Injection formulation

Abstract

To provide a sugammadex sodium injection formulation that is capable of inhibiting increase or decrease of impurities such as analogs and can be stably stored for a long period of time.SOLUTION: An injection formulation includes: a medical container having an oxygen-permeable container that is filled with a sugammadex sodium aqueous solution containing sugammadex sodium as an active ingredient and sterilized with high-pressure steam; and a poorly oxygen-permeable packaging container; where (i) the medical container is accommodated and sealed in the poorly oxygen-permeable packaging container together with an oxygen absorber or (ii) the medical container is accommodated and sealed in the poorly oxygen-permeable packaging container purged with an inert gas.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to injectable liquid formulations. [Background technology]

[0002] Sugammadex sodium is a 6-mercapto-cyclodextrin derivative, and is a compound used to reverse muscle relaxation induced by rocuronium bromide or vecuronium bromide (Japanese Patent Publication No. 3880041 (WO 2001 / 040316)).

[0003] Currently available sugammadex sodium injection preparations are in vial preparations (100 mg / mL) containing 200 mg of sugammadex sodium in 2 mL vials, or 500 mg of sugammadex sodium in 5 mL vials, and when using the product, the liquid must be drawn from the vial into a syringe.

[0004] On the other hand, in recent years, from the viewpoints of preventing drug mix-ups and hospital infections, improving disposability, and reducing the burden on medical personnel, prefilled syringes, which are pharmaceutical products that are prefilled with drug solution, are used.The drug solution container of such prefilled syringes, that is, the material of the outer cylinder, is made of glass or various plastics.Compared to glass-made syringes, plastic prefilled syringes are lighter and less likely to break, and have the advantage of being able to perform dispensing work more safely in medical settings.

[0005] From the above viewpoint, it is desirable to make the injection preparation into a plastic prefilled syringe preparation. However, filling the drug into a plastic container may reduce the stability of the preparation. In addition, the plastic material of the syringe outer tube or the elastomer material of the gasket may cause some interaction with the drug, i.e., the drug may be adsorbed to the plastic, or the material components of the outer tube or gasket may be dissolved into the drug solution, so careful consideration is required for the formulation into a prefilled syringe.

[0006] It has been reported that sugammadex sodium contains 14 related substances as impurities (Bridion Injection 200 mg and 500 mg Injection Review Report (October 27, 2009, Pharmaceuticals and Food Safety Bureau, Inspection and Licensing Division)). It is known that the amount of related substances increases or decreases over time due to light exposure, so the drug must be stored in a dark place. It is also known that the amount of related substances may exceed the standard depending on the storage conditions. Furthermore, sugammadex sodium is considered to be stable against oxygen, and strict oxygen management has not been carried out during the manufacturing or storage of sugammadex injection preparations to date, and it is believed that the need for such management has not been recognized at all. Summary of the Invention

[0007] However, the present inventors have found that when a sugammadex sodium injection formulation is filled into a plastic syringe and stored for a long period of time, there is a problem that the formulation cannot be stored stably for a long period of time, and have discovered that the cause of this problem is that impurities increase or decrease over time due to the effect of oxygen.

[0008] Therefore, an object of the present invention is to provide a sugammadex sodium injection formulation which can suppress the increase or decrease of impurities such as related substances and can be stably stored for a long period of time.

[0009] The present inventors have conducted extensive research to solve the above problems. As a result, the present invention provides a medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium containing sugammadex sodium as an active ingredient and sterilized by high-pressure steam, A packaging container having poor oxygen permeability; (i) The medical container is housed in the poorly oxygen-permeable packaging container together with an oxygen scavenger and sealed; or (ii) The present inventors found that the above-mentioned problems can be solved by an injectable preparation, which is obtained by sealing the medical container in the poorly oxygen-permeable packaging container, which has been purged with an inert gas, and thus completed the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] An embodiment according to one aspect of the present invention will be described below, but the present invention is not limited to the following embodiment.

[0011] In this specification, the range "X to Y" means "X or more and Y or less." Furthermore, unless otherwise specified, operations and measurements of physical properties are performed at room temperature (1 to 30° C.).

[0012] <Injection preparations> One aspect of the present invention is a medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium containing sugammadex sodium as an active ingredient and sterilized by high-pressure steam; A packaging container having poor oxygen permeability; (i) The medical container is housed in the poorly oxygen-permeable packaging container together with an oxygen scavenger and sealed; or (ii) The injection preparation, which is obtained by sealing the medical container in the poorly oxygen-permeable packaging container, which has been purged with an inert gas.

[0013] The injectable liquid formulation of this form can suppress the increase or decrease of impurities such as sugammadex sodium analogues and can be stored stably for a long period of time.

[0014] As mentioned above, sugammadex sodium is considered to be stable against oxygen. Until now, strict and consistent control of oxygen has not been carried out during the manufacturing and storage of sugammadex injection preparations, and the need for such control has not been recognized at all.

[0015] However, the present inventors have found that when an aqueous solution of sugammadex sodium is filled into a plastic syringe and stored for a long period of time, impurities increase or decrease over time due to the influence of oxygen, and therefore the aqueous solution cannot be stably stored for a long period of time.

[0016] Therefore, the present inventors re-examined the effect of oxygen on the stability of sugammadex sodium in an aqueous solution of sugammadex sodium.

[0017] First, we investigated the increase or decrease in the amount of impurities in oxygen-permeable plastic syringes filled with an aqueous solution of sugammadex sodium after high-pressure steam sterilization under the introduction of inert gas or in an inert gas atmosphere, and after high-pressure steam sterilization in air. As a result, no increase or decrease in the amount of impurities after sterilization was observed, regardless of whether oxygen was removed from the sterilization atmosphere.

[0018] However, when the syringes were stored for a long period of time and the amount of impurities was measured, an increase or decrease in the amount of related substances was confirmed.

[0019] Therefore, the inventors speculated that since the increase or decrease in the amount of impurities does not depend on oxygen management during the high-pressure sterilization stage but occurs during the subsequent storage, sugammadex sodium does not react rapidly with oxygen but is a type of compound that reacts slowly with oxygen.

[0020] Therefore, in order to gradually but surely remove oxygen remaining in the aqueous solution of sugammadex sodium in the syringe and oxygen present outside the syringe, the present inventors sealed the syringe after high-pressure sterilization in an oxygen-impermeable bag together with an oxygen scavenger and stored it at 60°C for 3 weeks or at 40°C for 6 months. The syringe was also sealed in an oxygen-impermeable bag substituted with an inert gas and stored it at 60°C for 3 weeks or at 40°C for 6 months. When the aqueous solution of sugammadex sodium in the syringe was analyzed after 3 weeks or 6 months, it was confirmed that the increase or decrease of related substances was suppressed (see Examples).

[0021] (Medical containers) The injectable liquid preparation of this embodiment is provided with a medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium containing sugammadex sodium as an active ingredient and sterilized by high-pressure steam.

[0022] Sugammadex sodium has a structure in which a thiopropionic acid side chain is introduced to the 6-hydroxyl group of all glucose units of γ-cyclodextrin (cyclic glucose octamer). As the sugammadex sodium of this embodiment, any sugammadex sodium that can be used as an injection preparation can be used.

[0023] The sugammadex sodium aqueous solution according to this embodiment contains sugammadex sodium as an active ingredient. In this specification, "containing sugammadex sodium as an active ingredient" means containing the above sugammadex sodium in an amount sufficient to recover from the muscle relaxant state caused by curonium bromide or vecuronium bromide (i.e., an effective amount). In a preferred embodiment, the concentration of sugammadex sodium in the sugammadex sodium aqueous solution is 50 to 200 mg / mL. When the concentration of sugammadex sodium is 50 mg / mL or more, an increase in the amount of liquid administered to a patient can be suppressed. Also, when the concentration of sugammadex sodium is 200 mg / mL or less, sugammadex sodium can be sufficiently dissolved.

[0024] The pH of the sugammadex sodium aqueous solution is, for example, 7 to 8.

[0025] The sugammadex sodium aqueous solution contains water as a solvent. There are no particular limitations on the water, so long as it is pharmacologically and physiologically acceptable water. Examples of water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. The definition of water is based on the 17th revised edition of the Japanese Pharmacopoeia.

[0026] The sugammadex sodium aqueous solution may contain other ingredients, such as pH adjusting agents, isotonicity agents, antioxidants, buffering agents, analgesics, anti-inflammatory agents, antiemetic agents, antiepileptic agents, antidepressants, antiviral agents, polyols, complexing agents, alkanols, vitamins, in addition to sugammadex sodium and water.

[0027] In one embodiment, the sugammadex sodium aqueous solution contains at least one selected from a pH adjusting agent, an isotonicity agent, an antioxidant, and a buffering agent.

[0028] The pH regulator may be any pH regulator that is conventionally used in injections. Examples of pH regulators include bases such as sodium hydroxide and potassium hydroxide, inorganic acids such as hydrochloric acid, and organic acids such as citric acid, lactic acid, acetic acid, succinic acid, and malic acid.

[0029] The content of the pH adjuster can be appropriately adjusted so that the pH of the sugammadex sodium aqueous solution falls within the above-mentioned range.

[0030] The isotonicity agent may be any isotonicity agent that has been used in the past in injection preparations. Examples of the isotonicity agent include nonionic isotonicity agents such as mannitol, sorbitol, inositol, glucose, propylene glycol, and glycerol; and ionic isotonicity agents such as sodium chloride.

[0031] The content of the isotonic agent is preferably such that the osmotic pressure ratio of the sugammadex sodium aqueous solution becomes about 1 to 2 (ratio to physiological saline).

[0032] The antioxidant can be any antioxidant that is conventionally used in injection preparations. Examples of antioxidants include organic compounds having a thiol functional group such as cysteine, its salts or their hydrates (e.g., cysteine ​​hydrochloride hydrate), sulfites such as sodium hydrogen sulfite, ascorbic acid or its salts, dibutylhydroxytoluene, etc.

[0033] The buffering agent may be any buffering agent that is conventionally used in injection preparations. Examples of the buffering agent include phosphoric acid, its salts or their hydrates (such as sodium hydrogen phosphate hydrate), citric acid, its salts or its hydrates, acetic acid, its salts or its hydrates, etc.

[0034] The method for preparing the sugammadex sodium aqueous solution is not particularly limited, and the sugammadex sodium aqueous solution can be prepared by mixing sugammadex sodium and water, and, if necessary, other components.

[0035] The preparation of the sugammadex sodium aqueous solution is not particularly limited as long as the conditions are such that a uniformly dissolved sugammadex sodium aqueous solution can be obtained without alteration or decomposition of sugammadex sodium and other components.

[0036] The preparation of the sugammadex sodium aqueous solution can be carried out in the atmosphere (air), in an inert gas atmosphere, or in a mixed gas atmosphere of air and an inert gas. As the inert gas, nitrogen gas, argon gas, carbon dioxide gas, etc. can be used.

[0037] The sugammadex sodium aqueous solution according to the present embodiment is filled in a medical container having an oxygen-permeable container and sterilized under high pressure.

[0038] The medical container having an oxygen-permeable container may be a medical container in which the medical container itself is an oxygen-permeable container, or a medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium as a component.

[0039] The shape, size, etc. of the medical container are not particularly limited and can be appropriately selected depending on the amount of the sugammadex sodium aqueous solution to be filled, the purpose, the form of use, etc.

[0040] Examples of the form of the medical container include a syringe, a vial, a bag, an ampoule, a cartridge, a bottle, and the like, and a syringe or a vial is preferable.

[0041] When the medical container is a syringe, at least the outer cylinder constituting the syringe is an oxygen-permeable container, and when the medical container is a vial, at least the vial container constituting the vial is an oxygen-permeable container.

[0042] The material for forming the oxygen-permeable container is a resin, preferably a resin having excellent steam sterilization resistance, transparency, moldability and versatility. Examples of such resins include polyesters such as polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly-(4-methylpentene-1), acrylic resins, acrylonitrile-butadiene-styrene copolymers, and polyethylene terephthalate, and cyclic polyolefins such as cyclic olefin polymers (COP) and cyclic olefin copolymers (COC).

[0043] Examples of the cyclic olefin constituting the cyclic polyolefin include monocyclic cyclic olefins, polycyclic cyclic olefins, polycyclic cyclic olefins having a bridged structure, etc. One or more kinds of cyclic olefins can be used.

[0044] Examples of the cyclic olefin include substituted or unsubstituted norbornene-based monomers, substituted or unsubstituted tetracyclododecene-based monomers, substituted or unsubstituted dicyclopentadiene-based monomers, and cyclic polyolefins having a cyclohexyl group or a phenyl group in the side chain.

[0045] When the cyclic olefin copolymer is a copolymer of a cyclic olefin and a non-cyclic olefin, the non-cyclic olefin may be ethylene, propylene, butene, isobutylene, methylpentene, etc. One or more non-cyclic olefins may be used.

[0046] The cyclic polyolefin may be synthesized or may be a commercially available product, such as "ZEONEX (registered trademark)" (manufactured by Zeon Corporation), "ZEONOR (registered trademark)" (manufactured by Zeon Corporation), "APEL (registered trademark)" (manufactured by Mitsui Chemicals, Inc.), or "TOPAS (registered trademark)" (manufactured by Polyplastics Co., Ltd.).

[0047] From the viewpoint of exerting the effect of the present invention, the oxygen permeability of the material forming the oxygen permeable container is preferably 50 cm when measured at 23° C. and 90% RH. 3 / m 2 ·day·atm(120μm) or more.

[0048] When the injectable preparation of this form is packaged in a medical container together with an oxygen scavenger and sealed in an oxygen-impermeable packaging container, the oxygen permeability is 50 cm 3 / m 2 If the oxygen suction capacity is 120 μm or more, the oxygen contained in the sugammadex sodium aqueous solution, headspace, etc. in the oxygen-permeable container can be sufficiently absorbed through the oxygen-permeable container by the oxygen scavenger while blocking the passage of air (oxygen) from outside the packaging container into the packaging container, thereby reducing the amount of oxygen in the oxygen-permeable container.

[0049] When the injectable preparation of this form is sealed in a medical container that is filled with an inert gas and has poor oxygen permeability, the oxygen permeability is 50 cm 3 / m 2 If the oxygen permeability is 1.0 MPa or more, the oxygen contained in the sugammadex sodium aqueous solution, headspace, etc. in the oxygen permeable container is gradually replaced by inert gas in the poorly oxygen permeable packaging container, thereby reducing the amount of oxygen in the oxygen permeable container.

[0050] The upper limit of the oxygen permeability of the material forming the oxygen-permeable container is not particularly limited.

[0051] The oxygen permeability of the material forming the oxygen-permeable container is a value measured by the method described in the Examples.

[0052] In one embodiment, the medical container is a syringe, and the oxygen permeable container is the resin outer cylinder that constitutes the syringe.From the viewpoint of ease of molding, heat resistance, drug stability, etc., the resin is preferably polypropylene (PP) or cyclic polyolefin, more preferably polypropylene.Therefore, the medical container of this embodiment is preferably a plastic prefilled syringe.

[0053] The syringe may have a gasket made of an elastomer. The elastomer is not particularly limited, and examples thereof include rubbers (particularly vulcanized ones) such as natural rubber, isoprene rubber, chlorinated or brominated butyl rubber, chloroprene rubber, nitrile-butadiene rubber, styrene-butadiene rubber, and silicone rubber; thermoplastic elastomers such as styrene-based elastomers, hydrogenated styrene-based elastomers, polyvinyl chloride-based elastomers, olefin-based elastomers, polyester-based elastomers, polyamide-based elastomers, and polyurethane-based elastomers; and mixtures of styrene-based elastomers, polyolefins such as polyethylene, polypropylene, polybutene, and α-olefin polymers, oils such as liquid paraffin and process oil, and powdered inorganic materials such as talc, cast, and mica. The elastomer may be one type alone or a mixture of two or more types.

[0054] The elastomer is preferably butyl rubber or a thermoplastic elastomer, more preferably butyl rubber or a styrene-based elastomer, from the viewpoints of having elastic properties and being capable of being sterilized by gamma rays, electron beams, and high-pressure steam.

[0055] It is preferable that the gasket that constitutes the syringe be in a form that fits tightly against the inside of the barrel, seals the rear end opening side of the internal space of the barrel, is easily slidable within the barrel, and allows a plunger to be attached to its rear end.

[0056] The aqueous solution of sugammadex sodium can be filled into the oxygen-permeable container according to a conventional method. The filling can be carried out in the atmosphere (air), in an inert gas atmosphere, or in a mixed gas atmosphere of air and an inert gas. As the inert gas, nitrogen gas, argon gas, carbon dioxide gas, etc. can be used.

[0057] The medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium is sterilized by high-pressure steam. The method of high-pressure steam sterilization is not particularly limited, and a conventionally known method can be used. Steam can be used as a sterilization medium for high-pressure steam sterilization. A mixed gas of an inert gas and air or air can be used as a pressurized medium for high-pressure steam sterilization. That is, high-pressure steam sterilization may be performed using steam as a sterilization medium and air as a pressurized medium, or using steam as a sterilization medium and an inert gas as a pressurized medium, or using steam as a sterilization medium and a mixed gas of air and an inert gas as a pressurized medium.

[0058] Inert gases used in high-pressure steam sterilization include nitrogen gas, argon gas, carbon dioxide gas, etc., with nitrogen gas being preferred because it is inexpensive.

[0059] The sterilization conditions such as temperature, pressure, and time during high-pressure steam sterilization may be the same as those usually used for sterilizing injection preparations. For example, the temperature is usually 100 to 129°C, preferably 115 to 124°C.

[0060] The method for producing the oxygen-permeable container and medical container is not particularly limited, and a known method such as injection molding, extrusion molding, blow molding, rotational molding, blow molding, transfer molding, press molding, solution casting, etc. can be appropriately selected depending on the type and shape of the material forming the oxygen-permeable container and medical container.

[0061] (Oxygen-impermeable packaging container) The injectable liquid preparation of this embodiment is provided with a poorly oxygen-permeable packaging container.

[0062] The poorly oxygen-permeable packaging container according to the present embodiment is a container capable of storing and sealing the medical container and is not particularly limited as long as it is a non-toxic container. In addition, the poorly oxygen-permeable packaging container may be a soft container or a hard container.

[0063] From the viewpoint of exerting the effect of the present invention more effectively, the oxygen permeability of the material forming the oxygen-impermeable packaging container is preferably 1.0 cm or less when measured at 23° C. and 90% RH. 3 / m 2 ·day·atm or less, and more preferably 0.3cm 3 / m 2 ·day·atm or less, and more preferably 0.1 cm 3 / m 2 ·day·atm or less.

[0064] The lower the oxygen permeability of the material forming the oxygen-impermeable packaging container, the more easily oxygen contained in the sugammadex sodium aqueous solution, headspace, etc. filled in the oxygen-permeable container can be removed by being absorbed by an oxygen scavenger or replaced with an inert gas, which is preferable.

[0065] The oxygen permeability of the material forming the poorly oxygen-permeable packaging container is a value measured by the method described in the Examples.

[0066] The material for forming the oxygen-impermeable packaging container is not particularly limited as long as it has a certain degree of strength and hardness and has oxygen barrier properties. Examples of such materials include metal foils such as aluminum, gold, and silver, metal-deposited films and sheets such as aluminum, gold, and silver, inorganic-deposited films and sheets such as SiOx, films and sheets formed from polyvinylidene chloride, polyvinylidene chloride-polyvinyl chloride, polyvinylidene chloride-acrylic acid ester copolymers, ethylene-vinyl alcohol copolymers, high-density polyethylene, and the like.

[0067] Examples of materials for the substrate of the metal vapor deposition film, metal vapor deposition sheet, inorganic vapor deposition film and inorganic vapor deposition sheet include polyolefin resins such as polypropylene and polyethylene, polyamide, polyvinyl chloride, polyester, and polystyrene / polypropylene resin.

[0068] The material forming the oxygen-impermeable packaging container may be a laminate. At least one layer of the laminate contains the material having the oxygen barrier property. The materials of the other layers constituting the laminate are not particularly limited.

[0069] In one embodiment of the present invention, the poorly oxygen-permeable packaging container is formed from a poorly oxygen-permeable film or sheet.

[0070] Materials for forming oxygen-impermeable films or sheets include metal foils such as aluminum, silver, and gold, metal-deposited films with aluminum, silver, gold, etc., deposited on their surfaces, and SiO X and oxygen barrier resin films (for example, films of polyvinylidene chloride, polyvinylidene chloride-polyvinyl chloride, polyvinylidene chloride-acrylic acid ester copolymer, ethylene-vinyl alcohol copolymer, high density polyethylene, etc.).

[0071] Examples of materials for the substrate of the metal vapor deposition film, metal vapor deposition sheet, inorganic vapor deposition film and inorganic vapor deposition sheet include polyolefin resins such as polypropylene and polyethylene, polyamide, polyvinyl chloride, polyester, and polystyrene / polypropylene resin.

[0072] Since the oxygen-refractory film or sheet is often folded and the periphery heat-sealed to form a packaging container, it is preferable that the portion that will become the innermost surface when folded is formed from at least a heat-sealable adhesive resin layer (e.g., polyolefin resins such as polypropylene and polyethylene, polystyrene / polypropylene resin, ethylene-vinyl acetate resin, ethylene-acrylic acid resin, polyvinyl chloride resin, various thermoplastic elastomers).

[0073] Specific examples of materials that can be used in the present invention as materials for packaging containers with poor oxygen permeability include, but are not limited to, · Multilayer film or sheet made of polypropylene (PP) / silica-deposited polyethylene terephthalate (PET) / polypropylene (PP) laminated in that order; ·Multilayer film or sheet made of biaxially oriented polyamide (OPA) / polyethylene (PE) / aluminized PET / polyethylene (PE) laminated in that order; ·Multi-layer film or sheet made of OPA / PE / aluminized PET / PE laminated in that order; ·Multi-layer film or sheet made by laminating OPA / PE / aluminum foil / PE / PE in this order; ·Multi-layer film or sheet made of OPA / PE / aluminum foil / PE / PET / PE laminated in this order; · Multilayer film or sheet made of PET / PE / aluminized PET / PE / ethylene-vinyl acetate copolymer (EVA) / PE in that order; ·Multilayer film or sheet made of polyvinylidene chloride / PE / aluminized PET / PE laminated in that order; · Multilayer film or sheet made of PET / aluminized ethylene-vinyl alcohol copolymer (EVOH) / PE laminated in that order; · Multilayer film or sheet made of biaxially oriented nylon (ONY) / EVOH / PE laminated in that order; Some examples include:

[0074] Examples of the oxygen-impermeable packaging container according to this embodiment include a blister container, a bag, a tube, and the like.

[0075] The method for producing the poorly oxygen-permeable packaging container is not particularly limited, and a known method can be appropriately selected depending on the type and shape of the material forming the poorly oxygen-permeable packaging container.

[0076] In one embodiment, the poorly oxygen-permeable packaging container is formed from a packaging container body having a recess for accommodating a medical container, and a peelable sealing film that seals the opening of the recess of the packaging container body.

[0077] The material for the packaging container body preferably has a certain degree of strength and hardness, and examples of such materials include polyolefin resins such as polypropylene and polyethylene, polyvinyl chloride, polyester, and polystyrene / polypropylene resin, and examples of such materials include a laminate of a layer of such a resin and a layer of a resin with poor oxygen permeability (e.g., polyvinylidene chloride, ethylene-vinyl alcohol copolymer, polyethylene terephthalate, etc.).

[0078] A sealing film is airtightly attached to the upper surface of the packaging container body so as to seal the medical container storage recess. The sealing film is preferably formed of an oxygen barrier film, an adhesive resin layer attached to at least the outer periphery of the lower surface of the oxygen barrier film, and a surface protection layer provided on the upper surface of the oxygen barrier film. The oxygen barrier film suppresses the transmission of oxygen from the outside of the packaging container. Examples of the oxygen barrier film include metal foils such as aluminum, silver, and gold, metal deposition films with aluminum, silver, gold, etc. deposited on the surface, SiO X and oxygen barrier resin films (for example, films of polyvinylidene chloride, polyvinylidene chloride-polyvinyl chloride, polyvinylidene chloride-acrylic acid ester copolymer, ethylene-vinyl alcohol copolymer, high density polyethylene, etc.).

[0079] The adhesive resin layer is for heat-sealing the oxygen barrier film and the packaging container body in a peelable manner, and various easy peeling mechanisms can be used, such as the following. For example, when polypropylene is used on the heat-sealed surface of the packaging container body, olefin resins such as ethylene-vinyl acetate resins, ethylene-acrylic acid resins, and blends of polypropylene and polyethylene, and two-component curing urethane dry laminate adhesives can be suitably used as the adhesive resin layer. When polyvinyl chloride is used as the packaging container body, olefin resins such as ethylene-vinyl acetate resins and ethylene-acrylic acid resins, blends of polystyrene with styrene-butadiene block copolymers, vinyl chloride-vinyl acetate copolymers, and two-component curing urethane dry laminate adhesives can be suitably used as the adhesive resin layer. When polyester is used as the packaging container body, olefin resins such as ethylene-vinyl acetate resins and ethylene-acrylic acid resins, copolyesters, and two-component curing urethane dry laminate adhesives can be suitably used.

[0080] The surface protective layer is preferably formed by coating a synthetic resin (e.g., polyester, polypropylene, polyethylene, nylon, polyethylene terephthalate (PET), epoxy resin, polyamide resin) or by laminating the above-mentioned synthetic resin film, paper, etc. The surface protective layer can also be used as a printing layer for recording necessary information such as the name and filling amount of the drug filled in the medical container having the oxygen-permeable container to be stored. A light-shielding material such as white ink may be interposed between the surface protective layer and the oxygen barrier film to form a light-shielding film.

[0081] Specific examples of sealing films include a film (oxygen barrier specification) formed from four layers of polyethylene terephthalate / ethylene-vinyl alcohol copolymer / oriented nylon / adhesive resin, and a film formed from three layers of polyethylene terephthalate / oriented nylon / adhesive resin.

[0082] The method for producing the poorly oxygen-permeable packaging container is not particularly limited, and any conventionally known method can be used.

[0083] (Placement and sealing of medical containers in oxygen-impermeable packaging containers) The injectable preparation of this form comprises a medical container having the oxygen-permeable container and the poorly oxygen-permeable packaging container, and (i) the medical container is housed in the poorly oxygen-permeable packaging container together with an oxygen scavenger and sealed; or (ii) the medical container is housed in the poorly oxygen-permeable packaging container whose atmosphere has been replaced with an inert gas and sealed.

[0084] In one embodiment, the medical container is contained and sealed in the poorly oxygen-permeable packaging container together with an oxygen scavenger.

[0085] The oxygen scavenger according to the present embodiment is not particularly limited as long as it does not pose problems such as toxicity during use and can efficiently absorb oxygen to reduce the amount of oxygen in the atmosphere.

[0086] Examples of oxygen scavengers include iron compounds such as iron hydroxide, iron oxide, and iron carbide; oxygen scavengers based on inorganic substances such as nitrites and metal halides; oxygen scavengers based on organic substances such as ascorbic acid and polyphenols; and oxygen scavengers that utilize the enzymatic action of glucose and glucose oxidase.

[0087] The oxygen scavenger may be one that absorbs oxygen and carbon dioxide gas at the same time, or one that absorbs oxygen and releases carbon dioxide gas.

[0088] The form of the oxygen absorber is not particularly limited as long as it is non-toxic and exhibits excellent oxygen absorbing properties. For example, an oxygen-permeable container in which the above-mentioned substance having oxygen absorbing properties is enclosed, a film in which the oxygen absorber is kneaded, a molded container using an oxygen absorber, a laminated structure in which both surface layers are oxygen-impermeable layers and an oxygen-absorbing layer is disposed inside the layers, and oxygen is absorbed from the side of the laminate, etc. can be used.

[0089] Commercially available oxygen absorbers include Ageless (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.), Moduran (manufactured by Nippon Kayaku Food Techno Co., Ltd.), and Secur (registered trademark) (manufactured by Nisso Fine Co., Ltd.).

[0090] The oxygen scavenging performance of the oxygen scavenger is as follows: for 2 mL or 5 mL of sugammadex sodium aqueous solution filled in an oxygen permeable container, the oxygen scavenging performance is 10 cm3 at room temperature (25°C), atmospheric pressure, and for 20 hours. 3 More than 20cm, preferably 20cm 3 An oxygen scavenger capable of absorbing the above amount of oxygen is preferred. Specifically, the oxygen scavenger “Ageless (registered trademark) Z-10PTR” (oxygen absorption capacity = 10 cm3) manufactured by Mitsubishi Gas Chemical Company, Inc. 3 / 20 hours or more (atmospheric pressure)), Mitsubishi Gas Chemical Company, Inc.'s "Ageless (registered trademark) Z-20PT" (oxygen absorption capacity = 20 cm 3 / 20 hours or more (atmospheric pressure)).

[0091] The medical container can be placed in the poorly oxygen-permeable packaging container and sealed in a conventional manner. The placement and sealing can be carried out in the atmosphere (air), in an inert gas atmosphere, or in a mixed gas atmosphere of air and inert gas. The placement and sealing can also be carried out after replacing the atmosphere in the poorly oxygen-permeable packaging container with an inert gas.

[0092] In one embodiment, the medical container is housed and sealed in the poorly oxygen-permeable packaging container, which has been substituted with an inert gas.

[0093] Examples of the inert gas in this embodiment include nitrogen gas, argon gas, and carbon dioxide gas, and nitrogen gas is preferred.

[0094] The method for replacing the inside of the poorly oxygen-permeable packaging container with an inert gas is not particularly limited, and any known method can be adopted. In addition, the placement and sealing of the medical container in the poorly oxygen-permeable packaging container is not particularly limited as long as it is in an inert gas atmosphere, and any known method can be adopted. EXAMPLES

[0095] The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. Unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[0096] Example 1 (1) 10 g of sugammadex sodium was added to and dissolved in water for injection, and then water for injection was added to make the total volume 100 mL to obtain a 100 mg / mL aqueous solution of sugammadex sodium (pH about 7.5). (2) 2 mL of the sugammadex sodium aqueous solution obtained in (1) above was filled into a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of butyl rubber) and sealed to obtain a container containing the sugammadex sodium aqueous solution. (3) The container containing the sugammadex sodium aqueous solution obtained in (2) above was subjected to high-pressure steam sterilization (121°C, 20 minutes) using nitrogen gas as the pressure medium. (4) The container containing the sugammadex sodium aqueous solution after high-pressure steam sterilization obtained in (3) above and an oxygen scavenger (Ageless (registered trademark), manufactured by Mitsubishi Gas Chemical Company, Inc.) were packaged in a bag (a three-layer film consisting of, from the outer layer, a biaxially oriented nylon (ONY) layer (15 μm), an ethylene-vinyl alcohol copolymer (EVOH) layer (15 μm), and a polyester (PE) layer (50 μm)) to produce an injectable formulation.

[0097] Example 2 An injectable liquid preparation was produced in the same manner as in Example 1, except that in (3) of Example 1, air was used as the pressurized medium instead of nitrogen gas.

[0098] Example 3 An injectable liquid formulation was prepared in the same manner as in Example 1, except that in (2) of Example 1, a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP); gasket: made of butyl rubber) was used instead of a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP); gasket: made of styrene-based thermoplastic elastomer).

[0099] Example 4 An injectable liquid formulation was prepared in the same manner as in Example 2, except that a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of butyl rubber) was used instead of the 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of styrene-based thermoplastic elastomer).

[0100] Example 5 (1) A container containing an aqueous solution of sugammadex sodium was obtained in the same manner as in (1) and (2) of Example 1. (2) The container containing the sugammadex sodium aqueous solution obtained in (1) above was subjected to high-pressure steam sterilization (121°C, 20 minutes) using air as the pressurizing medium. (3) The containers containing the sugammadex sodium aqueous solution after high-pressure steam sterilization obtained in (2) above were packaged in a bag (a three-layer film consisting of, from the outer layer, a biaxially oriented nylon (ONY) layer (15 μm), an ethylene-vinyl alcohol copolymer (EVOH) layer (15 μm), and a polyester (PE) layer (50 μm)), after which the inside of the bag was replaced with nitrogen gas, to produce an injectable formulation.

[0101] Example 6 An injectable liquid formulation was prepared in the same manner as in Example 5, except that in (1) of Example 5, a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP); gasket: made of butyl rubber) was used instead of a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP); gasket: made of styrene-based thermoplastic elastomer).

[0102] Example 7 An injectable liquid formulation was prepared in the same manner as in Example 2, except that a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of butyl rubber) was used instead of the 2.5 mL plastic syringe (outer cylinder: made of cyclic olefin polymer (COP), gasket: made of butyl rubber) in Example 2.

[0103] Example 8 An injectable liquid formulation was prepared in the same manner as in Example 5, except that a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of butyl rubber) was used instead of the 2.5 mL plastic syringe (outer cylinder: made of cyclic olefin polymer (COP), gasket: made of butyl rubber) in Example 5.

[0104] Comparative Example 1 An injectable formulation was produced in the same manner as in Example 1, except that in (4) of Example 1, no oxygen scavenger was used and the container containing the aqueous sugammadex sodium solution after high-pressure steam sterilization was packaged in a low-density polyethylene (LDPE) (40 μm) bag.

[0105] Comparative Example 2 An injectable liquid formulation was prepared in the same manner as in Comparative Example 1, except that a 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of butyl rubber) was used instead of the 2.5 mL plastic syringe (outer cylinder: made of polypropylene (PP), gasket: made of styrene-based thermoplastic elastomer).

[0106] (Reference example 1) (1) In the same manner as in Example 1(1), a 100 mg / mL aqueous solution of sugammadex sodium was obtained (pH about 7.5). (2) 2 mL of the sugammadex sodium aqueous solution obtained in (1) above was filled into a 2.0 mL glass vial and sealed to obtain a container containing the sugammadex sodium aqueous solution. (3) The glass vial containing the sugammadex sodium aqueous solution obtained in (2) above was sterilized by high-pressure steam (121°C, 20 minutes) using nitrogen gas as a pressure medium to produce an injectable preparation.

[0107] (Oxygen permeability measurement) The oxygen permeability of the material (thickness 120 μm) forming the outer cylinder and the material (bag) forming the packaging container used in Examples 1 to 8 and Comparative Examples 1 and 2 was measured using an oxygen permeability measuring device (OX-TRAN (registered trademark) MODEL2 / 21 manufactured by MOCON) under conditions of a temperature of 23°C and a humidity of 90% RH.

[0108] The characteristics of the injectable preparations produced in Examples 1 to 8, Comparative Examples 1 and 2, and Reference Example 1 are summarized in Table 1.

[0109] [Table 1]

[0110] (Test Example 1) Stability test: Residual rate of sugammadex sodium The injection preparations prepared in Examples 1 to 6, Comparative Examples 1 and 2, and Reference Example 1 were stored for 3 weeks at 60° C. The residual rate (%) of sugammadex sodium after 3 weeks relative to the start of the test was measured (the values ​​in the table are the average values ​​of n=2).

[0111] [Method for measuring residual rate of sugammadex sodium] Immediately before the start of the test and after 3 weeks, 1 mL of the sugammadex sodium aqueous solution in the injection formulation was accurately measured and made up to exactly 50 mL with water. 2 mL of this solution was accurately measured and made up to exactly 100 mL with water to obtain the sample solution.

[0112] 20 mg of sugammadex sodium standard was precisely weighed and dissolved in water to make exactly 100 mL. 10 mL of this solution was precisely weighed and water was added to make 50 mL to obtain the standard solution.

[0113] 50μL of each of the sample solution and standard solution was subjected to liquid chromatography (HPLC) under the following conditions. The peak area of ​​each sample was measured by automatic integration method, and the content (%) of sugammadex sodium was calculated by area percentage method. Furthermore, for the sugammadex sodium in the injection preparation after 3 weeks, the remaining rate (%) was calculated when the content of sugammadex sodium in the injection preparation immediately before the start of the test was set as 100%. In addition, the remaining rate (%) of sugammadex sodium was calculated by correcting the amount of evaporation of the oral solution during storage.

[0114] Detection Conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: 3.90 g of sodium dihydrogen phosphate dihydrate was dissolved in 900 mL of water, diluted phosphoric acid solution (1 → 10) was added to adjust the pH to 3.0, and water was added to make 1000 mL. 200 mL of acetonitrile was added to 800 mL of this solution. Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B. Flow rate: 0.5mL per minute.

[0115] The results are shown in Table 2.

[0116] [Table 2]

[0117] As shown in Table 2, the results of the injection preparations of the Examples and Comparative Examples were similar to those of the injection preparation contained in the glass vial (Reference Example 1), and it is understood that sugammadex sodium was stably maintained. Note that the increase in the residual rate of sugammadex sodium is thought to be due to the effect of evaporation of the internal solution during storage, so the residual rate of sugammadex sodium corrected based on the amount of evaporation of the internal solution during storage is shown.

[0118] (Test Example 2) Stability test: pH For the injection preparations produced in Examples 1 to 6, Comparative Examples 1 and 2, and Reference Example 1, the pH of the aqueous solutions of sugammadex sodium immediately before storage and after storage at 60°C for 3 weeks was measured using a pH meter (manufactured by DKK-TOA Corporation). (The values ​​in the table are the average values ​​of n=2.) The results are shown in Table 3.

[0119] [Table 3]

[0120] As shown in Table 3, the injection preparations of the Examples and Comparative Examples showed the same results as the injection preparation contained in the glass vial (Reference Example 1), and it can be seen that the pH of the sugammadex sodium aqueous solution was kept stable.

[0121] (Test Example 3) Change in sugammadex sodium analogues in injection preparations The injectable preparations produced in Examples 1 to 6, Comparative Examples 1 and 2, and Reference Example 1 were stored at 60°C, and the rate of change (%) of sugammadex sodium analogues after 3 weeks from the start of the test was measured (the values ​​in the table are the average values ​​of n=2).

[0122] [Method for measuring changes in sugammadex sodium analogues] Just before the start of the test and after 3 weeks had elapsed, 1 mL of the aqueous solution of sugammadex sodium in the injection formulation was accurately measured, and water was added to make exactly 50 mL to obtain a sample solution.

[0123] 20 mg of sugammadex sodium standard substance was precisely weighed and dissolved in water to make exactly 100 mL to obtain a standard solution.

[0124] 10 μL of each of the sample solution and standard solution was subjected to liquid chromatography (HPLC) under the following conditions. The area percentage (%) of the peak area of ​​each related substance peak in the obtained chromatogram was calculated, and the content (%) of each related substance was calculated. Furthermore, for the sugammadex sodium related substances in the injection solution after 3 weeks, the rate of change (%) was calculated when the content of each related substance in the injection solution formulation immediately before the start of the test was set at 100%.

[0125] In addition, related substances I, II, and III were related substances with relative retention times of approximately 0.49, approximately 0.65, and approximately 1.30 to the peak of sugammadex sodium, respectively.

[0126] Detection Conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: 3.90 g of sodium dihydrogen phosphate dihydrate was dissolved in 900 mL of water, diluted phosphoric acid solution (1 → 10) was added to adjust the pH to 3.0, and water was added to make 1000 mL. 200 mL of acetonitrile was added to 800 mL of this solution. Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B. Flow rate: 0.5mL per minute.

[0127] The results are shown in Table 4.

[0128] [Table 4]

[0129] As shown in Table 4, the injectable preparations of Examples 1 to 6 are able to suppress the increase or decrease in the rate of change of related substances compared to the comparative examples and reference examples, and therefore are extremely excellent in long-term storage stability.

[0130] (Test Example 4) Stability test: Residual rate of sugammadex sodium The injection preparations prepared in Examples 2, 4-5, Comparative Examples 1-2, and Reference Example 1 were stored for 6 months at 40° C. The residual rate (%) of sugammadex sodium after 6 months relative to the start of the test was measured (the values ​​in the table are the average values ​​of n=2).

[0131] [Method for measuring residual rate of sugammadex sodium] Immediately before the start of the study and after 6 months, 1 mL of the sugammadex sodium aqueous solution in the injection formulation was accurately measured and made up to 50 mL with water. 2 mL of this solution was accurately measured and made up to 100 mL with water to obtain the sample solution.

[0132] 20 mg of sugammadex sodium standard was precisely weighed and dissolved in water to make exactly 100 mL. 10 mL of this solution was precisely weighed and water was added to make 50 mL to obtain the standard solution.

[0133] 50μL of each of the sample solution and standard solution was subjected to liquid chromatography (HPLC) under the following conditions. The peak area of ​​each sample was measured by automatic integration method, and the content (%) of sugammadex sodium was calculated by area percentage method. Furthermore, for the sugammadex sodium in the injection preparation after 6 months, the remaining rate (%) was calculated when the content of sugammadex sodium in the injection preparation immediately before the start of the test was set as 100%. In addition, the remaining rate (%) of sugammadex sodium was calculated by correcting the amount of evaporation of the oral solution during storage.

[0134] Detection Conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: 3.90 g of sodium dihydrogen phosphate dihydrate was dissolved in 900 mL of water, diluted phosphoric acid solution (1 → 10) was added to adjust the pH to 3.0, and water was added to make 1000 mL. 200 mL of acetonitrile was added to 800 mL of this solution. Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B. Flow rate: 0.5mL per minute.

[0135] The results are shown in Table 5.

[0136] [Table 5]

[0137] As shown in Table 5, the results of the injection preparations of the Examples and Comparative Examples were similar to those of the injection preparation contained in the glass vial (Reference Example 1), and it is understood that sugammadex sodium was stably maintained. Note that the increase in the residual rate of sugammadex sodium is thought to be due to the effect of evaporation of the internal solution during storage, so the residual rate of sugammadex sodium corrected based on the amount of evaporation of the internal solution during storage is shown.

[0138] (Test Example 5) Stability test: pH The injection preparations prepared in Examples 2, 4-5, Comparative Examples 1-2, and Reference Example 1 were stored at 40°C, and the pH of the aqueous sugammadex sodium solution after 6 months was measured using a pH meter (manufactured by DKK-TOA Corporation). (The values ​​in the table are the average values ​​of n=2.) The results are shown in Table 6.

[0139] [Table 6]

[0140] As shown in Table 6, the injection preparations of the Examples and Comparative Examples showed the same results as the injection preparation contained in the glass vial (Reference Example 1), and it can be seen that the pH of the sugammadex sodium aqueous solution was kept stable.

[0141] (Test Example 6) Change in sugammadex sodium analogues in injection preparations The injectable preparations prepared in Examples 2, 4-5, Comparative Examples 1-2, and Reference Example 1 were stored at 40°C, and the rate of change (%) of sugammadex sodium analogues after 6 months from the start of the test was measured (the values ​​in the table are the average values ​​of n=2).

[0142] [Method for measuring the change in the amount of sugammadex sodium analogues] Just before the start of the study and after 6 months had elapsed, 1 mL of the aqueous solution of sugammadex sodium in the injection formulation was accurately measured, and water was added to make exactly 50 mL to obtain a sample solution.

[0143] 20 mg of sugammadex sodium standard substance was precisely weighed and dissolved in water to make exactly 100 mL to obtain a standard solution.

[0144] 10 μL of each of the sample solution and standard solution was subjected to liquid chromatography (HPLC) under the following conditions. The area percentage (%) of the peak area of ​​each related substance peak in the obtained chromatogram was calculated, and the content (%) of each related substance was calculated. Furthermore, for the sugammadex sodium related substances in the injection solution after 6 months, the rate of change (%) was calculated when the content of each related substance in the injection solution formulation immediately before the start of the test was set to 100%.

[0145] In addition, related substances I, II, and III were related substances with relative retention times of approximately 0.49, approximately 0.65, and approximately 1.30 to the peak of sugammadex sodium, respectively.

[0146] Detection Conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: 3.90 g of sodium dihydrogen phosphate dihydrate was dissolved in 900 mL of water, diluted phosphoric acid solution (1 → 10) was added to adjust the pH to 3.0, and water was added to make 1000 mL. 200 mL of acetonitrile was added to 800 mL of this solution. Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B. Flow rate: 0.5mL per minute.

[0147] The results are shown in Table 7.

[0148] [Table 7]

[0149] As shown in Table 7, the injectable formulations of the Examples are able to suppress the increase or decrease in the rate of change of related substances compared to the Comparative Examples and Reference Examples, and therefore are found to have extremely excellent long-term storage stability.

[0150] This application is based on Japanese Patent Application No. 2019-158309 filed on August 30, 2019, the disclosure of which is incorporated by reference in its entirety.

Claims

1. a medical container having an oxygen-permeable container filled with an aqueous solution of sugammadex sodium containing sugammadex sodium as an active ingredient and sterilized by high-pressure steam; A packaging container having poor oxygen permeability; (i) The medical container is housed in the poorly oxygen-permeable packaging container together with an oxygen scavenger and sealed; or (ii) An injection preparation, the medical container being housed and sealed in the poorly oxygen-permeable packaging container, the atmosphere of which has been replaced with an inert gas.

2. 2. The injection preparation according to claim 1, wherein the medical container is sterilized by high-pressure steam using an inert gas, a mixed gas of an inert gas and air, or air as a pressurizing medium.

3. The injection preparation according to claim 1 or 2, wherein the concentration of sugammadex sodium in the aqueous sugammadex sodium solution is 50 to 200 mg / mL.

4. The injection preparation according to any one of claims 1 to 3, wherein the medical container is a syringe, and the oxygen-permeable container is a resin outer cylinder constituting the syringe.

5. The injectable formulation according to claim 4, wherein the resin is polypropylene or a cyclic polyolefin.

6. The injectable formulation of claim 4 or 5, wherein the syringe has an elastomeric gasket.

7. The injectable liquid formulation according to claim 6, wherein the elastomer is butyl rubber or a thermoplastic elastomer.

8. The oxygen permeability of the material forming the oxygen permeable container is 50 cm when measured at 23 ° C and 90% RH. ３ / m ２ The injectable liquid preparation according to any one of claims 1 to 7, wherein the viscosity is 1 / day·atm (120 μm) or more.

9. The oxygen permeability of the material forming the oxygen-impermeable packaging container is less than 1.0 cm when measured at 23° C. and 90% RH. ３ / m ２ The injectable formulation according to any one of claims 1 to 8, wherein the dosage is less than or equal to day atm.

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