a fed and / or fasted state. In some embodiments, bioequivalence is determined by: (i) a 90% confidence interval for the AUC being between approximately 80% and approximately 125% (e.g., approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 12%). (a) 4% or approximately 125%), and (b) the 90% confidence interval for Cmax is between approximately 80% and approximately 125% (e.g., approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%). (Approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, or approximately 125%). In some embodiments, the 90% confidence intervals of the AUC and / or the Cmax may be included within more stringent confidence limits, for example, approximately 90% to approximately 120%, approximately 90% to approximately 115%, approximately 90% to approximately 110%, or approximately 90% to approximately 100%.

[0139] Some embodiments of this disclosure provide larger single-unit dose strength MR tablets (e.g., about 15 mm in length and about 6.5 mm in width), which, for example, are bioequivalent to smaller round 20 mg tablets at each dose level used in current titration protocols: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg.

[0140] In some embodiments, at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within a predetermined time period upon administration to a subject. In some embodiments, the predetermined time period may be in the range of about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours).

[0141] In some embodiments, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 1 hour to about 12 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours) when administered to a subject. In some embodiments, about 5% to about 25% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 1 hour to about 2 hours when administered to a subject. In some embodiments, about 25% to about 50% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 2 hours to about 4 hours upon administration to a subject. In some embodiments, about 50% to about 75% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 3 hours to about 7 hours upon administration to a subject. In some embodiments, about 75% to about 100% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 6 hours to about 10 hours upon administration to a subject. In some embodiments, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 7 hours upon administration to a subject. In some embodiments, about 90% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II), such as PRAX-944 HCl) is released within about 9 hours when administered to a subject.

[0142] In some embodiments, the dosage form comprises about 1 mg to about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) (e.g., about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg). mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg or about 195 mg to about 200 mg).

[0143] In some embodiments, the dosage form comprises about 1 mg to about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 ... mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, or approximately 200 mg).

[0144] In some embodiments, the dosage forms, formulations, and dosage forms of compounds comprising formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II), such as PRAX-944 HCl) described herein have a dose strength in the range of about 1 mg to about 200 mg (e.g., about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 200 mg). mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg or about 195 mg to about 200 mg).

[0145] In some embodiments, the dosage forms, formulations, and dosage forms comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) described herein have a dose strength in the range of about 1 mg to about 200 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 165 mg, about 165 mg, about 165 mg, about 165 mg, about 160 ... (mg, approximately 170mg, approximately 175mg, approximately 180mg, approximately 185mg, approximately 190mg, approximately 195mg, or approximately 200mg).

[0146] In some embodiments, the compositions, formulations, and dosage forms described herein contain amounts equivalent to about 1 mg to about 200 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg). PRAX-944 free base / dose unit (e.g., per tablet) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944HCl).

[0147] In some embodiments, the single-unit dosage form contains an amount equivalent to about 1.0 mg to about 200 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg). mg) PRAX-944 free base / dose unit (e.g., per tablet) of the compound of formula (I) or its pharmaceutically acceptable salt (e.g., the compound of formula (II), such as PRAX-944HCl). In some embodiments, the single-unit dosage form comprises about 1% to about 50% by weight (e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight) of PRAX-944 HCl, optionally wherein the total dose unit (e.g., tablet) weight is about 50 mg to about 500 mg (e.g., about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 28 ... (mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, or approximately 500 mg).

[0148] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 5 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 1 mg to about 10 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0149] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 10 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 5 mg to about 15 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0150] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 15 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 10 mg to about 20 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0151] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 20 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 15 mg to about 25 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0152] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 25 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 20 mg to about 30 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0153] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 30 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 25 mg to about 35 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0154] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 35 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 30 mg to about 40 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0155] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 40 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 35 mg to about 45 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0156] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 45 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 40 mg to about 50 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0157] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 50 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 45 mg to about 55 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0158] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 55 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 50 mg to about 60 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0159] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 60 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 55 mg to about 65 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0160] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 65 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 60 mg to about 70 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0161] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 70 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 65 mg to about 75 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0162] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 75 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 70 mg to about 80 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0163] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 80 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 75 mg to about 85 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0164] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 85 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 80 mg to about 90 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0165] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 90 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 85 mg to about 95 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0166] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 95 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 90 mg to about 100 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0167] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 100 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 95 mg to about 105 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0168] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 105 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 100 mg to about 110 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0169] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 110 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 105 mg to about 115 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0170] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 115 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 110 mg to about 120 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0171] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 120 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 115 mg to about 125 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0172] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 125 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 120 mg to about 130 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0173] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 130 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 125 mg to about 135 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0174] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 135 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 130 mg to about 140 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0175] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 140 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 135 mg to about 145 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0176] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 145 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 140 mg to about 150 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0177] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 150 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 145 mg to about 155 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0178] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in an amount equivalent to about 155 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 150 mg to about 160 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0179] In some embodiments, the compositions, formulations and dosage forms described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl, in amounts equivalent to about 160 mg of PRAX-944 free base per dose unit (e.g., per tablet) and optionally about 155 mg to about 165 mg of PRAX-944 HCl per dose unit (e.g., per tablet).

[0180] In some embodiments, the dosage form comprises about 1% to about 70% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) (e.g., about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, about 60% to about 65% by weight, or about 65% to about 70% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl).

[0181] In some embodiments, the dosage form comprises about 1% to about 70% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) (e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl).

[0182] Table 6-16 provides exemplary dosage forms containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) as an active agent.

[0183] Modulated polymers In some embodiments, the dosage form comprises a modulated release polymer.

[0184] In some embodiments, the release modulating polymer is used in formulations (e.g., tablets and capsules) to alter the release rate of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944HCl) upon administration to a subject. In some embodiments, the release modulating polymer is used to dissolve a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944HCl) over time to allow for a slower, more stable, or slower and more stable release into the bloodstream.

[0185] In some embodiments, the modulating polymer is a controlled-release polymer. In some embodiments, the modulating polymer or the controlled-release polymer is a cellulose ether. In some embodiments, the modulating polymer or the controlled-release polymer is HPMC (hydroxypropyl methylcellulose). In some embodiments, the modulating polymer or the controlled-release polymer is selected from the group consisting of: METHOCEL® E50LV, K100LV, K100LV CR, K4M, K15M, K100M, E4M, E10M, K4MCR, K15MCR, K100MCR, E4MCR, E10MCR, and combinations thereof. In some embodiments, the modulating polymer or the controlled-release polymer is HPMC K100 LV Premium CR. In some embodiments, the modulating polymer or the controlled-release polymer is HPMC (hydroxypropyl methylcellulose) selected from the group consisting of: Methocel K4M, Methocel K100LV, Methocel E50LV, and combinations thereof. In some embodiments, the modulating polymer may comprise a matrix polymer (e.g., a hydrophilic matrix polymer, a hydrophobic matrix polymer, a polyacrylate polymer, and combinations thereof). In some embodiments, the modulating polymer comprises a hydrophilic matrix polymer (e.g., hydroxypropyl methylcellulose, HPMC (hydroxypropyl methylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose, ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100). In some embodiments, the modulating polymer is a hydrophilic matrix polymer. In some embodiments, the modulating polymer is hydroxypropyl methylcellulose. In some embodiments, the modulating polymer is HPMC (hydroxypropyl methylcellulose). In some embodiments, the modulating polymer is a hydrophobic matrix polymer. In some embodiments, the modulating polymer is ethylcellulose. In some embodiments, the modulating polymer is ethocel. In some embodiments, the modulating polymer is a polyacrylate polymer. In some embodiments, the modulating polymer is Eudragit RL100. In some embodiments, the modulating polymer is Eudragit RS100.

[0186] In some embodiments, the dosage form comprises about 5 mg to 300 mg of the modulated polymer (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg). mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 235 mg mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg or about 295 mg to about 300 mg of modulated polymer).

[0187] In some embodiments, the dosage form comprises about 5 mg to 300 mg of a modulating polymer (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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 ...0 mg, about 205 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 (approximately 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of modulated polymer).

[0188] In some embodiments, the dosage form comprises about 10% to about 70% by weight of a modulating polymer (e.g., about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, about 60% to about 65% by weight, or about 65% to about 70% by weight of the modulating polymer).

[0189] In some embodiments, the dosage form comprises about 10% to about 70% by weight of a modulating polymer (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, or about 70% by weight).

[0190] In some embodiments, the dosage form comprises about 5 mg to 300 mg of hydroxypropyl methylcellulose (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg). mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 235 mg mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg or about 295 mg to about 300 mg hydroxypropyl methylcellulose).

[0191] In some embodiments, the dosage form comprises about 5 mg to 300 mg of hydroxypropyl methylcellulose (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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 ...0 mg, about 205 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 2 200 mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, or approximately 300 mg of hydroxypropyl methylcellulose.

[0192] In some embodiments, the dosage form comprises about 10% to about 70% by weight of hydroxypropyl methylcellulose (e.g., about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, about 60% to about 65% by weight, or about 65% to about 70% by weight of hydroxypropyl methylcellulose).

[0193] In some embodiments, the dosage form comprises about 10% to about 70% by weight of hydroxypropyl methylcellulose (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of hydroxypropyl methylcellulose).

[0194] diluent In some embodiments, the dosage form includes a diluent.

[0195] In some embodiments, the dosage form includes a soluble diluent.

[0196] In some embodiments, the diluent is used as a filler in formulations (e.g., tablets and capsules).

[0197] In some embodiments, the term diluent includes excipients, for example, for increasing weight and improving content uniformity. In some embodiments, the diluent may comprise cellulose derivatives (e.g., microcrystalline cellulose, such as silicified microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol), and combinations thereof.

[0198] In some embodiments, the diluent may contain PEARLITOL® mannitol.

[0199] In some embodiments, the diluent may comprise mannitol, optionally in grades selected from the group consisting of: MQ, 100SD, 200SD, EZ, XL, M100, M200, 300DC, 400DC, 500DC, 2080, AG, GF, GS, GR, and combinations thereof.

[0200] In some embodiments, the dosage form comprises a diluent of about 5 mg to about 300 mg (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg). mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 235 mg mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg or about 295 mg to about 300 mg diluent).

[0201] In some embodiments, the dosage form comprises a diluent of about 5 mg to about 300 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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 ...0 mg, about 205 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 200 mg, about 20 (approximately 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg or 300 mg diluent).

[0202] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a diluent (e.g., about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, or about 45% to about 50% by weight).

[0203] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a diluent (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight). (by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight or approximately 50% by weight of diluent).

[0204] In some embodiments, the dosage form comprises microcrystalline cellulose (MCC), such as silicified microcrystalline cellulose (SMCC). MCC and SMCC are commercially available under various trade names (e.g., AVICEL®; EMCOCEL®; MICROCEL®; COMPRECEPL®; E460; COELUSKG®; PHARMACEL®; FIBROCEL®; and PROSOLV®) and in different particle sizes, densities, and moisture grades.

[0205] In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC) selected from the group consisting of: PH101, PH102, PH103, PH105, PH112, PH200, PH113, PH301, PH302, PH200LM, and combinations thereof.

[0206] In some embodiments, the dosage form may comprise silanized microcrystalline cellulose (SMCC) comprising microcrystalline cellulose (MCC) and colloidal silica (CSD). In some embodiments, the silanized microcrystalline cellulose comprises about 90% to about 99% by weight (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight) of microcrystalline cellulose (MCC) and about 1% to about 10% by weight (e.g., 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight) of colloidal silica (CSD). In some embodiments, the dosage form may comprise PROSOLV® SMCC. In some embodiments, the dosage form may comprise siliconized microcrystalline cellulose (SMCC) selected from the group consisting of: PROSOLV® SMCC 50, 50LD, 90, HD 90, 90 LM and combinations thereof.

[0207] In some embodiments, the dosage form may contain microcrystalline cellulose (MCC) with a particle size of less than about 50 µm, such as silanized microcrystalline cellulose cellulose (SMCC). In some embodiments, the dosage form may contain microcrystalline cellulose (MCC) with a particle size greater than about 50 µm, such as silanized microcrystalline cellulose cellulose (SMCC). In some embodiments, the dosage form may comprise an average particle size of about 50 µm to about 200 µm (e.g., about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, about 120 µm, about 125 µm, about 130 µm, about 135 µm, about 140 µm, about 145 µm, about 150 µm, about 155 µm, about 160 µm, about 165 µm, about 170 µm, about 175 µm, about 180 µm, about 185 µm, about 190 µm, about 195 µm, or about 200 µm). Microcrystalline cellulose (MCC) of µm or less, such as silanized microcrystalline cellulose cellulose (SMCC). In some embodiments, the dosage form may contain microcrystalline cellulose (MCC) of about 0.1% to about 5% (e.g., about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5%), such as silanized microcrystalline cellulose cellulose (SMCC). In some embodiments, the dosage form may contain microcrystalline cellulose (MCC) of less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 2.5%, less than about 3%, less than about 3.5%, less than about 4%, less than about 4.5%, or less than about 5% moisture content, such as silanized microcrystalline cellulose cellulose (SMCC).

[0208] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of microcrystalline cellulose, for example, silicified microcrystalline cellulose (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 ... mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 23 ... mg to about 235 mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg, or about 295 mg to about 300 mg microcrystalline cellulose, for example, silanized microcrystalline cellulose).

[0209] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of microcrystalline cellulose, for example, silicified microcrystalline cellulose (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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 1 ... mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg microcrystalline cellulose, for example, silanized microcrystalline cellulose).

[0210] In some embodiments, the dosage form comprises about 5% to about 50% by weight of microcrystalline cellulose, such as silanized microcrystalline cellulose (e.g., about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, or about 45% to about 50% by weight of microcrystalline cellulose, such as silanized microcrystalline cellulose).

[0211] In some embodiments, the dosage form comprises about 5% to about 50% by weight of microcrystalline cellulose, for example, silanized microcrystalline cellulose (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight). Microcrystalline cellulose, for example, silicified microcrystalline cellulose, by weight%, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, or approximately 50% by weight.

[0212] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of a sugar alcohol, such as mannitol (e.g., about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 ... mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 225 mg. mg to about 235 mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg, or about 295 mg to about 300 mg of sugar alcohol, such as mannitol).

[0213] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of a sugar alcohol, such as mannitol (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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 20 ...0 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of sugar alcohol, such as mannitol).

[0214] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a sugar alcohol, such as mannitol (e.g., about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, or about 45% to about 50% by weight of a sugar alcohol, such as mannitol).

[0215] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a sugar alcohol, such as mannitol (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight). Sugar alcohols, such as mannitol, at % by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, or approximately 50% by weight.

[0216] Flow aid In some embodiments, the dosage form includes a gliding agent.

[0217] In some embodiments, the flow aid comprises excipients, for example, for promoting powder flow by reducing interparticle friction and adhesion. In some embodiments, the flow aid comprises fumed silica (e.g., colloidal silica), talc, and magnesium carbonate. In some embodiments, the flow aid comprises colloidal silica. In some embodiments, the colloidal silica may comprise AEROSIL® 200 Pharma, also known as "colloidal silica (Aerosil 200)".

[0218] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of a flow aid (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg of a flow aid).

[0219] In some embodiments, the dosage form contains about 1 mg to about 10 mg of a flow aid (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of a flow aid).

[0220] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a flow aid (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, or about 9% to about 10% by weight of a flow aid).

[0221] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a gliding agent (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of a gliding agent).

[0222] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of fumed silica, such as colloidal silica (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg of fumed silica, such as colloidal silica).

[0223] In some embodiments, the dosage form contains about 1 mg to about 10 mg of fumed silica, for example, colloidal silica (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg of fumed silica, for example, colloidal silica).

[0224] In some embodiments, the dosage form comprises about 1% to about 10% by weight of fumed silica, such as colloidal silica (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, or about 9% to about 10% by weight of fumed silica, such as colloidal silica).

[0225] In some embodiments, the dosage form comprises about 1% to about 10% by weight of fumed silica, such as colloidal silica (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of fumed silica, such as colloidal silica).

[0226] lubricant In some embodiments, the composition comprises a lubricant.

[0227] In some embodiments, the lubricant includes, for example, excipients for preventing the ingredients from clumping and sticking to the tablet punch or capsule filling machine. In some embodiments, the lubricant also serves to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. In some embodiments, the lubricant includes magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable fats). In some embodiments, the lubricant includes magnesium stearate.

[0228] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of lubricant (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg of lubricant).

[0229] In some embodiments, the dosage form contains about 1 mg to about 10 mg of lubricant (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of lubricant).

[0230] In some embodiments, the formulation comprises about 1% to about 10% by weight of a lubricant (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, or about 9% to about 10% by weight of a lubricant).

[0231] In some embodiments, the formulation comprises about 1% to about 10% by weight of a lubricant (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of a lubricant).

[0232] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of magnesium stearate (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg of magnesium stearate).

[0233] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of magnesium stearate (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of magnesium stearate).

[0234] In some embodiments, the dosage form comprises about 1% to about 10% by weight of magnesium stearate (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, or about 9% to about 10% by weight).

[0235] In some embodiments, the dosage form comprises about 1% to about 10% by weight of magnesium stearate (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of magnesium stearate).

[0236] Coating In some embodiments, the composition comprises a coating.

[0237] In some embodiments, the coating comprises, for example, excipients that protect the tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow. In some embodiments, the coating comprises a film coating agent. In some embodiments, the coating comprises Opadry® II White 85F18422, which comprises pharmacopoeia-grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and talc.

[0238] In some embodiments, the dosage form comprises a coating of about 1 mg to about 20 mg, such as a film coating (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, about 9 mg to about 10 mg, about 10 mg to about 11 mg, about 11 mg to about 12 mg, about 12 mg to about 13 mg, about 13 mg to about 14 mg, about 14 mg to about 15 mg, about 15 mg to about 16 mg, about 16 mg to about 17 mg, about 17 mg to about 18 mg, about 18 mg to about 19 mg, or about 19 mg to about 20 mg coating, such as a film coating).

[0239] In some embodiments, the dosage form comprises a coating of about 1 mg to about 20 mg, for example, a film coating (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg coating, for example, a film coating).

[0240] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a coating, such as a film coating agent (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, about 9% to about 10% by weight of a coating, such as a film coating agent).

[0241] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a coating, such as a film coating agent (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, about 9% to about 10%, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of a coating, such as a film coating agent).

[0242] In some embodiments, the dosage form comprises about 1 mg to about 20 mg of Opadry® II White 85F18422 (e.g., about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, about 9 mg to about 10 mg, about 10 mg to about 11 mg, about 11 mg to about 12 mg, about 12 mg to about 13 mg, about 13 mg to about 14 mg, about 14 mg to about 15 mg, about 15 mg to about 16 mg, about 16 mg to about 17 mg, about 17 mg to about 18 mg, about 18 mg to about 19 mg, or about 19 mg to about 20 mg of Opadry® II White 85F18422).

[0243] In some embodiments, the dosage form comprises about 1 mg to about 20 mg of Opadry® II White 85F18422 (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of Opadry® II White 85F18422).

[0244] In some embodiments, the dosage form comprises about 1% to about 10% by weight of Opadry® II White 85F18422 (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, about 9% to about 10% by weight).

[0245] In some embodiments, the dosage form comprises about 1% to about 10% by weight of Opadry® II White 85F18422 (e.g., about 1% to about 2% by weight, about 2% to about 3% by weight, about 3% to about 4% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, about 6% to about 7% by weight, about 7% to about 8% by weight, about 8% to about 9% by weight, about 9% to about 10%, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of Opadry® II White 85F18422).

[0246] Contributing factors The compositions, formulations, and dosage forms described herein can be manufactured using any suitable manufacturing method known in the art, including but not limited to direct compression, dry granulation (e.g., briquetting or rolling), wet granulation, and any combination thereof. The compositions, formulations, and dosage forms described herein should advantageously have a shape, size, and weight that facilitates oral administration, for example. Therefore, in one aspect, the compositions, formulations, and dosage forms described herein can be solid dosage forms suitable for oral administration. Dosage forms can be selected from the group consisting of tablets, capsules, films, powders, granules, solutions, solids, suspensions, and another acceptable oral dosage form. In some embodiments, the dosage form is a tablet, such as a capsule. In other embodiments, the dosage form is a capsule. In some embodiments, the dosage form is a suspension.

[0247] In some embodiments, dosage forms (e.g., tablets) may be compressed or molded during their manufacture, and they may have virtually any size, shape, weight, and color. In some embodiments, dosage forms (e.g., tablets) are in the shape of capsules (also known as “capsule tablets”). Most tablets are intended to be swallowed whole, and therefore, preferred tablets are designed for oral administration. However, in some embodiments, tablets may dissolve in the mouth, be chewed, or dissolve in a liquid before swallowing, and some tablets may be placed in a body cavity.

[0248] In some embodiments, the total dosage form (e.g., tablet) weight can be adjusted to vary with the total size of the dosage form (e.g., tablet) in order to provide an optimal trade-off between desired pharmacokinetics (PK) and patient compliance.

[0249] In some embodiments, the total weight of the dosage form (e.g., tablets) is about 50 mg to about 600 mg (e.g., about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 300 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, about 400 mg to about 425 mg, about 425 mg to about 450 mg, about 450 mg to about 475 mg, about 475 mg to about 500 mg, about 500 mg to about 525 mg, about 525 mg to about 550 mg, about 550 ... (mg to about 575 mg or about 575 mg to about 600 mg).

[0250] In some embodiments, the total weight of the dosage form (e.g., tablets) is from about 50 mg to about 600 mg (e.g., about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 ... mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, approximately 300 mg, approximately 305 mg, approximately 310 mg, approximately 315 mg, approximately 320 mg, approximately 325 mg, approximately 330 mg, approximately 335 mg, approximately 340 mg, approximately 345 mg, approximately 350 mg, approximately 355 mg, approximately 360 mg, approximately 365 mg, approximately 370 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, approximately 505 mg, approximately 510 mg, approximately 515 mg, approximately 520 mg, approximately 525 mg, approximately 530 mg, approximately 535 mg, approximately 540 mg, approximately 545 mg, approximately 550 mg, approximately 555 mg, approximately 560 mg, approximately 565 mg, approximately 570 mg, approximately 575 mg, approximately 580 mg, approximately 585 mg, approximately 590 mg, approximately 595 mg, or approximately 600 mg).

[0251] In some embodiments, the dosage form is a round tablet. In some embodiments, the diameter of the tablet is in the range of about 1 mm to about 30 mm (e.g., about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, about 23 mm, about 24 mm, about 25 mm, about 26 mm, about 27 mm, about 28 mm, about 29 mm, or about 30 mm). In some embodiments, the diameter of the tablet is not in the range of about 1 mm to about 6 mm (e.g., about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm).

[0252] In some embodiments, the dosage form is a rectangular tablet. In some embodiments, for example, opening the blister pack of a rectangular tablet, handling the rectangular tablet, and taking one or more rectangular tablets are less challenging and convenient for patients with movement disorders such as essential tremor (ET).

[0253] In some embodiments, the dosage form is an oval tablet. In some embodiments, for example, opening the blister pack of an oval tablet, handling the oval tablet, and taking one or more oval tablets is less challenging and convenient for patients with movement disorders such as essential tremor (ET).

[0254] In some embodiments, the dosage form is a capsule-shaped tablet (e.g., a capsule tablet). In some embodiments, for example, opening the blister pack of a capsule-shaped tablet, handling the capsule-shaped tablet, and taking one or more capsule-shaped tablets is less challenging and convenient for patients with movement disorders such as essential tremor (ET).

[0255] In some embodiments, the length of the dosage form (e.g., tablet) can be from about 1 mm to about 30 mm (e.g., about 1 mm to about 2 mm, about 2 mm to about 3 mm, about 3 mm to about 4 mm, about 4 mm to about 5 mm, about 5 mm to about 6 mm, about 6 mm to about 7 mm, about 7 mm to about 8 mm, about 8 mm to about 9 mm, about 9 mm to about 10 mm, about 10 mm to about 11 mm, about 11 mm to about 12 mm, about 12 mm to about 13 mm, about 13 mm to about 14 mm, about 14 mm to about 15 mm, about 15 mm to about 16 mm, about 16 mm to about 17 mm, about 17 mm to about 18 mm, about 18 mm to about 19 mm, about 19 mm to about 20 mm, about 20 mm to about 21 mm, about 21 mm to about 22 mm, about 22 mm to about 23 mm, about 23 mm to about 24 mm, about 24 mm to about 25 mm, about 25 mm to about 26 mm, about 26 mm to about 27 mm, about 27 mm to about 28 mm). mm, approximately 28 mm to approximately 29 mm or approximately 29 mm to approximately 30 mm).

[0256] In some embodiments, the length of the dosage form (e.g., tablet) can be from about 1 mm to about 30 mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, about 15 mm, about 15.5 mm, about 16 mm, about 16.5 mm, about 17 mm, about 17.5 mm, about 18 mm, about 18.5 mm, about 19 mm, about 19.5 mm, about 20 mm, about 20.5 mm, about 21 ... mm, approximately 21.5 mm, approximately 22 mm, approximately 22.5 mm, approximately 23 mm, approximately 23.5 mm, approximately 24 mm, approximately 24.5 mm, approximately 25 mm, approximately 25.5 mm, approximately 26 mm, approximately 26.5 mm, approximately 27 mm, approximately 27.5 mm, approximately 28 mm, approximately 28.5 mm, approximately 29 mm, approximately 29.5 mm, or approximately 30 mm).

[0257] In some embodiments, the width of the dosage form (e.g., tablet) can be from about 1 mm to about 30 mm (e.g., about 1 mm to about 2 mm, about 2 mm to about 3 mm, about 3 mm to about 4 mm, about 4 mm to about 5 mm, about 5 mm to about 6 mm, about 6 mm to about 7 mm, about 7 mm to about 8 mm, about 8 mm to about 9 mm, about 9 mm to about 10 mm, about 10 mm to about 11 mm, about 11 mm to about 12 mm, about 12 mm to about 13 mm, about 13 mm to about 14 mm, about 14 mm to about 15 mm, about 15 mm to about 16 mm, about 16 mm to about 17 mm, about 17 mm to about 18 mm, about 18 mm to about 19 mm, about 19 mm to about 20 mm, about 20 mm to about 21 mm, about 21 mm to about 22 mm, about 22 mm to about 23 mm, about 23 mm to about 24 mm, about 24 mm to about 25 mm, about 25 mm to about 26 mm, about 26 mm to about 27 mm, about 27 mm to about 28 mm). mm, approximately 28 mm to approximately 29 mm or approximately 29 mm to approximately 30 mm).

[0258] In some embodiments, the width of the dosage form (e.g., tablet) can be from about 1 mm to about 30 mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, about 15 mm, about 15.5 mm, about 16 mm, about 16.5 mm, about 17 mm, about 17.5 mm, about 18 mm, about 18.5 mm, about 19 mm, about 19.5 mm, about 20 mm, about 20.5 mm). mm, approximately 21 mm, approximately 21.5 mm, approximately 22 mm, approximately 22.5 mm, approximately 23 mm, approximately 23.5 mm, approximately 24 mm, approximately 24.5 mm, approximately 25 mm, approximately 25.5 mm, approximately 26 mm, approximately 26.5 mm, approximately 27 mm, approximately 27.5 mm, approximately 28 mm, approximately 28.5 mm, approximately 29 mm, approximately 29.5 mm, or approximately 30 mm).

[0259] In some embodiments, the width of the dosage form (e.g., tablet) may be from about 1 mm to about 10 mm (e.g., from about 1 mm to about 2 mm, from about 2 mm to about 3 mm, from about 3 mm to about 4 mm, from about 4 mm to about 5 mm, from about 5 mm to about 6 mm, from about 6 mm to about 7 mm, from about 7 mm to about 8 mm, from about 8 mm to about 9 mm, or from about 9 mm to about 10 mm).

[0260] In some embodiments, the width of the dosage form (e.g., tablet) is from about 1 mm to about 10 mm (e.g., widths of about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3 mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm). mm, approximately 4.8 mm, approximately 4.9 mm, approximately 5 mm, approximately 5.1 mm, approximately 5.2 mm, approximately 5.3 mm, approximately 5.4 mm, approximately 5.5 mm, approximately 5.6 mm, approximately 5.7 mm, approximately 5.8 mm, approximately 5.9 mm, approximately 6 mm, approximately 6.1 mm, approximately 6.2 mm, approximately 6.3 mm, approximately 6.4 mm, approximately 6.5 mm, approximately 6.6 mm, approximately 6.7 mm, approximately 6.8 mm, approximately 6.9 mm, approximately 7 mm, approximately 7.1 mm, approximately 7.2 mm, approximately 7.3 mm, approximately 7.4 mm, approximately 7.5 mm, approximately 7.6 mm, approximately 7.7 mm, approximately 7.8 mm, approximately 7.9 mm, approximately 8 mm, approximately 8.1 mm, approximately 8.2 mm, approximately 8.3 mm, approximately 8.4 mm, approximately 8.5 mm, approximately 8.6 mm, approximately 8.7 mm, approximately 8.8 mm, approximately 8.9 mm mm, approximately 9 mm, approximately 9.1 mm, approximately 9.2 mm, approximately 9.3 mm, approximately 9.4 mm, approximately 9.5 mm, approximately 9.6 mm, approximately 9.7 mm, approximately 9.8 mm, approximately 9.9 mm, or approximately 10 mm).

[0261] In some embodiments, the width of the dosage form (e.g., tablet) may be from about 1 mm to about 10 mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, or about 10 mm).

[0262] In some embodiments, the length of the dosage form (e.g., tablet) may be from about 10 mm to about 20 mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, about 15 mm, about 15.5 mm, about 16 mm, about 16.5 mm, about 17 mm, about 17.5 mm, about 18 mm, about 18.5 mm, about 19 mm, about 19.5 mm, or about 20 mm) and the width is from about 1 mm to about 10 mm. mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, or about 10 mm).

[0263] In some embodiments, the length of the dosage form (e.g., tablet) may be from about 14 mm to about 16 mm (e.g., about 14 mm, about 14.1 mm, about 14.2 mm, about 14.3 mm, about 14.4 mm, about 14.5 mm, about 14.6 mm, about 14.7 mm, about 14.8 mm, about 14.9 mm, about 15 mm, about 15.1 mm, about 15.2 mm, about 15.3 mm, about 15.4 mm, about 15.5 mm, about 15.6 mm, about 15.7 mm, about 15.8 mm, about 15.9 mm, or about 16 mm), and the width is from about 5 mm to about 7 mm (e.g., 5 mm, about 5.1 mm, about 5.2 mm, about 5.3 mm, about 5.4 mm, about 5.5 mm, about 5.6 mm, about 5.7 mm, about 5.8 mm, about 5.9 mm, about 6 mm, about 6.1 mm, about 6.2 mm). mm, approximately 6.3 mm, approximately 6.4 mm, approximately 6.5 mm, approximately 6.6 mm, approximately 6.7 mm, approximately 6.8 mm, approximately 6.9 mm, approximately 7 mm).

[0264] In some embodiments, the thickness of the dosage form (e.g., tablet) may be from about 1 mm to about 10 mm (e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, or about 10 mm).

[0265] Tablet hardness can be measured using any technique or device known in the art for testing tablet hardness. For example, a force gauge can be used to determine the breaking force, which indicates the strength of the tablet. Typical units of hardness measurement include kilogram-force (kp), strong Cobb unit (SCU), and newton (N). In some embodiments, the hardness of the dosage form (e.g., tablet) may be about 75 N, about 76 N, about 77 N, about 78 N, about 79 N, about 80 N, about 81 N, about 82 N, about 83 N, about 84 N, about 85 N, about 86 N, about 87 N, about 88 N, about 89 N, about 90 N, about 91 N, about 92 N, about 93 N, about 94 N, about 95 N, about 96 N, about 97 N, about 98 N, about 99 N, about 100 N, about 101 N, about 102 N, about 103 N, about 104 N, about 105 N, about 106 N, about 107 N, about 108 N, about 109 N, about 110 N, about 111 N, about 112 N, about 113 N, about 114 N, about 115 N, about 116 N, about 117 N, etc. N, approximately 118 N, approximately 119 N, approximately 120 N, approximately 121 N, approximately 122 N, approximately 123 N, approximately 124 N, approximately 125 N, approximately 126 N, approximately 127 N, approximately 128 N, approximately 129 N, approximately 130 N, approximately 131 N, approximately 132 N, approximately 133 N, approximately 134 N, approximately 135 N, approximately 136 N, approximately 137 N, approximately 138 N, approximately 139 N, approximately 140 N, approximately 141 N, approximately 142 N, approximately 143 N, approximately 144 N, approximately 145 N, approximately 146 N, approximately 147 N, approximately 148 N, approximately 149 N, approximately 150 N, approximately 151 N, approximately 152 N, approximately 153 N, approximately 154 N, approximately 155 N, approximately 156 N, approximately 157 N, approximately 158 N, approximately 159 N, approximately 160 N, approximately 161 N, approximately 162 N, approximately 163 N, approximately 164 N, approximately 165 N, approximately 166 N, approximately 167 N, approximately 168 N, approximately 169 N, approximately 170 N, approximately 171 N, approximately 172 N, approximately 173 N, approximately 174 N, approximately 175 N, approximately 176 N, approximately 177 N, approximately 178 N, approximately 179 N, approximately 180 N, approximately 181 N, approximately 182 N, approximately 183 N, approximately 184 N, approximately 185 N, approximately 186 N, approximately 187 N, approximately 188 N, approximately 189 N, approximately 190 N, approximately 191 N, approximately 192 N, approximately 193 N, approximately 194 N, approximately 195 N, approximately 196 N, approximately 197 N, approximately 198 N, approximately 199 N or approximately 200 N).In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 90 N to about 110 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 100 N to about 120 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 110 N to about 130 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 120 N to about 140 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 130 N to about 150 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 140 N to about 160 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 150 N to about 170 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 160 N to about 180 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 170 N to about 190 N. In some embodiments, the hardness of the dosage form (e.g., tablet) can be from about 180 N to about 200 N.

[0266] In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 5 N to about 35 N (e.g., about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, about 10 N, about 11 N, about 12 N, about 13 N, about 14 N, about 15 N, about 16 N, about 17 N, about 18 N, about 19 N, about 20 N, about 21 N, about 22 N, about 23 N, about 24 N, about 25 N, about 26 N, about 27 N, about 28 N, about 29 N, about 30 N, about 31 N, about 32 N, about 33 N, about 34 N, or about 35 N). In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 5 N to about 15 N. In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 10 N to about 20 N. In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 15 N to about 25 N. In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 20 N to about 30 N. In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 25 N to about 35 N. In some embodiments, the dosage form (e.g., tablet) may have compressive force at an observed hardness of about 30 N to about 35 N.

[0267] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 5.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0268] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 10.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0269] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 20.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0270] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 30.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0271] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 40.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0272] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 50.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0273] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 60.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0274] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 70.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0275] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 80.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0276] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 90.0 mg of PRAX-944 free base per dose unit (e.g., per tablet).

[0277] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 100.0 mg of PRAX-944 free base / dose unit (e.g., per tablet).

[0278] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 110.0 mg of PRAX-944 free base / dose unit (e.g., per tablet).

[0279] In some embodiments, the dosage form comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) equivalent to about 120.0 mg of PRAX-944 free base / dose unit (e.g., per tablet).

[0280] Pharmaceutical Composition This disclosure covers the preparation and use of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) as an active agent. Such pharmaceutical compositions may consist of a single active agent, as a combination of at least one active agent (e.g., an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl)) in a form suitable for administration to a subject, or the pharmaceutical composition may comprise an active agent and one or more pharmaceutically acceptable carriers, one or more additional (active and / or inactive) ingredients, or some combinations thereof.

[0281] On one hand, the pharmaceutical compositions provided in this disclosure include single-unit dosage forms comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the single-unit dosage form comprises up to 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the single-unit dosage form comprises a length of up to 16 mm, for example, from about 14 mm to about 16 mm, and / or a width of up to 7 mm, for example, from about 5 mm to about 7 mm. In some embodiments, the single-unit dosage form is bioequivalent to a reference composition having the same dose strength administered as a plurality of dosage forms, such as a modulated-release (MR) formulation of the compound of formula (I) obtained in round and small-sized (e.g., with a diameter of about 6 mm) 5 mg and 20 mg tablets. In some embodiments, bioequivalence can be established by: (a) a 90% confidence interval for AUC between about 80% and about 125%, and (b) a 90% confidence interval for Cmax between about 80% and about 125%.

[0282] Table 6-16 provides exemplary pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) as an active agent.

[0283] The pharmaceutical compositions disclosed herein may contain a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl). However, those skilled in the art will recognize that the pharmaceutical compositions may contain more than a therapeutically effective amount (as in the bulk composition) or less than a therapeutically effective amount, i.e., a single unit dose designed for multiple administrations to achieve a therapeutically effective amount. Typically, the composition will contain about 1 mg to about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl), the actual amount depending on the formulation itself, route of administration, frequency of administration, etc. According to one embodiment, compositions suitable for oral dosage forms may, for example, contain about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, or about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl).

[0284] The pharmaceutical compositions of this disclosure are designed to provide a larger and more convenient dosage form of PRAX-944 compared to currently available PRAX-944 dosage forms, which are obtained in the form of small, round 5 mg and 20 mg tablets (6 mm in diameter). For example, the pharmaceutical compositions of this disclosure are designed to minimize the total number of dose units (e.g., tablets) required to deliver a specific dose level of PRAX-944 and to increase the physical size of the tablets to make them easier to grasp and more convenient for patients, especially those with movement disorders (e.g., essential tremor (ET)). Furthermore, the pharmaceutical compositions of this disclosure, comprising larger tablets, have substantially the same bioavailability, for example, with respect to the rate of absorption (maximum plasma drug concentration; Cmax) and extent (area under the plasma concentration-time curve; AUC) of PRAX-944, compared to multiple small, round 20 mg tablets having the same total dose.

[0285] The pharmaceutical compositions disclosed herein can be administered in a manner suitable for treating (or preventing) a symptom, disease, and / or condition. The amount and frequency of administration will be determined by factors such as the patient's symptom and the type and severity of the symptom, disease, and / or condition, although an appropriate dose may be determined through clinical trials. The pharmaceutical compositions can be administered in any convenient manner, including, for example, oral administration.

[0286] As used herein, the term "pharmaceutically acceptable carrier" means a chemical composition in which an active agent can be combined and, after such combination, the chemical composition can be used to administer the active agent to a subject. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences (the standard reference textbook in the field), which is incorporated herein by reference.

[0287] The formulations of the pharmaceutical compositions described herein can be prepared by any method known in or developed in the field of pharmacology. Typically, such preparation methods include the steps of associating an active agent with a carrier or one or more other auxiliary components, and then, if desired, shaping or packaging the product into a desired single or multiple dose units.

[0288] Reagent test kit On the one hand, one or more dosage forms as described herein (e.g., one or more 5 mg tablets, one or more 10 mg tablets, one or more 20 mg tablets, one or more 40 mg tablets, one or more 80 mg tablets, and / or one or more 120 mg tablets) may be provided, for example, in packaging (e.g., a kit packaged together, a blister pack, a bag, or a bottle). In one embodiment, a kit is provided containing multiple oral dosage forms packaged together, along with instructions for administering the oral dosage forms according to the methods described herein. The oral dosage forms may be selected from the group consisting of tablets, capsules, films, powders, granules, solutions, solids, and suspensions.

[0289] Packaged oral dosage forms may contain a filler supply of a drug typically prescribed for an intended therapy (e.g., a titration regimen). Depending on the specific therapy, a series of unit doses may be packaged together according to a prescribed regimen or treatment (e.g., supply for 1-90 days). In some embodiments, a series of unit doses may comprise one or more 5 mg tablets, one or more 10 mg tablets, one or more 20 mg tablets, one or more 40 mg tablets, one or more 80 mg tablets, and / or one or more 120 mg tablets as described herein. In some embodiments, each dose of about 5 mg to about 200 mg, supplied for up to about 90 days (e.g., one or more 5 mg tablets, one or more 10 mg tablets, one or more 20 mg tablets, one or more 40 mg tablets, one or more 80 mg tablets, and / or one or more 120 mg tablets as described herein) may be provided together, for example, in the package.

[0290] In one embodiment, an oral dosage form (e.g., tablets) as described herein may be included in a blister pack having instructions for daily administration of one or more tablets to provide a sufficient dose of the formulation described herein. In one embodiment, an oral dosage form (e.g., tablets) as described herein may be included in a blister pack having instructions for daily administration of two or more tablets to provide a sufficient dose of the formulation described herein. In another embodiment, an oral dosage form is included in a blister pack having instructions for every other day administration of one or more tablets to provide adequate daily dose. In one embodiment, an oral dosage form (e.g., tablets) as described herein may be included in a blister pack having instructions for weekly administration of one or more tablets to provide a sufficient dose of the formulation described herein.

[0291] Methods for treating diseases or symptoms related to abnormal function or activity of T-type calcium channels. On the one hand, this disclosure provides a method for treating a disease or condition (such as essential tremor (ET)) in a subject in need that is associated with abnormal function or activity of T-type calcium channels, the method comprising administering to the subject daily (e.g., once, twice, three times) a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt (e.g., a cocrystal) or solvate thereof, such as a compound of formula (II): (II).

[0292] Equation (I) can also be called N -((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, while the compound of formula (II) can be called N -((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride.

[0293] In some embodiments, the methods of this disclosure include administering a single-unit dosage form to a subject in need, the single-unit dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)), wherein the composition is bioequivalent to a reference composition having the same dose strength when administered as a plurality of smaller circular tablets.

[0294] In some embodiments, the method of this disclosure comprises administering a titrated dose of a compound of formula (I) or (II) to a subject in need. In some embodiments, the maximum titrated dose is 60 mg / day or 100 mg / day. In one embodiment, the maximum titrated dose is 60 mg / day.

[0295] This document discloses a method for treating diseases or symptoms associated with abnormal function or activity of T-type calcium channels, the method comprising administering a titrated dose such that the ending or maintenance dose exceeds the initial dose or the dose at which adverse events might occur without titration (the maximum tolerated dose achievable without titration). As used herein, administering a titrated dose refers to the practice of starting with a low dose and increasing to one or more higher doses. For example, in some embodiments, administering a titration dose according to the method described herein may include: (i) administering a first dose to the subject, such as about 5 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a first time period (e.g., a first week); (ii) administering a second dose to the subject, such as about 10 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a second time period (e.g., a second week); (iii) administering a second dose to the subject, such as about 20 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a third time period (e.g., a third week); (iv) administering a second dose to the subject, such as about 40 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a fourth time period (e.g., a fourth week); (v) administering a second dose to the subject, such as about 60 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a fifth time period (e.g., a fifth week); (vi) administering a second dose to the subject, such as about 80 mg of compound (I) or a pharmaceutically acceptable salt thereof daily for a fifth time period (e.g., a fifth week); (vii) administering a second dose to the subject, such as about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for a sixth time period (e.g., week six); and / or (ix) administering a second dose to the subject, such as about 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for a seventh time period (e.g., week seven); and / or (ix) administering a second dose to the subject, such as about 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for an eighth time period (e.g., week eight). In some embodiments, the compositions, formulations, and dosage forms described herein enable the use of a single tablet for each dose strength, rather than requiring the use of multiple tablets.

[0296] For example, in some embodiments, this document discloses a method for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject of need, the method comprising: (a) administering to the subject a first dose (such as about 20 mg or about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period, wherein, after administration of the first dose of the compound for the first time period, the subject's maximum plasma drug concentration (C0) is... max Within the range of approximately 30 ng / mL to approximately 130 ng / mL and / or the area under the plasma concentration-time curve from the time of administration to 24 hours post-administration ( AUC24) At approximately 490 ng h / mL to approximately 2030 ng (a) increasing the amount of the compound in the first dose and administering one or more increased doses of the compound to the subject to reach the maximum titration dose; and (c) administering the maximum titration dose of the compound to the subject to maintain a C in the subject within the range of about 280 ng / mL to about 470 ng / mL. max and / or at approximately 3480 ng h / mL to approximately 5800 ng AUC in the range of h / mL 24 Typically, each dose is administered daily, preferably once a day; however, this should be done whenever the desired C is achieved. max and / or AUC 24 The value can be used to change the application frequency, as discussed in other parts of this application.

[0297] For example, in some embodiments, step (b) includes increasing the first dose to a second dose, for example, a dose of about 40 mg to about 80 mg, and administering the second dose of the compound to the subject for a second time period, wherein after administering the second dose of the compound for the second time period, the subject's C max Within the range of approximately 80 ng / mL to approximately 300 ng / mL (e.g., approximately 80 ng / mL to approximately 220 ng / mL, approximately 80 ng / mL to approximately 130 ng / mL, or approximately 130 ng / mL to approximately 300 ng / mL), and / or AUC 24 At approximately 1220 ng h / mL to approximately 4070 ng Within the range of h / mL, such as AUC 24 At approximately 1220 ng h / mL to approximately 3330 ng h / mL or approximately 1220 ng h / mL to approximately 2030 ng Within the range of h / mL.

[0298] In some embodiments, step (b) may further include increasing the second dose to a third dose, such as a dose in the range of about 60 mg to about 100 mg, and administering the third dose of the compound to the subject for a third time period, wherein after administration of the third dose, the subject's C maxWithin the range of approximately 130 ng / mL to approximately 380 ng / mL, such as 130 ng / mL to approximately 220 ng / mL, approximately 180 ng / mL to approximately 300 ng / mL, or 230 ng / mL to approximately 380 ng / mL, and / or AUC 24 In approximately 2000 ng h / mL to approximately 4700 ng h / mL, such as approximately 2000 ng h / mL to approximately 3330 ng h / mL, approximately 2440 ng h / mL to approximately 4070 ng h / mL or approximately 2820 ng h / mL to approximately 4700 ng Within the range of h / mL.

[0299] This document also discloses further embodiments comprising: increasing the third dose to a fourth dose, such as a dose of about 80 mg to about 100 mg, and administering the fourth dose of the compound to the subject for a fourth time period, wherein after administering the fourth dose of the compound for the fourth time period, the subject's C max Within the range of approximately 180 ng / mL to approximately 380 ng / mL, such as approximately 180 ng / mL to approximately 300 ng / mL or approximately 230 ng / mL to approximately 380 ng / mL, and / or AUC 24 At approximately 2440 ng h / mL to approximately 4700 ng h / mL, such as approximately 2440 ng mL / mL to approximately 4070 ng h / mL or approximately 2820 ng mL to approximately 4700 ng Within the range of h / mL. In some aspects, the method disclosed herein may further include increasing the fourth dose to a fifth dose, such as a dose of about 100 mg, and administering the fifth dose of the compound to the subject for a fifth time period, wherein after administering the fifth dose of the compound for the fifth time period, the subject's C max Within the range of approximately 230 ng / mL to approximately 380 ng / mL, and AUC 24 At approximately 2820 ng h / mL to approximately 4700 ng Within the range of h / mL.

[0300] In some embodiments of the titration dosing regimens disclosed herein, the maximum titration dose may be increased to maintain a dose greater than 470 ng / mL and / or AUC in the subject. 24 Greater than 5800 ng The Cmax is achieved at h / mL, provided that the subject can safely tolerate higher doses. For example, in some embodiments, the method includes one or more additional titration steps to achieve the maximum titration dose administered to the subject to maintain Cmax. max Within the range of approximately 450 ng / mL to approximately 750 ng / mL, including, for example, approximately 450 ng / mL to approximately 650 ng / mL, approximately 450 ng / mL to approximately 550 ng / mL, or approximately 450 ng / mL to approximately 500 ng / mL, and / or AUC 24 At approximately 5500 ng h / mL to approximately 9500 ng Within the range of h / mL, including, for example, approximately 5500 ng h / mL to approximately 8500 ng h / mL, 5500 ng h / mL to approximately 7500 ng h / mL or approximately 5500 ng h / mL to approximately 6500 ng h / mL.

[0301] This article also discloses a method for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject requiring treatment, the method comprising: (a) administering to the subject about 5 mg to about 40 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period; (b) administering to the subject about 10 mg to about 100 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a second time period; and (c) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a third time period. Typically, each of the first, second, and third time periods ranges from about 3 days to about 9 days. However, shorter or longer time periods may be used depending on the subject's tolerance, the clinician's judgment, etc.

[0302] This article also discloses a method for treating a subject with a disease or symptom related to abnormal function or activity of T-type calcium channels, the method comprising: (a) administering to the subject about 5 mg to about 40 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period; (b) administering to the subject about 10 mg to about 100 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a second time period; (c) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a third time period; (d) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a fourth time period; (e) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a fifth time period; (f) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a sixth time period; and (g) administering to the subject about 0 mg to 100 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a sixth time period; and (g) administering to the subject about 0 mg to 100 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a sixth time period; The seventh time period consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, at a dose of approximately 1 mg to approximately 120 mg / day. Typically, each of the first, second, third, fourth, and fifth time periods ranges from approximately 3 to approximately 9 days, the sixth time period ranges from approximately 3 to approximately 16 days, and the seventh time period is extended to more than 14 days. However, depending on the subject's tolerability, the clinician's judgment, etc., shorter or longer time periods may be used for each time period.

[0303] In some embodiments, the subject does not experience adverse events at any dose level in the titration dosing regimen. In some embodiments, in the absence of administration of the first dose level for a continuous first dosing period (e.g., about 5 mg to about 40 mg), the subject will experience adverse events at a second dose level administered during a second dosing period (e.g., about 10 mg to about 100 mg, such as at least about 60 mg to about 100 mg). In some embodiments, in the absence of administration of the first and second dose levels during the first and second dosing periods, the subject will experience adverse events at a third dose level administered during a third dosing period (e.g., about 20 mg to about 120 mg, such as at least about 60 mg to about 120 mg).

[0304] In some embodiments, where a subject is likely to experience an adverse event at a second dose level administered during a second dosing period if the first dose level is not administered during the first dosing period, the dose may be titrated to a dose level greater than the second dose level administered during the second dosing period, such as at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 250%, or at least about 300% greater than the dose level at which an adverse event could have occurred without titration.

[0305] In some aspects of all the embodiments disclosed herein, the application period, such as the first, second, third, fourth, or fifth period, can range from about 3 days to about 9 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days. In some aspects of the embodiments disclosed herein, the application period (such as the sixth period) can range from about 3 days to about 16 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, or 16 days. In other aspects of the embodiments disclosed herein, the application period, for example, the first, second, third, fourth, fifth, sixth, or seventh period, can be extended to more than 14 days.

[0306] In some respects, the dose increase relative to the previous dose does not exceed 40 mg / day. For example, in some embodiments, the second dose increases by no more than 40 mg / day relative to the first dose, and in some respects, the third dose increases by no more than 40 mg / day relative to the second dose.

[0307] On the other hand, this disclosure provides a method for treating a subject in need of a disease or symptom related to abnormal function or activity of T-type calcium channels, the method comprising administering to the subject daily (e.g., once, twice, three times) up to about 120 mg (e.g., about 5 mg to about 120 mg, about 10 mg to about 120 mg, about 15 mg to about 120 mg, about 20 mg to about 120 mg, about 40 mg to about 120 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 100 mg, about 5 mg to about 80 mg, about 10 mg to about 80 mg, about 15 mg to about 80 mg, about 20 mg to about 80 mg, about 40 mg to about 80 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, or about 40 mg to about 60 mg). Compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of formula (II)).

[0308] On the other hand, this disclosure provides a method for treating a disease or condition in a subject of need related to abnormal function or activity of T-type calcium channels, the method comprising: (a) Administer 5 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)) to the subject once daily for a first time period (e.g., 3, 4, 5, 6, 7, 8 or 9 days). (b) Administer 10 mg of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II)) to the said subject once daily for a second period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days); and (c) Administer 20 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)) to the subject once daily for a third time period (e.g., 3, 4, 5, 6, 7, 8 or 9 days).

[0309] On the other hand, this disclosure provides a method for treating a condition in a subject in need, the method comprising: (a) Administer 20-40 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)) to the subject daily for a first time period (e.g., 3, 5, 6, 7, 8 or 9 days). (b) Administering the subject 20-60 mg of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II)) daily for a second time period (e.g., 3, 5, 6, 7, 8, or 9 days); and (c) Administer 20-80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) to the subject daily for a third time period (e.g., 3, 4, 5, 6, 7, 8 or 9 days).

[0310] In some embodiments, the method further comprises (d) administering 20-100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) to the subject daily for a fourth time period (e.g., 3, 4, 5, 6, 7, 8 or 9 days).

[0311] In other embodiments, the method further comprises (e) administering 20-120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) to the subject daily for a fifth time period (e.g., 3, 4, 5, 6, 7, 8 or 9 days).

[0312] In some embodiments, the method further comprises (f) administering 20-120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) to the subject daily for a sixth time period (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 days).

[0313] In some embodiments, the method further comprises (g) administering 20-120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) to the subject daily as needed for a seventh time period (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days or more).

[0314] In some aspects of these embodiments, the physician may choose not to continue escalating the dose of compound (I) or its pharmaceutically acceptable salt, such that the dosing time intervals are less than the seven time intervals described above. For example, only one, two, three, four, five, or six dose escalation time intervals may be required to achieve the desired therapeutic effect. More than the seven dose escalation time intervals described above may also be possible, provided that the subject's tolerability and the physician's judgment allow.

[0315] For example, in some embodiments, a method for treating a subject in need of a disease or symptom related to abnormal function or activity of T-type calcium channels is disclosed, the method comprising: (a) administering to the subject about 5 mg to about 40 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., 20 mg or 40 mg / day) for a first time period ranging from about 3 days to about 9 days; (b) administering to the subject about 10 mg to about 100 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., 40 mg, 60 mg or 80 mg / day) for a second time period ranging from about 3 days to about 9 days; and (c) administering to the subject about 20 mg to about 120 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., 60 mg, 80 mg, 100 mg or 120 mg / day) for a third time period ranging from about 3 days to about 9 days.

[0316] In some respects, this document discloses a method for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject of need, the method comprising: (a) administering to the subject once daily a first dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof of about 20 mg to about 40 mg / day for a first time period; (b) increasing the amount of the compound in the first dose and administering to the subject one or more additional doses of the compound to reach a maximum titration dose of about 80 mg to about 120 mg / day; and (c) administering the maximum titration dose to the subject once daily as needed.

[0317] In relevant embodiments, the physician may, if necessary, adjust the dose of compound (I) upward or downward in increments of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, or 20 mg based on the subject’s response to a previous dose of compound (I).

[0318] In various embodiments of this disclosure, the method disclosed herein includes: (a) administering a first dose of 20 mg / day for a first period of 3 days; (b) administering a second dose of 40 mg / day for a second period of 3 days; (c) administering a third dose of 60 mg / day for a third period of 7 days; (d) administering a fourth dose of 80 mg / day for a fourth period of 7 days; (e) administering a fifth dose of 100 mg / day for a fifth period of 7 days; and (f) subsequently administering a sixth dose of 120 mg / day as needed. In various other embodiments, the method disclosed herein includes: (a) administering a first dose of 20 mg / day for a first period of 3 days; (b) administering a second dose of 40 mg / day for a second period of 3 days; (c) administering a third dose of 80 mg / day for a third period of 3 days; and (d) administering a fourth dose of 120 mg / day as needed.

[0319] In some embodiments, a method for treating a subject in need of a disease or symptom related to abnormal function or activity of T-type calcium channels is disclosed, the method comprising: (a) administering to the subject about 20 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first period of 3 days; (b) administering to the subject about 40 mg / day of the compound for a second period of about 3 days; (c) administering to the subject about 60 mg / day of the compound for a third period of about 3 days; (d) administering to the subject about 80 mg / day of the compound for a fourth period of about 3 days; (e) administering to the subject about 100 mg / day of the compound for a fifth period of about 3 days; and (f) administering to the subject about 120 mg / day of the compound for a sixth period. The dosage may also be administered every 4, 5, or 6 days instead of every 3 days.

[0320] This article also discloses a method for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject of need, the method comprising: (a) administering to the subject about 20 mg / day of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period of 7 days; (b) administering to the subject about 40 mg / day of the compound for a second time period of about 7 days; (c) administering to the subject about 60 mg / day of the compound for a third time period of about 7 days; (d) administering to the subject about 80 mg / day of the compound for a fourth time period of about 7 days; (e) administering to the subject about 100 mg / day of the compound for a fifth time period of about 7 days; and (f) administering to the subject about 120 mg / day of the compound for a sixth time period.

[0321] In some embodiments, a method for treating a subject in need of a disease or symptom related to abnormal function or activity of T-type calcium channels is disclosed, the method comprising: (a) administering to the subject about 40 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period of 3 days; (b) administering to the subject about 80 mg / day of the compound for a second time period of about 3 days; and (c) administering to the subject about 120 mg / day of the compound for a third time period. The dosage may also be administered every 4, 5, or 6 days instead of every 3 days.

[0322] This article also discloses a method for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject in need, the method comprising: (a) administering to the subject about 40 mg / day of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a first time period of 7 days; (b) administering to the subject about 80 mg / day of the compound for a second time period of about 7 days; and (c) administering to the subject about 120 mg / day of the compound for a third time period.

[0323] In some embodiments, a method for treating a subject in need of a disease or symptom related to abnormal function or activity of T-type calcium channels is disclosed, the method comprising: (a) administering to the subject about 20 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first period of 7 days; (b) administering to the subject about 40 mg / day of the compound for a second period of about 7 days; (c) administering to the subject about 60 mg / day of the compound for a third period of about 7 days; (d) administering to the subject about 80 mg / day of the compound for a fourth period of about 7 days; (e) administering to the subject about 100 mg / day of the compound for a fifth period of about 7 days; (f) administering to the subject about 120 mg / day of the compound for a sixth period of about 14 days; and (g) thereafter administering to the subject about 1-120 mg / day of the compound as needed.

[0324] In certain embodiments of methods for treating a disease or symptom related to abnormal function or activity of T-type calcium channels in a subject in need, the physician may choose to discontinue the escalating dose of compound (I) or a pharmaceutically acceptable salt thereof once the subject demonstrates the desired therapeutic effect. At this point, the physician may choose to have the subject continue taking the dose already taken to achieve the desired therapeutic effect, or may choose to reduce the dose of compound (I) or a pharmaceutically acceptable salt thereof to maintain the desired therapeutic effect. Achieving the desired therapeutic effect may be the result of improvements to any treatment measure, such as the subject's TETRAS performance score, accelerometer performance score, or Archimedes spiral task test.

[0325] In some embodiments, the subjects are people from birth to 100 years of age, such as 10 to 90 years, 20 to 70 years, 18 to 55 years, or 55 to 75 years.

[0326] In various respects, the methods disclosed herein result in a reduction in the EEG Σ band during the subject's NREM sleep, such as a reduction of about 0.4 to 0.7, such as about 0.5 to about 0.6, or about 0.5 compared to baseline. In some embodiments, the methods disclosed herein reduce the EEG γ band during the subject's awakening under EO or EC conditions, such as a reduction of at least about 25% compared to the baseline γ band, for example, a reduction of about 50%.

[0327] In some embodiments, when C is administered to the subject max It is approximately 30 ng / mL to approximately 470 ng / mL, such as C. max When a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at doses ranging from about 30 ng / mL to about 50 ng / mL, about 80 ng / mL to about 130 ng / mL, about 130 ng / mL to about 222 ng / mL, about 180 ng / mL to about 300 ng / mL, about 230 ng / mL to 380 ng / mL, or about 280 ng / mL to about 470 ng / mL, the methods disclosed herein cause a decrease in EEG Σ frequency during NREM sleep and / or a decrease in the EEG γ band during EO or EC states. In some embodiments, when administered to a subject, the AUC 24 At approximately 490 ng h / mL to approximately 5800 ng Within the range of h / mL, such as AUC 24 At approximately 490 ng h / mL to 820 ng h / mL, approximately 1220 ng h / mL to 2030 ng h / mL, approximately 2000 ng h / mL to 3330 ng h / mL, approximately 2440 ng h / mL to 4070 ng h / mL, approximately 2820 ng h / mL to 4700 ng h / mL or approximately 3480 ng h / mL to 5800 ng When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used at a dose within the range of h / mL, the methods disclosed herein cause a decrease in the EEG Σ frequency during NREM sleep and / or a decrease in the EEG γ band during EO or EC states in the subject.

[0328] In some embodiments, when administering C to the subject max It is approximately 5 ng / mL to approximately 470 ng / mL, such as C. max When a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 ng / mL to about 300 ng / mL, the methods disclosed herein cause a decrease in the frequency of NREM Σ in the subject. In some embodiments, when the subject is administered the mean plasma concentration (C) during the period of EEG recording (i.e., over a time period of about 24 hours), the mean plasma concentration (C) is... ave () is approximately 10 ng / mL to approximately 200 ng / mL, such as C ave When a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 12 ng / mL to about 150 ng / mL, the methods disclosed herein cause a decrease in the frequency of NREM Σ in the subject. In some embodiments, when the compound is administered to the subject at a dose that results in a decrease in the C max It is an agreement, as in C. max When a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 280 ng / mL to about 470 ng / mL, the methods disclosed herein cause a reduction in the EO or EC γ band in the subject. In some embodiments, when a subject is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose that results in a plasma concentration of about 75 ng / mL to about 310 ng / mL, such as a plasma concentration of about 90 ng / mL to about 190 ng / mL, the methods disclosed herein cause a reduction in the EO or EC γ band in the subject.

[0329] In other embodiments, the diseases or symptoms associated with abnormal function or activity of T-type calcium channels are selected from the group consisting of: mental disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizures (e.g., absence seizures) and epilepsy or epilepsy syndromes (e.g., juvenile myoclonic epilepsy).

[0330] In some aspects of all embodiments of the titration dosing regimens disclosed herein, it is possible to increase the maximum titration dose, including, for example, increasing the maximum titration dose to more than 120 mg in one or more additional titration steps, provided that the subject can safely tolerate the higher dose.

[0331] In some aspects of all embodiments of the titration dosing regimens disclosed herein, the maximum titration dose achieved is greater than 20 mg, greater than 40 mg, greater than 60 mg, such as about 80 mg, about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, or about 220 mg. In some aspects of the invention, if the subject has achieved the desired therapeutic outcome, the maximum dose achieved by the subject is, for example, 40 mg, 60 mg, or 80 mg.

[0332] In some aspects of all embodiments of the titration dosing protocols disclosed herein, the maximum titration dose is reached within 42 days or less (e.g., 31 days or less, 28 days or less, 18 days or less, 10 days or less, or 7 days or less). In some embodiments, the maximum titration dose is reached within about 10 days to about 42 days, for example, about 36-42 days, about 22-28 days, about 16-18 days, or about 10-12 days.

[0333] application In some embodiments, 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).

[0334] In some embodiments, the dosage form is administered to the subject once daily (e.g., a 5 mg tablet once daily, a 10 mg tablet once daily, a 20 mg tablet once daily, a 40 mg tablet once daily, an 80 mg tablet once daily, or a 120 mg tablet once daily). In some embodiments, the dosage form is administered to the subject twice daily (e.g., a 5 mg tablet twice daily, a 10 mg tablet twice daily, a 20 mg tablet twice daily, a 40 mg tablet twice daily, an 80 mg tablet twice daily, or a 120 mg tablet twice daily).

[0335] In some embodiments, the dosage form is administered to the subject once daily (e.g., one 20 mg tablet once daily, two 20 mg tablets once daily, three 20 mg tablets once daily, four 20 mg tablets once daily, five 20 mg tablets once daily, or six 20 mg tablets once daily). In some embodiments, the dosage form is administered to the subject twice daily (e.g., one 10 mg tablet twice daily, one 20 mg tablet twice daily, two 20 mg tablets twice daily, three 20 mg tablets twice daily, four 20 mg tablets twice daily, five 20 mg tablets twice daily, or six 20 mg tablets twice daily).

[0336] In some embodiments, the dosage form is administered to the subject every other day. In other embodiments, the dosage form is administered to the subject once or twice a week.

[0337] In some embodiments, the method of this disclosure comprises administering a titrated dose of a compound of formula (I) or (II) to a subject in need. In some embodiments, the maximum titrated dose is 60 mg / day or 100 mg / day. In one embodiment, the maximum titrated dose is 60 mg / day.

[0338] In some embodiments, the subject is administered about 1 mg to 10 mg (e.g., 2 mg to 5 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 20 mg (e.g., 5 mg to 10 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 30 mg (e.g., 10 mg to 20 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 40 mg (e.g., 20 mg to 30 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 50 mg (e.g., 30 mg to 40 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 60 mg (e.g., 40 mg to 50 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 70 mg (e.g., 50 mg to 60 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 80 mg (e.g., 60 mg to 70 mg) of compound (I) or a pharmaceutically acceptable salt thereof (e.g., compound (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 90 mg (e.g., 70 mg to 80 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 100 mg (e.g., 80 mg to 90 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) daily. In some embodiments, the subject is administered about 1 mg to 110 mg (e.g., 90 mg to 100 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) daily.In some embodiments, the subject is given approximately 1 mg to 120 mg (e.g., 100 mg to 110 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), such as PRAX-944 HCl) daily.

[0339] In some embodiments, the dosage form has substantially the same bioavailability when administered to a subject as multiple small 20 mg round tablets, for example, regarding the rate of absorption (maximum plasma drug concentration; Cmax) and extent (area under the plasma concentration-time curve; AUC) of PRAX-944.

[0340] In some embodiments, when administered to a subject, the dosage form has a reduced C0 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, or a dosage form without a modulated release polymer, such as an HPMC polymer). max Value. In some embodiments, when administered to a subject, the dosage form has a larger t value 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, or a dosage form without a modulated release polymer, such as an HPMC polymer). max value.

[0341] Tremor The methods described herein can be used to treat tremors, for example, the doses 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 rubral tremor. Tremors can be categorized as follows: genetic, degenerative, and congenital disorders, such as Wilson's disease (genetic), Parkinson's disease (degenerative), and essential tremor (congenital); metabolic disorders; peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy syndrome, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced tremors (neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be neurogenic and can be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor), essential orthostatic tremor, task- and position-specific tremor, dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (i.e., rubra tremor), palatal tremor, toxic or drug-induced tremor, and psychogenic tremor. The tremor may also be familial.

[0342] Tremor is an involuntary, rhythmic oscillation of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0343] 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 or its pathways, such as tumors, strokes, or other focal diseases (e.g., multiple sclerosis) or neurodegenerative diseases.

[0344] Dystonic tremor occurs in individuals affected by dystonia (movement disorders 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.

[0345] 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 tremors may decrease with age, but the severity may increase. Worsening emotions, stress, fever, fatigue, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms typically progress over time and can be noticeable and persistent after onset. Tremors (including essential tremor) can interfere with any or all of a person's daily activities, such as personal hygiene, cooking, eating, dressing, performing home repairs, and interacting with others. Tremors (including essential tremor) can interfere with career choices or job performance (e.g., typing on a computer or mobile phone, using tools, sewing, restaurant work (cooking or serving), caring for others (medical or veterinary work), or any job requiring mobility may be difficult). Tremors can also have profound emotional effects, such as worry about being discovered, worry about how others will react, or worry about being rejected.

[0346] 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.

[0347] 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. Motor dysfunction usually begins on one side of a limb or body and can progress to include the other side.

[0348] 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.

[0349] In some embodiments, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor. In some embodiments, the tremor is essential tremor.

[0350] essential tremor The compositions described herein are for the treatment of essential tremor (ET). ET is the most common movement disorder in adults, affecting up to 2% of the U.S. population (approximately 7 million Americans) (Louis and Ottman 2014). ET is characterized by 5 Hz to 12 Hz postural and kinetic tremor in the upper limbs (i.e., tremor during voluntary movement) (Bhidayasiri 2005, Louis 2009). The most characteristic clinical feature is kinetic tremor of the arms and hands, but tremors can also occur in the head and voice, and are less common in the face, legs, and trunk. Diagnosis of ET is based on medical history and neurological examination, as described in the consensus statement on tremor classification by the International Parkinson's Disease and Movement Disorders Association (Bhatia et al. 2018).

[0351] The severity of ET varies; some patients do not require treatment, while others suffer from severe disability and impairment in activities of daily living, such as dressing and eating. By definition, ET is usually independent of other neurological signs (Deuschl et al. 2011), although there is growing recognition that ET can also be associated with other motor features, such as postural instability, dystonia, mild to moderate gait ataxia, and oculomotor abnormalities (Louis 2009). ET is also associated with an increased prevalence of comorbid mental disorders, including anxiety and depression (Dogu et al. 2005, Miller et al. 2007). ET typically worsens over time, with more severe tremors and corresponding disability progression occurring over years to decades (Louis 2019).

[0352] ET can be sporadic, but a family history of autosomal dominant inheritance is common (Clark and Louis 2018), and importantly, variants in the calcium voltage-gated channel subunit α1G (CACNA1G) gene (which encodes the T-type Ca2+ channel isotype Cav3.1) have been identified as the cause of ET in at least three families (Odgerel et al. 2019). The importance of the CACNA1G gene for cerebellar development and function is further highlighted by the observation that variants in this gene may also cause childhood cerebellar atrophy (Chemin et al. 2018) and spinocerebellar ataxia type 42 (Coutelier et al. 2015). The functional consequences of these genetic variants are consistent with the expression of T-type Ca2+ channels in the cerebellum and distal CTC circuits and their physiological contribution to oscillatory bursts of discharge in the thalamus, which are synchronized with and may drive clinically observable tremors (Milosevic et al. 2018).

[0353] Propranolol is the only FDA-approved oral treatment for the treatment of acute exacerbation (ET). Originally developed for hypertension, propranolol has shown limited efficacy in the treatment of ET, with side effects (e.g., bradycardia) often leading to discontinuation (Hedera 2017, Louis 2015). The unmet medical need for ET has led to the off-label use of drugs in various classes, including anticonvulsants, barbiturates, benzodiazepines, and antipsychotics, with limited and apparent therapeutic benefits for patients with ET. A recent evidence-based review concluded that, of the 28 drugs studied for ET, only propranolol, primidone, and topiramate had sufficient evidence to support efficacy (Ferreira et al. 2019). Surgical interventions that interrupt the explosive activity of CTCs (such as deep brain stimulation or focused ultrasound) are effective treatments for ET, but they carry risks such as sensory disturbances, mild hemiparesis, dysarthria, ataxia, gait disturbances, delirium, cognitive decline, tissue damage, venous thrombotic events, and intracerebral hemorrhage (Dallapiazza et al. 2019, Insightec, Inc. 2016).

[0354] In some embodiments, this disclosure also provides a method for treating essential tremor, the method comprising administering the composition described herein to a subject in need. In some embodiments, the method results in a reduction of the essential tremor, as assessed by a Essential Tremor Rating Assessment Scale (TETRAS) score. As used herein, the term "Essential Tremor Rating Assessment Scale (TETRAS)" 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.

[0355] In some embodiments, the reduction of essential tremor is assessed using the Essential Tremor Assessment Scale (TETRAS) upper limb score.

[0356] In some embodiments, the reduction of essential tremor is assessed by TETRAS performance subscale scores or TETRAS performance individual items.

[0357] In some embodiments, subjects treated according to the methods provided herein have moderate essential tremor (i.e., a TETRAS score of 10-15). In some embodiments, prior to treatment according to the methods provided herein, the TETRAS score of the subjects treated herein was about 10 to about 15, or about 12. Treatment using the compositions described herein can reduce the TETRAS score of the subjects. In some embodiments, subjects treated with the compositions described herein experienced an average reduction of about 2 to 5 (e.g., about 3) in their TETRAS score. In some embodiments, subjects treated with the compositions described herein experienced an average reduction of about 30% to about 50% (e.g., about 40%) in their TETRAS score.

[0358] In some embodiments, this disclosure also provides a method for treating essential tremor, the method comprising administering the composition described herein to a subject in need. In some embodiments, the method reduces the essential tremor, as assessed by an accelerometer-based upper limb score (e.g., an accelerometer-based upper limb score). In some embodiments, the method reduces the essential tremor, as assessed by a CGI score.

[0359] In some embodiments, the idiopathic tremor is an upper limb tremor.

[0360] In some embodiments, subjects are selected to be treated with the compound of formula (I) based on a clinical diagnosis of essential tremor. In some embodiments, subjects selected to be treated with the compound of formula (I) have essential tremor but not intention tremor.

[0361] The efficacy of the compounds or compositions described herein for the treatment of essential tremor can be measured by methods known in the art, such as those described in the following references: Ferreira, JJ et al., “An MDS-based review of the treatment of essential tremor,” *Movement Disorders*. Mov. Disord .)》 July 2019; 34(7):950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor", Motion Disorders, November 2013; 28(13):1793-800; Deuschl G. et al., "Treatment of patients with essential tremor", The Lancet Neurology Lancet Neurol.(2011; 10:148–61); and Reich SG et al., “Essential Tremor”, *North American Clinical Internal Medicine* 2011; 10:148–61; ... Med. Clin. N. Am. (2019;103:351–356. The publicly available information in the references is incorporated herein by reference in its entirety.)

[0362] In some embodiments, the methods described herein reduce upper limb tremor scores by at least 25%, wherein the tremor score can be converted to amplitude compared to baseline. For example, in some embodiments, such as those measured by the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score, the methods described herein reduce tremor amplitude by an average of approximately 40%, as described in Elble, RJ, “The Essential Tremor Rating Assessment Scale”, *Journal of Neurology and Neuromedicine*. J. Neurol. Neuromed. As described in 2016; 1(4):34-38. In some embodiments, the methods described herein reduce TETRAS performance scores by at least 25% compared to baseline. In some embodiments, as measured by TETRAS performance scores, the methods described herein reduce symptom severity by at least 35% on average compared to baseline.

[0363] Parkinson's disease The compositions described herein are for the treatment of Parkinson's disease (PD). PD is a debilitating neurodegenerative disease with approximately one million diagnosed patients in the United States (US) and approximately ten million diagnosed patients worldwide. In the United States alone, approximately 60,000 patients are diagnosed with PD each year (Marras et al. 2018). Diagnosis of PD is typically based on medical history and neurological examination, as described in the International Parkinson's Disease and Movement Disorders Society (MDS) Clinical Diagnostic Criteria for Parkinson's Disease (Postuma et al. 2015).

[0364] PD is characterized by bradykinesia (slowness of movement) accompanied by resting tremor (4-6 Hz) and / or rigid tremor (Postuma et al. 2015). Symptoms are usually unilateral, mild, and non-disabling, but severity progresses over time and involves both sides of the body, often impairing activities of daily living (ADL), such as dressing and eating. In addition to the main symptoms mentioned above, patients with PD may also experience abnormal posture (dystonia), severe forward flexion of the thoracolumbar spine (anterior trunk flexion), dysarthria (arthropathy), gait instability, and gait freezing. Non-motor symptoms (such as impaired sense of smell, recurring dream behaviors (rapid eye movement [REM] sleep behavior disorder [RBD]), constipation, depression, psychosis, and dementia) also play a key role in the daily lives of patients with PD (Jankovic and Tan 2020).

[0365] Because degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) of PD patients leads to a loss of dopaminergic output, dopaminergic replacement therapy is the cornerstone of PD treatment (Armstrong and Okun 2020). L-DOPA or levodopa (a dopamine alternative) is considered the gold standard treatment for PD. Levodopa is very effective in improving motor symptoms such as bradykinesia and rigidity, especially in the early stages of the disease, but its effect on tremor is variable. Most other common PD medications primarily reduce dopamine metabolism or are dopamine receptor agonists.

[0366] While effective, chronic dopaminergic therapy can have side effects including motor complications (movement disorders or involuntary chorea-like movements), impulse control disorders, and psychosis (Poewe et al. 2017). These adverse effects can be disabling in themselves and often require medication to counteract them. Therefore, there is a need for non-dopaminergic therapies with better safety and tolerability profiles for symptom management.

[0367] Adjunctive oral non-dopaminergic therapy to relieve PD symptoms can also reduce the need for dose escalation of dopaminergic therapy.

[0368] Surgical treatment (i.e., deep brain stimulation (DBS)) can be very successful for uncontrolled tremors and motor complications, and typically affects basal ganglia function downstream of the nigrostriatal pathway (Fasano et al. 2012). Depending on the patient's specific symptoms, DBS electrodes can be placed within the globus pallidus, the ventral intermediate nucleus of the thalamus, or the subthalamic nucleus (STN), and may affect aberrant bursts of discharge in these areas (see below). DBS is generally reserved for patients who respond to dopaminergic therapy but have received maximum dopaminergic therapy and continue to have disturbing motor symptoms. Furthermore, DBS carries significant risks associated with neurosurgery, including intracerebral hemorrhage, infection, mild hemiparesis, and cognitive decline (Pahwa et al. 2006). The prospect of neurosurgery in the coming years is often anxiety-inducing or contraindicated (e.g., due to the presence of cognitive impairment), and many patients are not treated with DBS. Therefore, there is a clinical need for pharmacological therapies that can mimic the effects of DBS. PRAX-944 modulates bursts of discharge downstream of SNc degeneration by modulating T-type Ca2+ channels.

[0369] Animal models and human PD patient data have shown that degeneration of dopaminergic neurons in the substantia nigra transforms the downstream STN from tetanic discharges to an aberrant burst phenotype (Ammari et al. 2011, Tai et al. 2011, Pan et al. 2016). This burst activity drives symptoms of bradykinesia and rigidity in animal models, and blocking T-type Ca2+ channels has been shown to reduce this phenotype (Tai et al. 2011, Yang et al. 2014, Pan et al. 2016). T-type Ca2+ channels are widely expressed throughout the brain, including in the STN (Talley et al. 1999, Weiss and Zamponi 2019). Eliminating this burst discharge by blocking T-type Ca2+ channels has been shown to improve motor function in a 6-hydroxydopamine rat model of PD (Pan et al. 2016). Therefore, inhibitors of T-type Ca2+ channels could provide non-surgical and non-dopaminergic treatment options to alleviate motor symptoms of PD.

[0370] Epilepsy and Epilepsy Syndromes 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 recurrent seizures that can manifest as abnormal movement, abnormal behavior, 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.

[0371] Epilepsy can involve generalized seizures, affecting multiple areas of the brain, 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 several seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes may be open, and / or the person may appear not breathing and turn blue. Recovery of consciousness may be gradual, and the person may be confused for minutes to hours. The main types of generalized seizures are: tonic-clonic, tonic, clonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, and absence (typical, atypical, myoclonic, eyelid myoclonic) seizures 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.

[0372] 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.

[0373] The compositions described herein can also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction, caused at least in part by aspects of epilepsy, are also known as epileptic encephalopathy. These are associated with treatment-resistant, frequent seizures and severe cognitive impairment, such as West syndrome.

[0374] In some embodiments, the epilepsy syndrome includes epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 deficiency, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency syndrome. 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, epilepsy syndromes are 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), as in, for example, Feng, YCA et al., “Ultra-Rare Genetic Variation in the Epilepsies: AWhole-Exome Sequencing Study of 17,606 Individuals,” *American Journal of Human Genetics*. Am. J. Human Gen. The epilepsy syndrome discussed in [Journal Name] 2019; 105(2):267-282. In some embodiments, the epilepsy syndrome is epilepsy with myoclonic-atonic seizures (Doose syndrome) or myoclonic unstable epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spikes and waves (CSWS) during sleep. In some embodiments, the epilepsy syndrome is Landau-Clifton syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0375] Absence seizures 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, followed by a rapid return of consciousness without postictal confusion. On accompanying EEG recordings, the seizures are characterized by the sudden onset and deviation of generalized 1–6 Hz (e.g., 3 Hz) spike 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 episodes of loss of consciousness. Typically, absence seizures begin in early childhood and resolve during adolescence. However, in a minority of patients, they persist into adulthood, often developing 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 period of loss of consciousness associated with the seizure poses a safety risk, and are associated with severe psychosocial dysfunction (Wirrell et al., 1997).

[0376] 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 in 45% and 44% of patients, 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 in 21% of patients at 12 months. Furthermore, both ethosuximide and valproate are often associated with intolerable side effects (occurring in 24% of patients treated with either of these drugs) (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 having proven efficacy, and these drugs are often poorly tolerated due to sedative and cognitive side effects. Absence seizures persisting into adulthood are particularly difficult to treat, often requiring multiple medications, leading to severe side effects and sometimes failing to achieve seizure control.

[0377] Extensive evidence suggests that low-threshold (T-type) calcium channels play a role in the occurrence and maintenance of absence seizures, and are a key component of the oscillatory bursts of discharge that occur in thalamic cortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, this disclosure relates to a method for treating absence seizures using 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).

[0378] 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.

[0379] In some embodiments, the method described herein further includes identifying a subject suffering from absence seizures.

[0380] In some embodiments, this disclosure provides a method for treating a subject with generalized epilepsy syndrome accompanied by absence seizures, the method comprising administering an effective amount of the composition described herein to the subject. In some embodiments, the method results in a reduction in the frequency of seizures.

[0381] In some embodiments, this disclosure provides a method for treating a subject with generalized epilepsy syndrome accompanied by absence seizures, the method comprising administering an effective amount of the composition described herein to the subject.

[0382] In some embodiments, the method for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduces the average or total duration of seizures.

[0383] In some embodiments, the methods for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduce the frequency, duration, or both of seizures, as measured by electroencephalography (EEG).

[0384] In some embodiments, the methods for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduce the average seizure duration, as measured by EEG.

[0385] In some embodiments, the methods for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduce the cumulative duration of seizures, as measured by EEG.

[0386] In some embodiments, the method for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduces the total time of 2.5-4 Hz spike discharges after hyperventilation and light stimulation challenges, as measured by EEG.

[0387] In some embodiments, the methods for treating generalized epilepsy syndromes with absence seizures provided in this disclosure result in a reduction 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.

[0388] In some embodiments, the method for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduces the frequency of seizures.

[0389] In some embodiments, the method for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduces the seizure density, as measured by electroencephalography (EEG).

[0390] In some embodiments, the methods for treating generalized epilepsy syndrome with absence seizures provided in this disclosure reduce the average seizure duration, as measured by EEG.

[0391] Hereditary epilepsy In some embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is hereditary generalized epilepsy. In some embodiments, the 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 mutations, 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 mutations, cryptogenic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, 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.

[0392] In some embodiments, the methods described herein further include identifying subjects suffering from epilepsy or epilepsy syndromes (e.g., epilepsy or epilepsy syndromes including 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, 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) prior to administration of the compositions described herein.

[0393] In some embodiments, the present invention is characterized by a method of treating epilepsy or epilepsy syndromes (e.g., epilepsy or epilepsy syndromes including epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, 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 mutations, cryptogenic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, 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), said method comprising administering the composition described herein to a subject in need.

[0394] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has mutations in one or more of the following: 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, KCNQ. 2. KCNQ3, KCNT1, 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.

[0395] In some embodiments, the methods described herein further include identifying a subject having mutations in one or more of the following prior to administration of the compositions described herein: 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, KC NQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC 13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0396] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has mutations in one or more of the following: 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, DNA JC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, G NAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCN Q3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PI GN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A , SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, S PTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT,ARHGEF15, 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.,

[0397] In some embodiments, the methods described herein further include identifying subjects having mutations in one or more of the following: 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, D NAJC5, DNM1, DOCK7, 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, KC NQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, P IGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A , SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, S PTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT,ARHGEF15, 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.,

[0398] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has mutations in one or more of the following: 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, DNAJC5 (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EP M2A, 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. 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, SLC2A 1. SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0399] In some embodiments, the methods described herein further comprise identifying subjects having mutations in one or more of the following: 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, DNAJC5 (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, E PM2A, 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. 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, SLC2A 1. SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0400] The compositions of the present invention can also be used to treat epileptic encephalopathy, wherein the subject has mutations in one or more of the following: 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, KCN C1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCD H19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0401] In some embodiments, the methods described herein further comprise identifying subjects having mutations in one or more of the following: 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, KC NC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCD H19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0402] Mood Disorders This article also provides methods for treating mental 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, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide therapeutic effects for subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or conditions described herein (e.g., neuroendocrine disorders and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or health conditions or symptoms in women).

[0403] Clinical depression, also known as major depressive disorder (MDD), severe depression, 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.

[0404] 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.

[0405] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a group of clinical depressions 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).

[0406] In some embodiments, subjects with perinatal depression also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression have an increased risk of developing perinatal depression.

[0407] 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.

[0408] 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.

[0409] Major psychotic depression (PMD) or psychotic depression refers to a severe depressive episode, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0410] Catatonic depression is a major depressive disorder characterized by disordered motor behavior and other symptoms. Individuals may become silent and catatonic, and may be immobile or exhibit meaningless or strange movements.

[0411] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals exhibit a seasonal pattern of depressive episodes during the fall or winter.

[0412] Dysphoria refers to the symptoms associated with unipolar depression in which the same physical and cognitive problems are present. These problems are less severe and tend to be more persistent (e.g., at least 2 years).

[0413] Double depression refers to a persistent, significantly depressed mood (dysphoric state) lasting at least two years, with a stage that highlights major depressive disorder.

[0414] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive features.

[0415] Recurrent transient depression (RBD) refers to a condition in which an individual experiences depressive episodes approximately once a month, each lasting 2 weeks or less and typically less than 2-3 days.

[0416] Mild depressive disorder or mild depression means that at least two symptoms of depression have been present for two weeks.

[0417] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, 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 condition have a high 20-year suicide risk (greater than 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.

[0418] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0419] 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 have not relieved 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).

[0420] Postoperative depression refers to feelings of depression following surgery (e.g., due to the experience of facing death). For example, an individual may experience persistent sadness or emptiness, lose enjoyment or interest in hobbies and activities they normally enjoy, or feel worthless or hopeless.

[0421] Mood disorders related to a woman’s health condition or illness are mood disorders (e.g., depression) that are related to (e.g., caused by) a woman’s health condition or illness, as described herein.

[0422] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual focus on suicide. The range of suicidal ideation varies greatly, from fleeting thoughts to broad ideas, detailed plans, role-playing, and / or incomplete attempts. Symptoms include talking about suicide, acquiring means of suicide, withdrawing from social life, being preoccupied with death, feeling confused or hopeless about a situation, increasing alcohol or drug use, doing dangerous or self-destructive things, and saying goodbye to people as if they would never see them again.

[0423] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, 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).

[0424] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, mood disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0425] 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-Asperger's Depression Rating Scale (MADRS). In some embodiments, treatment effectiveness can be determined by a reduction in the total HAM-D score performed by the subject. Treatment effectiveness can be assessed across specified treatment time periods. For example, treatment effectiveness can be determined by a decrease in the total HAM-D score relative to 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 longer; 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).

[0426] In some embodiments, the subject has a mild depressive disorder, such as mild-severe depressive disorder. In some embodiments, the subject has a moderate depressive disorder, such as moderate-severe depressive disorder. In some embodiments, the subject has a severe depressive disorder, such as severe-major depressive disorder. In some embodiments, the subject has extremely severe depressive disorder, such as extremely severe-major 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 from the baseline total HAM-D score to the total HAM-D 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 the baseline HAM-D total score to the 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 the HAM-D total score relative to the baseline HAM-D total score after treatment with the composition described herein.

[0427] In some embodiments, methods for treating depressive disorders (e.g., major depressive disorder) provide therapeutic effects within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or within 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in HAM-D score). In some embodiments, methods for treating depressive disorders (e.g., major depressive disorder) provide therapeutic effects within the first or second day of treatment with the composition described herein (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, methods for treating depressive disorders (e.g., major depressive disorder) provide therapeutic effects within 14 days or less after initiation of treatment with the composition described herein (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, methods for treating depressive disorders (e.g., major depressive disorder) provide therapeutic effects within 21 days or less after initiation of treatment with the composition described herein (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (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 after initiation of treatment with the composition described herein. In some embodiments, the therapeutic effect is a decrease in the total HAM-D score relative to baseline after treatment with the composition described herein. In some embodiments, the subject's total HAM-D score before treatment with the composition described herein is at least 24. In some embodiments, the subject's total HAM-D score before treatment with the composition described herein is at least 18. In some embodiments, the subject's total HAM-D score before 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 with the composition 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 with the compositions described herein does not exceed 7.

[0428] In some embodiments, the method provides a therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in the Clinical Global Impression-Improvement Scale (CGI)). In some embodiments, the CNS condition 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 on the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score relative to baseline at the end of the treatment period (e.g., 14 days after administration).

[0429] The effectiveness of treatment for major depressive disorder can be determined by a decrease in the Montgomery-Asperger's Depression Rating Scale (MADRS) score, as demonstrated by the subject. For example, the MADRS score may decrease within 4 days, 3 days, 2 days, or 1 day; or within 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. The MADRS is a ten-item diagnostic questionnaire (regarding overt sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, numbness, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. In some embodiments, the effectiveness of treatment is a decrease in the MADRS score relative to baseline at the end of the treatment period (e.g., 14 days after administration).

[0430] pain 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.

[0431] In some embodiments, the methods described herein further include 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 a 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), e.g., PRAX-944HCl)).

[0432] Ataxia The dosage forms and compositions described herein can be used to treat ataxia. Ataxia, including cerebellar ataxia and spinal ataxia (e.g., postspinal 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, thereby severely interfering with daily activities of life.

[0433] As noted above, ataxia can be caused by a variety of underlying diseases and conditions in patients, including cerebellar disorders and neurodegenerative diseases, as well as diseases resulting from chronic or long-term exposure to toxins. Symptoms of ataxia can be caused by a variety of diseases, conditions, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol), etc.; in one embodiment, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or a disease resulting from long-term or chronic exposure to toxins. Diseases, conditions, syndromes, and symptoms 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), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endostomy), and cerebellar hypoplasia (retinal). The following are listed as examples of cerebellar parenchymal disorders: 1. Carpet degeneration; 2. Cerebellar parenchymal autosomal recessive disorder; 3. Cerebellar parenchymal disorder; 4. Cerebellar hypoplasia (hydrocerebrospinal fluid); 5. Cerebral amyloid angiopathy (familial); 6. Cerebral palsy; 7. Demyelination disorder; 8. Spinal disorders; 9. Autonomic dysfunction; 10. Balance disorder; 11. Sensory delay; 12. Endocrine disorders; 13. Disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, relaxants); 14. Fragile X / tremor ataxia syndrome; 15. Friedreich's ataxia. Ataxia), frontal lobe dysfunction, hereditary diseases, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathy, hydrocephalus (e.g., hypobaric or normobaric), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, episodic spinocerebellar ataxia in infants, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus-ataxia, neurodegenerative diseases, olivopontocerebellar atrophy, paraneoplastic disorders, Parkinson's disease (atypical), peroneal muscle atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-poliomyelitis syndrome, severe brain injury (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 23, spastic paraplegia glaucoma-related 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 disease 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 base artery insufficiency, and diseases caused by vitamin deficiency, etc. In one embodiment, ataxia is a result of a disease selected from spinocerebellar ataxia, Friedreich ataxia, and fragile X-chromosome / tremor ataxia syndrome. In another specific embodiment, ataxia is a result of spinocerebellar ataxia or fragile X / tremor ataxia syndrome.

[0434] tinnitus This article provides a method for treating tinnitus in subjects in need, and the method comprises administering a dosage form or composition as disclosed herein. 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.

[0435] Sleep disorders This document provides methods for treating or preventing sleep disorders (e.g., narcolepsy), methods comprising administering the doses or compositions disclosed herein. For example, sleep disorders may 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 a drug or substance, hypersomnia associated with a mental disorder, sleep deprivation syndrome, circadian rhythm sleep-wake disorders, delayed sleep-wake disorders, late sleep-wake disorders, irregular sleep-wake rhythms, non-24-hour sleep-wake rhythm disorders, shift work disorders, jet lag disorders, or no further details (NOS) circadian rhythm sleep-wake disorders.

[0436] combination therapy The dosage forms or compositions described herein (e.g., for modulating T-type calcium channels) may be administered in combination with at least one other agent or therapy. Subjects to whom the compounds disclosed herein are to be administered may suffer from a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another agent or therapy. In some embodiments, 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).

[0437] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuximide, ezogabine, felbamate, gabapentin, and lacosamide. Lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0438] Painkillers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine-like substances such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. Given the ability of the compounds disclosed herein to treat pain by inhibiting T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combinations with analgesics are particularly envisioned.

[0439] Tremor drugs Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0440] Example To provide a more comprehensive understanding of the embodiments described herein, the following examples are illustrated. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0441] Example 1: Evaluation of the pharmacokinetics and relative bioavailability of two PRAX-944 modulated-release tablet formulations in healthy adults. A phase 1, randomized, open-label trial to assess dosage, safety, tolerability, and food effects. PRAX-944 is a small molecule selective inhibitor of T-type calcium channels developed for the treatment of essential tremor. Figure 1 PRAX-944 is also under development for the treatment of Parkinson's disease. Developing a more convenient dosage form prior to later-stage studies is crucial for the project's success. This involves the dosage units required to deliver specific dose levels. For example Minimizing the total number of tablets and customizing the physical size and shape of the tablets to make them easier to grasp may be more convenient and usable for patients, especially those with essential tremor (ET). Figure 2A Tablets of various shapes and sizes are shown, and Figure 2BThis study presents a comparison between currently available PRAX-944 dosage forms (obtained as modulated-release (MR) formulations in the form of small, round (6 mm in diameter) 5 mg and 20 mg tablets) and the exemplary bioequivalent single-unit dosage forms described herein. The aim of this trial was to evaluate the pharmacokinetics (PK) of the new PRAX-944 tablets designed to provide greater convenience to patients.

[0442] The current PRAX-944 dosage form is a modulated-release (MR) formulation obtained in small, round (6 mm in diameter) 5 mg and 20 mg tablets. The current maximum planned clinical dose is up to 120 mg. This 120 mg dose level requires study participants to take six small, round 20 mg PRAX-944 tablets.

[0443] In some cases, titration is required to reach a dose >40 mg. The current PRAX-944 titration schedule uses 20 mg, 40 mg, and 80 mg as intermediate dose levels to reach the current maximum planned dose of 120 mg. Each dose level above 20 mg requires participants to take multiple 20 mg tablets. The new tablets used in the current trial will be larger than those used in previous trials and will include single-unit dose intensities of 20 mg, 40 mg, 80 mg, and 120 mg.

[0444] This trial will evaluate the pharmacokinetic (PK) of the new, larger capsule-shaped single-unit dose-strength MR tablet (15 mm in length and 6.5 mm in width) compared to the current small, round 20 mg tablets used in the current titration protocol at each dose level: 20 mg, 40 mg, 80 mg, and 120 mg. The primary objective of this relative bioavailability study is to compare the rate of absorption (maximum plasma drug concentration; Cmax) and extent (area under the plasma concentration-time curve; AUC) of PRAX-944 from the larger 120 mg tablet relative to the multiple smaller, round 20 mg tablets. These parameters are relevant to the potential safety and efficacy of PRAX-944. Comparisons will also be made with other dose levels.

[0445] In a previous study (Z944-103), administration of a single small, round 20 mg PRAX-944 MR tablet on a high-fat, high-calorie diet resulted in a 14% to 15% increase in AUC and a 49% increase in Cmax compared to administration on a fasting state. No clinically significant differences in adverse events (AEs) were observed between the feeding and fasting states. This study will further evaluate the food effects of PRAX-944 when administered in combination with the new, larger 120 mg tablets.

[0446] Overall research design This ongoing single-center, randomized, open-label, phase 1 relative bioavailability clinical trial will evaluate the pharmacokinetic (PK), safety, and tolerability of large single-unit doses of PRAX-944 tablets (20 mg, 40 mg, 80 mg, and 120 mg) in healthy male or female participants aged 18 to 55 years compared to the same dose level delivered with small, round 20 mg PRAX-944 tablets (1, 2, 4, and 6 tablets, respectively). Participants will be randomized 1:1 to receive a drop-dose formulation (i.e., a single unit or a small 20 mg tablet). After steady-state at the 120 mg dose, all participants will subsequently be switched to the other formulation at a 120 mg dose. Additionally, the PK effect of food on the 120 mg single-unit dose of PRAX-944 tablets will be assessed. Food effects will be assessed only at the 120 mg dose level. Comparisons between dosage forms at the 120 mg dose level will be intra-participant comparisons, as will comparisons between fed and fasted states. Figure 3A Comparisons between dosage forms at 20 mg, 40 mg, and 80 mg dose levels will be between-group comparisons.

[0447] The test products were large single-unit dose PRAX-944 tablets (20 mg, 40 mg, 80 mg, and 120 mg), and the reference therapy was small round 20 mg PRAX-944 tablets.

[0448] An overview of the experimental design and tablet formulation, as follows: Figures 3A-3C As shown in Table 2, the study drugs administered are shown in Table 3, and the tablet formulations are shown in Table 4. The trial will consist of three time periods: screening / baseline, intervention, and safety follow-up. Full details of the required assessment and PK analysis time points are provided in the activity schedule (SoA; Table 5). Figure 3D A schematic diagram of an exemplary phase 3 clinical trial design is depicted to evaluate the efficacy of large single-unit doses of PRAX-944 tablets (20 mg, 40 mg, 80 mg, and 120 mg) compared to the same dose level delivered by small, round 20 mg PRAX-944 tablets (1, 2, 4, and 6 tablets, respectively).

[0449] Table 2. Goals and Endpoints Table 3. Study drugs used Table 4. PRAX-944 MR Tablets Intervention period The plan is to recruit approximately 24 healthy male and female participants aged between 18 and 55, with a body mass index (BMI) between 18 kg / m² and 32 kg / m². 2 Participants must be between [age range missing] and weigh at least 50 kg. Participants will be randomized in a 1:1 ratio to receive either small, round 20 mg PRAX-944 tablets (titration group 1) or large, single-unit dose PRAX-944 tablets (titration group 2) for dose titration. The formulations will not be blinded. The dose levels administered in both groups are 20 mg, 40 mg, 80 mg, and 120 mg; see [link missing] for the complete titration protocol. Figure 3A From day 1 to day 15, all participants received PRAX-944 in the morning after a 10-hour overnight fast. Participants remained fast for 4 hours after administration.

[0450] Participants will receive the same dosage form from day 1 to day 12 (small, round 20 mg PRAX-944 tablets in titration group 1 and large, single-unit PRAX-944 tablets in titration group 2). On day 13 (after participants have received 120 mg PRAX-944 for 3 days), participants in titration group 1 will crossover to receive 120 mg PRAX-944 as a large, single-unit PRAX-944 tablet, and participants in titration group 2 will crossover to receive 120 mg PRAX-944 as six small, round 20 mg tablets. This 120 mg PRAX-944 dose will be administered over 3 days while fasting.

[0451] On day 16, all participants will receive a single 120 mg dose of PRAX-944 tablets while on an empty stomach. Dosing while on an empty stomach will continue for 3 days (days 16 to 18). During these days, all participants will then receive a single 120 mg dose of PRAX-944 tablets in conjunction with a high-fat, high-calorie diet. Participants will be observed at the study facility for 2 days following the last dose of the study drug.

[0452] Pharmacokinetic assessment Pharmacokinetics will be assessed using consecutive plasma samples collected on day 3 of dosing at each dose level (days 3, 6, 9, 12, 15, and 18). This timeline allows for the calculation of steady-state AUCτ. Plasma concentrations of PRAX-944 and its metabolites will b...

Claims

1. A single unit dosage form comprising: a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HC1), wherein the single unit dosage form is bioequivalent to a reference composition having the same dose strength administered as one or more dosage forms.

2. The single unit dosage form of claim 1, wherein the single unit dosage form and the reference composition have: (i) different sizes; (ii) different shapes; (iii) both different sizes and different shapes; (iv) the same shape but different sizes; or (v) the same size but different shapes.

3. The single unit dosage form of claim 1, wherein the single unit dosage form is larger than the reference composition.

4. The single unit dosage form of claim 3, wherein the reference composition comprises a smaller round 20 mg PRAX-944 tablet.

5. The single unit dosage form of any one of the preceding claims, wherein: (i) the single unit dosage form is a larger dosage form that exhibits bioequivalence when administered to a subject in a fed state and / or a fasted state as compared to a reference composition having the same dose strength administered as one or more smaller round 20 mg PRAX-944 tablets administered to a subject in a fed state and / or a fasted state; wherein bioequivalence is determined by: (a) a 90% confidence interval for AUC of between about 80% and about 125%, and (b) a 90% confidence interval for Cmax of between about 80% and about 125%.

6. The single unit dosage form of any one of the preceding claims, which: (i) reduces the total number of dosage units (e.g., tablets) needed to deliver a particular dose strength to a subject; (ii) is characterized by a physical size and shape (e.g., tablet size and shape) that makes it easier and more convenient for a subject with a movement disorder, optionally essential tremor (ET), to grasp; (iii) is capable of being formulated in single unit dose strengths of 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg; and / or (iv) does not require titration to reach a dose > 40 mg.

7. The single unit dosage form of any one of the preceding claims, wherein at least about 50% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), e.g., PRAX-944 HC1) is released within about 1 hour to about 12 hours when administered to a subject, optionally wherein at least about 50% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), e.g., PRAX-944 HC1) is released within about 1 hour to about 12 hours using USP Apparatus Type I, a medium containing 900 mL of 0.1 M HC1, and a paddle speed of 100 rpm.

8. The single unit dosage form of any one of the preceding claims, comprising about 1 mg to about 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), e.g., PRAX-944 HC1).

9. The single unit dosage form of any one of the preceding claims, comprising about 1 wt% to about 70 wt% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), e.g., PRAX-944 HC1).

10. The single unit dosage form of any one of the preceding claims, further comprising a modified-release polymer.

11. The single unit dosage form of any one of the preceding claims, wherein the modified- release polymer comprises a matrix polymer optionally selected from the group consisting of a hydrophilic matrix polymer, a hydrophobic matrix polymer, a polyacrylate polymer, and combinations thereof.

12. The single unit dosage form of any one of the preceding claims, wherein the modified- release polymer comprises (i) a hydrophilic matrix polymer optionally selected from the group consisting of hypromellose, HPMC (hydroxy-propyl methylcellulose), and combinations thereof, optionally wherein the HPMC (hydroxy-propyl methylcellulose) is selected from the group consisting of Methocel K4M, Methocel K100LV, Methocel E50LV, and combinations thereof; (ii) a hydrophobic matrix polymer optionally selected from the group consisting of ethyl cellulose, ethocel, and combinations thereof; and / or (iii) a polyacrylate polymer optionally selected from the group consisting of Eudragit RL100, Eudragit RS100, and combinations thereof.

13. The single unit dosage form of any one of the preceding claims, comprising about 5 mg to 300 mg of a modified-release polymer.

14. The single unit dosage form of any one of the preceding claims, comprising about 10 wt% to about 70 wt% of the modified-release polymer.

15. The single unit dosage form of any one of the preceding claims, wherein the modified- release polymer is hypromellose.

16. The single unit dosage form of any one of the preceding claims, further comprising a diluent.

17. The single unit dosage form of any one of the preceding claims, wherein the diluent comprises: (i) a cellulose derivative, optionally microcrystalline cellulose, optionally siliconized microcrystalline cellulose; (ii) a starch optionally selected from the group consisting of a hydrolyzed starch, a pregelatinized starch, and combinations thereof; (iii) anhydrous lactose; (iv) lactose monohydrate; (v) dicalcium phosphate (DCP); and / or (vi) a sugar alcohol optionally selected from the group consisting of sorbitol, xylitol, mannitol, and combinations thereof.

18. The single unit dosage form of any one of the preceding claims, comprising about 5 mg to about 300 mg of diluent.

19. The single unit dosage form of any one of the preceding claims, comprising about 5% to about 50% by weight of diluent.

20. The single unit dosage form of any one of the preceding claims, wherein the diluent is microcrystalline cellulose, optionally siliconized microcrystalline cellulose.

21. The single unit dosage form of any one of the preceding claims, wherein the diluent is a sugar alcohol, optionally mannitol.

22. The single unit dosage form of any one of the preceding claims, further comprising a glidant.

23. The single unit dosage form of any one of the preceding claims, wherein the glidant is selected from the group consisting of fumed silica, optionally colloidal silicon dioxide, talc, magnesium carbonate, and combinations thereof.

24. The single unit dosage form of any one of the preceding claims, comprising about 1 mg to about 10 mg of glidant.

25. The single unit dosage form of any one of the preceding claims, comprising about 1% to about 10% by weight of glidant.

26. The single unit dosage form of any one of the preceding claims, wherein the glidant is fumed silica, optionally colloidal silicon dioxide.

27. The single unit dosage form of any one of the preceding claims, further comprising a lubricant.

28. The single unit dosage form of any one of the preceding claims, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, a fat, optionally vegetable stearin, and combinations thereof.

29. The single unit dosage form of any one of the preceding claims, comprising about 1 mg to about 10 mg of lubricant.

30. The single unit dosage form of any one of the preceding claims, comprising about 1% to about 10% by weight of lubricant.

31. The single unit dosage form of any one of the preceding claims, wherein the lubricant comprises magnesium stearate.

32. The single unit dosage form of any one of the preceding claims, further comprising a coating.

33. The single unit dosage form of any one of the preceding claims, wherein the coating comprises a film coating agent.

34. The single unit dosage form of any one of the preceding claims, wherein the coating comprises pharmacopeial grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and / or talc.

35. The single unit dosage form of any one of the preceding claims, comprising about 1 mg to about 20 mg of coating.

36. The single unit dosage form of any one of the preceding claims, comprising about 1% to about 10% by weight of coating.

37. The single unit dosage form of any one of the preceding claims, wherein the coating comprises Opadry® II White 85F18422.

38. The single unit dosage form of any one of the preceding claims, which is a tablet, optionally formulated for oral administration.

39. The single unit dosage form of any one of the preceding claims which is a oblong tablet, an oval tablet, or a capsule-shaped tablet, optionally wherein the tablet is not a round tablet.

40. The single unit dosage form of any one of the preceding claims which has a total weight of about 200 mg to about 600 mg per dosage unit (e.g., per tablet).

41. The single unit dosage form of any one of the preceding claims which has a length of about 1 mm to about 30 mm.

42. The single unit dosage form of any one of the preceding claims which has a width of about 1 mm to about 10 mm.

43. The single unit dosage form of any one of the preceding claims which has a length of about 14 mm to about 16 mm and a width of about 5 mm to about 7 mm.

44. The single unit dosage form of any one of the preceding claims which comprises an amount of PRAX-944 HC1 equivalent to about 5.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

45. The single unit dosage form of any one of the preceding claims which comprises an amount of PRAX-944 HC1 equivalent to about 10.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

46. The single unit dosage form of any one of the preceding claims which comprises an amount of PRAX-944 HC1 equivalent to about 20.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

47. The single unit dosage form of any one of the preceding claims which comprises about 1 wt% to about 10 wt% PRAX-944 HC1, optionally about 15 mg to about 25 mg PRAX-944 HC1 per dosage unit (e.g., per tablet).

48. The single unit dosage form of any one of the preceding claims which comprises an amount of PRAX-944 HC1 equivalent to about 40.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

49. The single unit dosage form of any one of the preceding claims which comprises about 5 wt% to about 15 wt% PRAX-944 HC1, optionally about 40 mg to about 50 mg PRAX-944 HC1 per dosage unit (e.g., per tablet).

50. The single unit dosage form of any one of the preceding claims which comprises an amount of PRAX-944 HC1 equivalent to about 80.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

51. The single unit dosage form of any one of the preceding claims which comprises about 15 wt% to about 25 wt% PRAX-944 HC1, optionally about 85 mg to about 95 mg PRAX-944 HC1 per dosage unit (e.g., per tablet).

52. The single unit dosage form of any one of the preceding claims, comprising an amount of PRAX-944 HC1 equivalent to about 120.0 mg PRAX-944 free base per dosage unit (e.g., per tablet).

53. The single unit dosage form of any one of the preceding claims, comprising about 25% to about 35% by weight of PRAX-944 HC1, optionally about 125 mg to about 135 mg PRAX-944 HC1 per dosage unit (e.g., per tablet).

54. The single unit dosage form of any one of the preceding claims, further comprising one or more of the following: (i) a release modifying polymer, optionally about 35% to about 45% by weight of a release modifying polymer, optionally about 175 mg to about 185 mg of a release modifying polymer per dosage unit (e.g., per tablet); (i) a soluble diluent, optionally about 6% to about 10% by weight of a soluble diluent, optionally about 34 mg to about 38 mg of a soluble diluent per dosage unit (e.g., per tablet); (iii) a glidant, optionally about 1% to about 3% by weight of a glidant, optionally about 6 mg to about 8 mg of a glidant per dosage unit (e.g., per tablet); (iv) a lubricant, optionally about 0.5% to about 2% by weight of a lubricant, optionally about 3 mg to about 6 mg of a lubricant per dosage unit (e.g., per tablet); and (v) a coating, optionally about 12% to about 15% by weight of a coating, optionally about 1 mg to about 5 mg of a coating per dosage unit (e.g., per tablet).

55. The single unit dosage form of any one of the preceding claims, comprising a formulation as set forth in any one of Tables 6-16, optionally comprising: (i) Large Tablet Prototype 01 (58% K4M Round) (DC); (ii) Large Tablet Prototype 01 (58% K4M Caplets) (DC); (iii) Large Tablet Prototype 04 (58% K4M) (DG); (iv) Large Tablet Prototype 23 (50% K4M); (v) Large Tablet Prototype 28 (58% K100LV); (vi) Large Tablet Prototype 34 (50% K100LV, 8% Mannitol EG); (vii) Large Tablet Prototype 36 (50% K100LV, 8% Mannitol IG); (viii) Large Tablet Prototype 52 (28% K100LV, 30% E50LV); (ix) Large Tablet Prototype 53 (40% K100LV, 8% Mannitol IG); or (x) Large Tablet Prototype 54 (46% K100LV, 12% Mannitol IG).

56. The single unit dosage form of any one of the preceding claims, comprising Large Tablet Prototype 53 (40% K100LV, 8% Mannitol IG).

57. A pharmaceutical composition comprising the single unit dosage form of any one of the preceding claims, and at least one pharmaceutically acceptable carrier or excipient.

58. A method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the single unit dosage form of any one of claims 1-56 or the pharmaceutical composition of claim 57.

59. A method of treating tremor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the single unit dosage form of any one of claims 1-56 or the pharmaceutical composition of claim 57.

60. A method of treating essential tremor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the single unit dosage form of any one of claims 1-56 or the pharmaceutical composition of claim 57.

61. The method of claim 60, which results in a reduction of the essential tremor as assessed by Tremor Rating Assessment Evaluation Scale (TETRAS) score.

62. The method of claim 60 or 61, wherein the reduction of the essential tremor is assessed by TETRAS upper limb score.

63. The method of any one of claims 60-62, wherein the reduction of the essential tremor is assessed by TETRAS-ADL (activities of daily living).

64. The method of any one of claims 60-63, wherein the reduction of the essential tremor is assessed by TETRAS performance subscale score or TETRAS performance individual items.

65. The method of any one of claims 60-64, which results in a reduction of the essential tremor as assessed by accelerometer-based upper limb score.

66. The method of any one of claims 60-65, which results in a reduction of the sum band.

67. The method of any one of claims 60-66, wherein the essential tremor is upper limb tremor.

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