Novel salt of tegoprazan and preparation method therefor

Abstract

The present invention provides a tegoprazan sugar acid salt and a preparation method therefor, the salt being pharmaceutically usable for gastroesophageal disease, gastroesophageal reflux disease, gastritis, peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, non-erosive reflux disease (NERD) and the like. The tegoprazan sugar acid salt of the present invention has excellent water solubility and stability of tegoprazan, and thus can be particularly useful as a pharmaceutical injection preparation.

Description

Novel salt of tegoprazan and method of preparing the same

[0001] The present invention relates to a novel salt of tegoprazan, and more specifically, to a novel salt of tegoprazan having high water solubility and excellent stability, and a method for manufacturing the same.

[0002] Tegoprazan is the generic name for (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, represented by the following chemical formula.

[0003] (Tegoprazan)

[0004] Tegoprazan is a potassium-competitive acid blocker (P-CAB) developed for the treatment of erosive and non-erosive gastroesophageal reflux disease, as well as acid-related gastrointestinal diseases such as peptic ulcers; it is an acid secretion inhibitor with a mechanism different from that of conventional proton pump inhibitors (PPIs).

[0005] Conventional PPIs inhibit gastric acid secretion by acting as prodrugs that are activated under acidic conditions and form irreversible covalent bonds with the thiol groups (-SH) of H+ / K+-ATPase (Proton Pump), which is responsible for final acid secretion in gastric parietal cells. In contrast, tegoprazan inhibits the proton pump competitively with potassium ions without unnecessary activation, making it a treatment for gastric acid-related diseases that inhibits gastric acid secretion more rapidly and potently.

[0006] When comparing the in vitro and in vivo pharmacological properties of tegoprazan with esomeprazole, a representative proton pump inhibitor, tegoprazan at 2.0 mg / kg ED in a gastroesophageal reflux disease (GERD) model 50It showed dose-dependent efficacy in inhibiting esophageal damage and gastric acid secretion, and was reported to be 15 times more potent than esomeprazole (Kim DK et al., Effects of Tegoprazan, a Novel Potassium-Competitive Acid Blocker, on Rat Models of Gastric Acid-Related Disease. J Pharmacol Exp Ther. 2019 Jun;369(3):318-327).

[0007] Tegoprazan was first disclosed in International Patent Publication No. WO2007 / 072146, and a new crystalline form and method of preparation of tegoprazan are disclosed in International Patent Publication No. WO2016 / 117814.

[0008] Tegoprazan has a very low solubility of 0.02 mg / ml in a buffer solution at pH 6.8 and exhibits very low water solubility under in vivo pH conditions. Although the solubility of the compound increases as conditions become more acidic, the solubility remains low at 0.7 mg / ml at pH 3.0, and the dissolution effect is still not significant. Furthermore, under acidic conditions, the ester bond between benzimidazole and chromane breaks, leading to an increase in degradation products. Additionally, using solubilizers such as surfactants to improve solubility presents difficulties because it requires an excessive amount of excipients.

[0009] Korean Patent Registration No. 10-1829706 discloses acid addition salts to increase the water solubility of tegoprazan. Experiments on amino acid salts of tegoprazan confirmed that the degree of improvement in solubility is relatively higher in amorphous solids compared to crystalline solids. Among 12 types of amorphous acid addition salts, acid addition salts of fumaric acid, oxalic acid, citric acid, L-pyroglutamic acid, L-malic acid, and tartaric acid exhibit excellent solubility, and among these, phytolate salts and maleate salts show excellent water solubility and precipitation stability, and disclose that they can be used as injectable preparations.

[0010] Tegoprazan is currently produced only as an oral drug due to its low water solubility, but if it can be made into an injectable formulation, the dosage can be significantly reduced to one-tenth of that of the oral drug, making it highly economical and capable of showing its pharmacological effects more quickly than the oral drug, so there is a continuous demand for the development of technology to increase the solubility of tegoprazan in vivo.

[0011] The present invention aims to provide a novel salt of tegoprazan having excellent water solubility to increase pharmacological activity in the body, and furthermore, to provide a novel salt of tegoprazan having high solubility at biological pH, which can be used as an oral agent as well as an injectable agent.

[0012] The present invention provides a tegoprazan sugar acid salt represented by the following chemical formula 1.

[0013] [Chemical Formula 1]

[0014]

[0015] In one embodiment of the present invention, the sugar acid of the degoprazan sugar acid salt may be one or more selected from glycolic acid, lactic acid, glyceric acid, D-xylonic acid, arabinonic acid, D-gluconic acid, D-galactonic acid, ascorbic acid, glucuronic acid, galacturonic acid, iduronic acid, D-glucaric acid, mucinic acid, and lactobionic acid, which are composed of the following chemical formulas 2 to 15.

[0016] [Chemical Formula 2]

[0017] (Glycolic acid)

[0018] [Chemical Formula 3]

[0019] (Lactic acid)

[0020] [Chemical Formula 4]

[0021] (Glyceric acid)

[0022] [Chemical Formula 5]

[0023] (D-Xylonic acid)

[0024] [Chemical Formula 6]

[0025] (Arabinoic acid)

[0026] [Chemical Formula 7]

[0027] (D-Gluconic acid)

[0028] [Chemical Formula 8]

[0029] (D-Galactonic acid)

[0030] [Chemical Formula 9]

[0031] (Ascorbic acid)

[0032] [Chemical Formula 10]

[0033] (Glucuronic acid)

[0034] [Chemical Formula 11]

[0035] (Galacturonic acid)

[0036] [Chemical Formula 12]

[0037] (Iduronic acid)

[0038] [Chemical Formula 13]

[0039] (D-Glucaric acid)

[0040] [Chemical Formula 14]

[0041] (Mucic acid)

[0042] [Chemical Formula 15]

[0043] (Lactobionic acid)

[0044] In one embodiment of the present invention, the sugar acid salt may be amorphous or partially crystalline.

[0045] Meanwhile, the present invention provides a method for preparing a tegoprazan sugar acid salt, comprising: a) dissolving a tegoprazan compound represented by the following chemical formula 1 and a sugar acid in an organic solvent; b) concentrating the solution prepared in step a) under reduced pressure to precipitate a solid, and then adding an organic solvent and stirring; and c) filtering and drying the precipitated solid.

[0046] [Chemical Formula 1]

[0047]

[0048] In one embodiment of the present invention, the sugar acid may be one or more selected from glycolic acid, lactic acid, glyceric acid, D-xylonic acid, arabinonic acid, D-gluconic acid, D-galactonic acid, ascorbic acid, glucuronic acid, galacturonic acid, iduronic acid, D-glucaric acid, mucinous acid, and lactobionic acid.

[0049] In one embodiment of the present invention, the organic solvent of step a) may be methanol.

[0050] In one embodiment of the present invention, the organic solvent of step b) may be hexane or acetone / ethyl acetate.

[0051] The present invention provides a pharmaceutical composition comprising the tegoprazan glycan salt as an active ingredient.

[0052] In one embodiment of the present invention, the pharmaceutical composition may be in the form of an injection, suspension, tablet, capsule, powder, or granule.

[0053] Meanwhile, the present invention provides a pharmaceutical composition comprising tegoprazan glycan salt as an active ingredient.

[0054] The above pharmaceutical composition has high solubility at biological pH, so it can be used as an injectable, but it can also be used as an oral formulation such as a suspension, tablet, capsule, powder, or granule.

[0055] The tegoprazan glycan salt according to the present invention not only has increased solubility in the body compared to the amorphous or crystalline forms of tegoprazan, but also possesses effective solubility and stability even under conditions of body pH, thereby enabling its use as an injectable agent.

[0056] Figure 1 shows the X-ray rotational analysis results of a tegoprazan gluconic acid (D-Gluconic acid) salt prepared according to Example 1 of the present invention.

[0057] Figure 2 shows the X-ray rotational analysis results of a tegoprazan glucuronic acid (D-Glucuronic acid) salt prepared according to Example 2 of the present invention.

[0058] Figure 3 shows the X-ray rotational analysis results of the tegoprazan ascorbic acid salt prepared according to Example 3 of the present invention.

[0059] Figure 4 shows the X-ray rotational analysis results of the tegoprazan glycolic acid salt prepared according to Example 4 of the present invention.

[0060] Figure 5 shows the X-ray rotational analysis results of the tegoprazan glyceric acid salt prepared according to Example 5 of the present invention.

[0061] Figure 6 shows the X-ray rotational analysis results of the tegoprazan lactobionic acid salt prepared according to Example 6 of the present invention.

[0062] Figure 7 shows the X-ray rotational analysis results of the tegoprazan lactic acid (L-Lactic acid) salt prepared according to Example 7 of the present invention.

[0063] Figure 8 shows the X-ray rotational analysis results of the tegoprazan mandelic acid salt prepared according to Comparative Example 1 of the present invention.

[0064] The inventors conducted various studies to develop a tegoprazan acid addition salt having excellent water solubility and precipitation stability in vivo. As a result of experiments focusing on sugar acids, they confirmed that the tegoprazan sugar salt exhibits amorphous characteristics and possesses excellent water solubility and stability in vivo, thereby completing the present invention.

[0065] Sugar acid is a compound in which one or both ends of a monosaccharide are oxidized and substituted with a carboxyl group. In the present invention, 'sugar acid' includes a compound in which a carbohydrate [Cn(H2O)m] or a carbohydrate derivative is oxidized to have a carboxyl group.

[0066] The present invention provides a tegoprazan sugar acid salt represented by the following chemical formula 1.

[0067] [Chemical Formula 1]

[0068]

[0069] The sugar acid of the above-mentioned degoprazan sugar acid salt may be one or more selected from glycolic acid, lactic acid, glyceric acid, D-xylonic acid, arabinonic acid, D-gluconic acid, D-galactonic acid, ascorbic acid, glucuronic acid, galacturonic acid, iduronic acid, D-glucaric acid, mucinic acid, and lactobionic acid, which are composed of the following chemical formulas 2 to 15, but is not limited thereto.

[0070] [Chemical Formula 2]

[0071] (Glycolic acid)

[0072] [Chemical Formula 3]

[0073] (Lactic acid)

[0074] [Chemical Formula 4]

[0075] (Glyceric acid)

[0076] [Chemical Formula 5]

[0077] (D-Xylonic acid)

[0078] [Chemical Formula 6]

[0079] (Arabinoic acid)

[0080] [Chemical Formula 7]

[0081] (D-Gluconic acid)

[0082] [Chemical Formula 8]

[0083] (D-Galactonic acid)

[0084] [Chemical Formula 9]

[0085] (Ascorbic acid)

[0086] [Chemical Formula 10]

[0087] (Glucuronic acid)

[0088] [Chemical Formula 11]

[0089] (Galacturonic acid)

[0090] [Chemical Formula 12]

[0091] (Iduronic acid)

[0092] [Chemical Formula 13]

[0093] (D-Glucaric acid)

[0094] [Chemical Formula 14]

[0095] (Mucic acid)

[0096] [Chemical Formula 15]

[0097] (Lactobionic acid)

[0098] The structure and effects of the present invention will be explained in more detail below through examples and experimental examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to the following examples.

[0099] Example 1: Preparation of Tegoprazan D-Gluconic acid salt

[0100] 20.0 g of Tegoprazan and 10.1 g (1.0 eq) of D-Gluconic acid were completely dissolved in 500 ml of methanol, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 27.4 g of a white amorphous solid (yield 91.0%).

[0101] Example 2: Preparation of Tegoprazan D-Glucuronic acid salt

[0102] 20.0g of Tegoprazan and 10.0g (1.0 eq) of D-Glucuronic acid were completely dissolved in 400ml of methanol and 400ml of purified water, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 28.6g of a white amorphous solid (yield 95.4%).

[0103] Example 3: Preparation of Tegoprazan Ascorbic Acid Salt

[0104] 20.0 g of Tegoprazan and 9.1 g (1.0 eq) of Ascorbic acid were completely dissolved in 400 ml of methanol and 400 ml of purified water, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 27.4 g of a white amorphous solid (yield 94.2%).

[0105] Example 4: Preparation of Tegoprazan Glycolic acid salt

[0106] 20.0 g of Tegoprazan and 3.9 g (1.0 eq) of Glycolic acid were completely dissolved in 500 ml of methanol, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 23.1 g of a white amorphous solid (yield 96.8%).

[0107] Example 5: Preparation of Tegoprazan Glyceric Acid Salt

[0108] 20.0 g of Tegoprazan and 25.8 ml (1.0 eq) of 2.0 M Glyceric Acid solution were completely dissolved in 500 ml of methanol, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 23.4 g of a white amorphous solid (yield 91.9%).

[0109] Example 6: Preparation of Tegoprazan Lactobionic Acid Salt

[0110] 15.0 g of Tegoprazan and 13.9 g (1.0 eq) of Lactobionic acid were completely dissolved in 400 ml of methanol and 100 ml of purified water, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 27.5 g of a white amorphous solid (yield 95.2%).

[0111] Example 7: Preparation of Tegoprazan L-Lactic Acid Salt

[0112] 20.0 g of Tegoprazan and 4.7 g (1.0 eq) of L-Lactic acid were completely dissolved in 500 ml of methanol, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 23.1 g of a white amorphous solid (yield 93.7%).

[0113] Comparative Example 1: Preparation of Tegoprazan Mandelic acid salt

[0114] 20.0 g of Tegoprazan and 7.9 g (1.0 eq) of Mandelic acid were completely dissolved in 500 ml of methanol, and the solution was concentrated under reduced pressure at 40°C to precipitate a solid. 400 ml of hexane was added to the concentrated residue and vigorously stirred for 2 hours. The solid was filtered and vacuum dried at 40°C for 24 hours to obtain 26.3 g of a white amorphous solid (yield 94.4%).

[0115] Experimental Example 1: Comparison Test of Water Acceptability

[0116] The solubility of 1 g of each of the eight amorphous acid addition salts prepared in Examples 1 to 7 and Comparative Example 1 was measured in 10 ml of purified water at room temperature. The solubility of each was measured based on the acid addition salt itself, without converting to the standard of Tegoprazan free base. For reference, Tegoprazan free base exhibits a solubility of 3 mg / ml. It was confirmed that the solubility of seven of the eight acid addition salts increased significantly compared to Tegoprazan free base.

[0117] No. Type of acid used in acid addition salt Solubility (1g / 10mL) Example 1 D-Gluconic acid solubility (gel type) Example 2 D-Glucuronic acid solubility Example 3 Ascorbic acid solubility (gel type) Example 4 Glycolic acid solubility (gel type) Example 5 Glyceric acid solubility (gel type / opaque) Example 6 Lactobionic acid solubility (gel type) Example 7 L-Lactic acid solubility (gel type) Comparative Example 1 Mandelic acid insoluble

[0118] As shown in Table 1 above, it was confirmed that the tegoprazan glycan salt according to the present invention dissolves completely in 1g of purified water (10ml), whereas the amorphous mandelic acid salt of Comparative Example 1 does not dissolve in purified water. The above results indicate that the tegoprazan glycan salt according to the present invention can be particularly useful for use as an injectable.

[0119] Experimental Example 2: Precipitation Stability

[0120] To confirm the in vivo stability of each of the eight types of acid addition salts prepared in Examples 1 to 7 and Comparative Example 1, they were completely dissolved in a pH 6.8 buffer solution at a concentration of 10 mg / ml, stored at 37°C for 24 hours, and then the state of the solution was observed and reported.

[0121] No. Type of acid used for acid addition salting Whether solid precipitates Example 1: D-Gluconic acid precipitates Example 2: D-Glucuronic acid maintains homogeneous solution Example 3: Ascorbic acid precipitates Example 4: Glycolic acid maintains homogeneous solution Example 5: Glyceric acid precipitates Example 6: Lactobionic acid maintains homogeneous solution Example 7: L-Lactic acid precipitates Comparative Example 1: Mandelic acid insoluble

[0122] As shown in Table 2 above, it was confirmed that the gluconate, glycolate, and lactobionate salts among the tegoprazan glycanate salts according to the present invention form homogeneous solutions even after long-term storage in a buffer solution of pH 6.8. The above results particularly indicate that the gluconate, glycolate, and lactobionate salts of tegoprazan according to the present invention can be usefully utilized in the form of solutions for injectables.

[0123] Experimental Example 3: Storage Stability (Powder X-ray Diffraction (PXRD) Analysis)

[0124] X-ray diffraction (PXRD) analysis was performed to analyze whether the amorphous nature of the tegoprazan glycan salt according to the present invention changes to crystalline after long-term storage, and the results are shown in FIGS. 1 to 8.

[0125] The tegoprazan saccharide salt according to the present invention exhibited amorphous form even during its preparation, and it was confirmed that all types of salts maintained their amorphous nature and no crystal transition was observed even after being placed in a PE-bag and stored in a stability chamber under conditions of 40°C and 75% RH for one month.

[0126] The tegoprazan glycan salt of the present invention or a pharmaceutical composition thereof may be pharmaceutically used for any one or more diseases selected from the group including gastroesophageal disease, gastroesophageal reflux disease, gastritis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by NSAIDs, and non-erosive reflux disease (NERD).

[0127] The tegoprazan glycan salt of the present invention or the pharmaceutical composition thereof may be any one formulation selected from the group consisting of injectables, suspensions, tablets, capsules, syrups, powders, and granules, but is not limited thereto.

[0128] The tegoprazan glycan salt or the pharmaceutical composition thereof according to the present invention may have a single dose of, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, but is not limited thereto.

[0129] The tegoprazan glycan salt or a pharmaceutical composition thereof according to the present invention may be used as an injectable preparation using water for injection. The injectable preparation according to the present invention may be distributed after being manufactured into an injectable formulation, or may be prepared as an injectable preparation using water for injection prior to administration to a patient. The injectable preparation of the present invention may optionally include, without limitation, isotonic agents, buffers, osmotic agents, etc., commonly used in the art.

[0130]

[0131] The present invention relates to a novel salt of tegoprazan, and more specifically, to a novel salt of tegoprazan having high water solubility and excellent stability, and a method for manufacturing the same.

Claims

1. A tegoprazan sugar acid salt represented by the following chemical formula 1. [Chemical Formula 1] 2. In Paragraph 1, The sugar acid of the above-mentioned degoprazan sugar acid salt is characterized by being one or more selected from glycolic acid, lactic acid, glyceric acid, D-xylonic acid, arabinonic acid, D-gluconic acid, D-galactonic acid, ascorbic acid, glucuronic acid, galacturonic acid, iduronic acid, D-glucaric acid, mucinous acid, and lactobionic acid, which are composed of the following chemical formulas 2 to 15. Tegoprazan acid salt. [Chemical Formula 2] (Glycolic acid) [Chemical Formula 3] (Lactic acid) [Chemical Formula 4] (Glyceric acid) [Chemical Formula 5] (D-Xylonic acid) [Chemical Formula 6] (Arabinoic acid) [Chemical Formula 7] (D-Gluconic acid) [Chemical Formula 8] (D-Galactonic acid) [Chemical Formula 9] (Ascorbic acid) [Chemical Formula 10] (Glucuronic acid) [Chemical Formula 11] (Galacturonic acid) [Chemical Formula 12] (Iduronic acid) [Chemical Formula 13] (D-Glucaric acid) [Chemical Formula 14] (Mucic acid) [Chemical Formula 15] (Lactobionic acid) 3. In Paragraph 1, The above sugar acid salt is amorphous or partially crystalline, Tegoprazan acid salt. 4.a) A step of dissolving a tegoprazan compound represented by the following chemical formula 1 and a sugar acid in an organic solvent; b) a step of precipitating a solid by concentrating the solution prepared in step a) under reduced pressure, and then adding an organic solvent and stirring; and c) A method for preparing the tegoprazan saccharide salt of claim 1, comprising the step of filtering and drying the precipitated solid. [Chemical Formula 1] 5. In Paragraph 4, The above sugar acid is characterized by being one or more selected from glycolic acid, lactic acid, glyceric acid, D-xylonic acid, arabinonic acid, D-gluconic acid, D-galactonic acid, ascorbic acid, glucuronic acid, galacturonic acid, iduronic acid, D-glucaric acid, mucinous acid, and lactobionic acid. Method for manufacturing tegoprazan saccharide salt.

6. In Paragraph 4, The organic solvent in step a) above is methanol, Method for manufacturing tegoprazan saccharide salt.

7. In Paragraph 4, The organic solvent in step b) above is hexane or acetone / ethyl acetate, Method for manufacturing tegoprazan saccharide salt.

8. A pharmaceutical composition comprising the tegoprazan glycan salt of claim 1 as an active ingredient.

9. In Paragraph 8, The above pharmaceutical composition is a pharmaceutical composition in the form of an injection, suspension, tablet, capsule, powder, or granule.

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