The drug container contains a liquid pharmaceutical product containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrol-3-yl)-N-methylmethanamine

Abstract

The invention relates to a drug container for a liquid pharmaceutical product containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrol-3-yl)-N-methylmethanamine, or its pharmaceutical salts.

Description

Pharmaceutical container comprising a liquid pharmaceutical composition of 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. 10-2021-0067635, filed May 26, 2021, and Korean Patent Application No. 10-2022-0064452, filed May 26, 2022, the entire contents of which are incorporated herein by reference.

[0003]

[0004] The present invention relates to a pharmaceutical container comprising a liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

[0005]

[0006] 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, and is therefore a useful substance for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0007]

[0008] However, the inventors of the present invention confirmed that the stability of the composition is reduced when stored for a long time in a liquid form, and as a result of thorough research on the cause of such long-term stability problem, it was confirmed that the substance reacts with acid or base and the amount of decomposition products increases, and in particular, the acid / base reaction is accelerated in the stage of wet heat sterilization and dry sterilization, which are high-temperature sterilization processes generally required in the manufacturing process for liquid formulations, making it difficult to develop a stable liquid formulation including the chemical formula 1 described below.

[0009]

[0010] Accordingly, the inventors of the present invention have found that when 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, is stored as a liquid formulation in a standard glass vial for a long period of time, it is difficult to ensure stability due to the possibility of a reaction between the alkaline substance derived from the inner surface of the vial and the solution, which can lead to great difficulties in commercialization, and as a result of efforts to provide a pharmaceutical container for long-term stable storage, it has been confirmed that when a container of a specific material is used, the reaction between the pharmaceutical composition and the container is minimized, thereby providing a pharmaceutical product in the form of an injection solution that is easy to store and ready to use, and is stable even after going through a high-temperature sterilization process, thereby completing the present invention.

[0011]

[0012] The present invention provides a pharmaceutical container comprising 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.

[0013]

[0014] In order to solve the above problem, the present invention provides a pharmaceutical container comprising a liquid pharmaceutical composition comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and which is a plastic container; a glass container having an interior coated with silicone oil, SiO2, or SiOCH; or a dealkalized glass container.

[0015] [Chemical Formula 1]

[0016] .

[0017]

[0018] 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.

[0019]

[0020] The compound represented by the above chemical formula 1 is an active ingredient that exhibits the pharmacological effect of the liquid pharmaceutical composition 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.

[0021]

[0022] In addition, as an active ingredient exhibiting the pharmacological effect of the liquid pharmaceutical composition 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.

[0023]

[0024] Pharmaceutically acceptable salts can be obtained by conventional methods using inorganic or organic acids. 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, 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 salt 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.

[0025]

[0026] Meanwhile, since the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof may react with an acid or a base to increase decomposition products, there is a possibility that the solution may react with an alkaline substance derived from the inner surface of the container when the liquid pharmaceutical composition thereof is stored for a long period of time in a standard container. In particular, there is a problem that the reaction is more active when a general standard glass container is used. Therefore, in order to store the liquid preparation for a long period of time more easily, the pharmaceutical container including the liquid pharmaceutical composition is a plastic container rather than a glass container, a glass container functionally coated with a specific material, or a dealkalized container. When a plastic container is used, the plastic container is not particularly limited, but may preferably be a cyclic olefin polymer (COP) or a cyclic olefin copolymer (COC). More preferably, it may be a cyclic olefin polymer. In addition, silicone oil, SiO2, or SiOCH, which have low reactivity with the liquid formulation, can be used as the inner coating material of the glass container, and a dealkalized glass container, which is a general glass container that has been acid-treated to remove alkaline substances from the inner surface of the container, can be used. By coating or treating with a specific material in this way, or by using a container of a specific material, the stability of the liquid pharmaceutical composition increases, enabling it to be commercialized, and it can also be usefully used as a ready-to-use injection solution.

[0027]

[0028] In addition, acid / base reactions may be accelerated during steps such as moist heat sterilization and dry sterilization, which are high-temperature sterilization processes generally required for liquid formulations, but the stability of the compound can be maintained even during these steps when using a specific container.

[0029]

[0030] Meanwhile, the liquid pharmaceutical composition may preferably additionally include cyclodextrin and a tonicity agent.

[0031]

[0032] 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 prepare a liquid pharmaceutical composition, such as an injectable pharmaceutical composition. However, there is a concern that an excessive amount of a solubilizer, etc. may cause hypersensitivity when administered to a patient. Therefore, in the present invention, by using the above-described ingredients instead of a solubilizer generally used in liquid pharmaceutical compositions, it is possible to prepare a liquid pharmaceutical composition having both excellent solubility and stability of the compound represented by the above chemical formula 1.

[0033]

[0034] The above cyclodextrin 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 are 'HP-β-CD' and 'SBE-β-CD', respectively. Most preferably, the beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD).

[0035]

[0036] Among stabilizers generally used in liquid pharmaceutical compositions, the cyclodextrin is suitable for stabilizing the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0037]

[0038] 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 liquid pharmaceutical composition 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, which may increase the viscosity of the liquid pharmaceutical composition or cause hypersensitivity when administered to a patient.

[0039]

[0040] 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.

[0041]

[0042] Meanwhile, the 'tonicity agent' is an additive added to make the osmotic pressure of the liquid pharmaceutical composition contained in the container similar to the osmotic pressure in the body. Since the liquid pharmaceutical composition 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 tonicity agent may be sodium chloride (NaCl), D-mannitol, dextrose, glycerin, or KCl (potassium chloride), more preferably, sodium chloride (NaCl), dextrose, glycerin, or KCl (potassium chloride), and most preferably, sodium chloride (NaCl), dextrose, or KCl (potassium chloride).

[0043]

[0044] Depending on whether the isotonic agent is an electrolyte or a non-electrolyte, the amount required to achieve the desired osmolarity of the liquid pharmaceutical composition may vary. Therefore, the isotonic agent is preferably included so that the osmolarity of the liquid pharmaceutical composition 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 preparation can be 150 to 650 mOsmol / L, 150 to 450 mOsmol / L, 250 to 450 mOsmol / L, or 270 to 420 mOsmol / L.

[0045]

[0046] Preferably, the liquid pharmaceutical composition may further comprise a lyophilization aid. Generally, liquid pharmaceutical compositions 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 substance must be maintained during the lyophilization process, and therefore, the present invention may further comprise a lyophilization aid. Preferably, the lyophilization aid may be D-mannitol, sucrose, sorbitol, or trehalose, and more preferably, the lyophilization aid may be D-mannitol.

[0047]

[0048] Preferably, the freeze-drying aid 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 liquid pharmaceutical composition is difficult or there is a problem that flexible substances increase during long-term storage. In addition, if the content exceeds 25.0 parts by weight, the amount of the freeze-drying aid used is excessively large, so that the viscosity of the liquid pharmaceutical composition increases or there is a concern that hypersensitivity may be induced when administered to a patient.

[0049]

[0050] 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.

[0051]

[0052] 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.

[0053]

[0054] Preferably, a conventional solvent known in the art to which the present invention pertains can be used to prepare the pharmaceutical composition in liquid form. For example, the solvent for the liquid pharmaceutical composition is distilled water, water for injection, acetate buffer, or physiological saline.

[0055]

[0056] Preferably, the pH of the liquid pharmaceutical composition according to the present invention is 4.0 to 6.0, more preferably 5.0 to 6.0. Due to the chemical properties of the liquid pharmaceutical composition of the present invention, an additional pH adjusting agent may not be used to adjust the pH. Here, the pH adjusting agent 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. As examples, 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 may be used.

[0057]

[0058] Preferably, the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is included in the liquid pharmaceutical composition 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 can 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 liquid pharmaceutical composition.

[0059]

[0060] More preferably, the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition 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; and 7 mg / mL or less, 6 mg / mL or less, or 5.5 mg / mL or less.

[0061]

[0062] Meanwhile, the 'amount of flexible substances' described later is analyzed using the flexible substance test method established in accordance with ICH Guideline Q2 Analytical Validation, and the total amount of flexible substances is calculated through a proportional formula between the concentration of a standard with known purity and the peak area measured by HPLC and the concentration of the test solution and the peak area of ​​the flexible substances measured by HPLC. Specifically, the 'amount of flexible substances (%)' can be calculated as '(concentration of standard solution (mg / mL) / concentration of test solution (mg / mL)) * (peak area of ​​flexible substances in the test solution / peak area of ​​the standard solution) * 100'.

[0063]

[0064] When the pharmaceutical container is stored under harsh conditions of 60°C and 80% RH for 4 weeks, the amount of flexible substances generated in the liquid pharmaceutical composition may be 0.5% or less. Preferably, the amount of flexible substances in the liquid pharmaceutical composition in the pharmaceutical container stored under the harsh conditions for 4 weeks may be 0.48% or less, 0.47% or less, 0.46% or less, or 0.45% or less.

[0065]

[0066] In addition, the difference between the amount of flexible substances in the liquid pharmaceutical composition measured after storing the pharmaceutical container under harsh conditions of 60°C and 80% RH for 4 weeks and the amount of flexible substances before the harsh conditions treatment may be 0.45% or less. Preferably, the difference between the amount of flexible substances in the liquid pharmaceutical composition measured after storing for 4 weeks and the amount of flexible substances before the harsh conditions treatment may be 0.43% or less, 0.4% or less, 0.38% or less, 0.36% or less, or 0.35% or less.

[0067]

[0068] Preferably, the amount of flexible substances in the liquid pharmaceutical composition measured after heat sterilization of the pharmaceutical container at 100°C to 150°C for 3 to 30 minutes and storage under harsh conditions of 60°C and 80% RH for 4 weeks may be 0.5% or less. Preferably, the amount of flexible substances in the liquid pharmaceutical composition in the pharmaceutical container after heat sterilization and storage under harsh conditions for 4 weeks may be 0.48% or less, 0.47% or less, 0.46% or less, or 0.45% or less. More preferably, the heat sterilization treatment conditions may be 121°C for 15 minutes, 126°C for 10 minutes, or 134°C for 3 minutes.

[0069]

[0070] Preferably, the difference between the amount of reactive substances in the liquid pharmaceutical composition measured after heat sterilization of the pharmaceutical container at 100°C to 150°C for 3 to 30 minutes and storage under harsh conditions of 60°C and 80% RH for 4 weeks and the amount of reactive substances before the harsh conditions treatment may be 0.45% or less. Preferably, the difference between the amount of reactive substances in the liquid pharmaceutical composition measured after heat sterilization and storage for 4 weeks and the amount of reactive substances before the harsh conditions treatment may be 0.43% or less, 0.4% or less, 0.38% or less, 0.36% or less, or 0.35% or less. More preferably, the heat sterilization treatment conditions may be 121°C for 15 minutes, 126°C for 10 minutes, or 134°C for 3 minutes.

[0071]

[0072] If necessary, the liquid pharmaceutical composition 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.

[0073]

[0074] In addition, the liquid pharmaceutical composition according to the present invention can be prepared by mixing the above-described components excluding the solvent into a solvent, and in this process, the order of addition of each component to the solvent can be adjusted as needed, or all components can be mixed and added to the solvent before being added to the solvent.

[0075]

[0076] As described above, the pharmaceutical container of the present invention can stably store a liquid pharmaceutical composition comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, or a pharmaceutically acceptable salt thereof, so that the pharmaceutical container comprising the liquid pharmaceutical composition can be usefully used as a ready-to-use injection solution.

[0077]

[0078] 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.

[0079]

[0080] Example 1

[0081] As shown in Table 1 below, a liquid pharmaceutical composition containing the hydrochloride of the compound represented by the above-described chemical formula 1 (hereinafter referred to as “API”) was prepared.

[0082]

[0083] #1-1#1-2API40 mgHP-β-CD200 mgD-mannitol200 mgNaCl90 mgWater for injection10 mLpH (HCl / NaOH)Added6.0Not added5.0

[0084]

[0085] Each preparation solution was filled into vials of different materials as shown in Table 2 below, and stored in liquid form in a harsh condition (60℃, 80% RH) chamber for 4 weeks. The stability was evaluated and shown in Table 3. The stability was measured by analyzing the amount of flexible substances in the liquid solution using HPLC and measuring the total amount of flexible substances detected.

[0086] Specifically, the amount of flexible substances was analyzed using the flexible substance test method established in accordance with ICH Guideline Q2 Analytical Validation, and the total amount of flexible substances was calculated through a proportional equation between the concentration of a standard product with known purity and the peak area measured by HPLC and the concentration of the test solution and the peak area of ​​the flexible substances measured by HPLC.

[0087]

[0088] The plastic vials used in #2-9 and #2-10 in Table 2 below are Daikyo Crystal Zenith vials.

[0089]

[0090] #2-1#2-2#2-3#2-4#2-5#2-6#2-7#2-8#2-9#2-10API40 mgHP-β-CD200 mgD-mannitol200 mgNaCl90 mgWater for injection10 mLvialOrdinary glass vialSilicone oil-coated glass vialSiO2-coated glass vialSiOCH-coated glass vialPlastic vialpH (HCl / NaOH)Added 6.0Not added 5.0Added 6.0Not added 5.0Added 6.0Not added 5.0Added 6.0Not added 5.0

[0091] Total flexible substances % Before treatment 4 weeks After treatment Before treatment 4 weeks After treatment #2-1 Colorless transparent liquid Colorless transparent liquid 0.03 0.63 #2-2 Colorless transparent liquid Colorless transparent liquid 0.05 0.51 #2-3 Colorless transparent liquid Colorless transparent liquid 0.04 0.33 #2-4 Colorless transparent liquid Colorless transparent liquid 0.04 0.33 #2-5 Colorless transparent liquid Colorless transparent liquid 0.04 0.19 #2-6 Colorless transparent liquid Colorless transparent liquid 0.02 0.26 #2-7 Colorless transparent liquid Colorless transparent liquid 0.04 0.17 #2-8 Colorless transparent liquid Colorless transparent liquid 0.04 0.12 #2-9 Colorless transparent liquid Colorless transparent liquid 0.03 0.13 #2-10 Colorless transparent liquid Colorless transparent liquid 0.04 0.28

[0092]

[0093] As shown in Table 3 above, when stored in a liquid solution state under harsh conditions for 4 weeks for each container, there was no change in the properties, but it was confirmed that the total amount of flexible substances produced was relatively lower in the functional container of one embodiment of the present invention than in comparative examples #2-1 and #2-2 using general glass vials. In other words, it was confirmed that the pharmaceutical container of one embodiment of the present invention had stability when storing a liquid solution.

[0094]

[0095] Example 2

[0096] We also wanted to determine whether the same long-term stability improvement effect was observed for a composition that was subjected to moist heat sterilization (sterilization at 121°C for 15 minutes), which is necessary during the liquid formulation manufacturing process but can accelerate the reactivity with acids / bases.

[0097] A liquid composition was prepared in the same manner as in Example 1, and its stability was evaluated in the same manner as in Example 1.

[0098] Acid-treated glass vials are dealkalized vials that have had their inner surface treated with acid to remove alkaline substances.

[0099]

[0100] #2-2#3-1#3-2#3-3#2-4#3-4API40 mgHP-β-CD200 mgD-mannitol200 mgNaCl90 mgWater for injection10 mLpH (HCl / NaOH)Unadded vialGeneral glass vialAcid-treated glass vial (dealkali)Silicone oil-coated glass vialMoist heat sterilization (121℃, 15 minutes)Not appliedNot appliedNot appliedNot appliedApplied

[0101] Total flexible material % Before treatment 4 weeks After treatment Before treatment 4 weeks After treatment #2-2 Colorless transparent liquid Colorless transparent liquid 0.05 0.51 #3-1 Colorless transparent liquid Colorless transparent liquid 0.2 0.88 #3-2 Colorless transparent liquid Colorless transparent liquid 0.06 0.29 #3-3 Colorless transparent liquid Colorless transparent liquid 0.1 0.45 #2-4 Colorless transparent liquid Colorless transparent liquid 0.04 0.33 #3-4 Colorless transparent liquid Colorless transparent liquid 0.08 0.41

[0102]

[0103] As shown in Table 5 above, when moist heat sterilization was not applied, there was no change in the properties when each container was stored in a liquid solution state under harsh conditions for 4 weeks, but it was confirmed that the total amount of flexible substances produced was relatively lower in the functional containers (#3-2 and #2-4) of one embodiment of the present invention than in the comparative example #2-1 using a general glass vial, and in particular, it was confirmed that the containers treated with dealkalization had greater stability.

[0104] When the moist heat sterilization step, which is generally required for liquid formulations, is applied, it can be confirmed that there is more reactive material before the harsh condition treatment than when moist heat sterilization is not applied, which can be inferred that the acid / base reactivity is increased during the moist heat sterilization process. In addition, it can be confirmed that the increase in reactive material in each vial after 4 weeks is higher when moist heat sterilization is applied than when it is not applied, which is presumed to be due to the increased alkali activation of the inner surface of the vial due to the high temperature during moist heat sterilization. Nevertheless, the acid-treated vial and the internally coated vial minimized the effect of this heat sterilization step, showing an excellent stability maintenance effect compared to general vials, suggesting the possibility of commercializing a liquid formulation including Chemical Formula 1.

[0105] From the above examples, it was confirmed that the liquid solution was stable when stored in a pharmaceutical container of one embodiment of the present invention.

Claims

1. A liquid pharmaceutical composition comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, Plastic container; interior is filled with silicone oil, SiO 2 , or a glass container coated with SiOCH; or a glass container that has been dealkalized, Pharmaceutical containers: [Chemical Formula 1] .

2. In paragraph 1, The above liquid pharmaceutical composition further comprises cyclodextrin and an isotonic agent. Pharmaceutical containers.

3. In paragraph 2, The above cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin, The above-mentioned topic is D-mannitol. Pharmaceutical containers.

4. In paragraph 1, The pH of the above liquid pharmaceutical composition is 4.0 to 6.0, Pharmaceutical containers.

5. In paragraph 1, The amount of flexible substances in the liquid pharmaceutical composition measured after storing the pharmaceutical container for 4 weeks under harsh conditions of 60℃ and 80% RH is 0.5% or less. Pharmaceutical containers.

6. In paragraph 1, The difference between the amount of flexible substances in the liquid pharmaceutical composition measured after storing the pharmaceutical container under harsh conditions of 60℃ and 80% RH for 4 weeks and the amount of flexible substances before treatment under harsh conditions is 0.45% or less. Pharmaceutical containers.

7. In paragraph 1, The amount of flexible substances in the liquid pharmaceutical composition measured after heat sterilization of the above pharmaceutical container at 100°C to 150°C for 3 to 30 minutes and storage under harsh conditions of 60°C and 80% RH for 4 weeks is 0.5% or less. Pharmaceutical containers.

8. In paragraph 1, The amount of flexible substances in the liquid pharmaceutical composition measured after heat sterilization of the above pharmaceutical container at 100°C to 150°C for 3 to 30 minutes and storage under harsh conditions of 60°C and 80% RH for 4 weeks and the difference between the amount of flexible substances before harsh conditions treatment and the amount of flexible substances before harsh conditions treatment is 0.45% or less. Pharmaceutical containers.