Sugammadex, or liquid preparation containing pharmacologically acceptable salt thereof

Abstract

To provide sugammadex with improved light stability and / or thermal stability or liquid preparation containing a pharmacologically acceptable salt thereof.SOLUTION: Provided is Sugammadex in which oxygen concentration of a space part in a storage container is 0 to 15 vol.%, dissolved oxygen concentration in liquid is 0 to 5.0 mg / L and liquid is stored in the storage container, or liquid preparation containing a pharmacologically acceptable salt thereof. It is preferable that the storage container block oxygen. It is preferable that the storage container be housed in the secondary packaging material which blocks oxygen. It is preferable that deoxidizer present in a secondary packaging material which blocks oxygen.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solution containing sugammadex or a pharmacologically acceptable salt thereof.

Background Art

[0002] The efficacy and effect of sugammadex sodium are the recovery from the muscle relaxation state caused by rocuronium bromide or vecuronium bromide (Non-Patent Document 1). Conventional solutions containing sugammadex or a pharmacologically acceptable salt thereof require storage in the dark as an essential storage method, and the expiration date is set to 3 years (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, since storage in the dark complicates storage management, it is required that storage in the dark is not necessarily required, and the above conventional solutions are required to improve their photostability. In addition, the above conventional solutions have low thermal stability, that is, when stored in the dark for a long period of time, the decomposition products when not irradiated with light increase. Therefore, in order to extend the expiration date, the above conventional solutions are also required to improve their thermal stability.

[0005] The present invention has been made based on the above circumstances, and an object thereof is to provide a solution containing sugammadex or a pharmacologically acceptable salt thereof, which has improved photostability and / or thermal stability.

Means for Solving the Problems

[0006] As a result of intensive research to solve the above problems, the present inventors have found that a solution containing sugammadex or a pharmacologically acceptable salt thereof can improve both the photo-stability and the thermal stability by making the oxygen concentration in the headspace of the storage container and the dissolved oxygen concentration in the solution not more than certain values respectively. Based on this finding, further research was conducted and the present invention was completed.

[0007] The invention made to solve the above problems is a solution containing sugammadex or a pharmacologically acceptable salt thereof, characterized in that the oxygen concentration in the headspace of the storage container is 0 to 15% by volume, the dissolved oxygen concentration in the solution is 0 to 5.0 mg / L, and the solution is stored in the storage container.

[0008] More specifically, the present invention relates to the following inventions and the like. [1] A solution containing sugammadex or a pharmacologically acceptable salt thereof, characterized in that the oxygen concentration in the headspace of the storage container is 0 to 15% by volume, the dissolved oxygen concentration in the solution is 0 to 5.0 mg / L, and the solution is stored in the storage container. [2] The solution containing sugammadex or a pharmacologically acceptable salt thereof according to [1], characterized in that the storage container blocks oxygen. [3] The solution containing sugammadex or a pharmacologically acceptable salt thereof according to [1] or [2], characterized in that the storage container is housed in a secondary packaging material that blocks oxygen. [4] The solution containing sugammadex or a pharmacologically acceptable salt thereof according to [3], characterized in that the oxygen scavenger is present in the secondary packaging material that blocks oxygen. [5] The solution containing sugammadex or a pharmacologically acceptable salt thereof according to any one of [1] to [4], characterized in that the amount of substances other than sugammadex or a pharmacologically acceptable salt thereof after storage at 60°C for 22 days and irradiation with light having a total illuminance of 1.2 million lux·hour is 14% by mass or less based on the whole solution. [6](a) A step of performing gas replacement with an oxygen-free gas, (b) a step of bubbling with an oxygen-free gas, and / or (c) a step of housing the storage container in a secondary packaging material that blocks oxygen and allowing a deoxidizer to be present inside the secondary packaging material and outside the storage container. A method for producing a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof, characterized by having these steps, and having improved photo-stability and thermal stability. [7](a) A step of performing gas replacement with an oxygen-free gas, (b) a step of bubbling with an oxygen-free gas, and / or (c) a step of housing the storage container in a secondary packaging material that blocks oxygen and allowing a deoxidizer to be present inside the secondary packaging material and outside the storage container. A method for improving the photo-stability and thermal stability of a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof, characterized by having these steps. [Effect of the Invention]

[0009] The present invention can provide a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof with improved photo-stability and / or thermal stability. Since the liquid preparation of the present invention has improved photo-stability, it does not necessarily require light-shielded storage. Also, since the liquid preparation of the present invention has improved thermal stability, it can be stored for a longer period compared to conventional liquid preparations. [Modes for Carrying Out the Invention]

[0010] [Liquid Preparation Containing Sugamadex or a Pharmaceutically Acceptable Salt Thereof] As one aspect of the present invention, there is provided a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof, characterized in that the oxygen concentration in the space part of the storage container is 0 to 15% by volume, and the dissolved oxygen concentration in the liquid is 0 to 5.0 mg / L. Hereinafter, this is also simply referred to as "the said liquid preparation".

[0011] [Sugamadex or a Pharmaceutically Acceptable Salt Thereof] The said liquid preparation contains sugamadex or a pharmaceutically acceptable salt thereof. The said liquid preparation usually contains a solvent, and may contain other components as long as the effects of the present invention are not impaired.

[0012] Sugammadex or a pharmacologically acceptable salt thereof can be obtained, for example, by the synthesis method described in Example 4 of Japanese Patent No. 3880041 or a method analogous thereto. Regarding the method for producing sodium sugammadex, that is, 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin, sodium salt, in Example 4 of Japanese Patent No. 3880041, it is described as follows in paragraph 0046 of the specification. 3-Mercaptopropionic acid (1.22 ml, 14.0 mmol) was dissolved in dry DMF (45 ml) at room temperature under N2. Sodium hydride (1.23 g, 30.8 mmol; 60%) was added to this solution in three portions, and the mixture was further stirred for 30 minutes. To this mixture, a 45 ml dry DMF solution of 6-per-deoxy-6-per-iodo-γ-cyclodextrin (3.12 g, 1.40 mmol) was added dropwise. After the addition, the reaction mixture was heated at 70 °C for 12 hours. After cooling, water (10 ml) was added to the mixture, the volume was reduced to 40 ml under reduced pressure, and ethanol (250 ml) was added thereto, resulting in precipitation. The solid precipitate was collected by filtration and dialyzed for 36 hours. Next, the volume was reduced to 20 ml under reduced pressure. Ethanol was added thereto, and the precipitate was collected by filtration and dried to obtain the title compound (6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin, sodium salt) as a white solid (1.3 g, 43%). 1 1H-NMR (D2O) δ 2.47~2.51 (m, 16H); 2.84~2.88 (m, 16H); 3.00~3.02 (t, 8H); 3.11~3.14 (t, 8H); 3.62~3.68 (m, 16H); 3.92~3.97 (m, 8H); 4.04~4.06 (m, 8H); 5.19 (m, 8H) ppm. MS FIA + ion at 2024.9 m / z

[0013] Examples of the pharmacologically acceptable salts of sugammadex include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. Among these, alkali metal salts such as sodium salt or potassium salt are preferred.

[0014] In the present disclosure, the terms "about" and "around" are used with the intention of including, for example, cases of slightly deviating. These terms may mean, for example, within ±5%, within ±2%, within ±1%, within ±0.5%, within ±0.2%, within ±0.1% or within ±0.05%. Such ranges also include cases within the experimental error specific to the standard methods used for the measurement and / or quantification of a given value or range.

[0015] The concentration of sugammadex or its pharmacologically acceptable salt in the said solution is preferably about 1 to 250 mg / mL, more preferably about 10 to 250 mg / mL, and particularly preferably about 10 to 200 mg / mL.

[0016] (Solvent) The solvent used for the said solution is not particularly limited as long as it does not impair the effects of the present invention. For example, water (such as water for injection, purified water, distilled water, etc.), glycerin, ethanol, propylene glycol, polyethylene glycol, macrogol, edible oil (such as sesame oil, corn oil, olive oil, etc.) or a mixture thereof, etc. may be mentioned. Among these, water (such as water for injection, purified water, distilled water, etc.) is preferred.

[0017] The content of the solvent is not particularly limited as long as it does not impair the effects of the present invention. However, it is usually about 75 to 99.9% by mass, preferably about 75 to 99% by mass, and particularly preferably about 80 to 99% by mass with respect to the whole solution.

[0018] (Other components) The liquid preparation may contain other components in addition to sugammadex or its pharmacologically acceptable salts and solvents, if necessary. Examples of other components include pH adjusters, solubilizing agents, isotonic agents, antioxidants, preservatives, stabilizers, suspending agents, buffers, and the like. The liquid preparation may also contain other known additives or pharmacologically acceptable additives commonly used in the pharmaceutical field, if necessary. These other components can be used alone or in combination of two or more depending on the intended form of the liquid preparation. These other components may be manufactured by known methods or commercially available products may be used. When containing other components, their content is preferably about 0.001 to 5% by mass, more preferably about 0.001 to 3% by mass, and particularly preferably about 0.01 to 3% by mass based on the total amount of the liquid preparation. Within the above content range, usually, the actions of these components can be sufficiently exerted and the effects of the present invention are not impaired.

[0019] Examples of pH adjusters include acids such as organic acids (e.g., acetic acid, carbonic acid, trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, D-tartaric acid, citric acid, DL-malic acid, lactic acid, oxalic acid, benzoic acid, besylic acid, ascorbic acid, adipic acid, gluconic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, edetic acid, etc.), inorganic acids (e.g., hydrochloric acid, phosphoric acid, boric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, etc.), ammonia, monoethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine, tromethamine, triethylamine, meglumine, organic or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc., and salts of the above acids and bases (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.). The above acids, bases, and salts may be hydrates.

[0020] Examples of solubilizing agents include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.

[0021] Examples of the isotonic agent include, for example, glucose, D-sorbitol, sodium chloride, D-mannitol, glycerin, etc. Among these, sodium chloride is preferred. The content of the isotonic agent can be determined by a well-known calculation method to make the whole liquid preparation isotonic.

[0022] Examples of the antioxidant include, for example, t-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, L-cysteine hydrochloride, L-methionine, L-cystine, sodium bisulfite, α-tocopherol, polyphenol, ascorbic acid, potassium metabisulfite, α-thioglycerol, sodium thioglycolate, thiomalic acid, ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid or their derivatives, etc. Among these, diethylenetriaminepentaacetic acid or butylhydroxyanisole is preferred.

[0023] Examples of the preservative include, for example, ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc.

[0024] Examples of the stabilizer include, for example, casein, sodium caseinate, etc.

[0025] The said liquid preparation may contain other medicinal ingredients, or may be used in combination with other medicinal ingredients. Such other medicinal ingredients are not particularly limited as long as the effects of the present invention are not impaired. For example, rocuronium bromide or vecuronium bromide; a drug having the efficacy and effect of recovering from a muscle relaxation state caused by rocuronium bromide or vecuronium bromide, etc.; or a drug having an efficacy and effect different from such efficacy and effect may also be used.

[0026] The pH of the liquid preparation is preferably about 6 to 8, for example. When the pH is significantly lower than 6, precipitates are likely to form, and when the pH significantly exceeds 8, the pH is likely to decrease. Further, within the above range, irritation to the subject can be reduced. The pH can be adjusted, for example, by including the pH adjuster in the liquid preparation.

[0027] The osmotic pressure of the liquid preparation is not particularly limited and may be, for example, about 250 to 1000 mOsmol / kg, or may be 260 to 600 mOsmol / kg. By being within the above range, irritation to the subject can be reduced.

[0028] The dosage form of the liquid preparation may be, for example, any of a solution form, a suspension form, an emulsion form, etc., but a solution form is preferred.

[0029] [Storage container] The liquid preparation of the present invention is enclosed in a storage container. Inside the storage container, a space is formed other than the liquid portion of the liquid preparation.

[0030] The storage container for enclosing the liquid preparation is not particularly limited, and examples include fixed containers such as wide-mouth bottles, narrow-mouth bottles, medicine bottles, vial bottles, ampoules, petri dishes, test tubes with lids, drip containers, eye drop containers, infusion bags, infusion bottles, and containers for infusion kits; and movable containers such as syringes, cylinders, pre-filled syringes, and disposable syringes.

[0031] The shape of the storage container is not particularly limited, and examples include an ampoule shape, a vial shape, a cup shape, an envelope shape, a stick shape, and a syringe shape.

[0032] The material of the storage container is not particularly limited, and examples thereof include plastics such as glass, polyethylene (PE), polypropylene (PP), polystyrene, ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride, cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polyethylene terephthalate (PET), polycarbonate (PC), and polymethylpentene; metals such as aluminum; and metal laminates such as aluminum laminate. Further, the material of the gasket of the prefilled syringe or the stopper portion of the prefilled syringe or vial is not particularly limited, and examples thereof include various rubber materials such as natural rubber, butyl rubber, chlorobutyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, and silicone rubber; various thermoplastic elastomers such as polyurethane-based, polyester-based, polyamide-based, olefin-based, and styrene-based; or elastic materials such as mixtures thereof.

[0033] As the storage container, those that block oxygen are preferable. When the storage container blocks oxygen, secondary packaging materials for storing this storage container can be made unnecessary. "Blocking oxygen" means that, for example, the oxygen transmission rate (OTR) of the entire storage container is preferably 20 cm 3 / m 2 / day (the unit may also be mL / m 2 ·atm·24 hr. The same applies hereinafter) or less, more preferably 10 cm 3 / m 2 / day or less, more preferably 5.0 cm 3 / m 2 / day or less, still more preferably 2.5 cm 3 / m 2 / day or less, and most preferably 1.0 cm 3 / m 2 / day or less. Here, the oxygen transmission rate (OTR) is a value determined under the condition of a temperature of 23°C in accordance with JIS K7126-1 or -2:2006 "Plastics - Films and Sheets - Test Method for Gas Permeability".

[0034] As the storage container for blocking oxygen, either a soft container or a hard container may be used, but it is preferably formed from an oxygen-impermeable film or sheet using an organic polymer, and more preferably formed from an oxygen-impermeable soft (flexible) film or sheet using an organic polymer. Examples of materials for forming the storage container for blocking oxygen include, for example, glass, metal, oxygen barrier resin, vapor deposition films or sheets such as aluminum oxide, silicon oxide or titanium oxide, or containers made of aluminum foil laminated films, etc. Examples of oxygen barrier resins include, for example, polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer (EVOH), oriented polypropylene (OPP), barrier nylon, polyvinyl alcohol (PVA), oriented nylon (CNY), biaxially oriented polyamide (OPA), ethylene-vinyl acetate copolymer (EVA), etc. As more specific examples of materials for forming the storage container for blocking oxygen, oxygen-impermeable metal foils such as aluminum foil, vapor deposition films or sheets obtained by vapor depositing ceramics or metals such as silicon oxide-based, aluminum oxide-based, titanium oxide-based, etc. on a base film or sheet made of an organic polymer (for example, aluminum vapor deposition organic polymer films and sheets, silica vapor deposition organic polymer films and sheets, titanium oxide vapor deposition organic polymer films and sheets), organic polymer films and sheets having a DLC (diamond-like coating) layer, oxygen-impermeable films and sheets formed from resins having oxygen impermeability such as polyvinyl alcohol and ethylene vinyl alcohol, laminated films and sheets obtained by laminating resin layers having oxygen impermeability such as polyvinyl alcohol and ethylene vinyl alcohol, multilayer films and multilayer sheets obtained by laminating one or more of the above-mentioned oxygen-impermeable films and sheets with a layer made of another organic polymer, etc. can be mentioned. When a storage container that blocks oxygen is formed from an oxygen-barrier film or sheet made of an organic polymer, since the storage container is often formed by folding the oxygen-barrier film or sheet and heat-sealing the periphery, it is preferable that the portion that becomes the innermost surface when folded is formed of at least a heat-sealable organic polymer. Although not limited thereto, specific examples of the materials that can be used in the present invention as materials for storage containers that block oxygen include · A multilayer film or multilayer sheet in which polypropylene (PP) / silica-deposited polyethylene terephthalate (PET) / polypropylene (PP) are laminated in this order; · A multilayer film or multilayer sheet in which biaxially stretched polyamide (OPA) / polyethylene (PE) / aluminum-deposited PET / polyethylene (PE) are laminated in this order; · A multilayer film or multilayer sheet in which OPA / PE / aluminum-deposited PET / PE are laminated in this order; · A multilayer film or multilayer sheet in which OPA / PE / aluminum foil / PE / PE are laminated in this order; · A multilayer film or multilayer sheet in which OPA / PE / aluminum foil / PE / PET / PE are laminated in this order; · A multilayer film or multilayer sheet in which PET / PE / aluminum-deposited PET / PE / ethylene-vinyl acetate copolymer (EVA) / PE are laminated in this order; · A multilayer film or multilayer sheet in which polyvinylidene chloride / PE / aluminum-deposited PET / PE are laminated in this order; · A multilayer film or multilayer sheet in which PET / aluminum-deposited ethylene-vinyl alcohol copolymer (EVOH) / PE are laminated in this order; and the like can be mentioned. When the storage container that blocks oxygen is formed from an oxygen-impermeable film or sheet made of an organic polymer, in order to achieve the performance as a storage container that blocks oxygen, it is preferably formed from an oxygen-impermeable film or sheet with a thickness of 50 to 150 μm, particularly 65 to 100 μm. If the thickness of the film or sheet forming the storage container that blocks oxygen is 50 μm or more, it is easy to obtain suitable strength as a storage container, and if it is 150 μm or less, when the liquid agent according to the present invention is a soft bag type preparation, it is easy to impart appropriate flexibility and light weight.

[0035] (Secondary packaging material) The storage container can be stored inside the secondary packaging material.

[0036] As the secondary packaging material, it is preferably one that blocks oxygen. Even when the oxygen barrier property of the storage container is low, by storing the storage container inside the secondary packaging material that blocks oxygen, it becomes possible to make the oxygen concentration inside the storage container a concentration below a certain value.

[0037] Examples of the secondary packaging material that blocks oxygen include a glass bottle, a container made of an oxygen barrier resin, a multilayer film container having an oxygen barrier resin layer, etc. Examples of the multilayer film having an oxygen barrier resin layer include PET / polyamide (PA) / EVOH, PET / aluminum / PE, aluminum vapor-deposited PET / PE, PE / EVOH / PE, PET / PA / EVOH, OPP / EVOH / PE, silica vapor-deposited PET / PE, PP / PET / PP, OPA / PE / aluminum vapor-deposited PET / PE, barrier nylon / PE, PVDC-coated OPP / PE, PVDC-coated PET / PE, PVDC-coated CNY / PE, etc.

[0038] When storing the storage container inside the secondary packaging material that blocks oxygen, it is preferable to have an oxygen absorber present inside this secondary packaging material, and it is more preferable to have it present inside the secondary packaging material and outside the storage container.

[0039] Examples of the deoxidizer include those utilizing the oxidation reaction of iron powder or iron compounds, those utilizing the adsorption action of activated carbon, reductones such as L-ascorbic acid and reductonic acid, and those utilizing the oxidation reaction of sugars, phenols, catechols, etc.

[0040] Examples of commercially available deoxidizers include the registered trademark "Ageless" of Mitsubishi Gas Chemical Company, the product name "Modulan" of Nippon Kayaku Co., Ltd., the product name "Secul" of Nippon Soda Co., Ltd., the registered trademark "Tamotsu" of Oji Chemical Industry Co., Ltd., etc.

[0041] [Oxygen concentration] In the liquid agent, the oxygen concentration in the space part of the storage container is 0 to 15% by volume, the dissolved oxygen concentration in the liquid is 0 to 5.0 mg / L, and the liquid is stored in the storage container.

[0042] By setting the oxygen concentration of the liquid agent within the above range, excellent light stability and thermal stability can be achieved. When the oxygen concentration significantly exceeds the upper limit, the light stability and / or thermal stability will decrease.

[0043] As the upper limit of the oxygen concentration in the space part of the storage container, 15% by volume is preferred, 12% by volume is more preferred, 11% by volume is further preferred, and 10% by volume is particularly preferred. As the lower limit of the oxygen concentration in the space part of the storage container, 1.0% by volume is preferred, 0.1% by volume is more preferred, 0.01% by volume is further preferred, and 0.001% by volume is particularly preferred. By setting the oxygen concentration in the space part of the storage container below the upper limit, the light stability and thermal stability can be further improved. To make the oxygen concentration in the space part of the storage container significantly lower than the lower limit requires a complicated process.

[0044] As the upper limit of the dissolved oxygen concentration in the liquid, 5.0 mg / L is preferred, 4.8 mg / L is more preferred, 4.5 mg / L is even more preferred, and 4.0 mg / L is particularly preferred. As the lower limit of the dissolved oxygen concentration in the liquid, 0.1 mg / L is preferred, 0.01 mg / L is more preferred, 0.001 mg / L is even more preferred, and 0.0001 mg / L is particularly preferred. By setting the dissolved oxygen concentration in the liquid below the upper limit, the light stability and thermal stability can be further improved. To make the dissolved oxygen concentration in the liquid significantly lower than the lower limit requires a complicated process.

[0045] The oxygen concentration (volume %) in the space part of the storage container and the dissolved oxygen concentration (mg / L) in the liquid can be measured, for example, using an oxygen concentration meter (e.g., "Pack Master (plus / minus pressure sampler: S-2, DO measuring device: MA-300 attached)" of Iijima Electronics Industry Co., Ltd.) and following the procedure faithfully according to the instruction manual of this measuring device. The timing for measuring these oxygen concentrations may be "immediately after production" of the liquid agent, or "after storage at room temperature (e.g., 1 to 30 °C) for a certain period (e.g., any time point within 7 years from the production date) immediately after production", or "after storage at high temperature (e.g., 40 to 60 °C) for a certain period (e.g., any time point within 1 month from the production date) immediately after production or immediately after production", or "after storage at room temperature or high temperature immediately after production or for a certain period, and then after performing light irradiation with a total illuminance of 1.2 million lux·hour using a light tester (manufactured by Nagano Science Co., Ltd.) with a D65 lamp as the light source", etc., but it is preferably "immediately after production" or "after storage at room temperature (e.g., 1 to 30 °C) for a certain period (e.g., any time point within 7 years from the production date) immediately after production". Also, in the case of the liquid agent, when there is a space part in the storage container that does not block oxygen and the storage container is housed in a secondary packaging material that blocks oxygen, since there is an equilibrium relationship regarding the oxygen concentration between the space part of the storage container and the space part inside and outside the storage container within the secondary packaging material, by measuring the oxygen concentration in the space part inside and outside the storage container within the secondary packaging material, the obtained oxygen concentration may be treated as the oxygen concentration in the space part of the storage container. In addition, in the case where there is no empty space in the storage container for the liquid preparation, the oxygen concentration in the empty space of the storage container may be handled as 0% by volume. In addition, in the case where there is almost no empty space in the storage container for the liquid preparation to the extent that the oxygen concentration in the empty space of the storage container cannot be measured, and the storage container blocks oxygen and is not stored in a secondary packaging material, the oxygen concentration in the empty space of the storage container may be handled as 0% by volume.

[0046] The method for setting the oxygen concentration in the liquid preparation within the above range is not particularly limited and may be carried out according to a known method. For example, methods such as gas replacement with an oxygen-free gas, bubbling with an oxygen-free gas, and vacuum degassing may be mentioned. Examples of the oxygen-free gas include inert gases such as nitrogen, argon, and helium. In addition, examples of the above method include a method using an oxygen scavenger, and a method of allowing an oxygen scavenger to be present in the storage container. When the storage container does not block oxygen, it is preferable to store this storage container in a secondary packaging material that blocks oxygen and allow the oxygen scavenger to be present in the secondary packaging material, and it is more preferable to allow the oxygen scavenger to be present inside the secondary packaging material and outside the storage container.

[0047] [Sterilization treatment] The liquid preparation is preferably subjected to a sterilization treatment. Examples of the sterilization treatment include filtration sterilization, autoclave sterilization, a method of performing autoclave sterilization after filtration sterilization, a method of performing filtration sterilization after autoclave sterilization, and other sterilization methods (γ-ray sterilization, dry heat sterilization, etc.). Among these, a method of performing autoclave sterilization after filtration sterilization or a method of performing filtration sterilization is preferable.

[0048] Autoclave sterilization is usually synonymous with autoclaving. Autoclave sterilization is carried out using an autoclave at, for example, 115 to 118°C for 30 minutes, 121 to 124°C for 15 to 20 minutes, or 126 to 129°C for 10 minutes, and it is preferably carried out until the object reaches a sterile state.

[0049] Filtration sterilization has been well established conventionally and may be carried out accordingly in the present invention. That is, the filtration sterilization method is not particularly limited as long as it does not interfere with the effects of the present invention, and may be carried out according to known or self-known methods. The maximum pore size of the membrane filter used for filtration sterilization is preferably about 0.1 to 0.5 μm. The material of the membrane filter used for filtration sterilization is preferably PVDF (polyvinylidene fluoride), PES (polyethersulfone), PTFE (polytetrafluoroethylene), MCE (cellulose mixed ester), or the like.

[0050] Examples of preferred embodiments of the liquid preparation are shown below. All of these satisfy the conditions that "the oxygen concentration in the space part of the storage container is 0 to 15% by volume, the dissolved oxygen concentration in the liquid is 0 to 5.0 mg / L, and the liquid is stored in the storage container." (1) A liquid preparation containing sugammadex or a pharmaceutically acceptable salt thereof, enclosed in a storage container that blocks oxygen. (2) A liquid preparation containing sugammadex or a pharmaceutically acceptable salt thereof, enclosed in a storage container that blocks oxygen and housed in a secondary packaging material that blocks oxygen. (3) A liquid preparation containing sugammadex or a pharmaceutically acceptable salt thereof, enclosed in a storage container that does not block oxygen and housed in a secondary packaging material that blocks oxygen. (4) A liquid preparation containing sugammadex or a pharmaceutically acceptable salt thereof, enclosed in a storage container that does not block oxygen and housed in a secondary packaging material that blocks oxygen, and having an oxygen scavenger present in the secondary packaging material.

[0051] <Method of using the liquid preparation> The liquid preparation can be used, for example, by administering it to humans and other mammals (such as rats, mice, guinea pigs, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.). Since the liquid preparation is safe and has low toxicity, a sufficient amount can be administered to, for example, humans and other mammals.

[0052] The liquid preparation is preferably an injection solution, an eye drop, an oral preparation, etc., and particularly preferably an injection solution.

[0053] The dosage varies depending on the administration subject, target organ, symptoms, administration method, etc. For example, in the case of an injection solution, when the human body weight is about 60 kg, it is convenient to administer about 0.01 to 1000 mg, preferably about 50 to 1000 mg in terms of sugamadex per day by a known administration method. The total daily dosage may be a single dosage or a divided dosage.

[0054] In addition, the liquid preparation may be administered systemically or locally from transdermal, subcutaneous, intradermal, intramuscular, near the nerve, intramedullary, intraspinal, epidural space, intravenous, or transmucosal such as eye drops. The dosage can be changed according to the common sense of those skilled in the art to obtain and / or maximize the therapeutic effect of the liquid preparation.

[0055] The usage and dosage of the liquid preparation may be the same as those of conventionally known sugamadex or a pharmaceutically acceptable salt-containing liquid preparation thereof. Of course, it may be determined by the doctor according to the patient's condition and symptoms.

[0056] <Method for confirming the solved problem> The improvement of the photo-stability of the liquid preparation can be recognized, for example, by using a light tester (manufactured by Nagano Science Co., Ltd.), using a D65 lamp or the like as a light source, and comparing the amount of substances other than sugamadex or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "total amount of related substances") after light irradiation with a total illuminance of 1.2 million lux·hour, with the liquid preparation being less than that of "a sugamadex or a pharmaceutically acceptable salt-containing liquid preparation in which the oxygen concentration in the space part of the storage container is not 0 to 15% by volume and the dissolved oxygen concentration in the liquid is not 0 to 5.0 mg / L". In addition, the "after" in "after light irradiation with a total illuminance of 1,200,000 lux·hour" may be any point in time from immediately after irradiation to one month after irradiation. Substances other than sugamadex or its pharmacologically acceptable salts refer to, for example, solutes other than sugamadex or its pharmacologically acceptable salts in a liquid preparation, excluding solvents and the above other components, and include analogs of sugamadex or its pharmacologically acceptable salts (for example, intermediates, degradation products, and impurities of sugamadex or its pharmacologically acceptable salts; in other words, intermediates generated during the production of sugamadex or its pharmacologically acceptable salts, degradation products derived from sugamadex or its pharmacologically acceptable salts, and other impurities, etc.). The method of irradiating light with a total illuminance of 1,200,000 lux·hour using a D65 lamp or the like, and the method of measuring the amount of substances other than sugamadex or its pharmacologically acceptable salts with respect to the entire liquid (for example, the method of determining by the area percentage method using high-performance liquid chromatography, etc.) may follow known or self-known methods, and more specifically, reference can be made to the examples described later.

[0057] In addition, the fact that the thermal stability of the liquid preparation is improved can be recognized, for example, by a method of confirming the following (A) and / or (B) ((in the case of (A) and (B), (B) is performed after (A))). (A) Regarding the total amount of analog substances after production by autoclaving, the liquid preparation has less amount compared to "a liquid preparation containing sugamadex or its pharmacologically acceptable salt in which the liquid is stored in a storage container and the oxygen concentration in the space part of the storage container is not 0 to 15% by volume and the dissolved oxygen concentration in the liquid is not 0 to 5.0 mg / L". (B) Regarding the total amount of analog substances after storage at 60°C for 22 days from the production date, the liquid preparation has less amount compared to "a liquid preparation containing sugamadex or its pharmacologically acceptable salt in which the liquid is stored in a storage container and the oxygen concentration in the space part of the storage container is not 0 to 15% by volume and the dissolved oxygen concentration in the liquid is not 0 to 5.0 mg / L".

[0058] In addition to the methods for confirming that the thermal stability and photo-stability of the liquid preparation are improved, for example, after production by autoclaving and / or after storage at 60°C for 22 days from the production date (for the cases after production by autoclaving and after storage at 60°C for 22 days (in this order)), regarding the total amount of related substances after the above light irradiation, it can be recognized that the liquid preparation has less amount compared to "a Sucamadex or a liquid preparation containing a pharmacologically acceptable salt thereof, where the liquid is stored in a storage container and the oxygen concentration in the space part of the storage container is not 0 to 15% by volume and the dissolved oxygen concentration in the liquid is not 0 to 5.0 mg / L", that is, by a method for confirming that the decrease in photo-stability due to thermal load is suppressed.

[0059] After storage at 60°C for 22 days and irradiation with light having a total illuminance of 1.2 million lux·hour, the total amount of related substances is preferably 14% by mass or less (more preferably 13% by mass or less, more preferably 12% by mass or less, more preferably 11% by mass or less, more preferably 10% by mass or less, more preferably 7.5% by mass or less, more preferably 5% by mass or less, still more preferably 3% by mass or less) based on the whole liquid. The period from the production date to the start date of storage at 60°C is not particularly limited as long as the effects of the present invention are not lost, but it is preferably within 7 years, more preferably within 6 years, 5 years, 4 years, 3 years, 2 years, 1 year, 6 months, 3 months, 2 months or 1 month. The period from the completion of storage at 60°C for 22 days to the start of irradiation with a total illuminance of 1.2 million lux·hour is not particularly limited as long as the effects of the present invention are not lost, but it is preferably within 1 month from the production date, more preferably within 2 weeks, 1 week, 3 days, 1 day or half a day. The period from the completion of irradiation with 1.2 million lux·hour to the start of measurement of the total amount of related substances is not particularly limited as long as the effects of the present invention are not lost, but it is preferably within 1 month, more preferably within 2 weeks, 1 week, 3 days, 1 day or half a day. The method of storing at 60°C for 22 days may follow a known or self-known method such as using an incubator or the like.

[0060] Since the light stability of the said liquid preparation is improved, usually, it is not necessary to store the said liquid preparation in a light-shielded manner. When the said liquid preparation is not stored in a light-shielded manner, the options for storing the liquid preparation increase, the storage management of the liquid preparation becomes easier, which leads to a reduction in the burden on medical staff and patients. Also, even if the said liquid preparation is stored in a light-shielded manner, since it does not prevent the improvement of light stability which is the effect of the present invention, the said liquid preparation may be stored in a light-shielded manner.

[0061] Since the thermal stability of the said liquid preparation is improved, management becomes easier, the options for storing the liquid preparation increase, which leads to a reduction in the burden on medical staff and patients. Also, since the thermal stability of the said liquid preparation is improved, the use period of the said liquid preparation can be made longer, for example, it can be 4 years (preferably 5 years, more preferably 6 years, still more preferably 7 years).

[0062] <Method for manufacturing a liquid preparation> The said liquid preparation can be manufactured, for example, by a manufacturing method including a step of setting the oxygen concentration in the space part of the storage container to 0 to 15% by volume and the dissolved oxygen concentration in the aqueous solution to 0 to 5.0 mg / L (hereinafter, referred to as the "oxygen concentration reduction step").

[0063] The said manufacturing method may further include a mixing step of mixing sugar dex or a pharmacologically acceptable salt thereof and a solvent, and, if necessary, an additive or a medicinal ingredient other than sugar dex or a pharmacologically acceptable salt thereof. The said manufacturing method may further include an introduction step of introducing the liquid preparation into the storage container. The introduction step may be performed either before the oxygen concentration reduction step or after the oxygen concentration reduction step. That is, the oxygen concentration reduction step may be performed after introducing the liquid preparation into the storage container, or after performing the oxygen concentration reduction step on the liquid preparation outside the storage container, the obtained liquid preparation may be introduced into the storage container. In addition, the method for producing the liquid preparation may further include a sterilization step of sterilizing the liquid preparation. The sterilization step may be performed before, during, or after the mixing step, but it is preferably performed at least after the mixing step.

[0064] (Oxygen concentration reduction step) In this step, the oxygen concentration in the space part of the storage container is set to 0 to 15% by volume, and the dissolved oxygen concentration in the liquid is set to 0 to 5.0 mg / L.

[0065] This step can be carried out, for example, by a method of performing gas replacement or gas bubbling using an oxygen-free gas on the liquid preparation in the storage container, a method of performing vacuum degassing, etc. Also, when a storage container that does not block oxygen is housed in a secondary packaging material that blocks oxygen, it can also be carried out by placing an oxygen scavenger in the secondary packaging material.

[0066] As one aspect of the present invention, there is provided a method for producing a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof with improved photo-stability and thermal stability, which comprises (a) a step of performing gas replacement with an oxygen-free gas, (b) a step of performing bubbling with an oxygen-free gas, and / or (c) a step of housing the storage container in a secondary packaging material that blocks oxygen and placing an oxygen scavenger inside the secondary packaging material and outside the storage container. For terms such as oxygen-free gas, gas replacement, bubbling, storage container, oxygen scavenger, secondary packaging material, etc. and each step of (a) to (c), refer to the descriptions of them in the above "said liquid preparation". The improvement in photo-stability can be recognized, for example, by using a light tester (manufactured by Nagano Science Co., Ltd.), using a D65 lamp as a light source, and comparing the total amount of related substances after light irradiation with a total illuminance of 1.2 million lux·hour for the liquid preparation with that of "a liquid preparation containing sugamadex or a pharmaceutically acceptable salt thereof produced by a method having none of the steps (a) to (c) above" to confirm that it is less. In addition, the improvement in thermal stability can be recognized, for example, by a method of confirming the following (C) and / or (D) ((in the case of (C) and (D), (D) is performed after (C))). Regarding the total amount of related substances after production by autoclaving, the liquid preparation has less amount compared to the "liquid preparation containing sugammadex or a pharmacologically acceptable salt thereof produced by a method having none of the steps (a) to (c) above". Regarding the total amount of related substances after storage at 60°C for 22 days from the production date, the liquid preparation has less amount compared to the "liquid preparation containing sugammadex or a pharmacologically acceptable salt thereof produced by a method having none of the steps (a) to (c) above".

[0067] In addition, that the thermal stability and light stability are improved can be recognized by, in addition to the methods for confirming that each of the above thermal stability and light stability is improved, for example, regarding the total amount of related substances after performing the above light irradiation after production by autoclaving and / or after storage at 60°C for 22 days from the production date (for after production by autoclaving and after storage at 60°C for 22 days (from the production date), in this order), the liquid preparation has less amount compared to the "liquid preparation containing sugammadex or a pharmacologically acceptable salt thereof produced by a method having none of the steps (a) to (c) above", that is, by a method for confirming that the decrease in light stability due to the heat load is suppressed.

[0068] In addition, as one aspect of the present invention, there is provided a method for improving the light stability and thermal stability of a liquid preparation containing sugammadex or a pharmacologically acceptable salt thereof, which comprises the steps of: (a) performing gas replacement with an oxygen-free gas; (b) bubbling with an oxygen-free gas; and / or (c) accommodating the storage container in a secondary packaging material that blocks oxygen and disposing an oxygen scavenger outside the storage container and inside the secondary packaging material. For terms such as oxygen-free gas, gas replacement, bubbling, storage container, oxygen scavenger, secondary packaging material, etc. and each of the steps (a) to (c), refer to the descriptions thereof in the above "said liquid preparation". In addition, for the method for confirming that the light stability and thermal stability are improved, refer to the descriptions thereof in the paragraph immediately preceding this paragraph.

[0069] The present invention includes embodiments in which the above-described configurations are variously combined within the technical scope of the present invention as long as the effects of the present invention are achieved.

Example

[0070] Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples, and many modifications are possible by those having ordinary knowledge in the art within the technical idea of the present invention.

[0071] In the following examples, high-pressure steam sterilization was performed using an autoclave (trade name SM200; manufactured by Yamato Scientific Co., Ltd.) at 121°C for 20 minutes. Filtration sterilization was performed by filtering using a PVDF membrane filter with a maximum pore size of 0.22 μm. 1.2 million lux·hour indicates that light with an illuminance of 4,000 to 3,500 lux per hour and a total illuminance of 1.2 million lux·hour was irradiated using a D65 lamp, which is a standard light source defined by the International Commission on Illumination (CIE). The total amount of related substances was determined by the area percentage method using high-performance liquid chromatography (detector: ultraviolet absorptiometer, column: octadecylsilylated silica gel, column temperature: 40°C, mobile phase: phosphate buffer / acetonitrile, flow rate of sample: 20 μL). The oxygen concentration (volume %) in the space part of the storage container and the dissolved oxygen concentration (mg / L) in the liquid were measured and determined by following the procedure faithfully according to the instruction manual of an oxygen concentration meter (for example, "Packmaster (pressure addition / subtraction sampler: S-2, DO measuring device: MA-300 attached)" of Iijima Electronics Industry Co., Ltd.).

[0072] (Production of Sugamadex Sodium) Sugamadex sodium was obtained by the synthesis method described in Example 4 of Japanese Patent No. 3880041.

[0073] Sugamadex sodium was dissolved in Japanese Pharmacopoeia Water for Injection, and the pH was adjusted to 7.5 with hydrochloric acid and / or sodium hydroxide to prepare an aqueous solution of 100 mg / mL as sugamadex.

[0074] <Manufacture of the agent enclosed in a vial (evaluation of photo stability)> The agent enclosed in the vial was manufactured according to the following procedure. (Storage container) As the storage container, a vial ("CS-2" manufactured by Nippon Sheet Glass Co., Ltd.) was used. This vial is made of glass (the lid is made of butyl rubber) and is an oxygen barrier container.

[0075] [Example 1] First, 2 mL of the filtrated and sterilized agent was introduced into the storage container. Nitrogen substitution was performed on the agent introduced into this storage container. The nitrogen substitution was performed by blowing nitrogen gas into the space part of the vial to replace the air atmosphere with a nitrogen atmosphere. The storage container was capped and autoclaved to obtain the agent enclosed in the storage container. The volume of the liquid in the storage container was 2 mL.

[0076] [Example 2] An agent enclosed in a storage container was obtained in the same manner as in Example 1, except that nitrogen bubbling was performed instead of nitrogen substitution. The nitrogen bubbling was performed by bubbling nitrogen gas into the liquid enclosed in the vial. The volume of the liquid in the storage container was 2 mL.

[0077] [Comparative Example 1] An agent enclosed in a storage container was obtained in the same manner as in Example 1, except that nitrogen substitution was not performed. The volume of the liquid in the storage container was 2 mL.

[0078] [Example 3] An agent enclosed in a storage container was obtained in the same manner as in Example 1, except that autoclaving was not performed.

[0079] [Example 4] An agent enclosed in a storage container was obtained in the same manner as in Example 2, except that autoclaving was not performed.

[0080] [Comparative Example 2] An agent enclosed in a storage container was obtained in the same manner as in Example 3, except that nitrogen substitution was not performed.

[0081] For the evaluation of photo-stability, for the obtained liquid preparation, after irradiation with 1.2 million lux·hour, the appearance was evaluated and the pH, oxygen concentration (oxygen concentration in the space part, dissolved oxygen concentration in the liquid), and total amount of related substances were measured. The results are shown in Table 1. Each measurement may be at any point within one month immediately after irradiation with 1.2 million lux·hour.

[0082] [Table 1]

[0083] In Comparative Example 2, before irradiation with 1.2 million lux·hour, the appearance was colorless and clear, the pH was 7.58, and the total amount of related substances was 2.48%.

[0084] From the results in Table 1, it was confirmed that in Examples 1 and 2, the total amount of related substances was less compared to Comparative Example 1, and in Examples 3 and 4, the total amount of related substances was less compared to Comparative Example 2. From the above, it was confirmed that by performing nitrogen substitution or nitrogen bubbling and suppressing the oxygen concentration of the liquid preparation to a low concentration, the photo-stability of the sugammadex or its pharmaceutically acceptable salt-containing liquid preparation was improved.

[0085] <Manufacture of Prefilled Syringe Stored in Secondary Packaging (Evaluation of Photo-Stability)> A prefilled syringe stored in a secondary packaging was manufactured by the following procedure. (Storage Container) As the storage container, a syringe ("Terumo Syringe 2.5 mL" manufactured by Terumo Corporation) was used. The material of the barrel of this syringe was polypropylene, and the material of the gasket was butyl rubber. A non-oxygen barrier container was used. (Secondary Packaging) As the secondary packaging, a bag made of an oxygen barrier film ("Transparent High Gas Barrier" manufactured by Hishikawa Chemical Co., Ltd.) was used. This secondary packaging was made of ceramic-deposited polyethylene terephthalate and is an oxygen barrier container. (Oxygen Absorber) As the deoxidizer, "Ageless ZH-100" manufactured by Mitsubishi Gas Chemical Company, Inc. was used.

[0086] [Example 5] First, 2 mL of the liquid agent that had been subjected to filtration sterilization was introduced into the syringe. After the syringe containing this liquid agent was autoclaved, it was stored in the bag made of the oxygen barrier film. One deoxidizer was stored together in the bag made of the oxygen barrier film outside the prefilled syringe.

[0087] [Comparative Example 3] A syringe filled with the liquid agent, which was stored in the bag made of the oxygen barrier film, was obtained in the same manner as in Example 5, except that no deoxidizer was stored in the bag made of the oxygen barrier film.

[0088] [Example 6] A product was obtained in which a syringe filled with the liquid agent and a deoxidizer were stored in the bag made of the oxygen barrier film in the same manner as in Example 5, except that autoclaving was not performed.

[0089] [Comparative Example 4] A product was obtained in which a syringe filled with the liquid agent was stored in the bag made of the oxygen barrier film in the same manner as in Example 6, except that no deoxidizer was stored in the bag made of the oxygen barrier film.

[0090] For the obtained liquid agent, after irradiation with 1.2 million lux·hour, the appearance was evaluated, and the pH, oxygen concentration (the oxygen concentration in the space inside the bag made of the oxygen barrier film outside the prefilled syringe, the dissolved oxygen concentration in the liquid), and the total amount of related substances were measured. The results are shown in Table 2. Note that each measurement may be at any time point from immediately after irradiation with 1.2 million lux·hour to one month. Also, it can be said that the oxygen concentration in the space inside the bag made of the oxygen barrier film outside the prefilled syringe is equivalent to the oxygen concentration in the space of the prefilled syringe.

[0091]

Table 2

[0092] In Comparative Example 4, before irradiation with 1.2 million lux·hour, the appearance was colorless and clear, the pH was 7.55, and the total amount of related substances was 2.43%.

[0093] From the results in Table 2, it was confirmed that in Example 5, the total amount of related substances was less compared to Comparative Example 3, and in Example 6, the total amount of related substances was less compared to Comparative Example 4. From the above, it was confirmed that due to the presence of the deoxidizer, the oxygen concentration in the liquid agent was suppressed to a low concentration, thereby improving the photostability of the liquid agent containing sugamadex or its pharmacologically acceptable salt. Also, from the results of Example 5 and Comparative Example 3 in Table 2, it was clear that by storing the deoxidizer in the oxygen barrier film bag outside the prefilled syringe, the dissolved oxygen concentration in the liquid in the prefilled syringe was reduced. This is considered to be because the oxygen in the oxygen barrier film bag and the oxygen in the liquid reach an equilibrium relationship.

[0094] <Manufacture of liquid agent enclosed in vial (evaluation of thermal stability, and thermal and photostability)> For Example 2 and 4 and Comparative Example 1 and 2, the oxygen concentration (oxygen concentration in the space part, dissolved oxygen concentration in the liquid) and the total amount of related substances were measured immediately after manufacture or after storage at 60°C for 22 days and before irradiation with 1.2 million lux·hour. Also, for Example 2 and 4 and Comparative Example 1 and 2, the appearance, pH, and total amount of related substances were comparatively evaluated at any time point from immediately after irradiation with 1.2 million lux·hour to 2 months after manufacture or after storage at 60°C for 22 days.

[0095]

Table 3

[0096] From the results in Table 3, it was confirmed that in Example 2, compared with Comparative Example 1, the total amount of related substances after storage at 60°C for 22 days (before light irradiation) was less, and even after light irradiation was performed after storage at 60°C for 22 days, the total amount of related substances was less. Further, in Example 4, compared with Comparative Example 2, the total amount of related substances after storage at 60°C for 22 days (before light irradiation) was less, and even after light irradiation was performed after storage at 60°C for 22 days, the total amount of related substances was less. From the above, it was confirmed that by performing nitrogen bubbling and suppressing the oxygen concentration of the liquid preparation to a low concentration, the thermal stability, as well as the thermal and photo stabilities, of a liquid preparation containing sugammadex or a pharmaceutically acceptable salt thereof were improved.

[0097] <Manufacture of Secondary Packaging-Containing Prefilled Syringe (Evaluation of Thermal Stability, Thermal Stability and Photo Stability)> For Example 5 and 6 and Comparative Example 3 and 4, the oxygen concentration in the space part inside the oxygen barrier film bag outside the prefilled syringe at the time immediately after manufacture or after storage at 60°C for 22 days and when not irradiated with 1.2 million lux·hour was measured. It can be said that the oxygen concentration in the space part inside the oxygen barrier film bag outside the prefilled syringe is equivalent to the oxygen concentration in the space part of the prefilled syringe. Further, for Example 5 and 6 and Comparative Example 3 and 4, the appearance, pH and total amount of related substances were comparatively evaluated at any time point from immediately after irradiation with 1.2 million lux·hour to 2 months after storage at 60°C for 22 days or immediately after manufacture.

[0098]

Table 4

[0099] From the results in Table 4, it was confirmed that in Example 5, the total amount of related substances after storage at 60°C for 22 days (before light irradiation) was less than that in Comparative Example 3, and the total amount of related substances was also less even after light irradiation after storage at 60°C for 22 days. Further, in Example 6, it was confirmed that the total amount of related substances after storage at 60°C for 22 days (before light irradiation) was less than that in Comparative Example 4, and the total amount of related substances was also less even after light irradiation after storage at 60°C for 22 days. From the above, it was confirmed that the presence of the deoxidizer suppresses the oxygen concentration of the liquid agent to a low concentration, thereby improving the thermal stability, as well as the thermal and photo stabilities of the solution containing sugamadex or its pharmacologically acceptable salt.

Industrial Applicability

[0100] The present invention can provide a solution containing sugamadex or its pharmacologically acceptable salt with improved photo stability and / or thermal stability. Since the solution of the present invention has improved photo stability, it does not necessarily require light-shielded storage. Further, since the solution of the present invention has improved thermal stability, it can be stored for a longer period than conventional solutions.

Claims

1. (a) A step of enclosing a solution containing sugammadex or a pharmacologically acceptable salt thereof in a storage container; (b) A step of subjecting the solution to gas replacement with an oxygen-free gas, (c) A step of bubbling the solution with an oxygen-free gas, and / or, (d) A step of housing the storage container in a secondary packaging material that blocks oxygen and having an oxygen scavenger present inside the secondary packaging material and outside the storage container, wherein the solution has an oxygen concentration in the headspace of the storage container of 0 to 15% by volume, a dissolved oxygen concentration in the liquid of 0 to 5.0 mg / L, and the liquid is stored in the storage container, and the solution is stored at 60° C. for 22 days and irradiated with light having a total illuminance of 1,200,000 lux·hour, and the amount of substances other than sugammadex or a pharmacologically acceptable salt thereof is 14% by mass or less based on the whole liquid, and a method for improving both the photo-stability and thermal stability of a solution containing sugammadex or a pharmacologically acceptable salt thereof.

2. (a) A step of enclosing a solution containing sugammadex or a pharmacologically acceptable salt thereof in a storage container; (c) A step of bubbling the solution with an oxygen-free gas, and / or, (d) A step of housing the storage container in a secondary packaging material that blocks oxygen and having an oxygen scavenger present inside the secondary packaging material and outside the storage container, wherein the solution has an oxygen concentration in the headspace of the storage container of 0 to 15% by volume, a dissolved oxygen concentration in the liquid of 0 to 5.0 mg / L, and the liquid is stored in the storage container, and the solution is stored at 60° C. for 22 days and irradiated with light having a total illuminance of 1,200,000 lux·hour, and the amount of substances other than sugammadex or a pharmacologically acceptable salt thereof is 14% by mass or less based on the whole liquid, and a method for manufacturing a solution containing sugammadex or a pharmacologically acceptable salt thereof, in which both the photo-stability and thermal stability are improved.

3. Further comprising (b) a step of subjecting the solution to gas replacement with an oxygen-free gas, the manufacturing method according to Claim 2.

4. (a) A step of enclosing a solution containing sugammadex or a pharmacologically acceptable salt thereof in a storage container; Step (b): performing gas substitution on the liquid agent with an oxygen-free gas; Step (c): bubbling the liquid agent with an oxygen-free gas; and / or Step (d): housing the storage container in a secondary packaging material that blocks oxygen and allowing an oxygen scavenger to exist inside the secondary packaging material and outside the storage container, wherein the liquid agent is characterized in that the oxygen concentration in the space part of the storage container is 0 to 15% by volume, the dissolved oxygen concentration in the liquid is 0 to 5.0 mg / L, and the liquid is stored in the storage container, and the liquid agent is stored at 60°C for 22 days and irradiated with light having a total illuminance of 1,200,000 lux·hour, and the amount of substances other than sugammadex or its pharmacologically acceptable salts is 14% by mass or less based on the whole liquid, and it is a method for producing a sugammadex or its pharmacologically acceptable salt-containing liquid agent with improved light stability and thermal stability (however, excluding the case where the storage container is an ampoule or a vial).

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