Preparation of triphenylcalcilytic compounds

Abstract

The present disclosure provides a tablet formulation containing a triphenylcalcilytic compound for the treatment of autosomal dominant hypocalcemia (ADH), comprising the formula (I): Formula (I) A compound represented by JPEG2023536667000033.jpg47133, a solvate, a hydrate, a pharmaceutically acceptable salt, or a combination thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 061,050, filed August 4, 2020, which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Autosomal dominant hypocalcemia type 1 (ADH1) is a rare disorder of systemic calcium homeostasis caused by activating mutations in the calcium-sensing receptor (CaSR) gene, resulting in hypocalcemia (Hannan et al. Human Molecular Genetics, 2012, 21 (12), pp. 2768-2778; and Hofer et al., Nature Reviews: Molecular Cell Biology, 2003, 4 (7), pp. 530-538). CaSR plays a central role in regulating systemic calcium homeostasis by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion in response to changes in blood calcium levels (Hofer et al., Nature Reviews: Molecular Cell Biology, 2003; and Gunn et al., Ann. Clin. Biochem., 2004, 41 (Pt 6):pp. 441-58). Negative allosteric modulators of the CaSR (so-called calcilytic agents) may represent potential targeted therapeutics for ADH1.

[0003] The prevalence of ADH1 is unknown and has previously been estimated at 1 in 70,000 (Gunn et al., Ann. Clin. Biochem., 2004) or 3.9 in 100,000 (Dershem et al., Am. J. Hum. Genet., 2020). However, the condition is recognized as rare by the National Institutes of Health (NIH) Office of Rare Disease Research (GARD Number: 2877) and Orphanet (Orpha Number: 428).

[0004] ADH1 is characterized by varying degrees of hypocalcemia accompanied by abnormally low parathyroid hormone levels, hyperphosphatemia, and low magnesium levels that are usually accompanied by persistent hypercalciuria (Roszko et al., Frontiers in Physiology, 2016, 7, p. 458). Symptoms of hypocalcemia most commonly include paresthesias, muscle spasms, cramps, tetany, and perioral numbness and can vary in intensity, including causing stroke. Hypocalcemia may also present with laryngospasm, neuromuscular responsiveness, cognitive impairment, personality disorders, long QT syndrome, electrocardiographic changes resembling myocardial infarction, and / or heart failure.

[0005] In patients with ADH1, hypocalcemia occurs primarily due to increased sensitivity of the CaSR to extracellular calcium ions, which suppresses iPTH secretion and leads to low levels of 1,25-dihydroxyvitamin D3 (reducing calcium absorption from the intestine) and low levels of calcium reabsorption in the kidney (leading to hypercalciuria). Hypercalciuria is aggravated by two mechanisms: reduced PTH-mediated calcium reabsorption from the renal proximal filtrate and reduced calcium reabsorption in the distal tubules, where mutant CaSRs are exposed to high calcium concentrations. Furthermore, standard treatment with oral calcium and calcitriol (e.g., 1,25-dihydroxyvitamin D3) supplementation tends to exacerbate hypercalciuria, which is associated with long-term pathologies such as nephrolithiasis, nephrocalcinosis, and chronic kidney disease, which can progress to renal failure (Khan et al., European Journal of Endocrinology, 2018; and Li et al., Clinical Interventions in Aging, 2018, 13, pp. 2443-2452).

[0006] For this reason, the consensus approach to ADH1 management is to balance oral calcium and calcitriol supplementation with the known high risk of renal calcification, kidney stones, and renal failure. This means that healthcare providers must help patients find a regimen that will maintain the lowest serum calcium concentration compatible with symptomatic relief that minimizes hypercalciuria. Thiazide diuretics are sometimes added because of their modest urinary calcium-lowering effect.

[0007] Experimental treatment with PTH(1-34) in ADH1 patients was able to correct serum calcium but failed to prevent hypercalciuria (Winer et al., The Journal of Clinical Endocrinology and Metabolism, 2012, 97 (2), pp. 391-399; Winer et al., The Journal of Pediatrics, 2014, 165 (3), 556-63; and Gafni et al., Journal of Bone and Mineral Research, 2015, 30 (11), pp. 2112-2118). Exogenous PTH(1-84) is approved for orphan indication of hypoparathyroidism, but the clinical studies supporting its approval in patients with established hypoparathyroidism excluded patients with hypoparathyroidism due to calcium-sensing receptor mutations (Chomsky et al., World Journal of Surgery, 2018, 42 (2), p. 431-436; and Natpara Product Insert).

[0008] Triphenylcalcilytic compounds refer to a class of compounds with calcium-sensing receptor antagonist activity, and are disclosed in U.S. Pat. No. 7,304,174 and have the following formula: [ka] R2″ is expressed as C 1-6 R4" is a methyl group or a cyclopropyl group, R6 is a halogen atom or a C 1-6 and R7" is a hydrogen atom, a halogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group, or C 1-6 A haloalkyl group, an optically active form thereof, a pharmaceutically acceptable salt thereof, or an optically active form of the salt thereof. In particular, the triphenylcalcilytic compound Formula (I): [ka] or a combination thereof. In certain embodiments, the compound of Formula (I) has the following formula: [ka] The compound is CLTX-305, which is expressed as

[0009] The compound of formula (I) or CLTX-305 may offer a therapeutic approach that individually targets the underlying pathogenesis of altered calcium homeostasis in ADH1 patients. In such patients, resetting the CaSR "set point" may normalize serum calcium with minimal oral supplementation requirements and without increasing the risk of iatrogenic chronic hypercalciuria.

[0010] Therefore, there is a need for the development of formulations containing compounds of formula (I), particularly CLTX-305, that can be administered orally for the treatment of ADH1. Summary of the Invention

[0011] The present disclosure provides calcium-sensing receptor antagonism, for example, formulations comprising the compounds of formula (I) provided herein. The present disclosure also provides methods for treating ADH1 using the formulations provided herein.

[0012] Thus, in a first aspect, the present disclosure provides a tablet formulation. The tablet formulation includes: a) Formula (I): [ka] a compound represented by the formula: b) one or more pharmaceutically acceptable excipients selected from one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof; wherein the compound is present in an amount of at least about 12% by weight on a salt-free and anhydrous basis.

[0013] In a second aspect, the present disclosure provides tablet formulations as a universal blend across all dosage strengths. This common combination tablet formulation includes: a) CLTX-305, which has the following formula: [ka] b) seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant; CLTX-305 is present at about 13% to about 30% by weight; The first excipient is mannitol; The second excipient is microcrystalline cellulose; The superplasticizer is colloidal silicon dioxide; Disintegrants include croscarmellose sodium; The surfactant is a sucrose fatty acid ester containing one or more sucrose palmitates; The binder is hydroxypropyl methylcellulose; Lubricants include magnesium stearate; The ratio of the compound weight to the total weight of seven or more pharmaceutically acceptable excipients is: Consistent across two or more dosage strengths.

[0014] In a third aspect, the disclosure provides a method for treating autosomal dominant hypocalcemia type 1 (ADH), comprising administering to a subject in need of treatment an effective amount of a tablet formulation provided herein, e.g., a tablet formulation comprising a compound of Formula (I), or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof (e.g., CLTX-305), and one or more pharmaceutically acceptable excipients present in at least about 12% by weight, on a salt-free and anhydrous basis, selected from one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the dissolution profiles of tablets containing 10 mg, 30 mg, and 60 mg of CLTX-305.

[0016] [Detailed Description of the Invention] I. General The present disclosure provides tablet formulations containing a triphenylcalcilytic compound of Formula (I), or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof (e.g., CLTX-305). The formulations may be co-blended formulations, in which the ratio of the compound to one or more excipients may be maintained constant across a range of dosage strengths. For example, in some embodiments, a formulation containing approximately 14.3% CLTX-305 may be successfully prepared as a tablet. Various dosage strengths (10 mg, 30 mg, and 60 mg of CLTX-305 per tablet) meet the stability and pharmacokinetic requirements necessary for an oral formulation. The tablet formulations provided herein may be well suited for oral administration to human and animal subjects alike for the treatment of autosomal dominant hypocalcemia type 1 (ADH1).

[0017] II. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Furthermore, any methods or materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. For purposes of this disclosure, the following terms are defined:

[0018] Tablet refers to a solid pharmaceutical formulation, with or without a coating. The term "tablet" also refers to a solid pharmaceutical formulation having one, two, three, or more layers, where each of the aforementioned types of tablets may have one or more coatings. In some embodiments, the tablets of the present disclosure can be prepared by roller compaction or other suitable means known in the art. The term "tablet" also includes minitablets, melt tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets. In some embodiments, the tablets provided herein comprise CLTX-305 and one or more pharmaceutically acceptable excipients selected from one or more excipients, one or more binders, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablets provided herein further comprise a coating. The amount of coating is not included in the calculation of the weight percent of a tablet formulation. That is, the weight percent reported herein is for the uncoated tablet.

[0019] "Pharmaceutically acceptable excipient" means a substance that aids in the administration and / or absorption of an active agent by a subject. Pharmaceutically acceptable excipients useful in the present disclosure include, but are not limited to, binders, fillers, glidants, disintegrants, surfactants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents.

[0020] "Administering" means therapeutically providing a formulation to a subject, such as by oral administration.

[0021] "Patient" or "subject" means a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition provided herein. Non-limiting examples include humans, non-human primates (e.g., monkeys), goats, pigs, sheep, cows, deer, horses, bovines, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, and other non-mammals. In some embodiments, the subject is a human.

[0022] A "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The precise amount will vary depending on the therapeutic objectives, safety, and response of the subject, and will be ascertained by a clinician, pharmacist, or the like. (See, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0023] "Treating," "treatment," and "therapy" refer to indicators of success in treating or ameliorating an injury, pathology, or disease, or a symptom thereof, and include objective or subjective parameters, such as relief, remission, alleviation of symptoms, or making the injury, pathology, or disease more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, or improving the patient's physical or mental health. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, assays (e.g., analysis of a subject's bodily fluids, such as blood, plasma, urine, etc.), imaging analysis, neuropsychiatric testing, and / or psychiatric evaluation.

[0024] "About" refers to a range of values ​​inclusive of the specified value that one of ordinary skill in the art would reasonably consider to be close to the specified value. In some embodiments, the term "about" refers to within a range of standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range of ±10% of the specified value. In some embodiments, about refers to the specified value.

[0025] "Salt" refers to an acid salt or a base salt of a compound of the present disclosure. Examples of pharmaceutically acceptable acid addition salts are salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid) and salts with organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid). Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0026] "Solvate" means a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0027] "Hydrate" refers to a compound provided herein or a salt thereof complexed with a water molecule. The compound or salt thereof of the present disclosure can be complexed with 1 / 2 water molecule or 1 to 10 water molecules.

[0028] Unless otherwise specified, the content of the compound of formula (I) in the tablet formulation is calculated based on the normalized weight of the compound of formula (I) on a salt-free, anhydrous basis, i.e., the content of salts and / or water in the compound of formula (I) is not included in the calculation.

[0029] III. Preparations The present disclosure provides a tablet formulation comprising: a) Formula (I): Formula (I) [ka] A compound represented by the formula: b) one or more pharmaceutically acceptable excipients selected from one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. The compound is present in an amount of at least about 12% by weight on a salt-free and anhydrous basis.

[0030] In some embodiments, the present disclosure provides tablet formulations as a common blend formulation across a range of dosage strengths. Common combination tablet formulations include: a) Formula (I): Formula (I) [ka] A compound represented by the formula: b) one or more pharmaceutically acceptable excipients selected from one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. wherein the compound is present in at least about 12% by weight on a salt-free and anhydrous basis, and the ratio of the weight of the compound to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0031] The compounds of formula (I) may exist in pharmaceutically acceptable salt, zwitterionic or neutral form, any of which may optionally exist in solvate or hydrate form.

[0032] In some embodiments, the pharmaceutically acceptable acid addition salt of the compound of Formula (I) is represented by Formula (Ia): Formula (Ia) [ka] wherein HX is a pharmaceutically acceptable acid additive.

[0033] Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, and phosphorous acid, as well as those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. In some embodiments, the compound of Formula (I) is present in the sulfate salt form. In some embodiments, the compound of Formula (I) is present in the hemisulfate salt form.

[0034] In some embodiments, the pharmaceutically acceptable base addition salt of the compound of Formula (I) is represented by Formula (Ib): Formula (Ib) [ka] wherein M is a pharmaceutically acceptable cation of a base.

[0035] A base addition salt can be obtained by contacting the neutral form of the compound of formula (I) with a sufficient amount of a desired base, either neat or in the presence of a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. In some embodiments, the compound of formula (I) is its sodium salt.

[0036] In some embodiments, the compound of Formula (I) exists in a zwitterionic form having the formula (Ic): Formula (Ic) [ka]

[0037] In some embodiments, the compound of Formula (I) exists in a neutral form.

[0038] In some embodiments, the compound of any one of Formulas (I), (Ia), (Ib), and (Ic) exists in solvate and / or hydrate form. In some embodiments, the compound of any one of Formulas (I), (Ia), (Ib), and (Ic) exists in hydrate form.

[0039] In some embodiments, the compound of formula (I) has the formula: [ka] CLTX-305 exists as a hemihydrate hemisulfate salt, represented by the formula:

[0040] The tablet formulations provided herein may be in one or more dosage strengths, and the compound of Formula (I) (e.g., CLTX-305) is present in an amount of at least about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or more, on a salt-free and anhydrous basis. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in each tablet in an amount of about 1 to about 1000 mg, about 1 to about 750 mg, about 1 to about 500 mg, about 1 to about 250 mg, about 50 to about 1000 mg, about 50 to about 750 mg, about 50 to about 500 mg, about 50 to about 250 mg, about 100 to about 1000 mg, about 100 to about 750 mg, about 100 to about 500 mg, or about 100 to about 250 mg, on a salt-free and anhydrous basis. g, about 200 to about 1000 mg, about 200 to about 750 mg, about 200 to about 500 mg, about 300 to about 1000 mg, about 300 to about 750 mg, about 300 to about 500 mg, about 400 to about 1000 mg, about 400 to about 750 mg, about 500 to about 1000 mg, about 500 to 750 mg, about 600 to about 1000 mg, about 5 to about 250 mg, or about 5 to 100 mg, or any suitable range therein. In some embodiments, the tablet formulation is present in two or more different dosage strengths. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, on an anhydrous basis. In some embodiments, the compound (e.g., CLTX-305) is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 700 mg, on an anhydrous basis.

[0041] The tablet formulations provided herein can be in one or more dosage strengths, and CLTX-305 is present in an amount of at least about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or more. In some embodiments, CLTX-305 is present in each tablet in an amount of about 1 to about 1000 mg, about 1 to about 750 mg, about 1 to about 500 mg, about 1 to about 250 mg, about 50 to about 1000 mg, about 50 to 750 mg, about 50 to 500 mg, about 50 to 250 mg, about 100 to about 1000 mg, about 100 to 750 mg, about 100 to about 500 mg, about 100 to 250 mg, or about 200 to about 1000 mg. In some embodiments, the tablet formulation is present in two or more different dosage strengths, such as about 200 to about 750 mg, about 200 to about 500 mg, about 300 to about 1000 mg, about 300 to about 750 mg, about 300 to about 500 mg, about 400 to about 1000 mg, about 400 to about 750 mg, about 500 to about 1000 mg, about 500 to 750 mg, about 600 to about 1000 mg, about 5 to about 250 mg, or about 5 to 100 mg, or any suitable range therein. In some embodiments, CLTX-305 is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 300 mg, about 360 mg, about 420 mg, about 480 mg, about 540 mg, about 600 mg, about 660 mg, or about 720 mg. In some embodiments, CLTX-305 is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0042] The tablet formulations of the present disclosure may be common blend formulations, and the ratio of the weight of the compound to the total weight of one or more pharmaceutically acceptable excipients is constant across multiple dosage strengths. In some embodiments, the ratio of the weight of the compound to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of the compound (e.g., CLTX-305) to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dosage strengths, and the compound of Formula (I) (e.g., CLTX-305) is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 700 mg, on a salt-free and anhydrous basis. In some embodiments, the ratio of the weight of the compound (e.g., CLTX-305) to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dosage strengths, and the compound is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0043] In some embodiments, the weight / weight ratio of the compound of Formula (I) (e.g., CLTX-305) to one or more pharmaceutically acceptable excipients is at least about 1:5, e.g., at least about 1:5, about 1:6, about 1:7, or more, e.g., at least 1:7.4, and the compound is on an anhydrous basis. In some embodiments, the weight / weight ratio of the compound of Formula (I) (e.g., CLTX-305) to one or more pharmaceutically acceptable excipients is from about 1:7.4 to about 1:2, and the compound is on an anhydrous basis. In some embodiments, the weight / weight ratio of the compound (e.g., CLTX-305) to one or more pharmaceutically acceptable excipients is about 1:7, and the compound is on an anhydrous basis. In some embodiments, the weight / weight ratio of the compound (e.g., CLTX-305) to one or more pharmaceutically acceptable excipients is about 1:7 across two or more dosage strengths, and the compound of Formula (I) is present in each tablet in an amount of about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 700 mg on a salt-free and anhydrous basis.

[0044] In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is at least about 1:6.5. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6.5 to about 1:2, e.g., about 1:3. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6 across two or more dosage strengths, and CLTX-305 is present in each tablet in an amount of about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0045] In some embodiments, the total weight of the solid dosage form (e.g., tablet) (e.g., active ingredient and excipients, excluding coating agents) is about 30 mg to 3000 mg. In some embodiments, the total weight of the solid dosage form (e.g., tablet) is about 70 mg, 210 mg, 420 mg, 700 mg, 1050 mg, 1400 mg, or 1750 mg. In some embodiments, the total weight of the solid dosage form (e.g., tablet) is about 70 mg, 210 mg, or 420 mg.

[0046] In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in the tablet formulation in an amount of at least about 12% by weight, based on the anhydrous salt. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in the tablet formulation in an amount of about 12% to about 32% by weight, based on the anhydrous salt. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in the tablet formulation in an amount of about 12% to about 30% by weight, about 12% to about 25% by weight, about 12% to about 20% by weight, or about 12% to about 15% by weight, based on the anhydrous salt. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in the tablet formulation in an amount of about 12% to about 15% by weight, based on the anhydrous salt. In some embodiments, the compound of Formula (I) (e.g., CLTX-305) is present in the tablet formulation at about 13% by weight on a salt-free and anhydrous basis.

[0047] In some embodiments, CLTX-305 is present in the tablet formulation at at least about 13% by weight. In some embodiments, CLTX-305 is present in the tablet formulation at about 13% to about 35% by weight. In some embodiments, CLTX-305 is present in the tablet formulation at about 13% to about 30% by weight, about 13% to about 25% by weight, about 13% to about 20% by weight, or about 13% to about 15% by weight. In some embodiments, CLTX-305 is present in the tablet formulation at about 13% to about 15% by weight. In some embodiments, CLTX-305 is present in the tablet formulation at about 14.3% by weight.

[0048] In some embodiments, the tablet formulation comprises at least two pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation comprises at least three pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation comprises at least four pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation comprises at least five pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation contains at least six pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation contains at least seven pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation contains at least eight pharmaceutically acceptable excipients selected from one or more excipients, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet formulation contains two excipients (i.e., a first excipient, a second excipient), one glidant, one disintegrant, one surfactant, one binder, and one lubricant.

[0049] In some embodiments, the tablet formulation includes one or more excipients. In some embodiments, the tablet formulation includes two or more excipients. Suitable excipients are described herein. In some embodiments, the one or more excipients are present in the tablet formulation at about 15% to about 70% by weight, about 20% to about 70% by weight, about 30% to about 70% by weight, about 40% to about 70% by weight, about 50% to about 70% by weight, about 40% to about 60% by weight, or about 50% to about 60% by weight. In some embodiments, the one or more excipients are present in the tablet formulation at about 40% to about 70% by weight, about 50% to about 70% by weight, about 40% to about 60% by weight, or about 50% to about 60% by weight. In some embodiments, the one or more excipients are present in the tablet formulation at about 50% to about 60% by weight. In some embodiments, the one or more excipients are present at about 55.2% by weight.

[0050] In some embodiments, the tablet formulation includes one to three excipients. In some embodiments, the tablet formulation includes one to two excipients. In some embodiments, the tablet formulation includes two to three excipients. In some embodiments, the tablet formulation includes two excipients (i.e., a first excipient, a second excipient).

[0051] Suitable excipients include oligosaccharides (e.g., lactose), sugars, starches, modified starches, sugar alcohols (e.g., mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, cellulose), calcium sulfate, aluminum silicate, and magnesium silicate complexes and oxides. Examples of inorganic salt excipients include phosphates, such as calcium hydrogen phosphate, and sulfates. In some embodiments, one or more excipients include a sugar, a sugar alcohol, a cellulose derivative, or a combination thereof. In some embodiments, one or more excipients include a sugar alcohol, a cellulose derivative, or a combination thereof. In some embodiments, one or more excipients are mannitol, sorbitol, xylitol, lactitol, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof. In some embodiments, one or more excipients include mannitol and microcrystalline cellulose. In some embodiments, a first excipient includes a sugar alcohol, and a second excipient includes a cellulose derivative. In some embodiments, the first excipient is mannitol and the second excipient is microcrystalline cellulose. In some embodiments, the first excipient is mannitol and the second excipient is microcrystalline cellulose, and the ratio of mannitol to microcrystalline cellulose is 5 or less. In some embodiments, the first excipient is mannitol and the second excipient is microcrystalline cellulose, and the ratio of mannitol to microcrystalline cellulose is 3 or less. In some embodiments, the first excipient is mannitol and the second excipient is microcrystalline cellulose, and the ratio of mannitol to microcrystalline cellulose is about 2.5.

[0052] In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 15% to about 70% by weight, about 20% to about 70% by weight, about 30% to about 70% by weight, about 40% to about 70% by weight, about 40% to about 60% by weight, about 50% to about 70% by weight, or about 50% to about 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 40% to about 70% by weight, about 40% to about 60% by weight, about 50% to about 70% by weight, or about 50% to about 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 50% to about 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 55.2% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 55.2% by weight, and the ratio of mannitol to microcrystalline cellulose is about 3.0 or less. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 55.2% by weight, and the ratio of mannitol to microcrystalline cellulose is about 2.5. In some embodiments, mannitol is present in the tablet formulation at about 10% to about 60% by weight, about 20% to about 60% by weight, about 30% to about 60% by weight, or about 30% to about 50% by weight. In some embodiments, mannitol is present in the tablet formulation at about 30% to about 50% by weight. In some embodiments, mannitol is present in the tablet formulation at about 39.5% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at about 10% to about 25% by weight, or about 10% to about 20% by weight. In some embodiments, the microcrystalline cellulose is present in the tablet formulation at about 10% to about 25% by weight, or about 10% to about 20% by weight. In some embodiments, the microcrystalline cellulose is present in the tablet formulation at about 10% to about 20% by weight. In some embodiments, the microcrystalline cellulose is present in the tablet formulation at about 15.7% by weight.

[0053] In some embodiments, the tablet formulation includes one or more glidants. Suitable glidants are described below. In some embodiments, the one or more glidants are present in the tablet formulation at about 0.1% to about 5% by weight, about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, or about 2% to about 4% by weight. In some embodiments, the one or more glidants are present in the tablet formulation at about 1% to about 5% by weight, about 1% to about 4% by weight, or about 2% to about 4% by weight. In some embodiments, the one or more glidants are present in the tablet formulation at about 2% to about 4% by weight. In some embodiments, the one or more glidants are present in the tablet formulation at about 3% by weight.

[0054] In some embodiments, the tablet formulation includes one or two glidants. In some embodiments, the tablet formulation includes one glidant.

[0055] Suitable glidants include, for example, magnesium carbonate, fumed silica (colloidal silicon dioxide), and talc. In some embodiments, one or more glidants are silicon dioxide, talc, magnesium carbonate, or a combination thereof. In some embodiments, one or more glidants include colloidal silicon dioxide. In some embodiments, the tablet formulation includes one glidant, and the one glidant is colloidal silicon dioxide.

[0056] In some embodiments, the colloidal silicon dioxide is present in the tablet formulation at about 0.1% to about 5% by weight, about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, or about 2% to about 4% by weight. In some embodiments, the colloidal silicon dioxide is present in the tablet formulation at about 1% to about 5% by weight, about 1% to about 4% by weight, or about 2% to about 4% by weight. In some embodiments, the colloidal silicon dioxide is present in the tablet formulation at about 2% to about 4% by weight. In some embodiments, the colloidal silicon dioxide is present in the tablet formulation at about 3% by weight.

[0057] In some embodiments, the tablet formulation includes one or more disintegrants. Suitable disintegrants are described below. In some embodiments, the one or more disintegrants are present in the tablet formulation at about 1% to about 30% by weight, about 5% to about 30% by weight, about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight. In some embodiments, the one or more disintegrants are present in the tablet formulation at about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight. In some embodiments, the one or more disintegrants are present in the tablet formulation at about 15% to about 25% by weight. In some embodiments, the one or more disintegrants are present in the tablet formulation at about 20% by weight.

[0058] When wet granulation is used, in some embodiments, a portion of one or more disintegrants is added during granulation so that the disintegrant remains within the granules (i.e., intragranular). The remaining portion of the one or more disintegrants is then added to the final blend so that the disintegrant is present outside the granules (i.e., extragranular). In some embodiments, one or more disintegrants are present intragranularly, extragranularly, or a combination thereof. In some embodiments, one or more disintegrants are present both intragranularly and extragranularly. In some embodiments, one or more disintegrants are present in the tablet formulation at about 1% to about 15% by weight intragranularly. In some embodiments, one or more disintegrants are present in the tablet formulation at about 10.0% by weight intragranularly. In some embodiments, one or more disintegrants are present in the tablet formulation at about 1% to about 15% by weight extragranularly. In some embodiments, one or more disintegrants are present in the tablet formulation at about 10.0% by weight extragranularly.

[0059] In some embodiments, the tablet formulation contains 1 to 2 disintegrants. In some embodiments, the tablet formulation contains 1 disintegrant.

[0060] Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, sodium starch glycolate, and cornstarch. In some embodiments, one or more disintegrants include croscarmellose sodium. In some embodiments, the tablet formulation contains one disintegrant, and the one disintegrant is croscarmellose sodium.

[0061] In some embodiments, croscarmellose sodium is present in the tablet formulation at about 1% to about 30% by weight, about 5% to about 30% by weight, about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at about 20.0% by weight. In some embodiments, croscarmellose sodium is present intragranularly, extragranularly, or a combination thereof. In some embodiments, croscarmellose sodium is present both intragranularly and extragranularly. In some embodiments, croscarmellose sodium is present intragranularly in the tablet formulation at about 1% to about 15% by weight. In some embodiments, croscarmellose sodium is present intragranularly in the tablet formulation at about 10.0% by weight. In some embodiments, croscarmellose sodium is present extragranularly in the tablet formulation at about 1% to about 15% by weight. In some embodiments, croscarmellose sodium is present extragranularly in the tablet formulation at about 10.0% by weight.

[0062] In some embodiments, the tablet formulation includes one or more surfactants. Suitable surfactants are described below. In some embodiments, the one or more surfactants are present in the tablet formulation at about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, or about 1% to about 3% by weight. In some embodiments, the one or more surfactants are present in the tablet formulation at about 1% to about 5% by weight, about 1% to about 4% by weight, or about 1% to about 3% by weight. In some embodiments, the one or more surfactants are present in the tablet formulation at about 1% to about 3% by weight. In some embodiments, the one or more surfactants are present in the tablet formulation at about 2.0% by weight.

[0063] In some embodiments, the tablet formulation comprises one or two surfactants. In some embodiments, the tablet formulation comprises one surfactant.

[0064] Surfactants that can be used in the present disclosure include, but are not limited to, nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, ampholytic surfactants, fatty alcohols, fatty acids, and salts of fatty acids. In some embodiments, one or more surfactants comprise a nonionic surfactant. Suitable nonionic surfactants include polyol esters (sucrose, glycol, glycerol, sorbitan fatty acid esters), polyoxyethylene esters, and poloxamers. In some embodiments, one or more surfactants comprise a polyol fatty acid ester. In some embodiments, one or more surfactants are sucrose fatty acid esters, glycol fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters, or combinations thereof. In some embodiments, one or more surfactants are one or more sucrose fatty acid esters. In some embodiments, one or more surfactants are one or more sucrose fatty acid esters including sucrose palmitate. In some embodiments, the tablet formulation comprises one surfactant, and the one surfactant is one or more sucrose fatty acid esters including sucrose palmitate.

[0065] In some embodiments, the one or more sucrose fatty acid esters are present in the tablet formulation at about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, or about 1% to about 3% by weight. In some embodiments, the one or more sucrose fatty acid esters are present in the tablet formulation at about 1% to about 3% by weight. In some embodiments, the one or more sucrose fatty acid esters are present in the tablet formulation at about 2.0% by weight.

[0066] In some embodiments, the tablet formulation includes one or more binders. Suitable binders are described below. In some embodiments, the one or more binders are present in the tablet formulation at about 1% to about 5%, about 2% to about 5%, or about 3% to about 5% by weight. In some embodiments, the one or more binders are present in the tablet formulation at about 3% to about 5% by weight. In some embodiments, the one or more binders are present in the tablet formulation at about 4.0% by weight.

[0067] In some embodiments, the tablet formulation includes 1 to 2 binders. In some embodiments, the tablet formulation includes 1 binder.

[0068] Suitable binders include, for example, povidone, lactose, starch, modified starch, sugars, gum acacia, tragacanth gum, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone, gelatin, sodium alginate, etc. In some embodiments, one or more binders are cellulose binders. In some embodiments, one or more binders are methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or combinations thereof. In some embodiments, one or more binders include hydroxypropylmethylcellulose. In some embodiments, the tablet formulation includes one binder, and the one binder is hydroxypropylmethylcellulose.

[0069] In some embodiments, the hydroxypropyl methylcellulose is present in the tablet formulation at about 1% to about 5%, about 2% to about 5%, or about 3% to about 5% by weight. In some embodiments, the hydroxypropyl methylcellulose is present in the tablet formulation at about 3% to about 5% by weight. In some embodiments, the hydroxypropyl methylcellulose is present in the tablet formulation at about 4.0% by weight.

[0070] In some embodiments, the tablet formulation includes one or more lubricants. Suitable lubricants are described below. In some embodiments, the one or more lubricants are present in the tablet formulation at about 0.2% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, or about 1% to about 2% by weight. In some embodiments, the one or more lubricants are present in the tablet formulation at about 1% to about 3% by weight, or about 1% to about 2% by weight. In some embodiments, the one or more lubricants are present in the tablet formulation at about 1% to about 2% by weight. In some embodiments, the one or more lubricants are present in the tablet formulation at about 1.5% by weight.

[0071] In some embodiments, the tablet formulation contains 1 to 2 lubricants. In some embodiments, the tablet formulation contains 1 lubricant.

[0072] Suitable lubricants include, for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, ethyl oleate, ethyl laurate, stearic acid, palmitic acid, sodium lauryl sulfate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, and polyethylene glycol. In some embodiments, one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, ethyl oleate, ethyl laurate, stearic acid, palmitic acid, sodium lauryl sulfate, or a combination thereof. In some embodiments, one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, sodium lauryl sulfate, or a combination thereof. In some embodiments, one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof. In some embodiments, one or more lubricants include magnesium stearate. In some embodiments, the tablet formulation includes one lubricant, and the one lubricant is magnesium stearate.

[0073] In some embodiments, magnesium stearate is present in the tablet formulation at about 0.2% to about 5% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, or about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at about 1% to about 3% by weight, or about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at about 1.5% by weight.

[0074] In some embodiments, one or more lubricants are present in the tablet formulation. In some embodiments, magnesium stearate is present in the tablet formulation. In some embodiments, magnesium stearate is present in the tablet formulation at about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at about 1.5% by weight.

[0075] Other suitable excipients, glidants, disintegrants, surfactants, binders, lubricants and other pharmaceutical additives that may be used are described in Handbook of Pharmaceutical Excipients, 5th Edition, 2006, American Lachman, Leon; Pharmaceutical Dosage Forms: Tablets Volume 1, 3rd Edition, 2008, Lieberman, Herbert A., et al.; Modern Pharmaceutics, 4th Edition, 2002, Banker, Gilbert and Rhodes, Christopher T; and Remington's Pharmaceutical Sciences, 23rd Edition, 2020, each of which is incorporated by reference in its entirety.

[0076] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) two or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0077] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Three or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0078] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Four or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0079] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Five or more pharmaceutically acceptable excipients selected from the group consisting of primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders, and lubricants. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0080] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) six or more pharmaceutically acceptable excipients selected from the group consisting of primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders, and lubricants. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0081] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. the first excipient is mannitol, sorbitol, xylitol, lactitol, or a combination thereof; the second excipient is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof; the fluidizing agent is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrating agent is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or a combination thereof; the surfactant is one or more sucrose fatty acid esters, one or more glycol fatty acid esters, one or more glycerol fatty acid esters, one or more sorbitan fatty acid esters, or a combination thereof; the binder is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or a combination thereof; and the lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof.

[0082] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) two or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0083] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Three or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0084] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Four or more pharmaceutically acceptable excipients selected from the group consisting of a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0085] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Five or more pharmaceutically acceptable excipients selected from the group consisting of primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders, and lubricants. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0086] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) six or more pharmaceutically acceptable excipients selected from the group consisting of primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders, and lubricants. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0087] In some embodiments, the tablet formulation comprises: a) about 13% to about 35% by weight of CLTX-305, and b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrating agent is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0088] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 40% by weight to about 70% by weight of the first excipient and the second excipient c) about 1% by weight to about 5% by weight of a superplasticizer d) about 10% by weight to about 30% by weight of a disintegrant e) about 1% by weight to about 5% by weight of a surfactant f) about 1% to about 5% by weight of a binder, and g) about 1% to about 3% by weight of a lubricant The total weight of the components a) to g) is 100%.

[0089] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 40% by weight to about 70% by weight of the first excipient and the second excipient c) about 1% to about 4% by weight of a superplasticizer d) about 15% to about 30% by weight of a disintegrant e) about 1% by weight to about 4% by weight of a surfactant f) about 2% to about 5% by weight of a binder, and g) about 1% to about 3% by weight of a lubricant The total weight of the components a) to g) is 100%.

[0090] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 45% by weight to about 65% by weight of the first excipient and the second excipient c) about 2% to about 4% by weight of a superplasticizer d) about 15% to about 25% by weight of a disintegrant e) about 1% by weight to about 3% by weight of a surfactant f) about 3% to about 5% by weight of a binder, and g) about 1% to about 2% by weight of a lubricant The total weight of the components a) to g) is 100%.

[0091] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% by weight to about 60% by weight of a first excipient c) about 10% by weight to about 30% by weight of a second excipient d) about 1% to about 5% by weight of a superplasticizer e) about 10% by weight to about 30% by weight of a disintegrant f) about 1% by weight to about 5% by weight of a surfactant g) about 1% to about 10% by weight of a binder, and h) about 1% by weight to about 3% by weight of a lubricant The total weight of the components a) to h) is 100%.

[0092] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% by weight to about 50% by weight of a first excipient c) about 10% to about 20% by weight of a second excipient d) about 2% to about 4% by weight of a superplasticizer e) about 15% to about 25% by weight of a disintegrant f) about 1% by weight to about 3% by weight of a surfactant g) about 3% to about 5% by weight of a binder, and h) about 1% by weight to about 2% by weight of a lubricant The total weight of the components a) to h) is 100%.

[0093] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% by weight to about 50% by weight of a first excipient c) about 10% to about 20% by weight of a second excipient d) about 2% to about 4% by weight of a superplasticizer e) about 5% by weight to about 15% by weight of a granular intradisintegrant f) about 5% to about 15% by weight of an extragranular disintegrant g) about 1% by weight to about 3% by weight of a surfactant h) about 3% to about 5% by weight of a binder, and i) about 1% to about 2% by weight of a lubricant The total weight of the components a) to i) is 100%.

[0094] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% to about 50% by weight of a first excipient selected from the group consisting of mannitol, sorbitol, xylitol, and lactitol; c) about 10% to about 20% by weight of a second excipient selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose. d) about 2% to about 4% by weight of a fluidizing agent selected from the group consisting of silicon dioxide, talc, and magnesium carbonate. e) about 15% to about 25% by weight of a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and cornstarch. f) about 1% to about 3% by weight of a surfactant selected from the group consisting of sucrose fatty acid esters, glycol fatty acid esters, glycerol fatty acid esters, and sorbitan fatty acid esters g) about 3% to about 5% by weight of a binder selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and h) about 1% to about 2% by weight of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearyl fumarate The total weight of the components a) to h) is 100%.

[0095] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% to about 50% by weight of a first excipient selected from the group consisting of mannitol, sorbitol, xylitol, and lactitol; c) about 10% to about 20% by weight of a second excipient selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose. d) about 2% to about 4% by weight of a fluidizing agent selected from the group consisting of silicon dioxide, talc, and magnesium carbonate. e) about 5% to about 15% by weight of a first disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and cornstarch, wherein the first disintegrant is present within the granules. f) about 5% to about 15% by weight of a second ingredient selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and cornstarch. In the disintegrant, the second disintegrant is present extragranularly. g) about 1% to about 3% by weight of a surfactant selected from the group consisting of sucrose fatty acid esters, glycol fatty acid esters, glycerol fatty acid esters, and sorbitan fatty acid esters h) about 3% to about 5% by weight of a binder selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and i) about 1% to about 2% by weight of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearyl fumarate The total weight of the components a) to i) is 100%.

[0096] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% to about 50% by weight of mannitol c) about 10% to about 20% by weight of microcrystalline cellulose d) about 2% to about 4% by weight of colloidal silicon dioxide e) about 15% to about 25% by weight of croscarmellose sodium f) one or more sucrose fatty acid esters containing about 1% to about 3% by weight of sucrose palmitate g) about 3% to about 5% by weight of hydroxypropyl methylcellulose, and h) about 1% to about 2% by weight of magnesium stearate The total weight of the components a) to h) is 100%.

[0097] In some embodiments, the tablet formulation comprises: a) about 13% to about 15% by weight of CLTX-305 b) about 30% to about 50% by weight of mannitol c) about 10% to about 20% by weight of microcrystalline cellulose d) about 2% to about 4% by weight of colloidal silicon dioxide e) about 5% to about 15% by weight of granular croscarmellose sodium f) about 5% to about 15% by weight of extragranular croscarmellose sodium g) one or more sucrose fatty acid esters containing about 1% to about 3% by weight of sucrose palmitate h) about 3% to about 5% by weight of hydroxypropyl methylcellulose, and i) about 1% to about 2% by weight of magnesium stearate The total weight of the components a) to i) is 100%.

[0098] In some embodiments, the tablet formulation comprises: a) about 14.3% by weight of CLTX-305 b) about 39.5% by weight of mannitol c) about 15.7% by weight of microcrystalline cellulose d) about 3.0% by weight of colloidal silicon dioxide e) about 20.0% by weight of croscarmellose sodium f) one or more sucrose fatty acid esters containing about 2.0% by weight of sucrose palmitate g) about 4.0% by weight of hydroxypropyl methylcellulose, and h) about 1.5% by weight of magnesium stearate The total weight of the components a) to h) is 100%.

[0099] In some embodiments, the tablet formulation comprises: a) about 14.3% by weight of CLTX-305 b) about 39.5% by weight of mannitol c) about 15.7% by weight of microcrystalline cellulose d) about 3.0% by weight of colloidal silicon dioxide e) about 10.0% by weight of granular croscarmellose sodium f) about 10.0% by weight of extragranular croscarmellose sodium g) one or more sucrose fatty acid esters containing about 2.0% by weight of sucrose palmitate h) about 4.0% by weight of hydroxypropyl methylcellulose, and i) about 1.5% by weight of magnesium stearate The total weight of the components a) to i) is 100%.

[0100] In some embodiments of any one of the formulations described above, the tablet formulation is a common blend formulation, and the ratio of the weight of CLTX-305 to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of two or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of three or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of four or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of five or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of six or more pharmaceutically acceptable excipients is constant across two or more dosage strengths. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of seven or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0101] In another aspect, the present disclosure provides a tablet formulation as a common blend formulation across two or more dosage strengths, the common blend formulation comprising: a) CLTX-305, which has the following formula: [ka] b) Seven or more pharmaceutically acceptable excipients, including primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders and lubricants. and CLTX-305 is present at about 13% to about 30% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate; and the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0102] In some embodiments, the common co-formulation comprises: a) CLTX-305, which has the following formula: [ka] b) Seven or more pharmaceutically acceptable excipients, including primary excipients, secondary excipients, glidants, disintegrants, surfactants, binders and lubricants. and CLTX-305 is present at about 13% to about 15% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate; and the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0103] In some embodiments of the common combination formulation, the tablet formulations are in two or more dosage strengths, and CLTX-305 is present in each tablet in an amount of about 5 to about 1000 mg. In some embodiments, CLTX-305 is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0104] In some embodiments of the common combined formulation, the ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6.5 to about 1:5 by weight. In some embodiments, the ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6 by weight. In some embodiments, the ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6 by weight in all three dosage strengths. CLTX-305 is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0105] In some embodiments of the common mixed formulation, the ratio of mannitol to microcrystalline cellulose is about 3 or less. In some embodiments of the common mixed formulation, mannitol and microcrystalline cellulose are present in the tablet formulation at about 40% to about 70% by weight, about 40% to about 60% by weight, about 50% to about 70% by weight, or about 50% to about 60% by weight, and the ratio of mannitol to microcrystalline cellulose is about 3 or less. In some embodiments of the common mixed formulation, mannitol and microcrystalline cellulose are present in the tablet formulation at about 50% to about 60% by weight, and the ratio of mannitol to microcrystalline cellulose is about 3 or less. In some embodiments, mannitol and microcrystalline cellulose are present in the tablet formulation at about 55.2% by weight, and the ratio of mannitol to microcrystalline cellulose is about 2.5. In some embodiments, mannitol is present in the tablet formulation at about 20% to about 60% by weight, about 30% to about 60% by weight, or about 30% to about 50% by weight. In some embodiments, mannitol is present in the tablet formulation at about 30% to about 50% by weight. In some embodiments, mannitol is present in the tablet formulation at about 39.5% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at about 10% to about 25% by weight, or about 10% to about 20% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at about 10% to about 20% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at about 15.7% by weight.

[0106] In some embodiments of the common blend formulation, the colloidal silicon dioxide is present in the tablet formulation at about 2% to about 4% by weight, hi some embodiments, the colloidal silicon dioxide is present in the tablet formulation at about 3.0% by weight.

[0107] In some embodiments of the common blend formulation, croscarmellose sodium is present in the tablet formulation at about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at about 20% by weight. In some embodiments, croscarmellose sodium is present intragranularly, extragranularly, or a combination thereof. In some embodiments, croscarmellose sodium is present both intragranularly and extragranularly. In some embodiments, croscarmellose sodium is present intragranularly at about 5% to about 15% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present intragranularly at about 10.0% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present extragranularly at about 5% to about 15% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present extragranularly at about 10.0% by weight in the tablet formulation.

[0108] In some embodiments of the common blend formulation, the one or more sucrose fatty acid esters are present in the tablet formulation at about 1% to about 3% by weight, hi some embodiments, the one or more sucrose fatty acid esters are present in the tablet formulation at about 2.0% by weight.

[0109] In some embodiments of the common blend formulation, hydroxypropyl methylcellulose is present in the tablet formulation at about 3% to about 5% by weight, hi some embodiments, hydroxypropyl methylcellulose is present in the tablet formulation at about 4.0% by weight.

[0110] In some embodiments of the common blend formulation, magnesium stearate is present extragranularly at about 1% to about 2% by weight in the tablet formulation. In some embodiments, magnesium stearate is present extragranularly at about 1% to about 2% by weight in the tablet formulation. In some embodiments, magnesium stearate is present extragranularly at about 1.5% by weight in the tablet formulation.

[0111] In some embodiments of the common combination formulation, the tablet formulation includes: a) CLTX-305, which has the following formula: [ka] b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and CLTX-305 is present at about 14.3% by weight, the first excipient is mannitol and is present at about 39.5% by weight, the second excipient is microcrystalline cellulose and is present at about 15.7% by weight, the glidant is colloidal silicon dioxide and is present at about 3.0% by weight, the disintegrant is croscarmellose sodium and is present intragranularly at about 10.0% by weight and extragranularly at about 10.0% by weight, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate and is present at about 2.0% by weight, the binder is hydroxypropyl methylcellulose and is present at about 4.0% by weight, and the lubricant is magnesium stearate and is present at about 1.5% by weight.

[0112] In some embodiments of any one of the formulations described herein, the tablet is coated with a coating. Suitable coatings include hypromellose, polyvinylacetone, ethylcellulose, and polymethacrylate, as well as coatings such as those sold by OPADRY®. In some embodiments, the coating is Opadry White Coating System, Opadry coating system 03B680008 or equivalent, Opadry Clear, Opadry Blue 13B50579, Opadrya QX 321A180025, or Opadry II (33G28707). In some embodiments, the coating is Opadry White Coating System. In some embodiments, the coating is Opadry White Coating System, which includes hydroxypropyl methylcellulose, titanium dioxide, and macrogol / PEG (molecular weight 400). In some embodiments, the coating is Opadry coating system 03B680008 or equivalent. For purposes of calculating the percent weight of the tablet formulation, the amount of coating is not included in the calculation, i.e., the percent weight reported herein is of the uncoated tablet.

[0113] In some embodiments of any one of the formulations described herein, the tablet has a solubility of at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 10 mg of CLTX-305 has a solubility of at least about 90% or at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 10 mg of CLTX-305 has a solubility of at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 30 mg of CLTX-305 has a solubility of at least about 90% or at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 30 mg of CLTX-305 has a solubility of at least about 90% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 60 mg of CLTX-305 has a solubility of at least about 80%, at least about 85%, or at least about 90% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 60 mg of CLTX-305 has a solubility of at least about 85% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablet containing about 60 mg of CLTX-305 has a solubility of at least about 90% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0114] In some embodiments of any one of the formulations described herein, the tablet has a maximum dissolution of nearly 100% after about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments of any one of the formulations described herein, the tablet has a maximum dissolution of about 95% after about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments, the tablet containing about 10 mg of CLTX-305 has a maximum dissolution of about 95% after about 20 minutes or about 30 minutes. In some embodiments, the tablet containing about 10 mg of CLTX-305 has a maximum dissolution of about 95% after about 20 minutes. In some embodiments, the tablet containing about 30 mg of CLTX-305 has a maximum dissolution of about 95% after about 20 minutes or about 30 minutes. In some embodiments, the tablet containing about 30 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 20 minutes. In some embodiments, the tablet containing about 30 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 30 minutes. In some embodiments, the tablet containing about 60 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments, the tablet containing about 60 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 20 minutes. In some embodiments, the tablet containing about 60 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 30 minutes. In some embodiments, the tablet containing about 60 mg of CLTX-305 has a maximum dissolution rate of about 95% after about 45 minutes. In some embodiments, the tablet containing about 60 mg of CLTX-305 has a maximum dissolution of about 95% after about 60 minutes.

[0115] The tablet formulations of the present disclosure exhibit good stability under storage conditions of either 25°C / 60% relative humidity (RH) or 40°C / 75% relative humidity, during which no significant changes in impurities, assay (content of compound of Formula (I)), dissolution, or tablet appearance are observed. In some embodiments, the tablets are stable at a temperature of about 40°C and about 75% relative humidity for a period of about 6 months or longer. In some embodiments, the tablets are stable at a temperature of about 25°C and about 60% relative humidity for a period of about 9 months or longer. In some embodiments, the tablets are stable at a temperature of about 25°C and about 60% relative humidity for a period of about 1 year or longer. In some embodiments, the tablets are stable at a temperature of about 25°C and about 60% relative humidity for a period of about 2 years or longer. In some embodiments, the tablets are stable at a temperature of about 25°C and about 60% relative humidity for a period of about 3 years or longer.

[0116] In some embodiments, a tablet containing about 10 mg of CLTX-305 is stable at about 40°C and about 75% relative humidity for a period of about 6 months or more, during which the content of the compound of Formula (I) changes by less than about 2%, about 1%, or about 0.5% compared to the initial content. The tablet's dissolution reaches at least about 90% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 10 mg of CLTX-305 is stable at about 40°C and about 75% relative humidity for a period of about 6 months or more, during which the content of the compound of Formula (I) changes by less than about 0.5% compared to the initial content. The tablet's dissolution reaches at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 30 mg of CLTX-305 is stable at about 40°C and about 75% relative humidity for a period of about 6 months or more, during which the content of the compound of Formula (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content. The tablet's dissolution reaches at least about 75% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 30 mg of CLTX-305 is stable at about 40°C and about 75% relative humidity for a period of about 6 months or more, during which the content of the compound of Formula (I) changes by less than about 1% compared to the initial content. The tablet's dissolution reaches at least about 80% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 60 mg of CLTX-305 is stable at about 40°C and about 75% relative humidity for a period of about 6 months or more, during which the compound of Formula (I) content changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content, and the tablet dissolution reaches at least about 75% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).In some embodiments, a tablet containing about 60 mg of CLTX-305 is stable for about 6 months or more at about 40° C. and about 75% relative humidity, during which the content of the compound of Formula (I) changes by less than about 3% compared to the initial content, and the dissolution of the tablet reaches at least about 80% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0117] In some embodiments, a tablet containing about 10 mg of CLTX-305 is stable at about 25°C and about 60% relative humidity for a period of about 9 months or more, during which the content of the compound of Formula (I) changes by less than about 2%, about 1%, or about 0.5% compared to the initial content. The tablet's dissolution reaches at least about 90% after about 60 minutes in a buffer solution at pH 6.8 containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 10 mg of CLTX-305 is stable at about 25°C and about 60% relative humidity for a period of about 9 months or more, during which the content of the compound of Formula (I) changes by less than about 0.5% compared to the initial content. The tablet's dissolution reaches at least about 95% after about 60 minutes in a buffer solution at pH 6.8 containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 30 mg of CLTX-305 is stable at about 25°C and about 60% relative humidity for a period of about 9 months or more, during which the content of the compound of Formula (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content. The tablet's dissolution reaches at least about 75% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 30 mg of CLTX-305 is stable at about 25°C and about 60% relative humidity for a period of about 9 months or more, during which the content of the compound of Formula (I) changes by less than about 1% compared to the initial content. The tablet's dissolution reaches at least about 80% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, a tablet containing about 60 mg of CLTX-305 is stable at about 25°C and about 60% relative humidity for a period of about 6 months or more, during which the content of the compound of Formula (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content, and the dissolution of the tablet reaches at least about 75% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).In some embodiments, a tablet containing about 60 mg of CLTX-305 is stable at about 25° C. and about 60% relative humidity for a period of about 9 months or more, during which the content of the compound of Formula (I) changes by less than about 3% compared to the initial content, and the dissolution of the tablet reaches at least about 80% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0118] method In a third aspect, the present disclosure provides a method for treating autosomal dominant hypocalcemia (ADH, e.g., autosomal dominant hypocalcemia type 1 (ADH1)). The method includes administering to a subject in need thereof an effective amount of a tablet formulation including a compound of Formula (I), solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, and one or more pharmaceutically acceptable excipients selected from one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof, wherein the compound of Formula (I) is present in at least about 12% by weight on a salt-free and anhydrous basis.

[0119] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of the tablet formulation comprising: a) CLTX-305, which has the following formula: [ka] b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and CLTX-305 is present at about 13% to about 30% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate; and the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0120] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of the tablet formulation comprising: a) CLTX-305, which has the following formula: [ka] b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and CLTX-305 is present at about 13% to about 15% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizing agent is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate; and the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant across two or more dosage strengths.

[0121] In some embodiments, the ADH is autosomal dominant hypocalcemia type 1 (ADH1).

[0122] In some embodiments, the subject has hypocalcemia, hyperphosphatemia, and / or hypercalciuria. In some embodiments, the subject has hypocalcemia. In some embodiments, the subject has hyperphosphatemia. In some embodiments, the subject has hypercalciuria. In some embodiments, the subject has hypocalcemia and hypercalciuria. In some embodiments, the subject has hypocalcemia, hyperphosphatemia, and hypercalciuria. In some embodiments, the subject has previously been diagnosed with ADH1. In some embodiments, the subject has previously been treated for ADH1.

[0123] In some embodiments, the tablet formulation comprising a compound of formula (I) is administered orally.

[0124] In some embodiments, the method comprises administering to a subject in need of treatment an effective amount of the tablet formulation comprising: a) CLTX-305 and b) Seven or more pharmaceutically acceptable excipients, including a first excipient, a second excipient, a glidant, a disintegrant, a surfactant, a binder, and a lubricant. and CLTX-305 is present at about 14.3% by weight, the first excipient is mannitol and is present at about 39.5% by weight, the second excipient is microcrystalline cellulose and is present at about 15.7% by weight, the glidant is colloidal silicon dioxide and is present at about 3.0% by weight, the disintegrant is croscarmellose sodium and is present intragranularly at about 10.0% by weight and extragranularly at about 10.0% by weight, the surfactant is one or more sucrose fatty acid esters including sucrose palmitate and is present at about 2.0% by weight, the binder is hydroxypropyl methylcellulose and is present at about 4.0% by weight, and the lubricant is magnesium stearate and is present at about 1.5% by weight.

[0125] In some embodiments, the tablet formulation is a tablet of about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg, and CLTX-305 is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0126] In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) increases blood calcium levels (cCa) relative to the normal range. In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) alleviates symptoms associated with hypocalcemia.

[0127] In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) increases intact parathyroid hormone (iPTH) in the blood relative to the normal range.

[0128] In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) reduces high urinary calcium levels. In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) increases urinary calcium clearance. In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) minimizes the severity of hypercalciuria.

[0129] In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) reduces blood phosphate levels to the normal range. In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) minimizes the degree of hyperphosphatemia.

[0130] In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) increases blood magnesium levels to the normal range. In some embodiments, an effective amount of the tablet formulation comprising a compound of Formula (I) (e.g., CLTX-305) minimizes the severity of hypomagnesemia.

[0131] Therapeutic methods of the present disclosure can be administered alone or in combination with other forms of drug therapy, such as a second compound with calcium-sensing receptor antagonist activity, a vitamin D supplement, and / or a calcium supplement. In some embodiments, the method further comprises administering an oral calcium supplement. In some embodiments, "in combination with" means that the tablet formulation of the present disclosure and the other pharmaceutical agent are administered to a subject as part of a treatment regimen or plan. In some embodiments, used in combination does not require that the tablet formulation of the present disclosure and the other pharmaceutical agent be physically mixed prior to administration or that they be administered over the same time frame.

[0132] V. Working Examples Analysis procedure The analytical methods used to test the 10 mg, 30 mg, and 60 mg tablets were identical. A summary of the analytical procedures is provided below.

[0133] exterior : Visual evaluation of the tablet formulation was performed by appearance test.

[0134] Identification, analysis, and content uniformity by HPLC The identity, assay, and content uniformity of this tablet formulation were determined by a gradient reverse-phase HPLC method. The method uses a C18 column gradient eluted with a mobile phase of 0.1% (volume / volume, v / v) trifluoroacetic acid (TFA) in water and 0.1% TFA in 50 / 50 (v / v) acetonitrile and tetrahydrofuran. Ultraviolet (UV) detection is at 220 nanometers (nm). Content uniformity was determined according to USP <905> It was decided by.

[0135] Related substances The levels of related substances in this tablet formulation were determined by a gradient reversed-phase HPLC method. The method uses a C18 column with a gradient elution of a mobile phase of 0.1% (v / v) trifluoroacetic acid (TFA) in water and 0.1% TFA in 50 / 50 (v / v) acetonitrile and tetrahydrofuran. UV detection is at 220 nm. This method is similar to the HPLC method for identification, analysis, and content uniformity, with the main difference being the longer run time of the method to obtain higher resolution of the related substance peaks.

[0136] Dissolution measurement by HPLC :USP <711> A standard USP type 2 (paddle) apparatus was used with a paddle speed of 50 RPM or 75 RPM according to the method. The dissolution method utilized a buffer solution (pH 6.8) containing sodium lauryl sulfate as the dissolution medium to create the sink conditions shown in the table. Samples were analyzed by gradient reversed-phase HPLC on a C18 column. Standard assays were performed to determine the sample concentrations.

[0137] water content :USP <921> The water content was determined by volumetric KF titration according to

[0138] Microbial Limit Testing Method :USP <61> and USP <62> Microbiological tests were performed according to the method described above.

[0139] Example 1: Preparation of tablet formulation Table 1 lists the composition of the tablet formulation. Table 2 lists the composition of a suitable Opadry Film Coating System. Other coating systems may also be suitable. [Table 1] [Table 2]

[0140] The tablets containing a compound of formula (I) (eg, CLTX-305) and pharmaceutically acceptable excipients were prepared according to the following steps.

[0141] Step 1: Dispensing Before being used to manufacture tablets of the present disclosure, CLTX-305 and the excipients were weighed according to the composition in Table 1 and then separated through a sieve.

[0142] Step 2: Fluid bed granulation Before the start of the fluid bed granulation operation, hydroxypropyl methylcellulose and sucrose fatty acid ester were mixed with purified water to prepare a binder solution.

[0143] CLTX-305, mannitol, microcrystalline cellulose, colloidal silicon dioxide, and croscarmellose sodium were charged into a fluid bed granulator. The granulation operation included the following steps: binder spray, binder solvent spray, drying, and preheating / premixing by fluidizing the powders before delumping began.

[0144] Depending on the batch size for a given batch, the fluid bed granulation operation may be carried out in sublots. The granulation sublots were combined prior to the start of final blending.

[0145] Step 3: Final Mix The granules from the fluid bed granulation operation were charged into a blender bin. If the batch consisted of sublots of granules, all sublots were added to the blender bin. The extragranular excipients, croscarmellose sodium and magnesium stearate, were separated and charged into the blender bin to perform the final blend.

[0146] Step 4: Compression The final blend was compressed into tablets using a tablet press and after compression the tablets were dusted and metal detected. The core tablets were tested for weight uniformity, hardness, thickness and friability.

[0147] Step 5: Coating The tablet cores were coated in a pan coater with a suspension of Opadry white in purified water using an aqueous spray system and then dried in the coater. The tablet weight gain was monitored during the coating process.

[0148] Step 6: Packing Thirty tablets and a desiccant were packed into high-density polyethylene (HDPE) bottles. Each bottle was induction sealed and then sealed with a child-resistant polypropylene cap. The packing process was monitored for tablet count, induction seal integrity, and cap torque.

[0149] Step 7: Labeling The filled bottles were labeled with the approved label.

[0150] Example 2: Tablet dissolution Dissolution of tablets containing 10 mg, 30 mg, and 60 mg of CLTX-305 was carried out in a buffer solution (pH 6.8) containing sodium lauryl sulfate (SLS) as the dissolution medium according to the dissolution method described above.

[0151] As shown in Figure 1, after approximately 20 minutes, all tablet strengths reached a plateau relative to maximum dissolution.

[0152] Example 3: Stability of tablet formulation (non-GMP batch) To evaluate the stability of this formulation, 10 mg and 60 mg CLTX-305 tablets were used. Given that the tablet formulation in this application is a common blend, the stability study pooled the 30 mg dosage strength tablets. Stability data from the stability study was obtained at accelerated storage conditions of 40°C / 75% relative humidity (RH) for up to 6 months and at long-term storage conditions of 25°C / 60% RH for up to 12 months. Stability may be evaluated, for example, with follow-up testing at 3-month and 6-month intervals. Stability data for appearance, analysis, total impurities, and dissolution are shown in Tables 3-6. No significant changes in impurities, analysis, dissolution, or tablet appearance were observed at either 25°C / 60% RH or 40°C / 75% RH storage conditions. [Table 3] [Table 4] [Table 5] [Table 6]

[0153] Example 4: Stability of tablet formulation (GMP batch) To evaluate the stability of this formulation, 10 mg, 30 mg, and 60 mg CLTX-305 tablets were used. Stability data from the stability study was obtained at accelerated storage conditions of 40°C / 75% relative humidity (RH) for up to 6 months and at long-term storage conditions of 25°C / 60% RH for up to 9 months. Stability may be evaluated with follow-up testing at 3-month and 6-month intervals. Stability data for appearance, analysis, total impurities, and dissolution are shown in Tables 7-12. No significant changes in impurities, analysis, dissolution, or tablet appearance were observed at either 25°C / 60% RH or 40°C / 75% RH storage conditions. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0154] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall control.

Claims

1. below: Formula (I): 【Chemistry 1】 a compound represented by the formula: 50-70% by weight combined mannitol and microcrystalline cellulose in the tablet formulation; 1-4% by weight of colloidal silicon dioxide in the tablet formulation; 10-30% by weight of croscarmellose sodium in a tablet formulation; 2-5% by weight of hydroxypropyl methylcellulose in the tablet formulation; and 1-2% by weight of magnesium stearate in the tablet formulation; 1. A tablet formulation comprising:

2. The tablet formulation of claim 1, wherein the compound of formula (I) is present in the tablet formulation in an amount of 12 to 32% by weight on an unsalted and anhydrous basis.

3. The tablet formulation of claim 1, wherein the compound of formula (I) is present in the tablet formulation in an amount of 12 to 15% by weight on an anhydrous and salt-free basis.

4. 4. The tablet formulation of any one of claims 1 to 3, wherein the compound of formula (I) is a hemihydrate hemisulfate salt.

5. The tablet formulation of claim 4, wherein the hemihydrate hemisulfate salt of the compound of formula (I) is present in an amount of 13% to 35% by weight of the tablet formulation.

6. The tablet formulation of claim 5, wherein the hemihydrate hemisulfate salt of the compound of formula (I) is present in an amount of 14.3% by weight of the tablet formulation.

7. The tablet formulation of claim 1, wherein at least 75% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a buffer solution of pH 6.8 containing sodium lauryl sulfate (SLS).

8. The tablet formulation of claim 1, wherein at least 80% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a buffer solution of pH 6.8 containing sodium lauryl sulfate (SLS).

9. The tablet formulation of claim 1, wherein at least 85% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a buffer solution of pH 6.8 containing sodium lauryl sulfate (SLS).

10. The tablet formulation of any one of claims 1 to 9, wherein at least 90% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a buffer solution of pH 6.8 containing sodium lauryl sulfate (SLS).

11. The tablet formulation of claim 1, wherein at least 95% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a buffer solution of pH 6.8 containing sodium lauryl sulfate (SLS).

12. A tablet formulation according to any one of claims 1 to 11 for the treatment of autosomal dominant hypocalcemia type 1 (ADH1).

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