Pharmaceutical containers comprising a liquid pharmaceutical composition of 1 - (5 - (2, 4-difluorophenyl) - 1 - ((3-fluorophenyl) sulphonyl) - 4-methoxy - 1h - pyrrol-3-yl) - n-methylmethanamine

Abstract

To provide a vessel for stably storing a medicine containing a liquid pharmaceutical composition of 1 - (5 - (2, 4-difluorophenyl) - 1 - ((3-fluorophenyl) sulphonyl) - 4-methoxy - 1H - pyrrol-3-yl) - N-methylmethanamine, or pharmaceutically acceptable salts thereof, for a long period of time.SOLUTION: A pharmaceutical composition comprising 1 - (5 - (2, 4-difluorophenyl) - 1 - ((3-fluorophenyl) sulphonyl) - 4-methoxy - 1H - pyrrol-3-yl) - N-methylmethanamine, or pharmaceutically acceptable salts thereof, wherein the pharmaceutical composition is a plastic vessel; a glass vessel whose inside is coated with silicone oil, SiO2, or SiOCH; or a dealkalized glass vessel.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority based on Korean Patent Application No. 10-2021-0067635, filed May 26, 2021, and Korean Patent Application No. 10-2022-0064452, 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 pharmaceutical container containing a liquid pharmaceutical composition of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. [Background technology]

[0003] 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. It has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori (H. pylori) eradication activity, and GPCR inhibitory activity, and is therefore useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0004] However, the present inventors have confirmed that the stability of the composition decreases when stored for a long period of time as a liquid formulation, and as a result of extensive research into the cause of this long-term stability problem, have found that the substance reacts with an acid or a base to increase the amount of decomposition products. In particular, the acid / base reaction accelerates during moist heat sterilization, dry sterilization, and other high-temperature sterilization processes that are generally required in the manufacturing process of liquid dosage forms, making it difficult to develop a stable liquid dosage form containing Chemical Formula 1 described below.

[0005] Therefore, the inventors of the present invention have realized 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 in a standard glass vial as a liquid formulation for a long period of time, the alkaline substance on the inner surface of the vial may react with the solution, making it difficult to ensure stability and leading to significant difficulties in commercialization. As a result, they have striven to provide a pharmaceutical container for long-term stable storage. As a result, they have found that when a container made of a specific material is used, the reaction between the pharmaceutical composition and the container is minimized, making it easy to store, and it is possible to provide a pharmaceutical product in the form of a ready-to-use liquid for injection, and that the pharmaceutical product remains stable even after high-temperature sterilization, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a pharmaceutical container containing 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. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention provides a pharmaceutical container which contains a liquid pharmaceutical composition comprising a compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof, and which is a plastic container; a glass container the interior of which is coated with silicone oil, SiO2, or SiOCH; or a dealkalized glass container. [ka]

[0008] 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.

[0009] The compound represented by Chemical Formula 1 is an active ingredient that exhibits the pharmacological effects of the liquid pharmaceutical composition 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.

[0010] In addition to the compound represented by Chemical Formula 1, pharmaceutically acceptable salts thereof may also be used as the active ingredient exhibiting the pharmacological effects of the liquid pharmaceutical composition 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, may 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 is relatively non-toxic and harmless to patients, does not exhibit side effects that diminish the beneficial efficacy of the compound.

[0011] Pharmaceutically acceptable salts can be prepared using inorganic or organic acids in a conventional manner. 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 salt can be prepared by reducing the pressure on the reaction mixture to which the acid has been added, removing the solvent and excess acid, and drying the residue, or by adding another organic solvent and filtering the precipitated salt. Preferred salts include those 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.

[0012] Meanwhile, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may react with an acid or base to increase decomposition products. Therefore, when the liquid pharmaceutical composition is stored in a standard container for a long period of time, alkaline substances present on the inner surface of the container may react with the solution. This reaction is particularly vigorous when a standard glass container is used. Therefore, to facilitate long-term storage of the liquid formulation, the pharmaceutical container containing the liquid pharmaceutical composition may be a plastic container, a glass container functionally coated with a specific substance, 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). A cyclic olefin polymer may be used. Silicone oil, SiO2, or SiOCH, which are less reactive with the liquid formulation, may be used as the inner coating material for the glass container. A dealkalized glass container, in which the interior of a general glass container is acid-treated to remove alkaline substances from the interior surface of the container, may also be used. By coating or treating the liquid pharmaceutical composition with a specific material or using a container made of a specific material, the stability of the liquid pharmaceutical composition is increased, making it possible to commercialize the composition and it can also be useful as a ready-to-use liquid for injection.

[0013] In addition, acid / base reactions may be accelerated during moist heat sterilization, dry sterilization, and other high-temperature sterilization processes generally required for liquid dosage forms, but the stability of the compound can be maintained even during these processes if a specific container is used.

[0014] On the other hand, the liquid pharmaceutical composition may preferably further comprise a cyclodextrin and an isotonicity agent.

[0015] 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 a liquid pharmaceutical composition, e.g., an injectable pharmaceutical composition. However, excessive solubilizer may cause hypersensitivity upon administration to a patient. Therefore, in the present invention, instead of using a solubilizer typically used in liquid pharmaceutical compositions, the above-mentioned components are used to produce a liquid pharmaceutical composition having excellent solubility and stability of the compound represented by Chemical Formula 1.

[0016] The cyclodextrin 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. Most preferably, the beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD).

[0017] Generally, among the stabilizers used in liquid pharmaceutical compositions, the cyclodextrin is suitable for stabilizing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0018] 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 liquid pharmaceutical composition 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 liquid pharmaceutical composition or causing hypersensitivity upon administration to patients.

[0019] 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.

[0020] Meanwhile, the "isotonicity agent" is an additive added to the container to make the osmotic pressure of the liquid pharmaceutical composition similar to that of the body. Since liquid pharmaceutical compositions are directly administered to the body without a separate dilution process, they must be prepared to have the same osmotic pressure as the body to reduce side effects upon administration. Preferably, the isotonicity agent is 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).

[0021] The amount of the isotonicity agent required to achieve the desired osmolarity of the liquid pharmaceutical composition 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 liquid pharmaceutical composition according to the present invention is 100 to 700 mOsmol / L, depending on the specific type of agent. More preferably, the osmolarity of the liquid pharmaceutical composition may be 150 to 650 mOsmol / L, 150 to 450 mOsmol / L, 250 to 450 mOsmol / L, or 270 to 420 mOsmol / L.

[0022] Preferably, the liquid pharmaceutical composition may further comprise a lyophilization aid. Generally, liquid pharmaceutical compositions are mass-produced, frozen, 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 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.

[0023] 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 liquid pharmaceutical composition 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 liquid pharmaceutical composition or causing hypersensitivity when administered to a patient.

[0024] 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.

[0025] Preferably, the freeze-drying adjuvant is used in an amount of 0.5 to 5.0 parts by weight relative to 1 part by weight of the cyclodextrin, and more preferably, the freeze-drying adjuvant 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, and is 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, a solvent commonly used in the art to which the present invention pertains can be used to prepare the liquid pharmaceutical composition, for example, distilled water, water for injection, acetate buffer, or saline.

[0027] 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. Depending on the chemical properties of the liquid pharmaceutical composition according to the present invention, an additional pH adjuster may not be used to adjust the pH. Here, a pH adjuster is a substance that adjusts the pH of the solution by adding it to improve 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.

[0028] Preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is contained in the liquid pharmaceutical composition in an amount 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 liquid pharmaceutical composition.

[0029] More preferably, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is present 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; or 7 mg / mL or less, 6 mg / mL or less, or 5.5 mg / mL or less.

[0030] Meanwhile, the "amount of related substances" described below is analyzed using the related substances test method established based on ICH Guideline Q2 Analytical Validation, and the total amount of related substances is calculated using the proportional formula between the concentration of a standard product of known purity and the peak area measured by HPLC, and the concentration of the test solution and the peak area of ​​related substances measured by HPLC. Specifically, the "amount of related substances (%)" is calculated as "(concentration of standard solution (mg / mL) / concentration of test solution (mg / mL)) * (peak area of ​​related substances in test solution / peak area of ​​standard solution) * 100."

[0031] When the pharmaceutical container is stored under harsh conditions of 60°C and 80% RH for 4 weeks, the amount of related substances generated in the liquid pharmaceutical composition may be 0.5% or less. Preferably, the amount of related substances in the liquid pharmaceutical composition in the pharmaceutical container after storage 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.

[0032] Furthermore, the difference between the amount of related 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 related substances before the harsh conditions treatment may be 0.45% or less. Preferably, the difference between the amount of related substances in the liquid pharmaceutical composition measured after storing the pharmaceutical container for 4 weeks and the amount of related 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.

[0033] Preferably, the amount of related 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 related substances in the liquid pharmaceutical composition in the pharmaceutical container stored under harsh conditions for 4 weeks after heat sterilization may be 0.48% or less, 0.47% or less, 0.46% or less, or 0.45% or less. More preferably, the heat sterilization conditions may be 121°C for 15 minutes, 126°C for 10 minutes, or 134°C for 3 minutes.

[0034] Preferably, the difference between the amount of related 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 related substances before the harsh condition treatment may be 0.45% or less. Preferably, the difference between the amount of related substances in the liquid pharmaceutical composition measured after the heat sterilization and storage for 4 weeks and the amount of related substances before the harsh condition 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 conditions may be 121°C for 15 minutes, 126°C for 10 minutes, or 134°C for 3 minutes.

[0035] If necessary, the liquid pharmaceutical composition 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.

[0036] In addition, the liquid pharmaceutical composition according to the present invention can be prepared by mixing the above-mentioned components, excluding the solvent, with 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 before being added to the solvent. [Effects of the Invention]

[0037] As described above, the pharmaceutical container of the present invention is capable of stably storing 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, and the pharmaceutical container containing the liquid pharmaceutical composition can be useful as a ready-to-use solution for injection. DETAILED DESCRIPTION OF THE INVENTION

[0038] 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]

[0039] As shown in Table 1 below, a liquid pharmaceutical composition containing the hydrochloride salt of the compound represented by Chemical Formula 1 above (hereinafter referred to as "API") was prepared.

[0040] [Table 1]

[0041] Each preparation was filled into a vial made of a different material as shown in Table 2 below, and stored in a chamber under severe conditions (60°C, 80% RH) in liquid form for 4 weeks, after which the stability was evaluated and the results are shown in Table 3. Stability was evaluated by analyzing the amount of related substances in the liquid solution by HPLC, and the amount of total related substances detected was measured.

[0042] Specifically, the amount of related substances was analyzed using the related substance test method established based on ICH Guideline Q2 Analytical Validation, and the total amount of related substances was calculated using the proportional formula between the concentration of a standard product of known purity and the peak area measured by HPLC, and the concentration of the test solution and the peak area of ​​related substances measured by HPLC.

[0043] The plastic vials used for #2-9 and #2-10 in Table 2 below are Daikyo Crystal Zenith vials.

[0044] [Table 2]

[0045] [Table 3]

[0046] As shown in Table 3, when each container was stored in a liquid solution state under harsh conditions for 4 weeks, there was no change in the properties, and it was confirmed that the functional container of an embodiment of the present invention produced a relatively lower amount of total related substances than the comparative examples #2-1 and #2-2, which used ordinary glass vials. In other words, it was confirmed that the liquid solution was stable when stored in the pharmaceutical container of an embodiment of the present invention. [Example]

[0047] We attempted to confirm whether the same long-term stability improvement effect would be achieved for compositions that have undergone moist heat sterilization (sterilization at 121°C for 15 minutes), which is necessary during the liquid dosage form manufacturing process but can accelerate reactivity with acids and bases.

[0048] A liquid composition was produced in the same manner as in Example 1, and its stability was evaluated in the same manner as in Example 1.

[0049] The acid-treated glass vial is a dealkalized vial in which the inner surface of a general glass vial is treated with an acid to remove alkaline substances.

[0050] [Table 4]

[0051] [Table 5]

[0052] As shown in Table 5, when moist heat sterilization was not applied, the properties of each container were not changed when stored in a liquid solution state under harsh conditions for 4 weeks. However, it was confirmed that the functional containers of an embodiment of the present invention (#3-2 and #2-4) produced relatively less total related substances than the comparative example #2-1 using a general glass vial. In particular, it was confirmed that the containers that had been dealkalized had greater stability.

[0053] When moist heat sterilization, a step commonly required for liquid dosage forms, was applied, it was confirmed that there were more related substances before harsh conditions treatment than when moist heat sterilization was not applied, which suggests that acid / base reactivity increased during moist heat sterilization. Furthermore, when moist heat sterilization was applied, the increase in the amount of related substances in each vial after 4 weeks was higher than when moist heat sterilization was not applied, which is presumed to be due to increased alkaline activation on the vial's inner surface caused by the high temperature during moist heat sterilization. Nevertheless, acid-treated vials and inner-coated vials minimized the effects of this heat sterilization step and showed superior stability maintenance compared to regular vials, demonstrating the feasibility of commercializing liquid dosage forms containing Chemical 1.

[0054] From the above examples, it was confirmed that the liquid solution was stable when stored in the pharmaceutical container of one embodiment of the present invention.

Claims

1. The present invention includes a liquid pharmaceutical composition comprising a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: Plastic container; inside is silicone oil, SiO ２ or a glass container coated with SiOCH; or a dealkalized glass container, Pharmaceutical container. 【Chemistry 1】

2. The liquid pharmaceutical composition additionally comprises a cyclodextrin and a tonicity agent. The pharmaceutical container of claim 1.

3. the cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin; The tonicity agent is D-mannitol or sodium chloride (NaCl). The pharmaceutical container according to claim 2.

4. The liquid pharmaceutical composition has a pH of 4.0 to 6.

0. The pharmaceutical container of claim 1.

5. The amount of related substances in the liquid pharmaceutical composition is 0.5% or less as measured after storing the pharmaceutical container under harsh conditions of 60°C and 80% RH for 4 weeks. The pharmaceutical container of claim 1.

6. The difference between the amount of related 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 related substances before the harsh conditions treatment is 0.45% or less. The pharmaceutical container of claim 1.

7. The pharmaceutical container is heat sterilized at 100°C to 150°C for 3 to 30 minutes, and then stored under harsh conditions of 60°C and 80% RH for 4 weeks. After this, the amount of related substances in the liquid pharmaceutical composition is measured and is 0.5% or less. The pharmaceutical container of claim 1.

8. The pharmaceutical container is heat sterilized at 100°C to 150°C for 3 to 30 minutes, and then stored under harsh conditions of 60°C and 80% RH for 4 weeks. The difference between the amount of related substances in the liquid pharmaceutical composition measured after the harsh condition treatment and the amount of related substances before the harsh condition treatment is 0.45% or less. The pharmaceutical container of claim 1.

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