Pharmaceutical compositions comprising ryanodine receptor modulators and uses thereof - Patents.com

Abstract

The present disclosure provides a modified release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate and a pharma- ceutically acceptable excipient. The present disclosure discloses a method for treating conditions associated with RyR, including, for example, cardiac dysfunction or disease, musculoskeletal disorders or diseases, muscle weakness associated with cancer, malignant hyperthermia, and diabetes.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 191,142, filed May 20, 2021, which is incorporated by reference in its entirety herein. Government Support Statement

[0002] This invention was made in the fulfillment of a Cooperative Research and Development Agreement with the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. The U.S. Government has certain rights in this invention. [Background technology]

[0002]

[0003] The sarcoplasmic reticulum (SR) contains, among other things, specialized intracellular calcium (Ca 2+ Ryanodine receptors (RyRs) are structures in cells that function as Ca stores. They transport Ca from the SR into the intracellular cytoplasm of the cell. 2+ Ca channels in the SR that open and close to regulate the release of Ca from the SR to the cytoplasm. 2+ When released, cytoplasmic Ca 2+ The open probability of the RyR is the probability that the RyR is open at any given moment and therefore allows Ca2+ to enter the cytoplasm from the SR. 2+ Three RyR isoforms are known: RyR1 is the predominant isoform expressed in mammalian skeletal muscle, RyR2 is found primarily in cardiac muscle, and RyR3 expression is low in skeletal muscle.

[0003]

[0004] Ca from SR 2+Release is regulated by several RyR-binding proteins. Calstabin1 (FKBP12) stabilizes the closed state of RyR1, and calstabin2 (FKBP12.6) stabilizes the closed state of RyR2. Mutations in RYR1 or RYR2 are characterized by reduced binding of calstabin1 or calstabin2, respectively, and inappropriate channel opening that is not associated with contractile signals. This channel opening is further exacerbated by post-translational modifications, such as PKA phosphorylation, oxidation, or nitrosylation of the RyR channel. The resulting dissociation of calstabins can result in the formation of leak channels that exhibit a pathological increase in resting open probability. SR Ca 2+ Leakage of SR Ca 2+ This leads to a decrease in the amount of Ca available for release. 2+ This results in weaker muscle contractions. Summary of the Invention [Means for solving the problem]

[0004]

[0005] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient in a unit dosage form, wherein in a control study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is achieved in the subject.

[0005]

[0006] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof occurs in the subject at a time point between about 2 hours and about 6 hours after administration.

[0006]

[0007] In some embodiments, the disclosure provides a method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, wherein in a control study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in the subject is achieved.

[0007]

[0008] In some embodiments, the present disclosure provides a tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer, - the core comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - The coating layer includes hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0008]

[0009] In some embodiments, the disclosure provides a tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer, and then in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma-ceutically acceptable ion thereof occurs in the subject at a time point between about 2 hours and about 6 hours after administration. In some embodiments, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma-ceutically acceptable salt thereof or a pharma-ceutically acceptable ion thereof occurs in the subject at a time point between about 3 hours and about 4 hours after administration. [Brief description of the drawings]

[0009] [Figure 1]

[0010] FIG. 1 shows the in vitro dissolution time profiles of gastro-resistant tablets (pH 1-2) (0.1 N HCl) or pH 4.5 buffer followed by pH 6.8 buffer of Example 2 (Formulation B1) and Example 3 (Formulation B2). [Diagram 2]

[0011] FIG. 2 shows the in vitro dissolution time profiles of gastro-resistant tablets of Example 2 (pH 6.8, ●) and Example 3 (pH 5.5, △). [Diagram 3]

[0012] FIG. 1 shows the mean plasma concentration (+ / -SD) time profile of Compound I on Day 1 (Phase I: single dose, healthy volunteers) (ng / mL). [Figure 4]

[0013] FIG. 1 shows the mean plasma concentration (+ / -SD) time profile of Compound I on Day 1 (Phase II: Repeated Dose, Healthy Volunteers) (units: ng / mL). [Diagram 5]

[0014] FIG. 1 shows the mean plasma concentration (+ / -SD) time profile of Compound I on day 14 (Phase II: repeated dosing, healthy volunteers) (units: ng / mL). [Figure 6]

[0015] FIG. 1 shows individual plasma concentration-time profiles of Compound I one day after a single oral dose of 120 mg (6 tablets per dose) of Compound I formulated in gastro-resistant tablets in three patients with RYR1-related myopathy. [Figure 7]

[0016] FIG. 1 shows individual plasma concentration-time profiles of Compound I after 28 days of multiple daily oral administration of 120 mg of Compound I (6 tablets per administration) formulated in gastro-resistant tablets to three patients with RYR1-related myopathy. [Figure 8]

[0017] FIG. 1 shows individual plasma concentration-time profiles of Compound I one day after a single oral dose of 200 mg (10 tablets per dose) of Compound I formulated in gastro-resistant tablets in three patients with RYR1-related myopathy. [Figure 9]

[0018] FIG. 1 shows individual plasma concentration-time profiles of Compound I after 28 days of multiple daily oral administration of 200 mg (10 tablets per dose) of Compound I formulated in gastro-resistant tablets to three patients with RYR1-related myopathy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010]

[0019] The present disclosure provides a modified-release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, e.g., the hemifumarate salt, and a pharma- ceutically acceptable excipient. The present disclosure discloses a method of treating conditions associated with RyR, including, for example, cardiac dysfunction or disease, musculoskeletal disorders or diseases, muscle weakness associated with cancer, malignant hyperthermia, and diabetes.

[0011]

[0020] The compound 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid has the following chemical structure:

[0012] [ka]

[0013]

[0021] In some embodiments, 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid is provided in the form of a salt with a pharma- ceutically acceptable acid or base. Non-limiting examples of salts include sodium salt, potassium salt, magnesium salt, hemifumarate, hydrochloride, and hydrobromide salts, and the like. In one embodiment, the salt is a sodium salt. In another embodiment, the salt is a hemifumarate salt.

[0014]

[0022] When present as the hemifumarate salt, the compound is designated herein as Compound (I). Compound (I) has an empirical formula having the following structure or its ionized form:

[0015] [ka]

[0016]

[0023] For example, the compound of formula (I) may be in an ionized form that includes two ionized molecules of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0017] [ka]

[0018] Pharmaceutical Compositions

[0024] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient in a unit dosage form, wherein in a control study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is achieved in the subject.

[0019]

[0025] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form, and a pharma- ceutically acceptable excipient, wherein in a controlled study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is achieved in the subject.

[0020]

[0026] In some embodiments, the pharmaceutical composition provides a modified release of the active ingredient, i.e., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides a sustained release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides a controlled release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides an extended release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides sustained release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides delayed release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof.

[0021]

[0027] In some embodiments, the pharmaceutical composition provides a modified release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the pharmaceutical composition provides a sustained release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the pharmaceutical composition provides a controlled release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the pharmaceutical composition provides an extended release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the pharmaceutical composition provides sustained release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the pharmaceutical composition provides delayed release of the active ingredient, e.g., 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0022] Gastric resistant formulation

[0028] In some forms, the modified release formulation is a gastroresistant formulation. In some embodiments, the modified release formulation is a gastroresistant formulation in unit dosage form. In some embodiments, the modified release formulation is a gastroresistant formulation in unit solid dosage form.

[0023]

[0029] In some forms, the delayed release formulation is a gastroresistant formulation. In some embodiments, the delayed release formulation is a gastroresistant formulation in unit dosage form. In some embodiments, the delayed release formulation is a gastroresistant formulation in unit solid dosage form. In some embodiments, the gastroresistant formulation is a gastroresistant tablet.

[0024]

[0030] Gastro-resistant tablets are delayed-release tablets that can resist the acidic gastric juice and release their active substances in intestinal juice. Gastro-resistant tablets can be prepared from granules or particles already coated with a gastro-resistant coating, or can be prepared by coating tablets with a gastro-resistant coating (e.g., enteric-coated tablets). The pH range of the body fluids in the various segments of the digestive tract provides an environmental stimulus for responsive drug release.

[0025]

[0031] In some embodiments, the enteric coated gastroresistant tablet consists of three layers: (1) a drug-containing core tablet (immediate release function); (2) a subcoat layer that substantially covers the core [the subcoat layer can include a swellable hydrophobic polymer layer (e.g., hydroxypropyl cellulose or hypromellose (hydroxypropyl methylcellulose) (timed release function)]; and (3) an enteric coating layer that includes an enteric polymer [the enteric coating layer substantially covers the subcoat layer (acid resistance function)]. The tablet does not substantially release the drug in the stomach due to the acid resistance of the outer enteric coating layer. The enteric coating layer dissolves rapidly after gastric emptying, and the intestinal fluids begin to gradually degrade the subcoat polymer layer. After gastric emptying, the erosion front reaches the core tablet, and then rapid drug release occurs. The time required for the core tablet to become available by dissolving the slowly degrading layer is the lag phase, the duration of which can be controlled by the mass or composition of the polymer in the subcoat layer.

[0026]

[0032] In some embodiments, the gastroresistant formulation is a delayed release formulation, e.g., due to the sensitivity to pH resulting from the enteric coating, e.g., a modified release formulation, e.g., due to the presence of a polymer in the subcoat layer. In some embodiments, the formulation is characterized by a delayed release profile, such that all or substantially all of the formulation passes through the stomach and is released in the small intestine. Furthermore, the presence of a polymer in the subcoat layer can cause the formulation to slowly and gradually degrade (lag phase), resulting in a sustained release of the active ingredient compared to immediate release formulations. In some embodiments, the gastroresistant formulation has a release profile that is a combination of a delayed release profile, e.g., due to the presence of an enteric coating, and an extended release profile, e.g., due to the presence of a polymer, e.g., due to the presence of a polymer in the subcoat layer.

[0027]

[0033] In some embodiments, the gastroresistant formulation is resistant to disintegration in gastric fluid. For example, in some embodiments, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the active ingredient is released from the formulation in gastric fluid or at a pH that mimics that of gastric fluid. The pH of gastric fluid varies with the presence or absence of food and generally ranges from about 1.5 to about 3.5. In some embodiments, the gastroresistant formulation does not substantially disintegrate for at least about 15 minutes after exposure to gastric fluid. For example, the gastroresistant formulation does not substantially disintegrate for at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, or at least about 120 minutes, at least about 180 minutes, or more after exposure to gastric fluid. In some embodiments, the gastroresistant formulation is resistant to disintegration in gastric fluid in the absence of food. In some embodiments, gastroresistant formulations are resistant to disintegration in gastric fluids in the presence of food.

[0028]

[0034] In some embodiments, the gastro-resistant formulation (e.g., gastro-resistant tablet) does not substantially disintegrate at pH 5.5 or less. For example, the gastro-resistant formulation (e.g., gastro-resistant tablet) releases less than about 10% of the active ingredient at pH 5.5 or less. For example, the gastro-resistant formulation (e.g., gastro-resistant tablet) releases less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the active ingredient at pH about 5.5 or less.

[0029]

[0035] In some embodiments, the gastro-resistant formulation does not substantially disintegrate after exposure to a pH of about 5.5 or less, for example, a pH of about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0 or less. In some embodiments, the gastro-resistant formulation does not substantially disintegrate for at least about 15 minutes after exposure to a pH of about 5.5 or less. For example, the gastro-resistant formulation does not substantially disintegrate for at least about 30 minutes, or at least about 45 minutes, or at least about 60 minutes, or at least about 75 minutes, or at least about 90 minutes, or at least about 120 minutes, or at least about 180 minutes, or more, after exposure to a pH of about 5.5 or less.

[0030]

[0036] In some embodiments, the gastroresistant formulation (e.g., gastroresistant tablet) substantially disintegrates at neutral pH (pH=7) or near neutral pH, e.g., pH 6.8 or higher. In some embodiments, the delayed release formulation releases at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% at a pH of about 6.8 or higher. Such release can occur rapidly, e.g., within 30, or 40, or 50, or 60, or 120, or 180 minutes after the enteric layer and / or subcoat layer slowly degrades to expose the drug-containing core.

[0031]

[0037] In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an enteric coating layer. An enteric-coated tablet is a solid oral dosage unit designed to pass through the stomach and release the drug in the small intestine. In some embodiments, the enteric coating prevents the active ingredient from being released before the tablet reaches the small intestine. When the formulation reaches the small intestine, the enteric coating dissolves and the active ingredient is released. The release of the active ingredient can follow an immediate release profile, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the active ingredient is released within 1 hour of reaching the small intestine.

[0032]

[0038] In some embodiments, disintegration is determined by measuring the dissolution of the gastroresistant formulation in a medium having a pH below 5.5, e.g., a pH between about 1.0 and about 2.0, or a pH between about 4.0 and about 5.0, e.g., a pH of about 4.5. In some embodiments, disintegration is determined by measuring the dissolution of the gastroresistant formulation in a medium having a pH between about 6.5 and about 7.0, e.g., a pH of about 6.8.

[0033]

[0039] In some embodiments, the medium with a pH of less than 5.5 is an HCl solution with a pH of about 1.2. In some embodiments, the medium with a pH of less than 5.5 is a 0.1 N HCl solution with a pH of about 1.2. In some embodiments, the pH 6.8 medium is a phosphate buffer.

[0034]

[0040] In some embodiments, the enteric coating layer dissolves rapidly after gastric emptying, and the intestinal fluids begin to slowly degrade the subcoat polymer layer. After gastric emptying, rapid drug release occurs after the slowly degrading layer reaches the core tablet. The time required for the core tablet to become available by dissolving the slowly degrading layer is called the "lag phase". In some embodiments, the duration of the lag phase can be controlled by varying the mass of the polymer in the subcoat layer. In some embodiments, the duration of the lag phase is controlled by varying the nature of the polymer in the subcoat layer. In some embodiments, the duration of the lag phase is controlled by varying the mass and composition of the polymer in the subcoat layer. In other embodiments, the polymer is hydroxypropyl cellulose. In some embodiments, the polymer is hypromellose (hydroxypropyl methylcellulose).

[0035]

[0041] In some embodiments, the gastroresistant pharmaceutical composition of the present disclosure is administered to a subject in a fed state (e.g., during a meal or within at most about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or about 7 hours after a meal). In some embodiments, the gastroresistant pharmaceutical composition of the present disclosure is administered to a subject in a fasted state (e.g., at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours, or more, after a meal). In some embodiments, the meal is a high-fat meal. In some embodiments, the meal is a low-fat meal.

[0036]

[0042] In some embodiments, the gastric resistant pharmaceutical composition of the present disclosure is administered in combination with a gastric acid-reducing agent. For example, the subject receiving the gastric resistant composition is also administered a regimen of gastric acid-reducing agents. In some embodiments, the gastric acid-reducing agent is administered simultaneously with the gastric resistant pharmaceutical composition. In some embodiments, the gastric acid-reducing agent is administered sequentially, before or after the gastric resistant pharmaceutical composition. In some embodiments, the gastric acid-reducing agent is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours before the gastric resistant formulation. In some embodiments, the gastric acid-reducing agent is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours after the gastro-resistant formulation.

[0037]

[0043] In some embodiments, the subject receiving the combination of the gastroresistant composition and the gastric acid reducing agent has been diagnosed with or is exhibiting symptoms of acid reflux disease or gastroesophageal reflux disease (GERD). Symptoms of acid reflux disease / GERD include, but are not limited to, heartburn, indigestion, reflux, indigestion, abdominal bloating, burping, dysphagia, hiccups, nausea, weight loss, wheezing, coughing, hoarseness, sore throat, and intestinal bleeding.

[0038]

[0044] In some embodiments, the subject receiving the combination of the gastroresistant composition and the gastric acid reducing agent has been diagnosed with or is exhibiting symptoms of esophagitis, including but not limited to, difficulty swallowing, painful swallowing, chest pain, esophageal food impaction, heartburn, acid reflux, and the like.

[0039]

[0045] In some embodiments, the subject receiving the combination of the gastroresistant composition and the gastric acid reducing agent has been diagnosed with or is showing symptoms of peptic ulcer disease. In some embodiments, the peptic ulcer disease includes gastric ulcers. In some embodiments, the peptic ulcer disease includes duodenal ulcers. Symptoms of peptic ulcers include burning stomach pain, feeling full, abdominal bloating or belching, intolerance to fatty foods, heartburn, and nausea.

[0040]

[0046] In some embodiments, the subject receiving the combination gastroresistant composition and gastric acid reducing agent has been diagnosed with or is exhibiting symptoms of Zollinger-Ellison syndrome, including, but not limited to, nausea, vomiting, weight loss, diarrhea, abdominal pain, heartburn, GERD, and intestinal bleeding.

[0041]

[0047] In some embodiments, the subject receiving the combination of the gastroresistant composition and the gastric acid reducing agent has been diagnosed with or is exhibiting symptoms of Helicobacter pylori infection, including but not limited to stomach pain, nausea, loss of appetite, belching, abdominal bloating, or weight loss.

[0042]

[0048] In some embodiments, subjects receiving the combination of a gastroresistant composition and a gastric acid reducing agent are administered the gastric acid reducing agent to reduce the likelihood of developing nonsteroidal anti-inflammatory drug ulcers.

[0043]

[0049] In some embodiments, the pharmaceutical composition is administered in the absence of a gastric acid reducing agent, for example, a subject receiving a gastroresistant composition is not on a regimen of gastric acid reducing agents.

[0044]

[0050] In some embodiments, the gastric acid reducing agent is a proton pump inhibitor (PPI). Non-limiting examples of proton pump inhibitors include omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and the like.

[0045]

[0051] In some embodiments, the stomach acid reducing agent is an antacid. Non-limiting examples of antacids include sodium bicarbonate, calcium bicarbonate, aluminum hydroxide, magnesium hydroxide, and the like.

[0046]

[0052] In some embodiments, the gastric acid reducing agent is a histamine H2 receptor antagonist. Non-limiting embodiments of histamine H2 receptor antagonists include cimetidine, ranitidine, famotidine, and nizatidine.

[0047]

[0053] In some embodiments, the subject administered the gastroresistant composition has been diagnosed with achlorhydria or has symptoms of achlorhydria. In some embodiments, the subject administered the gastroresistant composition has been diagnosed with hypochlorhydria or has symptoms of hypochlorhydria. Achlorhydria refers to a state in which hydrochloric acid production in the stomach is absent, or hypochlorhydria refers to a state in which hydrochloric acid production in the stomach is reduced. Symptoms of achlorhydria and hypochlorhydria include, but are not limited to, epigastric pain, weight loss, heartburn, nausea, abdominal bloating, diarrhea, abdominal pain, acid reflux, early satiety, vomiting, postprandial bloating, constipation, dysphagia, and glossitis.

[0048]

[0054] In some embodiments, the present disclosure provides a gastro-resistant tablet comprising a tablet core comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof as an active ingredient, a subcoat layer substantially surrounding the core, and an enteric coating comprising an enteric polymer, the enteric coating substantially surrounding the subcoat.

[0049]

[0055] In some embodiments, the present disclosure provides a gastro-resistant tablet comprising a tablet core comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate as an active ingredient, a subcoat layer substantially surrounding the core, and an enteric coating comprising an enteric polymer, the enteric coating substantially surrounding the subcoat.

[0050]

[0056] In some embodiments, the present disclosure provides a tablet comprising a core, a subcoating layer substantially coating the core, and a coating layer substantially coating the subcoating layer, - the core comprises 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - The coating layer includes hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0051]

[0057] In some embodiments, the present disclosure provides a tablet comprising a core, a subcoating layer substantially coating the core, and a coating layer substantially coating the subcoating layer, - the core comprises 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - The coating layer includes hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0052]

[0058] In some embodiments, the present disclosure provides a tablet comprising a core, a subcoating layer substantially coating the core, and a coating layer substantially coating the subcoating layer, - the core comprises 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - The coating layer includes hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0053]

[0059] In some embodiments, the enteric polymer is hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMC-AS), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid / methacrylic acid ester copolymer (e.g., poly(methacrylic acid-co-methyl methacrylate), methacrylic acid / acrylic acid ester copolymer, or shellac (ester of aleurtic acid). In some embodiments, the enteric polymer is hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMC-AS).

[0054]

[0060] In some embodiments, the enteric coating and subcoat are each independently provided in an amount between about 0.1% and about 50% by weight of the composition, e.g., between about 0.1% and about 45%, between about 0.1% and about 40%, between about 0.1% and about 35%, between about 0.1% and about 30%, between about 0.1% and about 25%, between about 0.1% and about 20%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, or between about 0.1% and about 1% by weight of the formulation.

[0055]

[0061] The enteric coating and the subcoat each independently comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 , about 20 mass%, about 21 mass%, about 22 mass%, about 23 mass%, about 24 mass%, about 25 mass%, about 26 mass%, about 27 mass%, about 28 mass%, about 29 mass%, about 30 mass%, about 31 mass%, about 32 mass%, about 33 mass%, about 34 mass%, about 35 mass%, It may be present at about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%, by weight.

[0056]

[0062] In some embodiments, the formulation comprises about 1% to about 5% by weight of the polymer in the subcoat layer, hi some embodiments, the formulation comprises about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% or more by weight of the polymer in the subcoat layer.

[0057]

[0063] In some embodiments, the formulation comprises about 5% to about 20% by weight of the polymer in the enteric coating layer. In some embodiments, the formulation comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or about 13%, about 14%, or about 15% or more by weight of the polymer in the enteric coating layer. The pharmaceutical composition of the present disclosure comprises one or more pharma- ceutically acceptable excipients or carriers. The pharma-ceutically acceptable excipients are provided, for example, as components of the core, subcoating, or coating layer of the composition. The pharma-ceutically acceptable excipients are, for example, compatible with other components of the composition and not deleterious to the recipient thereof.

[0058]

[0064] In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. Pharmaceutical compositions for solid oral administration include tablets, dragees, sublingual tablets, sachets, capsules including gelatin capsules, powders, and granules, while pharmaceutical compositions for liquid oral, nasal, buccal, or ocular administration include emulsions, solutions, suspensions, drops, syrups, and aerosols. The compound can also be administered as a suspension or solution through drinking water or with food. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a gastroresistant tablet.

[0059]

[0065] The pharma- ceutically acceptable excipients or carriers can be selected from a variety of organic and inorganic materials used as ingredients in pharmaceutical formulations. Such materials can be incorporated as any one or more of fillers, diluents, binders, disintegrants, lubricants, glidants, plasticizers, surfactants (wetting agents), buffers (pH adjusters), suspending agents, colorants, emulsifiers, flavor-improving agents, gelling agents, preservatives, solubilizers, stabilizers, sweeteners, tonicity agents, dispersants, swelling agents, retardants, absorption agents, and / or viscosity-increasing agents.

[0060]

[0066] Non-limiting examples of pharma-ceutically acceptable fillers / diluents include microcrystalline cellulose, silicified microcrystalline cellulose carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), ethylcellulose, starch, sugars such as mannitol, sucrose, lactose, sorbitol, or dextrins (such as maltodextrin), and amino sugars.

[0061]

[0067] Non-limiting examples of pharma-ceutically acceptable binders include microcrystalline cellulose, gum tragacanth, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose (hypromellose), and starch.

[0062]

[0068] Non-limiting examples of pharma-ceutically acceptable disintegrants include croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

[0063]

[0069] Non-limiting examples of pharma- ceutically acceptable lubricants include stearates, such as magnesium stearate or zinc stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, and hydrogenated vegetable oils.

[0064]

[0070] Non-limiting examples of pharma- ceutically acceptable lubricants include colloidal silicon dioxide, talc, tricalcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, magnesium stearate, talc, and mineral oil.

[0065]

[0071] A non-limiting example of a moisture barrier agent includes stearic acid.

[0066]

[0072] Non-limiting examples of pharma-ceutically acceptable plasticizers include trialkyl citrates, such as triethyl citrate.

[0067]

[0073] Non-limiting examples of pharma- ceutically acceptable surfactants include sodium lauryl sulfate or polysorbates, polyvinyl alcohol (PVA), polyethylene glycols, polyoxyethylene-polyoxypropylene block copolymers known as "poloxamers", polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, and hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil.

[0068]

[0074] Non-limiting examples of pharma- ceutically acceptable flavoring agents include sweeteners, such as sucralose, synthetic flavor oils and flavoring aromatics, natural oils, extracts from plants, leaves, flowers, and fruits, and combinations thereof.Non-limiting examples of flavoring agents include cinnamon oil; oil of wintergreen; peppermint oil; clover oil; hay oil; anise oil; eucalyptus; peppermint; vanilla; citrus oils, such as lemon oil, orange oil, grape and grapefruit oil, and fruit essences, including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0069]

[0075] Non-limiting examples of pharma- ceutically acceptable pigments or colorants include alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, beta-carotene, cochineal extract, carmine, sodium potassium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dentifrice, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide.

[0070]

[0076] Non-limiting examples of buffers or pH adjusters include acidic buffers such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid, and fumaric acid; and basic buffers such as Tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide.

[0071]

[0077] Non-limiting examples of tonicity enhancing agents include ionic and non-ionic agents such as alkali or alkaline earth metal halides, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose.

[0072]

[0078] Non-limiting examples of humectants include glycerin, cetyl alcohol, and glycerol monostearate.

[0073]

[0079] Non-limiting examples of preservatives include benzalkonium chloride, benzoxonium chloride, thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl alcohol, chlorhexidine, and polyhexamethylene biguanide.

[0074]

[0080] Non-limiting examples of antioxidants include sorbic acid, ascorbic acid, ascorbate, glycine, α-tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0075]

[0081] In some embodiments, the core of the pharmaceutical composition comprises mannitol. In some embodiments, the core of the pharmaceutical composition comprises microcrystalline cellulose. In some embodiments, the core of the pharmaceutical composition comprises croscarmellose sodium. In some embodiments, the core of the pharmaceutical composition comprises magnesium stearate. In some embodiments, the core of the pharmaceutical composition comprises maltodextrin. In some embodiments, the core of the pharmaceutical composition comprises colloidal anhydrous silica. In some embodiments, the core of the pharmaceutical composition comprises sodium stearyl fumarate.

[0076]

[0082] In some embodiments, the subcoat of the pharmaceutical composition comprises hydroxypropyl methylcellulose (HPMC, hypromellose). In some embodiments, the subcoat of the pharmaceutical composition comprises microcrystalline cellulose. In some embodiments, the subcoat of the pharmaceutical composition comprises stearic acid.

[0077]

[0083] In some embodiments, the enteric coating of the pharmaceutical composition comprises hypromellose acetate succinate. In some embodiments, the enteric coating of the pharmaceutical composition comprises triethyl citrate. In some embodiments, the enteric coating of the pharmaceutical composition comprises sodium lauryl sulfate. In some embodiments, the enteric coating of the pharmaceutical composition comprises talc.

[0078]

[0084] The pharma- ceutically acceptable excipient may be present in the pharmaceutical composition at a mass of between about 0.1% and about 99% by mass of the composition. For example, the pharma- ceutically acceptable excipient may be present at a mass of between about 0.1% and about 95% by mass, between about 0.1% and about 90% by mass, between about 0.1% and about 85% by mass, between about 0.1% and about 80% by mass, between about 0.1% and about 75% by mass, between about 0.1% and about 70% by mass, between about 0.1% and about 65% by mass, between about 0.1% and about 60% by mass, between about 0.1% and about 55% by mass, between about 0.1% and about 50% by mass, or between about 0.1% and about 100% by mass. %, between about 0.1% and about 45% by mass, between about 0.1% and about 40% by mass, between about 0.1% and about 35% by mass, between about 0.1% and about 30% by mass, between about 0.1% and about 25% by mass, between about 0.1% and about 20% by mass, between about 0.1% and about 15% by mass, between about 0.1% and about 10% by mass, between about 0.1% and about 5% by mass, or between about 0.1% and about 1% by mass.

[0079]

[0085] Pharmaceutically acceptable excipients may be present in the formulation at about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by weight, about 66% by weight, about 67% by weight, about 68% by weight, about 69% by weight, about 70% by weight, about 71% by weight, about 72% by weight, about 73% by weight, about 74% by weight, about 75% by weight, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight, about 85% by weight, about 86% by weight, about 87% by weight, about 88% by weight, about 89% by weight, about 90% by weight, about 91% by weight, about 92% by weight, about 93% by weight, about 94% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, about 99% by weight, about 99.1% by weight, about 99.2% by weight, about 99.3% by weight, about 99.4% by weight, about 99.5% by weight, about 99.6% by weight, about 99.7% by weight, about 99.8% by weight, or about 99.9% by weight.

[0080]

[0086] According to the methods of the present disclosure, any of these compounds can be administered to a subject (or contacted with a cell of a subject) in an amount effective to limit or reduce the likelihood of a decrease in the level of RyR-bound calstabins in the subject, particularly in the cells of the subject. Alternatively, the methods of the present disclosure include administering an amount of a compound effective to treat an RyR-associated condition or reduce the likelihood of an RyR-associated condition as described herein.

[0081]

[0087] The pharmaceutical compositions disclosed herein are suitable for administration to human or animal subjects in a biologically compatible form suitable for in vivo administration.Subjects can be, for example, elderly, adults, adolescents, prepubertals, children, infants, babies, newborns, and non-human animals.In some embodiments, subjects are patients.

[0082] Method of preparation

[0088] The pharmaceutical compositions described herein can be prepared by any suitable pharmaceutical technique. Suitable pharmaceutical techniques include, for example, one or a combination of the following methods: (1) wet granulation; (2) dry granulation; (3) dry blending; (4) direct compression; (5) milling; (6) roller compaction; or (7) melting. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0083]

[0089] In some embodiments, the tablet disclosed herein is prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and further mixed in the presence of liquid, e.g., water, to cause the powder to aggregate into granules. The granulation is dried and then screened and / or milled to a desired particle size. The granulation can then be tableted or other excipients, e.g., glidants and / or lubricants, can be added before tableting.

[0084]

[0090] In some embodiments, the active ingredient, for example, 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, is dissolved with one or more pharma- ceutically acceptable excipients, and the resulting mixture is granulated in the presence of a suitable solvent, for example, water. A wet granulation is obtained, which can be dried and optionally sieved to obtain a dry granulation. The dry granulation can be mixed with one or more additional pharma- ceutically acceptable excipients, optionally sieved, and compressed into tablets.

[0085]

[0091] In some embodiments, the tablets disclosed herein are prepared by dry granulation. In some embodiments, the dry granulation is a slugging process. Slugging is a dry granulation process in which the active ingredient, optionally combined with one or more excipients, is first compressed to form slugs, and then milled to form fine particles suitable for further processing. For example, the blended composition of the active ingredient and pharma-ceutically acceptable excipients can be compressed into slugs or sheets, and then milled into compacted granules. The compacted granules are then compressed into tablets. In some embodiments, the granulation of the active ingredient, such as 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepine-4(5H)yl)methyl]benzoic acid or a pharma-ceutically acceptable salt thereof, can be achieved by dry granulation.

[0086]

[0092] In other embodiments, the blended composition can be compressed directly into a compacted dosage form using direct compression techniques, which produces a more uniform tablet without granules.

[0087]

[0093] In some embodiments, the granulation process comprises a roller compaction process, where powder size expansion is achieved by feeding the active ingredient, optionally in combination with one or more wet or dry excipients, through a roller apparatus, followed by drying (if necessary), milling, and sizing the compacted mixture to form granules having the desired particle size.

[0088]

[0094] In some embodiments, the capsules described herein may contain any of the foregoing blends and granulations described with respect to tableting, but which are not subjected to a final tableting step.

[0089] Pharmaceutically acceptable salts

[0095] The present disclosure provides the use of any therapeutic compound described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid that forms the acid addition salt with the compound can be an organic acid or an inorganic acid. The base that forms the base addition salt with the compound can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

[0090]

[0096] Metal salts can result from the addition of inorganic bases to the compounds of the present disclosure. Inorganic bases consist of a metal cation paired with a basic counterion, such as hydroxide, carbonate, bicarbonate, phosphate, etc. The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0091]

[0097] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0092]

[0098] Ammonium salts can result from the addition of ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0093]

[0099] In some embodiments, the ammonium salt is a triethylamine salt, a trimethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0094]

[0100] Acid addition salts may result from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0095]

[0101] In some embodiments, the salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, pantothenate, acetate, trifluoroacetate, mandelate, cinnamate, aspartate, stearate, palmitate, glycolate, propionate, butyrate, fumarate, hemifumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate salt. Dosage and Dosing Regimen

[0102] In some embodiments, a suitable amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof effective to limit or reduce the potential for a decrease in the level of RyR-bound calstabins in a subject and / or to treat or reduce a condition associated with RyR ranges from about 100 to about 500 mg per day, e.g., about 100 mg per day, about 110 mg per day, about 120 mg per day, about 130 mg per day, about 140 mg per day, about 150 mg per day, about 160 mg per day, about 170 mg per day, about 180 mg per day, about 190 mg per day, about 200 mg per day, about 210 mg per day, about 220 mg per day, About 230mg per day, about 240mg per day, about 250mg per day, about 260mg per day, about 270mg per day, about 280mg per day, about 290mg per day, about 300mg per day, about 310mg per day, about 320mg per day, about 330mg per day, about 340mg per day, about 350mg per day, about 360mg per day, about about 370 mg per day, about 380 mg per day, about 390 mg per day, about 400 mg per day, about 410 mg per day, about 420 mg per day, about 430 mg per day, about 440 mg per day, about 450 mg per day, about 460 mg per day, about 470 mg per day, about 480 mg per day, about 450 mg per day, or about 500 mg per day.

[0096]

[0103] In some embodiments, a suitable amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof effective to limit or reduce the potential for a decrease in the level of RyR-bound calstabin in a subject and / or to treat or reduce a condition associated with RyR is from about 1 mg to about 2000 mg per day; from about 1 mg to about 1000 mg per day, from about 1 mg to about 500 mg per day, from about 5 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 5 mg to about 100 mg per day, from about 10 mg to about 50 mg per day, from about 50 mg to about 250 mg per day, from about 100 mg to about 200 mg per day, from about 1 mg to about 50 mg per day, from about 50 mg to about 10 mg per day, 0 mg, about 100 mg to about 150 mg per day, about 150 mg to about 200 mg per day, about 200 mg to about 250 mg per day, about 250 mg to about 300 mg per day, about 300 mg to about 350 mg per day, about 350 mg to about 400 mg per day, about 400 mg to about 450 mg per day, about 450 mg to about 500 mg per day, about 500 mg to about 550 mg per day, about 550 mg to about 600 mg per day, about 600 mg to about 650 mg per day, about 650 mg to about 700 mg per day, about 700 mg to about 750 mg per day, about 750 mg to about 800 mg per day, about 800 mg to about 850 mg per day, about 850 mg to about 900 mg per day, about 900 mg to about 950 mg per day, or about 950 mg to about 1000 mg per day.

[0097]

[0104] In some embodiments, 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3 In some embodiments, the compound is present in the composition in an amount of about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.

[0098]

[0105] In some embodiments, the daily dose of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is 120 mg based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the daily dose of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is 200 mg based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the daily dose of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is 141 mg. In some embodiments, the daily dose of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is 235 mg.

[0099]

[0106] In some embodiments, the disclosure provides a pharmaceutical composition comprising 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the disclosure provides a pharmaceutical composition comprising 23.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form.

[0100]

[0107] In some embodiments, the disclosure provides a pharmaceutical composition comprising 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the disclosure provides a pharmaceutical composition comprising 58.75 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form.

[0101]

[0108] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 117.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form.

[0102]

[0109] In some embodiments, the dosage can be expressed in terms of the amount of drug divided by the mass of the subject, e.g., milligrams of drug per kilogram of body weight of the subject. In some embodiments, the compound is administered in an amount ranging from about 5 mg / kg to about 50 mg / kg per day, about 250 mg / kg to about 2000 mg / kg per day, about 10 mg / kg to about 800 mg / kg per day, about 50 mg / kg to about 400 mg / kg per day, about 100 mg / kg to about 300 mg / kg per day, or about 150 mg / kg to about 200 mg / kg per day.

[0103] Pharmacokinetics

[0110] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, the unit dosage form being a delayed release, gastro-resistant dosage form that releases the active ingredient, 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, after a delay period of about 2 to 4 hours after administration. In some embodiments, the active ingredient is released from the composition in a controlled study manner such that, when the unit dosage form is administered to a test subject in a controlled study, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, the period of time being at least about 12 hours. In some embodiments, the active ingredient is released from the composition in a controlled study manner such that when the unit dosage form is administered to a test subject in a controlled study, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, the period of time being at least about 24 hours. The pharmaceutical compositions of the present disclosure are suitable for once-daily administration.

[0104]

[0111] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a control study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, the period of time being at least about 6 hours. In some embodiments, the period is at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours after administration.

[0105]

[0112] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, there is a maximum plasma concentration (C max ) is present in the subject about 2 to about 6 hours after administration (t maxIn some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration (C max ) is present in the subject about 2 to about 5 hours after administration (t max In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration (C max ) is present in the subject about 2 to about 4 hours after administration (t max In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration (C max ) is present in the subject about 3 to about 4 hours after administration (t maxIn some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached about 3 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,3.5-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached about 3.5 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,4-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached about 4 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,4.5-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 4.5 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,5-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 5 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,5.5-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 5.5 hours after administration. In some embodiments, the maximum plasma concentration of 4-[(7-methoxy-2,6-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt or ion thereof, is reached about 6 hours after administration.

[0106]

[0113] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, there is a maximum steady-state plasma concentration (C max ) is present in the subject about 2 to about 6 hours after administration (t max In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, there is a maximum steady-state plasma concentration (C max ) is present in the subject about 2 to about 5 hours after administration (t max In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, there is a maximum steady-state plasma concentration (C max ) is present in the subject about 2 to about 4 hours after administration (t max). In some embodiments, the steady-state maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 3 hours after administration. In some embodiments, the steady-state maximum plasma concentration of 4-[(7-methoxy-2,3.5-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma-ceutically acceptable salt or ion thereof is reached at about 3.5 hours after administration. In some embodiments, the steady-state maximum plasma concentration of 4-[(7-methoxy-2,4-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma-ceutically acceptable salt or ion thereof is reached at about 4 hours after administration. In some embodiments, the maximum steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 4.5 hours after administration. In some embodiments, the maximum steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 5 hours after administration. In some embodiments, the maximum steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached at about 5.5 hours after administration. In some embodiments, the maximum steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is reached about 6 hours after administration. In some embodiments, the salt is a hemifumarate salt.

[0107]

[0114] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, an in-vivo terminal half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of about 14 to about 21 hours is obtained in the subject. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or an ion thereof is about 14 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 15 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 16 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 17 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 18 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 19 hours. In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or ion thereof is about 20 hours.In some embodiments, the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt or ion thereof, is about 21 hours. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt. In some embodiments, the half-life (t 1 / 2、z or t1 / 2) is the terminal elimination half-life of the compound, t 1 / 2,z =ln(2) / λ z (λ z is the rate constant for the terminal phase).

[0108]

[0115] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, the C of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, or a pharma- ceutical ion thereof, is between about 1.4 and about 1.8. max A cumulative ratio of C to C is present in the subject, the cumulative ratio being C at day 28 max / Day 1 C max It is calculated as the common ratio of C max is the maximum observed plasma concentration. For example, the cumulative ratio C max can be between about 1.4 and about 1.5, between about 1.4 and about 1.6, between about 1.4 and about 1.7, between about 1.5 and about 1.7, between about 1.5 and about 1.8, between about 1.6 and about 1.7, or between about 1.7 and about 1.8. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt.

[0109]

[0116] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, a cumulative ratio of AUC of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of between about 1.4 and about 1.8 is present in the subject. For example, the cumulative ratio AUC can be between about 1.4 and about 1.5, between about 1.4 and about 1.6, between about 1.4 and about 1.7, between about 1.5 and about 1.7, between about 1.5 and about 1.8, between about 1.6 and about 1.7, or between about 1.7 and about 1.8. In some embodiments, the pharma- ceutically acceptable salt is a hemifumarate salt. The cumulative ratio for AUC is AUC tau / AUC on day 1 0-24 About AUC tau It is calculated as the ratio of - AUC is the area under the concentration-time curve; - AUC tau is the area under the concentration-time curve during the dosing interval (tau) at steady state; - AUC 0-24 is the area under the concentration-time curve from 0 to 24 hours after administration.

[0110]

[0117] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, and in a controlled study, when the unit dosage form is administered to a test subject, there is a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof, of less than about 35 ug / mL in the subject. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt.

[0111]

[0118] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof is about 10 to about 15 ng / mL in the subject after a single dose of 120 mg. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt.

[0112]

[0119] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof is about 17 to about 21 ng / mL in the subject after a dose of 120 mg administered once daily for 14 days. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt.

[0113]

[0120] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, wherein in a controlled study, when the unit dosage form is administered to a test subject, a steady state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof occurs in the test subject in a range of about 3 to about 7 days after the first administration. In some embodiments, the steady state is reached about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after a once-daily administration. In some embodiments, the pharma- ceutically acceptable salt thereof is a hemifumarate salt.

[0114]

[0121] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, comprising about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, based on the weight of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0115]

[0122] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, the pharmaceutical composition comprising about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0116]

[0123] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, comprising 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the weight of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0117]

[0124] In some embodiments, the disclosure provides a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof in a unit dosage form, comprising 23.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0118] Treatment purpose

[0125] In some embodiments, the present disclosure provides oral modified release formulations of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate that are capable of treating conditions, disorders, and diseases associated with the ryanodine receptor (RyR).

[0119]

[0126] In some embodiments, the present disclosure provides compounds that are RyR modulators, such as Rycal compounds. Rycal compounds are small molecule compounds that can, for example, bind to leaky RyR subunits, restore calstabin binding, and repair channel leakage. In some embodiments, Rycal binds to leaky RyR channels, restores calstabin binding, and repairs channel leakage without blocking the RyR channel. In some embodiments, Rycal compounds can repair leakage of RyR channels, such as RyR1, RyR2, and / or RyR3 channels. In some embodiments, the compositions of the present disclosure enhance the association and / or inhibit the dissociation of RyR and calstabins (e.g., RyR1 and calstabin1; RyR2 and calstabin2; and RyR3 and calstabin1).

[0120]

[0127] Non-limiting examples of RyR-related conditions, disorders and diseases include disorders and diseases that can be treated and / or prevented by regulating RyR, such as cardiac dysfunction or disease, musculoskeletal disorder or disease, muscle weakness associated with cancer, malignant hyperthermia, and diabetes.The compounds herein can also reduce the likelihood of such conditions occurring.

[0121]

[0128] In some embodiments, the disclosure provides a method of treating a condition or reducing the likelihood of occurrence of a condition by administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharmaceutically acceptable excipient.

[0122]

[0129] In some embodiments, the disclosure provides a method of treating a condition or reducing the likelihood of occurrence of a condition by administering to a subject in need thereof a modified release pharmaceutical composition comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate and a pharma- ceutically acceptable excipient. In some embodiments, the composition is in a solid dosage form. In some embodiments, the composition is in a form suitable for oral administration.

[0123]

[0130] In some embodiments, the disclosure provides a modified release pharmaceutical composition comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharma- ceutically acceptable excipient, for use in a method of treating a condition or reducing the likelihood of occurrence of a condition.

[0124]

[0131] In some embodiments, the present disclosure provides a modified release composition comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharma- ceutically acceptable excipient, for use in the manufacture of a medicament.

[0125]

[0132] In some embodiments, the condition, disorder, or disease is associated with dysfunction of RyR1. In some embodiments, the condition, disorder, or disease is associated with dysfunction of RyR2. In some embodiments, the condition, disorder, or disease is associated with dysfunction of RyR3.

[0126]

[0133] In some embodiments, the condition is a cardiac dysfunction or disease. In some embodiments, the condition is a musculoskeletal disorder or disease. In certain embodiments, the condition is muscle weakness associated with cancer. In some embodiments, the condition is malignant hyperthermia. In some embodiments, the condition is diabetes. Ryanodine receptor excitation-contraction coupling (ECC) process

[0134] The sarcoplasmic reticulum (SR) contains, among other things, specialized intracellular calcium (Ca 2+ Ryanodine receptors (RyRs) are structures in cells that function as Ca stores. They transport Ca from the SR into the intracellular cytoplasm of the cell. 2+ It is a channel in the SR that opens and closes to regulate the release of Ca from the SR to the cytoplasm. 2+ When released, cytoplasmic Ca 2+ The open probability of the RyR is the probability that the RyR is open at any given moment, thus allowing Ca concentration to flow from the SR to the cytoplasm. 2+ This refers to the possibility that it is possible to release

[0127]

[0135] RyR is the major Ca receptor on the SR responsible for excitation-contraction coupling (ECC) in striated muscles. 2+ RyR is a release channel. Among the three known RyR isoforms (RyR1, RyR2, and RyR3), RyR1 is widely expressed and is the predominant isoform expressed in mammalian skeletal muscle. RyR2 is also widely expressed and is the predominant form found in cardiac muscle. Expression of RyR3 is low in adult skeletal muscle. RyR subtypes show a high degree of structural and functional homology. The subtypes are involved in the release of Ca2+ bound to proteins such as kinases, phosphatases, phosphodiesterases, and other regulatory subunits. 2+ It forms a large sarcoplasmic membrane complex consisting of four monomers that constitute the release channel.

[0128]

[0136] Ca from SR 2+ Ca release is regulated by several RyR-binding proteins. 2+ Calmodulin, the primary mediator of signal transduction, exerts both positive and negative influences on the open probability of RyR. Calstabin1 (FKBP12) stabilizes the closed state of RyR1, and calstabin2 (FKBP12.6) stabilizes the closed state of RyR2. Calstabin1 associates primarily with skeletal muscle RyR1, whereas cardiac muscle RyR2 has the highest affinity for calstabin2.

[0129]

[0137] Mutations in RYR1 or RYR2 reduce binding of calstabin1 and calstabin2, respectively. Stress-induced post-translational modifications of RyR, including PKA phosphorylation, oxidation, and nitrosylation, can also reduce calstabin binding to RyR channels. Genetic mutations and / or stress-induced post-translational modifications of the channel can dissociate calstabins from RyR, causing the channel to become leaky. Dissociation of calstabins can result in the formation of leak channels that exhibit a pathological increase in resting open probability. SR Ca 2+ Leakage of SR Ca 2+ This leads to a decrease in the amount of Ca available for release. 2+ This results in less calcium in the muscle, resulting in weaker muscle contractions. Intracellular calcium leak has different pathological consequences depending on which tissue is involved.

[0130] Ryanodine receptor 2 and heart disease

[0138] In some embodiments, the RyR-associated condition is a cardiac dysfunction or disease involving ryanodine receptor 2 (RyR2). The RyR2 channel mediates Ca release from the sarcoplasmic reticulum (SR) in cardiomyocytes, which is required for ECC in the myocardium. 2+ RyR2 channels play a major role in intracellular calcium handling by regulating the release of calcium from the SR. The RyR2 channel is a macromolecular complex that contains four identical RyR2 subunits, each of which binds one calstabin2 (FKBP12.6) and other interacting proteins, such as phosphatases and kinases. Calstabin2 binding stabilizes the channel in a closed state during cardiac rest (diastole), thereby preventing diastolic calcium leakage from the SR, and allows functional coupling of RyR2 channels during excitation-contraction coupling to allow synchronous opening.

[0131]

[0139] Phosphorylation of RyR2 by protein kinase A (PKA) is an important part of the fight-or-flight response. Phosphorylation increases the Ca released in response to a given trigger. 2+ Increasing the amount of RyR2 increases the coupling gain of myocardial ECs. This process enhances muscle contraction and improves exercise capacity. This signaling pathway provides a mechanism to increase cardiac output in response to stress through activation of the sympathetic nervous system (SNS). Phosphorylation of RyR2 by PKA sensitizes the channel to calcium-dependent activation. Increased sensitivity increases the open probability and increases calcium release from the SR into the intracellular cytoplasm.

[0132]

[0140] Heart failure (HF) is characterized by a persistent hyperadrenergic state in which serum catecholamine levels are chronically elevated. One consequence of this chronic hyperadrenergic state is persistent PKA hyperphosphorylation of RyR2, such that three to four of the four Ser2808s in the homotetrameric RyR2 channel are chronically phosphorylated. Chronic PKA hyperphosphorylation of RyR2 is associated with depletion of the channel-stabilizing subunit calstabin2 from the RyR2 channel macromolecular complex. Calstabin2 depletion results in the loss of diastolic SR Ca from the RyR complex. 2+ This diastolic SR Ca leaks out and contributes to impaired contractility. Activation of the inward depolarizing current increases the SR Ca 2+ Leakage is also associated with lethal arrhythmias. Indeed, mice engineered with RyR2 lacking the PKA phosphorylation site (RyR-S2808A) are protected from HF progression after myocardial infarction (MI). Furthermore, chronic PKA hyperphosphorylation of RyR2 in HF is associated with remodeling of the RyR2 macromolecular complex. This remodeling includes depletion of the phosphatases PP1 and PP2a (impairing the dephosphorylation of Ser2808) as well as cAMP-specific type 4 phosphodiesterase (PDE4D3) from the RyR2 complex. Depletion of PDE4D3 from the RyR2 complex leads to persistent elevation of local cAMP levels. Thus, diastolic SR Ca 2+Leakage contributes to HF progression and arrhythmias. Further post-translational modifications of RyR channels (oxidation and nitrosylation) further promote leakage.

[0133]

[0141] RyR leakage is associated with various cardiac dysfunctions, conditions, and diseases. In some embodiments, the cardiac dysfunction or disease is heart failure. In some embodiments, the cardiac dysfunction or disease is myocardial infarction (MI). In some embodiments, the heart failure is congestive heart failure. In some embodiments, the heart failure is chronic heart failure. In some embodiments, the heart failure is systolic heart failure. In some embodiments, the heart failure is diastolic heart failure. In some embodiments, the heart failure is acute decompensated heart failure. In some embodiments, the heart failure is heart failure with reduced or preserved ejection fraction. In some embodiments, the heart failure is acute heart failure, for example, due to cardiac function preservation after myocardial infarction or cardiomyopathy.

[0134]

[0142] In some embodiments, the cardiac dysfunction or disease comprises cardiac ischemia / reperfusion (I / R) injury. I / R injury may occur after coronary angioplasty or after thrombolysis for the treatment of myocardial infarction (MI), or during / after cardiac bypass surgery or heart transplantation.

[0135]

[0143] In some embodiments, the cardiac dysfunction or disease is characterized by an irregular heartbeat or arrhythmia. In some embodiments, the cardiac dysfunction or disease is catecholamine-induced polymorphic ventricular tachycardia (CPVT). In some embodiments, the cardiac dysfunction or disease is or is characterized by atrial arrhythmia. In some embodiments, the cardiac dysfunction or disease is or is characterized by ventricular arrhythmia. In some embodiments, the cardiac dysfunction or disease is or is characterized by atrial fibrillation. In some embodiments, the cardiac dysfunction or disease is or is characterized by ventricular fibrillation. In some embodiments, the cardiac dysfunction or disease is or is characterized by atrial tachycardia. In some embodiments, the cardiac dysfunction or disease is or is characterized by ventricular tachyarrhythmia. In some embodiments, the cardiac dysfunction or disease is or is characterized by atrial tachycardia. In some embodiments, the cardiac dysfunction or disease is or is characterized by ventricular tachycardia. In some embodiments, the cardiac dysfunction or disease is or is characterized by sick sinus syndrome. In some embodiments, the cardiac dysfunction or disease is or is characterized by sudden infant death syndrome (SDIS). In some embodiments, the cardiac dysfunction or disease is or is characterized by sudden unexplained death (SUD).

[0136]

[0144] In some embodiments, the cardiac dysfunction or disease is catecholamine-induced polymorphic ventricular tachycardia (CPVT). In some embodiments, the cardiac dysfunction or disease is CPVT type 1. CPVT is one of the most lethal inherited arrhythmogenic disorders. CPVT is characterized by adrenergic-mediated ventricular arrhythmias that occur in the absence of organic heart disease and are associated with a high incidence of sudden cardiac death (SCD). Patients usually present in the first decade of life or in their teens with stress-induced syncope. CPVT is associated with mutations in two genes that code for proteins associated with the sarcoplasmic reticulum (SR) of cardiomyocytes. The most frequently observed form is CPVT type 1, an autosomal dominant form of inheritance due to mutations in RyR2. This form codes for the intracellular SR calcium release channel. CPVT-associated RyR2 mutations result in leaky RyR2 channels due to reduced binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the channel in its closed state. Mice heterozygous for the R2474S mutation in RyR2 (RyR2-R2474S mice), which occurs in humans with CPVT1, can exhibit exercise-induced ventricular arrhythmias and sudden cardiac death. Treatment with Lycal, which enhances calstabin2 binding to mutant RyR2-R2474S channels, inhibits channel leakage and prevents arrhythmias.

[0137] Ryanodine receptor 1 and musculoskeletal disorders

[0145] In some embodiments, the RyR-related disease is a musculoskeletal disorder or disease involving ryanodine receptor 1 (RyR1). The RyR1 macromolecular complex consists of a tetramer of 560 kDa RyR1 subunits that form a scaffold for proteins that regulate channel function, including PKA and phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PP1), and calstabin1. A-kinase anchoring protein (mAKAP) recruits PKA and PDE4D3 to RyR1, and spinophilin recruits PP1 to the channel. The catalytic and regulatory subunits of PKA, PP1, and PDE4D3 regulate PKA-mediated phosphorylation of RyR1 at Ser2843 (Ser2844 in mice). PKA-mediated phosphorylation of RyR1 at Ser2844 promotes cytoplasmic Ca 2+ It increases the sensitivity of the channel to , reduces the binding affinity of calstabin1 for RyR1, and destabilizes the closed state of the channel.

[0138]

[0146] Calstabin1 concentrations in skeletal muscle can be approximately 200 nM. PKA phosphorylation of RyR1 reduces the binding affinity of calstabin1 for RyR1 from approximately 100-200 nM to over 600 nM. Thus, under physiological conditions, the reduction in the binding affinity of calstabin1 for RyR1 caused by PKA phosphorylation of RyR1 at Ser2843 is sufficient to substantially reduce the amount of calstabin1 present in the RyR1 complex. Chronic PKA hyperphosphorylation of RyR1 at Ser2843 creates leaky channels (i.e., channels that tend to open at rest) and contributes to skeletal muscle dysfunction associated with persistent hyperadrenergic states such as those in patients with heart failure.

[0139]

[0147] Furthermore, modulation of RyR1 by post-translational modifications other than phosphorylation, such as nitrosylation of free sulfhydryl groups on cysteine ​​residues (S-nitrosylation), and channel oxidation, can increase RyR1 channel activity. S-nitrosylation and oxidation of RyR1 can each decrease calstabin1 binding to RyR1.

[0140]

[0148] In some embodiments, the musculoskeletal disorder or disease is congenital myopathy or congenital muscular dystrophy (CMD). Congenital muscular dystrophies are present at birth. CMDs are classified based on genetic mutations: 1) genes that code for structural proteins of the basement membrane or extracellular matrix of skeletal muscle fibers; 2) genes that code for putative or proven glycosyltransferases that affect the glycosylation of dystroglycan, an outer membrane protein of the basement membrane; and 3) others. Non-limiting examples of CMD include RYR1-related myopathy (RYR1-RM), laminin-α2-deficient CMD (MDC1A), Ullrich CMG (UCMD1, 2 and 3), Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), CMD plus secondary laminin deficiency 1 (MDC1B), CMD plus secondary laminin deficiency 2 (MDC1C), CMD with mental retardation and pachygyria (MDC1D), and stiff spine with muscular dystrophy type 1 (RSMD1).

[0141]

[0149] In some embodiments, the musculoskeletal disease is RYR1-related congenital myopathy (RYR1-RM). RYR1-RM is a group of rare neuromuscular diseases. Affected individuals generally exhibit delayed motor milestones, muscle weakness, gait disturbances, and in severe cases, scoliosis due to skeletal muscle weakness, ophthalmoplegia, and respiratory distress. RYR1-RM is the major calcium deficiency disorder (Ca) in skeletal muscles. 2+ Causative variants of RYR1, which encodes a Ca release channel, exert different effects on the RyR1 channel. These variants generally disrupt the normal Ca channel transport between the sarcoplasmic reticulum (SR) and muscle cell cytosol. 2+Disrupting the flow of Ca and allowing excess Ca into the cytosol 2+ Leakage occurs. Sustained Ca2 + Leakage of SR Ca required for ECC 2+ Furthermore, chronic SR Ca 2+ Leakage leads to mitochondrial calcium overload and impairs mitochondrial function manifested as oxidative overload and reduced ATP production. SR Ca 2+ Leakage can also activate the calcium-activated protease calpain, which can cause cell injury. Oxidative stress further increases the Ca2+ receptor agonism in RyR1 by oxidizing and nitrosylating the channel. 2+ This can contribute to leakage.

[0142]

[0150] In some embodiments, the musculoskeletal disorder or disease is muscular dystrophy.Non-limiting examples of muscular dystrophy include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral dystrophy, myotonic muscular dystrophy, congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy.

[0143]

[0151] Duchenne muscular dystrophy (DMD) is one of the major fatal pediatric genetic disorders. Dystrophin mutations associated with DMD result in a complete absence of dystrophin protein, thereby disrupting the link between the sarcoplasmic cytoskeleton and the extracellular matrix. This link is essential to protect and stabilize muscles against contraction-induced injury. Sarcolemmal instability due to dystrophin mutations has cascading effects. One of the main effects is the depletion of cytoplasmic Ca 2+ This is an increase in Ca 2+It activates a mitochondrial-dependent protease (calpain). Another effect is inflammation and increased iNOS activity, which can lead to oxidation / nitrosylation of proteins, lipids, and DNA. DMD muscle pathology is progressive and goes far beyond sarcolemmal instability. Thus, the pathology is consistent with sarcolemmal instability increasing susceptibility to further injury. Excessive oxidation or nitrosylation of RyR1 may disrupt the interaction of calstabin1 with the RyR1 complex, leading to RyR1 leakage and muscle weakness. Treatment with Lycal improves indices of muscle function.

[0144]

[0152] In some embodiments, the musculoskeletal disorder or disease is cancer-associated muscle weakness. In some embodiments, the musculoskeletal disorder or disease is cancer cachexia, i.e., cancer-associated muscle loss and / or muscle weakness. In some embodiments, the cancer-associated muscle weakness is due to bone metastasis of cancer. Muscle weakness and muscle atrophy (cachexia) are common paraneoplastic conditions in cancer patients. These conditions cause significant fatigue and dramatically reduce the patient's quality of life. In certain cancers, such as prostate and breast cancer with bone metastasis, RyR1 becomes oxidized and leaky. Repairing the leak by administration of Lycal compounds improves muscle strength and function. Non-limiting examples of cancers associated with cachexia or muscle weakness that can be treated with the compounds herein include breast cancer, prostate cancer, bone cancer, pancreatic cancer, lung cancer, colon cancer, and gastrointestinal cancer.

[0145] These conditions cause significant fatigue and dramatically reduce the patient's quality of life.The present disclosure provides a method for treating, preventing and reducing the likelihood of developing muscle weakness in cancer patients, for example, based on the presence of a modified state (e.g., the oxidative state of RyR1), which induces RyR1 to become leaky.Preventing or reducing the likelihood of leaking by administering Lycalcium compounds can improve muscle strength and / or function.

[0146]

[0153] In some embodiments, the musculoskeletal condition or disease is age-related loss of muscle mass and strength (sarcopenia). Sarcopenia contributes to physical disability and increased mortality. RyR1 from aged mice may be oxidized, cysteine ​​nitrosylated, and depleted of calstabin1 compared to RyR1 from young adults (3-6 months). Treatment of aged mice with Lycalc stabilizes the binding of calstabin1 and RyR1, reduces intracellular calcium leak, reduces reactive oxygen species (ROS), and increases tetanic Ca2+ expression. 2+ release, muscle-specific strength, and exercise capacity are enhanced.

[0147]

[0154] In some embodiments, the compositions of the present disclosure are useful for treating type II diabetes by reducing the likelihood of intracellular calcium leak occurring via leaky RyR2. This leak causes mitochondrial calcium overload, reduces ATP production, and increases K ATP Decreased channel activation blocks plasma membrane depolarization. This blocking reduces activation of plasma membrane voltage-gated calcium channels, which are the main source of calcium required for insulin secretion.

[0148] Example 1: Gastro-resistant tablets (Formulation A)

[0155] Gastro-resistant tablets containing 20, 40 or 200 mg (based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate (Compound I)) are shown in Table 1.

[0149] [Table 1]

[0150]

[0156] Preparation method: Compound I was mixed with microcrystalline cellulose, povidone, and crospovidone. The mixture was granulated using standard wet granulation method. Polysorbate was added to purified water to act as granulation liquid. The wet granulation was dried in oven system and sieved. The dry granulation was mixed with external phase: crospovidone, magnesium stearate, anhydrous colloidal silica, lubricated granulation was sieved and compressed into tablets.

[0151]

[0157] The core tablets are then coated (subcoating) with a premix (white Sepifilm LP 770). After drying, an enteric coating is applied as an AQOAT suspension to obtain gastro-resistant tablets.

[0152] Example 2: Gastro-resistant tablets (Formulation B1)

[0158] A gastro-resistant tablet containing 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate (Compound I) (based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid) is shown in Table 2.

[0153] [Table 2]

[0154]

[0159] Preparation method: Compound I was mixed with microcrystalline cellulose, maltodextrin, and croscarmellose. The mixture was granulated by standard wet granulation method. Purified water was added as granulation liquid. The wet granulation was dried in oven system and sieved. The dry granulation was mixed with external phase: croscarmellose, magnesium stearate, sodium stearyl fumarate, and anhydrous colloidal silica, the lubricated granulation was sieved, and compressed into tablets.

[0155]

[0160] The core tablets are then coated (subcoating) with a premix (colourless Sepifilm LP 010). After drying, an enteric coating is applied as an AQOAT suspension to obtain gastro-resistant tablets.

[0156] Example 3: Gastro-resistant tablets (Formulation B2)

[0161] A gastro-resistant tablet containing 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate (Compound I) (based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid) is shown in Table 3.

[0157] [Table 3]

[0158]

[0162] Preparation method: Compound I was mixed with mannitol, microcrystalline cellulose, and maltodextrin. The mixture was granulated by standard wet granulation method. The resulting wet granulation was dried and sieved. The dry granulation was then mixed with croscarmellose, magnesium stearate, anhydrous colloidal silica, and sodium stearyl fumarate. The lubricated granulation was sieved and compressed into tablets.

[0159]

[0163] The core tablets were then coated with a subcoating (colorless Sepifilm LP 010). After drying, an enteric coating (AQOAT suspension AS-MF) was applied to obtain enteric coated tablets.

[0160] Example 4: Placebo

[0164] The placebo enteric coated tablet formulation is shown in Table 4.

[0161] [Table 4]

[0162]

[0165] Preparation method: Lactose monohydrate and microcrystalline cellulose were mixed. Then magnesium stearate was added. The core tablets were then coated with sub-coating (colorless Sepifilm LP 010). After drying, enteric coating (AQOAT suspension AS-MF) was applied to obtain enteric coated tablets.

[0163] Example 5: Dissolution Test

[0166] Dissolution tests were used to compare the tablets of Example 2 and Example 3. The gastroresistant oral tablets are designed to remain unchanged in the stomach and then release the active substance along the gastrointestinal tract, and therefore dissolve under acidic conditions (pH 1.2) for 2 hours, followed by dissolution in a near-neutral medium (such as pH 6.8). In addition, dissolution was evaluated at higher pH (e.g., in the range of 3-5) to evaluate dissolution conditions representative of the fed state (e.g., when the subject is administered the formulation during or shortly after a meal). Thus, dissolution was performed at pH 4.5 for 2 h, followed by dissolution in a near-neutral medium (such as pH 6.8).

[0164]

[0167] This study was conducted to determine the fraction of drug substance released from enteric coated tablets in dissolution medium over a specified period of time for each individual tablet tested.

[0165]

[0168] The dissolution conditions are shown in Table 5.

[0166] [Table 5]

[0167] Analysis conditions

[0169] The active substance released from these units is assessed by UV spectroscopy under the following conditions: Optical path length of quartz cell: 10mm Absorbance wavelength: 250nm Reference wavelength: 350nm

[0170] Disintegration times are determined by incubating tablets in 0.1 N hydrochloric acid as the liquid medium for 2 hours (pH=1.2); or in a buffer solution at pH 4.5 for 2 hours, then replacing the acid with phosphate buffer pH 6.8 for 60 minutes.

[0168]

[0171] The drug release profile was evaluated in vitro using a paddle dissolution apparatus (75±3 rpm, 37.0±0.5°C). Samples were withdrawn at regular intervals and analyzed by UV spectroscopy at 250 nm and 350 nm. The resulting in vitro dissolution time profiles are shown in Figure 1.

[0169]

[0172] These in vitro data show that formulations of Example 2 (20 mg / formulation B1) and Example 3 (20 mg / formulation B2) gave similar dissolution profiles.

[0170]

[0173] The in-vitro dissolution time profiles of the formulation of Example 2 at pH 6.8 and the formulation of Example 3 at pH 5.5 are shown in FIG.

[0171]

[0174] According to these in vitro data, pH values ​​equal to or below 5.5 at the time of administration maintain the integrity of the gastroresistant form. The tablets disintegrate rapidly at pH 6.8.

[0172] Example 6: Clinical Trials in Healthy Volunteers

[0175] A Phase 1, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and pharmacokinetics (PK) of Compound I following single, ascending, and multiple oral doses in healthy male volunteers.

[0173] Research purpose Part I (Single Ascending Dose - SAD)

[0176] The primary objective was to evaluate the safety of single ascending oral doses of Compound I compared with placebo in healthy male volunteers. The secondary objective was to measure plasma pharmacokinetic (PK) parameters of Compound I.

[0174] Part II (Multiple Ascending Dose - MAD)

[0177] The primary objective was to evaluate the safety of ascending repeated oral doses of Compound I compared to placebo over 14 days in healthy male volunteers. Secondary objectives were to measure plasma pharmacokinetic (PK) parameters of Compound I and to assess concentrations of Compound I in quadriceps muscle.

[0175] material and method 1. Test drug

[0178] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate (compound I) was administered in a gastroresistant tablet according to Example 1. The formulations contained 20 mg, 40 mg or 200 mg of compound I (based on the mass of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid). Placebo tablets according to Example 4 were used as control.

[0176] 2. Test Plan

[0179] The study was subdivided into two parts (I and II). Each part was randomized, double-blind, and placebo-controlled.

[0177]

[0180] In phase I, participants in groups A, B, C, D, and E received a single dose of 40 mg, 80 mg, 160 mg, 240 mg, or 400 mg of compound I or matching placebo, respectively. Forty subjects completed part I: 30 active (6 per cohort), 10 placebo.

[0178]

[0181] In Phase II, participants in groups I, J, K, and L received compound I or a matching placebo at 20 mg, 60 mg, 120 mg, or 240 mg, respectively, repeated once daily for 14 days. Forty-one subjects completed Phase II: 7 / 7 / 8 / 7 in cohorts I, J, K, and L, and 12 in placebo.

[0179] 3. Pharmacokinetic Measurements 3a.Blood Sampling:

[0182] In Phase I, blood samples were collected from each participant as follows: pre-dose, then 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, and 96 hours after dosing.

[0180]

[0183] In phase II, blood samples were collected from each participant as follows: Day 1: 12 samples from before to 16 h after the morning dose (pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 h); Days 2–13: 12 samples at pre-dose (i.e., morning dose); Day 14: 16 samples from before to 96 h after the morning dose (D14 pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 h; D15–18: 1 sample before the theoretical morning dose.

[0181]

[0184] The following pharmacokinetic parameters were calculated from the plasma concentration-time profiles: AUC last (AUClast): Time from zero (drug administration time) to t last Area under the concentration-time curve up to AUC: Area under the concentration-time curve from time zero (time of drug administration) to infinity AUC 24 (AUC24): Area under the concentration-time curve from time zero to 24 h Day 1.

[0182] AUC τ (AUCtau): Area under the concentration-time curve over the dosing interval at steady state on day 14.

[0183] C max (Cmax): Maximum blood concentration C maxds (Cmaxds):C max / Dosage t max (tmax):C max The time corresponding to t lag (tlag): Lag time: the time prior to the time corresponding to the first measurable concentration C last (Clast): Final quantifiable concentration R ac(AUCτ) (RacAUC): Cumulative ratio of AUC (AUC τ / AUC 24 ) R acCmax (RacCmax):C max Cumulative ratio (C max Day 14 / C max Day 1) t last (tlast):C last The time corresponding to λ z (k): First-order rate constant of the terminal phase t 1 / 2,z (t1 / 2):t 1 / 2,z =ln(2) / λ z (λ z where is the terminal phase rate constant.

[0184]

[0185] The areas under the plasma concentration-time curves were calculated using a combined linear and logarithmic trapezoidal rule. Interpolation was linear in the constant and ascending parts of the plasma concentration-time profiles. Interpolation was logarithmic in the descending parts.

[0185]

[0186] In Phase I, the mean AUC last , and C max was calculated and plotted for each dose.

[0186]

[0187] For Phase II, AUC τ (14th day), AUC 24(Day 1), and C max The same approach was used for

[0187] 3b. Muscle biopsy

[0188] For Phase II of the study (all groups), on day 13, concentrations of Compound I were determined in muscle by performing muscle biopsies in the quadriceps at least 3 hours after the morning dose.

[0188] 3c. Statistical methods

[0189] For each group and treatment, descriptive statistics (N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation, geometric mean, and geometric CV, as appropriate) were calculated for Compound I concentrations and pharmacokinetic parameters.

[0189] 3d.Analysis method

[0190] Plasma and muscle samples were analyzed by LC-MS / MS method.

[0190] result 1. Pharmacokinetics 1a. Part I: Single Ascending Dose

[0191] The mean concentration time profiles for Part I (single dose) are shown in Figure 3. Concentrations are shown in ng / mL.

[0191]

[0192] Table 6 summarizes the pharmacokinetic parameters after a single dose (arithmetic and geometric means, standard deviations (SD), coefficients of variation (CV%) and geometric CV%, medians and ranges).

[0192] [Table 6]

[0193] 1b. Part II: Multiple Ascending Doses

[0193] The mean concentration time profiles for Part II (repeated dosing) on ​​Day 1 are shown in Figure 4. Concentrations are shown in ng / mL.

[0194]

[0194] The mean concentration time profiles for Part II (repeated dosing) on ​​Day 14 are shown in Figure 5. Concentrations are shown in ng / mL.

[0195]

[0195] Table 7 summarizes the pharmacokinetic parameters after multiple dosing (arithmetic and geometric means, SD, CV% and geometric CV%, median and range).

[0196] [Table 7]

[0197] 2. Muscle Biopsy

[0196] Muscle biopsies were performed to assess the concentration of Compound I in the quadriceps muscle. Biopsies were performed on day 13, at least 3 hours after dosing.

[0198]

[0197] Table 8 shows the concentrations of Compound I in muscle summarized by median and range.

[0199] [Table 8]

[0200]

[0198] Table 9 summarizes the ratio of each total unbound concentration at 3 hours post-dose on day 13 divided by the plasma concentration at 3 hours post-dose on day 14.

[0201] [Table 9]

[0202] 3. Discussion Part I: Following single oral doses of 20, 40, 80, 160, 240 and 400 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in young healthy males, rapid absorption was observed after a lag time consistent with the gastric resistance (GR) characteristics of the administered tablet. No evidence of non-linearity with dose was observed. Inter-individual variability across treatment groups was small. Geometric mean t1 / 2,z The mean mean mean CV ranged from 17.5 h in the 160 mg cohort to 22.7 h in the 80 mg cohort, with geometric %CVs ranging from 12.3% to 16.8%. last and C max Dose proportionality is shown for

[0203]

[0200] Part II: After repeated oral administration of 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate once daily for 14 days, C max and T max Median values ​​ranged from 3 to 3.5 hours. Steady state was reached after 3 to 7 days of daily treatment (e.g., day 4 in the 20 mg, 60 mg, and 120 mg cohorts, day 5 in the 240 mg cohort). Geometric %CVs for AUC on days 1 and 14 ranged from 10.5% (120 mg cohort, day 1) to 22.3% (120 mg cohort, day 14). Interindividual variability across treatment groups was small. Geometric mean t on day 14 1 / 2,z The mean mean time to effect (Tmax) ranged from 19.3 h in the 20 mg and 120 mg cohorts to 19.8 h in the 240 mg cohort. The %CV ranged from 11.3% to 22.2%. Graphical analysis revealed that the AUC τ , resp. AUC 0-24 and C max The geometric mean cumulative ratios based on AUC ranged from 1.60 to 1.72, and the C max Cumulative ratios based on CI ranged from 1.39 to 1.46 and appeared similar between treatment groups.

[0204] Median unbound and total 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate concentrations in quadriceps muscle appeared to be proportional to dose. The geometric mean ratios of concentrations in muscle divided by concentrations in plasma ranged from 0.0440 to 0.0808 (ng / g) / (ng / mL) for Kp and 0.0081 to 0.0106 (ng / g) / (ng / mL) for Kpu. The geometric %CVs ranged from 22.6% to 65.3% for Kp and 31.3% to 60.7% for Kpu.

[0205] 4.Safety

[0202] No serious adverse events were reported. The compound was shown to be well tolerated at the doses and dosing regimens tested.

[0206] 5. Summary and Conclusion

[0203] After single oral administration of 20 to 400 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, max and T max The median is t lag After 3-4.5 hours, this is consistent with the gastrotolerance profile of the tablet (less than 2 hours).

[0207]

[0204] After repeated oral administration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate at doses of 20, 60, 120 and 240 mg / d for 14 days, C max and T max The median was 3-4 hours. Based on the results of single- and multiple-dose studies, the mean apparent terminal half-life was approximately 20 hours. No evidence of nonlinearity with time and dose was observed. Overall, C maxInterindividual variability in and AUC24 was low at 20, 60, 120, and 240 mg / day. Steady state was reached after 5-7 days of daily treatment. After repeated dosing of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate at 20, 60, 120, and 240 mg / day for 14 days, C max and AUC 24 In the case of K, the cumulative ratios were approximately 1.4-1.8, consistent with the half-life and dosing regimen of Compound I. p and K. pu The results were consistent within the dose range (20-240 mg). p is [0.04~0.08], K pu was [0.008~0.01].

[0208]

[0205] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate was well tolerated at the doses and dose regimens tested.

[0209] Example 7: Clinical Trials in Patients with Ryr1-Associated Myopathy

[0206] A Phase 1b trial will be conducted in patients with RYR1-related myopathy (RYR1-RM).

[0210] Research purpose

[0207] The primary objective is to determine the safety and tolerability of Compound I in individuals with RYR1-RM.

[0211]

[0208] The secondary objectives are: (1) to determine the pharmacokinetics of Compound I when administered for 28 days in patients with RYR1-RM; (2) to explore whether Compound I increases RyR1-calstabin1 binding in skeletal muscle of patients with RYR1-RM; and (3) to explore whether treatment with Compound I improves muscle function, motor activity, and fatigue in patients with RYR1-RM.

[0212] material and method 1. Test drug Compound I was administered in daily doses as gastroresistant tablets according to Example 3. The formulation contained 20 mg of Compound I (based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid). The first three participants were administered 120 mg of Compound I (6 x 20 mg tablets) daily for approximately 28 days. The second group was administered 200 mg of Compound I (10 x 20 mg tablets) daily for approximately 28 days.

[0213] 2. Test Plan 2a. Pharmacokinetic measurements Blood samples for PK assessment were collected at baseline (Day 0, 24h PK), mid-study (Day 14±2, trough PK), and at the final study visit (Day 28, 24h PK). Pharmacokinetic analysis was performed on plasma samples. PK parameters are described below:

[0214] [Table 10-1]

[0215] [Table 10-2]

[0216] 2b. Muscle biopsy Skeletal muscle tissue is obtained from pre- and post-intervention participants by needle biopsy. The tissue is evaluated for RyR1-calstabin1 binding by co-immunoprecipitation followed by protein detection. The percentage of calstabin1 binding to RyR1 before administration is compared to the percentage obtained after administration in each patient (arbitrary units; AU). The change from baseline in calcium permeability (Fluo-4 signal) using the thapsigargin assay (AU) can also be ascertained from muscle membrane preparations.

[0217] 2c.RyR1-calstabin binding assay Participants will undergo two needle muscle biopsies during the study to determine the pharmacodynamics (PD) of Compound I in the RYR1-RM population. Biopsy 1 will be performed pre-dose on study visit day 1 (Day-1 / Day1). Biopsy 2 will be performed post-dose (Day27 / 28). Muscle biopsies will be performed on the tibialis anterior or other suitable muscle (i.e., muscle with minimal fatty infiltration). Comparison of pre- and post-treatment muscle tissue will assess whether sufficient amounts of the test drug are reaching the muscle to act on the RyR1 target at any dose level.

[0218] Participants' skeletal muscle tissue is analyzed for RyR1-calstabin1 association. The assay involves evaluating the change in the percentage of calstabin1 binding before administration compared to the percentage obtained after administration. The percentage of RyR1-calstabin1 binding is expressed as a percentage of normal control muscle as determined by RyR1-calstabin1 co-immunoprecipitation and quantification of RyR1 and calstabin1.

[0219] 2d. Calcium leakage assay

[0214] Ca from RyR1 2+ Percent leakage (%) was determined using the thapsigargin calcium leakage assay, i.e., the Ca release from isolated microsomal vesicles containing RyR1 after pharmacological inhibition of SERCA in vitro with thapsigargin to inhibit the reuptake pump. 2+ To visualize and quantify leakage, Ca 2+ The fluorescence produced by the indicator is measured using a plate reader assay and the results are expressed as the change from baseline in relative Fluo-4 signal (AU).

[0220]

[0215] The remaining muscle tissue is used for single channel measurements or for inducing myotubes in cell culture.

[0221] 2e. Functional measurements

[0216] The following endpoints will be measured: grip strength (kg), pinch strength (kg), quantitative muscle strength assessment (kg), time (seconds) taken to complete each of the following: walk 10 m, stand from supine, climb 4 steps, and descend 4 steps, MFM-32 scores (% of maximum score) for domains 1, 2, 3, and total, PROMIS-Fatigue subscale score (t-score).

[0222] Grip and pinch strength: Participants are seated with elbows bent at 90 degrees and forearms and wrists in a neutral position. Participants are then instructed to squeeze the dynamometer and grasp the gauge. This process is repeated three times and the best effort is used for the final analysis.

[0223] Quantitative Muscle Strength Assessment: Participants undergo a muscle strength assessment in standardized sitting and supine positions. Participants are asked to exert force against force transducers using elastic straps.

[0224] Graded Functional Testing: Participants will complete a graded functional test before and after the intervention. Participants will complete a timed 10m walk, supine to standing, and up and down four flights of stairs. Times recorded will be recorded for each subject and a descriptive summary will be provided for each test to compare pre- and post-treatment results.

[0225] MFM-32: The MFM-32 scale is a validated measure of motor function and provides a measure of the impact of muscle weakness in neuromuscular diseases (NMDs). The assessment is based on posture and whole body movement. The test is administered pre- and post-intervention. Participants are asked to turn, sit, lift head from prone and supine positions, rise from lying position, support arms, kneel, crawl, stand, and step. The test is combined with timed tests (e.g., rise from floor, climb 4 steps, etc.). Motor function is recorded on day 1 versus day 28 and is quantitatively (% of maximum score) for each subject using the MFM32 scoring: total score, domain 1 (standing and locomotion), domain 2 (axial and proximal motor function), domain 3 (distal motor function). The obtained scores are summarized descriptively to compare the results before and after treatment.

[0226]

[0221] Fatigue Questionnaire: Administer the validated PROMIS-Fatigue subscale. Participants will be asked to complete responses to fatigue-related quality of life questions pre- and post-intervention.

[0227] 2f. Safety and tolerability

[0222] Safety and tolerability of Compound I will be determined by patient interview, patient diary review, physical examination, echocardiogram, electrocardiogram (ECG), vital signs, and laboratory safety tests, and by monitoring adverse events (AEs) over approximately 28 days of treatment.

[0228] result 1. Pharmacokinetics 1a. Pharmacokinetics - Daily dose 120mg

[0223] Pharmacokinetic parameters for three subjects following a single oral dose of 120 mg of Compound I (relative to the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid) on Day 1 are shown in Table 10.

[0229] [Table 11]

[0230] As shown in Table 10, the geometric mean C max was approximately 13.1 μg / mL, with individual values ​​ranging from 11.1 to 16.3 μg / mL. max was 3 h for all participants. Geometric mean AUC 0-t is 171h * μg / mL, AUC 0-inf is 257h * μg / mL, and the individual values ​​are 150 to 190 * μg / mL and 212-290 h * The mean half-life of Compound I was 14.14 hours, with individual values ​​of 14.40 hours, 12.75 hours, and 15.28 hours.

[0231]

[0225] Individual plasma concentrations of Compound I following a single dose of 120 mg of Compound I on Day 1 are shown in FIG.

[0232]

[0226] Pharmacokinetic parameters after multiple daily oral administration of 120 mg of Compound I for 28 days are shown in Table 11.

[0233] [Table 12]

[0234]

[0227] Geometric mean C max,ss was approximately 19.2 μg / mL, with individual values ​​ranging from 16.9 to 21.3 μg / mL. max,ss was 4 hours after dosing in two participants and 6 hours after dosing in the third. Geometric mean AUC 0-tau is approximately 271 hours * μg / mL, and the individual values ​​ranged from 243 to 287 h * The change ranged from 0.1 to 0.5 μg / mL. min The C ranged from 5.80 to 7.76 μg / mL and occurred 1 hour after dosing in one subject and 24 hours after dosing in two subjects.trough The geometric mean value of was 7.97 μg / mL, and the individual C trough The values ​​ranged from 6.71 to 9.40 μg / mL. AUC and C max The geometric mean (geometric CV%) cumulative ratio for was 1.59 (4.9), and C max The geometric mean (geometric CV%) cumulative ratio for was 1.47 (17.7).

[0235]

[0228] Individual plasma concentrations of Compound I following multiple daily doses of 120 mg of Compound I on Day 28 are shown in FIG. 1b. Pharmacokinetics – Daily dose 200mg The mean plasma concentrations obtained from three subjects after a single oral dose of 200 mg of Compound I (relative to the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid) are shown in Table 12. Individual plasma concentrations are shown in FIG. max ranged from 5 to 6 hours for all participants.

[0236] [Table 13]

[0237]

[0230] The mean plasma concentrations obtained from three subjects after multiple daily oral administration of 200 mg of Compound I (based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid) for 28 days are shown in Table 13. Individual plasma concentrations are shown in Figure 9. max ranged from 5 to 6 hours for all participants.

[0238] [Table 14]

[0239]

[0231] RyR1-calstabin1 binding, calcium leak and functional assays are determined, respectively.

[0240] Example 8: Preparation of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared as described below. Stage 1: 7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine ("amine")

[0241] [ka]

[0242] 2-(4-Methoxyphenylthio)ethanamine(1) 4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K2CO3 (78.8 g, 0.57 mol), and diisopropylethylamine (32 mL, 0.178 mol) were mixed in tetrahydrofuran (THF). The mixture was degassed under reduced pressure for 5 min and heated at reflux under argon overnight. The solvent was removed and water was added to the flask. The mixture was extracted with dichloromethane. The organic layer was collected, dichloromethane was removed, concentrated hydrochloric acid was added, followed by water. The solution was extracted with ethyl acetate (EtOAc) / hexane 1:1. The aqueous layer was adjusted to pH 10 with 2M NaOH and extracted with dichloromethane. The combined organic solution was dried over anhydrous sodium sulfate. Removal of the solvent afforded the target compound. Benzyl 2-(4-methoxyphenylthio)ethylcarbamate (2) To a flask containing compound I (8.0 g, 43.7 mmol), sodium bicarbonate (12.1 g, 144 mmol), water, and dichloromethane, benzyl chloroformate (8.2 g, 48.1 mmol, diluted with 100 mL dichloromethane) was added dropwise at 0° C. After addition, the mixture was stirred at room temperature for 5 hr. The organic layer was collected and the aqueous layer was extracted with 100 mL dichloromethane. The combined organic solution was dried over sodium sulfate. The solvent was removed and the resulting solid was triturated with THF / hexane (1:10). The solid was collected and dried leaving the target product.

[0243] Benzyl 7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate (3) A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol), and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in toluene was stirred at 70° C. overnight. After cooling to rt, the solid was filtered off. The solution was extracted with saturated sodium carbonate, and the organic layer was dried over anhydrous sodium sulfate to yield the target product as a liquid after removal of the solvent.

[0244] 7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine hydrobromide (amine) Compound 3 (10 g, 30 mmol) was mixed with concentrated HCl, water and dioxane. The mixture was stirred at 100° C. overnight. After cooling to rt, most of the solvent and hydrochloric acid were removed under reduced pressure. Water was added to the solution and the solid was filtered off. The aqueous solution was extracted with EtOAc / hexane (1:1) and made basic by adding 15 g of NaOH. The mixture was extracted with dichloromethane. The combined solution was dried over anhydrous sodium sulfate. Removal of the solvent produced a liquid that solidified after standing at rt to produce the target compound.

[0245] Stage 2: -[7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid

[0246] [ka]

[0247] In Scheme 2, L is a leaving group, which is, for example, a halogen or a sulfonate (OSO2R', where R' is alkyl or aryl, e.g., OM (mesylate), OT (tosylate)). Amine (4) (1 mmol) was dissolved in dichloromethane. To this solution was added alkylating reagent (5) (1 mmol), followed by N,N-diisopropylethylamine (2 mmol). The mixture was stirred at rt overnight. This solution was directly loaded onto a silica gel column and eluted with hexane / EtOAc (2:1, v / v) to produce the desired product. Preparation of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate - Form 1 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared similarly to Example 1. To form the hemifumarate salt, 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was salified with fumaric acid in the presence of isopropanol as shown in Scheme 3. After cooling, the resulting product was filtered and washed with isopropanol to give the title product.

[0248] [ka]

[0249] Form 1 can be finely ground, if necessary, to the particle size distribution set forth in Table 12.

[0250] [Table 15]

[0251] Preparation of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate - Form 2 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared similarly to Example 1. To form the hemifumarate salt, 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was salified with fumaric acid in the presence of a mixture of dimethylsulfoxide and water as shown in Scheme 4. After cooling, the resulting product was filtered and washed with water and acetone to obtain the desired product.

[0252] [ka]

[0253] Form 2 can be finely ground, if necessary, to the particle size distribution set forth in Table 13.

[0254] [Table 16]

[0255] Incorporation by Reference

[0242] All publications, patents, and patent applications mentioned in this specification are incorporated by reference in this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Embodiment

[0243] Embodiment 1. A pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, wherein, in a controlled study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is achieved in the subject.

[0256]

[0244] Embodiment 2. The pharmaceutical composition of embodiment 1, comprising a pharma- ceutically acceptable salt, wherein the pharma- ceutically acceptable salt is a hemifumarate salt.

[0257]

[0245] Embodiment 3. A pharmaceutical composition according to embodiment 1 or 2, wherein the sustained release is modified release.

[0258]

[0246] Embodiment 4. A pharmaceutical composition according to embodiment 1 or 2, wherein the sustained release is an extended release.

[0259]

[0247] Embodiment 5. A pharmaceutical composition according to embodiment 1 or 2, wherein the sustained release is a delayed release.

[0260]

[0248] Embodiment 6. A pharmaceutical composition described in any one of embodiments 1 to 5, wherein the unit dosage form is suitable for oral administration.

[0261]

[0249] Embodiment 7. A pharmaceutical composition described in any one of embodiments 1 to 6, wherein the unit dosage form is a solid dosage form.

[0262]

[0250] Embodiment 8. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 12 hours.

[0263]

[0251] Embodiment 9. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 24 hours.

[0264]

[0252] Embodiment 10. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein, in a control study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof occurs in the subject from about 2 hours to about 6 hours after administration.

[0265]

[0253] Embodiment 11. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof occurs in the subject from about 2 hours to about 4 hours after administration.

[0266]

[0254] Embodiment 12. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof occurs in the subject from about 3 hours to about 4 hours after administration.

[0267]

[0255] Embodiment 13. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, an in-vivo half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of about 14 to about 21 hours is obtained in the subject.

[0268]

[0256] Embodiment 14. The pharmaceutical composition described in embodiment 13, wherein the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof is about 14 hours.

[0269]

[0257] Embodiment 15. The pharmaceutical composition described in embodiment 13, wherein the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof is about 20 hours.

[0270]

[0258] In a controlled study, when the unit dosage form is administered to a test subject, the C of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, is between about 1.4 and about 1.8. max A cumulative ratio of C to C at day 28 is present in the subject, max / Day 1 C max It is calculated as the ratio of C max is the maximum observed plasma concentration.

[0271]

[0259] In a controlled study, when the unit dosage form is administered to a test subject, a cumulative ratio of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt or ion thereof, to AUC of between about 1.4 and about 1.8 is present in the subject, and said cumulative ratio to AUC is greater than or equal to AUC on day 28. tau / AUC on day 1 0-24 Calculated as a ratio - AUC is the area under the concentration-time curve; - AUC tau is the area under the concentration-time curve during the dosing interval (tau) at steady state; - AUC 0-24 is the area under the concentration-time curve from 0 to 24 hours after administration.

[0272]

[0260] Embodiment 18. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of less than about 35 ug / mL is present in the subject.

[0273]

[0261] Embodiment 19. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of about 10 to about 15 ng / mL is present in the subject after administration of a single 120 mg dose.

[0274]

[0262] Embodiment 20. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form was administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof of about 17 to about 21 ng / mL was present in the subject after administration of a 120 mg dose once daily for 14 days.

[0275]

[0263] Embodiment 21. A pharmaceutical composition described in any one of embodiments 1 to 7, wherein in a controlled study, when the unit dosage form is administered to a test subject, a steady state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is achieved in the test subject in a range of about 3 to about 7 days after the initial administration.

[0276]

[0264] Embodiment 22. A pharmaceutical composition described in any one of embodiments 1 to 21, comprising about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0277]

[0265] Embodiment 23. A pharmaceutical composition described in any one of embodiments 1 to 21, comprising about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0278]

[0266] Embodiment 24. A pharmaceutical composition described in any one of embodiments 1 to 23, comprising 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0279]

[0267] Embodiment 25. A pharmaceutical composition according to any one of embodiments 1 to 23, comprising 23.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0280]

[0268] Embodiment 26. A pharmaceutical composition described in any one of embodiments 1 to 23, comprising 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0281]

[0269] Embodiment 27. A pharmaceutical composition according to any one of embodiments 1 to 23, comprising 58.75 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0282]

[0270] Embodiment 28. A pharmaceutical composition described in any one of embodiments 1 to 23, comprising 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0283]

[0271] Embodiment 29. A pharmaceutical composition described in any one of embodiments 1 to 23, comprising 117.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0284]

[0272] Embodiment 30. A pharmaceutical composition described in any one of embodiments 1 to 29, wherein the unit dosage form is a tablet.

[0285]

[0273] Embodiment 31. A pharmaceutical composition described in any one of embodiments 1 to 29, wherein the unit dosage form is a tablet, and the tablet is prepared by wet granulation.

[0286]

[0274] Embodiment 32. A pharmaceutical composition described in any one of embodiments 1 to 29, wherein the unit dosage form is a tablet, and the tablet is prepared by dry granulation.

[0287]

[0275] Embodiment 33. A pharmaceutical composition described in any one of embodiments 1 to 32, wherein the unit dosage form is a gastroresistant tablet.

[0288]

[0276] Embodiment 34. A pharmaceutical composition described in embodiment 33, wherein the gastro-resistant tablet does not substantially disintegrate at a pH of 5.5 or less, and the disintegration is determined by measuring the dissolution of the gastro-resistant tablet in a medium having a pH of 5.5 or less.

[0289]

[0277] Embodiment 35. The pharmaceutical composition described in embodiment 34, wherein the medium having a pH of 5.5 or less is a 0.1N HCl solution having a pH of 1.2.

[0290]

[0278] Embodiment 36. A pharmaceutical composition described in embodiment 33, wherein the gastro-resistant tablet substantially disintegrates at a pH of at least about 6.8, and the disintegration is determined by measuring the dissolution of the gastro-resistant tablet in a medium having a pH of 6.8.

[0291]

[0279] Embodiment 37. A pharmaceutical composition described in embodiment 36, wherein the medium having a pH of 6.8 is a phosphate buffer solution.

[0292]

[0280] Embodiment 38. A pharmaceutical composition described in embodiment 33, wherein the gastroresistant tablet does not substantially disintegrate in gastric juice.

[0293]

[0281] Embodiment 39. A pharmaceutical composition described in embodiment 33, wherein the gastroresistant tablet substantially disintegrates in intestinal fluids.

[0294]

[0282] Embodiment 40. A pharmaceutical composition described in any one of embodiments 1 to 39, wherein the unit dosage form is a gastroresistant tablet, the gastroresistant tablet comprising a core and a coating layer substantially covering the core.

[0295]

[0283] Embodiment 41. A pharmaceutical composition described in embodiment 40, wherein the coating layer comprises an enteric polymer.

[0296]

[0284] Embodiment 42. A pharmaceutical composition described in embodiment 41, wherein the enteric polymer is hypromellose acetate succinate.

[0297]

[0285] Embodiment 43. A pharmaceutical composition described in embodiment 40, wherein the coating layer is about 20% by weight of the tablet.

[0298]

[0286] Embodiment 44. A pharmaceutical composition described in embodiment 40, further comprising a subcoating layer between the core and the coating layer.

[0299]

[0287] Embodiment 45. A pharmaceutical composition described in embodiment 44, wherein the subcoating layer comprises a polymer.

[0300]

[0288] Embodiment 46. A pharmaceutical composition described in embodiment 45, wherein the polymer is hypromellose.

[0301]

[0289] Embodiment 47. A pharmaceutical composition described in any one of embodiments 44 to 46, wherein the subcoating layer is about 3% by weight of the tablet.

[0302]

[0290] Embodiment 48. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a binder.

[0303]

[0291] Embodiment 49. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a diluent.

[0304]

[0292] Embodiment 50. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a disintegrant.

[0305]

[0293] Embodiment 51. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a glidant.

[0306]

[0294] Embodiment 52. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a lubricant.

[0307]

[0295] Embodiment 53. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is a surfactant.

[0308]

[0296] Embodiment 54. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is mannitol.

[0309]

[0297] Embodiment 55. A pharmaceutical composition described in embodiment 54, wherein mannitol is present in an amount of about 5% to about 15% by weight of the composition.

[0310]

[0298] Embodiment 56. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is microcrystalline cellulose.

[0311]

[0299] Embodiment 57. A pharmaceutical composition described in embodiment 56, wherein the microcrystalline cellulose is present in an amount of about 10% to about 20% by weight of the composition.

[0312]

[0300] Embodiment 58. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is croscarmellose sodium.

[0313]

[0301] Embodiment 59. A pharmaceutical composition described in embodiment 58, wherein croscarmellose sodium is present in an amount of about 1% to about 5% by weight of the composition.

[0314]

[0302] Embodiment 60. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is magnesium stearate.

[0315]

[0303] Embodiment 61. A pharmaceutical composition described in embodiment 60, wherein magnesium stearate is present in an amount of about 0.5% to about 2% by weight of the composition.

[0316]

[0304] Embodiment 62. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is maltodextrin.

[0317]

[0305] Embodiment 63. A pharmaceutical composition described in embodiment 62, wherein maltodextrin is present in an amount of about 5% to about 15% by weight of the composition.

[0318]

[0306] Embodiment 64. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is colloidal anhydrous silica.

[0319]

[0307] Embodiment 65. A pharmaceutical composition described in embodiment 64, wherein the colloidal anhydrous silica is present in an amount of about 0.1% to about 0.5% by weight of the composition.

[0320]

[0308] Embodiment 66. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is sodium stearyl fumarate.

[0321]

[0309] Embodiment 67. A pharmaceutical composition described in embodiment 66, wherein sodium stearyl fumarate is present in an amount of about 0.5% to about 1% by weight of the composition.

[0322]

[0310] Embodiment 68. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is hypromellose.

[0323]

[0311] Embodiment 69. A pharmaceutical composition described in embodiment 68, wherein hypromellose is present in an amount of about 1% by weight to about 5% by weight of the composition.

[0324]

[0312] Embodiment 70. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is stearic acid.

[0325]

[0313] Embodiment 71. A pharmaceutical composition described in embodiment 70, wherein stearic acid is present in an amount of about 0.1% to about 0.5% by weight of the composition.

[0326]

[0314] Embodiment 72. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is hypromellose acetate succinate.

[0327]

[0315] Embodiment 73. A pharmaceutical composition described in embodiment 72, wherein hypromellose acetate succinate is present in an amount of about 5% to about 15% by weight of the composition.

[0328]

[0316] Embodiment 74. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is triethyl citrate.

[0329]

[0317] Embodiment 75. A pharmaceutical composition described in embodiment 74, wherein triethyl citrate is present in an amount of about 1% to about 5% by weight of the composition.

[0330]

[0318] Embodiment 76. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is sodium lauryl sulfate.

[0331]

[0319] Embodiment 77. A pharmaceutical composition described in embodiment 76, wherein sodium lauryl sulfate is present in an amount of about 0.1% to about 0.5% by weight of the composition.

[0332]

[0320] Embodiment 78. A pharmaceutical composition described in any one of embodiments 1 to 47, wherein the pharma- ceutically acceptable excipient is talc.

[0333]

[0321] Embodiment 79. A pharmaceutical composition described in embodiment 78, wherein talc is present in an amount of about 1% by weight to about 5% by weight of the composition.

[0334]

[0322] Embodiment 80. A method for treating a condition comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, and wherein in a control study, when the unit dosage form is administered to a test subject, a sustained release of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is achieved in the subject.

[0335]

[0323] Embodiment 81. The method of embodiment 80, wherein the condition is a cardiac condition.

[0336]

[0324] Embodiment 82. The method of embodiment 81, wherein the cardiac condition is characterized by an irregular heartbeat.

[0337]

[0325] Embodiment 83. The method of embodiment 81 or 82, wherein the cardiac condition is catecholamine-induced polymorphic ventricular tachycardia.

[0338]

[0326] Embodiment 84. The method of embodiment 81, wherein the cardiac condition is heart failure.

[0339]

[0327] Embodiment 85. The method of embodiment 84, wherein the heart failure is congestive heart failure.

[0340]

[0328] Embodiment 86. The method of embodiment 84, wherein the heart failure is chronic heart failure.

[0341]

[0329] Embodiment 87. The method of embodiment 84, wherein the heart failure is heart failure with reduced ejection fraction.

[0342]

[0330] Embodiment 88. The method of embodiment 84, wherein the heart failure is heart failure with preserved ejection fraction.

[0343]

[0331] Embodiment 89. The method of any one of embodiments 84 to 86, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, and the implantable cardioverter-defibrillator is implanted in the patient.

[0344]

[0332] Embodiment 90. The method of embodiment 84, wherein the chronic heart failure is acute heart failure.

[0345]

[0333] Embodiment 91. The method of embodiment 84, wherein the subject is a heart failure patient in need of preservation of cardiac function after myocardial infarction.

[0346]

[0334] Embodiment 92. The method of embodiment 81, wherein the cardiac condition is myocardial infarction.

[0347]

[0335] Embodiment 93. The method of embodiment 81, wherein the cardiac condition includes cardiac ischemia / reperfusion injury.

[0348]

[0336] Embodiment 94. The method of embodiment 80, wherein the condition is a musculoskeletal condition.

[0349]

[0337] Embodiment 95. The method of embodiment 94, wherein the musculoskeletal condition is a congenital myopathy.

[0350]

[0338] Embodiment 96. The method of embodiment 95, wherein the congenital myopathy is RYR1-associated myopathy.

[0351]

[0339] Embodiment 97. The method of embodiment 94, wherein the musculoskeletal condition is muscular dystrophy.

[0352]

[0340] Embodiment 98. The method of embodiment 97, wherein the muscular dystrophy is Duchenne muscular dystrophy.

[0353]

[0341] Embodiment 99. The method of embodiment 94, wherein the musculoskeletal condition is sarcopenia.

[0354]

[0342] Embodiment 100. The method of embodiment 80, wherein the condition is muscle weakness associated with cancer.

[0355]

[0343] Embodiment 101. The method of embodiment 100, wherein the cancer-associated muscle weakness is cancer cachexia.

[0356]

[0344] Embodiment 102. The method of embodiment 101, wherein the cancer cachexia is due to a cancer having bone metastasis.

[0357]

[0345] Embodiment 103. The method of embodiment 80, wherein the musculoskeletal condition is diabetes.

[0358]

[0346] Embodiment 104. The method of embodiment 80, wherein the condition is malignant hyperthermia.

[0359]

[0347] Embodiment 105. The method of any one of embodiments 80 to 104, wherein the therapeutically effective amount is about 100 to about 200 mg per day.

[0360]

[0348] Embodiment 106. The method of any one of embodiments 80 to 105, wherein the therapeutically effective amount is about 120 mg per day.

[0361]

[0349] Embodiment 107. The method of any one of embodiments 80 to 105, wherein the therapeutically effective amount is about 200 mg per day.

[0362]

[0350] Embodiment 108. The method of any one of embodiments 80 to 107, wherein administration is oral.

[0363]

[0351] Embodiment 109. The method of any one of embodiments 80 to 108, wherein the salt is a hemifumarate salt.

[0364]

[0352] Embodiment 110. The method of any one of embodiments 80 to 109, wherein the sustained release is modified release.

[0365]

[0353] Embodiment 111. The method of any one of embodiments 80 to 110, wherein the sustained release is an extended release.

[0366]

[0354] Embodiment 112. The method of any one of embodiments 80 to 111, wherein the sustained release is a delayed release.

[0367]

[0355] Embodiment 113. The method of any one of embodiments 80 to 112, wherein the unit dosage form is a solid dosage form.

[0368]

[0356] Embodiment 114. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 12 hours.

[0369]

[0357] Embodiment 115. A method according to any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 24 hours.

[0370]

[0358] Embodiment 116. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof occurs in the subject from about 2 to about 6 hours after administration.

[0371]

[0359] Embodiment 117. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof occurs in the subject from about 2 to about 4 hours after administration.

[0372]

[0360] Embodiment 118. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof occurs in the subject from about 3 to about 4 hours after administration.

[0373]

[0361] Embodiment 119. A method according to any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, an in-vivo half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof of about 14 to about 21 hours is obtained in the subject.

[0374]

[0362] Embodiment 120. The method of embodiment 119, wherein the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is about 14 hours.

[0375]

[0363] Embodiment 121. The method of embodiment 119, wherein the half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof is about 20 hours.

[0376]

[0364] In embodiment 122, when the unit dosage form is administered to a test subject in a controlled study, the C of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, is between about 1.4 and about 1.8. max A cumulative ratio of C to C at day 28 is present in the subject, max / Day 1 C max It is calculated as the ratio of C max is the maximum observed plasma concentration.

[0377]

[0365] Embodiment 123. In a controlled study, when the unit dosage form is administered to a test subject, there is a cumulative ratio of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, to AUC of between about 1.4 and about 1.8 in the subject, and said cumulative ratio to AUC is greater than or equal to AUC on day 28. tau / AUC on day 1 0-24 It is calculated as a ratio, - AUC is the area under the concentration-time curve; - AUC tau is the area under the concentration-time curve during the dosing interval (tau) at steady state; - AUC 0-24The method of any one of embodiments 80 to 113, wherein is the area under the concentration-time curve from 0 to 24 hours after administration.

[0378]

[0366] Embodiment 124. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of less than about 35 ug / mL is present in the subject.

[0379]

[0367] Embodiment 125. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is present in the subject after administration of a single 120 mg dose of about 10 to about 15 ng / mL.

[0380]

[0368] Embodiment 126. The method of any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is present in the subject after administration of a 120 mg dose once daily for 14 days.

[0381]

[0369] Embodiment 127. A method according to any one of embodiments 80 to 113, wherein in a controlled study, when the unit dosage form is administered to a test subject, a steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is achieved in the test subject in a range of about 3 to about 7 days after the initial administration.

[0382]

[0370] Embodiment 128. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0383]

[0371] Embodiment 129. The method of any one of embodiments 80 to 127, wherein the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0384]

[0372] Embodiment 130. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0385]

[0373] Embodiment 131. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 23.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0386]

[0374] Embodiment 132. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0387]

[0375] Embodiment 133. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 58.75 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0388]

[0376] Embodiment 134. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0389]

[0377] Embodiment 135. The method of any one of embodiments 80 to 127, wherein the unit dosage form contains 117.5 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0390]

[0378] Embodiment 136. The method of any one of embodiments 80 to 135, wherein the unit dosage form is a tablet.

[0391]

[0379] Embodiment 137. The method according to any one of embodiments 80 to 135, wherein the unit dosage form is a tablet and the tablet is prepared by wet granulation.

[0392]

[0380] Embodiment 138. The method according to any one of embodiments 80 to 135, wherein the unit dosage form is a tablet and the tablet is prepared by dry granulation.

[0393]

[0381] Embodiment 139. The method of any one of embodiments 80 to 138, wherein the unit dosage form is a gastroresistant tablet.

[0394]

[0382] Embodiment 140. The method described in embodiment 139, wherein the gastroresistant tablet does not substantially disintegrate at a pH of 5.5 or less, and disintegration is determined by measuring the dissolution of the gastroresistant tablet in a medium having a pH of 5.5 or less.

[0395]

[0383] Embodiment 141. The method of embodiment 140, wherein the medium having a pH of 5.5 or less is a 0.1N HCl solution having a pH of 1.2.

[0396]

[0384] Embodiment 142. The method described in embodiment 139, wherein the gastro-resistant tablet substantially disintegrates at a pH of about 6.8, and the disintegration is determined by measuring the dissolution of the gastro-resistant tablet in a medium having a pH of 6.8.

[0397]

[0385] Embodiment 143. The method of embodiment 142, wherein the medium having a pH of 6.8 is a phosphate buffer.

[0398]

[0386] Embodiment 144. The method of embodiment 139, wherein the gastroresistant tablet does not substantially disintegrate in gastric juice.

[0399]

[0387] Embodiment 145. The method of embodiment 139, wherein the gastroresistant tablet substantially disintegrates in intestinal fluids.

[0400]

[0388] Embodiment 146. The method of any one of embodiments 80 to 145, wherein the subject is in a fed state.

[0401]

[0389] Embodiment 147. The method of any one of embodiments 80 to 145, wherein the subject is in a fasting state.

[0402]

[0390] Embodiment 148. A method according to any one of embodiments 80 to 147, further comprising administering to the subject a therapeutically effective amount of a gastric acid reducing agent.

[0403]

[0391] Embodiment 149. The method of embodiment 148, wherein the gastric acid reducing agent is administered simultaneously with the pharmaceutical composition.

[0404]

[0392] Embodiment 150. The method of embodiment 148, wherein the gastric acid reducing agent is administered sequentially before or after the pharmaceutical composition.

[0405]

[0393] Embodiment 151. The method of any one of embodiments 148 to 150, wherein the gastric acid reducing agent is a proton pump inhibitor.

[0406]

[0394] Embodiment 152. The method of any one of embodiments 148 to 151, wherein the gastric acid reducing agent is an antacid.

[0407]

[0395] Embodiment 153. A method according to any one of embodiments 148 to 151, wherein the gastric acid reducing agent is a histamine H2 receptor antagonist.

[0408]

[0396] Embodiment 154. A method according to any one of embodiments 80 to 147, wherein the pharmaceutical composition is administered in the absence of a gastric acid reducing agent.

[0409]

[0397] Embodiment 155. The method according to any one of embodiments 80 to 154, wherein the unit dosage form is a gastroresistant tablet, the gastroresistant tablet comprising a core and a coating layer substantially covering the core.

[0410]

[0398] Embodiment 156. The method of embodiment 155, wherein the coating layer comprises an enteric polymer.

[0411]

[0399] Embodiment 157. The method of embodiment 156, wherein the enteric polymer is hypromellose acetate succinate.

[0412]

[0400] Embodiment 158. The method of embodiment 155, wherein the coating layer is about 20% by weight of the tablet.

[0413]

[0401] Embodiment 159. The method described in embodiment 155, wherein the gastroresistant tablet further comprises a subcoating layer between the core and the coating layer.

[0414]

[0402] Embodiment 160. The method of embodiment 159, wherein the subcoating layer comprises a polymer.

[0415]

[0403] Embodiment 161. The method of embodiment 160, wherein the polymer is hypromellose.

[0416]

[0404] Embodiment 162. The method described in any one of embodiments 159, wherein the subcoating layer is about 3% by weight of the tablet.

[0417]

[0405] Embodiment 163. A method according to any one of embodiments 80 to 162, wherein the treatment increases RyR1-calstabin1 binding in the subject's skeletal muscle.

[0418]

[0406] Embodiment 164. A method according to any one of embodiments 80 to 163, wherein the treatment reduces calcium leak from RyR1 channels in the subject.

[0419]

[0407] Embodiment 165. A pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, wherein, in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof occurs in the subject at a time point between about 2 hours and about 6 hours after administration.

[0420]

[0408] Embodiment 166. A pharmaceutical composition described in embodiment 165, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof occurs in the subject at a time point between about 3 hours and about 4 hours after administration.

[0421]

[0409] Embodiment 167. A pharmaceutical composition according to embodiment 165 or embodiment 166, comprising a pharma- ceutically acceptable salt, wherein the pharma- ceutically acceptable salt is a hemifumarate salt.

[0422]

[0410] Embodiment 168. A pharmaceutical composition described in any one of embodiments 165 to 167, wherein the unit dosage form is a modified release dosage form.

[0423]

[0411] Embodiment 169. A pharmaceutical composition described in any one of embodiments 165 to 168, wherein the unit dosage form is a delayed release dosage form.

[0424]

[0412] Embodiment 170. A pharmaceutical composition described in any one of embodiments 165 to 169, wherein the unit dosage form is suitable for oral administration.

[0425]

[0413] Embodiment 171. A pharmaceutical composition described in any one of embodiments 165 to 170, wherein the unit dosage form is a solid dosage form.

[0426]

[0414] Embodiment 172. A pharmaceutical composition described in any one of embodiments 165 to 171, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 12 hours.

[0427]

[0415] Embodiment 173. A pharmaceutical composition described in any one of embodiments 165 to 171, wherein in a controlled study, when the unit dosage form is administered to a test subject, a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof is present in the subject for a period of time, the period of time occurring after administration, and the period of time being at least about 24 hours.

[0428]

[0416] Embodiment 174. A pharmaceutical composition described in any one of embodiments 165 to 171, wherein in a controlled study, when the unit dosage form is administered to a test subject, an in-vivo half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of about 14 to about 21 hours is obtained in the subject.

[0429]

[0417] In embodiment 175, when the unit dosage form is administered to a test subject in a controlled study, the C of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, is between about 1.4 and about 1.8. max A cumulative ratio of C to C at day 28 is present in the subject, max / Day 1 C max It is calculated as the ratio of C max is the maximum observed plasma concentration.

[0430]

[0418] Embodiment 176. In a controlled study, when the unit dosage form is administered to a test subject, a cumulative ratio of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt or ion thereof, to AUC of between about 1.4 and about 1.8 is present in the subject, and said cumulative ratio to AUC is greater than or equal to AUC on day 28. tau / AUC on day 1 0-24 Calculated as a ratio - AUC is the area under the concentration-time curve; - AUC tau is the area under the concentration-time curve during the dosing interval (tau) at steady state; - AUC 0-24 is the area under the concentration-time curve from 0 to 24 hours after administration.

[0431]

[0419] Embodiment 177. A pharmaceutical composition described in any one of embodiments 165 to 171, wherein in a controlled study, when the unit dosage form is administered to a test subject, a maximum observed plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable ion thereof of less than about 35 ug / mL is present in the subject.

[0432]

[0420] Embodiment 178. A pharmaceutical composition described in any one of embodiments 165 to 171, wherein in a controlled study, when the unit dosage form is administered to a test subject, a steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof is achieved in the test subject in a range of about 3 to about 7 days after the initial administration.

[0433]

[0421] Embodiment 179. A pharmaceutical composition described in any one of embodiments 165 to 178, comprising 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0434]

[0422] Embodiment 180. A pharmaceutical composition described in any one of embodiments 165 to 178, comprising 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0435]

[0423] Embodiment 181. A pharmaceutical composition described in any one of embodiments 165 to 178, comprising 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0436]

[0424] Embodiment 182. A pharmaceutical composition described in any one of embodiments 165 to 181, wherein the unit dosage form is a gastroresistant tablet.

[0437]

[0425] Embodiment 183. A pharmaceutical composition described in embodiment 182, wherein the gastro-resistant tablet does not substantially disintegrate at a pH of 5.5 or less, and the disintegration is determined by measuring the dissolution of the gastro-resistant tablet in a medium having a pH of 5.5 or less.

[0438]

[0426] Embodiment 184. The pharmaceutical composition described in embodiment 182, wherein the gastro-resistant tablet substantially disintegrates at a pH of at least about 6.8, and the disintegration is determined by measuring the dissolution of the gastro-resistant tablet in a medium having a pH of 6.8.

[0439]

[0427] Embodiment 185. A pharmaceutical composition described in any one of embodiments 165 to 184, wherein the unit dosage form is a gastroresistant tablet, the gastroresistant tablet comprising a core and a coating layer substantially covering the core.

[0440]

[0428] Embodiment 186. A pharmaceutical composition described in embodiment 185, wherein the coating layer comprises an enteric polymer.

[0441]

[0429] Embodiment 187. A pharmaceutical composition described in embodiment 186, wherein the enteric polymer is hypromellose acetate succinate.

[0442]

[0430] Embodiment 188. A pharmaceutical composition described in embodiment 185, further comprising a subcoating layer between the core and the coating layer.

[0443]

[0431] Embodiment 189. A pharmaceutical composition described in embodiment 188, wherein the subcoating layer comprises a polymer.

[0444]

[0432] Embodiment 190. A pharmaceutical composition described in embodiment 189, wherein the polymer is hypromellose.

[0445]

[0433] Embodiment 191. A method for treating a condition, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, and in a control study, when the unit dosage form is administered to a test subject, a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof occurs in the subject at a time point between about 2 hours and about 6 hours after administration.

[0446]

[0434] Embodiment 192. The method of embodiment 191, wherein the condition is catecholamine-induced polymorphic ventricular tachycardia.

[0447]

[0435] Embodiment 193. The method of embodiment 191, wherein the condition is RYR1-associated myopathy.

[0448]

[0436] Embodiment 194. A tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer. - the core comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - a tablet, wherein the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0449]

[0437] Embodiment 195. A tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer. - the core comprises 20 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - a tablet, wherein the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0450]

[0438] Embodiment 196. A tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer. - the core comprises 50 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - a tablet, wherein the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0451]

[0439] Embodiment 197. A tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer. - the core comprises 100 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the subcoating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - a tablet, wherein the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

[0452]

[0440] Embodiment 198.

[0453] [Table 17]

[0454] Tablets containing:

Claims

1. 1. A pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, in a unit dosage form, wherein, when administered to a subject, the unit dosage form provides a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable ion thereof to the subject from about 2 to about 6 hours after administration.

2. 2. The pharmaceutical composition of claim 1, comprising a pharma- ceutically acceptable salt, wherein the pharma- ceutically acceptable salt is a hemifumarate salt.

3. 2. The pharmaceutical composition of claim 1, wherein the sustained release is a delayed release.

4. The pharmaceutical composition of claim 1 , wherein the unit dosage form is suitable for oral administration.

5. The pharmaceutical composition of claim 1 , wherein the unit dosage form is a solid dosage form.

6. The pharmaceutical composition of claim 1, wherein the unit dosage form, when administered to a subject, provides a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof to the subject for a period of time, the period of time occurring after administration, the period of time being at least about 12 hours.

7. The pharmaceutical composition of claim 1, wherein the unit dosage form, when administered to a subject, provides a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharma- ceutically acceptable salt thereof to the subject for a period of time, the period of time occurring after administration, the period of time being at least about 24 hours.

8. The pharmaceutical composition of claim 1, wherein the unit dosage form, when administered to a subject, provides a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof, to the subject from about 2 hours to about 4 hours after administration.

9. The pharmaceutical composition of claim 1, wherein the unit dosage form, when administered to a subject, provides to the subject an in vivo half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable ion thereof, of about 14 to about 21 hours.

10. When the unit dosage form is administered to a subject, it has a C of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, between about 1.4 and about 1.

8. ｍａｘ A cumulative ratio of the C ｍａｘ / Day 1 C ｍａｘ It is calculated as the ratio of C ｍａｘ is the maximum observed plasma concentration.

11. The unit dosage form, when administered to a subject, provides a cumulative ratio to AUC of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutical acceptable salt or a pharma-ceutical acceptable ion thereof, of between about 1.4 and about 1.8 to a subject, and said cumulative ratio to AUC is greater than or equal to the AUC on day 28. ｔａｕ / AUC on Day 1 ０－２４ Calculated as a ratio - AUC is the area under the concentration-time curve; - AUC ｔａｕ is the area under the concentration-time curve during the dosing interval (tau) at steady state; - AUC ０－２４ is the area under the concentration-time curve from 0 to 24 hours after administration.

12. The pharmaceutical composition of claim 1, wherein the unit dosage form, when administered to a subject, provides a steady state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable ion thereof to the subject for a period ranging from about 3 to about 7 days after the initial administration.

13. 2. The pharmaceutical composition of claim 1, wherein the unit dosage form is a gastroresistant tablet.

14. 14. The pharmaceutical composition according to claim 13, wherein the gastroresistant tablet does not substantially disintegrate at a pH of 5.5 or less, the disintegration being determined by measuring the dissolution of the gastroresistant tablet in a medium having a pH of 5.5 or less.

15. 14. The pharmaceutical composition of claim 13, wherein the gastroresistant tablet substantially disintegrates at a pH of at least about 6.8, the disintegration being determined by measuring the dissolution of the gastroresistant tablet in a medium having a pH of 6.

8.

16. 2. The pharmaceutical composition according to claim 1, wherein the unit dosage form is a gastroresistant tablet, the gastroresistant tablet comprising a core and a coating layer substantially covering the core.

17. 17. The pharmaceutical composition of claim 16, wherein the coating layer comprises an enteric polymer, and the enteric polymer is hypromellose acetate succinate.

18. 17. The pharmaceutical composition of claim 16, further comprising a sub-coating layer between the core and the coating layer.

19. 20. The pharmaceutical composition of claim 18, wherein the subcoating layer comprises a polymer, and the polymer is hypromellose.

20. A pharmaceutical composition according to any one of claims 1 to 19 for use in treating a condition in a subject.

21. 21. The pharmaceutical composition of claim 20, wherein the condition is a cardiac condition.

22. 22. The pharmaceutical composition of claim 21, wherein the cardiac condition is characterized by an irregular heartbeat.

23. 22. The pharmaceutical composition of claim 21, wherein the cardiac condition is catecholaminergic polymorphic ventricular tachycardia.

24. 22. The pharmaceutical composition of claim 21, wherein the cardiac condition is heart failure.

25. 21. The pharmaceutical composition of claim 20, wherein the condition is a musculoskeletal condition.

26. 26. The pharmaceutical composition of claim 25, wherein the musculoskeletal condition is a congenital myopathy.

27. 26. The pharmaceutical composition of claim 25, wherein the condition is an RYR1-associated myopathy.

28. 26. The pharmaceutical composition of claim 25, wherein the musculoskeletal condition is a muscular dystrophy.

29. 29. The pharmaceutical composition of claim 28, wherein the muscular dystrophy is Duchenne muscular dystrophy.

30. 26. The pharmaceutical composition of claim 25, wherein the musculoskeletal condition is sarcopenia.

31. 21. The pharmaceutical composition of claim 20, wherein the condition is malignant hyperthermia.

32. 21. The pharmaceutical composition of claim 20, wherein the therapeutically effective amount is from about 100 to about 500 mg per day.

33. The pharmaceutical composition of claim 20, for oral administration.

34. A tablet comprising a core, a subcoating layer substantially covering the core, and a coating layer substantially covering the subcoating layer. the core comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; - the sub-coating layer comprises hypromellose, microcrystalline cellulose and stearic acid; - A tablet, wherein the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.

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