Novel injectable formulations containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine

Abstract

The present invention relates to an injectable formulation comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority based on Korean Patent Application No. 10-2021-0067636, filed May 26, 2021, and Korean Patent Application No. 10-2022-0064451, filed May 26, 2022, and all contents disclosed in the documents of said Korean patent applications are incorporated herein by reference.

[0002] The present invention relates to a novel injectable formulation comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. [Background technology]

[0003] It is known that even formulations containing the same active ingredient can exhibit differences in pharmaceutically important properties such as the solubility, dissolution characteristics, and bioavailability of the active ingredient depending on the additional components contained in the formulation. Therefore, along with the development of new compounds, it is also very important to develop components to be contained in formulations that can maximize the pharmacological effects of the developed compounds.

[0004] Meanwhile, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine is a substance described in Korean Patent Registration No. 10-1613245, and has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori (H. pylori) eradication activity, and GPCR inhibitory activity, making it useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0005] However, this substance or its hydrochloride salt has low aqueous solubility in a neutral pH environment (2.17 mg / ml, pH 6.8), and exhibits poor stability in an acidic environment where it has good solubility, such as an increase in acid degradation products, making it difficult to formulate for injection through dissolution and stabilization in an aqueous solution. Therefore, there is a need to research the appropriate pH adjustment and the combination of ingredients other than the pharmaceutically active ingredient in order to develop an injectable formulation that can balance solubility and stability.

[0006] Therefore, the present inventors attempted to prepare an injectable formulation by improving the solubility and stability of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. As a result, they found that the above problems can be solved when a specific isotonic agent is added within a specific pH range, and thus completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides an injectable formulation of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, or a pharmaceutically acceptable salt thereof, which has high solubility and excellent stability. [Means for solving the problem]

[0008] In order to solve the above problems, the present invention provides an injectable formulation comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; cyclodextrin; and an isotonic agent, wherein the pH is 4.0 to 6.0. [ka]

[0009] The chemical name of the compound represented by Chemical Formula 1 is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, which is a substance described in Korean Patent Registration No. 10-1613245.

[0010] The compound represented by Chemical Formula 1 is an active ingredient exhibiting pharmacological effects in the injectable preparation of the present invention, and has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori (H. pylori) eradication activity, and GPCR inhibitory activity, making it a useful substance for preventing and treating gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0011] In addition to the compound represented by Chemical Formula 1, pharmaceutically acceptable salts thereof can also be used as the active ingredient exhibiting the pharmacological effects of the injectable formulation of the present invention. As the salt, any salt commonly used in the art, such as an acid addition salt formed with a pharmaceutically acceptable free acid, can be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which, at a concentration that has a relatively non-toxic, harmless effective effect on patients, does not suffer from side effects attributable to the salt and does not diminish the beneficial efficacy of the compound.

[0012] A pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 can be obtained by a conventional method using an inorganic or organic acid. For example, the compound represented by Chemical Formula 1 can be dissolved in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid can be added. The precipitated crystals can be filtered and dried to obtain a pharmaceutically acceptable salt. Alternatively, the pharmaceutically acceptable salt can be obtained by reducing the pressure of the reaction mixture to which the acid has been added to remove the solvent and excess acid, and drying the residue, or by adding another organic solvent and filtering the precipitated salt. In this case, preferred salts include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

[0013] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has low aqueous solubility, and therefore requires an excess of solubilizer and organic solvent to prepare an injectable formulation. However, excessive solubilizer may cause hypersensitivity when administered to a patient. Therefore, in the present invention, instead of using a solubilizer commonly used in injectable formulations, a cyclodextrin and an isotonicity agent are used, and the pH is adjusted to obtain an injectable formulation having excellent solubility and stability of the compound represented by Chemical Formula 1.

[0014] Cyclodextrin, a component used in the injectable formulation of the present invention, is a cyclic oligosaccharide in which 6 to 12 glucose molecules are linked by alpha-1,4-glycosidic bonds, and is used as a stabilizer in the present invention. Preferably, the cyclodextrin is beta-cyclodextrin or gamma-cyclodextrin, more preferably beta-cyclodextrin. More preferably, the beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin or sulfobutylether-beta-cyclodextrin, abbreviated as "HP-β-CD" and "SBE-β-CD," respectively.

[0015] Among stabilizers generally used in injection preparations, the cyclodextrin is suitable for stabilizing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0016] Preferably, the cyclodextrin is used in an amount of 3.0 to 25.0 parts by weight relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the amount is less than 3.0 parts by weight, the compound represented by Chemical Formula 1 may not be sufficiently stabilized, resulting in difficulty in rehydrating the injectable formulation or an increase in the total amount of related substances during long-term storage. If the amount is more than 25.0 parts by weight, the amount of stabilizer used may be too high, increasing the viscosity of the injectable formulation or causing hypersensitivity upon administration to patients.

[0017] More preferably, the cyclodextrin is present in an amount of 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof; or 20.0 parts by weight or less, 19.0 parts by weight or less, 18.0 parts by weight or less, 17.0 parts by weight or less, 16.0 parts by weight or less, 15.0 parts by weight or less, 14.0 parts by weight or less, 13.0 parts by weight or less, 12.0 parts by weight or less, 11.0 parts by weight or less, or 10.0 parts by weight or less.

[0018] Meanwhile, the "isotonicity agent" used in the injectable formulation according to the present invention is an additive added to make the osmotic pressure of the injectable formulation similar to that of the body. Since the injectable formulation is directly administered to the body without a separate dilution process, it must be prepared to have the same osmotic pressure as that of the body to reduce side effects upon administration. Preferably, the isotonicity agent may be sodium chloride (NaCl), D-mannitol, dextrose, glycerin, or potassium chloride (KCl), more preferably sodium chloride (NaCl), dextrose, glycerin, or potassium chloride (KCl), and most preferably sodium chloride (NaCl), dextrose, or potassium chloride (KCl).

[0019] The amount of the isotonicity agent required to achieve the desired osmolarity of the injectable formulation varies depending on whether it is an electrolyte or a non-electrolyte. Therefore, the isotonicity agent is preferably included so that the osmolarity of the injectable formulation according to the present invention is 100 to 700 mOsmol / L, depending on the specific type of agent. More preferably, the osmolarity of the injectable formulation may be 150 to 650 mOsmol / L, 150 to 450 mOsmol / L, 250 to 450 mOsmol / L, or 270 to 420 mOsmol / L.

[0020] Preferably, the pH of the injectable formulation according to the present invention is 5.0 to 6.0. Preferably, the injectable formulation according to the present invention can have this pH range due to the chemical properties of the liquid pharmaceutical composition of the present invention itself, and the injectable formulation may not contain an additional pH adjuster for pH adjustment. Here, the pH adjuster is a substance that adjusts the pH of the solution by adding it and improves the solubility of a poorly water-soluble or insoluble compound, and is a pharmaceutically acceptable acidic or alkaline agent. Examples of pH adjusters that can be used include one or more of hydrochloric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, potassium monohydrogen phosphate, potassium dihydrogen phosphate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, potassium carbonate, and triethanolamine.

[0021] Preferably, the injectable formulation according to the present invention further comprises a lyophilization aid. Generally, after mass production, injectable formulations are frozen and stored and distributed under reduced pressure, which can enhance the stability of the active ingredient and improve long-term storage stability. Therefore, the stability of the active ingredient must be maintained during the lyophilization process, and therefore, the present invention can further comprise a lyophilization aid. Preferably, the lyophilization aid is D-mannitol, sucrose, sorbitol, or trehalose, more preferably D-mannitol.

[0022] Preferably, the lyophilization adjuvant is used in an amount of 3.0 to 25.0 parts by weight relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the amount is less than 3.0 parts by weight, the compound represented by Chemical Formula 1 may not be sufficiently stabilized, resulting in difficulty in rehydrating the injectable formulation or an increase in related substances during long-term storage. If the amount is more than 25.0 parts by weight, the amount of lyophilization adjuvant used may be too high, increasing the viscosity of the injectable formulation or causing hypersensitivity upon administration to patients.

[0023] More preferably, the lyophilization aid is present in an amount of 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof; or 20.0 parts by weight or less, 15.0 parts by weight or less, 13.0 parts by weight or less, 10.0 parts by weight or less, 9.0 parts by weight or less, 8.0 parts by weight or less, 7.0 parts by weight or less, or 6.0 parts by weight or less.

[0024] Preferably, the freeze-drying auxiliary is used in an amount of 0.5 to 5.0 parts by weight relative to 1 part by weight of the cyclodextrin. More preferably, the freeze-drying auxiliary is used in an amount of 0.6 parts by weight or more, 0.7 parts by weight or more, or 0.8 parts by weight or more relative to 1 part by weight of the cyclodextrin. Weight partor more; 4.5 parts by weight or less, 4.0 parts by weight or less, 3.5 parts by weight or less, 3.0 parts by weight or less, 2.5 parts by weight or less, 2.3 parts by weight or less, 2.0 parts by weight or less, 1.9 parts by weight or less, 1.8 parts by weight or less, 1.7 parts by weight or less, 1.6 parts by weight or less, 1.5 parts by weight or less, 1.4 parts by weight or less, 1.3 parts by weight or less, or 1.2 parts by weight or less.

[0025] Preferably, the injectable formulation may be prepared using a solvent commonly used in the art to which the present invention pertains, such as distilled water, water for injection, acetate buffer, or saline, to prepare a liquid pharmaceutical composition.

[0026] Preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the injectable formulation at a concentration of 1 to 8 mg / mL. That is, the content of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof can be defined as the content (mg) of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof divided by the total volume (mL) of the injectable formulation.

[0027] More preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the injectable formulation at a concentration of 2 mg / mL or more, 3 mg / mL or more, 4 mg / mL or more, or 5 mg / mL or more; or 7 mg / mL or less, 6 mg / mL or less, or 5.5 mg / mL or less.

[0028] Furthermore, if necessary, the injectable formulation according to the present invention may additionally contain a preservative, an antioxidant, etc., and the preservative and antioxidant are not particularly limited as long as they are commonly used in the technical field to which the present invention pertains.

[0029] Furthermore, the injectable formulation according to the present invention may be prepared by mixing the above-mentioned components, excluding the solvent, with a solvent, and during this process, the order of adding each component to the solvent may be adjusted as needed, or all components may be mixed before being added to the solvent and then added to the solvent. However, the present invention is not limited to this preparation method, and the preparation of the injectable formulation may be modified by methods known in the art.

[0030] The prepared injectable formulation may be subjected to a sterilization and / or filtration step as necessary, and may be lyophilized for storage and distribution. [Effects of the Invention]

[0031] As described above, the injectable formulation of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof of the present invention satisfies a specific pH range, contains an isotonic agent, and exhibits high solubility and excellent stability, and can be used as an injectable formulation useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori. DETAILED DESCRIPTION OF THE INVENTION

[0032] Hereinafter, preferred examples will be presented to aid in understanding the present invention. 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. [Example]

[0033] Solutions were prepared by adjusting the pH of each of the compounds represented by Chemical Formula 1 (40 mg of the hydrochloride salt (hereinafter referred to as "API")) to the compositions shown in Table 1 below.

[0034] Each preparation was then filled into a vial and stored in liquid form in a chamber under severe conditions (60°C, 80% RH) for 4 weeks, after which the stability was evaluated, and the results are shown in Table 2. Stability was evaluated by analyzing the content of related substances in the liquid solution by HPLC, and the total amount of related substances detected was measured.

[0035] [Table 1]

[0036] [Table 2]

[0037] As shown in Table 2, when stored in a liquid solution state under harsh conditions for 4 weeks, compositions #1-2 to #1-4 with a pH of 4.0 to 6.0 were found to be relatively stable, with no significant increase in the production of total related substances. [Example]

[0038] In Example 1, pH 6.0 was selected, which resulted in the least production of total related substances, and the following experiment was carried out.

[0039] The browning pattern depending on the concentration was confirmed by preparing solutions with different API concentrations as shown in Table 3 below. Each prepared solution was visually evaluated, and the results are shown in Table 4 below.

[0040] [Table 3]

[0041] [Table 4]

[0042] As shown in Table 4, it was confirmed that the properties of #2, which has a low concentration, did not change even after storage for 4 weeks under harsh conditions. [Example]

[0043] In Example 2, the concentration (4 mg / mL) at which the properties were stable was selected, and the following experiment was carried out.

[0044] As shown in Table 5 below, different amounts of each isotonic agent were added to the solution so that the osmotic pressure of the solution was 380 mOsmol / L (or similar to the osmotic pressure in the body). The prepared solutions were stored in a chamber under severe conditions (60°C, 80% RH) for 4 weeks in the same manner as in Example 1, and the properties and stability were evaluated. The results are shown in Table 6 below.

[0045] [Table 5]

[0046] [Table 6]

[0047] As shown in Table 6, even the solutions containing the isotonicity agent showed no change in properties after 4 weeks of storage under harsh conditions. In particular, compositions #3-1 to #3-4 showed more stable values ​​for the production of total related substances than the comparative group #2.

[0048] Reference example 1 In Example 3, NaCl was selected from the relatively stable isotonicity agents, and the following experiment was carried out.

[0049] As shown in Table 7 below, solutions were prepared without or with different types of pH adjusters. The prepared solutions were stored in a chamber under severe conditions (60°C, 80% RH) for 4 weeks in the same manner as in Example 1, and the properties and stability were evaluated. The results are shown in the table below. 8 shown in.

[0050] [Table 7]

[0051] [Table 8]

[0052] As shown in Table 8, #4-1, which does not contain a pH adjuster, produced less total related substances than #3-1 or #4-2, which contain a pH adjuster, demonstrating superior stability.

[0053] Reference example 2 Two experimental groups (with and without HCl / NaOH pH adjuster) were selected from those confirmed in Example 3 and Reference Example 1, and a long-term storage experiment was carried out in the liquid composition state. The composition of each experimental group is shown in Table 9 below.

[0054] Each prepared solution was stored in a chamber under accelerated conditions (40°C, 75% RH) for 6 months, and the properties and stability were evaluated in the same manner as in Example 1. The results are shown in Table 10 below.

[0055] [Table 9]

[0056] [Table 10]

[0057] As shown in Table 10, #4-1, which does not contain a pH adjuster, was stored in liquid form for a long period of time without any change in properties and with almost no production of related substances, demonstrating excellent stability.

Claims

1. The present invention comprises a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof; a cyclodextrin; and an isotonicity agent, the cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin or sulfobutylether-beta-cyclodextrin; the tonicity agent is sodium chloride (NaCl), D-mannitol, dextrose, or potassium chloride (KCl); the pH is 4.0 to 6.0; Injectable preparation. 【Chemistry 1】

2. The composition contains 4.5 to 15.0 parts by weight of the cyclodextrin relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. The injectable formulation according to claim 1.

3. The osmolality of the injectable formulation is 100-700 mOsmol / L. The injectable formulation according to claim 1.

4. The pH is 5.0 to 6.

0. The injectable formulation according to claim 1.

5. The injectable formulation does not contain a pH adjuster. The injectable formulation according to claim 1.

6. The injectable formulation additionally comprises a lyophilization aid; The lyophilization aid is D-mannitol, sucrose, sorbitol, or trehalose. The injectable formulation according to claim 1.

7. The composition contains 3.0 to 25.0 parts by weight of the freeze-drying auxiliary agent relative to 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. The injectable formulation according to claim 6.

8. The solvent of the injectable formulation is distilled water, water for injection, acetate buffer, or physiological saline; The injectable formulation according to claim 1.

9. The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the injectable formulation at a concentration of 1 to 8 mg / mL. The injectable formulation according to claim 1.

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