The injectable preparation contains 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmetanamine

Abstract

The invention relates to an injectable preparation containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

Description

A novel injectable formulation comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2021-0067636, filed May 26, 2021, and Korean Patent Application No. 10-2022-0064451, filed May 26, 2022, the entire contents of which are incorporated herein by reference.

[0003]

[0004] 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.

[0005]

[0006] It is known that even formulations containing the same active ingredient can exhibit differences in pharmaceutically important properties, such as solubility, dissolution characteristics, and bioavailability, depending on the additional components included in the formulation. Therefore, in addition to developing novel compounds, it is also crucial to develop formulation components that can maximize the pharmacological effects of the developed compound.

[0007]

[0008] 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.) and Helicobacter pylori eradication activity and GPCR inhibitory activity, making it a useful substance for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0009]

[0010] However, the above substance or its hydrochloride has low water solubility in a neutral pH environment (2.17 mg / ml, pH 6.8) and poor stability, such as an increase in acidic decomposition products in an acidic environment with good solubility, making it very difficult to prepare an injectable formulation through dissolution and stabilization in an aqueous solution. Therefore, in order to develop an injectable formulation that can achieve a balance between solubility and stability, it has become necessary to study the control of the appropriate pH and the combination of ingredients other than the active pharmaceutical ingredient.

[0011]

[0012] Accordingly, the inventors of the present invention 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, and as a result, confirmed that the above problem could be solved by including a specific isotonic agent within a specific pH range, thereby completing the present invention.

[0013]

[0014] 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, having high solubility and excellent stability.

[0015]

[0016] To solve the above problem, 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:

[0017] [Chemical Formula 1]

[0018] .

[0019]

[0020] The chemical name of the compound represented by the above 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.

[0021]

[0022] The compound represented by the above chemical formula 1 is an active ingredient exhibiting a pharmacological effect in the injectable preparation of the present invention, and has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and Helicobacter pylori eradication activity and GPCR inhibitory activity, and is therefore a useful substance for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0023]

[0024] In addition, as an active ingredient exhibiting the pharmacological effect of the injectable preparation of the present invention, in addition to the compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof may be used. As the salt, any salt commonly used in the art, such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation. The term "pharmaceutically acceptable salt" of the present invention means any and all organic or inorganic addition salts of the compound represented by the above chemical formula 1 at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not reduce the beneficial effects of the compound represented by the above chemical formula 1.

[0025]

[0026] A pharmaceutically acceptable salt of the compound represented by the above chemical formula 1 can be obtained by a conventional method using an inorganic acid or an organic acid. For example, the compound represented by the above chemical formula 1 can be dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, an organic or inorganic acid can be added, the precipitated crystals can be filtered, and the resulting crystals can be dried to obtain a pharmaceutically acceptable salt. Alternatively, the compound can be prepared by removing the solvent or excess acid from a reaction mixture to which an acid has been added under reduced pressure, drying the residue, or by adding another organic solvent and filtering the precipitated salt. At this time, preferable 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.

[0027]

[0028] The compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof has low water solubility, and thus requires an excessive amount of a solubilizer and an organic solvent to be manufactured into an injectable preparation. However, an excessive amount of a solubilizer, etc., may cause hypersensitivity when administered to a patient. Therefore, in the present invention, instead of using a solubilizer generally used in injectable preparations, cyclodextrin and an isotonic agent are used, and by controlling the pH, an injectable preparation having both excellent solubility and stability of the compound represented by the above chemical formula 1 is secured.

[0029]

[0030] Cyclodextrin, a component used in the injectable preparation according to the present invention, is a cyclic oligosaccharide in which 6 to 12 glucose molecules are bonded 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, and more preferably, beta-cyclodextrin. More preferably, the beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin, and the English abbreviations thereof are 'HP-β-CD' and 'SBE-β-CD', respectively.

[0031]

[0032] Among the stabilizers generally used in injectable preparations, the cyclodextrin is suitable for stabilizing the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0033]

[0034] Preferably, the cyclodextrin is used in an amount of 3.0 to 25.0 parts by weight based on 1 part by weight of the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof. If the content is less than 3.0 parts by weight, it is not sufficient to stabilize the compound represented by the chemical formula 1, so that rehydration of the injectable preparation is difficult or the total flexible substance increases during long-term storage. In addition, if the content exceeds 25.0 parts by weight, the amount of stabilizer used is excessive, so that the viscosity of the injectable preparation increases or there is a concern that hypersensitivity may be induced when administered to a patient.

[0035]

[0036] More preferably, the cyclodextrin is 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more, based on 1 part by weight of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; 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.

[0037]

[0038] Meanwhile, the 'isotonic agent' used in the injectable preparation according to the present invention is an additive added to make the osmotic pressure of the injectable preparation similar to the osmotic pressure in the body. Since the injectable preparation is administered directly into the body without a separate dilution process, it must be manufactured with the same osmotic pressure as the body in order to reduce side effects when administered into the body. Preferably, the isotonic 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).

[0039]

[0040] Depending on whether the isotonic agent is an electrolyte or a non-electrolyte, the amount required to achieve the desired osmolarity of the injectable formulation may vary. Therefore, the isotonic agent is preferably included so that the osmolarity of the injectable formulation according to the present invention can be 100 to 700 mOsmol / L, depending on the type of specific substance. More preferably, the osmolarity of the injectable formulation can be 150 to 650 mOsmol / L, 150 to 450 mOsmol / L, 250 to 450 mOsmol / L, or 270 to 420 mOsmol / L.

[0041]

[0042] Preferably, the pH of the injectable preparation according to the present invention is 5.0 to 6.0. Preferably, the injectable preparation of the present invention can have the above pH range due to the chemical properties of the liquid pharmaceutical composition of the present invention itself, and thus the injectable preparation may not include an additional pH adjuster for pH control. Here, the pH adjuster is a substance that improves the solubility of a poorly soluble or insoluble compound by adjusting the pH of the solution by adding it, and a pharmaceutically acceptable acid or alkaline agent is used. Examples thereof include at least one 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.

[0043]

[0044] Preferably, the injectable formulation according to the present invention further comprises a lyophilization adjuvant. Typically, injectable formulations are mass-produced, then frozen, and stored and distributed under reduced pressure. This 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 thus, the present invention may further comprise a lyophilization adjuvant. Preferably, the lyophilization adjuvant is D-mannitol, sucrose, sorbitol, or trehalose, and more preferably D-mannitol.

[0045]

[0046] Preferably, the freeze-drying auxiliary agent is used in an amount of 3.0 to 25.0 parts by weight based on 1 part by weight of the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof. If the content is less than 3.0 parts by weight, it is not sufficient to stabilize the compound represented by the chemical formula 1, so that rehydration of the injectable preparation is difficult or there is a problem that volatile substances increase during long-term storage. In addition, if the content exceeds 25.0 parts by weight, the amount of the freeze-drying auxiliary agent used is excessive, which may increase the viscosity of the injectable preparation or cause hypersensitivity when administered to a patient.

[0047]

[0048] More preferably, the freeze-drying aid is 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more, based on 1 part by weight of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; 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.

[0049]

[0050] Preferably, the freeze-drying aid 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 aid 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; 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.

[0051]

[0052] Preferably, the injectable formulation may utilize a solvent commonly used in the art to which the present invention pertains, in order to prepare a pharmaceutical composition in liquid form. For example, the solvent for the injectable formulation may be distilled water, water for injection, acetate buffer, or physiological saline.

[0053]

[0054] Preferably, the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is included in the above injectable preparation at 1 to 8 mg / mL. That is, the content of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof may be defined as a value obtained by dividing the content (mg) of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof by the total volume (mL) of the above injectable preparation.

[0055]

[0056] More preferably, the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is contained in the injectable preparation in an amount of 2 mg / mL or more, 3 mg / mL or more, or 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.

[0057]

[0058] In addition, if necessary, the injectable preparation according to the present invention may additionally include 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 belongs.

[0059]

[0060] In addition, the injectable formulation according to the present invention can be manufactured by mixing the above-described components, excluding the solvent, into a solvent. During this process, the order in which each component is added to the solvent can be adjusted as needed, or all components can be mixed and added to the solvent before being added. However, the present invention is not limited to this manufacturing method, and the manufacturing of the injectable formulation can be modified according to methods known in the art.

[0061]

[0062] The above-mentioned injectable preparation may be subjected to sterilization and / or filtration steps as needed, and may be lyophilized for storage and distribution.

[0063]

[0064] 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 can satisfy a specific pH range, and exhibit high solubility and excellent stability by including an isotonic agent, and thus 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.

[0065]

[0066] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0067]

[0068] Example 1

[0069] A solution was prepared by adjusting the pH of 40 mg of the hydrochloride of the compound represented by the above-described chemical formula 1 (hereinafter referred to as 'API') according to the composition shown in Table 1 below.

[0070]

[0071] Afterwards, each preparation solution was filled into a vial and stored in liquid form in a harsh condition (60 ℃, 80% RH) chamber for 4 weeks to evaluate stability, and the results are shown in Table 2. Stability was evaluated by analyzing the content of flexible substances in the liquid solution using HPLC, and measuring the total amount of flexible substances detected.

[0072]

[0073] #1-1#1-2#1-3#1-4#1-5API40 mgHP-β-CD200 mgD-mannitol200 mgWater for injection4 mLpH (HCl / NaOH)3.04.05.06.07.0

[0074] Total flexible material % Initial 4 weeks #1-10.211.48 #1-20.180.44 #1-30.170.30 #1-40.150.25 #1-50.170.69

[0075]

[0076] As shown in Table 2 above, it was confirmed that the compositions #1-2 to #1-4 having a pH of 4.0 to 6.0 had stability in which the total flexible substance production did not increase significantly when stored for 4 weeks under harsh conditions in a liquid solution state.

[0077]

[0078] Example 2

[0079] In Example 1, pH 6.0, which produced the least amount of total flexible substances, was selected and the following experiment was conducted.

[0080]

[0081] As shown in Table 3 below, the browning pattern of the product according to the concentration was confirmed by manufacturing the product with different concentrations of API. Each manufactured solution was visually evaluated, and the results are shown in Table 4 below.

[0082]

[0083] #1-4#2API40 mg40 mgHP-β-CD200 mg200 mgD-mannitol200 mg200 mgWater for injection4 mL10 mLpH6.06.0

[0084] Early stage of development: 4 weeks #1-4 Colorless transparent liquid Browning #2 Colorless transparent liquid Colorless transparent liquid

[0085]

[0086] As shown in Table 4 above, it was confirmed that the properties of low-concentration #2 did not change even when stored for 4 weeks under harsh conditions.

[0087]

[0088] Example 3

[0089] In Example 2, the concentration at which the properties were stable (4 mg / mL) was selected and the following experiment was performed.

[0090]

[0091] As shown in Table 5 below, each isotonic agent was prepared in different amounts so that the osmotic pressure of the solution was 380 mOsmol / L (or similar to the osmotic pressure in the body). The prepared solution was stored in a harsh condition (60°C, 80% RH) chamber for 4 weeks in the same manner as in Example 1 to evaluate the properties and stability, and the results are shown in Table 6 below.

[0092]

[0093] #2#3-1#3-2#3-3#3-4API40 mgHP-β-CD200 mgD-mannitol200 mgInjection water10 mLpH6.0Isotonic agentNaCl-90 mg---D-mannitol--400 mg--Dextrose---400 mg-KCl----90 mg

[0094] Total flexible substance % Initial 4 weeks Initial 4 weeks #2 Colorless transparent liquid Colorless transparent liquid 0.04 0.68 #3-1 Colorless transparent liquid Colorless transparent liquid 0.03 0.63 #3-2 Colorless transparent liquid Colorless transparent liquid 0.05 0.62 #3-3 Colorless transparent liquid Colorless transparent liquid 0.03 0.58 #3-4 Colorless transparent liquid Colorless transparent liquid 0.03 0.57

[0095]

[0096] As shown in Table 6 above, it was confirmed that all solutions with added isotonic agents did not change in properties even after 4 weeks of storage under harsh conditions. In particular, it was confirmed that compositions #3-1 to #3-4 showed more stable values ​​in terms of total flexible substance production than the comparative group #2.

[0097]

[0098] Reference Example 1

[0099] Among the isotropic agents that showed relative stability in Example 3, NaCl was selected and the following experiment was performed.

[0100]

[0101] As shown in Table 7 below, each solution was prepared without adding a pH adjuster or with a different type. The prepared solutions were stored in a harsh condition (60°C, 80% RH) chamber for 4 weeks using the same method as Example 1, and the properties and stability were evaluated, and the results are shown in Table 6 below.

[0102]

[0103] #4-1#3-1#4-2API40 mgHP-β-CD200 mgD-mannitol200 mgNaCl90 mgWater for injection10 mLpH adjusterHCl / NaOH-as needed-Phosporic acid / Sodium dihydrogen phosphate--as needed

[0104] Total flexible substance % Initial 4 weeks Initial 4 weeks #4-1 Colorless transparent liquid Colorless transparent liquid 0.05 0.51 #3-1 Colorless transparent liquid Colorless transparent liquid 0.03 0.63 #4-2 Colorless transparent liquid Browning 0.03 0.84

[0105]

[0106] As shown in Table 8 above, #4-1, which does not include a pH regulator, was confirmed to have excellent stability with a lower total amount of flexible substances produced than the compositions #3-1 or #4-2, which include a pH regulator.

[0107]

[0108] Reference Example 2

[0109] Two experimental groups (with / without HCl / NaOH pH adjuster) confirmed in Example 3 and Reference Example 1 were selected and a long-term storage experiment in a liquid composition state was performed. The composition of each experimental group is as shown in Table 9 below.

[0110]

[0111] Each manufactured solution was stored in an accelerated condition (40°C, 75% RH) chamber for 6 months, and the properties and stability were evaluated in the same manner as in Example 1, and the results are shown in Table 10 below.

[0112]

[0113] #4-1#3-1API40 mgHP-β-CD200 mgD-mannitol200 mgNaCl90 mgWater for injection10 mLHCl / NaOH not added

[0114] Total flexible substance % Initial acceleration 3 months Acceleration 6 months Initial acceleration 3 months Acceleration 6 months #4-1 Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid 0.05 0.16 0.18 #3-1 Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid 0.05 0.22 0.30

[0115]

[0116] As shown in Table 10 above, #4-1, which did not contain a pH regulator, was stored in a liquid form for a long period of time, but its properties did not change and there was almost no generation of total flexible substances, confirming its excellent stability.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; cyclodextrin; and an isotonic agent, The pH is 4.0 to 6.0, Injectable preparations: [Chemical Formula 1] .

2. In paragraph 1, The above cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin, or sulfobutyl ether-beta-cyclodextrin, Injectable preparations.

3. In paragraph 1, Comprising 4.5 to 15.0 parts by weight of the cyclodextrin relative to 1 part by weight of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, Injectable preparations.

4. In paragraph 1, The above-mentioned topical agent is sodium chloride (NaCl), D-mannitol, dextrose, glycerin or potassium chloride (KCl). Injectable preparations.

5. In paragraph 1, The osmolarity of the above injectable preparation is 100 to 700 mOsmol / L. Injectable preparations.

6. In paragraph 1, The pH is 5.0 to 6.0, Injectable preparations.

7. In paragraph 1, The above injectable preparation does not contain a pH regulator. Injectable preparations.

8. In paragraph 1, The above injectable formulation additionally contains a lyophilized adjuvant, The above freeze-dried auxiliary agent is D-mannitol, sucrose, sorbitol, or trehalose, Injectable preparations.

9. In paragraph 8, Comprising 3.0 to 25.0 parts by weight of the freeze-drying aid relative to 1 part by weight of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, Injectable preparations.

10. In paragraph 1, The solvent of the above injectable preparation is distilled water, water for injection, acetate buffer, or physiological saline. Injectable preparations.

11. In paragraph 1, The compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is contained in the above injectable preparation at 1 to 8 mg / mL. Injectable preparations.