Tenapanol oral formulation

Abstract

To provide a chemically stable, soluble tenapanol pharmaceutical tablet formulation. [Solution] The formulation comprises a bis-HCl form of amorphous tenapanol exceeding approximately 6% w / w, an acidifying agent, an antioxidant, a disintegrant, a lubricant, a flow enhancer, a bulking agent, and a fast-acting coating, wherein the total chloride content of the active ingredients exceeds 5.82%, and the particle size distribution D50 is approximately 18 μm to approximately 22 μm. The present invention relates to the field of pharmaceutical compositions, more specifically to the field of tablet compositions, and more specifically to the field of fast-acting tablet compositions.

Description

[Technical Field]

[0001] Cross-reference to Related Application This application claims the priority benefit of U.S. Provisional Application No. 63 / 199,078, filed on December 4, 2020. The entire content of the above application is hereby fully incorporated herein by reference. [Background Art]

[0002] Field of the Invention The present invention relates to the field of pharmaceutical compositions, specifically to the field of tablet compositions, and more specifically to the field of fast-acting tablet compositions. [Summary of the Invention] [Means for Solving the Problems]

[0003] Background of the Invention The main function of the gastrointestinal (GI) tract is to maintain intestinal water / sodium (Na+) homeostasis via the balance between secretory mechanisms and absorptive mechanisms. A Na+ / hydrogen (H+) antiporter termed sodium-hydrogen exchanger 3 (NHE3) plays a central role in the sodium uptake process. Tenapanor is an NHE3 inhibitor that acts locally in the gastrointestinal tract with minimal systemic bioavailability to inhibit the absorption of sodium from the lumen. [Chemical Formula]

[0004] Reduced sodium uptake increases the volume of fluid in the gastrointestinal tract, resulting in decreased fecal viscosity and faster GI passage in both animals and humans. Furthermore, tenapanol, in its bis-HCl salt form, has been clinically shown to alleviate abdominal pain in patients with irritable bowel syndrome (IBS-C) accompanied by constipation. In an animal model of IBS-like colonic irritability, tenapanol reduced visceral hyperalgesia and normalized the excitability of colonic sensory neurons and transient receptor potential vanilloid 1 (TRPV1) currents. TRPV1 is a well-known pain receptor that responds to a variety of harmful stimuli. Tenapanol suppressed increased permeability of the human colonic epithelial monolayer to macromolecules produced by cytokines or human fecal supernatant. The beneficial effect of tenapanol on abdominal pain in IBS-C patients may be a result of its ability to reduce colonic permeability to luminal macromolecules, which can decrease the hyperexcitability of sensory neurons.

[0005] Furthermore, tenapanol has been clinically demonstrated to lower serum phosphate levels in patients with hyperphosphatemia. Hyperphosphatemia is a serious condition characterized by abnormally high blood phosphate levels (above 5.5 mg / dL) and is often associated with kidney disease, which affects the organs involved in phosphate removal. Inhibition of NHE3 by tenapanol leads to conformational changes at the GI epithelial cell junction, significantly reducing paracellular uptake of phosphate in the primary phosphate absorption pathway. We have reported three successful Phase 3 trials demonstrating tenapanol's ability to lower phosphate levels, both as monotherapy and as part of a dual-mechanism approach using phosphate binders.

[0006] Despite treatment with phosphate binders (the only approved treatment for hyperphosphatemia), approximately 70% of CKD patients undergoing dialysis continue to experience elevated phosphorus levels at any given time (Spherix Global Insights: RealWorld). (Dynamix, Dialysis 2018). Phosphate levels above 5.5 mg / dL have been shown to be an independent risk factor for cardiovascular morbidity and mortality in patients requiring dialysis (Block 2004), and internationally recognized treatment guidelines recommend lowering elevated phosphate levels towards the normal range (<4.6 mg / dL). [Brief explanation of the drawing]

[0007] [Figure 1] Dissolution of 15 mg tenapanol HCl tablets and tenapanol free base tablets in FeSSIF medium pH 5.0. Dissolution method: 900 mL of medium at USP instrument II (paddle), 75 rpm, 37°C. [Figure 2] Dissolution of Capsule I, HPMC capsules containing pure tenapanolHCl powder (Vcaps® derived from Capsugel®), FaSSIF medium pH 6.5, FeSSIF medium pH 5, and 0.1N HCl. Dissolution method: 900 mL of medium at USP apparatus II (paddle), 75 rpm, 37°C. [Figure 3] Dissolution comparison of Capsule I (pure product) and Capsule II (excipient blended with tenapanol HCl) in V capsules in FeSSIF medium at pH 5. [Figure 4] Dissolution of prototype II tablets in FeSSIF pH 6.5 medium, FeSSIF pH 5 medium, and 0.1N HCl containing 14 mg of tenapanol HCl (a); 14 mg of tenapanol free base (b); and 50 mg of tenapanol HCl (c). The amount of tenapanol HCl expressed is the base equivalent. [Figure 5] Dissolution comparison of 15 mg Prototype II tablets containing tenapanol free base and tenapanol HCl, and Prototype III tablets containing FeSSIF pH 5.0. [Figure 6] Comparison of the solubility of large (60 mg) and small (5 mg) amounts of tenapanol free base and tenapanol HCl contained in Prototype III tablets in FeSSGF medium at pH 5.0. [Figure 7]Decreased solubility in 0.1N HCl of prototype Ib tablet formulations stored for 6 months at 25°C / 60% relative humidity and 40°C / 75% relative humidity. [Figure 8] A time-course comparison of impurities found in prototype II tablets containing 45 mg (a) and 1 mg (b) of tenapanol at 2-8°C, 25°C / 60% relative humidity, and 40°C / 75% relative humidity. [Figure 9] Comparison of impurities in coated and uncoated 5 mg Tenapanol Prototype III tablets stored over time at 40°C / 75%RH using a desiccant and an oxygen-absorbing desiccant (PharmaKeep®). [Figure 10] Changes in total impurities after 1 month of open storage at 40°C / 30% relative humidity for prototype III tenapanolHCl tablet formulations with chloride content of 6% and 10%. Each tablet formulation contained 1% tartaric acid and 0.02% propyl gallate. [Figure 11] This is a thermogravimetric analysis of a spray-dried dispersion of tenapanolHCl, taken at t(0) (Panel A) and after exposure to ambient temperature and humidity for 5 days (Panel B). The absence of a significant difference between the trace diagrams indicates that the spray-dried dispersion of tenapanolHCl is in equilibrium with water. [Figure 12] This is a flowchart of the process for formulating and tableting tenapanol. [Modes for carrying out the invention]

[0008] Detailed explanation Definition: "%w / w" refers to the proportion of a specific component of the formulation, or, if specified, the proportion of the active pharmaceutical ingredient (API) component.

[0009] In the context of the amount of a specific pharmaceutical ingredient, the term "approximately" means plus or minus 5% of the value it refers to. For example, approximately 1% means between 0.95% and 1.05%.

[0010] CSD means colloidal silicon dioxide.

[0011] The drug substance refers to tenapanor, the active pharmaceutical ingredient, which is also alternatively referred to as API or active pharmaceutical ingredient.

[0012] FeSSGF refers to Fed State Simulated Gastric Fluid medium, which mimics gastric fluid after a high-fat FDA diet compatible with USP apparatus.

[0013] FaSSIF refers to Fasted State Simulated Intestinal Fluid medium, which mimics fasted state intestinal fluid compatible with USP apparatus.

[0014] FeSSIF refers to Fed State that mimics postprandial intestinal fluid compatible with USP apparatus Simulated Intestinal Fluid medium.

[0015] FS means fumed silica, for example, Cab-O-Sil®.

[0016] L-HPC means low-substituted hydroxypropyl cellulose, and is also alternatively known as hydroxypropyl methylcellulose (HPMC), which is a disintegrant or a disintegrating agent that assists dissolution.

[0017] MCC means microcrystalline cellulose, for example, Avicel®.

[0018] PVP means cross-linked N-vinyl-2-pyrrolidone homopolymer, for example, Polyplasdone XL®.

[0019] SSF means sodium stearyl fumarate (for example, Pruv®).

[0020] Tenapanol refers to the free base compound 1-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinoline-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]-3-[4-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinoline-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethylcarbamoylamino]butyl]urea. The bis-HCl(di-HCl) salt form of tenapanol is interchangeably referred to as tenapanol hydrochloride or tenapanol HCl and has the following chemical structure. [ka]

[0021] A pharmacodynamic (PD) study (Phase 1, single-center, randomized, ternary, open-label trial) was conducted to evaluate the pharmacodynamics of various tenapanol formulations in healthy volunteers taking omeprazole and to investigate differences in PD effects between tenapanol free base and hydrochloride in equivalent tablet formulations. Since tenapanol is a locally acting, intestinal NHE3 inhibitor, it was thought to affect sodium absorption, resulting in higher levels of sodium excreted in feces as opposed to urine. Tablets of amorphous salt (equivalent to 15 mg and 14 mg free base) and crystalline free base (14 mg) were directly compared during formulation development using fecal and urinary sodium as PD markers in healthy volunteers also taking omeprazole as a proton pump inhibitor. These two tablet formulations showed different solubility profiles at pH 5.0 (Figure 1). The higher solubility of the amorphous HCl salt was greater at pH 5.0 compared to the crystalline free base. We also showed that the dissolution of potent free base (60 mg) tablets is dependent on the pH of the culture medium.

[0022] Dissolution Several capsule and tablet prototypes were prepared and tested for various properties, but solubility and stability were found to be particularly insufficient. Below are the compositions and maximum solubility of some capsule and tablet formulations observed in 0.1N HCl, pH 5 FeSSIF medium, and pH 6 FaSSIF medium. Tablets of the same prototype designation, although differing in tenapanol loading and salt / free base configuration, contained the same disintegrant, flow enhancer, and lubricant excipients at the same %w / w, but the %w / w of tenapanol and filler constituting the remaining portion of the tablet varied.

[0023] Table 1(a)-1(m): Prototype components of capsules and tablets, and the maximum solubility observed in 0.1N HCl solution, pH 5 FeSSIF medium, and pH 6.5 FaSSIF medium. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0024] The following findings were observed from dissolution experiments of the capsule and tablet formulations shown in Tables 1(a) to 1(m).

[0025] As shown in Figure 2, formulation is necessary for tenapanol to achieve acceptable solubility, with only about 40% of pure tenapanol dissolving after 120 minutes at low pH. At pH 5.0, pure tenapanol capsules showed only slight solubility, while tenapanol mixed with a flow enhancer, lubricant, and extender (Capsule II) in the same capsules showed approximately 85% solubility.

[0026] - Tenapanol dissolved well at low pH.

[0027] - The tenapanol HCl salt form showed superior solubility at high pH compared to the free base, as shown in Figure 1. This was also demonstrated with prototype II tablets (Figures 4a and 4b) and prototype III tablets (Figure 5) at high pH levels of 5 and 6.5.

[0028] - High doses of tenapanol negatively affected solubility. For example, 60 mg prototype III tablets at 22.2% w / w showed very little solubility in a pH 5 medium, while 5 mg prototype III tablets at 5% w / w showed approximately 40% solubility in the free base version and approximately 95% solubility in the HCl version.

[0029] Based on these results, Prototype III was determined to have superior solubility compared to Prototype II, as shown in Figure 5, and was subjected to further development and stability studies. Prototype I tablets showed reasonable solubility in 0.1N HCl (approximately 95% after 60 minutes), but as shown in Figure 7, solubility decreased significantly due to aging of the formulation.

[0030] chemical stability The chemical stability of the prototype III tablet formulation was studied. 5 mg tenapanol prototype III tablets were stored under accelerated stability conditions of high temperature and relative humidity. After two months, the formulation showed significant degradation and contained impurities. Analysis by reversed-phase liquid chromatography identified the following impurities. [ka]

[0031] In conducting these studies, it was found that the presence of a desiccant canister containing an oxygen absorber resulted in chemical stability for two months under these conditions, whereas the presence of a desiccant canister without an oxygen absorber significantly increased the content of decomposed impurities in the same tablets. See Figure 9. Based on this finding, prototype III tablets containing antioxidants were prepared and tested. The effect of chloride levels on the chemical stability of tenapanol tablets was also investigated. Tables 2 and 3 show the percentage changes in the organic impurities labeled tenapanol-B, tenapanol-D, tenapanol-N-oxide, and isoquinolinium after open storage for 1 month and 2.5 months under high temperature and relative humidity. [Table 2] [Table 3]

[0032] The effects of antioxidants When the drug dose was low (6% w / w) and the chloride content of the active pharmaceutical ingredient was low (5.6% w / w), the presence of antioxidants improved stability, but the stabilizing effect was not as significant as when the drug dose was high (10% w / w). For example, N3 tablets containing 0.2% propyl gallate and a low drug dose showed a 0.35% increase in impurities after one month, while N28 tablets, which were identical except for the absence of antioxidants, showed a 2.23% increase in impurities. However, at a drug dose of 10% w / w, N26 and N27 tablets containing 0.05% and 0.4% propyl gallate, respectively, did not show the same improvement as N2 tablets which did not contain propyl gallate.

[0033] Further effects of acidifying agents The addition of an acidifying agent was found to improve chemical stability when the chloride content of the active pharmaceutical ingredient (API) was stoichiometric. For example, N5 tablets containing 1% tartaric acid showed increases in impurities of 0.51% and 2.23% after 1 month and 2.5 months, respectively, while N28 tablets without tartaric acid showed increases of 2.23% and 3.68%. However, when APIs with hyperstoichiometric chloride content were made into tablets, the addition of an acidifying agent did not affect chemical stability. For example, N21 tablets using an API with a chloride content of 6.5% w / w and 1% tartaric acid showed similar increases in impurities after 1 month and 2.5 months, just like the same tablet formulation without tartaric acid.

[0034] Effect of chloride content The stoichiometric content of chloride in the tenapanol active pharmaceutical ingredient, i.e., a 2:1 ratio to tenapanol, is 5.82% w / w. It was observed that chloride content in the active pharmaceutical ingredient exceeding the stoichiometric ratio reduced the appearance of organic impurities over time. In particular, a 6.4% chloride content in the active pharmaceutical ingredient showed remarkable stability, regardless of drug dose, antioxidants, or the presence or absence of further acidifying agents. For example, N2 tablets, containing the same drug dose as N28 tablets (and without antioxidants or further acidifying agents), but with a higher chloride content, showed no increase in total impurities after 1 month and only a 0.07% increase after 2.5 months. On the other hand, N28 tablets with a lower chloride content showed increases of 2.23% after 1 month and 3.68% after 2.5 months. Similar effects were observed with the addition of antioxidants (N7 and N21 tablets) or acidifying agents (N6 and N20 tablets).

[0035] The results shown in Tables 1-3 demonstrate that an optimal balance of solubility and stability characteristics was achieved in tablet formulations containing more than approximately 6% w / w of tenapanolbis-HCl, which has a chloride content exceeding the 2:1 stoichiometry. The 2:1 stoichiometry corresponds to a chloride content of 5.82% of the active pharmaceutical ingredient. Therefore, the present embodiment is a pharmaceutical composition containing more than approximately 6% w / w of tenapanolbis-HCl as an active ingredient and a pharmaceutically acceptable excipient, and the total chloride content of the active ingredient exceeds 5.82%. In one embodiment, the chloride content of the active pharmaceutical ingredient is approximately 6.0% to approximately 6.8% w / w. In one embodiment, the chloride content is approximately 6.1%. In one embodiment, the chloride content is approximately 6.2%. In one embodiment, the chloride content is approximately 6.3%. In one embodiment, the chloride content is approximately 6.4%. In one embodiment, the chloride content is approximately 6.5%. In one embodiment, the chloride content is approximately 6.6%. In one embodiment, the chloride content is approximately 6.7%. In one embodiment, the chloride content is approximately 6.8%. In one embodiment, the chloride content is approximately 6.9%. In one embodiment, the chloride content is 6.4%.

[0036] In another embodiment of the present invention, a pharmaceutical formulation containing more than approximately 6% w / w of the bisHCl salt of tenapanol is provided, and the total amount of HCl in the formulation is more than twice the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.1 to 3 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.1 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.2 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.3 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.4 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.5 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.6 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.7 times the molar ratio of tenapanol. In one embodiment, the total amount of HCl in the formulation is 2.8 times the molar ratio of tenapanol. In another embodiment, the total amount of HCl in the formulation is 2.9 times the molar ratio of tenapanol. In yet another embodiment, the total amount of HCl in the formulation is 3 times the molar ratio of tenapanol.

[0037] In one embodiment of the pharmaceutical formulation of the present invention, tenapanol is in amorphous solid form. In another embodiment, tenapanol is a spray-dried dispersion. Tenapanol is in free base solid form. In another embodiment, tenapanol is in bishydrochloride form. In yet another embodiment, tenapanol is an amorphous solid in bishydrochloride form.

[0038] In another embodiment of the pharmaceutical formulation of the present invention, tenapanol is present in an amount of about 6% to 10% w / w. In another embodiment, tenapanol is present in an amount of about 6% w / w. In another embodiment, tenapanol is present in an amount of about 7% w / w. In another embodiment, tenapanol is present in an amount of about 8% w / w. In another embodiment, tenapanol is present in an amount of about 9% w / w. In another embodiment, tenapanol is present in an amount of about 10% w / w. In another embodiment, tenapanol is present in an amount of about 11% w / w. In another embodiment, tenapanol is present in an amount of about 12% w / w. In another embodiment, tenapanol is present in an amount of about 13% w / w. In another form, tenapanol is present in an amount of about 14% w / w. In another embodiment, tenapanol is present in an amount of about 15% w / w. In another embodiment, tenapanol is present in an amount of about 20% w / w. In another embodiment, tenapanol is present in an amount of approximately 25% w / w.

[0039] In another embodiment, the pharmaceutical formulation of the present invention further comprises an acidifying agent. In one embodiment, the acidifying agent is present in an amount of about 0.5% w / w to about 3% w / w. In one embodiment, the acidifying agent is citric acid, tartaric acid, fumaric acid, succinic acid, ascorbic acid, adipic acid, sorbic acid, glutaric acid, and malic acid.

[0040] In one embodiment, the acidifying agent is tartaric acid. In one embodiment, tartaric acid is present in an amount of about 0.5% w / w to about 3% w / w. In one embodiment, tartaric acid is present in an amount of about 1% w / w. In one embodiment, tartaric acid is present in an amount of 1% w / w.

[0041] In another embodiment, the pharmaceutical formulation of the present invention further comprises an antioxidant. In one embodiment, the antioxidant is selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, calcium stearate, anhydrous citric acid, citric acid monohydrate, cysteine, potassium pyrosulfite, propyl gallate, sodium pyrosulfite, sodium thiosulfate pentahydrate, vitamin E, and 3,4-dihydroxybenzoic acid. In one embodiment, the antioxidant is propyl gallate. In one embodiment, the antioxidant is present in an amount of about 0.01 to about 1.0% w / w. In one embodiment, the antioxidant is propyl gallate. In one embodiment, propyl gallate is present in an amount of about 0.1 to 0.5% w / w. In one embodiment, propyl gallate is present in an amount of about 0.05% w / w. In one embodiment, propyl gallate is present in an amount of about 0.2% w / w. In one embodiment, propyl gallate is present in an amount of approximately 0.4% w / w. In another embodiment, propyl gallate is present in an amount of 0.2% w / w.

[0042] In another embodiment, the pharmaceutical formulation of the present invention further comprises a disintegrant. In one embodiment, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch, glycolate, gelatin, cellulose, cellulose derivatives, and sucrose. In one embodiment, the disintegrant is a cellulose derivative. In one embodiment, the disintegrant is low-substituted hydroxypropylcellulose (L-HPC), also known as hydroxypropyl methylcellulose. In one embodiment, the disintegrant is present in an amount of about 1% w / w to about 20% w / w. In one embodiment, the disintegrant is present in an amount of about 5% w / w to about 15% w / w. In one embodiment, the disintegrant is hydroxypropyl methylcellulose present in an amount of about 5% w / w. In one embodiment, hydroxypropyl methylcellulose is present in an amount of 5% w / w.

[0043] In another embodiment, the pharmaceutical formulation of the present invention further comprises a flow promoter. In one embodiment, the flow promoter is fumed silica, or also known as colloidal silicon dioxide. In one embodiment, colloidal silicon dioxide is present in an amount of about 0.1% w / w to about 0.5% w / w. In one embodiment, colloidal silicon dioxide is present in an amount of about 0.25% w / w. In one embodiment, colloidal silicon dioxide is present in an amount of about 0.26% w / w. In one embodiment, colloidal silicon dioxide is present in an amount of 0.25% w / w. In one embodiment, colloidal silicon dioxide is present in an amount of 0.26% w / w.

[0044] In another embodiment, the pharmaceutical formulation of the present invention further comprises a lubricant. In one embodiment, the lubricant is stearic acid. In one embodiment, stearic acid is present in an amount of about 1% w / w to about 3% w / w. In one embodiment, stearic acid is present in an amount of about 2% w / w.

[0045] In another embodiment, the pharmaceutical formulation of the present invention further comprises a bulking agent. In one embodiment, the bulking agent is microcrystalline cellulose. In one embodiment, the microcrystalline cellulose is present in an amount that constitutes the remaining proportion of the tablet, relating to the remaining components, which include tenapanol.

[0046] In another embodiment of the pharmaceutical formulation of the present invention, the tenapanol active pharmaceutical ingredient (API or active pharmaceutical component) has a particle size distribution D50 of about 18 μm to about 22 μm. In one embodiment, the particle size distribution D50 is about 19 μm to about 21 μm. In one embodiment, the particle size distribution D50 is about 19 μm. In one embodiment, the particle size distribution D50 is about 20 μm. In one embodiment, the particle size distribution D50 is about 21 μm.

[0047] In another embodiment, the pharmaceutical formulation of the present invention is in tablet form. In one embodiment, the tablet includes a fast-acting film coating. In one embodiment, the fast-acting film coating includes polyvinyl acetate.

[0048] In one embodiment, the amount of tenapanol contained in the tablet is approximately 10 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 20 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 30 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 40 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 50 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 60 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 70 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 80 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 90 mg. In one embodiment, the amount of tenapanol contained in the tablet is approximately 100 mg.

[0049] In certain embodiments, the pharmaceutical formulation of the present invention comprises 10% w / w amorphous tenapanorbis-HCl, 1.0% w / w tartaric acid, and 0.2% w / w propyl gallate. In another embodiment, the pharmaceutical formulation further comprises 5.0% w / w low-substituted hydroxypropyl cellulose. In yet another embodiment, the pharmaceutical formulation further comprises 0.26% w / w colloidal silicon dioxide. In yet another embodiment, the pharmaceutical formulation further comprises 2.0% w / w stearic acid. In yet another embodiment, the pharmaceutical formulation further comprises 80.5% w / w microcrystalline cellulose.

[0050] In another specific embodiment, the pharmaceutical formulation comprises about 10 mg of tenapanol hydrochloride, about 0.2 mg of propyl gallate, about 1.0 mg of tartaric acid, about 1.2 mg of stearic acid, about 3.0 mg of low-substituted hydroxypropyl cellulose, about 0.26 mg of colloidal silicon dioxide, and about 81 mg of microcrystalline cellulose.

[0051] In another specific embodiment, the pharmaceutical formulation comprises 10.64 mg of tenapanol hydrochloride, 0.20 mg of propyl gallate, 1.00 mg of tartaric acid, 1.20 mg of stearic acid, 3.00 mg of low-substituted hydroxypropyl cellulose, 0.26 mg of colloidal silicon dioxide, and 80.96 mg of microcrystalline cellulose.

[0052] In another specific embodiment, the pharmaceutical formulation comprises about 20 mg of tenapanol hydrochloride, about 0.4 mg of propyl gallate, about 2.0 mg of tartaric acid, about 2.4 mg of stearic acid, about 6.0 mg of low-substituted hydroxypropyl cellulose, about 0.52 mg of colloidal silicon dioxide, and about 162 mg of microcrystalline cellulose.

[0053] In another specific embodiment, the pharmaceutical formulation comprises 21.28 mg of tenapanol hydrochloride, 0.40 mg of propyl gallate, 2.00 mg of tartaric acid, 2.40 mg of stearic acid, 6.00 mg of low-substituted hydroxypropyl cellulose, 0.52 mg of colloidal silicon dioxide, and 161.92 mg of microcrystalline cellulose.

[0054] In another specific embodiment, the pharmaceutical formulation comprises about 30 mg of tenapanol hydrochloride, about 0.6 mg of propyl gallate, about 3.0 mg of tartaric acid, about 3.6 mg of stearic acid, about 9.0 mg of low-substituted hydroxypropyl cellulose, about 0.78 mg of colloidal silicon dioxide, and about 243 mg of microcrystalline cellulose.

[0055] In another specific embodiment, the pharmaceutical formulation comprises 31.92 mg of tenapanol hydrochloride, 0.60 mg of propyl gallate, 3.00 mg of tartaric acid, 3.60 mg of stearic acid, 9.00 mg of low-substituted hydroxypropyl cellulose, 0.78 mg of colloidal silicon dioxide, and 242.88 mg of microcrystalline cellulose.

[0056] In another specific embodiment, the pharmaceutical formulation comprises about 50 mg of tenapanol hydrochloride, about 1.0 mg of propyl gallate, about 5.0 mg of tartaric acid, about 10.0 mg of stearic acid, about 25 mg of low-substituted hydroxypropyl cellulose, about 1.3 mg of colloidal silicon dioxide, and about 405 mg of microcrystalline cellulose.

[0057] In another specific embodiment, the pharmaceutical formulation comprises 53.2 mg of tenapanol hydrochloride, 1.0 mg of propyl gallate, 5.0 mg of tartaric acid, 10.0 mg of stearic acid, 25.0 mg of low-substituted hydroxypropyl cellulose, 1.3 mg of colloidal silicon dioxide, and 404.8 mg of microcrystalline cellulose. [Examples]

[0058] Example 1 Synthesis of tenapanol FB and tenapanol HCl [ka]

[0059] Triethylamine (5.2 g, 51.49 mmol, 2.01 equivalents) was added to dichloromethane (1000 mL) containing 2-(2-(2-aminoethoxy)ethoxy)ethaneamine (30.4 g, 205.41 mol, 8.01 equivalents). Subsequently, (S)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzene-1-sulfonyl chloride hydrochloride (10 g, 23.42 mmol, 1.00 equivalent; prepared from intermediate 244.1 and the procedure described in Example 1) was added in portions over 1 hour at 10°C. The resulting solution was stirred at room temperature for 15 minutes. The resulting mixture was washed with 3 × 500 mL of physiological saline, dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC under the following conditions: column, C18 silica gel; mobile phase, methanol / water / TFA (4 / 100 / 0.0005) increased to 8 / 10 / 0.0005 within 30 minutes; detector, ultraviolet 254 nm. As a result, 7.2 g (42%) of the intermediate (S or R)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide bis(2,2,2-trifluoroacetate) was obtained as a white solid.

[0060] To a 10 mL DCM containing the above-mentioned intermediate (500 mg, 0.69 mmol, 1.00 equivalent), triethylamine (138 mg, 1.37 mmol, 1.99 equivalents) was added, followed by the addition of 1,4-diisocyanatobutane (48 mg, 0.34 mmol, 0.50 equivalents). The resulting solution was stirred at room temperature for 10 minutes, and then the crude tenapanol free base product (500 mg) was purified by Flash-Prep-HPLC under the following conditions: column, C18 silica gel; mobile phase, methanol / water = 0.05 / 100, increased to 90 / 100 within 30 minutes; detector, ultraviolet 254 nm.

[0061] To the tenapanol free base product, 0.2 mL of hydrochloric acid (2N) was added, and the solution was freeze-dried to obtain 246.7 mg (59%) of amorphous tenapanolbis-HCl as a white solid. ¹H-NMR (400 MHz, CD3OD, ppm): 7.92 (d, J =7.2Hz,2H), 7.83 (s, 2H), 7.69-7.65(m, 2H), 7.60-7.55 (m, 4H), 6.81 (s, 2H), 4.87-4.8 3(m, 4H), 4.54-4.50 (m, 2H),3.94-3.91 (m, 2H), 3.69-3.49 (m, 18H), 3.39-3.32(m,4H), 3.21-3.15 (m, 10H), 3.08-3.05 (m, 4H), 1.57 (s, 4H). LCMS (ES, m / z): 1145 [M-2HCl+1] +.

[0062] Example 2 Preparation of amorphous tenapanorbis-HCl by spray-dried tenapanor free base Crude tenapanol free base is dissolved in a methanol / water solution, and then tenapanol free base seed crystals are added to induce crystallization. The resulting slurry is cooled, and the product is collected by filtration, washed with methanol / water, and then dried to obtain pure tenapanol free base. Concentrated hydrochloric acid is added to the stirred mixture of pure crystalline tenapanol free base in methanol until the pH becomes ≤0.6. The solution is spray-dried, the particle size is evaluated by laser diffraction, and the spray-drying parameters are adjusted as necessary to ensure a particle size distribution d(v,50) ≤20 μm and d(v,90): 20-40 μm. The obtained powder is secondarily dried to achieve a methanol content ≤3,000 ppm to obtain tenapanol hydrochloride.

[0063] Example 3: Dissolution experiment of tablets N1-N28 Dissolution was performed using a USP2 dissolution apparatus (paddle) at 75 rpm and 37°C. The dissolution medium (500 mL) was citrate buffer at pH 4 with an ionic strength of 0.1 M. The sample was recovered at the relevant time points, and the amount dissolved was analyzed using a reversed-phase liquid chromatography gradient system and quantified by UV response at 210 nm against a fully characterized reference standard. In embodiments of the present invention, for example, the following items are provided. (Item 1) A pharmaceutical formulation comprising more than approximately 6% w / w of tenapanorbis-HCl as an active ingredient, and a pharmaceutically acceptable excipient, wherein the total chloride content of the active ingredient exceeds 5.82%. (Item 2) The pharmaceutical preparation described in item 1, wherein the chloride content is approximately 6.0% to approximately 6.8% w / w. (Item 3) The pharmaceutical preparation described in item 1, wherein the chloride content is approximately 6.2%. (Item 4) The pharmaceutical preparation described in item 1, wherein the chloride content is approximately 6.4%. (Item 5) The pharmaceutical preparation described in item 1, wherein the chloride content is 6.4%. (Item 6) A pharmaceutical preparation comprising approximately 6% w / w or more of a bis-HCl salt of tenapanol, wherein the total amount of HCl in the preparation is in a molar ratio of more than twice that of tenapanol. (Item 7) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.1 to 3 times that of tenapanol. (Item 8) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.3 times that of tenapanol. (Item 9) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.4 times that of tenapanol. (Item 10) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.5 times that of tenapanol. (Item 11) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.6 times that of tenapanol. (Item 12) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.7 times that of tenapanol. (Item 13) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.8 times that of tenapanol. (Item 14) The pharmaceutical preparation according to item 6, wherein the total amount of HCl in the preparation is in a molar ratio of 2.9 times that of tenapanol. (Item 15) The pharmaceutical preparation according to item 1 or 6, wherein the tenapanol is in an amorphous form. (Item 16) The aforementioned tenapanol is a spray-dried dispersion, as described in item 1 or 6 of the pharmaceutical formulation. (Item 17) A pharmaceutical preparation according to any one of items 1, 6, and 16, wherein the aforementioned tenapanol is present in an amount of approximately 6% to 10% w / w. (Item 18) The pharmaceutical preparation described in item 17, wherein the tenapanol is substantially a free base. (Item 19) A pharmaceutical preparation according to any one of items 1, 6, and 16, wherein the tenapanol is in bis-HCl form. (Item 20) A pharmaceutical preparation according to any one of items 1, 6, and 16, wherein the aforementioned tenapanol is present in an amount of approximately 10% w / w. (Item 21) The pharmaceutical preparation described in item 20, wherein the tenapanol is in the form of a bishydrochloride salt. (Item 22) A pharmaceutical preparation according to any one of items 1, 6, 16, and 20, further comprising an acidifying agent. (Item 23) The pharmaceutical preparation according to item 22, wherein the acidifying agent is citric acid, tartaric acid, fumaric acid, succinic acid, ascorbic acid, adipic acid, sorbic acid, glutaric acid, or malic acid. (Item 24) The pharmaceutical preparation according to item 22, wherein the acidifying agent is tartaric acid. (Item 25) The pharmaceutical preparation described in item 24, wherein the tartaric acid is present in an amount of approximately 0.5% w / w to approximately 3% w / w. (Item 26) The pharmaceutical preparation described in item 24, wherein the aforementioned tartaric acid is present in an amount of approximately 1% w / w. (Item 27) The pharmaceutical preparation described in item 24, wherein the tartaric acid is present in an amount of 1% w / w. (Item 28) A pharmaceutical preparation according to any one of items 1, 6, 16, 21, and 26, further comprising an antioxidant. (Item 29) The pharmaceutical preparation according to item 28, wherein the antioxidant is selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, calcium stearate, anhydrous citric acid, citric acid monohydrate, cysteine, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate pentahydrate, vitamin E, and 3,4-dihydroxybenzoic acid. (Item 30) The pharmaceutical preparation according to item 28, wherein the antioxidant is propyl gallate. (Item 31) The pharmaceutical preparation described in item 30, wherein the propyl gallate is present in an amount of approximately 0.1-0.2% w / w. (Item 32) The pharmaceutical preparation described in item 30, wherein the propyl gallate is present in an amount of approximately 0.2% w / w. (Item 33) A pharmaceutical preparation according to any one of items 1, 6, 16, 21, 26, and 32, further comprising a disintegrant. (Item 34) The pharmaceutical preparation according to item 33, wherein the disintegrant is hydroxypropyl methylcellulose. (Item 35) The pharmaceutical preparation described in item 34, wherein the hydroxypropyl methylcellulose is present in an amount of approximately 5% w / w to approximately 15% w / w. (Item 36) The pharmaceutical preparation described in item 34, wherein the hydroxypropyl cellulose is present in an amount of approximately 5% w / w. (Item 37) A pharmaceutical preparation according to any one of items 1, 6, 16, 21, 26, 32, and 36, further comprising a lubricant. (Item 38) The pharmaceutical preparation according to item 37, wherein the lubricant is stearic acid. (Item 39) The pharmaceutical preparation described in item 38, wherein the aforementioned stearic acid is present in an amount of approximately 1% w / w to approximately 3% w / w. (Item 40) The pharmaceutical preparation described in item 38, wherein the aforementioned stearic acid is present in an amount of approximately 2% w / w. (Item 41) A pharmaceutical preparation according to any one of items 1, 6, 16, 21, 26, 32, 36, and 40, further comprising a flow promoter. (Item 42) The pharmaceutical preparation according to item 41, wherein the flow promoter is colloidal silicon dioxide. (Item 43) The pharmaceutical preparation described in item 42, wherein the flow promoter is present in an amount of approximately 0.1% w / w to approximately 0.5% w / w. (Item 44) The pharmaceutical preparation described in item 42, wherein the flow promoter is present in an amount of approximately 0.25% w / w. (Item 45) A pharmaceutical preparation according to any one of items 1, 6, 16, 21, 26, 32, 36, 40, and 44, further comprising a volume extender. (Item 46) The pharmaceutical preparation described in item 45, wherein the bulking agent is microcrystalline cellulose. (Item 47) A pharmaceutical preparation as described in item 1, wherein tenapanol has a particle size distribution D50 of approximately 18 μm to approximately 22 μm. (Item 48) The pharmaceutical preparation described in item 47, wherein the particle size distribution is approximately 19 μm to approximately 21 μm. (Item 49) The pharmaceutical preparation described in item 47, wherein the particle size distribution is approximately 19 μm. (Item 50) The pharmaceutical preparation described in item 47, wherein the particle size distribution is approximately 20 μm. (Item 51) The pharmaceutical preparation described in item 47, wherein the particle size distribution is approximately 21 μm. (Item 52) A pharmaceutical preparation in tablet form, as described in item 1. (Item 53) The pharmaceutical preparation according to item 52, wherein the tablet has a fast-acting film coating. (Item 54) The pharmaceutical formulation according to item 53, wherein the fast-acting film coating comprises polyvinyl acetate. (Item 55) A pharmaceutical preparation as described in item 1, containing approximately 10 mg of tenapanol. (Item 56) A pharmaceutical preparation as described in item 1, containing approximately 20 mg of tenapanol. (Item 57) A pharmaceutical preparation as described in item 1, containing approximately 30 mg of tenapanol. (Item 58) A pharmaceutical preparation as described in item 1, containing approximately 50 mg of tenapanol. (Item 59) A pharmaceutical preparation as described in item 1, comprising approximately 6-10% w / w amorphous tenapanol, approximately 1% w / w tartaric acid, and approximately 0.2% w / w propyl gallate. (Item 60) A process for manufacturing the pharmaceutical preparation described in item 1, The first blend is provided by mixing the aforementioned tenapanol, propyl gallate, and tartaric acid with hydroxypropyl cellulose. The first blend described above is crushed to remove any lumps, During or after the grinding step, stearic acid is added to the first blend to provide a second blend, and optionally, the second blend is mixed. The process including the process described above. (Item 61) The process according to item 60, further comprising compressing the second blend into tablets. (Item 62) The process according to item 61, wherein the tablet contains approximately 30 mg of tenapanol. (Item 63) The process according to item 61, wherein the tablet contains approximately 50 mg of tenapanol. (Item 64) The process described in item 60, further comprising compressing the second blend. (Item 65) The process described in item 64 involves rolling the second blend. (Item 66) The process described in item 65 for grinding the compressed second blend. (Item 67) The process according to item 66, further comprising adding stearic acid to the ground second blend to provide a third blend. (Item 68) The process according to item 67, further comprising compressing the third blend into tablets. (Item 69) The process described in item 60, wherein the tenapanol is spray-dried. (Item 70) The process according to item 69, wherein the tenapanol is spray-dried using a water-ethanol solvent mixture. (Item 71) The process according to item 60, wherein the tenapanol is a bis-HCl salt in an amorphous form.

Claims

[Claim 1] The invention described herein.

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