High-dose single-dose formulations and methods of use thereof

Abstract

Described herein, in part, are single-dose 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), which compositions are bioequivalent to an identical dose of a reference composition administered as multiple small, round tablets. The invention further includes methods useful for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor (e.g., essential tremor).

Description

[Technical Field]

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

[0002] Essential tremor (ET) is the most common adult movement disorder, affecting up to 2% of the US population (approximately 7 million Americans). ET is characterized by a 5-12 Hz postural and kinetic tremor (i.e., tremor during voluntary movement) in the upper extremities. The most distinctive clinical feature is a kinetic tremor of the arms and hands, but tremor can also occur in the head and voice, and less commonly in the face, legs, and trunk. The diagnosis of ET is based on clinical history and neurological examination, as described in the International Parkinson's Disease and Movement Disorder Society consensus statement on the classification of tremor.

[0003] ET ranges in severity, with some patients requiring no treatment, while others have severe impairment with impaired function in activities of daily living, such as dressing and eating. Although ET, by definition, is generally not associated with other neurological symptoms, there is increasing recognition that ET may also be associated with additional motor features, such as postural instability, dystonia, mild to moderate gait ataxia, and eye movement abnormalities. ET is also associated with an elevated prevalence of comorbid psychiatric disorders, including anxiety and depression. ET often worsens over time, with more severe tremors and corresponding worsening disability over the course of years to decades.

[0004] ET can be sporadic, however a family history of an autosomal dominant pattern of inheritance is commonly encountered and, importantly, T-type Ca 2+Variants in the calcium voltage-gated channel subunit alpha 1G (CACNA1G) gene, which encodes the channel isoform Cav3.1, have been identified as the cause of ET in at least three families. The importance of the CACNA1G gene for cerebellar development and function is further emphasized by the observation that variants in this gene can also cause childhood cerebellar atrophy and spinocerebellar ataxia type 42. The functional consequences of these genetic variants include increased T-type Ca2+ signaling in the cerebellum and distal cerebellar-thalamocortical (CTC) circuits. 2+ This is consistent with the expression of the channels and their physiological contribution to oscillatory burst firing in the thalamus that is synchronized with and may drive clinically observable tremor.

[0005] Propranolol is the only Food and Drug Administration (FDA)-approved oral treatment indicated for the treatment of ET. Although originally developed for hypertension, propranolol has shown limited efficacy in treating ET, often with side effects (e.g., bradycardia) that lead to discontinuation. Unmet medical needs in ET have led to the off-label use of medications in multiple drug classes, including anticonvulsants, barbiturates, benzodiazepines, antipsychotics, and others, with limited, discernible therapeutic benefit for patients with ET. A recent evidence-based review concluded that only propranolol, primidone, and topiramate had sufficient evidence to support efficacy among 28 drugs tested for ET. Surgical interventions that disrupt cerebellar-thalamo-cortical (CTC) burst activity, such as deep brain stimulation or focused ultrasound, are effective treatments for ET but carry risks, such as sensory impairment, hemiparesis, akinesia, gait disturbances, delirium, cognitive decline, tissue damage, venous thromboembolic 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. Voltage-gated ion channels, especially T-type Ca channels, play a crucial role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks. 2+Modification of the channel has been implicated in ET. T-type Ca channels, including three isoforms (CaV3.1, CaV3.2, and CaV3.3), are 2+ T-type calcium channels are widely expressed throughout the brain, particularly in CTC circuits. This class of calcium channels has been shown to play a crucial role in regulating neuronal firing patterns by controlling the switch between tonic, stable firing patterns to brief, high-frequency bursts of activity in wild-type rodents and in rodent models of tremor. Importantly, abnormal bursts in CTC circuits occur at the same frequency as upper limb tremors in ET, suggesting that reducing T-type calcium channel-mediated burst firing may have therapeutic benefit in reducing tremor-related burst firing in CTC circuits.

[0007] PRAX-944 (N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride) is being developed for the treatment of ET, a type 2 Ca2+ 2+ PRAX-944 is a high-affinity, state-dependent, selective inhibitor of T-type Ca channels. In vitro electrophysiological studies have demonstrated that PRAX-944 inhibits T-type Ca channels. 2+ It has been demonstrated to have specificity and nanomolar potency for channels (CaV3.1 and CaV3.3).

[0008] T-type Ca 2+By blocking the channel, PRAX-944 may reduce burst activity in CTC circuits and subsequently tremor and related disorders. PRAX-944 has demonstrated robust activity in animal models of ET. To date, the PRAX-944 program has completed five Phase 1 trials in healthy participants using dose levels ranging from 2.5 mg to 120 mg. Recent clinical trials with PRAX-944 have used the MR7 formulation and introduced an escalating dosing regimen to achieve higher dose levels. Collectively, these developments have contributed to improved safety and tolerability and a broader therapeutic window compared with the immediate-release (IR) formulation. The MR7 formulation, designed to delay tmax, reduce Cmax, and have minimal effects on AUC, has been associated with reduced CNS, psychiatric, and overall AEs compared with the IR formulation in two clinical trials, Z944-103 and Z944-104. Furthermore, the PRAX-944-105 trial has established that doses above 40 mg are well tolerated when administered in a 28-day ascending dosing regimen. No maximum tolerated dose has been observed for the MR7 formulation administered in this manner, and dosing up to 120 mg has been well tolerated. This program also collected preliminary efficacy data in an early Phase 2 trial in participants with ET.

[0009] With a sustained-release (MR) formulation supporting once-daily (QD) dosing over a 24-fold well-tolerated dose range demonstrating robust pharmacodynamic effects, in combination with preliminary efficacy data, there is clear clinical rationale supporting further testing of the safety and efficacy of PRAX-944 to address unmet needs in ET.

[0010] However, certain challenges associated with the use of currently available PRAX-944 MR formulations (i.e., placebo, 5 mg, and 20 mg tablets) have been identified during clinical trials. For example, for blinding purposes in clinical trials, different doses of PRAX-944 are provided in combinations of multiple tablets packaged in blisters. Opening the blister packages, handling the small, round tablets, and ingesting many pills have been found to be particularly difficult for patients suffering from movement disorders, such as essential tremor (ET). Therefore, there is a need to develop new single-dose tablets with appropriate dosages to improve patient usability, reduce the total number of dosage units (e.g., tablets) required to deliver a specific dose to a patient, and reduce or eliminate the risk of medication errors. Summary of the Invention [Means for solving the problem]

[0011] The present disclosure provides compositions, including single-dose dosage forms and pharmaceutical compositions, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl). In certain embodiments, the compositions described herein are bioequivalent to currently available oral dosage forms, such as current PRAX-944 dosage forms, which are sustained-release (MR) formulations available as 5 mg and 20 mg tablets that are round and small in size (e.g., approximately 6 mm in diameter). The present disclosure further includes methods useful for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor (e.g., essential tremor). The present disclosure further includes methods useful for preventing and / or treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as tremor, e.g., essential tremor.

[0012] In one aspect, the disclosure provides a single 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 HCl), wherein the single dosage form is bioequivalent to an identical dose of a reference composition administered as one or more dosage forms, such as multiple small, round 20 mg PRAX-944 tablets.

[0013] In some embodiments, the single 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 certain embodiments, the single dosage form is larger than the reference composition. In some embodiments, the reference composition contains a smaller, round, 20 mg PRAX-944 tablet.

[0014] In some embodiments, the single-unit dosage form is a larger tablet that exhibits bioequivalence upon administration to a subject in a fed and / or fasted state compared to administration of the same dose of a reference composition administered to a subject in a fed and / or fasted state as one or more smaller dosage forms, optionally one or more small, round 20 mg PRAX-944 tablets, wherein bioequivalence is established by: (a) 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%, 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 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110% 9%, 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% %, about 121%, about 122%, about 123%, about 124%, or about 125%, and (b) a 90% confidence interval for Cmax, that is 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%, 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 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, or about 125%). In some embodiments, the 90% confidence interval for AUC and / or Cmax may be included within tighter confidence limits, e.g., about 90% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 90% to about 100%.

[0015] In some embodiments, the single-dose dosage form (i) reduces the total number of dosage units (e.g., tablets) required to deliver a particular administered dose 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 formulated as single-dose dosages of 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg; and / or (iv) does not require escalating dosing to reach a dose >40 mg. In certain embodiments, escalating dosing can reduce and / or eliminate adverse events. In some embodiments, escalating dosing can include administering one or more of the single-dose 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 a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) is released within a predetermined period of time upon administration to a subject. In certain embodiments, the predetermined period of time can range from 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 1 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) upon administration 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 1 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) upon administration 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 2 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 3 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 7 hours upon administration to a subject.

[0023] In some embodiments, about 90% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 9 hours to about 12 hours upon administration 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within a predetermined period of time using a USP Type I apparatus, 900 mL of medium containing 0.1 M HCl, and a paddle speed of 100 rpm. In certain embodiments, the predetermined period of time can range from 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released in 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) using a USP Type I apparatus, medium containing 900 mL 0.1 M HCl, and a paddle speed of 100 rpm. 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released in 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) using a USP Type I apparatus, medium containing 900 mL 0.1 M HCl, and a paddle speed of 100 rpm.

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

[0027] In some embodiments, the single-dose dosage form further comprises a modified release polymer. In some embodiments, 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. In some embodiments, the modified release polymer comprises (i) a hydrophilic matrix polymer optionally selected from the group consisting of hypromellose, HPMC (hydroxyl-propyl methylcellulose), and combinations thereof, optionally wherein the HPMC (hydroxyl-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 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-dose dosage form comprises about 5 mg to 300 mg of the modified release polymer. In some embodiments, the single dosage form comprises about 10% to about 70% by weight of the modified release polymer, hi some embodiments, the modified release polymer is hypromellose.

[0028] In some embodiments, the single-dose dosage form further comprises a diluent, optionally a soluble diluent. In some embodiments, the diluent comprises (i) a cellulose derivative, optionally microcrystalline cellulose, optionally silicified microcrystalline cellulose, (ii) optionally a starch 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) optionally a sugar alcohol selected from the group consisting of sorbitol, xylitol, mannitol, and combinations thereof. In some embodiments, the single-dose dosage form comprises from about 5 mg to about 300 mg of diluent. In some embodiments, the single-dose dosage form comprises from about 5% to about 50% by weight of diluent. In some embodiments, the diluent is microcrystalline cellulose, optionally silicified microcrystalline cellulose. In some embodiments, the diluent is a sugar alcohol, optionally mannitol.

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

[0030] In some embodiments, the single-dose 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, fat, optionally vegetable stearin, and combinations thereof. In some embodiments, the single-dose form comprises from about 1 mg to about 10 mg of lubricant. In some embodiments, the single-dose form comprises from about 1% to about 10% by weight of lubricant. In some embodiments, the lubricant comprises magnesium stearate.

[0031] In some embodiments, the single-dose form further comprises a coating. In some embodiments, the coating comprises a film coating. In some embodiments, the coating comprises compendial grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and / or talc. In some embodiments, the single-dose form comprises about 1 mg to about 20 mg of coating. In some embodiments, the single-dose 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-dose form optionally comprises a tablet formulated for oral administration. In some embodiments, the single-dose form comprises an oblong tablet, an oval tablet, or a capsule-shaped tablet, optionally wherein the tablet is not a round tablet. In some embodiments, opening a blister package of oblong, oval, or capsule-shaped tablets, handling the oblong, oval, or capsule-shaped tablets, and ingesting one or more oblong, oval, or capsule-shaped tablets is less difficult and convenient for patients suffering from movement disorders, such as essential tremor (ET), compared to, for example, small round tablets (e.g., about 6 mm in diameter).

[0033] In some embodiments, the single dosage form comprises a total weight of about 200 mg to about 600 mg per dosage unit (e.g., per tablet). In some embodiments, the single dosage form comprises about 1% to about 100% by weight of PRAX-944 HCl, optionally wherein the total weight of the dosage unit (e.g., per tablet) is about 200 mg to about 600 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, 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 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 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 400 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 500 mg, about 510 mg, about mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, Approximately 385mg, approximately 390mg, approximately 395mg, approximately 400mg, approximately 405mg, approximately 410mg, approximately 415mg, approximately 420mg, approximately 425mg, approximately 430mg, approximately 435mg, approximately 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 49 5 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg).

[0034] In some embodiments, the single-dose dosage form has a length of 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, about 21.5 mm, about 22 mm, about 22.5 mm, about 23 mm, about 23.5 mm, about 24 mm, about 24.5 mm, about 25 mm, about 25.5 mm, about 26 mm, about 26.5 mm, about 27 mm, about 27.5 mm, about 28 mm, about 28.5 mm, about 29 mm, about 29.5 mm, or about 30 mm in length).

[0035] In some embodiments, the single-dose dosage form has a width of 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, about 21.5 mm, about 22 mm, about 22.5 mm, about 23 mm, about 23.5 mm, about 24 mm, about 24.5 mm, about 25 mm, about 25.5 mm, about 26 mm, about 26.5 mm, about 27 mm, about 27.5 mm, about 28 mm, about 28.5 mm, about 29 mm, about 29.5 mm, or about 30 mm width).

[0036] In some embodiments, the single-dose dosage form has a width of about 1 mm to about 10 mm (e.g., 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 3.0 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 4.0 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, about 4.9 mm, about 5.0 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 6.0 mm, about 6.1 mm, about 6.2 mm, about 6.3 mm, about 6.4 mm, about 6.5 mm, about 6.6 mm, about 6.7 mm, about 6.8 mm, about 6.9 mm, about 7.0 mm, about 7.1 mm, about 7.2 mm, about 7.3 mm, about 7.4 mm, about 7.5 mm, about 7.6 mm, about 7.7 mm, about 7.8 mm, about .9mm, approximately 3mm, approximately 3.1mm, approximately 3.2mm, approximately 3.3mm, approximately 3.4mm, approximately 3.5mm, approximately 3.6mm, approximately 3.7mm, approximately 3.8mm, approximately 3.9mm, approximately 4mm, approximately 4.1 mm, approximately 4.2mm, approximately 4.3mm, approximately 4.4mm, approximately 4.5mm, approximately 4.6mm, approximately 4.7mm, approximately 4.8mm, approximately 4.9mm, approximately 5mm, approximately 5.1mm, approximately 5.2mm, approximately 5.3m m, approximately 5.4mm, approximately 5.5mm, approximately 5.6mm, approximately 5.7mm, approximately 5.8mm, approximately 5.9mm, approximately 6mm, approximately 6.1mm, approximately 6.2mm, approximately 6.3mm, approximately 6.4mm, approximately 6.5m m, approximately 6.6mm, approximately 6.7mm, approximately 6.8mm, approximately 6.9mm, approximately 7mm, approximately 7.1mm, approximately 7.2mm, approximately 7.3mm, approximately 7.4mm, approximately 7.5mm, approximately 7.6mm, approximately 7.7mm , about 7.8 mm, about 7.9 mm, about 8 mm, about 8.1 mm, about 8.2 mm, about 8.3 mm, about 8.4 mm, about 8.5 mm, about 8.6 mm, about 8.7 mm, about 8.8 mm, about 8.9 mm, about 9 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, or about 10 mm width).

[0037] In some embodiments, the single-dose dosage form has a length of about 14 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, 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, about 30 mm, about 31 mm, about 32 mm, about 33 mm, about 34 mm, about 35 mm, about 36 mm, about 37 mm, about 38 mm, about 39 mm, about 40 mm, about 41 mm, about 42 mm, about 43 mm, about 44 mm, about 45 mm, about 46 mm, about 47 mm, about 48 mm, about 49 mm, about 50 mm, about 51 mm, about 52 mm, about 53 mm, about 54 mm, about 55 mm, about 56 mm, about 57 mm, about 58 mm, about 59 mm, about 60 mm, about 61 mm, about 62 mm, about 63 mm, about 64 mm, about 65 mm, about 66 mm, about 67 mm, about 68 mm, about 69 mm, about 69 mm, about 70 mm, about 71 mm, about 72 mm, and a length of about 5 mm to about 7 mm (e.g., a length 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, about 6.1 mm, about 6.2 mm, about 6.3 mm, about 6.4 mm, about 6.5 mm, about 6.6 mm, about 6.7 mm, about 6.8 mm, about 6.9 mm, or about 7 mm).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0070] In some embodiments, the single-dose dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 1.0 mg to about 200 mg of PRAX-944 free base per dosage unit (e.g., per tablet) (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, or about 100 mg of PRAX-944 free base). In some embodiments, the single-dosage form contains about 1% to about 50% by weight (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) of PRAX-944 by weight. HCl, optionally wherein the total dosage 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 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg).

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

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

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

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

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

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

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

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

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

[0080] In some embodiments, the single dosage form is (i) Large Tablet Prototype 01 (58% K4M Round) (DC), (ii) Large Tablet Prototype 01 (58% K4M Caplet) (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% In some embodiments, the single dose form comprises (i) Large Tablet Prototype 04 (58% K4M) (DG), (ii) Large Tablet Prototype 28 (58% K100LV), or (iii) Large Tablet Prototype 53 (40% K100LV, 8% mannitol IG).

[0081] In one aspect, the present disclosure provides a pharmaceutical composition comprising a unit dosage form according to any one of the preceding claims and at least one pharmaceutically acceptable carrier or excipient.

[0082] In one aspect, the disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a single administered dose or pharmaceutical composition described herein.

[0083] In one aspect, the present disclosure provides a method of treating tremor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a single administered dose or pharmaceutical composition described herein.

[0084] In one aspect, the present disclosure provides a method of treating essential tremor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a single administered dose or pharmaceutical composition described herein.

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

[0086] Other objects and advantages will be apparent to those skilled in the art upon consideration of the following brief description of the drawings, detailed description, examples, and claims. [Brief explanation of the drawings]

[0087] [Figure 1] FIG. 1 depicts the composition and characteristics of the active pharmaceutical ingredient PRAX-944 (also referred to herein as PRAX-944 HCl). [Figure 2A] FIG. 2A depicts tablets of various shapes and sizes. [Figure 2B] Figure 2B depicts a comparison between the currently available PRAX-944 dosage form, a sustained release (MR) formulation available as small (6 mm diameter) 5 mg and 20 mg round tablets in size, and an exemplary bioequivalent single-dose dosage form described herein. [Figure 3A] Figure 3A depicts the PRAX-944-107 study design. N = planned number of participants for the total population, n = planned number of participants per treatment group. Fasting: Each dose of study drug will be taken with 240 mL of water after an overnight fast. No food or drink, except water, will be allowed for at least 10 hours before dosing. Participants will remain fasting for 4 hours after dosing. Participants will not be allowed to drink water for 2 hours before and 1 hour after each dose. Fed: Study drug will be co-administered with a high-fat, high-calorie meal. [Figure 3B] FIG. 3B depicts the study drugs administered in PRAX-944-107. [Figure 3C] FIG. 3C depicts an exemplary high-dose PRAX-944 tablet formulation tested in Study 944-107. [Figure 3D] FIG. 3D depicts a schematic of an exemplary Phase 3 clinical trial study design to evaluate the efficacy of large, single-dose PRAX-944 tablets (20 mg, 40 mg, 80 mg, and 120 mg) compared to the same dose levels delivered using small, round 20 mg PRAX-944 tablets (1, 2, 4, and 6 tablets, respectively). [Figure 4A]Figures 4A-4B depict the in vitro (Figure 4A) and in vivo (Figure 4B) release profiles for 20 mg dose PRAX-944 sustained-release (MR) tablets and immediate-release (IR) capsules. For improved tolerability, PRAX-944 is formulated as a sustained-release (MR) tablet to prolong drug release and absorption, thus blunting Cmax and prolonging the plasma concentration-time profile compared to the immediate-release (IR) dosage form. As shown in Figure 4A, approximately 100% of PRAX-944 is released within about 1 hour for the immediate-release (IR) dosage form, and approximately 80% of PRAX-944 is released within about 7 hours for the sustained-release (MR) dosage form. [Figure 4B] As shown in Figure 4B, the IR formulation achieved a Cmax (ng / mL) (CV%) of 131 (25.6) and an AUC∞ (ng.hr / mL) (CV%) of 1090 (24.4), and the MR formulation achieved a Cmax (ng / mL) (CV%) of 47.1 (34.3) and an AUC∞ (ng.hr / mL) (CV%) of 1010 (34.2). [Figure 5A] FIG. 5A shows the results of the PRAX-944 large tablet prototypes (i.e., Large Tablet Prototype 01 (58% K4M Round) (DC), Large Tablet Prototype 01 (58% K4M Caplet) (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% The in vitro release profile for K100LV (12% mannitol IG) is depicted in comparison to a reference tablet (i.e., a 20 mg small round clinical tablet). DC and DG designate direct compression and dry granulation, respectively. [Figure 5B]FIG. 5B depicts the in vitro release profiles for large tablet prototypes of PRAX-944 (i.e., large tablet prototype 04, large tablet prototype 28, and large tablet prototype 53) compared to the reference tablet (i.e., 20 mg small round clinical tablet). [Figure 5C] FIG. 5C depicts the in vitro release profiles for PRAX-944 MR tablets (i.e., 20 mg large tablets, 40 mg large tablets, 80 mg large tablets, and 120 mg large tablets) compared to the reference tablet (i.e., 20 mg small round clinical tablet). [Figure 6A] Figures 6A-6B depict the relative bioavailability of the 120 mg large tablet (test) compared to the small round tablet (reference) in a crossover analysis. In a crossover analysis, the 120 mg large and small round tablets met the bioequivalence criteria (90% CI within 80-125%) for AUC and C (Figure 6B). Outlier subjects were excluded from the analysis. [Figure 6B] Figures 6A-6B depict the relative bioavailability of the 120 mg large tablet (test) compared to the small round tablet (reference) in a crossover analysis. In a crossover analysis, the 120 mg large and small round tablets met the bioequivalence criteria (90% CI within 80-125%) for AUC and C (Figure 6B). Outlier subjects were excluded from the analysis. [Figure 7] Figure 7 depicts dose proportionality with small round tablets or large tablets. Outlier subjects were excluded from the analysis. [Figure 8A] Figures 8A-8B depict the lack of a food effect with 120 mg PRAX-944. Coadministration of the 120 mg large tablet with a high-fat, high-calorie meal resulted in a 3-hour delay in tmax and small increases in AUC and Cmax, but within the no-effect boundary (90% CI within 80-125%). Outlier subjects were excluded from the analysis. [Figure 8B]Figures 8A-8B depict the lack of a food effect with 120 mg PRAX-944. Coadministration of the 120 mg large tablet with a high-fat, high-calorie meal resulted in a 3-hour delay in tmax and small increases in AUC and Cmax, but within the no-effect boundary (90% CI within 80-125%). Outlier subjects were excluded from the analysis. [Figure 9A] Figures 9A-9C depict the relative bioavailability from parallel analyses using the small round tablet and the large round tablet. While the large round tablet appears to have increased exposure compared to the small round tablet, this is likely an artifact of the parallel study design. When the relative bioavailability of the 120 mg tablet is assessed by crossover analysis, the bioequivalence (BE) criteria are met, while when assessed by parallel analysis, the large round tablet has a higher exposure than the small round tablet by a similar magnitude to the tablet at the lower dose. Outlier subjects were excluded from the analysis. [Figure 9B] Figures 9A-9C depict the relative bioavailability from parallel analyses using the small round tablet and the large round tablet. While the large round tablet appears to have increased exposure compared to the small round tablet, this is likely an artifact of the parallel study design. When the relative bioavailability of the 120 mg tablet is assessed by crossover analysis, the bioequivalence (BE) criteria are met, while when assessed by parallel analysis, the large round tablet has a higher exposure than the small round tablet by a similar magnitude to the tablet at the lower dose. Outlier subjects were excluded from the analysis. [Figure 9C]Figures 9A-9C depict the relative bioavailability from parallel analyses using the small round tablet and the large round tablet. While the large round tablet appears to have increased exposure compared to the small round tablet, this is likely an artifact of the parallel study design. When the relative bioavailability of the 120 mg tablet is assessed by crossover analysis, the bioequivalence (BE) criteria are met, while when assessed by parallel analysis, the large round tablet has a higher exposure than the small round tablet by a similar magnitude to the tablet at the lower dose. Outlier subjects were excluded from the analysis. [Figure 10A] FIG. 10A depicts an exemplary schematic of a crossover bioequivalence study. DETAILED DESCRIPTION OF THE INVENTION

[0088] The present disclosure provides compositions designed to provide a larger, more convenient PRAX-944 dosage form compared to currently available PRAX-944 dosage forms, which are extended-release (MR) formulations available as 5 mg and 20 mg tablets that are round and compact (6 mm diameter). For example, the pharmaceutical compositions of the present disclosure are designed to minimize the number of tablets required to deliver a particular dose level of PRAX-944 (FIG. 1), increase the tablet's physical size, and make it capsule-shaped, making it easier to grasp and more convenient and useful for patients, particularly those with essential tremor (ET). Figure 2A shows tablets of various shapes and sizes, and Figure 2B shows a comparison between currently available PRAX-944 dosage forms, which are extended-release (MR) formulations available as 5 mg and 20 mg tablets that are round and compact (6 mm diameter), and exemplary bioequivalent single-dose dosage forms described herein. Furthermore, pharmaceutical compositions of the present disclosure comprising larger capsule-shaped tablets have substantially the same bioavailability, e.g., in terms of rate (maximum plasma drug concentration, Cmax) and extent (area under the plasma concentration-time curve, AUC) of absorption of PRAX-944, as compared to multiple smaller, round 20 mg tablets.

[0089] definition Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound may 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. The effective amount encompasses both therapeutic and prophylactic treatments.

[0090] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay, reduce, or eliminate one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0091] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily succumb to or respond to therapy or treatment, or that is not controlled by therapy or treatment. In some embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy, or refractory absence seizures, or refractory essential tremor) and do not respond to standard therapy or treatment.

[0092] As used herein, a "subject" to which administration is intended includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the terms "patient" and "subject" are used interchangeably herein. In some embodiments, the subject is selected for treatment with a compound of Formula (I) due to a clinical diagnosis of essential tremor. In some embodiments, the subject selected for treatment with a compound of Formula (I) has essential tremor but does not have intention tremor.

[0093] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0094] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the identified disease, disorder, or condition and that reduce the severity of, or slow or delay the progression of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from the identified disease, disorder, or condition.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art; for example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange.Other pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, cyclamate, digluconate, dodecylsulfate, edisylate, ethanesulfonate, esylate, formate, fumarate, gentisate, glucoheptonate, glycerophosphate, gluconate, glucuronic acid, glutamate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydroiodide, 2-hydroxyethanesulfonate, and isethionate. , ketoglutarate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, napadisylate, napsylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, oroate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, stereoisomers (e.g., enantiomers, diastereomers) thereof, and the like.

[0096] Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, etc. In certain embodiments, the compound of formula (I) is a hydrochloride salt.

[0097] The term "modified release polymer" or "matrix polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to modify the release rate of a drug upon administration to a subject. For example, a modified release polymer is used to dissolve a drug over time, resulting in a slower and more stable release into the bloodstream. For example, a modified release polymer is a controlled release polymer. For example, a modified release polymer or controlled release polymer is an HPMC polymer. In some embodiments, the modified release polymer may include a hydrophilic matrix polymer (e.g., hypromellose, HPMC (hydroxyl-propylmethylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100).

[0098] As used herein, the term "diluent" or "filler" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0099] As used herein, the term "glidant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0100] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and sticking to the tablet punch or capsule filling machine. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solid material and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0101] As used herein, the term "coating" refers to excipients that protect tablet ingredients from deterioration due to moisture in the air and make oversized or unpleasant-tasting tablets easier to swallow. For example, the coating may include Opadry® II White 85F18422, which is composed of compendial grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and talc.

[0102] The term "bioavailability" refers to the extent to which an active moiety (eg, a drug and / or metabolite) is absorbed into the systemic circulation and becomes available at the site of drug action in the body.

[0103] The terms "bioequivalence" or "bioequivalent" mean that two drug products are not significantly different when the two products are administered at the same dose under similar conditions. A product (e.g., a single-dose dosage form or pharmaceutical composition described herein) can be considered bioequivalent to a second product (e.g., a reference composition) if there is no significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action when administered at the same molar dose as the second product under similar conditions in a properly designed study. Two products with different rates of absorption 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, reflected in the proposed labeling, not essential to achieving effective body drug concentrations during chronic use, and is considered medically insignificant for the drug. In some embodiments, bioequivalence may be based on a difference of about 20% or less between the AUC and C of a product versus the second product. In some embodiments, bioequivalence is less 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% or less between the AUC and Cmax of a product versus a second product. %, 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% difference.

[0104] In some embodiments, bioequivalence is measured, for example, by a 90% confidence interval for a target parameter (e.g., C maxand AUC), a range 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%, 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 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, or about 125%). In some embodiments, the 90% confidence interval for AUC and / or C may be included within tighter confidence limits, e.g., about 90% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 90% to about 100%. In some embodiments, bioequivalence may be determined based on steady-state studies and / or single-dose studies. In some embodiments, bioequivalence studies may be performed in the fasted and / or fed state.

[0105] In certain embodiments, the compositions described herein are bioequivalent to currently available oral dosage forms, such as the current PRAX-944 dosage form, which is a sustained release (MR) formulation available as 5 mg and 20 mg tablets that are round and small in size (e.g., approximately 6 mm diameter).

[0106] Thus, a test composition, such as a single-dose dosage form or pharmaceutical composition described herein, may have a 90% confidence interval of the mean area under the curve (AUC) (AUCt or AUCinf) of the plasma level of the test composition within about 80% to 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%, about 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%. 4%, or about 125%) of the mean value for the maximum plasma concentration (Cmax) of the test composition is within about 80% to about 125% of the corresponding mean 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 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, or about 125%). In some embodiments, the reference composition comprises PRAX-944 drug product supplied as 5 mg and 20 mg MR, white, round, film-coated tablets. Each reference tablet may contain PRAX-944 HCl DS equivalent to either 5 mg or 20 mg of PRAX-944 free base, and optionally the following inactive ingredients: microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium stearate, triacetin, titanium dioxide, and talc.

[0107] The terms "dose" and "dose level" are used interchangeably herein and may refer to the amount 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), measured in units of concentration. In certain embodiments, the terms "dose" and "dose level" may refer to the amount 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), as the free base, and do not refer to the amount of a salt or derivative of the active agent included in the compositions, formulations, and dosage forms described herein.

[0108] The terms "dosage form" and "dose unit" are used interchangeably herein and may 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-944 HCl), intended for administration or consumption. In some embodiments, a dosage form comprises physically discrete units suitable for administration to a subject, e.g., each unit comprising a predetermined amount and / or 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-944 HCl), either alone or in combination with one or more additional dosage units, calculated to produce a desired therapeutic effect. The route of administration (ROA) for delivery of an active agent may depend, for example, on the dosage form of the active agent. In certain embodiments, the compositions, formulations, and dosage forms described herein may be formulated and intended for oral administration to a subject. In some embodiments, the compositions, formulations, and dosage forms described herein, when formulated and intended for oral administration to a subject, may include capsules, tablets, pills, powders, lozenges, aqueous or oily suspensions, granules, emulsions, syrups, elixirs, and the like. In such dosage forms, 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), may be mixed with a pharmaceutically acceptable excipient or carrier.

[0109] The terms "single dose" and "single dosage form" are used interchangeably herein and can refer to compositions and formulations that include 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), but comprise one discrete dosage unit, e.g., one tablet. In some embodiments, the dosage forms, e.g., single dosage forms, described herein are bioequivalent to currently available PRAX-944 dosage forms, including sustained release (MR) formulations available, for example, as 5 mg and 20 mg round tablets having a compact size (approximately 6 mm diameter).

[0110] The terms "multiple unit doses" and "multiple unit dosage forms" are used interchangeably herein and can refer to compositions and formulations that include 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), but that include multiple dosage units, e.g., multiple tablets. In some embodiments, currently available PRAX-944 dosage forms include multiple unit dosage forms, including, for example, sustained release (MR) formulations available as 5 mg and 20 mg round tablets having a small size (approximately 6 mm diameter).

[0111] [Table 1-1] [Table 1-2] [Table 1-3]

[0112] Sustained-Release PRAX-944 Dosage Forms and Compositions PRAX-944 (Figure 1) is an orally active, high-affinity, state-dependent, selective inhibitor of T-type calcium (Ca2+) channels. The T-type Ca2+ channel family is composed of three distinct isoforms, CaV3.1, CaV3.2, and CaV3.3, which are widely but differentially expressed in thalamocortical and cerebellar circuits and are critical 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 produced as 5 mg and 20 mg sustained-release (MR), film-coated tablets for oral (PO), once-daily (QD) administration, and a matching placebo. The MR mechanism is achieved through the inclusion of a hydrophilic polymer that hydrates and gels in aqueous media, forming a matrix that controls the release of the active pharmaceutical ingredient (DS) from the tablet. Each active tablet contains, for example, PRAX-944 hydrochloride (HCl) DS equivalent to either 5 mg or 20 mg of PRAX-944 free base, and the following inactive ingredients: microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium stearate, triacetin, titanium dioxide, and talc. PRAX-944 was previously produced as an immediate-release (IR) tablet, for example, as described in the first clinical trial Z944-B01. The current 5 mg and 20 mg MR formulations were developed after observing in the first clinical trial Z944-B01 that central nervous system (CNS) and psychiatric adverse events (AEs) observed with a single daily dose of the IR formulation could be reduced by dividing the dose into multiple doses over the course of several hours, as described in clinical trial Z944-104, which evaluated the safety and tolerability of the PRAX-944 MR7 formulation.

[0113] The PRAX-944 MR7 formulation currently being used in clinical trials was designed to release 80% of the active drug in in vitro solution after 7 hours. This formulation was selected for further development after comparing the formulation with other MR formulations with faster dissolution. In general, previously tested MR formulations, produced as 5 mg and 20 mg MR, film-coated tablets, blunted Cmax and delayed tmax compared to the IR formulation, but had minimal effect on AUC. Additionally, the frequency of CNS, psychiatric, and global AEs was reduced with the MR formulation, with a corresponding greater reduction in AE frequency to the extent that Cmax was reduced, leading to the selection of the MR7 formulation for ongoing clinical trials. Additionally, escalating dosing has been shown to improve the tolerability profile of PRAX-944 MR7. However, certain challenges associated with the use of currently available PRAX-944 MR formulations (i.e., placebo, 5 mg, and 20 mg MR tablets) have been identified during clinical trials. For example, for clinical blinding purposes, different doses of PRAX-944 are provided in multi-tablet combinations (e.g., containing one or more of placebo, 5 mg, and 20 mg tablets) packaged in blisters. The need to handle small, round tablets, blister packaging, and multiple pills has been found to be particularly difficult for patients suffering from movement disorders such as essential tremor (ET). As such, there is a need to develop new single-dosage units that are larger, higher-dose tablets with appropriate shapes to improve patient comfort and convenience and reduce or eliminate the possibility of medication errors. Thus, in one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, in a single dosage form. In some embodiments, the compound has the following formula (II): [ka] is the HCl salt of the compound of formula (I), depicted as: In some embodiments, the compound is an acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, citrate, cyclamate, edisylate, esylate, isethionate, fumarate, gentisate, gluconate, glucuronate, glutamate, glutarate, ketoglutarate, glycolate, hippurate, lactobionate, maleate, malate, malonate, mesylate, napadisylate, napsylate, oleate, orate, oxalate, pamoate, phosphate, sebacate, succinate, or tartrate salt of a compound of Formula (I).

[0114] The compound of formula (I) is described, for example, in PCT Publication WO2009 / 146540, which is incorporated herein by reference. Crystalline salts of the compound of formula (I) are described, for example, in PCT Publication WO2021 / 007487, which is incorporated herein by reference. Deuterated analogs of the compound of formula (I) are described, for example, in PCT Publication WO2022 / 099207, which is incorporated herein by reference. The safety profile, efficacy, tolerability, and pharmacokinetics of the compound of formula (I) in sustained-release formulations with and without escalating dosing have been evaluated as described in PCT Publication WO2021 / 222342, which is incorporated herein by reference. In some embodiments, the compound of formula (I) is in a crystalline form. In certain embodiments, the crystalline form is a previously or contemporaneously described crystalline form, such as crystalline pattern B, crystalline pattern C, or crystalline pattern D. Crystalline pattern B and crystalline pattern C are described, for example, in WO2021 / 007487, the entire contents of which are incorporated herein by reference. Crystalline pattern D is: The peak at approximately 12.0° The peak at about 15.6° Peak at about 16.7°, Peak at about 19.8°, The peak at about 21.2° The peak at about 24.1° The peak at about 25.2° A peak at approximately 27.3°, and It is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group consisting of about 30.2°.

[0115] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) is PRAX-944 HCl (N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride).

[0116] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) can be in a dosage form, such as a single unit dosage form, or in a pharmaceutical composition.

[0117] In one aspect, the present invention provides a composition comprising a single 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 HCl).

[0118] In one aspect, the present invention provides a sustained release dosage form comprising a single dose 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 HCl).

[0119] In one aspect, the present invention provides a composition comprising a single 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 HCl), wherein the composition is bioequivalent to an identical dose of a reference composition administered as a plurality of small, round, 20 mg PRAX-944 tablets. In some embodiments, the composition exhibits bioequivalence, e.g., upon administration to a human subject in the fed and / or fasted state, compared to the administration of an identical dose of a reference composition administered as a plurality of small, round, 20 mg PRAX-944 tablets, e.g., to a human subject in the fed and / or fasted state. In some embodiments, bioequivalence is established by: (i) a 90% confidence interval for the AUC that is 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%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, approx. 99%, approx. 100%, approx. 101%, approx. 102%, approx. 103%, approx. 104%, approx. 105%, approx. 106%, approx. 107%, approx. 108%, approx. 109%, approx. 110%, approx. 111%, approx. 112%, approx. 113%, approx. 114%, approx. 115%, approx. 116%, approx. 117%, approx. 118%, approx. 119%, approx. 120%, approx. 121%, approx. 122%, approx. 123%, approx. 124 %, or about 125%), and (ii) a 90% confidence interval for Cmax, that is 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%, 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 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, or about 125%).In some embodiments, the 90% confidence interval for AUC and / or Cmax may be included within tighter confidence limits, e.g., about 90% to about 120%, about 90% to about 115%, about 90% to about 110%, or about 90% to about 100%.

[0120] Certain embodiments of the present disclosure provide larger, single-dose MR tablets (e.g., about 15 mm long and about 6.5 mm wide) that are bioequivalent to the smaller, round 20 mg tablets at each of the dose levels used in current escalating dosing regimens: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg.

[0121] 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 a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) is released within a predetermined period of time upon administration to a subject. In certain embodiments, the predetermined period of time can range from 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).

[0122] 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 1 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) upon administration 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 1 to about 2 hours upon administration 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 2 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 3 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 6 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., a compound of Formula (II), e.g., 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., a compound of Formula (II), e.g., PRAX-944 HCl) is released within about 9 hours upon administration to a subject.

[0123] In some embodiments, the dosage form contains from 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), e.g., 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 ~55mg, 55mg~60mg, 60mg~65mg, 65mg~70mg, 70mg~75mg, 75mg~80mg, 80mg~85mg, 85mg~90mg, 90mg~95mg, 95mg~100mg, 100mg~105mg, 10 5 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).

[0124] In some embodiments, the dosage form contains from 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), e.g., 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 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 15 5 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).

[0125] In some embodiments, a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944) is administered. HCl) in a concentration 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 10 150 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.

[0126] In some embodiments, compositions, formulations, and dosage forms comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof described herein (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) may be administered in an amount 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 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 3500 mg, about 4000 mg, about 4500 mg, about 5000 mg, about 5500 mg, about 6000 mg, about 6500 mg, about 7000 mg, about 7500 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2500 mg, about 3000 mg, about 2500 mg, about 3500 mg 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.

[0127] In some embodiments, the compositions, formulations, and dosage forms described herein contain from 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 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) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) equivalent to PRAX-944 free base.

[0128] In some embodiments, the single-dose dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 1.0 mg to about 200 mg of PRAX-944 free base per dosage unit (e.g., per tablet) (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, or about 100 mg of PRAX-944 free base). In some embodiments, the single-dosage form contains about 1% to about 50% by weight (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) of PRAX-944 by weight. HCl, optionally wherein the total dosage 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 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg).

[0129] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 5 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 1 mg to about 10 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0130] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 10 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 5 mg to about 15 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0131] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 15 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 10 mg to about 20 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0132] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 20 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 15 mg to about 25 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0133] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 25 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 20 mg to about 30 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0134] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 30 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 25 mg to about 35 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0135] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 35 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 30 mg to about 40 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0136] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 40 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 35 mg to about 45 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0137] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 45 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 40 mg to about 50 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0138] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 50 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 45 mg to about 55 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0139] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 55 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 50 mg to about 60 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0140] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 60 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 55 mg to about 65 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0141] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 65 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 60 mg to about 70 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0142] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 70 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 65 mg to about 75 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0143] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 75 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 70 mg to about 80 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0144] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 80 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 75 mg to about 85 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0145] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 85 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 80 mg to about 90 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0146] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 90 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 85 mg to about 95 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0147] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 95 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 90 mg to about 100 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0148] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 100 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 95 mg to about 105 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0149] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 105 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 100 mg to about 110 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0150] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 110 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally from about 105 mg to about 115 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0151] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 115 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 110 mg to about 120 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0152] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 120 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 115 mg to about 125 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0153] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 125 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 120 mg to about 130 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0154] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 130 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 125 mg to about 135 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0155] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 135 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 130 mg to about 140 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0156] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 140 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 135 mg to about 145 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0157] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 145 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 140 mg to about 150 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0158] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 150 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 145 mg to about 155 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0159] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 155 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 150 mg to about 160 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0160] In some embodiments, the compositions, formulations, and dosage forms described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) in an amount equivalent to about 160 mg of PRAX-944 free base per dosage unit (e.g., per tablet), optionally about 155 mg to about 165 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

[0161] In some embodiments, the dosage form contains 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), e.g., PRAX-944 HCl) (e.g., about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, 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), e.g., PRAX-944 HCl).

[0162] 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), e.g., 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, or about 70% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl).

[0163] Exemplary dosage forms comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., an exemplary compound of formula (II), e.g., PRAX-944 HCl) as the active agent are provided in Tables 6-16.

[0164] Modified Release Polymer In some embodiments, the dosage form comprises a modified release polymer.

[0165] In some embodiments, modified release polymers are used in formulations (e.g., tablets and capsules) to modify the release rate of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) upon administration to a subject. In some embodiments, modified release polymers are used to dissolve the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), e.g., PRAX-944 HCl) over time so that it is released into the bloodstream more slowly, more steadily, or both more slowly and more steadily.

[0166] In some embodiments, the modified release polymer is a controlled release polymer. In some embodiments, the modified release polymer or controlled release polymer is a cellulose ether. In some embodiments, the modified release polymer or controlled release polymer is HPMC (hydroxyl-propyl methylcellulose). In some embodiments, the modified release polymer or 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 modified release polymer or controlled release polymer is HPMC K100 LV Premium CR. In some embodiments, the modified release polymer or controlled release polymer is HPMC (hydroxyl-propyl methylcellulose) selected from the group consisting of Methocel K4M, Methocel K100LV, Methocel E50LV, and combinations thereof. In some embodiments, the modified release 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 modified release polymer comprises a hydrophilic matrix polymer (e.g., hypromellose, HPMC (hydroxyl-propylmethylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100). In some embodiments, the modified release polymer is a hydrophilic matrix polymer. In some embodiments, the modified release polymer is hypromellose. In some embodiments, the modified release polymer is HPMC (hydroxyl-propylmethylcellulose). In some embodiments, the modified release polymer is a hydrophobic matrix polymer. In some embodiments, the modified release polymer is ethylcellulose. In some embodiments, the modified release polymer is Ethocel. In some embodiments, the modified release polymer is a polyacrylate polymer. In some embodiments, the modified release polymer is Eudragit RL100.In some embodiments, the modified release polymer is Eudragit RS100.

[0167] In some embodiments, the dosage form comprises about 5 mg to 300 mg of modified release 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 90 mg, about 90 mg to about 100 mg, about 100 mg to about 150 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 100 mg). About 80mg, about 80mg to about 85mg, about 85mg to about 90mg, about 90mg to about 95mg, about 95mg to about 100mg, about 100mg to about 105mg, about 105mg to about 110mg, about 110mg to about 115mg, about 115mg to about 120mg, about 120mg to about 125mg, about 125mg to about 130mg, about 130mg to about 135mg, about 135mg to about 140mg, about 140mg to about 145mg, about 145mg to about 150mg, about 150mg to about 155mg, about 155mg to about 160mg, about 160mg to about 165mg, about 165mg to about 170mg, about 170mg to about 175mg, about 175mg to about 180mg, about 180mg to about 185mg, about 185mg to about 190mg, about 190mg to about 195mg, about 195mg to about 200mg, about 200mg to about 205mg, about 205mg to about 210mg, about 210mg to about 215mg, about 215mg to about 220mg, about 220mg to about 225mg, about 225mg to about 230mg, about 230 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 a modified release polymer).

[0168] In some embodiments, the dosage form comprises about 5 mg to 300 mg of modified release 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 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 a modified release polymer).

[0169] In some embodiments, the dosage form comprises about 10% to about 70% by weight of the modified release 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 modified release polymer).

[0170] In some embodiments, the dosage form comprises about 10% to about 70% by weight of the modified release polymer (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 the modified release polymer).

[0171] In some embodiments, the dosage form contains about 5 mg to 300 mg of hypromellose (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 80mg, about 80mg to about 85mg, about 85mg to about 90mg, about 90mg to about 95mg, about 95mg to about 100mg, about 100mg to about 105mg, about 105mg to about 110mg, about 110mg to about 115mg, about 115mg to about 120mg, about 120mg to about 125mg, about 125mg to about 130mg, about 130mg to about 135mg, about 135mg to about 140mg, about 140mg to about 145mg, about 145mg to about 150mg, about 150mg to about 155mg, about 155mg~about 160mg, about 160mg~about 165mg, about 165mg~about 170mg, about 170mg~about 175mg, about 175mg~about 180mg, about 180mg~about 185mg, about 185mg~about 190mg, about 190mg~ Approximately 195 mg, approximately 195 mg to approximately 200 mg, approximately 200 mg to approximately 205 mg, approximately 205 mg to approximately 210 mg, approximately 210 mg to approximately 215 mg, approximately 215 mg to approximately 220 mg, approximately 220 mg to approximately 225 mg, approximately 225 mg to approximately 230 mg, about 230 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 hypromellose).

[0172] In some embodiments, the dosage form contains between about 5 mg and 300 mg of hypromellose (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 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 hypromellose).

[0173] In some embodiments, the dosage form comprises about 10% to about 70% by weight of hypromellose (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 hypromellose).

[0174] In some embodiments, the dosage form comprises about 10% to about 70% by weight of hypromellose (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 hypromellose).

[0175] Diluent In some embodiments, the dosage form comprises a diluent.

[0176] In some embodiments, the dosage form comprises a soluble diluent.

[0177] In some embodiments, diluents are used as fillers in dosage forms (eg, tablets and capsules).

[0178] In some embodiments, the term diluent includes excipients used, for example, to increase weight and improve content uniformity. In some embodiments, diluents may include cellulose derivatives (e.g., microcrystalline cellulose, e.g., silicified microcrystalline cellulose), starches (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.

[0179] In some embodiments, the diluent may include PEARLITOL® mannitol.

[0180] In some embodiments, the diluent may include mannitol, optionally in a grade selected from the group consisting of MQ, 100SD, 200SD, EZ, XL, M100, M200, 300DC, 400DC, 500DC, 2080, AG, GF, GS, GR, and combinations thereof.

[0181] In some embodiments, the dosage form contains about 5 mg to about 300 mg of diluent (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). 0mg, about 80mg to about 85mg, about 85mg to about 90mg, about 90mg to about 95mg, about 95mg to about 100mg, about 100mg to about 105mg, about 105mg to about 110mg, about 110mg to about 115mg, about 115mg to about 1 20mg, about 120mg to about 125mg, about 125mg to about 130mg, about 130mg to about 135mg, about 135mg to about 140mg, about 140mg to about 145mg, about 145mg to about 150mg, about 150mg to about 155mg, about 155mg to about 160mg, about 160mg to about 165mg, about 165mg to about 170mg, about 170mg to about 175mg, about 175mg to about 180mg, about 180mg to about 185mg, about 185mg to about 190mg, about 190mg ~195mg, 195mg~200mg, 200mg~205mg, 205mg~210mg, 210mg~215mg, 215~220mg, 220mg~225mg, 225mg~230m g, about 230 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 diluent).

[0182] In some embodiments, the dosage form contains about 5 mg to about 300 mg of diluent (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). g, 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, 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 diluent).

[0183] In some embodiments, the dosage form comprises about 5% to about 50% by weight of 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 of diluent).

[0184] In some embodiments, the dosage form comprises about 5% to about 50% by weight of 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, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by %, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of diluent).

[0185] 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®, COMPRECEL®, E460, COELUS KG®, PHARMACEL®, FIBROCEL®, and PROSOLV®) and in different particle sizes, densities, and moisture grades.

[0186] In some embodiments, the dosage form may comprise a microcrystalline cellulose (MCC) selected from the group consisting of PH101, PH102, PH103, PH105, PH112, PH200, PH113, PH301, PH302, PH200LM, and combinations thereof.

[0187] In some embodiments, the dosage form may comprise silicified microcrystalline cellulose (SMCC), which comprises microcrystalline cellulose (MCC) and colloidal silicon dioxide (CSD). In some embodiments, the silicified 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%) microcrystalline cellulose (MCC) and about 1% to about 10% by weight (e.g., 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%) colloidal silicon dioxide (CSD). In some embodiments, the dosage form may comprise PROSOLV® SMCC. In some embodiments, the dosage form may comprise a silicified microcrystalline cellulose (SMCC) selected from the group consisting of PROSOLV® SMCC 50, 50LD, 90, HD 90, 90LM, and combinations thereof.

[0188] In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC) having a particle size of less than about 50 μm, e.g., silicified microcrystalline cellulose (SMCC). In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC) having a particle size of greater than about 50 μm, e.g., silicified microcrystalline cellulose (SMCC). In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC) having a 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 146 μm, about 147 μm, about 148 μm, about 149 μm, about 150 μm, about 152 μm, about 153 μm, about 154 μm, about 155 μm, about 156 μm, about 157 μm, about 158 ​​μm, about 159 μm, about 160 μm, about 161 μm, about 162 μm, about 163 μm, about 164 μm, about 165 μm, about 166 μm, about 167 μm, about 168 μm, about 169 μm, about 170 μm, about 172 μm, about 175 μm, about 176 μm, about 177 μm In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC), e.g., silicified microcrystalline cellulose (SMCC), having an average particle size of about 10 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. In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC), e.g., silicified microcrystalline cellulose (SMCC), having a moisture content 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%). In some embodiments, the dosage form may comprise microcrystalline cellulose (MCC), e.g., silicified microcrystalline cellulose (SMCC), having a moisture content 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%.

[0189] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of microcrystalline cellulose, e.g., 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). 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 11 5mg to about 120mg, about 120mg to about 125mg, about 125mg to about 130mg, about 130mg to about 135mg, about 135mg to about 140mg, about 140mg to about 145mg, about 145mg to about 150mg, about 150mg to about 155mg, Approximately 155mg to approximately 160mg, approximately 160mg to approximately 165mg, approximately 165mg to approximately 170mg, approximately 170mg to approximately 175mg, approximately 175mg to approximately 180mg, approximately 180mg to approximately 185mg, approximately 185mg to approximately 190mg, approximately 190mg to approximately 19 5mg, about 195mg to about 200mg, about 200mg to about 205mg, about 205mg to about 210mg, about 210mg to about 215mg, about 215mg to about 220mg, about 220mg to about 225mg, about 225mg to about 230mg, about 230mg to Contains 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 microcrystalline cellulose (e.g., silicified microcrystalline cellulose).

[0190] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of microcrystalline cellulose, e.g., 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). g, 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, 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 microcrystalline cellulose, e.g., silicified microcrystalline cellulose.

[0191] In some embodiments, the dosage form comprises about 5% to about 50% by weight of microcrystalline cellulose, e.g., silicified 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, e.g., silicified microcrystalline cellulose).

[0192] In some embodiments, the dosage form comprises about 5% to about 50% by weight of microcrystalline cellulose, e.g., silicified 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, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight In some embodiments, the cellulose comprises about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of microcrystalline cellulose, e.g., silicified microcrystalline cellulose.

[0193] In some embodiments, the dosage form contains 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 75mg to about 80mg, about 80mg to about 85mg, about 85mg to about 90mg, about 90mg to about 95mg, about 95mg to about 100mg, about 100mg to about 105mg, about 105mg to about 110mg, about 110mg to about 115mg, about 115m g ~ approx. 120 mg, approx. 120 mg ~ approx. 125 mg, approx. 125 mg ~ approx. 130 mg, approx. 130 mg ~ approx. 135 mg, approx. 135 mg ~ approx. 140 mg, approx. Approximately 155mg to approximately 160mg, approximately 160mg to approximately 165mg, approximately 165mg to approximately 170mg, approximately 170mg to approximately 175mg, approximately 175mg to approximately 180mg, approximately 180mg to approximately 185mg, approximately 185mg to approximately 190mg, approximately 190mg to approximately 1 95mg, about 195mg to about 200mg, about 200mg to about 205mg, about 205mg to about 210mg, about 210mg to about 215mg, about 215mg to about 220mg, about 220mg to about 225mg, about 225mg to about 230mg, about 230 The sugar alcohol (e.g., mannitol) is contained in an amount of 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.

[0194] In some embodiments, the dosage form comprises about 5 mg to about 300 mg of a sugar alcohol, e.g., 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). g, 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, 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 a sugar alcohol, e.g., mannitol.

[0195] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a sugar alcohol, e.g., 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, e.g., mannitol).

[0196] In some embodiments, the dosage form comprises about 5% to about 50% by weight of a sugar alcohol, e.g., 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, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of a sugar alcohol, e.g., mannitol.

[0197] Glidants In some embodiments, the dosage form comprises a glidant.

[0198] In some embodiments, glidants include excipients used to promote powder flow, for example, by reducing interparticle friction and cohesion. In some embodiments, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate. In some embodiments, glidants include colloidal silicon dioxide. In some embodiments, colloidal silicon dioxide may include AEROSIL® 200 Pharma, also referred to as "colloidal silicon dioxide (Aerosil 200)."

[0199] In some embodiments, the dosage form comprises from about 1 mg to about 10 mg of glidant (e.g., from about 1 mg to about 2 mg, from about 2 mg to about 3 mg, from about 3 mg to about 4 mg, from about 4 mg to about 5 mg, from about 5 mg to about 6 mg, from about 6 mg to about 7 mg, from about 7 mg to about 8 mg, from about 8 mg to about 9 mg, or from about 9 mg to about 10 mg of glidant).

[0200] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of glidant (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 glidant).

[0201] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a glidant (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 glidant).

[0202] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a glidant (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 a glidant).

[0203] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of fumed silica, e.g., colloidal silicon dioxide (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, e.g., colloidal silicon dioxide).

[0204] In some embodiments, the dosage form comprises about 1 mg to about 10 mg of fumed silica, e.g., colloidal silicon dioxide (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, e.g., colloidal silicon dioxide).

[0205] In some embodiments, the dosage form comprises about 1% to about 10% by weight of fumed silica, e.g., colloidal silicon dioxide (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, e.g., colloidal silicon dioxide).

[0206] In some embodiments, the dosage form comprises about 1% to about 10% by weight of fumed silica, e.g., colloidal silicon dioxide (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, e.g., colloidal silicon dioxide).

[0207] lubricant In some embodiments, the composition comprises a lubricant.

[0208] In some embodiments, lubricants include excipients used, for example, to prevent ingredients from clumping together and from sticking to tablet punches or capsule filling machines. In some embodiments, lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solids and the die wall. In some embodiments, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin). In some embodiments, lubricants include magnesium stearate.

[0209] In some embodiments, the dosage form comprises from about 1 mg to about 10 mg of lubricant (e.g., from about 1 mg to about 2 mg, from about 2 mg to about 3 mg, from about 3 mg to about 4 mg, from about 4 mg to about 5 mg, from about 5 mg to about 6 mg, from about 6 mg to about 7 mg, from about 7 mg to about 8 mg, from about 8 mg to about 9 mg, or from about 9 mg to about 10 mg of lubricant).

[0210] In some embodiments, the dosage form comprises 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).

[0211] In some embodiments, the dosage form comprises about 1% to about 10% by weight of 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 lubricant).

[0212] In some embodiments, the dosage form comprises about 1% to about 10% by weight of lubricant (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 lubricant).

[0213] In some embodiments, the dosage form contains from about 1 mg to about 10 mg of magnesium stearate (e.g., from about 1 mg to about 2 mg, from about 2 mg to about 3 mg, from about 3 mg to about 4 mg, from about 4 mg to about 5 mg, from about 5 mg to about 6 mg, from about 6 mg to about 7 mg, from about 7 mg to about 8 mg, from about 8 mg to about 9 mg, or from about 9 mg to about 10 mg of magnesium stearate).

[0214] In some embodiments, the dosage form contains 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).

[0215] 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 of magnesium stearate).

[0216] In some embodiments, the dosage form comprises about 1% to about 10% by weight of magnesium stearate (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 magnesium stearate).

[0217] coating In some embodiments, the composition comprises a coating.

[0218] In some embodiments, the coating includes excipients to protect the tablet ingredients from degradation by moisture in the air and to make large or unpleasant-tasting tablets easier to swallow. In some embodiments, the coating includes a film coating. In some embodiments, the coating includes Opadry® II White 85F18422, which is composed of compendial grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and talc.

[0219] In some embodiments, the dosage form comprises about 1 mg to about 20 mg of a coating, for example, a film coating agent (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 a coating, for example, a film coating agent).

[0220] In some embodiments, the dosage form comprises about 1 mg to about 20 mg of a coating, e.g., 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 of a coating, e.g., a film coating).

[0221] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a coating, e.g., a film coating (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, e.g., a film coating).

[0222] In some embodiments, the dosage form comprises about 1% to about 10% by weight of a coating, e.g., a film coating agent (e.g., about 1% to about 2%, about 2% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, 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, e.g., a film coating agent).

[0223] In some embodiments, the dosage form contains 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).

[0224] In some embodiments, the dosage form contains 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).

[0225] 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 of Opadry® II White 85F18422).

[0226] 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%, about 2% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of Opadry® II White 85F18422).

[0227] form factor 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., slugging or roller compaction), wet granulation, and any combination thereof. The compositions, formulations, and dosage forms described herein should advantageously be of a shape, size, and weight that allows for easy ingestion, e.g., orally. Thus, in one aspect, the compositions, formulations, and dosage forms described herein can be solid dosage forms suitable for oral administration. The dosage form may be selected from the group consisting of tablets, capsules, films, powders, granules, solutions, solids, suspensions, and other acceptable oral dosage forms. In some embodiments, the dosage form is a tablet, such as a caplet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[0228] In some embodiments, the dosage form (e.g., tablet) may be compressed or molded in its manufacture and may be of almost any size, shape, weight, and color. In some embodiments, the dosage form (e.g., tablet) is in the shape of a capsule (also referred to as a "caplet"). Most tablets are intended to be swallowed whole, and therefore preferred tablets are designed for oral administration. However, in some embodiments, the tablet may be dissolved in the mouth, chewed, or dissolved in liquid before swallowing, and a portion may be placed in a body cavity.

[0229] In some embodiments, the total dosage form (e.g., tablet) weight, which is a function of the total size of the dosage form (e.g., tablet), can be adjusted to provide the best compromise between desired pharmacokinetics (PK) and patient compliance.

[0230] In some embodiments, the dosage form (e.g., tablet) contains 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, The total weight of the compound may range from 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.

[0231] In some embodiments, the dosage form (e.g., tablet) contains 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 185 mg, about 190 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, 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 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 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 400 mg, about 4 5mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, About 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, Approximately 395mg, approximately 400mg, approximately 405mg, approximately 410mg, approximately 415mg, approximately 420mg, approximately 425mg, approximately 430mg, approximately 435mg, approximately 440mg, approximately 445mg, approximately 450mg, approximately 455mg, approximately 460mg, approximately 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg.

[0232] In some embodiments, the dosage form is a circular tablet. In some embodiments, the tablet may have a diameter 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 tablet does not have a diameter 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).

[0233] In some embodiments, the dosage form is an oblong tablet. In some embodiments, opening a blister package of oblong tablets, handling the oblong tablets, and ingesting one or more oblong tablets is less difficult and convenient for patients suffering from movement disorders, such as essential tremor (ET), compared to, for example, small round tablets (e.g., 6 mm diameter).

[0234] In some embodiments, the dosage form is an oval tablet. In some embodiments, opening a blister package of oval tablets, handling the oval tablets, and ingesting one or more oval tablets is less difficult and convenient for patients suffering from movement disorders, such as essential tremor (ET), compared to, for example, small round tablets (e.g., 6 mm diameter).

[0235] In some embodiments, the dosage form is a capsule-shaped tablet (e.g., a caplet). In some embodiments, opening a blister package of capsule-shaped tablets, handling the capsule-shaped tablets, and ingesting one or more capsule-shaped tablets is less difficult and convenient for patients suffering from movement disorders, such as essential tremor (ET), compared to, for example, small round tablets (e.g., 6 mm diameter).

[0236] In some embodiments, the dosage form (e.g., tablet) has a diameter of 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 20 mm, about 18 mm to about 21 mm, about 18 mm to about 22 mm, about 18 mm to about 23 mm, about 18 mm to about 24 mm, about 18 mm to about 25 mm, about 19 mm to about 26 mm, about 21 mm to about 28 mm, about 22 mm to about 29 mm, about 23 mm to about 30 mm, about 24 mm to about 31 mm, about 25 mm to about 32 mm, about 26 mm to about 33 mm, about 27 mm to about 34 mm, about 27 mm to about 35 mm, about 28 mm to about 36 mm, about 29 mm to about 37 mm, about 38 mm to about 39 mm, about 39 mm to about 40 mm, about 40 mm to about 41 mm, about 41 mm to about 42 mm, about 42 mm to about 43 mm, about 43 mm to about 44 mm, about 44 mm to about 45 mm, about The length may be from about 16 mm to about 17 mm, from about 17 mm to about 18 mm, from about 18 mm to about 19 mm, from about 19 mm to about 20 mm, from about 20 mm to about 21 mm, from about 21 mm to about 22 mm, from about 22 mm to about 23 mm, from about 23 mm to about 24 mm, from about 24 mm to about 25 mm, from about 25 mm to about 26 mm, from about 26 mm to about 27 mm, from about 27 mm to about 28 mm, from about 28 mm to about 29 mm, or from about 29 mm to about 30 mm.

[0237] In some embodiments, the dosage form (e.g., tablet) has a diameter of 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 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, about 30 mm, about 31 mm, about 32 mm, about 33 mm, about 34 mm, about 35 mm, about 36 mm, about 37 mm, about 38 mm, about 39 mm, about 40 mm, about 41 mm, about 42 mm, about 43 mm, about 44 mm, about 45 mm, about 46 mm, about 47 mm, about 48 mm, about 49 mm, about 50 mm, about 51 mm, about 52 mm, about 53 mm, about 54 mm, about 55 mm, about 56 mm, about 57 mm, about 58 mm, about 59 mm, about 60 mm, about 61 mm, about 62 mm, about 63 mm, about 64 The length may be about 5.5 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 21.5 mm, about 22 mm, about 22.5 mm, about 23 mm, about 23.5 mm, about 24 mm, about 24.5 mm, about 25 mm, about 25.5 mm, about 26 mm, about 26.5 mm, about 27 mm, about 27.5 mm, about 28 mm, about 28.5 mm, about 29 mm, about 29.5 mm, or about 30 mm.

[0238] In some embodiments, the dosage form (e.g., tablet) has a diameter of 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 20 mm, about 18 mm to about 21 mm, about 18 mm to about 22 mm, about 18 mm to about 23 mm, about 18 mm to about 24 mm, about 18 mm to about 25 mm, about 19 mm to about 26 mm, about 21 mm to about 28 mm, about 22 mm to about 29 mm, about 23 mm to about 30 mm, about 24 mm to about 31 mm, about 25 mm to about 32 mm, about 26 mm to about 33 mm, about 27 mm to about 34 mm, about 27 mm to about 35 mm, about 28 mm to about 36 mm, about 29 mm to about 37 mm, about 38 mm to about 39 mm, about 39 mm to about 40 mm, about 40 mm to about 41 mm, about 41 mm to about 42 mm, about 42 mm to about 43 mm, about 43 mm to about 44 mm, about 44 mm to about 45 mm, about The width may be from about 16 mm to about 17 mm, from about 17 mm to about 18 mm, from about 18 mm to about 19 mm, from about 19 mm to about 20 mm, from about 20 mm to about 21 mm, from about 21 mm to about 22 mm, from about 22 mm to about 23 mm, from about 23 mm to about 24 mm, from about 24 mm to about 25 mm, from about 25 mm to about 26 mm, from about 26 mm to about 27 mm, from about 27 mm to about 28 mm, from about 28 mm to about 29 mm, or from about 29 mm to about 30 mm.

[0239] In some embodiments, the dosage form (e.g., tablet) has a width of 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, about 21.5 mm, about 22 mm, about 22.5 mm, about 23 mm, about 23.5 mm, about 24 mm, about 24.5 mm, about 25 mm, about 25.5 mm, about 26 mm, about 26.5 mm, about 27 mm, about 27.5 mm, about 28 mm, about 28.5 mm, about 29 mm, about 29.5 mm, or about 30 mm).

[0240] In some embodiments, the dosage form (e.g., a tablet) may have a width of about 1 mm to about 10 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, or about 9 mm to about 10 mm).

[0241] In some embodiments, the dosage form (e.g., tablet) has a width of about 1 mm to about 10 mm (e.g., 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 2.9mm, approximately 3mm, approximately 3.1mm, approximately 3.2mm, approximately 3.3mm, approximately 3.4mm, approximately 3.5mm, approximately 3.6mm, approximately 3.7mm, approximately 3.8mm, approximately 3.9mm, approximately 4mm, approximately 4.1 mm, approximately 4.2mm, approximately 4.3mm, approximately 4.4mm, approximately 4.5mm, approximately 4.6mm, approximately 4.7mm, approximately 4.8mm, approximately 4.9mm, approximately 5mm, approximately 5.1mm, approximately 5.2mm, approximately 5.3m m, approximately 5.4mm, approximately 5.5mm, approximately 5.6mm, approximately 5.7mm, approximately 5.8mm, approximately 5.9mm, approximately 6mm, approximately 6.1mm, approximately 6.2mm, approximately 6.3mm, approximately 6.4mm, approximately 6.5m m, approximately 6.6mm, approximately 6.7mm, approximately 6.8mm, approximately 6.9mm, approximately 7mm, approximately 7.1mm, approximately 7.2mm, approximately 7.3mm, approximately 7.4mm, approximately 7.5mm, approximately 7.6mm, approximately 7.7mm , about 7.8 mm, about 7.9 mm, about 8 mm, about 8.1 mm, about 8.2 mm, about 8.3 mm, about 8.4 mm, about 8.5 mm, about 8.6 mm, about 8.7 mm, about 8.8 mm, about 8.9 mm, about 9 mm, about 9.1 mm, about 9.2 mm, about 9.3 mm, about 9.4 mm, about 9.5 mm, about 9.6 mm, about 9.7 mm, about 9.8 mm, about 9.9 mm, or about 10 mm width).

[0242] In some embodiments, the dosage form (e.g., a tablet) can have a width of 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).

[0243] In some embodiments, the dosage form (e.g., tablet) has a diameter of about 10 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). The length may be 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 a width of about 1 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).

[0244] In some embodiments, the dosage form (e.g., tablet) has a diameter of about 14 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, The length may be about 15.9 mm, or about 16 mm) and a width of 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, about 6.3 mm, about 6.4 mm, about 6.5 mm, about 6.6 mm, about 6.7 mm, about 6.8 mm, about 6.9 mm, or about 7 mm).

[0245] In some embodiments, the dosage form (e.g., a tablet) may have a thickness of 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).

[0246] Tablet hardness can be measured using any technique or device known in the art for testing tablet hardness. For example, a breaking strength tester can be used to measure the breaking strength, which can indicate the strength of the tablet. Typical hardness measurement units include kiloponds (kp), Strong Cobb units (SCU), and Newtons (N). In some embodiments, the dosage form (e.g., tablet) has a molecular weight of about 75N, about 76N, about 77N, about 78N, about 79N, about 80N, about 81N, about 82N, about 83N, about 84N, about 85N, about 86N, about 87N, about 88N, about 89N, about 90N, about 91N, about 92N, about 93N, about 94N, about 95N, about 96N, about 97N, about 98N, about 99N, about 100N, about 101N, about 102N, about 103N, about 104N, about 105N, about 106N, about 107N, about 109N, about 200N, about 201N, about 202N, about 203N, about 204N, about 205N, about 206N, about 207N, about 208N, about 209N, about 300N, about 301N, about 302N, about 303N, about 304N, about 305N, about 306N, about 307N, about 308N, about 309N, about 400N, about 401N, about 402N, about 403N, about 404N, about 405N, about 406N, about 407N, about 408N, about 409N, about 410N, about 411N, about 412N, about 413N, about 414N, about 415N, about 416N, about 417N, about 418N, about 419 7N, approximately 108N, approximately 109N, approximately 110N, approximately 111N, approximately 112N, approximately 113N, approximately 114N, approximately 115N, approximately 116N, approximately 117N, approximately 118N, approximately 119N, approximately 120N, approximately 121N, approximately 122N, approximately 1 23N, approximately 124N, approximately 125N, approximately 126N, approximately 127N, approximately 128N, approximately 129N, approximately 130N, approximately 131N, approximately 132N, approximately 133N, approximately 134N, approximately 135N, approximately 136N, approximately 137N, approximately 138N, approximately 1 39N, approximately 140N, approximately 141N, approximately 142N, approximately 143N, approximately 144N, approximately 145N, approximately 146N, approximately 147N, approximately 148N, approximately 149N, approximately 150N, approximately 151N, approximately 152N, approximately 153N, approximately 154N, approximately 155N, approximately 156N, approximately 157N, approximately 158N, approximately 159N, approximately 160N, approximately 161N, approximately 162N, approximately 163N, approximately 164N, approximately 165N, approximately 166N, approximately 167N, approximately 168N, approximately 169N, approximately 170N, In some embodiments, the dosage form (e.g., a tablet) may have a hardness of about 90N to about 110N. In some embodiments, the dosage form (e.g., a tablet) may have a hardness of about 100N to about 120N.In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 110N to about 130N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 120N to about 140N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 130N to about 150N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 140N to about 160N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 150N to about 170N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 160N to about 180N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 170N to about 190N. In some embodiments, the dosage form (e.g., tablet) may have a hardness of about 180N to about 200N.

[0247] In some embodiments, the dosage form (e.g., a tablet) may have a compression force with an observed hardness of about 5N to about 35N (e.g., about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N, about 12N, about 13N, about 14N, about 15N, about 16N, about 17N, about 18N, about 19N, about 20N, about 21N, about 22N, about 23N, about 24N, about 25N, about 26N, about 27N, about 28N, about 29N, about 30N, about 31N, about 32N, about 33N, about 34N, or about 35N). In some embodiments, the dosage form (e.g., a tablet) may have a compression force with an observed hardness of about 5N to about 15N. In some embodiments, the dosage form (e.g., tablet) may have a compression force with an observed hardness of about 10 N to about 20 N. In some embodiments, the dosage form (e.g., tablet) may have a compression force with an observed hardness of about 15 N to about 25 N. In some embodiments, the dosage form (e.g., tablet) may have a compression force with an observed hardness of about 20 N to about 30 N. In some embodiments, the dosage form (e.g., tablet) may have a compression force with an observed hardness of about 25 N to about 35 N. In some embodiments, the dosage form (e.g., tablet) may have a compression force with an observed hardness of about 30 N to about 35 N.

[0248] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 5.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0249] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 10.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0250] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 20.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0251] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 30.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0252] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 40.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0253] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 50.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0254] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 60.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0255] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 70.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0256] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 80.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0257] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 90.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0258] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 100.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0259] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 110.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0260] In some embodiments, the dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) equivalent to about 120.0 mg of PRAX-944 free base per dosage unit (e.g., per tablet).

[0261] Pharmaceutical Composition The present disclosure encompasses 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), e.g., PRAX-944 HCl) as an active agent. Such pharmaceutical compositions may consist of the active agent alone, 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), e.g., PRAX-944 HCl)) in a form suitable for administration to a subject, or the pharmaceutical composition may include the active agent and one or more pharmaceutically acceptable carriers, one or more additional (active and / or inactive) ingredients, or some combination thereof.

[0262] In one aspect, the pharmaceutical compositions provided by the present disclosure include a single dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the single dosage form comprises up to 200 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the single dosage form comprises a length of up to 16 mm, e.g., from about 14 mm to about 16 mm, and / or a width of up to 7 mm, e.g., from about 5 mm to about 7 mm. In some embodiments, the single dosage form is bioequivalent to an identical dose of a reference composition administered as a multiple dosage form, such as a sustained release (MR) formulation comprising the compound of Formula (I), available as 5 mg and 20 mg tablets that are round and small in size (e.g., about 6 mm diameter). In some embodiments, bioequivalence may 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%.

[0263] Exemplary pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) as the active agent are provided in Tables 6-16.

[0264] The pharmaceutical compositions of the present disclosure 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), e.g., PRAX-944 HCl). One of skill in the art will recognize, however, that the pharmaceutical composition may contain a greater than therapeutically effective amount, such as in a bulk composition, or a less than therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount. Typically, the composition will contain from 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), e.g., PRAX-944 HCl), although the actual amount will depend on the formulation itself, the route of administration, the frequency of dosing, etc. According to one embodiment, a composition suitable for oral dosage form may contain, for example, 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), e.g., PRAX-944 HCl).

[0265] The pharmaceutical compositions of the present disclosure are designed to provide a larger, more convenient PRAX-944 dosage form compared to currently available PRAX-944 dosage forms, which are extended-release (MR) formulations available as 5 mg and 20 mg tablets that are round and small (6 mm diameter). For example, the pharmaceutical compositions of the present disclosure are designed to minimize the total number of dosage units (e.g., tablets) required to deliver a particular dose level of PRAX-944 and increase the physical size of the tablets to make them easier to grasp and more convenient for patients, particularly those with movement disorders such as essential tremor (ET). Furthermore, pharmaceutical compositions of the present disclosure comprising larger tablets have substantially the same bioavailability, e.g., in terms of the rate (maximum plasma drug concentration, Cmax) and extent (area under the plasma concentration-time curve, AUC) of absorption of PRAX-944, compared to multiple small, round 20 mg tablets of the same total dose.

[0266] The pharmaceutical compositions of the present disclosure can be administered in a manner appropriate to the condition, disease, and / or disorder to be treated (or prevented). The amount and frequency of administration will be determined by factors such as the condition of the patient and the type and severity of the patient's condition, disease, and / or disorder, although suitable dosages can be determined through clinical trials. Administration of the pharmaceutical composition can be carried out in any convenient manner, including, for example, by oral administration.

[0267] As used herein, the term "pharmaceutically acceptable carrier" refers to a chemical composition with which an active agent may be combined and which, after combination, can be used to administer the active agent to a subject. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference.

[0268] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing into association the active agent with the carrier or one or more other accessory ingredients and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

[0269] kit In one aspect, one or more dosage forms 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) can be provided, for example, in a package, such as a shrink-wrapped kit, blister pack, packet, or bottle. In one embodiment, a kit is provided that includes multiple oral dosage forms together in a package and instructions for use to administer the oral dosage forms according to the methods described herein. The oral dosage form may be selected from the group consisting of a tablet, capsule, film, powder, granule, solution, solid, and suspension.

[0270] The packaged oral dosage form can include a fill supply of medication typically prescribed for an intended treatment, e.g., an ascending dosing regimen. A series of unit doses can be packaged together according to the prescribed regimen or treatment, e.g., a 1- to 90-day supply, depending on the particular treatment. In some embodiments, the series of unit doses can include 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, up to about a 90-day supply of about 5 mg to about 200 mg of each dosage (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) can be provided together, e.g., in a package.

[0271] In one embodiment, oral dosage forms, e.g., tablets, described herein can be included in a blister pack with instructions for administering one or more tablets daily to ensure a sufficient dose of the formulations described herein. In one embodiment, oral dosage forms, e.g., tablets, can be included in a blister pack with instructions for administering two or more tablets daily to ensure a sufficient dose of the formulations described herein. In another embodiment, oral dosage forms, e.g., tablets, can be included in a blister pack with instructions for administering one or more tablets every other day to ensure a sufficient daily dose. In one embodiment, oral dosage forms, e.g., tablets, can be included in a blister pack with instructions for administering one or more tablets weekly to ensure a sufficient dose of the formulations described herein.

[0272] Methods of treating diseases or conditions associated with abnormal function or activity of T-type calcium channels In one aspect, the disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as essential tremor (ET), in a subject in need thereof, the method comprising administering to the subject daily (e.g., once, twice, three times) a therapeutically effective amount of a compound of Formula (I): [ka] or a pharmaceutically acceptable salt (e.g., co-crystal) or solvate thereof, for example, a compound of formula (II): [ka] The method includes administering

[0273] Formula (I) may also be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, while formula (II) may be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride.

[0274] In some embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a single 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 the same dose of a reference composition administered as a multiple of smaller, circular tablets.

[0275] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof an escalating dose of a compound of Formula (I) or (II). In some embodiments, the maximum escalating dose is 60 mg per day or 100 mg per day. In one embodiment, the maximum escalating dose is 60 mg per day.

[0276] Disclosed herein are methods of treating diseases or conditions associated with abnormal T-type calcium channel function or activity, comprising administering escalating doses such that the final or maintenance dose exceeds the initial dose or the dose at which adverse events would likely be experienced in the absence of escalating doses (the maximum tolerated dose achieved without escalating doses). As used herein, administering escalating doses refers to the practice of starting with a low dose and gradually increasing to one or more higher doses. For example, in certain embodiments, administering escalating doses according to the methods described herein can include: (i) administering to the subject a first dose, such as about 5 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a first period of time (e.g., a first week); (ii) administering to the subject a second dose, such as about 10 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a second period of time (e.g., a second week); (iii) administering to the subject a second dose, such as about 20 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a third period of time (e.g., a third week); and (iv) administering to the subject a second dose, such as about 40 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a fourth period of time (e.g., a fourth week). (v) administering to the subject a second dose, such as, for example, a dose of about 60 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a fifth period of time (e.g., a fifth week), (vi) administering to the subject a second dose, such as, for example, a dose of about 80 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a sixth period of time (e.g., a sixth week), (vii) administering to the subject a second dose, such as, for example, a dose of about 100 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a seventh period of time (e.g., a seventh week), and / or (ix) administering to the subject a second dose, such as, for example, a dose of about 120 mg per day, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for an eighth period of time (e.g., an eighth week). In some embodiments, the compositions, formulations, and dosage forms described herein allow for the use of a single tablet for each dose, instead of requiring the use of multiple tablets.

[0277] For example, in certain embodiments, disclosed herein is 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, comprising: (a) administering to the subject a first dose, such as a dose of about 20 mg or about 40 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for a first period of time, wherein after administration of the first dose of the compound for the first period of time, the subject experiences a maximum plasma drug concentration (C) in the range of about 30 ng / mL to about 130 ng / mL. max ) and / or approximately 490 ng * h / mL ~ approx. 2030ng * The area under the plasma concentration-time curve (AUC) from the time of administration to 24 hours after administration was measured in the range of h / mL. 24 (b) increasing the amount of the compound at the first dose and administering one or more escalating doses of the compound to the subject until a maximum escalating dose is achieved; and (c) administering the maximum escalating dose of the compound to the subject to obtain a C in the range of about 280 ng / mL to about 470 ng / mL in the subject. max and / or approximately 3480 ng * hour / mL ~ approx. 5800ng * AUC in the range of hours / mL 24 Typically, each dose is administered daily, preferably once daily, however, the frequency of administration can vary depending on the desired C, as discussed in other sections of this application. max Value and / or AUC 24 It can be changed as long as the value is achieved.

[0278] For example, in certain embodiments, step (b) includes increasing the first dose to a second dose, such as a dose of about 40 to about 80 mg, and administering the second dose of the compound to the subject for a second period of time, wherein after administration of the second dose of the compound for the second period of time, the subject has a C in the range of about 80 ng / mL to about 300 ng / mL, such as about 80 ng / mL to about 220 ng / mL, about 80 ng / mL to about 130 ng / mL, or about 130 ng / mL to about 300 ng / mL.max , and / or approximately 1220 ng * hour / mL ~ approx. 4070ng * AUC in the range of hours / mL 24 , for example, about 1220 ng * hour / mL ~ approx. 3330ng * h / mL or approximately 1220 ng * hour / mL ~ approx. 2030ng * AUC in the range of hours / mL 24 etc.

[0279] In certain embodiments, step (b) can 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 period of time, wherein after administration of the third dose, the subject has a C in the range of about 130 ng / mL to about 380 ng / mL, such as 130 ng / mL to about 220 ng / mL, about 180 ng / mL to about 300 ng / mL, or 230 ng / mL to about 380 ng / mL. max , and / or about 2000 ng * hour / mL ~ approx. 4700ng * h / mL, e.g., about 2000 ng * hour / mL ~ approx. 3330ng * h / mL, approximately 2440ng * hour / mL ~ approx. 4070ng * h / mL, or approximately 2820 ng * hour / mL ~ approx. 4700ng * AUC in the range of h / mL etc. 24 It has.

[0280] Also disclosed herein are embodiments further 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 period of time, wherein after administration of the fourth dose of the compound for the fourth period of time, the subject has a C in the range of about 180 ng / mL to about 380 ng / mL, such as about 180 ng / mL to about 300 ng / mL or about 230 to about 380 ng / mL. max , and / or approximately 2440 ng* hour / mL ~ approx. 4700ng * h / mL, e.g., approximately 2440 ng * hour / mL ~ approx. 4070ng * hr / mL or approximately 2820 ng * hour / mL ~ approx. 4700ng * AUC in the range of h / mL etc. 24 In certain embodiments, the methods disclosed herein can 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 period of time, wherein after administration of the fifth dose of the compound for the fifth period of time, the subject has a C in the range of about 230 ng / mL to about 380 ng / mL. max and approximately 2820 ng * hour / mL ~ approx. 4700ng * AUC in the range of hours / mL 24 It has.

[0281] In some embodiments of the escalating dosing schedules disclosed herein, if the subject can safely tolerate the higher dose, the dose may be increased to a Cmax of 470 ng / mL or greater in the subject, and / or an AUC 24 5800ng * The maximum titration dose can be increased to maintain a C value of at least about 450 ng / mL. For example, in certain embodiments, the method provides a C value of at least about 450 ng / mL to about 750 ng / mL, including, for example, about 450 ng / mL to about 650 ng / mL, about 450 ng / mL to about 550 ng / mL, or about 450 ng / mL to about 500 ng / mL. max , and / or e.g., about 5500 ng * hour / mL~about 8500ng * h / mL, 5500ng * hour / mL~approx. 7500ng * h / mL, or approximately 5500 ng * hour / mL ~ approx. 6500ng * Approximately 5500 ng / mL * hour / mL ~ approx. 9500ng * AUC in the range of hours / mL 24The method includes one or more additional titration steps to achieve a maximum titrated dose administered to the subject to maintain a constant dose.

[0282] Also disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, comprising: (a) administering to the subject about 5 mg to about 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of time; (b) administering to the subject about 10 mg to about 100 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a second period of time; and (c) administering to the subject about 20 mg to about 120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a third period of time. Typically, each of the first, second, and third periods ranges from about 3 to about 9 days. However, shorter or longer periods may be used depending on subject tolerance, the clinician's judgment, and the like.

[0283] Also disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, comprising: (a) administering to the subject about 5 mg to about 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of time; (b) administering to the subject about 10 mg to about 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a second period of time; and (c) administering to the subject about 20 mg to about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a third period of time. (d) administering to the subject about 20 mg to about 120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a fourth period, (e) administering to the subject about 20 mg to about 120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a fifth period, (f) administering to the subject about 20 mg to about 120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a sixth period, and (g) administering to the subject about 0 mg to about 120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a seventh period. Typically, each of the first, second, third, fourth, and fifth periods is in the range of about 3 to about 9 days, the sixth period is in the range of about 3 to about 16 days, and the seventh period extends beyond 14 days. However, shorter or longer periods may be used for each period, depending on tolerance by the subject, the judgment of the clinician, and the like.

[0284] In certain embodiments, the subject does not experience an adverse event at any of the dose levels in the escalating dosing schedule. In certain embodiments, in the absence of administering a first dose level (e.g., about 5 mg to about 40 mg) over a first dosing period, the subject will experience an adverse event at a second dose level (e.g., about 10 mg to about 100 mg, such as at least about 60 mg to about 100 mg) administered during a second dosing period. In certain embodiments, in the absence of administering the first and second dose levels during the first and second dosing periods, the subject will experience an adverse event at a third dose level (e.g., about 20 mg to about 120 mg, such as at least about 60 mg to about 120 mg) administered during a third dosing period.

[0285] In certain embodiments, wherein a subject would likely experience an adverse event at the second dosage level administered during the second dosing period in the absence of administering the first dosage level during the first dosing period, but the dosage may continue to be escalated to a dosage level greater than the second dosage level administered during the second dosing period, e.g., a dosage level that is at least about 25% greater, at least about 50% greater, at least about 75% greater, at least about 100% greater, at least about 125% greater, at least about 150% greater, at least about 175% greater, at least about 200% greater, at least about 250% greater, or at least about 300% greater than the dosage level at which the adverse event would likely occur without escalating dosing.

[0286] In certain aspects of all embodiments disclosed herein, the period of administration, such as the first, second, third, fourth, or fifth period, can be in the range of about 3 to about 9 days, such as 3, 4, 5, 6, 7, 8, or 9 days. In certain aspects of the embodiments disclosed herein, the period of administration, such as the sixth period, can be in the range of about 3 to about 16 days, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days. In other aspects of the embodiments disclosed herein, the time period, such as the time period of the first, second, third, fourth, fifth, sixth, or seventh administration, can extend beyond 14 days.

[0287] In certain embodiments, the dosage increase compared to the previous dose is no more than 40 mg per day, e.g., in certain embodiments, the second dose is increased by no more than 40 mg per day compared to the first dose, and in certain embodiments, the third dose is increased by no more than 40 mg per day compared to the second dose.

[0288] In another aspect, the present disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, the method comprising administering 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). 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) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is administered to a subject daily (e.g., once, twice, or three times). In another aspect, the present disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, the method comprising: (a) administering to a subject 5 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) once daily for a first period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days); (b) administering 10 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to the subject once daily for a second period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days); and (c) administering to the subject 20 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) once daily for a third period (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0289] In another aspect, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: (a) administering to a subject 20 to 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) for a first period (e.g., 3, 5, 6, 7, 8, or 9 days); (b) administering to the subject 20 to 60 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) for a second period (e.g., 3, 5, 6, 7, 8, or 9 days); and

[0290] (c) administering to the subject 20 to 80 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) for a third period (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0291] In some embodiments, the method further includes (d) administering to the subject 20 to 100 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a fourth period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0292] In other embodiments, the method further includes (e) administering to the subject 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a fifth period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0293] In certain embodiments, the method further includes (f) administering to the subject 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a sixth period of time (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days).

[0294] In certain embodiments, the method further includes (e) administering to the subject 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a seventh period of time (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more).

[0295] In certain aspects of these embodiments, the physician may choose not to continue escalating the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, so that the dosing period may be less than the seven periods described above. For example, there may be only 1, 2, 3, 4, 5, or 6 periods of escalating dosage as needed to achieve the desired therapeutic effect. There may also be more than the seven periods of dose escalation described above, as warranted by subject tolerance and the physician's judgment.

[0296] For example, in certain embodiments, a method is disclosed for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, the method comprising: (a) administering to the subject about 5 to about 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 20 mg or 40 mg per day, for a first period of time ranging from about 3 to about 9 days; (b) administering to the subject about 10 to about 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 40 mg, 60 mg, or 80 mg per day, for a second period of time ranging from about 3 to about 9 days; and (c) administering to the subject about 20 to about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 60 mg, 80 mg, 100 mg, or 120 mg per day, for a third period of time ranging from about 3 to about 9 days.

[0297] In certain aspects, disclosed herein are methods of treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising: (a) administering a first dose of about 20 mg to about 40 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject once daily for a first period of time; (b) increasing the amount of the compound in the first dose to administer one or more increasing doses of the compound to the subject until a maximum escalating dose of about 80 mg to about 120 mg per day is reached; and (c) administering the maximum escalating dose to the subject once daily, as needed.

[0298] In a related embodiment, the dosage of the compound of formula (I) may be adjusted upward or downward in 1, 2, 3, 4, 5, 10, 15, 20 mg increments as deemed necessary by a physician, depending on the subject's response to a previous dose of the compound of formula (I).

[0299] In various embodiments of the present disclosure, the methods disclosed herein include (a) administering a first dose of 20 mg per day for a first period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 60 mg per day for a third period of 7 days, (d) administering a fourth dose of 80 mg per day for a fourth period of 7 days, (e) administering a fifth dose of 100 mg per day for a fifth period of 7 days, and (f) thereafter administering a sixth dose of 120 mg per day as needed. In various other embodiments, the methods disclosed herein include (a) administering a first dose of 20 mg per day for a first period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 80 mg per day for a third period of 3 days, and (d) administering a fourth dose of 120 mg per day, if needed.

[0300] In certain embodiments, a method is disclosed for treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising: (a) administering to the subject about 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of about 3 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 3 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 3 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 3 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 3 days; and (f) administering to the subject about 120 mg of the compound per day for a sixth period of about 3 days. Instead of every three days, the dose can also be administered every four, five, or six days.

[0301] Also disclosed herein are methods of treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising: (a) administering to the subject about 20 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 7 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 7 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 7 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 7 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 7 days; and (f) administering to the subject about 120 mg of the compound per day for a sixth period of time.

[0302] In certain embodiments, a method is disclosed for treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising: (a) administering to the subject about 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of three days; (b) administering to the subject about 80 mg of the compound per day for a second period of about three days; and (c) administering to the subject about 120 mg / day of the compound per day for a third period of time. Instead of every three days, the dose can also be administered every four, five, or six days.

[0303] Also disclosed herein is 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, comprising: (a) administering to the subject about 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 7 days; (b) administering to the subject about 80 mg of the compound per day for a second period of about 7 days; and (c) administering to the subject about 120 mg / day of the compound per day for a third period of time.

[0304] In certain embodiments, a method is disclosed for treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising: (a) administering to the subject about 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 7 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 7 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 7 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 7 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 7 days; (f) administering to the subject about 120 mg of the compound per day for a sixth period of about 14 days; and (g) thereafter, administering to the subject about 1-120 mg of the compound per day, if needed.

[0305] In certain embodiments of the method for treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, a physician may choose to stop titrating the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof once the subject demonstrates the desired therapeutic effect. At this point, the physician may choose to continue the dose the subject has been taking to achieve the desired therapeutic effect, or may choose to reduce the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for the subject to maintain the desired therapeutic effect. Achieving the desired therapeutic effect may be the result of an improvement in any therapeutic measure, for example, the subject's TETRAS performance score, accelerometer performance score, or Archimedes' spiral task test.

[0306] In some embodiments, the subject is a human between birth and 100 years of age, such as between 10 and 90 years of age, between 20 and 70 years of age, between 18 and 55 years of age, or between 55 and 75 years of age.

[0307] In various aspects, the methods disclosed herein result in an EEG sigma frequency band reduction during NREM sleep in a subject, such as an NREM sigma band frequency reduction of about 0.4 to 0.7, e.g., about 0.5 to about 0.6, or about 0.5, from baseline. In certain embodiments, the methods disclosed herein result in an EEG gamma band reduction during wakefulness in an EO or EC state in a subject, such as a gamma band reduction of at least about 25%, e.g., about 50%, compared to baseline gamma band.

[0308] In certain embodiments, the methods disclosed herein provide a method for treating a subject, comprising administering to the subject a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, which, when administered to the subject, results in a decrease in EEG sigma frequency during NREM sleep and / or a decrease in EEG gamma frequency band during EO or EC states, and a C of about 30 ng / mL to about 470 ng / mL. max , for example, a C in the range of about 30 to about 50 ng / mL, about 80 to about 130 ng / mL, about 130 to about 222 ng / mL, about 180 to about 300 ng / mL, about 230 to 380 ng / mL, or about 280 to about 470 ng / mL. max In certain embodiments, the methods disclosed herein provide a method for reducing EEG sigma frequency during NREM sleep and / or reducing EEG gamma frequency band during EO or EC states in a subject, wherein the AUC ranges from about 490 ng*h / mL to about 5800 ng*h / mL, when administered to the subject at a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 24 , for example, an AUC in the range of about 490 to 820 ng*h / mL, about 1220 to 2030 ng*h / mL, about 2000 to 3330 ng*h / mL, about 2440 to 4070 ng*h / mL, about 2820 to 4700 ng*h / mL, or about 3480 to 5800 ng*h / mL. 24 This results in:

[0309] In certain embodiments, the methods disclosed herein provide for NREM sigma frequency reduction in a subject, when the subject is administered a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, that results in a C of about 5 ng / mL to about 470 ng / mL. max , for example, about 180 to about 300 ng / mL C max In certain embodiments, the methods disclosed herein provide for NREM sigma frequency reduction in a subject, when administered to the subject a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, resulting in a mean plasma concentration (C) of about 10 ng / mL to about 200 ng / mL during EEG recording (i.e., over a period of about 24 hours). ave ), for example, about 12 to about 150 ng / mL C ave In certain embodiments, the methods disclosed herein provide for an EO or EC gamma frequency band reduction in a subject when the subject is administered a dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the C of the compound being about max , for example, about 280 to about 470 ng / mL C max In certain embodiments, the methods disclosed herein result in an EO or EC gamma frequency band reduction in a subject, resulting in a plasma concentration of about 75 ng / ml to about 310 ng / ml, such as about 90 to about 190 ng / ml, when the subject is administered a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0310] In other embodiments, the disease or condition associated with abnormal function or activity of T-type calcium channels is selected from the group consisting of psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), seizures (e.g., absence seizures), and epilepsy or epilepsy syndromes (e.g., juvenile myoclonic epilepsy).

[0311] In certain aspects of all of the embodiments of the escalating dose schedules disclosed herein, the maximum escalating dose can be increased, including, for example, increasing the maximum escalating dose above 120 mg in one or more additional escalation steps, provided that the subject can safely tolerate the higher dose.

[0312] In certain aspects of all of the embodiments of the escalating dosing schedules disclosed herein, the maximum escalating dose achieved is greater than 20 mg, greater than 40 mg, or greater than 60 mg, e.g., 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 certain aspects of the invention, the maximum dose achieved for a subject is, for example, 40 mg, 60 mg, or 80 mg, provided that the subject achieves the desired therapeutic outcome.

[0313] In certain aspects of all of the embodiments of the escalating dose schedules disclosed herein, the maximum escalating dose is reached in 42 days or less, such as 31 days or less, 28 days or less, 18 days or less, 10 days or less, or 7 days or less, etc. In certain embodiments, the maximum escalating dose is reached in about 10 to about 42 days, such as, for example, about 36 to 42 days, about 22 to 28 days, about 16 to 18 days, or about 10 to 12 days.

[0314] Administration In some embodiments, the dosage form is administered to a subject more than once a day (eg, twice a day, three times a day, or four times a day).

[0315] In some embodiments, the dosage form is administered to a subject once daily (e.g., one 5 mg tablet once daily, one 10 mg tablet once daily, one 20 mg tablet once daily, one 40 mg tablet once daily, one 80 mg tablet once daily, or one 120 mg tablet once daily). In some embodiments, the dosage form is administered to a subject twice daily (e.g., one 5 mg tablet twice daily, one 10 mg tablet twice daily, one 20 mg tablet twice daily, one 40 mg tablet twice daily, one 80 mg tablet twice daily, or one 120 mg tablet twice daily).

[0316] In some embodiments, the dosage form is administered to a 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 a 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).

[0317] In some embodiments, the dosage form is administered to the subject daily, hi other embodiments, the dosage form is administered to the subject once a week or twice a week.

[0318] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof an escalating dose of a compound of Formula (I) or (II). In some embodiments, the maximum escalating dose is 60 mg per day or 100 mg per day. In one embodiment, the maximum escalating dose is 60 mg per day.

[0319] In certain embodiments, about 1 mg to 10 mg, for example, 2 mg to 5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 20 mg, for example, 5 mg to 10 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 30 mg, for example, 10 mg to 20 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 40 mg, for example, 20 mg to 30 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 50 mg, for example, 30 mg to 40 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 60 mg, for example, 40 mg to 50 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 70 mg, for example, 50 mg to 60 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 80 mg, for example, 60 mg to 70 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 90 mg, for example, 70 mg to 80 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 100 mg, such as 80 mg to 90 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily.In certain embodiments, about 1 mg to 110 mg, such as 90 mg to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily. In certain embodiments, about 1 mg to 120 mg, such as 100 mg to 110 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), e.g., PRAX-944 HCl) is administered to a subject daily.

[0320] In some embodiments, the dosage form, upon administration to a subject, has substantially the same bioavailability, e.g., with respect to the rate (maximum plasma drug concentration, Cmax) and extent (area under the plasma concentration-time curve, AUC) of absorption of PRAX-944, as compared to multiple small, round 20 mg tablets.

[0321] In some embodiments, the dosage form, upon administration to a subject, has a reduced C relative to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with an improved release rate profile, a dosage form without an improved release rate profile, a dosage form without an improved release polymer, e.g., an HPMC polymer). max In some embodiments, the dosage form, upon administration to a subject, has a greater t than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with an improved release rate profile, a dosage form without an improved release rate profile, a dosage form without a modified release polymer, e.g., an HPMC polymer). max It has.

[0322] Tremor The methods described herein can be used to treat tremors, for example, the dosages or compositions disclosed herein can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, or rubral tremor. Tremor includes genetic, degenerative, and idiopathic disorders such as Wilson's disease (genetic), Parkinson's disease (degenerative), and essential tremor (idiopathic), metabolic diseases, peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, and complex regional pain syndrome), toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene), drug-induced (tricyclic neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine), and psychogenic disorders. Clinical tremor can be neuropathic tremor, but can also be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task-specific and position-specific tremor, dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, toxin- or drug-induced tremor, and psychogenic tremor. Tremor can also be familial tremor.

[0323] Tremor is an involuntary, rhythmic vibration of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0324] 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 pathways, such as tumors, stroke, or other focal lesion diseases (e.g., multiple sclerosis), or neurodegenerative diseases.

[0325] Dystonic tremor occurs in individuals suffering from dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and can often be alleviated by complete rest or certain sensory manipulations.

[0326] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, beginning on one side of the body and progressing slowly, typically affecting both sides. The hands are most often affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors can decrease with age, but the severity can increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally develop over time and can be both visible and persistent after onset. Tremor, including essential tremor, can interfere with any or all of a person's daily activities, such as personal hygiene, cooking, eating, dressing, home repairs, and interacting with other people. Tremor, including essential tremor, can interfere with career choices and job performance (e.g., typing on a computer or cell phone, using tools, sewing, working in food service (cooking or serving customers), caring for others (medical or veterinary work), or any job requiring physical movement may be difficult). Tremor can also have serious emotional effects, such as fear of the tremor being discovered, fear of others' reactions, or fear of rejection.

[0327] Orthostatic tremor is characterized by rapid (greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms can be felt in the thighs and legs, and subjects may experience uncontrollable shaking when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0328] Parkinson's tremor is caused by damage to structures in the brain that control movement. Parkinson's tremor is typically seen as a "pill-making" movement of the hands, which may also affect the jaw, lips, legs, and trunk. The onset of Parkinson's tremor typically begins after the age of 60. Motor dysfunction typically begins in one leg or on one side of the body and can progress to involve the other side.

[0329] Red nucleus tremor is characterized by a rough, slow tremor that can be present at rest, during posture, and with intention. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0330] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor, hi some embodiments, the tremor is essential tremor.

[0331] essential tremor The compositions described herein are useful in the treatment of essential tremor (ET). ET is the most common adult movement disorder, affecting up to 2% of the U.S. population (approximately 7 million Americans) (Louis and Ottman 2014). ET is characterized by a 5-12 Hz postural and kinetic tremor (i.e., tremor during voluntary movement) in the upper extremities (Bhidayasiri 2005, Louis 2009). The most distinctive clinical feature is a kinetic tremor in the arms and hands, but tremor can also occur in the head and voice, and less commonly in the face, legs, and trunk. Diagnosis of ET is based on medical history and neurological examination, as described in the International Parkinson and Movement Disorders Society Consensus Statement on the Classification of Tremors (Bhatia et al. 2018).

[0332] ET ranges in severity, with some patients requiring no treatment, while others have severe impairments with functional impairments in activities of daily living, such as dressing and eating. Although ET, by definition, is generally not associated with other neurological symptoms (Deuschl et al., 2011), there is increasing recognition that ET may also be associated with additional motor features, such as postural instability, dystonia, mild to moderate gait ataxia, and eye movement abnormalities (Louis, 2009). ET is also associated with an elevated prevalence of comorbid psychiatric disorders, including anxiety and depression (Dogu et al., 2005; Miller et al., 2007). ET often worsens over time, with more severe tremors and corresponding worsening disability over the course of years to decades (Louis, 2019).

[0333] Although ET can be sporadic, a family history of an autosomal dominant pattern of inheritance is commonly encountered (Clark and Louis 2018), and importantly, variants in the calcium voltage-gated channel subunit alpha 1G (CACNA1G) gene, which encodes the T-type Ca2+ channel isoform 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 to cerebellar development and function is further emphasized by the observation that variants in this gene can 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 their physiological contribution to the expression of T-type Ca2+ channels in the cerebellum and distal CTC circuits, and to oscillatory burst firing in the thalamus that synchronizes with, and the sponsors hypothesize, drives, clinically observable tremor (Milosevic et al., 2018).

[0334] Propranolol is the only Food and Drug Administration (FDA)-approved oral treatment indicated for the treatment of ET. Originally developed for hypertension, propranolol has demonstrated limited efficacy in treating ET, often with side effects (e.g., bradycardia) that lead to discontinuation (Hedera 2017, Louis 2015). Unmet medical needs in ET have led to the off-label use of medications across multiple drug classes, including anticonvulsants, barbiturates, benzodiazepines, antipsychotics, and others, with limited, discernible therapeutic benefit for patients with ET. A recent evidence-based review concluded that only propranolol, primidone, and topiramate had sufficient evidence to support efficacy among 28 drugs tested for ET (Ferreira et al. 2019). Surgical interventions that disrupt CTC burst activity, such as deep brain stimulation or focused ultrasound, are effective treatments for ET, but carry risks, such as sensory impairment, hemiparesis, akinesia, gait disturbances, delirium, cognitive decline, tissue damage, venous thromboembolic events, and intracerebral hemorrhage (Dallapiazza et al. 2019, Insightec, Inc. 2016).

[0335] In some embodiments, the present disclosure also provides a method for treating essential tremor, comprising administering a composition described herein to a subject in need thereof. In some embodiments, the method results in a reduction in essential tremor as assessed by the Essential Tremor Rating Assessment Scale (TETRAS) score. The term "Essential Tremor Rating Assessment Scale (TETRAS)" as used herein refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities. It has an Activities of Daily Living (ADL) section and a Performance section. The ADL section has 12 items rated from 0 to 4, and the Activity section has 9 items rated from 0 to 4.

[0336] In some embodiments, reduction in essential tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Extremity score.

[0337] In some embodiments, reduction in essential tremor is assessed by the TETRAS performance subscale score or individual items of the TETRAS performance.

[0338] In some embodiments, subjects treated according to the methods provided herein have moderate essential tremor (i.e., a TETRAS score of 10 to 15). In some embodiments, subjects treated herein have a TETRAS score of about 10 to about 15, or a TETRAS score of about 12, prior to treatment according to the methods of the present disclosure. Treatment with the compositions described herein may reduce the subject's TETRAS score. In some embodiments, subjects treated with the compositions described herein experience an average reduction in TETRAS score of about 2 to 5, e.g., about 3. In some embodiments, subjects treated with the compositions described herein experience an average reduction in TETRAS score of about 30% to about 50%, e.g., about 40%.

[0339] In some embodiments, the present disclosure also provides a method for treating essential tremor, comprising administering to a subject in need thereof the composition described herein.In some embodiments, the method results in the reduction of essential tremor, as assessed by accelerometer-based score, for example, accelerometer-based upper limb score.In some embodiments, the method results in the reduction of essential tremor, as assessed by CGI score.

[0340] In some embodiments, the essential tremor is upper limb tremor.

[0341] In some embodiments, a subject is selected for treatment with a compound of Formula (I) due to a clinical diagnosis of essential tremor. In some embodiments, a subject selected for treatment with a compound of Formula (I) has essential tremor but does not have intention tremor.

[0342] The effectiveness of a compound or composition disclosed herein for treating essential tremor can be measured by methods known in the art, such as those described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor," Mov. Disord. 2019 Jul; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor," Mov. Disord. 2013 Nov; 28(13): 1793-800; Deuschl G. et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011; 10: 148-61; and Reich SGet al., "Essential Tremor," Med. Clin. N. Am. 2019; 103: 351-356. The disclosures of the references are incorporated herein in their entireties.

[0343] In some embodiments, the methods described herein result in at least a 25% reduction in upper extremity tremor scores, where the tremor score can be converted to amplitude compared to baseline. For example, in certain embodiments, the methods described herein result in an approximately 40% average reduction in tremor amplitude as measured by the Essential Tremor Rating Assessment Scale (TETRAS) upper extremity score, as described, for example, in Elble, RJ, "The Essential Tremor Rating Assessment Scale," J. Neurol. Neuromed. 2016;1(4):34-38. In some embodiments, the methods described herein result in at least a 25% reduction in TETRAS performance scores compared to baseline. In some embodiments, the methods described herein result in at least a 35% average reduction in symptom severity compared to baseline, as measured by TETRAS performance scores.

[0344] Parkinson's disease The compositions described herein are useful in the treatment of Parkinson's disease (PD). PD is a debilitating neurodegenerative disorder with approximately 1 million diagnosed patients in the United States (US) and approximately 10 million diagnosed patients worldwide. Approximately 60,000 patients are diagnosed with PD each year in the US alone (Marras et al., 2018). Diagnosis of PD is often based on medical history and neurological examination as described in the International Parkinson's Disease and Movement Disorder Society (MDS) clinical diagnostic criteria for Parkinson's disease (Postuma et al., 2015).

[0345] PD is characterized by slow movements (ataxia) in combination with resting tremor (4–6 Hz) and / or rigidity (Postuma et al., 2015). Symptoms are typically unilateral in onset, mild, and non-disabling, but progress in severity over time, involve both sides of the body, and often impair activities of daily living (ADLs), such as dressing and eating. In addition to the above cardinal symptoms, patients with PD may develop abnormal posture (dystonia), severe forward bending of the thoracic and lumbar spine (camptocormia), slurred speech (dysarthria), gait instability, and freezing of the gait. Non-motor symptoms, such as impaired sense of smell, dream content behavior (rapid eye movement [REM] sleep behavior disorder [RBD]), constipation, depression, psychosis, and dementia, also play a central role in the daily lives of PD patients (Jankovic and Tan, 2020).

[0346] Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) of PD patients results in a loss of dopaminergic output, and therefore, the cornerstone of treatment for PD is dopaminergic replacement therapy (Armstrong and Ohun 2020). L-dopa, or levodopa, is a formulation of replacement dopamine and is considered the gold standard treatment for PD. Levodopa is highly effective in improving motor symptoms of bradykinesia and rigidity, especially early in the disease, but has variable effects on tremor. Most other common PD medications primarily decrease dopamine metabolism or are dopamine receptor agonists.

[0347] Effective side effects of chronic dopaminergic treatment include motor complications (dyskinesia or involuntary choreiform 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. Thus, symptom management using non-dopaminergic therapeutic agents with better safety and tolerability profiles is needed.

[0348] Adjunctive oral non-dopaminergic treatments that alleviate PD symptoms may also reduce the need for dose escalation of dopaminergic treatments.

[0349] Surgical treatment, i.e., deep brain stimulation (DBS), can be highly successful for uncontrollable tremor and motor complications but typically affects basal ganglia function downstream of the nigrostriatal pathway (Fasano et al., 2012). Depending on the patient's specific symptoms, DBS electrodes may be placed in the globus pallidus, the ventral intermediate nucleus of the thalamus, or the subthalamic nucleus (STN) to affect abnormal burst firing in these regions (see below). DBS is typically reserved for patients who respond to dopaminergic treatment but whose problematic motor symptoms persist with maximal efficacy. Furthermore, DBS carries significant risks associated with brain surgery, including intracerebral hemorrhage, infection, hemiplegia, and cognitive decline (Pahwa et al., 2006). The prospect of neurosurgery later in life is often anxiety-inducing and contraindicated (e.g., due to the presence of cognitive impairment), and many patients are not treated with DBS. Thus, there is a clinical need for pharmacological treatments that could mimic the effects of DBS. By modulating T-type Ca2+ channels, PRAX-944 may modulate burst firing downstream of SNc degeneration.

[0350] Data from animal models and human PD patients demonstrate that degeneration of nigral dopaminergic neurons converts the downstream STN from sustained firing to an abnormal bursting phenotype (Ammari et al., 2011, Tai et al., 2011, Pan et al., 2016). This bursting activity drives symptoms of bradykinesia and rigidity in animal models, and blockade of T-type Ca2+ channels has been shown to attenuate 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 the STN (Talley et al., 1999, Weiss and Zamponi, 2019). Eliminating this bursting through blockade of T-type Ca2+ channels has been shown to improve motor function in a 6-hydroxydopamine rat model of PD (Pan et al., 2016). Thus, inhibitors of T-type Ca2+ channels may be able to provide a non-surgical and non-dopaminergic treatment option for alleviating motor symptoms in PD.

[0351] Epilepsy and epilepsy syndromes The compositions described herein are useful in the treatment of epilepsy and epileptic syndromes. Epilepsy is a central nervous system disorder in which neuronal activity in the brain is disrupted, resulting in recurrent epileptic seizures that may manifest as abnormal movements, periods of unusual behavior, agitation, and occasionally loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for several seconds to repetitive twitching of the arms or legs during the seizure.

[0352] Epilepsy can include generalized seizures, which involve multiple areas of the brain, or partial or focal seizures. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of their arms and legs. Their eyes may be open, and / or they may appear not to be breathing and turn blue. Return of consciousness may be gradual, and the person may be confused for several minutes to several hours. The following are the main types of generalized seizures: tonic-clonic, tonic-clonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, and absence seizures (typical, atypical, myoclonic, and blepharo-myoclonic), as well as epileptic spasms. Partial or focal seizures involve only part of the brain, so only part of the body is affected. Symptoms can vary depending on the part of the brain with abnormal electrical activity.

[0353] Epilepsy, as described herein, includes generalized seizures, partial seizures, complex partial seizures (e.g., seizures involving only part of the brain, but in which consciousness is impaired), tonic-clonic seizures, clonic seizures, tonic seizures, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0354] The compositions described herein may also be useful in treating epilepsy syndromes. Severe syndromes involving diffuse brain dysfunction, at least in part caused by some forms of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive impairment, such as West syndrome.

[0355] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with a mutation in a gene encoding a T-type calcium channel (e.g., CACNA1G, EEF1A2, and GABRG2 for genetic generalized epilepsy (GGE) and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)), as discussed, for example, in Feng, Y.C.A., et al., "Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals," Am. J. Human Gen. 2019;105(2):267-282. In some embodiments, the epilepsy syndrome is Doze syndrome or myoclonic astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike-waves during slow wave sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0356] absence seizures Absence seizures are one of the most common seizure types in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures are relatively brief, nonconvulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10–30 seconds in duration, followed by a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of generalized 1–6 Hz (e.g., 3 Hz) spike-and-wave discharges on accompanying EEG recordings. Absence seizures often occur multiple times per day, interfere with learning and psychosocial functioning, and present a risk of injury due to frequent episodes of loss of consciousness. Absence seizures typically begin during early childhood and remit by the teenage years. However, in a minority of patients, they persist into adulthood, where they are often drug-resistant and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are usually highly disabling, particularly by disqualifying affected individuals from obtaining a driver's license or pursuing occupations and hobbies, in which seizure-related periods of loss of consciousness pose a safety risk and are associated with significant psychosocial impairments (Wirrell et al., 1997).

[0357] While there is a general perception that absence seizures are relatively "easily" treated, randomized controlled trials in patients with childhood absence epilepsy have shown that even the most effective antiepileptic drugs, ethosuximide and valproate, only completely controlled seizures in 53% and 58% of patients, respectively, at 16 weeks (Glauser et al., 2010) and 45% and 44% at 12 months (Glauser et al., 2013), as assessed by video-EEG recording. Lamotrigine, another AED commonly used to treat absence seizures, controlled seizures in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproate are generally associated with unacceptable 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; only benzodiazepines have established efficacy, and these are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, and patients are often treated with multiple medications, sometimes resulting in significant side effects without achieving seizure control.

[0358] There is abundant evidence that low-threshold (T-type) calcium channels play a role in the generation and maintenance of absence seizures and are an important component of the oscillatory burst firing that occurs in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the present disclosure is directed to methods 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).

[0359] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures include adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0360] In some embodiments, the methods described herein further include identifying a subject with absence seizures.

[0361] In some embodiments, the present disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition described herein. In some embodiments, the method results in a reduction in the number of seizures.

[0362] In some embodiments, the present disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition described herein.

[0363] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in mean or total seizure duration.

[0364] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a reduction in seizure frequency, duration, or both, as measured by electroencephalogram (EEG).

[0365] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in mean seizure duration as measured by EEG.

[0366] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in cumulative seizure duration as measured by EEG.

[0367] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in hyperventilation and total time with 2.5-4 Hz spike-wave discharges following a photic stimulus challenge, as measured by EEG.

[0368] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in global severity as measured by the Clinical Global Impression-Severity (CGI-S) score or the Clinical Global Impression-Improvement (CGI-I) score. The CGI-S is a 7-point scale used to assess the severity of a patient's illness at the time of evaluation compared to a clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale used to assess improvement in a patient's illness compared to baseline.

[0369] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a reduction in the number of seizures.

[0370] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a reduction in seizure density as measured by electroencephalogram (EEG).

[0371] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure result in a decrease in mean seizure duration as measured by EEG.

[0372] Hereditary epilepsy In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, epilepsy or epilepsy syndromes comprise epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0373] In some embodiments, the methods described herein further include identifying the subject with epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy associated with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome associated with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy associated with SCN3A mutations, cryptogenic childhood partial epilepsy associated with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) prior to administration of a composition described herein.

[0374] In one aspect, the present invention provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy associated with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome associated with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, good flu-like symptoms, etc.) comprising administering to a subject in need thereof a composition described herein. The present invention features methods for treating familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0375] The compositions of the invention may also be used to treat epileptic encephalopathy, in which a subject is taking any 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, KCNQ2, KCNQ3, The patient has a mutation in one or more of 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.

[0376] In some embodiments, the methods described herein include administering to the patient an effective amount of one or more of the following antibodies prior to administration of a composition 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, The method further includes identifying subjects with a mutation in one or more of KCNQ2, 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, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0377] The compositions of the invention may also be used to treat epileptic encephalopathy, in which a subject is diagnosed with ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5 , DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA 1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, K CNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8 A, 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,The patient has a mutation in one or more of 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.

[0378] Additionally, the following specifications are: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, and ARHGE F9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS 2. CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, C.S LN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7,D YRK1A, 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 KANSL1K CNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LG I1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF. NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNK D、PNKP、PNPO、POLG、PPT1、PRICKLE1、PRIMA1、PRRT2、PURA、QARS、RELN、ROG DI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, and SERPINI1 GCE、SIK1、SLC12A5、SLC13A5、SLC19A3、SLC25A12、SLC25A22、SLC2A1、SLC3 5A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STR ADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK 1. TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2.and further comprising identifying subjects with a mutation in one or more of 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.

[0379] The compositions of the invention may also be used to treat epileptic encephalopathy, in which a subject is diagnosed with 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, EPM2A, FLNA, FOL R1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KC NMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA The patient has a mutation in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0380] In some embodiments, the methods described herein comprise administering to a patient a therapeutically effective amount of at least one of: 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, EPM2A, FLNA, FOLR1, FOXG1, FOXG2, FOXG3, FOXG4, FOXG5, FOXG6, FOXG7, FOXG8, FOXG9, FOXG10, FOXG11, FOXG22, FOXG12, FOXG13, FOXG14, FOXG15, FOXG16, FOXG17, FOXG18, FOXG29, FOXG19, FOXG20, FOXG19, FOXG10, FOXG11, FOXG21, FOXG12, FOXG15, FOXG16, FOXG22, FOXG17, FOXG18, FOXG23, FOXG19, FOXG19, FOXG24, FOXG19, FOXG19, FOXG25, FOXG19, FOXG19, FOXG26, FOXG19, FOXG19, FOXG27, FOXG19, FOXG19, FOXG28, FOXG RRS1L, 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 The method further includes identifying subjects having a mutation in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0381] The compositions of the invention may also be used to treat epileptic encephalopathy, in which a subject is diagnosed with epileptic encephalopathy caused by a gene encoding any 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, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCN J10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC1 3A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0382] In some embodiments, the methods described herein include administering to a patient an effective amount of any 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, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCN T1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POL G, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2A The method further includes identifying subjects with a mutation in one or more of: SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0383] Mood disorders Also provided herein are methods for treating psychiatric disorders, such as mood disorders, including, for example, clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0384] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience sleep disturbances, weight loss, and generally agitated and irritable feelings. Clinical depression affects how individuals feel, think, and behave, and can lead to a variety of emotional and physical problems. Individuals with clinical depression have difficulty performing daily activities and can make individuals feel as if life is not worth living.

[0385] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, emotional withdrawal from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0386] Postpartum depression (PND), also referred to as postpartum depression (PPD), refers to a form of clinical depression that affects women after birth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, episodes of crying, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

[0387] In some embodiments, a subject with PND also experienced depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, a subject experiencing perinatal depression is at increased risk of experiencing PND.

[0388] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the legs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0389] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that is more prominent than sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0390] Psychotic major depression (PMD) or psychotic depression refers specifically to a major depressive episode of a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0391] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become silent and stuporous, immobile, or exhibit purposeless or bizarre movements.

[0392] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that fall in the fall or winter.

[0393] Dysthymia refers to conditions related to unipolar depression that manifest the same physical and cognitive problems. They tend to be less severe but last longer (e.g., at least 2 years).

[0394] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0395] Depressive personality disorder (DPD) refers to a personality disorder that involves depressive traits.

[0396] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting less than two weeks, typically less than two to three days.

[0397] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0398] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During mania, individuals may feel or act unusually happy, energetic, or irritable. They often make poorly considered decisions with little consideration for the consequences. The need for sleep is usually reduced. During depression, there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at over 6% over a 20-year period, while self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0399] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition, such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0400] Treatment-resistant depression refers to a state in which an individual is treated for depression, but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve their symptoms, but then relapse. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0401] Postoperative depression refers to feelings of depression after a surgical procedure (e.g., as a result of having to face the death of a person). For example, an individual may experience persistent sadness or a feeling of emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0402] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0403] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about or an abnormal preoccupation with suicide. The spectrum of suicidal ideation can vary widely, from fleeting thoughts to extensive thinking, to detailed plans, role-playing, and / or abortive attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, being preoccupied with death, feeling trapped or hopeless about the situation, increasing alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0404] 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 exercising, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thinking or planning, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. The symptoms of depression and their relief may be confirmed by a doctor or psychologist (e.g., by a mental status examination).

[0405] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder, hi some embodiments, the mood disorder is major depressive disorder.

[0406] In some embodiments, the method includes monitoring the subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, Clinical Global Impression-Improvement (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total scale exhibited by the subject. The therapeutic effect can be assessed over a specific treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total scale after administration of a composition described herein (e.g., 12, 24, or 48 hours, or 24, 48, 72, or 96 hours or more after administration, 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).

[0407] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a 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, inclusive, 14 and 18. In some embodiments, the subject's baseline HAM-D total score is between, inclusive, 19 and 22. In some embodiments, the subject's HAM-D total score before treatment with a 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 subject's HAM-D total score after treatment with a 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 HAM-D total score after treatment with a composition described herein is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D total 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 HAM-D total 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 a composition described herein. In some embodiments, the reduction in baseline HAM-D total score relative to the HAM-D total score after treatment with a composition described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50).In some embodiments, the percentage reduction in the baseline HAM-D total score relative to the HAM-D total score after treatment with a composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as the reduction in the HAM-D total score after treatment with a composition described herein compared to the baseline HAM-D total score.

[0408] In some embodiments, the methods of treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D score) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the methods of treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the methods of treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within less than or equal to 14 days of initiating treatment with a composition described herein. In some embodiments, the methods of treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within less than or equal to 21 days of initiating treatment with a composition described herein. 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 HAM-D total score) within less than or equal to 28 days of initiating treatment with a composition described herein. In some embodiments, the therapeutic effect is a reduction from baseline in the HAM-D total score after treatment with a composition described herein. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is between, inclusive, 14 and 18. In some embodiments, the reduction in the HAM-D total score after treating a subject with a composition described herein compared to the baseline HAM-D total score is at least 10.In some embodiments, the reduction in the HAM-D total score after treating a subject with a composition described herein compared to the baseline HAM-D total score is at least 15. In some embodiments, the HAM-D total score associated with treating a subject with a composition described herein is no greater than a number in the range of 6 to 8. In some embodiments, the HAM-D total scale associated with treating a subject with a composition described herein is no greater than 7.

[0409] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in CGI score at the end of the treatment period (e.g., 14 days after administration).

[0410] The therapeutic effect for major depressive disorder can be determined by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score exhibited by the subject. For example, the MADRS score can be reduced within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The MADRS is a 10-item diagnostic questionnaire (related to apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. In some embodiments, the therapeutic effect is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0411] pain The dosage forms and compositions described herein may be useful in the treatment of pain. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0412] 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-944 HCl)).

[0413] ataxia The dosage forms and compositions described herein may be useful in the treatment of ataxia. Ataxia includes both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia) and generally involves a loss or inability to coordinate. Patients with ataxia may have difficulty controlling the force, range, direction, speed, and rhythm involved in posture, balance, and limb movements. Trunk ataxia may manifest, for example, as increased postural instability and an inability to maintain the center of gravity over the base of support. Ataxia and primary or secondary symptoms of ataxic gait and leg tremor may be accompanied by speech disorders, dysphagia, abnormal ventilation and vocalization, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, thereby substantially interfering with activities of daily living.

[0414] As described above, ataxia can result from a wide range of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Ataxic symptoms can result from a wide range of diseases, disorders, 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), among others; in one embodiment, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxia symptoms that can be treated according to the methods described herein include, but are not limited to, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar insufficiency, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (pigment epithelial retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar agenesis (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal conditions, autonomic disorders, disequilibrium syndromes, paresthesia, endocrine disorders, disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptic drugs), fragile X / tremor syndrome, among others. Warren's ataxia syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, central nervous system granulomatous vasculitis, Hallervorden-Spatz syndrome, hereditary motor and sensory neuropathies, hydrocephalus (e.g., hypotensive or normal), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller-Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonic ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, parkinsonism (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe brain injury (e.g., head injury, brain surgery, multiple sclerosis or cerebral palsy), chronic alcohol / drug abuse, chronic exposure to toxins, viral infection,or those caused by brain tumors), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia, glaucoma, precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy hearing loss), spinocerebellar ataxia (dysmorphism), 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 Spinocerebellar ataxias include spinocerebellar ataxia (autosomal recessive 4), spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph type II), spinocerebellar ataxia (X-linked 2), spinocerebellar ataxia (X-linked 3), spinocerebellar ataxia (X-linked 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X-associated / tremor ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / tremor ataxia syndrome.

[0415] Tinnitus Provided herein are methods for treating tinnitus in a subject in need thereof, comprising administering a dosage form or composition disclosed herein. Tinnitus is a condition in which an affected person perceives sound in one or both ears or in the head in the absence of external sound. Tinnitus, often referred to as a "ringing" in the ears, occurs intermittently or consistently, with a perceived volume ranging from low to painfully loud. However, the perceived volume of tinnitus can vary from patient to patient, where an objective measure of tinnitus volume in one patient may be perceived as painful, while in another patient, the same volume may be perceived as faint.

[0416] Sleep disorders Provided herein are methods for treating or preventing sleep disorders (e.g., narcolepsy), comprising administering a dosage or composition disclosed herein. For example, the sleep disorder can be hypersomnia, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, progressive sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or a core disorder of circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0417] Combination therapy The dosage forms or compositions described herein (e.g., for use in modulating T-type calcium ion channels) can be administered in combination with at least one other drug or treatment. The subject to whom the compounds disclosed herein are administered can have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another drug or treatment. In certain embodiments, these diseases or conditions can relate to epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy) or tremor (e.g., essential tremor).

[0418] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0419] painkillers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opiates and morphine-like agents, such as fentanyl and morphine, paracetamol, NSAIDs, and COX-2 inhibitors. Given the ability of the compounds disclosed herein to treat pain through the inhibition of T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combinations with analgesics are particularly contemplated.

[0420] Tremor medications 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. [Example]

[0421] In order that the embodiments described herein may be more fully understood, the following examples are set forth: 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 the scope thereof in any way.

[0422] Example 1: A Phase 1, Randomized, Open-Label Study Evaluating the Pharmacokinetics, Relative Bioavailability, Safety, Tolerability, and Food Effect of Two PRAX-944 Extended-Release Tablet Formulations in Healthy Adults PRAX-944 is a small-molecule, selective inhibitor of T-type calcium channels in development for the treatment of essential tremor (Figure 1). PRAX-944 is also being developed for the treatment of Parkinson's disease. Development of a more convenient dosage form prior to late-stage trials is critical to the program's success. Minimizing the total number of dosage units (e.g., tablets) required to deliver a specific dose level and tailoring the tablet's physical size and shape for ease of gripping may be more convenient and useful for patients, particularly those with essential tremor (ET). Figure 2A shows tablets of various shapes and sizes, and Figure 2B shows a comparison between the currently available PRAX-944 dosage form, a sustained-release (MR) formulation available as round, compact-sized (6 mm diameter) 5 mg and 20 mg tablets, and an exemplary bioequivalent single-dose dosage form described herein. The purpose of this clinical trial is to evaluate the pharmacokinetics (PK) of a new PRAX-944 tablet designed to be more convenient for patients.

[0423] Current PRAX-944 dosage forms are 5 mg and 20 mg extended-release (MR) formulations, which are small, round tablets measuring 6 mm in diameter. The current maximum planned clinical dose is up to 120 mg. This 120 mg dose level requires study participants to ingest six small, round 20 mg tablets of PRAX-944.

[0424] In some instances, escalating dosing is necessary to reach a dose >40 mg. The current PRAX-944 escalating dosing schedule uses 20 mg, 40 mg, and 80 mg as interim 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 this trial are larger than those used in previous trials and will include single-administered doses of 20 mg, 40 mg, 80 mg, and 120 mg.

[0425] This study will evaluate the PK of a new, larger, capsule-shaped, single-dose MR tablet (15 mm long and 6.5 mm wide) compared to the current small, round 20 mg tablet at each of the dose levels used in the current escalating dosing regimen: 20 mg, 40 mg, 80 mg, and 120 mg. The primary objective of this relative bioavailability study is to compare the rate (maximum plasma drug concentration, Cmax) and extent (area under the plasma concentration-time curve, AUC) of absorption of PRAX-944 from the larger 120 mg tablet versus the small, round 20 mg tablets. These parameters are related to the potential safety and efficacy of PRAX-944. Comparisons of other dose levels will also be performed.

[0426] In a previous study (Z944-103), administration of a single small, round 20 mg PRAX-944 MR tablet with a high-fat, high-calorie meal resulted in a 14...

Claims

1. A single dose 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 HCl), A single dosage form, wherein said single dosage form is bioequivalent to the same dose of a reference composition administered in one or more dosage forms.

2. the single dosage form and the reference composition (i) different sizes; (ii) different shapes; (iii) both different sizes and different shapes; (iv) the same shape but different sizes, or 10. The single dosage form of claim 1, having (v) the same size but different shapes.

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

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

5. (i) the single dosage form is a larger dosage form that, upon administration to a subject in the fed and / or fasted state, exhibits bioequivalence compared to administration of the same dose of a reference composition administered as one or more smaller, round, 20 mg PRAX-944 tablets to a subject in the fed and / or fasted state; Bioequivalence is (a) a 90% confidence interval for the AUC between about 80% and about 125%, and (b) the single dosage form of any one of claims 1 to 4, as established by a 90% confidence interval for Cmax of between about 80% and about 125%.

6. (i) reducing the total number of dosage units (e.g., tablets) required to deliver a particular dose to a subject; (ii) characterized by a physical size and shape (e.g., tablet size and shape) that makes it easier and more convenient to grasp for a subject with a movement disorder, optionally essential tremor (ET); (iii) can be formulated as single-dose dosage strengths of 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg; and / or (iv) A single dosage form according to any one of claims 1 to 5, which does not require titration to reach a dose > 40 mg.

7. 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 HCl) is released within about 1 hour to about 12 hours upon administration to a subject; and optionally 7. The single-dose dosage form of any one of claims 1 to 6, 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 HCl) is released in about 1 hour to about 12 hours using USP Apparatus Type I, a medium comprising 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

8. 8. The single dosage form of any one of claims 1 to 7, comprising from 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 HCl).

9. It contains about 1% to about 70% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (eg, the compound of formula (II), eg, PRAX-944 HCl). A single dosage form according to any one of claims 1 to 8.

10. 10. The single dosage form of any one of claims 1 to 9, further comprising a modified release polymer.

11. 11. The single dosage form of any one of claims 1 to 10, wherein the modified release polymer optionally comprises a matrix polymer selected from the group consisting of a hydrophilic matrix polymer, a hydrophobic matrix polymer, a polyacrylate polymer, and combinations thereof.

12. the modified release polymer (i) optionally a hydrophilic matrix polymer selected from the group consisting of hypromellose, HPMC (hydroxyl-propyl methylcellulose), and combinations thereof, wherein optionally the HPMC (hydroxyl-propyl methylcellulose) is selected from the group consisting of Methocel K4M, Methocel K100LV, Methocel E50LV, and combinations thereof; (ii) optionally a hydrophobic matrix polymer selected from the group consisting of ethylcellulose, Ethocel, and combinations thereof; and / or (iii) optionally comprising a polyacrylate polymer selected from the group consisting of Eudragit RL100, Eudragit RS100, and combinations thereof.

13. 13. A single dosage form according to any one of claims 1 to 12, comprising from about 5 mg to 300 mg of modified release polymer.

14. 14. The single dosage form of any one of claims 1 to 13, comprising from about 10% to about 70% by weight of said modified release polymer.

15. 15. The single dosage form of any one of claims 1 to 14, wherein the modified release polymer is hypromellose.

16. 16. The single dosage form of any one of claims 1 to 15, further comprising a diluent.

17. The diluent is (i) a cellulose derivative, optionally microcrystalline cellulose, optionally silicified microcrystalline cellulose; (ii) optionally a starch 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) optionally comprising a sugar alcohol selected from the group consisting of sorbitol, xylitol, mannitol, and combinations thereof.

18. 18. The single dosage form of any one of claims 1 to 17, comprising from about 5 mg to about 300 mg of diluent.

19. 19. The single dosage form of any one of claims 1 to 18, comprising from about 5% to about 50% by weight of a diluent.

20. 20. The single dosage form of any one of claims 1 to 19, wherein the diluent is microcrystalline cellulose, optionally silicified microcrystalline cellulose.

21. 21. The single dosage form of any one of claims 1 to 20, wherein the diluent is a sugar alcohol, optionally mannitol.

22. 22. The single dosage form of any one of claims 1 to 21, further comprising a glidant.

23. 23. The single dosage form of any one of claims 1 to 22, wherein the glidant is selected from the group consisting of fumed silica, optionally colloidal silicon dioxide, talc, magnesium carbonate, and combinations thereof.

24. 24. The single dosage form of any one of claims 1 to 23, comprising from about 1 mg to about 10 mg of a glidant.

25. 25. The single dosage form of any one of claims 1 to 24, comprising from about 1% to about 10% by weight of a glidant.

26. 26. The single dosage form of any one of claims 1 to 25, wherein the glidant is fumed silica, and optionally colloidal silicon dioxide.

27. 27. The single dosage form of any one of claims 1 to 26, further comprising a lubricant.

28. 28. The single-dose dosage form of any one of claims 1 to 27, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, talc, silica, fats, optionally vegetable stearins, and combinations thereof.

29. 29. The single dosage form of any one of claims 1 to 28, comprising from about 1 mg to about 10 mg of lubricant.

30. 30. The single dosage form of any one of claims 1 to 29, comprising from about 1% to about 10% by weight of a lubricant.

31. 31. The single dosage form of any one of claims 1 to 30, wherein the lubricant comprises magnesium stearate.

32. 32. The single dosage form of any one of claims 1 to 31, further comprising a coating.

33. 33. The single dosage form of any one of claims 1 to 32, wherein the coating comprises a film coating agent.

34. 34. The single dosage form of any one of claims 1 to 33, wherein the coating comprises compendial grade polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and / or talc.

35. 35. The single dosage form of any one of claims 1 to 34, comprising from about 1 mg to about 20 mg of coating.

36. 36. The single dosage form of any one of claims 1 to 35, comprising from about 1% to about 10% by weight of a coating.

37. 37. The single dosage form of any one of claims 1 to 36, wherein the coating comprises Opadry® II White 85F18422.

38. 38. A single dosage form according to any one of claims 1 to 37, optionally a tablet formulated for oral administration.

39. 39. A single dosage form according to any one of claims 1 to 38, which is an oblong tablet, an oval tablet or a capsule-shaped tablet, optionally wherein the tablet is not a round tablet.

40. 40. The single dosage form of any one of claims 1 to 39 having a total weight of about 200 mg to about 600 mg per dosage unit (e.g., per tablet).

41. 41. The single dosage form of any one of claims 1 to 40, having a length of from about 1 mm to about 30 mm.

42. 42. The single dosage form of any one of claims 1 to 41, having a width of from about 1 mm to about 10 mm.

43. 43. The single dosage form of any one of claims 1 to 42, having a length of about 14 to about 16 mm and a width of about 5 mm to about 7 mm.

44. 44. The single dosage form of any one of claims 1 to 43, comprising PRAX-944 HCl in an amount equivalent to about 5.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

45. 45. The single dosage form of any one of claims 1 to 44, comprising PRAX-944 HCl in an amount equivalent to about 10.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

46. 46. ​​The single dosage form of any one of claims 1 to 45, comprising PRAX-944 HCl in an amount equivalent to about 20.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

47. 47. The single dosage form of any one of claims 1 to 46, comprising about 1% to about 10% by weight of PRAX-944 HCl, optionally from about 15 mg to about 25 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

48. 48. The single dosage form of any one of claims 1 to 47, comprising PRAX-944 HCl in an amount equivalent to about 40.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

49. 49. The single dosage form of any one of claims 1 to 48, comprising about 5% to about 15% by weight of PRAX-944 HCl, optionally about 40 mg to about 50 mg of PRAX-944 HCl per dosage unit (e.g., per tablet).

50. 50. The single dosage form of any one of claims 1 to 49, comprising PRAX-944 HCl in an amount equivalent to about 80.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

51. 51. The single dosage form of any one of claims 1-50, comprising about 15% to about 25% by weight PRAX-944 HCl, optionally about 85 mg to about 95 mg PRAX-944 HCl per dosage unit (e.g., per tablet).

52. 52. The single dosage form of any one of claims 1-51, comprising PRAX-944 HCl in an amount equivalent to about 120.0 mg of PRAX-944 free base per dosage unit (eg, per tablet).

53. 53. The single dosage form of any one of claims 1-52, comprising about 25% to about 35% by weight PRAX-944 HCl, optionally about 125 mg to about 135 mg PRAX-944 HCl per dosage unit (e.g., per tablet).

54. (i) a modified release polymer, optionally from about 35% to about 45% by weight of a modified release polymer, optionally from about 175 mg to about 185 mg of modified release polymer per dosage unit (e.g., per tablet); (i) a soluble diluent, optionally from about 6% to about 10% by weight of a soluble diluent, optionally from about 34 mg to about 38 mg of a soluble diluent per dosage unit (e.g., per tablet); (iii) a glidant, optionally from about 1% to about 3% by weight of a glidant, optionally from about 6 mg to about 8 mg of a glidant per dosage unit (e.g., per tablet); (iv) a lubricant, optionally from about 0.5% to about 2% by weight of a lubricant, optionally from about 3 mg to about 6 mg of a lubricant per dosage unit (e.g., per tablet); and (v) a coating, optionally from about 12% to about 15% by weight of a coating, optionally from about 1 mg to about 5 mg of a coating per dosage unit (e.g., per tablet).

55. 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 Caplet) (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 55. The single dosage form of any one of claims 1 to 54, comprising (x) Large Tablet Prototype 54 (46% K100LV, 12% Mannitol IG).

56. 56. The single dosage form of any one of claims 1 to 55, comprising Large Tablet Prototype 53 (40% K100LV, 8% Mannitol IG).

57. 57. A pharmaceutical composition comprising the single unit dosage form of any one of claims 1 to 56 and at least one pharmaceutically acceptable carrier or excipient.

58. 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, comprising administering to the subject a therapeutically effective amount of the single unit dosage form of any one of claims 1 to 56, or the pharmaceutical composition of claim 57.

59. 58. A method of treating tremor in a subject in need thereof, 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. 58. A method of treating essential tremor in a subject in need thereof, 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. 61. The method of claim 60, which results in a reduction in the essential tremor as assessed by an Essential Tremor Rating Assessment Scale (TETRAS) score.

62. 62. The method of claim 60 or 61, wherein the reduction in essential tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Extremity score.

63. 63. The method of any one of claims 60-62, wherein the reduction in essential tremor is assessed by TETRAS-ADL (Activities of Daily Living).

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

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

66. 66. A method according to any one of claims 60 to 65, resulting in a reduction of the sigma frequency band.

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

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