Preparations of triphenylcalcilic compounds

Abstract

This invention provides a tablet formulation containing a triphenylcalcilic compound for the treatment of autosomal dominant hypocalcemia (ADH). [Solution] A tablet formulation containing a triphenylcalcilic compound represented by formula (I) is provided. JPEG2026086851000030.jpg47133

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority of U.S. Provisional Patent Application No. 63 / 061,050, filed on August 4, 2020, and the entire disclosure of that application is incorporated herein by reference for all purposes.

Background Art

[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, which results in hypocalcemia. (Hannan et al. Human Molecular Genetics, 2012, 21 (12), p. 2768 - 2778; and Hofer et al., Nature Reviews: Molecular Cell Biology, 2003, 4 (7), p. 530 - 538). CaSR responds to changes in blood calcium levels and plays a dominant role in regulating systemic calcium homeostasis by controlling the secretion of parathyroid hormone (PTH) and calcium excretion in urine. (Hofer et al., Nature Reviews: Molecular Cell Biology, 2003; and Gunn et al., Ann. Clin. Biochem., 2004, 41 (Pt 6):p. 441 - 58). Negative allosteric regulators of CaSR (so - called calcilytic agents) may represent potential targeted therapies for ADH1.

[0003] The prevalence of ADH1 is unknown, and has previously been estimated at 1 in 70,000 people (Gunn et al., Ann. Clin. Biochem., 2004) or 3.9 in 100,000 people (Dershem et al., Am. J. Hum. Genet., 2020). However, the disease 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, usually associated with persistent hypercalciuria (Roszko et al., Frontiers in Physiology, 2016, 7, p. 458). Symptoms of hypocalcemia most commonly include paresthesia, muscle spasms, cramps, tetany, and numbness around the mouth, and can vary in severity, including causing a stroke. Hypocalcemia may also present with laryngospasm, neuromuscular responsiveness, cognitive impairment, personality disorders, QT prolongation syndrome, electrocardiogram changes similar to those of a myocardial infarction, and / or heart failure.

[0005] In patients with ADH1, hypocalcemia occurs primarily due to enhanced sensitivity of CaSR to extracellular calcium ions, which suppresses iPTH secretion and results in low levels of 1,25-dihydroxyvitamin D3 (reducing calcium absorption from the intestines) and low levels of calcium reabsorption in the kidneys (leading to hypercalciuria). Hypercalciuria is exacerbated by two mechanisms: a mechanism that reduces PTH-mediated calcium reabsorption from the proximal renal filtrate, and a mechanism by which mutant CaSR further reduces calcium reabsorption in the distal tubules exposed to high concentrations of calcium. Furthermore, standard treatment with oral calcium and calcitriol (e.g., 1,25-dihydroxyvitamin D3) supplementation tends to exacerbate hypercalciuria associated with long-term pathological conditions, 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, p. 2443-2452).

[0006] For this reason, the agreed-upon 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 can maintain the lowest possible serum calcium concentration while minimizing symptoms of hypercalciuria. Thiazide diuretics are sometimes added due to their gradual effect in lowering urinary calcium.

[0007] In ADH1 patients, experimental treatment with PTH(1-34) was able to correct serum calcium levels but failed to suppress hypercalciuria (Winer et al., The Journal of Clinical Endocrinology and Metabolism, 2012, 97 (2), p. 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), p. 2112-2118). Exogenous PTH(1-84) is approved as an orphan indication for hypoparathyroidism; however, 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] Triphenylcalcilic compounds refer to a class of compounds that exhibit calcium-sensing receptor antagonist activity, disclosed in U.S. Patent No. 7,304,174, and are formulated as follows: [ka] It is represented as follows: R2″ is C 1-6 It is an alkyl group, where R4″ is a methyl group or a cyclopropyl group, and R6 is a halogen atom or C 1-6 It is an alkyl group, and R7″ consists of a hydrogen atom, a halogen atom, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, or C 1-6 Haloalkyl groups, their optically active derivatives, their pharmaceutically acceptable salts, or optically active derivatives of their salts. In particular, this triphenylcalcilic compound is Equation (I): [ka] This refers to a compound, solvate, hydrate, pharmaceutically acceptable salt, or combination thereof represented by . In one embodiment, the compound of formula (I) is of the following formula: [ka] This is the CLTX-305, represented as follows.

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

[0010] Therefore, there is a need to develop a formulation containing the compound of formula (I), particularly CLTX-305, that can be administered orally for the treatment of ADH1. [Overview of the Initiative]

[0011] This disclosure provides formulations comprising, for example, a compound of formula (I) provided herein, which exhibits calcium-sensing receptor antagonist activity. This disclosure also provides methods for the treatment of ADH1 using the formulations provided herein.

[0012] Therefore, in the first embodiment, the present disclosure provides a tablet formulation. This tablet formulation contains the following: a) Equation (I): [ka] Compounds, solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof represented by; and b) One or more pharmaceutically acceptable pharmaceutical additives 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 and wherein the compound is present at at least about 12% by weight on a salt - free and anhydrous basis.

[0013] In a second aspect, the present disclosure provides a tablet formulation as a common blend formulation across all dosage strengths. This common blend tablet formulation comprises: a) CLTX - 305 represented by the following formula:

Chemical formula

[0014] In a third embodiment, the Disclosure provides a method for the treatment of autosomal dominant hypocalcemia type 1 (ADH). The method involves administering an effective amount of a tablet formulation provided herein, for example, 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 pharmaceutical additives, selected from one or more excipients, one or more fluidizers, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof, present in at least about 12% by weight on an unsalted and anhydrous basis, to a subject in need of treatment. [Brief explanation of the drawing]

[0015] [Figure 1] This figure 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 This disclosure provides tablet formulations comprising a triphenylcalcilic compound of formula (I), or a solvate, hydrate, pharmaceutically acceptable salt, or a combination thereof (e.g., CLTX-305). Herein, the formulation may be a common mixed formulation, and the ratio of the compound to one or more pharmaceutical excipients may be kept constant over a range of dose intensities. For example, in some embodiments, formulations containing about 14.3% CLTX-305 can be successfully prepared as tablets. Various single-dose intensities (10 mg, 30 mg, and 60 mg of CLTX-305 per tablet) satisfy the stability and pharmacokinetic requirements necessary for oral formulations. The tablet formulations provided herein may be well suited for oral administration to human and animal subjects for the treatment of autosomal dominant hypocalcemia type 1 (ADH1).

[0017] II. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure relates. Furthermore, any method or material similar or equivalent to the methods or materials described herein may be used in carrying out the compositions and methods described herein. For the purposes of this disclosure, the following terms are defined:

[0018] The term "tablet" means a solid pharmaceutical preparation, whether coated or not. The term "tablet" also means a solid pharmaceutical preparation having one, two, three, or more layers, where each of the aforementioned types of tablets may have or not have one or more coatings. In some embodiments, the tablets of this disclosure may be prepared by roller compression 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 contain CLTX-305 and one or more pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more binders, one or more fluidizers, 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 include coating agents. The amount of coating agent for the calculation of the weight % of the tablet preparation is not included in the calculation; that is, the weight % reported herein is for uncoated tablets.

[0019] "Pharmacologically acceptable pharmaceutical excipients" means substances that assist in the administration and / or absorption of an active substance to a subject. Useful pharmaceutically acceptable pharmaceutical excipients in this disclosure include, but are not limited to, binders, excipients, fluidizers, disintegrants, surfactants, lubricants, coatings, sweeteners, flavorings, and colorants.

[0020] "Administration" refers to the therapeutic provision of a drug to a target, such as through oral administration.

[0021] "Patient" or "Subject" means a living organism that is suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions 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 human.

[0022] "Therapeutally effective dose" refers to the amount of compound or pharmaceutical composition useful for treating or improving a specific disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount varies depending on the therapeutic objective, safety, and target response, and is determined by a clinician, pharmacist, etc. (See, for example, 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] "To treat," "treatment," and "treatment" refer to indicators of success in treating or improving an injury, pathology, or disease, or its symptoms, and include objective or subjective parameters such as reduction, remission, alleviation of symptoms or making the injury, pathology, or disease more tolerable to the patient, slowing the rate of degeneration or decay, making the final stages of degeneration less debilitating, and improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters including the results of physical examination, assays (e.g., analysis of bodily fluids of the subject such as blood, plasma, or urine), imaging analysis, neuropsychiatric examinations, and / or psychiatric assessments.

[0024] "Approximately" means a range of values ​​that includes the specified value and which a person skilled in the art would reasonably determine to be close to the specified value. In some embodiments, the term "approximately" means within the range of standard deviations using generally acceptable measurements in the art. In some embodiments, "approximately" means a range of ±10% of the specified value. In some embodiments, "approximately" means the specified value.

[0025] "Salt" means an acidic or basic salt of the compounds of this disclosure. Examples of pharmaceutically acceptable acid addition salts are salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid) and salts of organic acids (e.g., acetic acid, propionic acid, glutamic acid, citrate). 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 nontoxic. Additional information on appropriate 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 or salt thereof provided herein, further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0027] "Hydrate" means a compound or salt thereof provided herein that is complexed with a water molecule. The compounds or salts thereof of this disclosure can be complexed with 1 / 2 water molecule or 1 to 10 water molecules.

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

[0029] Tour. Pharmaceuticals This disclosure provides a tablet formulation. This tablet formulation includes: a) Equation (I): Equation (I) [ka] Compounds, solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof represented by . b) One or more excipients, one or more fluidizers, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and one or more pharmaceutically acceptable pharmaceutical additives selected from combinations thereof. Furthermore, the compound is present in an amount of at least about 12% by weight, on an unsalted and anhydrous basis.

[0030] In some embodiments, the present disclosure provides a tablet formulation as a common mixed formulation across various dosage intensities. Common mixed tablet formulations include: a) Equation (I): Equation (I) [ka] Compounds, solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof represented by . b) One or more excipients, one or more fluidizers, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and one or more pharmaceutically acceptable pharmaceutical additives selected from combinations thereof. Here, the compound is present in an amount of at least approximately 12% by weight, on an unsalted and anhydrous basis. Furthermore, the ratio of the compound's weight to the total weight of one or more pharmaceutically acceptable pharmaceutical excipients remains constant over two or more dosage intensities.

[0031] The compound of formula (I) may exist in a pharmaceutically acceptable salt form, a twinionic form, or a neutral form, and any of these may optionally exist in a solvate or hydrate form.

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

[0033] Acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid, and phosphorous acid, as well as salts 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) exists in sulfate form. In some embodiments, the compound of formula (I) exists in hemisulfate 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] In the formula, M is a pharmaceutically acceptable cation of the base.

[0035] Base addition salts can be obtained by contacting the neutral form of the compound of formula (I) with a sufficient amount of the desired base in the absence of a solvent or under a suitable inactivating 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 twinned ionic form having formula (Ic). Formula (Ic) [ka]

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

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

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

[0040] The tablet formulations provided herein may have one or more dose strengths, and the compound of formula (I) (e.g., CLTX-305) may be present in amounts 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 an unsalted and anhydrous basis. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in each tablet in amounts of approximately 1 to approximately 1000 mg, approximately 1 to approximately 750 mg, approximately 1 to approximately 500 mg, approximately 1 to approximately 250 mg, approximately 50 to approximately 1000 mg, approximately 50 to approximately 750 mg, approximately 50 to approximately 500 mg, approximately 50 to approximately 250 mg, approximately 100 to approximately 1000 mg, approximately 100 to approximately 750 mg, approximately 100 to approximately 500 mg, and approximately 100 to approximately 250 mg, on an unsalted and anhydrous basis. The dosage is present in amounts of approximately 200-1000 mg, approximately 200-750 mg, approximately 200-500 mg, approximately 300-1000 mg, approximately 300-750 mg, approximately 300-500 mg, approximately 400-1000 mg, approximately 400-750 mg, approximately 500-1000 mg, approximately 500-750 mg, approximately 600-1000 mg, approximately 5-250 mg, or approximately 5-100 mg, or any appropriate range within these amounts. In some embodiments, the tablet formulation is available in two or more different dosage intensities. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in amounts of approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, or approximately 1000 mg in each tablet, on an unsalted and anhydrous basis. In some embodiments, the compound (e.g., CLTX-305) is present in amounts of approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, or approximately 700 mg in each tablet, on an unsalted and anhydrous basis.

[0041] The tablet formulations provided herein may have one or more dose strengths, and CLTX-305 may be present in amounts 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 may be present in amounts 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, about 100 to about 250 mg, about 200 to about 1000 mg The tablets are available in amounts ranging from approximately 200 to 750 mg, 200 to 500 mg, 300 to 1000 mg, 300 to 750 mg, 300 to 500 mg, 400 to 1000 mg, 400 to 750 mg, 500 to 1000 mg, 500 to 750 mg, 600 to 1000 mg, 5 to 250 mg, or 5 to 100 mg, or any appropriate range within that range. In some embodiments, the tablet formulation is available in two or more different dosage intensities. In some embodiments, CLTX-305 is present in amounts of approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 60 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, approximately 300 mg, approximately 360 mg, approximately 420 mg, approximately 480 mg, approximately 540 mg, approximately 600 mg, approximately 660 mg, or approximately 720 mg in each tablet. In some embodiments, CLTX-305 is present in amounts of approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 60 mg, approximately 120 mg, approximately 240 mg, approximately 360 mg, or approximately 720 mg in each tablet.

[0042] The tablet formulations of this disclosure may be common mixed formulations, and the ratio of the compound weight to the total weight of one or more pharmaceutically acceptable pharmaceutical additives is constant over multiple dose strengths. In some embodiments, the ratio of the compound weight to the total weight of one or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose strengths. In some embodiments, the ratio of the compound (e.g., CLTX-305) weight to the total weight of one or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose strengths, and the compound of formula (I) (e.g., CLTX-305) is present in each tablet in amounts 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 unsalted 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 pharmaceutical excipients is constant over two or more dose intensities, and the compound is present in amounts of approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 60 mg, approximately 120 mg, approximately 240 mg, approximately 360 mg, or approximately 720 mg in each tablet.

[0043] In some embodiments, the weight / weight ratio of the compound of formula (I) (e.g., CLTX-305) to one or more pharmaceutically acceptable mixed pharmaceutical additives is at least about 1:5, for example, at least about 1:5, about 1:6, about 1:7, or higher, for example, at least 1:7.4, and the compound is on an unsalted and 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 mixed pharmaceutical additives is about 1:7.4 to about 1:2, where the compound is on an unsalted and anhydrous basis. In some embodiments, the weight / weight ratio of the compound (e.g., CLTX-305) to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:7, and the compound is on an unsalted and anhydrous basis. In some embodiments, the weight / weight ratio of the compound (e.g., CLTX-305) to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:7 over two or more dose intensities, and the compound of formula (I) is present in amounts 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 in each tablet, on an unsalted and anhydrous basis.

[0044] In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives is at least about 1:6.5. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:6.5 to about 1:2, for example, about 1:3. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:6. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:6 over two or more dose intensities, and CLTX-305 is present in amounts of about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg in each tablet.

[0045] In some embodiments, the total weight of the solid dosage form (e.g., tablets) (e.g., active ingredient and pharmaceutical additives, excluding coatings) is approximately 30 mg to 3000 mg. In some embodiments, the total weight of the solid dosage form (e.g., tablets) is approximately 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., tablets) is approximately 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, on an unsalted and anhydrous basis. 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, on an unsalted and anhydrous basis. 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, on an unsalted and anhydrous basis. 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, on an unsalted and anhydrous basis. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in the tablet formulation at a concentration of approximately 13% by weight, on an unsalted and anhydrous basis.

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

[0048] In some embodiments, the tablet formulation contains at least two pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 three pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 four pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 five pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 fluidizer, one disintegrant, one surfactant, one binder, and one lubricant.

[0049] In some embodiments, the tablet formulation contains one or more excipients. In some embodiments, the tablet formulation contains two or more excipients. Suitable excipients are described herein. In some embodiments, one or more excipients are present in the tablet formulation in an amount of 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, one or more excipients are present in the tablet formulation in an amount of 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, one or more excipients are present in the tablet formulation in an amount of about 50% to about 60% by weight. In some embodiments, one or more excipients are present in an amount of about 55.2% by weight.

[0050] In some embodiments, the tablet formulation contains 1 to 3 excipients. In some embodiments, the tablet formulation contains 1 to 2 excipients. In some embodiments, the tablet formulation contains 2 to 3 excipients. In some embodiments, the tablet formulation contains 2 excipients (i.e., a first excipient and a second excipient).

[0051] Suitable excipients include oligosaccharides (e.g., lactose), sugars, starch, modified starch, 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, etc. Examples of inorganic salt excipients include phosphates, e.g., calcium hydrogen phosphate, and sulfates. In some embodiments, one or more excipients include sugars, sugar alcohols, cellulose derivatives, or combinations thereof. In some embodiments, one or more excipients include mannitol, sorbitol, xylitol, lactitol, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or combinations thereof. In some embodiments, one or more excipients include mannitol and microcrystalline cellulose. In some embodiments, the first excipient contains a sugar alcohol, and the second excipient contains 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 tablet formulations at concentrations of approximately 15% to approximately 70% by weight, approximately 20% to approximately 70% by weight, approximately 30% to approximately 70% by weight, approximately 40% to approximately 70% by weight, approximately 40% to approximately 60% by weight, approximately 50% to approximately 70% by weight, or approximately 50% to approximately 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in tablet formulations at concentrations of approximately 40% to approximately 70% by weight, approximately 40% to approximately 60% by weight, approximately 50% to approximately 70% by weight, or approximately 50% to approximately 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in tablet formulations at concentrations of approximately 50% to approximately 60% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in tablet formulations at concentrations of approximately 55.2% by weight. In some embodiments, mannitol and microcrystalline cellulose are present in approximately 55.2% by weight of the tablet formulation, with a mannitol-to-microcrystalline cellulose ratio of approximately 3.0 or less. In some embodiments, mannitol and microcrystalline cellulose are present in approximately 55.2% by weight of the tablet formulation, with a mannitol-to-microcrystalline cellulose ratio of approximately 2.5. In some embodiments, mannitol is present in approximately 10% to approximately 60% by weight, approximately 20% to approximately 60% by weight, approximately 30% to approximately 60% by weight, or approximately 30% to approximately 50% by weight of the tablet formulation. In some embodiments, mannitol is present in approximately 30% to approximately 50% by weight of the tablet formulation. In some embodiments, mannitol is present in approximately 39.5% by weight of the tablet formulation. In some embodiments, microcrystalline cellulose is present in approximately 10% to approximately 25% by weight, or approximately 10% to approximately 20% by weight of the tablet formulation. In some embodiments, microcrystalline cellulose is present in the tablet formulation at a concentration of 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 a concentration of about 10% to about 20% by weight. In some embodiments, microcrystalline cellulose is present at a concentration of about 15.7% by weight.

[0053] In some embodiments, the tablet formulation contains one or more fluidizing agents. Suitable fluidizing agents are described below. In some embodiments, one or more fluidizing agents are present in the tablet formulation in an amount of 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, one or more fluidizing agents are present in the tablet formulation in an amount of 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, one or more fluidizing agents are present in the tablet formulation in an amount of about 2% to about 4% by weight. In some embodiments, one or more fluidizing agents are present in the tablet formulation in an amount of about 3% by weight.

[0054] In some embodiments, the tablet formulation contains one or two fluidizing agents.

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

[0056] In some embodiments, colloidal silicon dioxide is present in the tablet formulation at a concentration of 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, colloidal silicon dioxide is present in the tablet formulation at a concentration of 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, colloidal silicon dioxide is present in the tablet formulation at a concentration of about 2% to about 4% by weight. In some embodiments, colloidal silicon dioxide is present in the tablet formulation at a concentration of about 3% by weight.

[0057] In some embodiments, the tablet formulation contains one or more disintegrants. Suitable disintegrants are described below. In some embodiments, one or more disintegrants are present in the tablet formulation at a concentration of 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, one or more disintegrants are present in the tablet formulation at a concentration of 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, one or more disintegrants are present in the tablet formulation at a concentration of about 15% to about 25% by weight. In some embodiments, one or more disintegrants are present in the tablet formulation at a concentration of 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 disintegrants remain within the granules (i.e., intragranular). The remaining portion of one or more disintegrants is then added to the final mixture so that the disintegrants exist outside the granules (i.e., extragranular). In some embodiments, one or more disintegrants exist intragranular, extragranular, or a combination thereof. In some embodiments, one or more disintegrants exist both intragranular and extragranular. In some embodiments, one or more disintegrants exist in the tablet formulation at a concentration of about 1% to about 15% by weight within the granules. In some embodiments, one or more disintegrants exist in the tablet formulation at a concentration of about 10.0% by weight within the granules. In some embodiments, one or more disintegrants exist in the tablet formulation at a concentration of about 1% to about 15% by weight outside the granules. In some embodiments, one or more disintegrants exist in the tablet formulation at a concentration of about 10.0% by weight outside the granules.

[0059] In some embodiments, the tablet formulation contains one or two disintegrants. In some embodiments, the tablet formulation contains one disintegrant.

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

[0061] In some embodiments, croscarmellose sodium is present in tablet formulations at concentrations of 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 tablet formulations at concentrations of 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 tablet formulations at concentrations of about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in tablet formulations at concentrations of 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 in the tablet formulation at an amount of about 1% to about 15% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at an amount of about 10.0% by weight. In some embodiments, croscarmellose sodium is present outside the tablet formulation at an amount of about 1% to about 15% by weight. In some embodiments, croscarmellose sodium is present outside the tablet formulation at an amount of about 10.0% by weight.

[0062] In some embodiments, the tablet formulation contains one or more surfactants. Suitable surfactants are described below. In some embodiments, one or more surfactants are present in the tablet formulation at a concentration of 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, one or more surfactants are present in the tablet formulation at a concentration of 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, one or more surfactants are present in the tablet formulation at a concentration of about 1% to about 3% by weight. In some embodiments, one or more surfactants are present at a concentration of about 2.0% by weight.

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

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

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

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

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

[0068] Suitable binders include, for example, povidone, lactose, starch, modified starch, sugars, gum acacia, tragacanth gum, guar gum, pectin, wax binder, 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 a combination thereof. In some embodiments, one or more binders include hydroxypropylmethylcellulose. In some embodiments, the tablet formulation includes one binder, and that one binder is hydroxypropylmethylcellulose.

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

[0070] In some embodiments, the tablet formulation contains one or more lubricants. Suitable lubricants are described below. In some embodiments, one or more lubricants are present in the tablet formulation in an amount of 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, one or more lubricants are present in the tablet formulation in an amount of about 1% to about 3% by weight, or about 1% to about 2% by weight. In some embodiments, one or more lubricants are present in the tablet formulation in an amount of about 1% to about 2% by weight. In some embodiments, one or more lubricants are present in the tablet formulation in an amount of 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 contains one lubricant, which is magnesium stearate.

[0073] In some embodiments, magnesium stearate is present in the tablet formulation at a concentration of 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 a concentration of 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 a concentration of about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at a concentration of 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 a concentration of about 1% to about 2% by weight. In some embodiments, magnesium stearate is present in the tablet formulation at a concentration of about 1.5% by weight.

[0075] Other suitable excipients, fluidizers, disintegrants, surfactants, binders, lubricants, and other pharmaceutical additives 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 herein by reference in its entirety.

[0076] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Two or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Three or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Four or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Five or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Six or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Seven or more pharmaceutically acceptable pharmaceutical additives comprising a first excipient, a second excipient, a fluidizer, 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 fluidizer is silicon dioxide, talc, magnesium carbonate, or a combination thereof; the disintegrant 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, hydroxypropyl methylcellulose, 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 the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Two or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. The first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

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

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

[0085] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Five or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. The first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0086] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Six or more pharmaceutically acceptable pharmaceutical additives selected from the group consisting of a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. The first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0087] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 35% by weight of CLTX-305 and, b) Seven or more pharmaceutically acceptable pharmaceutical additives comprising a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. The first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer is colloidal silicon dioxide, the disintegrant is croscarmellose sodium, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

[0088] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) A first excipient and a second excipient in an amount of approximately 40% to 70% by weight. c) Approximately 1% to 5% by weight of a fluidizing agent d) Approximately 10% to 30% by weight of disintegrant e) Surfactants in an amount of approximately 1% to 5% by weight f) A binder in an amount of approximately 1% to 5% by weight, and g) Approximately 1% to 3% by weight of lubricant Furthermore, the total weight of components a) through g) is 100%.

[0089] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) A first excipient and a second excipient in an amount of approximately 40% to 70% by weight. c) Approximately 1% to 4% by weight of a fluidizing agent d) Approximately 15% to 30% by weight of disintegrant e) Surfactants in an amount of approximately 1% to 4% by weight f) A binder in an amount of approximately 2% to 5% by weight, and g) Approximately 1% to 3% by weight of lubricant Furthermore, the total weight of components a) through g) is 100%.

[0090] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) Approximately 45% to 65% by weight of the first and second excipients c) Approximately 2% to 4% by weight of a fluidizing agent d) Approximately 15% to 25% by weight of disintegrant e) Surfactants in an amount of approximately 1% to 3% by weight f) A binder in an amount of approximately 3% to 5% by weight, and g) Approximately 1% to 2% by weight of lubricant Furthermore, the total weight of components a) through g) is 100%.

[0091] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) Approximately 30% to 60% by weight of the first excipient c) Approximately 10% to 30% by weight of the second excipient d) Approximately 1% to 5% by weight of a fluidizing agent e) Approximately 10% to 30% by weight of disintegrant f) Surfactants in an amount of approximately 1% to 5% by weight g) Approximately 1% to 10% by weight of a binder, and h) Approximately 1% to 3% by weight of lubricant Furthermore, the total weight of components a) through h) is 100%.

[0092] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) Approximately 30% to 50% by weight of the first excipient c) Approximately 10% to 20% by weight of the second excipient d) Approximately 2% to 4% by weight of a fluidizing agent e) Approximately 15% to 25% by weight of disintegrant f) Surfactants in an amount of approximately 1% to 3% by weight g) Approximately 3% to 5% by weight of a binder, and h) Approximately 1% to 2% by weight of lubricant Furthermore, the total weight of components a) through h) is 100%.

[0093] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) Approximately 30% to 50% by weight of the first excipient c) Approximately 10% to 20% by weight of the second excipient d) Approximately 2% to 4% by weight of a fluidizing agent e) Approximately 5% to 15% by weight of granular disintegrant f) Approximately 5% to 15% by weight of granular disintegrant g) Approximately 1% to 3% by weight of surfactant h) A binder in an amount of approximately 3% to 5% by weight, and i) Approximately 1% to 2% by weight of a lubricant Furthermore, the total weight of components a) through i) is 100%.

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

[0095] In some embodiments, the tablet formulation comprises the following: a) Approximately 13% to 15% by weight of CLTX-305 b) A first excipient selected from the group consisting of mannitol, sorbitol, xylitol, and lactitol, in an amount of approximately 30% to 50% by weight. c) A second excipient selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose, in an amount of approximately 10% to 20% by weight. d) A fluidizing agent selected from the group consisting of silicon dioxide, talc, and magnesium carbonate, in an amount of approximately 2% to 4% by weight. e) A first disintegrant in an amount of about 5% to about 15% by weight, selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and corn starch, wherein the first disintegrant is present in granular form. f) Approximately 5% to 15% by weight of a second group selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and corn starch. The disintegrant is present outside the granular form. g) 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, in an amount of approximately 1% to 3% by weight. h) A binder selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose in an amount of about 3% to about 5% by weight, and i) A lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearyl fumarate in an amount of approximately 1% to 2% by weight. Furthermore, the total weight of components a) through i) is 100%.

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

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

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

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

[0100] In some embodiments of any one of the formulations described above, the tablet formulation is a common mixed formulation in which the ratio of the weight of CLTX-305 to the total weight of one or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose intensities. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of two or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose intensities. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of three or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose intensities. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of four or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose intensities. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of five or more pharmaceutically acceptable pharmaceutical additives is constant over two or more dose intensities. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of 6 or more pharmaceutically acceptable pharmaceutical additives is constant over dose intensities of 2 or more. In some embodiments, the ratio of the weight of CLTX-305 to the total weight of 7 or more pharmaceutically acceptable pharmaceutical additives is constant over dose intensities of 2 or more.

[0101] In other embodiments, the Disclosure provides a tablet formulation as a common mixed formulation across two or more dosage intensities. This common mixed formulation comprises: a) CLTX-305 can be expressed by the following formula: [ka] b) Seven or more pharmaceutically acceptable pharmaceutical additives, including a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in an amount of approximately 13% to 30% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer 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, 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 pharmaceutical additives is constant over dose intensities of two or more.

[0102] In some embodiments, the common mixed formulation includes the following: a) CLTX-305 can be expressed by the following formula: [ka] b) Seven or more pharmaceutically acceptable pharmaceutical additives, including a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in an amount of approximately 13% to 15% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer 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, 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 pharmaceutical additives is constant over dose intensities of two or more.

[0103] In some embodiments of the common mixed formulation, the tablet formulation has two or more dose strengths, and CLTX-305 is present in an amount of about 5 to about 1000 mg in each tablet. In some embodiments, CLTX-305 is present 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 in each tablet.

[0104] In some embodiments of the common mixed formulation, the ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives 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 mixed pharmaceutical additives is about 1:6 by weight. In some embodiments, the ratio of CLTX-305 to one or more pharmaceutically acceptable mixed pharmaceutical additives is about 1:6 by weight in all three dose strengths. CLTX-305 is present in amounts 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 in each tablet.

[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 a concentration of 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, with a ratio of mannitol to microcrystalline cellulose of about 3 or less. In some embodiments of the common mixed formulation, mannitol and microcrystalline cellulose are present in the tablet formulation at a concentration of about 50% to about 60% by weight, with a ratio of mannitol to microcrystalline cellulose of about 3 or less. In some embodiments, mannitol and microcrystalline cellulose are present at a concentration of about 55.2% by weight in the tablet formulation, with a ratio of mannitol to microcrystalline cellulose of about 2.5. In some embodiments, mannitol is present in the tablet formulation at an amount of 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 an amount of about 30% to about 50% by weight. In some embodiments, mannitol is present in the tablet formulation at an amount of about 39.5% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at an amount of 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 an amount of about 10% to about 20% by weight. In some embodiments, microcrystalline cellulose is present in the tablet formulation at an amount of about 15.7% by weight.

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

[0107] In some embodiments of the common mixed formulation, croscarmellose sodium is present in the tablet formulation at an amount of 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 an amount of about 15% to about 25% by weight. In some embodiments, croscarmellose sodium is present in the tablet formulation at an amount of about 20% by weight. In some embodiments, croscarmellose sodium is present in the granular form, outside the granular form, or a combination thereof. In some embodiments, croscarmellose sodium is present both inside and outside the granular form. In some embodiments, croscarmellose sodium is present in the granular form at an amount of about 5% to about 15% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present in the granular form at an amount of about 10.0% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present outside the granular form at an amount of about 5% to about 15% by weight in the tablet formulation. In some embodiments, croscarmellose sodium is present outside the granules at a concentration of approximately 10.0% by weight in the tablet formulation.

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

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

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

[0111] In some embodiments of the common mixed formulation, the tablet formulation comprises the following: a) CLTX-305 can be expressed by the following formula: [ka] b) Seven or more pharmaceutically acceptable pharmaceutical additives, including a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in approximately 14.3% by weight, the first excipient is mannitol, present in approximately 39.5% by weight, the second excipient is microcrystalline cellulose, present in approximately 15.7% by weight, the fluidizer is colloidal silicon dioxide, present in approximately 3.0% by weight, the disintegrant is croscarmellose sodium, present in approximately 10.0% by weight within the granules and approximately 10.0% by weight outside the granules, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, present in approximately 2.0% by weight, the binder is hydroxypropyl methylcellulose, present in approximately 4.0% by weight, and the lubricant is magnesium stearate, present in approximately 1.5% by weight.

[0112] In some embodiments of any of the formulations described herein, the tablets are coated with a coating agent. Suitable coating agents include hypromellose, polyvinylacetone, ethylcellulose, and polymethacrylate, as well as coatings sold by OPADRY®. In some embodiments, the coating agent is Opadry White Coating System, Opadry coating system 03B680008 or equivalent, Opadry Clear, Opadry Blue 13B50579, Opadrya QX 321A180025, or OpadryII (33G28707). In some embodiments, the coating agent is the Opadry White Coating System. In some embodiments, the coating agent is the Opadry White Coating System comprising hydroxypropyl methylcellulose, titanium dioxide, and macrogol / PEG (molecular weight 400). In some embodiments, the coating agent is Opadry coating system 03B680008 or equivalent. For the purpose of calculating the percentage weight of the tablet formulation, the amount of coating agent is not included in the calculation. That is, the percentage weight reported herein is for uncoated tablets.

[0113] In some embodiments of any 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% in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. 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%, in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. In some embodiments, the tablet containing about 10 mg of CLTX-305 has a solubility of at least about 95% in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. 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%, in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. In some embodiments, a 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, a 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, a 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, a 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 formulation described herein, the tablet has a maximum solubility of nearly 100% after about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments of any formulation described herein, the tablet has a maximum solubility 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 solubility 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 solubility of about 95% after about 20 minutes. In some embodiments, the tablet containing about 30 mg of CLTX-305 has a maximum solubility of about 95% after about 20 minutes or about 30 minutes. In some embodiments, a tablet containing approximately 30 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 20 minutes. In some embodiments, a tablet containing approximately 30 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 30 minutes. In some embodiments, a tablet containing approximately 60 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 20 minutes, approximately 30 minutes, approximately 45 minutes, or approximately 60 minutes. In some embodiments, a tablet containing approximately 60 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 20 minutes. In some embodiments, a tablet containing approximately 60 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 30 minutes. In some embodiments, a tablet containing approximately 60 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 45 minutes. In some embodiments, the tablet containing approximately 60 mg of CLTX-305 has a maximum solubility of approximately 95% after approximately 60 minutes.

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

[0116] In some embodiments, tablets containing approximately 10 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 40°C and a relative humidity of approximately 75%. During this time, the content of compound (I) changes by approximately 2%, approximately 1%, or less than approximately 0.5% compared to the initial content. The tablets then dissolve to at least approximately 90% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 30 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 40°C and a relative humidity of approximately 75%. During this time, the content of compound (I) changes by approximately 5%, approximately 4%, approximately 3%, approximately 2%, or less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 75% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 30 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 40°C and a relative humidity of approximately 75%. During this time, the content of compound (I) changes by less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 80% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 60 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 40°C and a relative humidity of approximately 75%. During this time, the content of the compound of formula (I) changes by approximately 5%, approximately 4%, approximately 3%, approximately 2%, or less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 75% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).In some embodiments, tablets containing approximately 60 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 40°C and a relative humidity of approximately 75%. During this time, the content of the compound of formula (I) changes by less than approximately 3% compared to the initial content. The tablets dissolve to at least approximately 80% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0117] In some embodiments, tablets containing approximately 10 mg of CLTX-305 are stable for a period of approximately 9 months or more at a temperature of approximately 25°C and a relative humidity of approximately 60%. During this time, the content of compound (I) changes by approximately 2%, approximately 1%, or less than approximately 0.5% compared to the initial content. The tablets then dissolve to at least approximately 90% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 30 mg of CLTX-305 are stable for a period of approximately 9 months or more at a temperature of approximately 25°C and a relative humidity of approximately 60%. During this time, the content of compound (I) changes by approximately 5%, approximately 4%, approximately 3%, approximately 2%, or less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 75% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 30 mg of CLTX-305 are stable for a period of approximately 9 months or more at a temperature of approximately 25°C and a relative humidity of approximately 60%. During this time, the content of compound (I) changes by less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 80% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, tablets containing approximately 60 mg of CLTX-305 are stable for a period of approximately 6 months or more at a temperature of approximately 25°C and a relative humidity of approximately 60%. During this time, the content of the compound of formula (I) changes by approximately 5%, approximately 4%, approximately 3%, approximately 2%, or less than approximately 1% compared to the initial content. The dissolution of the tablets reaches at least approximately 75% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).In some embodiments, tablets containing approximately 60 mg of CLTX-305 are stable for a period of approximately 9 months or more at a temperature of approximately 25°C and a relative humidity of approximately 60%. During this time, the content of the compound of formula (I) changes by less than approximately 3% compared to the initial content. The dissolution of the tablets reaches at least approximately 80% after approximately 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0118] method In a third aspect, the disclosure provides a treatment for autosomal dominant hypocalcemia (ADH, e.g., autosomal dominant hypocalcemia type 1 (ADH1)). The method involves administering to a subject in need an effective amount of a tablet formulation comprising a compound of formula (I), a solvate, a hydrate, a pharmaceutically acceptable salt, or a combination thereof, and one or more pharmaceutically acceptable pharmaceutical additives selected from one or more excipients, one or more fluidizers, 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 an amount of at least about 12% by weight on an unsalted and anhydrous basis.

[0119] In some embodiments, the method includes administering an effective amount of the tablet formulation, which contains the following, to a subject in need: a) CLTX-305 can be expressed by the following formula: [ka] b) Seven or more pharmaceutically acceptable pharmaceutical additives comprising a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in an amount of approximately 13% to 30% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer 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, 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 pharmaceutical additives is constant over dose intensities of two or more.

[0120] In some embodiments, the method includes administering an effective amount of the tablet formulation, which contains the following, to a subject in need: a) CLTX-305 can be expressed by the following formula: [ka] b) Seven or more pharmaceutically acceptable pharmaceutical additives comprising a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in an amount of approximately 13% to 15% by weight, the first excipient is mannitol, the second excipient is microcrystalline cellulose, the fluidizer 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, 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 pharmaceutical additives is constant over dose intensities of two or more.

[0121] In some embodiments, 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 been previously diagnosed with ADH1. In some embodiments, the subject has been previously treated for ADH1.

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

[0124] In some embodiments, the method includes administering an effective dose of the tablet formulation, which contains the following, to a subject in need of treatment. a) CLTX-305 and b) Seven or more pharmaceutically acceptable pharmaceutical additives comprising a first excipient, a second excipient, a fluidizer, a disintegrant, a surfactant, a binder, and a lubricant. Furthermore, CLTX-305 is present in approximately 14.3% by weight, the first excipient is mannitol, present in approximately 39.5% by weight, the second excipient is microcrystalline cellulose, present in approximately 15.7% by weight, the fluidizer is colloidal silicon dioxide, present in approximately 3.0% by weight, the disintegrant is croscarmellose sodium, present in approximately 10.0% by weight within the granules and approximately 10.0% by weight outside the granules, the surfactant is one or more sucrose fatty acid esters containing sucrose palmitate, present in approximately 2.0% by weight, the binder is hydroxypropyl methylcellulose, present in approximately 4.0% by weight, and the lubricant is magnesium stearate, present in approximately 1.5% by weight.

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

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

[0127] In some embodiments, an effective dose of the tablet formulation containing the 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 dose of the tablet formulation containing the compound of formula (I) (e.g., CLTX-305) reduces high urinary calcium levels. In some embodiments, an effective dose of the tablet formulation containing the compound of formula (I) (e.g., CLTX-305) increases urinary calcium clearance. In some embodiments, an effective dose of the tablet formulation containing the compound of formula (I) (e.g., CLTX-305) minimizes the severity of hypercalciuria.

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

[0130] In some embodiments, an effective dose of the tablet formulation containing the compound of formula (I) (e.g., CLTX-305) increases blood magnesium levels relative to the normal range. In some embodiments, an effective dose of the tablet formulation containing the compound of formula (I) (e.g., CLTX-305) minimizes the degree of hypomagnesemia.

[0131] The therapies of the present disclosure may consist of administration alone or in combination with other forms of pharmacotherapy, such as a second compound having calcium-sensing receptor antagonist activity, a vitamin D supplement, and / or a calcium supplement. In some embodiments, the method further includes the administration of an oral calcium supplement. In some embodiments, “in combination with” means that the tablet formulations of the present disclosure and other pharmaceuticals are administered to a subject as part of a treatment regimen or treatment plan. In some embodiments, being used in combination does not require that the tablet formulations of the present disclosure and other pharmaceuticals be physically mixed before administration or that they are administered over the same time frame.

[0132] V. Examples Analysis Procedure The same analytical method was used to test the 10 mg, 30 mg, and 60 mg tablets. A summary of the analytical procedure is provided below.

[0133] exterior The visual evaluation of the tablet formulation was performed by a visual inspection test.

[0134] Identification, analysis, and uniformity of content by HPLC The identification, analysis, and content uniformity of this tablet formulation were determined by gradient reversed-phase HPLC. This method uses a C18 column that gradient-elutes with mobile phases 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 performed at 220 nanometers (nm). Content uniformity is determined by USP <905> This was decided by [the relevant party].

[0135] Related substances The levels of the relevant substances in this tablet formulation were determined by gradient reversed-phase HPLC. This method uses a C18 column that undergoes gradient elution with mobile phases 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 performed at 220 nm. This method is similar to HPLC in terms of identification, analysis, and content homogeneity, but the main difference is the longer method run time required to obtain peaks of the relevant substances with higher resolution.

[0136] Dissolution measurement by HPLC :USP <711> A standard USP type 2 (paddle) instrument was used at a paddle speed of 50 RPM or 75 RPM. In this dissolution method, a buffer solution (pH 6.8) containing sodium lauryl sulfate was used 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 quantification was performed to determine the sample concentration.

[0137] water content :USP <921> Accordingly, the water content was determined by volumetric KF titration.

[0138] Microbial limit testing method :USP <61> and USP <62> Microbial testing was performed accordingly.

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

[0140] Tablets containing the compound of formula (I) (e.g., CLTX-305) and pharmaceutically acceptable pharmaceutical excipients were prepared according to the following steps.

[0141] Step 1: Dispensing Prior to use in the manufacture of the tablets of this disclosure, the weights of CLTX-305 and the pharmaceutical additives were measured according to the composition in Table 1, and then separated through a sieve.

[0142] Step 2: Fluidized bed granulation Before commencing the fluidized bed granulation operation, a binder solution was prepared by mixing hydroxypropyl methylcellulose and sucrose fatty acid ester using purified water.

[0143] CLTX-305, mannitol, microcrystalline cellulose, colloidal silicon dioxide, and croscarmellose sodium were loaded into a fluidized bed granulator. The granulation process included the following steps: spraying of a binder, spraying of a binder solvent, drying, and preheating / premixing by fluidizing the powder before the start of delamping.

[0144] Based on the batch size for a given batch, the fluidized bed granulation operation may be performed in sublots. The granulated sublots were combined before the start of the final mixing.

[0145] Step 3: Final Mixing Granules from the fluidized bed granulation process were loaded into blender bins. If the batch consisted of sublots of granules, all sublots were added to the blender bin. Non-granular pharmaceutical additives, croscarmellose sodium and magnesium stearate, were separated and loaded into the blender bin, and final mixing was performed.

[0146] Step 4: Compression The final mixture was compressed into tablets using a tablet press. After compression, dust was removed from the tablets, and metal detection was performed. Core tablets were tested for weight uniformity, hardness, thickness, and shatterability.

[0147] Step 5: Coating In a pan coater, the tablet core was coated with a suspension of Opadry white in purified water using an aqueous spray system, and then dried in the coater. The weight increase of the tablets 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. During the packing process, the number of tablets, the integrity of the induction seal, and the torque of the cap were checked.

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

[0150] Example 2: Dissolution of tablets Tablets containing 10 mg, 30 mg, and 60 mg of CLTX-305 were dissolved 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, the strength of all tablets 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 formulations in this application are a common mixture, the stability study grouped together 30 mg dose-strength tablets. Stability data from this stability study were obtained for up to 6 months under accelerated storage conditions at 40°C / 75% relative humidity (RH) and up to 12 months under long-term storage conditions at 25°C / 60% RH. Stability may be evaluated by additional tests, for example, at intervals of 3 and 6 months. Stability data for appearance, analysis, total impurities, and dissolution are shown in Tables 3 to 6. No significant changes in impurities, analysis, dissolution, or tablet appearance were observed under either the 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 this stability study were obtained under accelerated storage conditions of up to 6 months at 40°C / 75% relative humidity (RH) and under long-term storage conditions of up to 9 months at 25°C / 60% RH. Stability may also be evaluated by additional tests at intervals of 3 months and 6 months. Stability data for appearance, analysis, total impurities, and dissolution are shown in Tables 7 to 12. No significant changes in impurities, analysis, dissolution, or tablet appearance were observed under either the 25°C / 60% RH or 40°C / 75% RH storage conditions. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0154] While the foregoing disclosure is described in some detail by examples and embodiments for the purpose of clarifying 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 as a whole by reference to the same extent that each reference is incorporated as a reference individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. below: Equation (I): 【Chemistry 1】 Compounds, hydrates, or pharmaceutically acceptable salts thereof, or combinations thereof, represented by ; The tablet formulation contains 50-70% by weight of mannitol and microcrystalline cellulose; A tablet formulation containing 1 to 4% by weight of colloidal silicon dioxide; A tablet formulation containing 10-30% by weight of croscarmellose sodium; In the tablet formulation, 2 to 5% by weight of hydroxypropyl methylcellulose; and A tablet formulation containing 1-2% by weight of magnesium stearate; A tablet formulation containing the above.

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

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

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

5. The tablet formulation according to 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 according to 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 according to any one of claims 1 to 6, wherein at least 75% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

8. The tablet formulation according to any one of claims 1 to 7, wherein at least 80% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

9. The tablet formulation according to any one of claims 1 to 8, wherein at least 85% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

10. The tablet formulation according to 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 pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

11. The tablet formulation according to any one of claims 1 to 10, wherein at least 95% of the compound of formula (I) is released from the tablet formulation after 60 minutes in a pH 6.8 buffer solution 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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