Formulations of triphenylphosphonium sensitive compounds

Abstract

The present invention provides a tablet comprising a triphenylphosphonium calcium sensitive compound, or solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, for treating autosomal dominant hypocalcemia (ADH), the compound being of the formula (I):

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 061,050, filed August 4, 2020, the entire contents of which are incorporated herein by reference for all purposes. Background Technology

[0003] Type 1 autosomal dominant hypocalcemia (ADH1) is a rare disorder of systemic calcium homeostasis caused by activating mutations in the calcium-sensitive receptor (CaSR) gene (Hannan et al., Human Molecular Genetics, 2012, 21(12), pp. 2768–2778; and Hofer et al., Nature Reviews: Molecular Cell Biology, 2003, 4(7), pp. 530–538). CaSR plays a dominant role in regulating systemic calcium homeostasis by controlling parathyroid hormone (PTH) secretion and urinary calcium excretion in response to changes in serum calcium levels (Hofer et al., Nature Reviews: Molecular Cell Biology, 2003; and Gunn et al., Ann. Clin. Biochem., 2004, 41(Pt 6): pp. 441–58). Negative allosteric modulators of CaSR (so-called calcifiers) may represent a potential targeted therapy for ADH1. The prevalence of ADH1 is uncertain, with previous estimates of 1 in 70,000 people (Gunn et al., Annals of Clinical Biochemistry, 2004) or 3.9 in 100,000 people (Dershem et al., American Journal of Human Genetics, 2020); however, the disease is recognized as a rare disease by the National Institutes of Health (NIH) Office of Rare Diseases Research (GARD: 2877) and Orphanet (Orpha: 428).

[0004] ADH1 is characterized by varying degrees of hypocalcemia accompanied by abnormally low levels of parathyroid hormone (PTH), hyperphosphatemia, and hypomagnesemia, often with persistent hypercalciuria (Roszko et al., Frontiers in Physiology, 2016, 7, p. 458). The most common symptoms of hypocalcemia include paresthesia, muscle spasms, cramps, tetany, and perioral numbness, varying in intensity, including triggering seizures. Hypocalcemia can also manifest as laryngospasm, neuromuscular irritability, cognitive impairment, personality disorders, QT interval prolongation, infarct-like ECG changes, and / or heart failure.

[0005] In ADH1 patients, hypocalcemia primarily results from increased sensitivity of the CaSR to extracellular ionic calcium, which inhibits iPTH secretion and leads to decreased 1,25-dihydroxyvitamin D3 levels (reduced intestinal calcium absorption) and decreased calcium reabsorption in the kidneys (resulting in hypercalciuria). Hypercalciuria is based on two mechanisms that increase: reduced PTH-mediated calcium reabsorption from primary renal filtrate, and further reduced calcium reabsorption in the distal renal tubules, where the mutant CaSR is exposed to high calcium concentrations. Furthermore, standard treatment with oral calcium and calcitriol (e.g., 1,25-dihydroxyvitamin D3) supplements often exacerbates hypercalciuria, which is associated with long-term morbidity such as kidney stones, nephrocalcinosis, and chronic kidney disease that can progress to renal failure (Khan et al., European Journal of Endocrinology, 2018; and Li et al., Clinical Interventions in Aging, 2018, 13, pp. 2443–2452).

[0006] Therefore, the consensus approach to managing ADH1 is to balance oral calcium and calcitriol supplementation with the known high risk of renal calcification, kidney stones, and renal failure (Roszko et al., Frontiers in Physiology, 2016). This means healthcare providers must help patients find a regimen that maintains the lowest possible serum calcium concentration compatible with symptom relief to minimize hypercalciuria. Thiazide diuretics are sometimes added because they have a moderate effect in reducing urinary calcium.

[0007] Experimental treatment with PTH(1-34) in ADH1 subjects corrected serum calcium but did not eliminate hypercalciuria (Winer et al., The Journal of Clinical Endocrinology and Metabolism, 2012, 97(2), pp. 391–399; Winer et al., The Journal of Pediatrics, 2014, 165(3), 556–63; and Gafni et al., Journal of Bone and Mineral Research, 2015, 30(11), pp. 2112–2118). Exogenous PTH (1-84) has been approved for orphan indications of hypoparathyroidism, but approved clinical studies in patients with hypoparathyroidism have excluded patients with hypoparathyroidism due to calcium-sensitive receptor mutations (Chomsky et al., World Journal of Surgery, 2018, 42(2), pp. 431–436; and insert for Takeda's recombinant parathyroid hormone (Natpara) product).

[0008] Triphenylcalcilytic compounds refer to a class of compounds that antagonize calcium-sensitive receptors, as disclosed in U.S. Patent No. 7,304,174, as shown in the following formula:

[0009]

[0010] Among them, R 2 "for C" 1-6 Alkyl; R4” is methyl or cyclopropyl; R6” is a halogen atom or C 1-6 Alkyl group; R7” represents hydrogen atom, halogen atom, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups, their optically active forms, their pharmaceutically acceptable salts, or the optically active forms of their salts. Specifically, the triphenylcalcified compounds are as shown in formula (I):

[0011]

[0012] Its solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof. In a particular embodiment, the compound of formula (I) is CLTX-305 as shown below:

[0013]

[0014] Compound of formula (I) or CLTX-305 may prove to be a unique therapy targeting the underlying pathogenesis of calcium homeostasis changes in ADH1 patients, in which resetting the CaSR “set point” may normalize serum calcium with minimal requirements for oral supplementation and without increasing the risk of iatrogenic chronic hypercalciuria.

[0015] Therefore, there is a need to develop formulations of inclusion (I) compounds, particularly CLTX-305, which can be administered orally to treat ADH1. Summary of the Invention

[0016] This invention provides formulations that include calcium-sensitive receptor antagonism, such as the compound of formula (I) provided herein. This invention also provides a method for treating ADH1 using the formulations provided herein.

[0017] Therefore, in a first aspect, the present invention provides a tablet. The tablet comprises:

[0018] a) Compounds as shown in formula (I):

[0019]

[0020] Its solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof; and

[0021] b) One or more pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof;

[0022] The compound is present in an amount of at least about 12% by weight, on the basis of being salt-free and anhydrous.

[0023] In a second aspect, the present invention provides a tablet as a universal mixed formulation across all dose intensities. The universal mixed tablet comprises:

[0024] a) Compounds as shown in the following formula:

[0025]

[0026] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0027] CLTX-305 is present in amounts of approximately 13% to approximately 30% by weight;

[0028] The first filler is mannitol;

[0029] The second filler is microcrystalline cellulose;

[0030] The flow aid is colloidal silica;

[0031] The disintegrant is croscarmellose sodium;

[0032] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0033] The adhesive is hydroxypropyl methylcellulose;

[0034] The lubricant is magnesium stearate; and

[0035] In two or more dosage intensities, the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant.

[0036] In a third aspect, the present invention provides a method for treating autosomal dominant hypocalcemia type 1 (ADH1). The method comprises administering to a subject in need an effective amount of a tablet provided by the present invention, such as a tablet comprising: a compound of formula (I) or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof (e.g., CLTX-305); and one or more pharmaceutically acceptable excipients selected from the group consisting of: one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, or combinations thereof, wherein said compound is present in an amount of at least about 12% by weight, on a salt-free and anhydrous basis. Attached Figure Description

[0037] Figure 1 Dissolution profiles of tablets containing 10 mg, 30 mg, and 60 mg of CLTX-305 are shown. Detailed Implementation

[0038] I. Overview

[0039] This invention provides a tablet comprising a triphenylcalcium-sensitive compound of formula (I), its solvate, hydrate, pharmaceutically acceptable salt, or a combination thereof (e.g., CLTX-305), wherein the tablet can be a generic mixed formulation, and the ratio of the compound to one or more excipients can remain constant at different dose intensities. For example, in some embodiments, formulations containing about 14.3% CLTX-305 can be successfully prepared into tablets. Various dose intensities (e.g., 10 mg, 30 mg, and 60 mg CLTX-305 per tablet) meet the necessary stability and pharmacokinetic requirements for oral formulations. The tablets provided herein may be well-suited for oral administration to human and animal subjects for the treatment of type 1 autosomal dominant hypocalcemia (ADH1).

[0040] II. Definition

[0041] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art relating to this disclosure. Furthermore, any methods or materials similar to or equivalent to those described or made herein may be used to carry out the compositions and methods described herein. For the purposes of this disclosure, the following terms are defined.

[0042] “Tablet” refers to a solid pharmaceutical preparation with or without coating. The term “tablet” also refers to a solid pharmaceutical preparation having one, two, three, or more layers, wherein each of the aforementioned types of tablets may or may not have one or more layers of coating. In some embodiments, the tablets of the present invention can be prepared by roller compaction or other suitable methods known in the art. The term “tablet” also includes mini tablets, melt tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets. In some embodiments, the tablets provided by the present invention comprise CLTX-305 and one or more excipients selected from the group consisting of one or more fillers, one or more flow aids, 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 by the present invention further comprise a coating agent. The amount of coating agent is not included in the calculation of the weight percentage of the tablet. That is, the weight percentages reported herein are the weight percentages of uncoated tablets.

[0043] "Pharmaceutical-acceptable excipients" are substances that facilitate the administration of an active agent to a subject and / or aid in the absorption of the agent by the subject. Pharmaceutically acceptable excipients that may be used in this disclosure include, but are not limited to, binders, fillers, flow aids, disintegrants, surfactants, lubricants, coatings, sweeteners, flavorings, and colorings.

[0044] "Administration" means the therapeutic delivery of a formulation to a subject, such as by oral administration.

[0045] "Patient" or "subject" means a living organism that suffers from or is susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, non-human primates (e.g., monkeys), goats, pigs, sheep, cattle, deer, horses, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, and other non-mammals. In some embodiments, the subject is a human.

[0046] "Therapeutic effective amount" refers to the amount of a compound or pharmaceutical composition that can be used to treat or improve a known disease or condition, or to demonstrate a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of treatment, safety, and response of the subjects, and will be 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, edited by Gennaro, Lippincott, Williams & Wilkins).

[0047] "Treatment" refers to any indication of success in treating or improving an injury, pathology, or condition or its symptoms, including any objective or subjective parameters such as: relief; remission; reduction of symptoms or increased tolerance to the injury, pathology, or condition; slowing of the rate of degeneration or decline; making the last vestiges of degeneration less debilitating; and improvement of the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including physical examination, laboratory tests (e.g., analysis of the subject's fluids, such as blood, plasma, or urine), imaging analysis, neuropsychiatric examinations, and / or psychiatric evaluations.

[0048] "Approximately" refers to a range of values, including the specified value, that would be reasonably similar to the specified value by one of ordinary skill in the art. In some embodiments, the term "approximately" refers to a standard deviation using measurements generally acceptable in the art. In some embodiments, "approximately" represents a range extending to + / - 10% of the specified value. In some embodiments, "approximately" refers to a specific value.

[0049] “Salt” means an acid salt or base salt of the compounds disclosed herein. Examples of pharmaceutically acceptable acid addition salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) and salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.). 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 should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, PA, which is incorporated herein by reference.

[0050] "Solvate" means a compound or its salt as described herein, and further includes stoichiometric or non-stoichiometric amounts of solvents bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0051] "Hydrate" refers to the compounds or salts thereof provided herein that are complexed with water molecules. The compounds or salts thereof disclosed herein can be complexed with 1 / 2 water molecule or 1 to 10 water molecules.

[0052] Unless otherwise stated, the content of compound (I) in the tablet is calculated based on the normalized weight of compound (I) on a salt-free and anhydrous basis. That is, the salt and / or water content of compound (I) is not included in the calculation.

[0053] III. Preparations

[0054] This invention provides a tablet. The tablet comprises:

[0055] a) Compounds as shown in formula (I):

[0056]

[0057] Its solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof; and

[0058] b) One or more pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof;

[0059] The compound is present in an amount of at least about 12% by weight, on the basis of being salt-free and anhydrous.

[0060] In some embodiments, the present invention provides a tablet as a universal mixed formulation across all dose intensities. The universal mixed tablet comprises:

[0061] a) Compounds as shown in formula (I):

[0062]

[0063] b) One or more pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof;

[0064] The compound is present in an amount of at least about 12% by weight, on a salt-free and anhydrous basis; and in two or more dose intensities, the weight ratio of the compound to the total weight of the one or more pharmaceutically acceptable excipients is constant.

[0065] The compound of formula (I) may be in a pharmaceutically acceptable salt form, zwitterionic form or neutral form, any of which may optionally be in solvate or hydrate form.

[0066] In some embodiments, pharmaceutically acceptable acid addition salts of compounds of formula (I) are shown as those of formula (Ia):

[0067]

[0068] HX is a pharmaceutically acceptable acid adduct.

[0069] Examples of acceptable acid addition salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or 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, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. In some embodiments, the compound of formula (I) is in sulfate form. In some embodiments, the compound of formula (I) is in hemisulfate form.

[0070] In some embodiments, the pharmaceutically acceptable base addition salt of the compound of formula (I) is as shown in formula (Ib):

[0071]

[0072] Where M is a pharmaceutically acceptable basic cation.

[0073] A base addition salt can be obtained by contacting a neutral form of a compound of formula (I) with a sufficient amount of the desired base, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. In some embodiments, the compound of formula (I) is in its sodium salt form.

[0074] In some embodiments, the compound of formula (I) is in the zwitterionic form as shown in formula (Ic):

[0075]

[0076] In some embodiments, the compound of formula (I) is in a neutral form.

[0077] In some embodiments, any of the compounds represented by formulas (I), (Ia), (Ib), and (Ic) are in solvate and / or hydrate form. In some embodiments, any of the compounds represented by formulas (I), (Ia), (Ib), and (Ic) are in hydrate form.

[0078] In some embodiments, the compound of formula (I) is in the form of a hemihydrate hemisulfate, such as CLTX-305 as shown below:

[0079]

[0080] The tablets provided herein may be of one or more dosage strengths, wherein the amount of compound of formula (I) (e.g., CLTX-305), in anhydrous and salt-free form, is 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, the amount of compound of formula (I) (e.g., CLTX-305) in each tablet, in anhydrous and salt-free form, is 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 1 ... The dosage strength may be approximately 250 mg, approximately 200 mg to approximately 1000 mg, approximately 200 mg to approximately 750 mg, approximately 200 mg to approximately 500 mg, approximately 300 mg to approximately 1000 mg, approximately 300 mg to approximately 750 mg, approximately 300 mg to approximately 500 mg, approximately 400 mg to approximately 1000 mg, approximately 400 mg to approximately 750 mg, approximately 500 mg to approximately 1000 mg, approximately 500 mg to approximately 750 mg, approximately 600 mg to approximately 1000 mg, approximately 5 mg to approximately 250 mg, approximately 5 mg to approximately 100 mg, or any suitable range thereof. In some embodiments, the tablets have two or more different dosage strengths. In some embodiments, the amount of compound (I) (e.g., CLTX-305) present in each tablet, on an anhydrous and salt-free basis, is about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the amount of compound (I) (e.g., CLTX-305) present in each tablet, on an anhydrous and salt-free basis, is 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.

[0081] The tablets provided herein may be of one or more dosage strengths, wherein, for example, the amount of CLTX-305 present is 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, for example, the amount of CLTX-305 present in each tablet is 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 The dosage strength is 200 to about 1000 mg, about 200 to about 750 mg, about 200 to about 500 mg, about 300 to about 1000 mg, about 300 to about 750 mg, about 300 to about 500 mg, about 400 to about 1000 mg, about 400 to about 750 mg, about 500 to about 1000 mg, about 500 to about 750 mg, about 600 to about 1000 mg, about 5 to about 250 mg, about 5 to about 100 mg, or any suitable range thereof. In some embodiments, the tablet has two or more different dosage strengths. In some embodiments, the amount of CLTX-305 present in each tablet is about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 300 mg, about 360 mg, about 420 mg, about 480 mg, about 540 mg, about 600 mg, about 660 mg, or about 720 mg.

[0082] The tablets of the present invention can be a generalized mixture formulation in which the weight ratio of the compound to the total weight of one or more pharmaceutically acceptable excipients is constant across a variety of dose intensities. In some embodiments, the weight ratio of the compound to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of the compound (e.g., CLTX-305) to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dose intensities, wherein the amount of the compound of formula (I) (e.g., CLTX-305) present in each tablet, on an anhydrous and salt-free basis, is 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. In some embodiments, the weight ratio of the compound (e.g., CLTX-305) to the total weight of one or more pharmaceutically acceptable excipients is constant in two or more dose intensities, wherein the compound of formula (I) (e.g., CLTX-305) is present in each tablet in an amount of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0083] In some embodiments, the weight / weight ratio of the compound of formula (I) (e.g., CLTX-305) to one or more pharmaceutically acceptable excipients in combination is at least about 1:5, for example at least about 1:5, about 1:6, about 1:7 or greater, for example at least about 1:7.4, wherein said compound is on a salt-free 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 excipients in combination is from about 1:7.4 to about 1:2, wherein said compound is on a salt-free 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 excipients in combination is about 1:7, wherein said compound is on a salt-free 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 excipients in two or more dose strengths is about 1:7, wherein the amount of the compound of formula (I) in each tablet is about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 700 mg, on a salt-free and anhydrous basis.

[0084] In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is at least about 1:6.5. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is from 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 excipients is about 1:6. In some embodiments, the weight / weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is about 1:6 in two or more dose intensities, wherein the amount of CLTX-305 present in each tablet is about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg.

[0085] In some embodiments, the total weight of the solid dosage form (e.g., tablets) (e.g., active ingredient plus excipients—excluding coating) is about 30 to about 3000 mg. In some embodiments, the total weight of the solid dosage form (e.g., tablets) is about 70 mg, 210 mg, 420 mg, 700 mg, 1050 mg, 1400 mg, or 1750 mg. In some embodiments, the total weight of the solid dosage form (e.g., tablets) is about 70 mg, 210 mg, or 420 mg.

[0086] In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in an amount of at least about 12% by weight of the tablet, based on salt-free and anhydrous conditions. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in an amount of about 12% by weight to about 32% by weight of the tablet, based on salt-free and anhydrous conditions. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in an amount of about 12% by weight to about 30% by weight, about 12% by weight to about 25% by weight, about 12% by weight to about 20% by weight, or about 12% by weight to about 15% by weight of the tablet, based on salt-free and anhydrous conditions. In some embodiments, the compound of formula (I) (e.g., CLTX-305) is present in an amount of about 13% by weight of the tablet, based on salt-free and anhydrous conditions.

[0087] In some embodiments, CLTX-305 is present in an amount of at least about 13% by weight of the tablet. In some embodiments, CLTX-305 is present in an amount of about 13% by weight to about 35% by weight of the tablet. In some embodiments, CLTX-305 is present in an amount of about 13% by weight to about 30% by weight, about 13% by weight to about 25% by weight, about 13% by weight to about 20% by weight, or about 13% by weight to about 15% by weight of the tablet. In some embodiments, CLTX-305 is present in an amount of about 13% by weight to about 15% by weight of the tablet. In some embodiments, CLTX-305 is present in an amount of about 14.3% by weight of the tablet.

[0088] In some embodiments, the tablet comprises at least two (2) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least three (3) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least four (4) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least five (5) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least six (6) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least seven (7) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises at least eight (8) pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more flow aids, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof. In some embodiments, the tablet comprises two fillers (i.e., a first filler and a second filler), a flow aid, a disintegrant, a surfactant, a binder, and a lubricant.

[0089] In some embodiments, the tablet comprises one or more fillers. In some embodiments, the tablet comprises two or more fillers. Suitable fillers are as described herein. In some embodiments, the one or more fillers are present 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 of the tablet. In some embodiments, the one or more fillers are present in an amount of about 15% 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 of the tablet. In some embodiments, the one or more fillers are present in an amount of about 50% to about 60% by weight of the tablet. In some embodiments, the one or more fillers are present in an amount of about 55.2% by weight of the tablet.

[0090] In some embodiments, the tablet comprises one to three fillers. In some embodiments, the tablet comprises one to two fillers. In some embodiments, the tablet comprises two to three fillers. In some embodiments, the tablet comprises two fillers (i.e., a first filler and a second filler).

[0091] Suitable fillers include, for example, oligosaccharides (e.g., lactose), sugars, starches, modified starches, sugar alcohols (e.g., mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, cellulose), calcium sulfate, complexes and oxides of magnesium aluminum silicate, and similar fillers. Examples of inorganic salt fillers include phosphates (e.g., calcium hydrogen phosphate) and sulfates. In some embodiments, the one or more fillers comprise sugars, sugar alcohols, cellulose derivatives, or combinations thereof. In some embodiments, the one or more fillers comprise sugar alcohols, cellulose derivatives, or combinations thereof. In some embodiments, the one or more fillers are mannitol, sorbitol, xylitol, lactitol, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or combinations thereof. In some embodiments, the one or more fillers comprise mannitol and microcrystalline cellulose. In some embodiments, the first filler comprises a sugar alcohol; the second filler comprises a cellulose derivative. In some embodiments, the first filler is mannitol; the second filler is microcrystalline cellulose. In some embodiments, the first filler is mannitol; the second filler is microcrystalline cellulose, wherein the ratio of mannitol to microcrystalline cellulose is not greater than 5. In some embodiments, the first filler is mannitol; the second filler is microcrystalline cellulose, wherein the ratio of mannitol to microcrystalline cellulose is not greater than 3. In some embodiments, the first filler is mannitol; the second filler is microcrystalline cellulose, wherein the ratio of mannitol to microcrystalline cellulose is approximately 2.5.

[0092] In some embodiments, mannitol and microcrystalline cellulose are present in amounts 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 40% to about 60% by weight, about 50% to about 70% by weight, or about 50% to about 60% by weight of the tablet. In some embodiments, mannitol and microcrystalline cellulose are present in amounts 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 of the tablet. In some embodiments, mannitol and microcrystalline cellulose are present in amounts of about 50% to about 60% by weight of the tablet. In some embodiments, mannitol and microcrystalline cellulose are present in amounts of about 55.2% by weight of the tablet. In some embodiments, mannitol and microcrystalline cellulose are present in an amount of about 55.2% by weight of the tablet, wherein the ratio of mannitol to microcrystalline cellulose does not exceed about 3.0. In some embodiments, mannitol and microcrystalline cellulose are present in an amount of about 55.2% by weight of the tablet, wherein the ratio of mannitol to microcrystalline cellulose is about 2.5. In some embodiments, mannitol is present in an amount of about 10% to about 60% by weight, about 20% to about 60% by weight, about 30% to about 60% by weight, or about 30% to about 50% by weight of the tablet. In some embodiments, mannitol is present in an amount of about 30% to about 50% by weight of the tablet. In some embodiments, mannitol is present in an amount of about 39.5% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 10% to about 25% by weight or about 10% to about 20% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 10% to about 20% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 15.7% by weight of the tablet.

[0093] In some embodiments, the tablet comprises one or more flow aids. Suitable flow aids are described below. In some embodiments, the one or more flow aids are present in amounts 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 of the tablet. In some embodiments, the one or more flow aids are present in amounts of about 1% to about 5% by weight, about 1% to about 4% by weight, or about 2% to about 4% by weight of the tablet. In some embodiments, the one or more flow aids are present in amounts of about 2% to about 4% by weight of the tablet. In some embodiments, the one or more flow aids are present in amounts of about 3.0% by weight of the tablet.

[0094] In some embodiments, the tablet comprises one or two flow aids. In some embodiments, the tablet comprises one flow aid.

[0095] Suitable flow aids include, for example, magnesium carbonate, calcined silica (colloidal silica), and talc. In some embodiments, the one or more flow aids are silica, talc, magnesium carbonate, or a combination thereof. In some embodiments, the one or more flow aids include colloidal silica. In some embodiments, the tablet includes a flow aid; and the flow aid is colloidal silica.

[0096] In some embodiments, colloidal silica is present in amounts of about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 5 wt%, about 1 wt% to about 4 wt%, or about 2 wt% to about 4 wt% of the tablet. In some embodiments, colloidal silica is present in amounts of about 1 wt% to about 5 wt%, about 1 wt% to about 4 wt%, or about 2 wt% to about 4 wt% of the tablet. In some embodiments, colloidal silica is present in amounts of about 2 wt% to about 4 wt% of the tablet. In some embodiments, colloidal silica is present in amounts of about 3.0 wt% of the tablet.

[0097] In some embodiments, the tablet comprises one or more disintegrants. Suitable disintegrants are described below. In some embodiments, the one or more disintegrants are present in amounts 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 of the tablet. In some embodiments, the one or more disintegrants are present in amounts of about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight of the tablet. In some embodiments, the one or more disintegrants are present in amounts of about 15% to about 25% by weight of the tablet. In some embodiments, the one or more disintegrants are present in amounts of about 20.0% by weight of the tablet.

[0098] When wet granulation is used, in some embodiments, a portion of the one or more disintegrants is added during the granulation process such that the disintegrants remain within the granules (i.e., intragranular); and the remaining portion of the one or more disintegrants is added to the final mixture such that the disintegrants are present outside the granules (i.e., extragranular). In some embodiments, the one or more disintegrants are present intragranularly, extragranularly, or a combination thereof. In some embodiments, the one or more disintegrants are present both intragranularly and extragranularly. In some embodiments, the one or more disintegrants are present intragranularly at an amount of about 1% to about 15% by weight of the tablet. In some embodiments, the one or more disintegrants are present intragranularly at an amount of about 10.0% by weight of the tablet. In some embodiments, the one or more disintegrants are present extragranularly at an amount of about 1% to about 15% by weight of the tablet. In some embodiments, the one or more disintegrants are present extragranularly at an amount of about 10.0% by weight of the tablet.

[0099] In some embodiments, the tablet comprises one or two disintegrants. In some embodiments, the tablet comprises one disintegrant.

[0100] Suitable disintegrants include, for example, croscarmellose sodium, croscarmellose, sodium glycolate starch, and corn starch. In some embodiments, one or more disintegrants include croscarmellose sodium. In some embodiments, the tablet comprises a disintegrant; the disintegrant is croscarmellose sodium.

[0101] In some embodiments, croscarmellose sodium is present in amounts 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 of the tablet. In some embodiments, croscarmellose sodium is present in amounts of about 10% to about 30% by weight, about 15% to about 30% by weight, or about 15% to about 25% by weight of the tablet. In some embodiments, croscarmellose sodium is present in amounts of about 15% to about 25% by weight of the tablet. In some embodiments, croscarmellose sodium is present in amounts of about 20.0% by weight of the tablet. In some embodiments, croscarmellose sodium is present in granule-in-place, granule-out-of-place, or a combination thereof. In some embodiments, croscarmellose sodium is present both granule-in-place and granule-out-of-place. In some embodiments, croscarmellose sodium is present in granules in amounts of about 1% to about 15% by weight of the tablet. In some embodiments, croscarmellose sodium is present within the granules at an amount of about 10.0% by weight of the tablet. In some embodiments, croscarmellose sodium is present outside the granules at an amount of about 1% to about 15% by weight of the tablet. In some embodiments, croscarmellose sodium is present outside the granules at an amount of about 10.0% by weight of the tablet.

[0102] In some embodiments, the tablet comprises one or more surfactants. Suitable surfactants are described below. In some embodiments, the one or more surfactants are present in 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 of the tablet. In some embodiments, the one or more surfactants are present in an amount of about 1% to about 5% by weight, about 1% to about 4% by weight, or about 1% to about 3% by weight of the tablet. In some embodiments, the one or more surfactants are present in an amount of about 1% to about 3% by weight of the tablet. In some embodiments, the one or more surfactants are present in an amount of about 2.0% by weight of the tablet.

[0103] In some embodiments, the tablet comprises one or two surfactants. In some embodiments, the tablet comprises one surfactant.

[0104] Surfactants that can be used in this invention include, but are not limited to, nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, fatty alcohols, fatty acids, and fatty acid salts. In some embodiments, the one or more surfactants include nonionic surfactants. Suitable nonionic surfactants include polyol esters (sucrose fatty acid esters, ethylene glycol fatty acid esters, glycerol fatty acid esters, and sorbitol fatty acid esters), polyoxyethylene esters, and poloxamer. In some embodiments, the one or more surfactants include polyol fatty acid esters. In some embodiments, the one or more surfactants are sucrose fatty acid esters, ethylene glycol fatty acid esters, glycerol fatty acid esters, sorbitol fatty acid esters, or combinations thereof. In some embodiments, the one or more surfactants are one or more sucrose fatty acid esters. In some embodiments, the one or more surfactants are one or more sucrose fatty acid esters, including sucrose palmitate. In some embodiments, the tablet comprises a surfactant; the surfactant is one or more sucrose fatty acid esters, including sucrose palmitate.

[0105] In some embodiments, the one or more sucrose fatty acid esters are present in 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 of the tablet. In some embodiments, the one or more sucrose fatty acid esters are present in an amount of about 1% to about 3% by weight of the tablet. In some embodiments, the one or more sucrose fatty acid esters are present in an amount of about 2.0% by weight of the tablet.

[0106] In some embodiments, the tablet comprises one or more adhesives. Suitable adhesives are described below. In some embodiments, the one or more adhesives are present 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 of the tablet. In some embodiments, the one or more adhesives are present in an amount of about 3% to about 5% by weight of the tablet. In some embodiments, the one or more adhesives are present in an amount of about 4.0% by weight of the tablet.

[0107] In some embodiments, the tablet comprises one or two binders. In some embodiments, the tablet comprises one binder.

[0108] Suitable binders include, for example, povidone, lactose, starch, modified starch, sugar, gum arabic, astragalus gum, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone, gelatin, sodium alginate, etc. In some embodiments, one or more of the binders are cellulose binders. In some embodiments, one or more of the binders are methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or combinations thereof. In some embodiments, one or more of the binders include hydroxypropyl methylcellulose. In some embodiments, the tablet includes a binder; the binder is hydroxypropyl methylcellulose.

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

[0110] In some embodiments, the tablet comprises one or more lubricants. Suitable lubricants are described below. In some embodiments, the one or more lubricants are present in an amount of about 0.2% to about 5% by weight, 1% to about 5% by weight, 1% to about 4% by weight, about 1% to about 3% by weight, or about 1% to about 2% by weight of the tablet. In some embodiments, the one or more lubricants are present in an amount of about 1% to about 3% by weight or about 1% to about 2% by weight of the tablet. In some embodiments, the one or more lubricants are present in an amount of about 1% to about 2% by weight of the tablet. In some embodiments, the one or more lubricants are present in an amount of about 1.5% by weight of the tablet.

[0111] In some embodiments, the tablet comprises one or two lubricants. In some embodiments, the tablet comprises one lubricant.

[0112] Suitable lubricants include, for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl 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, the one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, ethyl oleate, ethyl laurate, stearic acid, palmitic acid, sodium lauryl sulfate, or combinations thereof. In some embodiments, the one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, stearic acid, sodium lauryl sulfate, or combinations thereof. In some embodiments, the one or more lubricants are magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or combinations thereof. In some embodiments, the one or more lubricants include magnesium stearate. In some embodiments, the tablet comprises a lubricant; the lubricant is magnesium stearate.

[0113] In some embodiments, magnesium stearate is present in amounts of about 0.2% to about 5% by weight, 1% to about 5% by weight, 1% to about 4% by weight, about 1% to about 3% by weight, or about 1% to about 2% by weight of the tablet. In some embodiments, magnesium stearate is present in amounts of about 1% to about 3% by weight or about 1% to about 2% by weight of the tablet. In some embodiments, magnesium stearate is present in amounts of about 1.5% by weight of the tablet.

[0114] Other suitable fillers, gliding agents, disintegrants, surfactants, binders, lubricants, and excipients available are described in the following references: Handbook of Pharmaceutical Excipients, 5th Edition, 2006, American Lachman, Leon; Pharmaceutical Dosage Forms: Tablets, Vol. 1, 3rd Edition, 2008, Lieberman, Herbert A. et al.; Modern Pharmaceutics, 4th Edition, 2002, Banker, Gilbert, and Rhodes, Christopher T.; and Remington: The Science and Practice of Pharmacy, 23rd Edition, 2020, each of which is incorporated herein by reference in its entirety.

[0115] In some embodiments, the tablet comprises:

[0116] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0117] b) Two or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0118] in:

[0119] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0120] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0121] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0122] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0123] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0124] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0125] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0126] In some embodiments, the tablet comprises:

[0127] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0128] b) Three or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0129] in:

[0130] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0131] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0132] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0133] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0134] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0135] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0136] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0137] In some embodiments, the tablet comprises:

[0138] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0139] b) Four or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0140] in:

[0141] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0142] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0143] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0144] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0145] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0146] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0147] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0148] In some embodiments, the tablet comprises:

[0149] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0150] b) Five or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0151] in:

[0152] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0153] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0154] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0155] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0156] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0157] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0158] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0159] In some embodiments, the tablet comprises:

[0160] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0161] b) Six or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0162] in:

[0163] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0164] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0165] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0166] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0167] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0168] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0169] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0170] In some embodiments, the tablet comprises:

[0171] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0172] b) Seven or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0173] in:

[0174] The first filler is mannitol, sorbitol, xylitol, lactitol, or a combination thereof;

[0175] The second filler is microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, or a combination thereof;

[0176] The flow aid is silica, talc, magnesium carbonate, or a combination thereof;

[0177] The disintegrant is croscarmellose sodium, croscarmellose, sodium glycolate starch, corn starch, or a combination thereof;

[0178] The surfactant is one or more sucrose fatty acid esters, one or more ethylene glycol fatty acid esters, one or more glycerol fatty acid esters, one or more dehydrated sorbitol fatty acid esters, or a combination thereof;

[0179] The adhesive is methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0180] The lubricant is magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, or a combination thereof.

[0181] In some embodiments, the tablet comprises:

[0182] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0183] b) Two or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0184] in:

[0185] The first filler is mannitol;

[0186] The second filler is microcrystalline cellulose;

[0187] The flow aid is colloidal silica;

[0188] The disintegrant is croscarmellose sodium;

[0189] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0190] The adhesive is hydroxypropyl methylcellulose; and

[0191] The lubricant is magnesium stearate.

[0192] In some embodiments, the tablet comprises:

[0193] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0194] b) Three or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0195] in:

[0196] The first filler is mannitol;

[0197] The second filler is microcrystalline cellulose;

[0198] The flow aid is colloidal silica;

[0199] The disintegrant is croscarmellose sodium;

[0200] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0201] The adhesive is hydroxypropyl methylcellulose; and

[0202] The lubricant is magnesium stearate.

[0203] In some embodiments, the tablet comprises:

[0204] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0205] b) Four or more pharmaceutically acceptable excipients selected from the group consisting of: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0206] in:

[0207] The first filler is mannitol;

[0208] The second filler is microcrystalline cellulose;

[0209] The flow aid is colloidal silica;

[0210] The disintegrant is croscarmellose sodium;

[0211] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0212] The adhesive is hydroxypropyl methylcellulose; and

[0213] The lubricant is magnesium stearate.

[0214] In some embodiments, the tablet comprises:

[0215] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0216] b) Five or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0217] in:

[0218] The first filler is mannitol;

[0219] The second filler is microcrystalline cellulose;

[0220] The flow aid is colloidal silica;

[0221] The disintegrant is croscarmellose sodium;

[0222] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0223] The adhesive is hydroxypropyl methylcellulose; and

[0224] The lubricant is magnesium stearate.

[0225] In some embodiments, the tablet comprises:

[0226] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0227] b) Six or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0228] in:

[0229] The first filler is mannitol;

[0230] The second filler is microcrystalline cellulose;

[0231] The flow aid is colloidal silica;

[0232] The disintegrant is croscarmellose sodium;

[0233] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0234] The adhesive is hydroxypropyl methylcellulose; and

[0235] The lubricant is magnesium stearate.

[0236] In some embodiments, the tablet comprises:

[0237] a) CLTX-305, approximately 13% to approximately 35% by weight; and

[0238] b) Seven or more pharmaceutically acceptable excipients selected from the following group: primary filler, secondary filler, glidant, disintegrant, surfactant, binder, and lubricant.

[0239] in:

[0240] The first filler is mannitol;

[0241] The second filler is microcrystalline cellulose;

[0242] The flow aid is colloidal silica;

[0243] The disintegrant is croscarmellose sodium;

[0244] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0245] The adhesive is hydroxypropyl methylcellulose; and

[0246] The lubricant is magnesium stearate.

[0247] In some embodiments, the tablet comprises:

[0248] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0249] b) Approximately 40% by weight to approximately 70% by weight of the first and second fillers;

[0250] c) Approximately 1% to approximately 5% by weight of a flow aid;

[0251] d) Approximately 10% by weight to approximately 30% by weight of disintegrant;

[0252] e) Approximately 1% to approximately 5% by weight of surfactant;

[0253] f) about 1% to about 5% by weight of the adhesive; and

[0254] g) about 1% to about 3% by weight of lubricant,

[0255] The total weight of components a) to g) is 100%.

[0256] In some embodiments, the tablet comprises:

[0257] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0258] b) Approximately 40% by weight to approximately 70% by weight of the first and second fillers;

[0259] c) Approximately 1% to approximately 4% by weight of a flow aid;

[0260] d) Approximately 15% by weight to approximately 30% by weight of disintegrant;

[0261] e) Approximately 1% to approximately 4% by weight of surfactant;

[0262] f) about 2% to about 5% by weight of adhesive; and

[0263] g) about 1% to about 3% by weight of lubricant,

[0264] The total weight of components a) to g) is 100%.

[0265] In some embodiments, the tablet comprises:

[0266] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0267] b) Approximately 45% by weight to approximately 65% ​​by weight of the first and second fillers;

[0268] c) Approximately 2% to approximately 4% by weight of a flow aid;

[0269] d) Approximately 15% to approximately 25% by weight of disintegrant;

[0270] e) Approximately 1% to approximately 3% by weight of surfactant;

[0271] f) about 3% to about 5% by weight of adhesive; and

[0272] g) about 1% to about 2% by weight of lubricant,

[0273] The total weight of components a) to g) is 100%.

[0274] In some embodiments, the tablet comprises:

[0275] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0276] b) Approximately 30% to approximately 60% by weight of the first filler;

[0277] c) About 10% to about 30% by weight of a second filler;

[0278] d) Approximately 1% to approximately 5% by weight of a flow aid;

[0279] e) Approximately 10% to approximately 30% by weight of disintegrant;

[0280] f) Approximately 1% to approximately 5% by weight of surfactant;

[0281] g) about 1% to about 10% by weight of adhesive; and

[0282] h) about 1% to about 3% by weight of lubricant,

[0283] The total weight of components a) to h) is 100%.

[0284] In some embodiments, the tablet comprises:

[0285] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0286] b) Approximately 30% to approximately 50% by weight of the first filler;

[0287] c) About 10% to about 20% by weight of a second filler;

[0288] d) Approximately 2% to approximately 4% by weight of a flow aid;

[0289] e) about 15% to about 25% by weight of disintegrant;

[0290] f) Approximately 1% to approximately 3% by weight of surfactant;

[0291] g) about 3% to about 5% by weight of the adhesive; and

[0292] h) about 1% to about 2% by weight of lubricant,

[0293] The total weight of components a) to h) is 100%.

[0294] In some embodiments, the tablet comprises:

[0295] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0296] b) Approximately 30% to approximately 50% by weight of the first filler;

[0297] c) About 10% to about 20% by weight of a second filler;

[0298] d) Approximately 2% to approximately 4% by weight of a flow aid;

[0299] e) Approximately 5% to approximately 15% by weight of an intraparticle disintegrant;

[0300] f) Approximately 5% to approximately 15% by weight of the ex-particle disintegrant;

[0301] g) about 1% to about 3% by weight of surfactant;

[0302] h) about 3% to about 5% by weight of the adhesive; and

[0303] i) about 1% to about 2% by weight of lubricant,

[0304] The total weight of components a) to i) is 100%.

[0305] In some embodiments, the tablet comprises:

[0306] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0307] b) From about 30% to about 50% by weight of a first filler selected from the group consisting of mannitol, sorbitol, xylitol and lactitol;

[0308] c) About 10% to about 20% by weight of a second filler selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose and cellulose;

[0309] d) Approximately 2% to approximately 4% by weight of a flow aid selected from the group consisting of silica, talc, and magnesium carbonate;

[0310] e) about 15% by weight to about 25% by weight of a disintegrant selected from the group consisting of: sodium croscarmellose, croscarmellose, sodium glycolate starch and corn starch;

[0311] f) From about 1% by weight to about 3% by weight of surfactants selected from the group consisting of sucrose fatty acid esters, ethylene glycol fatty acid esters, glycerol fatty acid esters and dehydrated sorbitol fatty acid esters;

[0312] g) about 3% to about 5% by weight of an adhesive selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and

[0313] h) From about 1% to about 2% by weight of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearoyl fumarate.

[0314] The total weight of components a) to h) is 100%.

[0315] In some embodiments, the tablet comprises:

[0316] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0317] b) From about 30% to about 50% by weight of a first filler selected from the group consisting of mannitol, sorbitol, xylitol and lactitol;

[0318] c) About 10% to about 20% by weight of a second filler selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose and cellulose;

[0319] d) Approximately 2% to approximately 4% by weight of a flow aid selected from the group consisting of silica, talc, and magnesium carbonate;

[0320] e) about 5% by weight to about 15% by weight of a first disintegrant selected from the group consisting of sodium croscarmellose, croscarmellose, sodium glycolate starch and corn starch, wherein the first disintegrant is present within the particles;

[0321] f) From about 5% to about 15% by weight of a second disintegrant selected from the group consisting of sodium croscarmellose, croscarmellose, sodium glycolate starch and corn starch, wherein the second disintegrant is present outside the particles;

[0322] g) about 1% by weight to about 3% by weight of surfactants selected from the group consisting of sucrose fatty acid esters, ethylene glycol fatty acid esters, glycerol fatty acid esters and dehydrated sorbitol fatty acid esters;

[0323] h) about 3% to about 5% by weight of an adhesive selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and

[0324] i) about 1% to about 2% by weight of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearoyl fumarate.

[0325] The total weight of components a) to i) is 100%.

[0326] In some embodiments, the tablet comprises:

[0327] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0328] b) Approximately 30% to approximately 50% by weight of mannitol;

[0329] c) about 10% to about 20% by weight of microcrystalline cellulose;

[0330] d) about 2% to about 4% colloidal silica;

[0331] e) about 15% to about 25% by weight of croscarmellose sodium;

[0332] f) About 1% to about 3% by weight of one or more sucrose fatty acid esters, including sucrose palmitate;

[0333] g) about 3% to about 5% by weight of hydroxypropyl methylcellulose; and

[0334] h) approximately 1% to approximately 2% by weight of magnesium stearate,

[0335] The total weight of components a) to h) is 100%.

[0336] In some embodiments, the tablet comprises:

[0337] a) Approximately 13% to approximately 15% by weight of CLTX-305;

[0338] b) Approximately 30% to approximately 50% by weight of mannitol;

[0339] c) about 10% to about 20% by weight of microcrystalline cellulose;

[0340] d) about 2% to about 4% colloidal silica;

[0341] e) Approximately 5% to approximately 15% by weight of intraparticle crosslinked sodium carboxymethyl cellulose;

[0342] f) Approximately 5% to approximately 15% by weight of externally cross-linked sodium carboxymethyl cellulose;

[0343] g) about 1% to about 3% by weight of one or more sucrose fatty acid esters, including sucrose palmitate; h) about 3% to about 5% by weight of hydroxypropyl methylcellulose; and

[0344] i) Magnesium stearate of about 1% to about 2% by weight

[0345] The total weight of components a) to i) is 100%.

[0346] In some embodiments, the tablet comprises:

[0347] a) Approximately 14.3% by weight of CLTX-305;

[0348] b) Approximately 39.5% by weight of mannitol;

[0349] c) Approximately 15.7% by weight of microcrystalline cellulose;

[0350] d) Approximately 3.0% by weight of colloidal silica;

[0351] e) Approximately 20.0% by weight of croscarmellose sodium;

[0352] f) about 2.0% by weight of one or more sucrose fatty acid esters, including sucrose palmitate;

[0353] g) Approximately 4.0% by weight of hydroxypropyl methylcellulose; and

[0354] h) Approximately 1.5% by weight of magnesium stearate,

[0355] The total weight of components a) to h) is 100%.

[0356] In some embodiments, the tablet comprises:

[0357] a) Approximately 14.3% by weight of CLTX-305;

[0358] b) Approximately 39.5% by weight of mannitol;

[0359] c) Approximately 15.7% by weight of microcrystalline cellulose;

[0360] d) Approximately 3.0% by weight of colloidal silica;

[0361] e) Approximately 10.0% by weight of intraparticle cross-linked sodium carboxymethyl cellulose;

[0362] f) Approximately 10.0% by weight of externally cross-linked sodium carboxymethyl cellulose;

[0363] g) about 2.0% by weight of one or more sucrose fatty acid esters, including sucrose palmitate;

[0364] h) Approximately 4.0% by weight of hydroxypropyl methylcellulose; and

[0365] i) Approximately 1.5% by weight of magnesium stearate,

[0366] The total weight of components a) to i) is 100%.

[0367] In any of the tablet embodiments described above, the tablet is a generic mixture formulation in which the weight ratio of CLTX-305 to the total weight of one or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of CLTX-305 to the total weight of two or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of CLTX-305 to the total weight of three or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of CLTX-305 to the total weight of four or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of CLTX-305 to the total weight of five or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some embodiments, the weight ratio of CLTX-305 to the total weight of six or more pharmaceutically acceptable excipients is constant across two or more dose intensities. In some implementations, the weight ratio of CLTX-305 to the total weight of seven or more pharmaceutically acceptable excipients is constant across two or more dose intensities.

[0368] In another aspect, the present invention provides a tablet as a universal mixture formulation in two or more dosage intensities. The universal mixture tablet comprises:

[0369] a) CLTX-305 as shown in the following formula:

[0370] and

[0371] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0372] CLTX-305 is present in amounts of approximately 13% to approximately 30% by weight;

[0373] The first filler is mannitol;

[0374] The second filler is microcrystalline cellulose;

[0375] The flow aid is colloidal silica;

[0376] The disintegrant is croscarmellose sodium;

[0377] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0378] The adhesive is hydroxypropyl methylcellulose;

[0379] The lubricant is magnesium stearate; and

[0380] In two or more dosage intensities, the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant.

[0381] In some embodiments, the universal mixed tablet comprises:

[0382] a) CLTX-305 as shown in the following formula:

[0383] and

[0384] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0385] CLTX-305 is present in amounts of approximately 13% to approximately 30% by weight;

[0386] The first filler is mannitol;

[0387] The second filler is microcrystalline cellulose;

[0388] The flow aid is colloidal silica;

[0389] The disintegrant is croscarmellose sodium;

[0390] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0391] The adhesive is hydroxypropyl methylcellulose;

[0392] The lubricant is magnesium stearate; and

[0393] In two or more dosage intensities, the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant.

[0394] In some embodiments of the universal mixed formulation, the tablets have two or more dose strengths, wherein CLTX-305 is present in each tablet in an amount of about 5 to about 1000 mg. In some embodiments, CLTX-305 is present in each tablet in 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.

[0395] In some embodiments of the generic mixed formulation, the weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is from about 1:6.5 to about 1:5. In some embodiments, the weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is from about 1:6. In some embodiments, the weight ratio of CLTX-305 to one or more pharmaceutically acceptable excipients is from about 1:6 across all three dose strengths, wherein CLTX-305 is present in each tablet 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.

[0396] In some embodiments of the universal mixture, the ratio of mannitol to microcrystalline cellulose is not greater than 3. In some embodiments of the universal mixture, mannitol and microcrystalline cellulose are present in amounts 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 of the tablet, wherein the ratio of mannitol to microcrystalline cellulose is not greater than 3. In some embodiments of the universal mixture, mannitol and microcrystalline cellulose are present in amounts of about 50% to about 60% by weight of the tablet, wherein the ratio of mannitol to microcrystalline cellulose is not greater than 3. In some embodiments of the universal mixture, mannitol and microcrystalline cellulose are present in amounts of about 55.2% by weight of the tablet, wherein the ratio of mannitol to microcrystalline cellulose is about 2.5. In some embodiments, mannitol is present in amounts of about 20% to about 60% by weight, about 30% to about 60% by weight, or about 30% to about 50% by weight of the tablet. In some embodiments, mannitol is present in an amount of about 30% to about 50% by weight of the tablet. In some embodiments, mannitol is present in an amount of about 39.5% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 10% to about 25% by weight or about 10% to about 20% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 10% to about 20% by weight of the tablet. In some embodiments, microcrystalline cellulose is present in an amount of about 15.7% by weight of the tablet.

[0397] In some embodiments of the generalized mixed formulation, colloidal silica is present in an amount of about 2% to about 4% by weight of the tablet. In some embodiments, colloidal silica is present in an amount of about 3.0% by weight of the tablet.

[0398] In some embodiments of the generalized mixed formulation, croscarmellose sodium is present in 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 of the tablet. In some embodiments, croscarmellose sodium is present in an amount of about 15% to about 25% by weight of the tablet. In some embodiments, croscarmellose sodium is present in an amount of about 20.0% by weight of the tablet. In some embodiments, croscarmellose sodium is present in an in-granule, out-of-granule, or combination thereof. In some embodiments, croscarmellose sodium is present both in-granule and out-of-granule forms. In some embodiments, croscarmellose sodium is present in the in-granule form of about 5% to about 15% by weight of the tablet. In some embodiments, croscarmellose sodium is present in the in-granule form of about 10.0% by weight of the tablet. In some embodiments, croscarmellose sodium is present in the out-of-granule form of about 5% to about 15% by weight of the tablet. In some embodiments, croscarmellose sodium is present in the out-of-granule form of about 10.0% by weight of the tablet.

[0399] In some embodiments of the generalized mixed formulation, the one or more sucrose fatty acid esters are present in an amount of about 1% to about 3% by weight of the tablet. In some embodiments, the one or more sucrose fatty acid esters are present in an amount of about 2.0% by weight of the tablet.

[0400] In some embodiments of the generalized mixed formulation, hydroxypropyl methylcellulose is present in an amount of about 3% to about 5% by weight of the tablet. In some embodiments, hydroxypropyl methylcellulose is present in an amount of about 4.0% by weight of the tablet.

[0401] In some embodiments of the generalized mixed formulation, magnesium stearate is present outside the granules in an amount of about 1% to about 2% by weight of the tablet. In some embodiments, magnesium stearate is present outside the granules in an amount of about 1% to about 2% by weight of the tablet. In some embodiments, magnesium stearate is present outside the granules in an amount of about 1.5% by weight of the tablet.

[0402] In some embodiments of the universal mixed formulation, the tablets comprise:

[0403] a) CLTX-305 as shown in the following formula:

[0404] and

[0405] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0406] in:

[0407] CLTX-305 was present in an amount of approximately 14.3% by weight;

[0408] The first filler is mannitol present in an amount of about 39.5% by weight;

[0409] The second filler is microcrystalline cellulose present in an amount of approximately 15.7% by weight;

[0410] The flow aid is colloidal silica present in an amount of about 3.0% by weight;

[0411] The disintegrant is croscarmellose sodium, which is present in the particles in an amount of about 10.0% by weight and in the particles in an amount of about 10.0% by weight.

[0412] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate, which is present in an amount of about 2.0% by weight;

[0413] The adhesive is hydroxypropyl methylcellulose present in an amount of about 4.0% by weight; and

[0414] The lubricant is magnesium stearate, which is present in an amount of about 1.5% by weight.

[0415] In some embodiments of any formulation as described in this invention, the tablets are coated with a coating agent. Suitable coating agents include hydroxypropyl methylcellulose, polyvinyl acetone, ethyl cellulose, and polymethyl methacrylate, as well as coating products, such as those from Opadry. TM The coated products sold herein. In some embodiments, the coating agent is the Opadry White Coating System, Opadry Coating System 03B680008 or its equivalents, Opadry Clear, Opadry Blue 13B50579, Opadry QX 321A180025 or Opadry II (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 polyethylene glycol (Macrogol) / PEG (MW 400). In some embodiments, the coating agent is Opadry Coating System 03B680008 or its equivalents. The amount of coating agent is not included in the calculation of the weight percentage of the tablet formulation. That is, the weight percentages reported herein are the weight percentages of uncoated tablets.

[0416] In some embodiments of any formulation as described in this invention, the tablets have a dissolution rate of at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablets containing 10 mg CLTX-305 have a dissolution rate of at least about 90% or at least about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablets containing 10 mg CLTX-305 have a dissolution rate of about 95% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS). In some embodiments, the tablets containing 30 mg CLTX-305 have a dissolution rate 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 tablets containing 30 mg CLTX-305 have a dissolution rate of at least about 90% in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 have a dissolution rate of at least about 80%, at least about 85%, or at least about 90% in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 have a dissolution rate of at least about 85% in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS) after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 have a dissolution rate of at least about 90% after about 60 minutes in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS).

[0417] In some embodiments of any formulation as described in this invention, the tablets have a maximum dissolution rate of nearly 100% after about 20, about 30, about 45, or about 60 minutes. In some embodiments of any formulation as described in this invention, the tablets have a maximum dissolution rate of about 95% after about 20, about 30, about 45, or about 60 minutes. In some embodiments, the tablets containing 10 mg CLTX-305 have a maximum dissolution rate of about 95% after about 20 or about 30 minutes. In some embodiments, the tablets containing 10 mg CLTX-305 have a maximum dissolution rate of about 95% after about 20 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 have a maximum dissolution rate of about 95% after about 20 or about 30 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 have a maximum dissolution rate of about 95% after about 20 minutes. In some embodiments, the tablet containing 30 mg CLTX-305 has a maximum dissolution rate of about 95% after about 30 minutes. In some embodiments, the tablet containing 60 mg CLTX-305 has a maximum dissolution rate of about 95% after about 20, about 30, about 45, or about 60 minutes. In some embodiments, the tablet containing 60 mg CLTX-305 has a maximum dissolution rate of about 95% after about 20 minutes. In some embodiments, the tablet containing 60 mg CLTX-305 has a maximum dissolution rate of about 95% after about 30 minutes. In some embodiments, the tablet containing 60 mg CLTX-305 has a maximum dissolution rate of about 95% after about 45 minutes. In some embodiments, the tablet containing 60 mg CLTX-305 has a maximum dissolution rate of about 95% after about 60 minutes.

[0418] The tablets of the present invention exhibit good stability under storage conditions of about 25°C / 60% relative humidity (RH) or about 40°C / 75% relative humidity (RH), with no significant changes observed in impurities, content (content of compound (I)), dissolution, or tablet appearance during storage. In some embodiments, the tablets are stable for about 6 months at about 40°C and about 75% relative humidity. In some embodiments, the tablets are stable for about 9 months at about 25°C and about 60% relative humidity. In some embodiments, the tablets are stable for about one (1) year at about 25°C and about 60% relative humidity. In some embodiments, the tablets are stable for about two (2) years at about 25°C and about 60% relative humidity. In some embodiments, the tablets are stable for about three (3) years at about 25°C and about 60% relative humidity.

[0419] In some embodiments, the tablets containing 10 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 2%, about 1%, or about 0.5% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 90% after about 60 minutes. In some embodiments, the tablets containing 10 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 0.5% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 95% after about 60 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 75% after about 60 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 80% after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 75% after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 are stable for about 6 months at a temperature of about 40°C and a relative humidity of about 75%, during which time the content of compound (I) changes by less than about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 80% after about 60 minutes.

[0420] In some embodiments, the tablets containing 10 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 2%, about 1%, or about 0.5% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 90% after about 60 minutes. In some embodiments, the tablets containing 10 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 0.5% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 95% after about 60 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 75% after about 60 minutes. In some embodiments, the tablets containing 30 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 80% after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 5%, about 4%, about 3%, about 2%, or about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 75% after about 60 minutes. In some embodiments, the tablets containing 60 mg CLTX-305 are stable for about 9 months at a temperature of about 25°C and a relative humidity of about 60%, during which time the content of compound (I) changes by less than about 1% compared to the initial content; and in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), the dissolution rate of the tablets reaches at least about 80% after about 60 minutes.

[0421] IV. Methods

[0422] In a third aspect, the present invention provides a method for treating autosomal dominant hypocalcemia (ADH, such as type 1 autosomal dominant hypocalcemia (ADH1)). The method comprises administering to a subject in need an effective amount of a tablet, said tablet comprising a compound of formula (I), its solvates, its hydrates, its pharmaceutically acceptable salts, or combinations thereof; and one or more pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof, wherein said compound of formula (I) is present in an amount of at least about 12% by weight, on a salt-free and anhydrous basis.

[0423] In some embodiments, the method includes administering an effective amount of a tablet to a subject in need, said tablet comprising:

[0424] a) CLTX-305 as shown in the following formula:

[0425] and

[0426] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0427] in:

[0428] CLTX-305 is present in amounts of about 13% by weight to about 30% by weight;

[0429] The first filler is mannitol;

[0430] The second filler is microcrystalline cellulose;

[0431] The flow aid is colloidal silica;

[0432] The disintegrant is croscarmellose sodium;

[0433] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0434] The adhesive is hydroxypropyl methylcellulose;

[0435] The lubricant is magnesium stearate; and

[0436] In two or more dosage intensities, the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant.

[0437] In some embodiments, the method includes administering an effective amount of a tablet to a subject in need, said tablet comprising:

[0438] a) CLTX-305 as shown in the following formula:

[0439] and

[0440] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0441] in:

[0442] CLTX-305 is present in amounts of about 13% to about 15% by weight;

[0443] The first filler is mannitol;

[0444] The second filler is microcrystalline cellulose;

[0445] The flow aid is colloidal silica;

[0446] The disintegrant is croscarmellose sodium;

[0447] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate;

[0448] The adhesive is hydroxypropyl methylcellulose;

[0449] The lubricant is magnesium stearate; and

[0450] At two or more dose intensities, the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant.

[0451] In some embodiments, the ADH is type 1 autosomal dominant hypocalcemia (ADH1).

[0452] 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 both 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 previously received treatment for ADH1.

[0453] In some implementations, tablets containing compound (I) are administered orally.

[0454] In some embodiments, the method includes administering an effective amount of a tablet to a subject in need, said tablet comprising:

[0455] a) CLTX-305; and

[0456] b) Seven or more pharmaceutically acceptable excipients, including a first filler, a second filler, a gliding agent, a disintegrant, a surfactant, a binder, and a lubricant;

[0457] in:

[0458] CLTX-305 was present in an amount of approximately 14.3% by weight;

[0459] The first filler is mannitol present in an amount of about 39.5% by weight;

[0460] The second filler is microcrystalline cellulose present at approximately 15.7% by weight;

[0461] The flow aid is colloidal silica present in an amount of about 3.0% by weight;

[0462] The disintegrant is croscarmellose sodium, which is present in the particles in an amount of about 10.0% by weight and in the particles in an amount of about 10.0% by weight.

[0463] The surfactant is one or more sucrose fatty acid esters, including sucrose palmitate, which is present in an amount of about 2.0% by weight;

[0464] The adhesive is hydroxypropyl methylcellulose present in an amount of about 4.0% by weight; and

[0465] The lubricant is magnesium stearate, which is present in an amount of about 1.5% by weight.

[0466] In some embodiments, the formulation is a tablet of about 10 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 720 mg, wherein CLTX-305 is present in each tablet 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.

[0467] In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) increases serum calcium concentration (cCa) to the normal range. In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) alleviates symptoms associated with hypocalcemia.

[0468] In some embodiments, tablets containing an effective amount of the compound of formula (I) (e.g., CLTX-305) increase the level of whole-segment parathyroid hormone (iPTH) in the blood to the normal range.

[0469] In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) reduces elevated urinary calcium levels. In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) increases urinary calcium clearance. In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) minimizes the degree of hypercalciuria.

[0470] In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) reduces serum phosphate levels to the normal range. In some embodiments, an effective amount of a tablet containing a compound of formula (I) (e.g., CLTX-305) minimizes the degree of hyperphosphatemia.

[0471] In some embodiments, a tablet containing an effective amount of the compound of formula (I) (e.g., CLTX-305) increases blood magnesium levels to the normal range. In some embodiments, a tablet formulation containing an effective amount of the compound of formula (I) (e.g., CLTX-305) minimizes the degree of hypomagnesemia.

[0472] The treatment methods of the present invention can be administered alone or in combination with another form of pharmaceutical therapy, such as a second compound having calcium-sensitive receptor antagonistic activity, vitamin D supplements, and / or calcium supplements. In some embodiments, the method further includes administration of an oral calcium supplement. In some embodiments, "combination" means administering the tablets of the present invention and another pharmaceutical agent as part of a treatment regimen or plan to a subject. In some embodiments, combined administration does not require that the tablets and another pharmaceutical agent of the present disclosure be physically combined prior to administration or administered within the same time frame.

[0473] V. Example

[0474] Analysis program

[0475] The analytical method used to test 10mg, 30mg, and 60mg tablets is the same. A brief description of the analytical procedure is provided below.

[0476] Appearance Visual evaluation of tablet formulations is conducted for appearance testing.

[0477] Identification, content, and content uniformity were performed using HPLC.The identification, content, and content uniformity of the tablets were determined by gradient reversed-phase HPLC. The method used a C18 column for gradient elution with a mobile phase of 0.1% (v / v) trifluoroacetic acid (TFA) aqueous solution and 0.1% TFA in a 50 / 50 (v / v) solution of acetonitrile and tetrahydrofuran. Ultraviolet (UV) detection was performed at 220 nm. According to USP... <905> Determine the uniformity of content.

[0478] Related substances The content of relevant substances in the tablets was determined by gradient reversed-phase HPLC. The method used a C18 column for gradient elution, with a mobile phase of 0.1% (v / v) trifluoroacetic acid (TFA) aqueous solution and a 50 / 50 (v / v) solution of 0.1% TFA in acetonitrile and tetrahydrofuran. UV detection was performed at 220 nm. This method is similar to HPLC for identification, content, and content uniformity, the main difference being a longer run time to provide higher resolution for relevant substance peaks.

[0479] Dissolution rate was determined by HPLC. According to USP <711> A standard USP Class 2 (paddle) instrument was used with a paddle speed of 50 RPM or 75 RPM. Dissolution was performed using a buffer solution (pH 6.8) containing sodium dodecyl sulfate (SLS) as the dissolution medium to establish sedimentation conditions for the tablets. Samples were analyzed using a gradient reversed-phase HPLC method with a C18 column. Sample concentrations were determined by standard quantification.

[0480] Water content According to USP <921> Water content was determined by volumetric KF titration.

[0481] Microbial limit test According to USP <61> and USP <62> Microbial testing was conducted.

[0482] Example 1: Preparation of tablets

[0483] Table 1 lists the composition of the tablet formulation. Table 2 lists the components of a suitable Opadry film coating system. Other coating systems may also be suitable.

[0484] Table 1: Composition of Tablets

[0485]

[0486]

[0487] 1. Remove during the processing

[0488] The ingredients of the 2-Opadry coating system meet USP or NF pharmacopoeia standards.

[0489] 3. Meets USP standards for sucrose palmitate.

[0490] Table 2: Composition of the Opadry film coating system 1

[0491] Hydroxypropyl methylcellulose USP, CFR (172.874), EP, JP Titanium dioxide USP, CFR(73.57573.1575), EP, JP Polyethylene glycol / PEG (MW 400) NF, CFR (172.820), EP, JP

[0492] 1. You can use the ObaDai coating system 03B680008 or equivalent products.

[0493] Tablets comprising a compound of formula (I) (e.g., CLTX-305) and pharmaceutically acceptable excipients are prepared according to the following steps.

[0494] Step 1: Allocation

[0495] CLTX-305 and the excipients were weighed according to the composition in Table 1 and then sieved through a sieve before being used to manufacture the tablets of this disclosure.

[0496] Step 2: Fluidized bed granulation

[0497] Before starting the fluidized bed granulation operation, hydroxypropyl methylcellulose and sucrose fatty acid esters are mixed with purified water to form a binder solution.

[0498] CLTX-305, mannitol, microcrystalline cellulose, colloidal silica, and croscarmellose sodium are loaded into a fluidized bed granulator. The granulation process includes the following steps: preheating / premixing the fluidized powder before applying the binder, applying the binder solution, drying, and dispersing.

[0499] Fluidized bed granulation can be performed in batches, depending on the batch size of a given batch. Granulation batches are then combined before final mixing begins.

[0500] Step 3: Final Mixing

[0501] Particles from the fluidized bed granulation operation are loaded into the mixer chamber. If the batch consists of granulation batches, all sub-batches are added to the mixer chamber. The excipients, cross-linked sodium carboxymethyl cellulose, and magnesium stearate are sieved and then loaded into the mixer chamber for final mixing.

[0502] Step 4: Suppression

[0503] The final mixture is compressed into tablets using a tableting machine. After compression, dust is removed and metals are detected. The weight uniformity, hardness, thickness, and friability of the tablet cores are tested.

[0504] Step 5: Coating

[0505] Using a water-spraying system, tablet cores were coated in a coating machine with a suspension of Opadry white in purified water, followed by drying in the coating machine. The weight gain of the tablets was monitored during the coating process.

[0506] Step 6: Packaging

[0507] Thirty tablets, along with a desiccant, are packaged in high-density polyethylene (HDPE) bottles. Each bottle is sensor-sealed and sealed with a child-safe polypropylene cap. The number of tablets, the integrity of the sensor seal, and the cap torque are checked throughout the packaging process.

[0508] Step 7: Label

[0509] The filled bottles were labeled with approval.

[0510] Example 2: Dissolution of tablets

[0511] According to the dissolution method described above, tablets containing 10 mg, 30 mg, and 60 mg of CLTX-305 were dissolved in a buffer solution (pH 6.8) containing sodium dodecyl sulfate (SLS) as the dissolution medium.

[0512] like Figure 1 As shown, the strength of all tablets reached a plateau of maximum dissolution after approximately 20 minutes.

[0513] Example 3: Stability of tablets (non-GMP batch)

[0514] The stability of the formulation was assessed using 10 mg and 60 mg CLTX-305 tablets. Given that the tablet formulation in this application is a generic mixture, stability studies omitted tablets at a 30 mg dose strength. Stability data were obtained for up to six (6) months of accelerated storage at 40°C / 75% RH and up to twelve (12) months of long-term storage at 25°C / 60% RH. Stability can be assessed at additional test intervals, such as 3 months and 6 months. Stability data for appearance, content, total impurities, and dissolution are listed in Tables 3 through 6. No significant changes were observed in impurities, content, dissolution, or tablet appearance under storage conditions of 25°C / 60% RH or 40°C / 75% RH.

[0515] Table 3: Stability of 10mg tablets at 25℃ / 60%RH

[0516]

[0517] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC.

[0518] Table 4: Stability of 10 mg tablets at 40℃ / 75%RH

[0519]

[0520] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC.

[0521] Table 5: Stability of 60 mg tablets at 25°C / 60%RH

[0522]

[0523] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC.

[0524] Table 6: Stability of 60 mg tablets at 40℃ / 75%RH

[0525]

[0526] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC.

[0527] Example 4: Tablet stability (GMP batch)

[0528] The stability of the formulation was assessed using 10 mg, 30 mg, and 60 mg CLTX-305 tablets. Stability data were obtained for up to six (6) months of accelerated storage at 40°C / 75% RH and up to twelve (12) months of long-term storage at 25°C / 60% RH. Stability could be assessed at additional test intervals, such as 3 months and 6 months. Stability data for appearance, content, total impurities, and dissolution are listed in Tables 7 through 12. No significant changes in impurities, content, dissolution, or tablet appearance were observed under storage conditions of 25°C / 60% RH or 40°C / 75% RH.

[0529] Table 7: Stability of 10mg tablets at 25℃ / 60%RH

[0530]

[0531] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities.

[0532] Table 8: Stability of 10 mg tablets at 40℃ / 75%RH

[0533]

[0534]

[0535] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities

[0536] Table 9: Stability of 30mg tablets at 25℃ / 60%RH

[0537]

[0538] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities

[0539] Table 10: Stability of 30 mg tablets at 40°C / 75%RH

[0540]

[0541] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities

[0542] Table 11: Stability of 60 mg tablets at 25°C / 60%RH

[0543]

[0544]

[0545] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities

[0546] Table 12: Stability of 60 mg tablets at 40℃ / 75%RH

[0547]

[0548] 1: AI content refers to the content of compound of formula (I) as active ingredient (AI) determined by HPLC; and 2: specific impurities

[0549] Although the invention has been described in detail herein by way of illustration and example for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by reference in its entirety as if it were incorporated separately by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A tablet comprising: Compounds as shown in formula (I): (I)， or a pharmaceutically acceptable salt thereof, or a combination thereof; and The total content of mannitol and microcrystalline cellulose is 50% to 70% of the tablet formulation weight; Colloidal silica in a content of 1% to 4% by weight of the tablet formulation; Sodium crostomethyl cellulose, present in a content of 10% to 30% of the total weight of the tablet formulation; Its content is 2% to 5% of the total weight of the tablet formulation, containing hydroxypropyl methylcellulose; and Magnesium stearate, in a content of 1% to 2% of the total weight of the tablet formulation.

2. The tablet as described in claim 1, characterized in that, The compound is present in an amount of 12% to 32% by weight of the total weight of the tablets, on a salt-free and anhydrous basis.

3. The tablet as described in claim 1, characterized in that, The compound is present in an amount of 12% to 15% by weight of the total weight of the tablets, based on the principle of salt-free and anhydrous.

4. The tablet as described in claim 1, characterized in that, The compound of formula (I) is a hemihydrate hemisulfate.

5. The tablet as described in claim 4, characterized in that, The compound of formula (I) hemihydrate hemisulfate is present in an amount of 13% to 35% by weight of the tablet.

6. The tablet as described in claim 5, characterized in that, The compound of formula (I) hemihydrate hemisulfate is present in an amount of 14.3% by weight of the tablet.

7. The tablet according to any one of claims 1 to 6, characterized in that, The tablets, when placed in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), release at least 75% by weight of the compound of formula (I) after 60 minutes.

8. The tablet according to any one of claims 1 to 6, characterized in that, The tablets, when placed in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), release at least 80% by weight of the compound of formula (I) after 60 minutes.

9. The tablet according to any one of claims 1 to 6, characterized in that, The tablets, when placed in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), release at least 85% by weight of the compound of formula (I) after 60 minutes.

10. The tablet according to any one of claims 1 to 6, characterized in that, The tablets, when placed in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), release at least 90% by weight of the compound of formula (I) after 60 minutes.

11. The tablet according to any one of claims 1 to 6, characterized in that, The tablets, when placed in a pH 6.8 buffer solution containing sodium lauryl sulfate (SLS), release at least 95% by weight of the compound of formula (I) after 60 minutes.

12. The tablet as claimed in claim 1, characterized in that, The tablets described herein are stable for 6 months at a temperature of 40°C and a relative humidity of 75%.

13. The tablet as claimed in claim 1, characterized in that, The tablets described herein are stable for 9 months at a temperature of 25°C and a relative humidity of 60%.

14. The use of the tablet according to claim 1, characterized in that, This is used to prepare a drug for treating autosomal dominant hypocalcemia type 1 (ADH1) in the subject.

15. The use as described in claim 14, characterized in that, The subjects described suffered from hypocalcemia, hyperphosphatemia, and / or hypercalciuria.

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