Liquid pharmaceutical composition

Abstract

The present invention relates to a liquid pharmaceutical composition comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; a filler for freeze drying; and a cyclodextrin; the filling agent for freeze drying is D-mannitol; the cyclodextrin is contained in an amount of 4.5 parts by weight to 10.0 parts by weight based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof; the content of the filler for freeze drying is 5.0, 10.0 or 15.0 parts by weight based on 1 part by weight of the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in a liquid pharmaceutical composition at a concentration of 1 mg / mL to 20 mg / mL, and the pH of the liquid pharmaceutical composition is 3.0 to 7.0. [Chemical Formula 1] # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with the application date of December 18, 2020, application number 202080087191.3, and invention name "Liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine". Technical Field

[0002] The present invention relates to a liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof. Background Art

[0003] The present invention relates to a liquid pharmaceutical composition suitable for 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. The above compound is a compound described in Korean Patent Registration No. 10-1613245, has excellent anti-ulcer activity (i.e., proton pump inhibition activity, etc.) and eradication activity against Helicobacter pylori (H.pylori), and can therefore be used to prevent and treat gastrointestinal ulcers, gastritis, reflux esophagitis or gastrointestinal damage caused by Helicobacter pylori.

[0004] The above-mentioned compound is a compound showing very low water solubility, and in order to prepare it as a liquid pharmaceutical composition, such as an injectable pharmaceutical composition, an excessive amount of solubilizer and organic solvent is required. However, when the active ingredient is administered in high doses, the pharmaceutical composition containing a large amount of solubilizer and organic solvent has the problem that allergic reactions may occur. That is, in general, for medicines with low water solubility, in order to develop liquid preparations with excellent solubility and stability at the same time, it is necessary to study the combination of various components except the medicine.

[0005] Solubilizers commonly used in liquid pharmaceutical compositions include ethanol, polysorbate, etc., but these compounds may have harmful effects on the human body, so it is necessary to develop a liquid pharmaceutical composition having both excellent solubility and stability without using such solubilizers.

[0006] Therefore, the present inventors have conducted intensive studies to overcome the problems caused by solubilizers and organic solvents, in which solubilizers and organic solvents are excessively used to solubilize the conventional poorly soluble drug 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine into a liquid pharmaceutical composition, and to improve the stability of the liquid pharmaceutical composition. As a result, it was found that the above-mentioned problems can be solved by using a specific stabilizer and a filler for freeze-drying as described below, thereby completing the present invention. Summary of the invention

[0007] [Technical issues]

[0008] The object of the present invention is to provide a liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.

[0009] [Technical solution]

[0010] In order to achieve the above object, according to the present invention, there is provided a liquid pharmaceutical composition, which includes a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and cyclodextrin;

[0011] [Chemical formula 1]

[0012]

[0013] The chemical name of the compound represented by the following Chemical Formula 1 is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, which is a compound described in Korean Patent Registration No. 10-1613245.

[0014] The above-mentioned compound is an active ingredient that exerts the pharmacological effect of the liquid pharmaceutical composition according to the present invention, and has excellent anti-ulcer activity (i.e., proton pump inhibition activity, etc.), eradication activity against Helicobacter pylori and GPCR inhibition, and can therefore be used to prevent and treat gastrointestinal ulcers, gastritis, reflux esophagitis or gastrointestinal damage caused by Helicobacter pylori. In addition, the above-mentioned compound and the pharmaceutically acceptable salt of the compound can also be used in the present invention.

[0015] In addition, in addition to the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt can also be used in the present invention. As the salt, salts commonly used in the art, such as acid addition salts formed from pharmaceutically acceptable free acids, can be used without limitation. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, the concentration of which is relatively nontoxic and harmless to the patient and effectively activated, and the side effects thereof do not reduce the beneficial effects of the above-mentioned compound.

[0016] Pharmaceutically acceptable salts can be obtained by conventional methods using inorganic or organic acids. For example, pharmaceutically acceptable salts can be prepared by dissolving the compound represented by Chemical Formula 1 in a water-soluble organic solvent such as acetone, methanol, ethanol or acetonitrile, then adding an organic acid or inorganic acid, filtering and drying the precipitated crystals. Alternatively, it can be prepared by subjecting the solvent or excess acid from the reaction mixture to which the acid is added to decompress, then drying the residue, or by adding different organic solvents and then filtering the precipitated salt. At this point, preferred salts may 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.

[0017] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has low water solubility. Therefore, in order to prepare a liquid pharmaceutical composition, such as an injectable pharmaceutical composition, an excess of a solubilizer and an organic solvent are required. However, an excess of a solubilizer, etc. may cause an allergic reaction when administered to a patient. Therefore, in the present invention, a solubilizer commonly used in a liquid pharmaceutical composition is not used, but the above-mentioned components are used, so that a liquid pharmaceutical composition having both excellent solubility and stability of the compound represented by Chemical Formula 1 can be achieved.

[0018] The cyclodextrin used as a component in the liquid pharmaceutical composition according to the present invention is a cyclic oligosaccharide in which 6 to 12 glucose molecules form an α-1,4-glycosidic bond, and is used as a stabilizer in the present invention. Preferably, the cyclodextrin is β-cyclodextrin or γ-cyclodextrin, more preferably β-cyclodextrin. More preferably, the β-cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin, and the English abbreviations are 'HP-β-CD' and 'SBE-β-CD', respectively.

[0019] Among stabilizers commonly used in liquid pharmaceutical compositions, cyclodextrin is suitable for stabilizing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. As in the examples described later, stabilizers other than the above are not sufficient to stabilize the compound represented by Chemical Formula 1.

[0020] Preferably, the amount of cyclodextrin is 3.0 to 25.0 parts by weight based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. When the content is less than 3.0 parts by weight, it is insufficient to stabilize the compound represented by Chemical Formula 1, which results in a problem that the liquid pharmaceutical composition is difficult to rehydrate or the total amount of related compounds increases during long-term storage. In addition, when the content exceeds 25.0 parts by weight, the amount of stabilizer used is too much, which increases the viscosity of the liquid pharmaceutical composition or causes allergies when applied to a patient.

[0021] More preferably, based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the content of cyclodextrin is 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more; and 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.

[0022] Preferably, the liquid pharmaceutical composition according to the present invention also includes a filler for freeze drying. Usually, the liquid pharmaceutical composition is produced in large quantities, and then frozen, stored and distributed under reduced pressure, so that the stability of the active ingredient can be enhanced and the long-term storage stability can be improved. Therefore, the stability of the active compound should be maintained during the freeze drying process, so that, in the present invention, a filler for freeze drying can be additionally included. Preferably, the filler for freeze drying is D-mannitol, sucrose, sorbitol or trehalose, more preferably D-mannitol.

[0023] Preferably, based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the amount of the filler used for freeze drying is 3.0 parts by weight to 25.0 parts by weight. When the content is less than 3.0 parts by weight, it is not enough to stabilize the compound represented by Chemical Formula 1, which leads to the problem that the liquid pharmaceutical composition is difficult to rehydrate or the related compounds increase during long-term storage. In addition, when the content exceeds 25.0 parts by weight, the amount of filler used for freeze drying is too much, which increases the viscosity of the liquid pharmaceutical composition or causes allergies when applied to patients.

[0024] More preferably, the content of the filler for freeze-drying is 3.5 parts by weight or more, 4.0 parts by weight or more, or 4.5 parts by weight or more, and 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, based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0025] Preferably, the amount of the filler used for freeze drying is 0.5 to 5.0 parts by weight based on 1 part by weight of cyclodextrin. More preferably, the content of the filler used for freeze drying is 0.6 parts by weight or more, 0.7 parts by weight or more, or 0.8 parts by weight or more based on 1 part by weight of cyclodextrin; and 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.

[0026] Preferably, the liquid pharmaceutical composition according to the present invention is an injectable pharmaceutical composition. Meanwhile, in order to prepare the pharmaceutical composition in liquid form, conventional solvents in the field to which the present invention belongs can be used. As an example, the solvent of the liquid pharmaceutical composition is distilled water, water for injection, acetate buffer or physiological saline.

[0027] Preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition at a concentration of 1 mg / mL to 30 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 value obtained by dividing the amount (mg) of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof by the total volume (mL) of the liquid pharmaceutical composition.

[0028] More preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition 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; and 29 mg / mL or less, 28 mg / mL or less, 27 mg / mL or less, 26 mg / mL or less, 25 mg / mL or less, 24 mg / mL or less, 23 mg / mL or less, 22 mg / mL or less, 21 mg / mL or less, 20 mg / mL or less, 19 mg / mL or less, 18 mg / mL or less, 17 mg / mL or less, 16 mg / mL or less, or 15 mg / mL or less.

[0029] Preferably, the pH of the liquid pharmaceutical composition according to the present invention is 3.0 to 7.0, more preferably 3.5 to 6.5, and even more preferably 4.0 to 6.0. The pH can be adjusted by a pH regulator, and conventional acids or bases in the field to which the present invention belongs can be used as pH regulators. As examples of pH regulators, any 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 can be used, but it is not limited thereto.

[0030] In addition, if necessary, the liquid pharmaceutical composition according to the present invention may also contain preservatives, antioxidants, etc. There are no particular limitations on the preservatives and antioxidants as long as they are commonly used in the technical field to which the present invention belongs.

[0031] In addition, the liquid pharmaceutical composition according to the present invention can be prepared by mixing the above-mentioned components except the solvent in a solvent. In the process, if necessary, the order in which each component is added to the solvent can be adjusted. Alternatively, all components can be mixed and added to the solvent before being added to the solvent.

[0032] The prepared liquid pharmaceutical compositions may be sterilized and / or filtered, if necessary, and may be freeze-dried for storage and distribution.

[0033] [Beneficial Effects]

[0034] The present invention can be effectively used as a liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0035] Below, the present invention will be described in more detail to help understand the present invention. However, the following examples are provided for illustrative purposes only and should not be construed as limiting the scope of the present invention to these examples.

[0036] Example 1

[0037] As shown in Table 1 below, each formulation liquid adjusted to pH 4.0 was gradually added to 20 mg of the hydrochloride of the compound represented by Chemical Formula 1 (hereinafter referred to as "API"), and the dissolution state was confirmed with the naked eye. Subsequently, the formulation liquid was further added to the undissolved experimental group, and the dissolution state was evaluated. The results are shown in Table 2 below. In Table 2 below, "O" refers to the case of complete dissolution, and "X" refers to the case of not completely dissolving, so a portion of the API can be observed with the naked eye.

[0038] [Table 1]

[0039]

[0040]

[0041] [Table 2]

[0042]

[0043] As shown in Table 2, it was confirmed that the solubility in water for injection, phosphate buffer, and acetate buffer such as #1-1 to #1-3 was good.

[0044] Example 2

[0045] The following experiments were conducted using water for injection, phosphate buffer, and acetate buffer having good solubility in Example 1.

[0046] As shown in Table 3 below, 10 mg of API and 50 mg each of α-cyclodextrin (α-CD), γ-cyclodextrin (γ-CD), (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), trehalose, PVP K-12, and Poloxamer 188 (Poloxamer 188) as a stabilizer were dissolved in water for injection (1 mL), and 0.1 N HCl was added thereto to adjust the pH to 4.0.

[0047] [Table 3]

[0048]

[0049]

[0050] Each of the prepared solutions was placed in a 10 mL sample bottle and dried by freeze drying. For freeze drying, the temperature, time and pressure shown in Table 4 were applied in sequence.

[0051] [Table 4]

[0052]

[0053] After freeze drying was completed, the freeze-dried samples were stored in a chamber under harsh conditions (60° C., 80% RH) for 4 weeks. The rehydration property and stability of each sample at the initial stage of storage and after 4 weeks of storage were evaluated as follows, respectively.

[0054] (1) Rehydration

[0055] A rehydration solution (4 mL each of water for injection, 0.9% saline, and 5% glucose solution) was applied to the freeze-dried product, and then observed with the naked eye. If it was completely dissolved and there was no foreign matter, it was evaluated as "O", if not, it was evaluated as "X", and if it was completely dissolved but then precipitated, it was evaluated as "Δ".

[0056] (2) Stability

[0057] The content of related compounds in the freeze-dried product was analyzed by HPLC to determine the total amount of related compounds detected.

[0058] The results are shown in Table 5 below.

[0059] [Table 5]

[0060]

[0061] As shown in Table 5, it was confirmed that the compositions #2-2 and #2-4 could be rehydrated even after storage for 4 weeks under severe conditions and showed excellent stability with almost no generation of total related compounds.

[0062] Example 3

[0063] HP-β-CD, which has excellent stabilizer effect in Example 2, was selected to conduct the following experiment.

[0064] As shown in Table 6 below, API and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) were dissolved in water for injection (1 mL), to which 0.1 N HCl was added to adjust the pH to 4.0.

[0065] [Table 6]

[0066]

[0067] Each of the prepared solutions was dried by freeze drying in the same manner as in the aforementioned Example 2, and then evaluated for rehydration and stability. The results are shown in Table 7 below.

[0068] [Table 7]

[0069]

[0070]

[0071] As shown in Table 7, it was confirmed that compositions #2-3 and #3-2 to #3-4 could be rehydrated even after storage for 4 weeks under severe conditions, and compositions #2-3 and #3-3 to #3-4 showed excellent stability with almost no generation of total related compounds.

[0072] Example 4

[0073] HP-β-CD, which has excellent stabilizer effect in Example 2, was selected to conduct the following experiment.

[0074] Experiments were conducted using three types of water for injection, acetate buffer, and phosphate buffer derived from Example 1. For this purpose, in addition to the composition #2-3 of Example 2, compositions were further prepared as shown in Table 8 below and dissolved in each buffer (1 mL), and acetic acid and phosphoric acid were added to adjust the pH to 4.0.

[0075] [Table 8]

[0076]

[0077] Each of the prepared solutions was dried by freeze drying in the same manner as in Example 2, and then evaluated for rehydration and stability. The results are shown in Table 9 below.

[0078] [Table 9]

[0079]

[0080] As shown in Table 9, #4-2 had problems with rehydration after 4 weeks of storage under harsh conditions. On the other hand, it was confirmed that #2-3 and #4-1 had no abnormalities in rehydration after 4 weeks of storage under harsh conditions and showed excellent stability with almost no generation of total related compounds.

[0081] Example 5

[0082] The properties of the preparation after freeze drying are one of the important factors affecting future quality, such as rehydration and total related compounds. A solution was prepared using the stabilizer HP-β-CD derived from Examples 1 to 4 and water for injection, to which a filler for freeze drying was then added, and 0.1N HCl was added to adjust the pH to 4.0, thereby preparing a composition.

[0083] [Table 10]

[0084]

[0085] Each of the prepared solutions was dried by freeze drying in the same manner as in Example 2, and then evaluated for properties and rehydration. The results are shown in Table 11 below.

[0086] [Table 11]

[0087]

[0088] As shown in Table 11, it can be confirmed that #5-1 to #5-4 are formulas that maintain the properties of the block and the solubility during the rehydration process. However, from the perspective of the manufacturing process, the optimal drying temperature and time vary depending on the type of the freeze-drying filler. Considering that this is a factor directly related to production efficiency, D-mannitol is most preferred.

[0089] Example 6

[0090] In order to confirm the relationship between the properties, rehydration properties and stability of the injectable composition and the content of the freeze-dried bulking agent D-mannitol (the D-mannitol was derived from Example 5), 0.1N HCl was added to the content shown in Table 12 below to adjust the pH to 4.0 to prepare the composition.

[0091] [Table 12]

[0092]

[0093] Each of the prepared solutions was dried by freeze drying in the same manner as in Example 2, and then evaluated for properties, rehydration and stability. The results are shown in Table 13 below.

[0094] [Table 13]

[0095]

[0096] As shown in Table 13, it was confirmed that #6-4 to #6-6 had excellent block properties without cracking and were formulas that could maintain solubility during rehydration when stored under severe conditions for 4 weeks. In addition, it was confirmed that they showed excellent stability with almost no generation of total related compounds.

[0097] Example 7

[0098] Compositions different in pH from the final compositions for injection derived from Examples 1 to 6 were prepared as shown in Table 14 below.

[0099] [Table 14]

[0100]

[0101] Each of the prepared solutions was dried by freeze drying in the same manner as in Example 2, and then evaluated for properties, rehydration and stability. The results are shown in Table 15 below.

[0102] [Table 15]

[0103]

[0104] As shown in Table 15, it was confirmed that: #7-5 and #7-6 were difficult to evaluate because the API was deposited during the preparation process; #6-4 and #7-1 to #7-4 had excellent block properties without cracking and were formulations that maintained solubility during rehydration even after storage for 4 weeks under harsh conditions. In addition, it was confirmed that they showed excellent stability with almost no generation of total related compounds.

[0105] Example 8

[0106] Compositions having different concentrations than in Example 7 were prepared as shown in Table 16 below.

[0107] [Table 16]

[0108]

[0109]

[0110] Each of the prepared solutions was dried by freeze drying in the same manner as in Example 2, and then evaluated for properties, rehydration and stability. The results are shown in Table 17 below.

[0111] [Table 17]

[0112]

[0113] As shown in Table 17, it was confirmed that #8-6 and #8-7 were difficult to evaluate because the API was deposited during the preparation process; #8-1 to #8-5 had excellent block properties without cracking and were formulations that maintained solubility during rehydration even after storage for 4 weeks under harsh conditions. In addition, it was confirmed that they exhibited excellent stability with almost no generation of total related compounds.

Claims

1. A liquid pharmaceutical composition comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof; a filler for freeze drying; and cyclodextrin; in, The filler used for freeze drying is D-mannitol; [Chemical formula 1] Wherein, based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the content of the cyclodextrin is 4.5 parts by weight to 10.0 parts by weight; Wherein, based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the content of the filler for freeze-drying is 5.0, 10.0 or 15.0 parts by weight; wherein the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition at a concentration of 1 mg / mL to 20 mg / mL, Wherein, the pH of the liquid pharmaceutical composition is 3.0-7.

0.

2. The liquid pharmaceutical composition according to claim 1, wherein The cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

3. The liquid pharmaceutical composition according to claim 2, wherein The β-cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.

4. The liquid pharmaceutical composition according to claim 1, wherein The content of the cyclodextrin is 5.0 parts by weight based on 1 part by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

5. The liquid pharmaceutical composition according to claim 1, wherein The liquid pharmaceutical composition is an injectable pharmaceutical composition.

6. The liquid pharmaceutical composition according to claim 1, wherein The solvent of the liquid pharmaceutical composition is distilled water, water for injection, acetate buffer or physiological saline.

7. The liquid pharmaceutical composition according to claim 1, wherein The pH of the liquid pharmaceutical composition is 4.0 to 6.

0.

8. The liquid pharmaceutical composition according to claim 1, wherein The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition at a concentration of 5 mg / mL to 20 mg / mL.

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