Packaging

Abstract

The present invention provides a means for preventing a decrease in viscosity and pH of a composition containing hyaluronic acid or a salt thereof and indigo carmine, which has excellent stability. [Solution] A medical container filled with a composition containing hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof is enclosed in an oxygen barrier container together with an oxygen scavenger, The weight average molecular weight of the hyaluronic acid or its salt is 600,000 or more, the concentration of the hyaluronic acid or a salt thereof in the composition is 0.1 to 0.5 w / v %, The concentration of the indigo carmine in the composition is 0.0002 to 0.012 w / v%, the content of the L-methionine in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, the content of the citric acid or a salt thereof in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, The intrinsic viscosity of the composition is 11.8 dL / g or more; A package in which the medical container is a syringe made of polypropylene.

Description

[Technical Field]

[0001] The present invention relates to a package. [Background technology]

[0002] We live in an age where one in two Japanese people will develop cancer and one in three will die from it. Advances in testing and treatment methods mean that cancer is a curable disease if detected and treated early. From a medical economic perspective, early cancer treatment of the gastrointestinal tract, particularly endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), is an extremely effective method, and demand for these procedures is expected to continue to increase. To perform EMR and ESD easily and safely, an appropriate amount of a highly viscous solution is injected into the submucosa at the site of the lesion to be resected or dissected, maintaining the mucosal protuberance formed, improving the ease of resection or dissection.

[0003] For large lesions or when fractional EMR is expected to take a long time to treat, sodium hyaluronate is used as a highly viscous substance suitable for forming and maintaining mucosal elevations (see, for example, the Gastrointestinal Endoscopy Handbook, Revised 2nd Edition, pp. 400-412). Products using sodium hyaluronate include "Mucoup (registered trademark)" and "Keismart (registered trademark)," which are clear, colorless, and slightly viscous liquids filled in glass vials (see the package insert for "Mucoup," a highly controlled medical device for endoscopic submucosal injection).

[0004] As a preliminary step for EMR and ESD, for example, to make the submucosal layer easier to recognize, it is necessary to add the coloring agent indigo carmine to a sodium hyaluronate solution at a concentration that makes the blood vessels and muscle layer transparent (see Gastrointestinal Endoscopy Handbook, Revised 2nd Edition, pp. 400-412). Indigo carmine is known to be easily oxidized and to fade due to the effects of oxygen in the air and light. Patent Document 1 discloses a technology relating to a composition containing highly stable hyaluronic acid or its salt and indigo carmine. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2022 / 065473 [Non-patent literature]

[0006] [Non-Patent Document 1] Gastrointestinal Endoscopy Handbook, Revised 2nd Edition, p400-p412 [Non-patent document 2] Package insert for "Mucoup," a submucosal injection material for endoscopy, designated as a specially controlled medical device Summary of the Invention [Problem to be solved by the invention]

[0007] The composition disclosed in Patent Document 1 has excellent stability of hyaluronic acid or a salt thereof and indigo carmine. However, there is a demand for further suppression of changes (decrease) in viscosity and pH of the composition.

[0008] Therefore, the present invention aims to provide a means for a composition containing hyaluronic acid or its salt and indigo carmine, which has excellent stability of the hyaluronic acid or its salt and indigo carmine and can suppress a decrease in viscosity and pH of the composition. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above problems. As a result, they have found that the above problems can be solved by filling a medical container, which is a polypropylene syringe, with a composition containing hyaluronic acid or its salt and indigo carmine, and have thus completed the present invention.

[0010] That is, the above problems can be solved by the present invention having the following configuration, and the present invention includes the following aspects and configurations.

[0011] One aspect of the present invention is (1) A package in which a medical container filled with a composition containing hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof is sealed in an oxygen-barrier container together with an oxygen scavenger, The weight average molecular weight of the hyaluronic acid or its salt is 600,000 or more, the concentration of the hyaluronic acid or a salt thereof in the composition is 0.1 to 0.5 w / v %, The concentration of the indigo carmine in the composition is 0.0002 to 0.012 w / v%, the content of the L-methionine in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, the content of the citric acid or a salt thereof in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof; The intrinsic viscosity of the composition is 11.8 dL / g or more, The medical container is a polypropylene syringe; (2) In the package described in (1) above, the oxygen barrier container has an oxygen permeability of 8.0 cm when measured at 23°C and 50% RH. 3 / m 2 ·day·atm or less is preferable; (3) In the package described in (1) or (2) above, the oxygen absorption capacity of the oxygen absorber is preferably 15 mL or more; (4) In the package according to any one of (1) to (3), the oxygen barrier container has an oxygen permeability (cm 3 / m 2 The ratio of the oxygen absorption amount (mL) of the oxygen scavenger to the oxygen scavenger temperature (°C / day / atm) is preferably 25 or more. [Effects of the Invention]

[0012] According to the present invention, a means can be provided for a composition containing hyaluronic acid or its salt and indigo carmine, which has excellent stability of the hyaluronic acid or its salt and indigo carmine and can suppress a decrease in viscosity and pH of the composition. DETAILED DESCRIPTION OF THE INVENTION

[0013] An embodiment of the present invention will be described below, but the present invention is not limited to the following embodiment.

[0014] In this specification, the range "X to Y" means "X or more and Y or less." Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20 to 25°C) and a relative humidity of 40 to 50% RH.

[0015] <Package> One embodiment of the present invention is a package in which a medical container filled with a composition containing hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof is sealed in an oxygen barrier container together with an oxygen scavenger, The weight average molecular weight of the hyaluronic acid or its salt is 600,000 or more, the concentration of the hyaluronic acid or a salt thereof in the composition is 0.1 to 0.5 w / v %, The concentration of the indigo carmine in the composition is 0.0002 to 0.012 w / v%, the content of the L-methionine in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, the content of the citric acid or a salt thereof in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof; The intrinsic viscosity of the composition is 11.8 dL / g or more, The medical container is the packaging body, and the syringe is made of polypropylene.According to this embodiment, in the composition that comprises hyaluronic acid or its salt and indigo carmine, the means that can provide the excellent stability of hyaluronic acid or its salt and indigo carmine, and can prevent the viscosity and pH of composition from decreasing.

[0016] (Hyaluronic acid or its salts) The composition of this embodiment contains hyaluronic acid or a salt thereof, the weight-average molecular weight of the hyaluronic acid or a salt thereof is 600,000 or more, and the concentration of the hyaluronic acid or a salt thereof in the composition is 0.1 to 0.5 w / v%.

[0017] Hyaluronic acid is composed of the basic structure (repeating unit) of GlcUA-GlcNAc, which is the combination of glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc).There is no particular limitation on the salt of hyaluronic acid, as long as it is in the form of a pharmaceutically or pharmacologically acceptable salt.The salt of hyaluronic acid can be exemplified by sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, calcium hyaluronate, magnesium hyaluronate, ammonium hyaluronate, etc.

[0018] The hyaluronic acid or its salt according to this embodiment can be any hyaluronic acid or its salt that can be used in endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).

[0019] In a preferred embodiment, the hyaluronic acid or salt thereof is sodium hyaluronate.

[0020] The weight-average molecular weight of hyaluronic acid or its salt is 600,000 or more, preferably 600,000 to 1,200,000. Hyaluronic acid or its salt with a weight-average molecular weight of less than 600,000 is unsuitable for use in EMR and ESD. The package according to this embodiment uses a polypropylene syringe to prevent the weight-average molecular weight of hyaluronic acid or its salt from decreasing over time, thereby keeping the rate of change in the weight-average molecular weight of hyaluronic acid or its salt within -20% when the package is stored at 60°C for two weeks (protected from light). The rate of change in weight-average molecular weight refers to the rate of change when the weight-average molecular weight at the start of storage is taken as 100%. The weight-average molecular weight of hyaluronic acid or its salt can be calculated using the method described in the Examples.

[0021] The concentration of hyaluronic acid or its salt in the composition is 0.1 to 0.5 w / v%, preferably 0.2 to 0.4 w / v%. If the concentration of hyaluronic acid or its salt in the composition is less than 0.1 w / v% or more than 0.5 w / v%, it is not preferable from the viewpoint of ease of pushing during injection and formation and maintenance of mucosal protuberance when the composition is used for EMR and ESD.

[0022] Hyaluronic acid and its salts may be naturally occurring or synthetic, and commercially available products may also be used.

[0023] (indigo carmine) The composition according to this embodiment contains indigo carmine (chemical name: disodium 3,3'-dioxo-2,2'-bis-indolidene-5,5'-disulfonate), and the concentration of indigo carmine in the composition is 0.0002 to 0.012 w / v%. Indigo carmine may be in the cis form or the trans form, and is preferably in the trans form.

[0024] The concentration (content) of indigo carmine in the composition is 0.0002 to 0.012 w / v%, preferably 0.001 to 0.004 w / v%. A concentration (content) of indigo carmine in the composition less than 0.0002 w / v% or more than 0.012 w / v% is undesirable from the viewpoint of visibility during EMR or ESD. The package according to this embodiment uses a polypropylene syringe to suppress the decrease in indigo carmine concentration (content) over time. Therefore, when the package is stored (protected from light) at 60°C for two weeks, the rate of change in indigo carmine concentration (content) can be kept within -20%, preferably within -15%. The rate of change in concentration (content) refers to the rate of change when the concentration (content) at the start of storage is taken as 100%. The concentration (content) of indigo carmine can be measured by the method described in the Examples.

[0025] The indigo carmine according to the present invention may be synthesized by referring to a conventionally known method, or a commercially available product may be used.

[0026] (L-methionine and citric acid or its salts) The composition of this embodiment comprises L-methionine and citric acid or its salt, and the content of L-methionine in the composition is 0.25-50 parts by mass relative to 100 parts by mass of hyaluronic acid or its salt, and the content of citric acid or its salt in the composition is 0.25-50 parts by mass relative to 100 parts by mass of hyaluronic acid or its salt.By using L-methionine and citric acid or its salt in combination, hyaluronic acid or its salt and indigo carmine can be stabilized.

[0027] In this specification, citric acid and its salts include hydrates thereof.

[0028] Examples of citric acid or a salt thereof include citric acid, sodium citrate, disodium citrate, trisodium citrate, and hydrates thereof. From the viewpoint of being able to more effectively exhibit the effects of the present invention, the citric acid or a salt thereof is preferably sodium citrate or sodium citrate hydrate.

[0029] The content of L-methionine in the composition is 0.25-50 parts by mass relative to 100 parts by mass of hyaluronic acid or its salt, and from the viewpoint of being able to more effectively exhibit the effects of the present invention, it is preferably 0.25-12.5 parts by mass, more preferably 0.50-5 parts by mass, and even more preferably 0.625-2.5 parts by mass. If the content of L-methionine in the composition is less than 0.25 parts by mass or more than 50 parts by mass relative to 100 parts by mass of hyaluronic acid or its salt and indigo carmine, it is not preferable from the viewpoint of stabilizing.

[0030] The content of citric acid or its salt in the composition is 0.25 to 50 parts by mass relative to 100 parts by mass of hyaluronic acid or its salt, and from the viewpoint of being able to more effectively exhibit the effects of the present invention, it is preferably 0.25 to 25 parts by mass, more preferably 1.25 to 25 parts by mass, and even more preferably 6.25 to 25 parts by mass. If the content of citric acid or its salt in the composition is less than 0.25 parts by mass or more than 50 parts by mass, it is not preferable from the viewpoint of stabilizing hyaluronic acid or its salt and indigo carmine.

[0031] Commercially available L-methionine and citric acid or a salt thereof can be used.

[0032] (Other ingredients) The composition of this embodiment may contain other components as needed, such as a solvent, a pH adjusting agent, a buffer, and a tonicity adjusting agent.

[0033] The solvent may be water. Examples of water include distilled water, tap water, purified water, sterile purified water, water for injection, distilled water for injection, etc. The definition of water is based on the 18th edition of the Japanese Pharmacopoeia.

[0034] Examples of pH adjusters include bases such as sodium hydroxide and potassium hydroxide; inorganic acids such as hydrochloric acid; and organic acids such as lactic acid, acetic acid, succinic acid, and malic acid.

[0035] Examples of the buffering agent include phosphoric acid, a salt thereof, or a hydrate thereof (such as sodium hydrogen phosphate hydrate, trisodium phosphate hydrate, and sodium dihydrogen phosphate hydrate), acetic acid, a salt thereof, or a hydrate thereof.

[0036] The concentrations of the pH adjuster and buffer are not particularly limited and can be adjusted appropriately to achieve the desired pH.

[0037] Examples of the isotonicity agent include non-ionic isotonicity agents such as mannitol, sorbitol, inositol, glucose, propylene glycol, glycerol, etc., and ionic isotonicity agents such as sodium chloride, etc. The isotonicity agent is preferably sodium chloride.

[0038] The concentration of the isotonic agent can be adjusted as appropriate. The osmotic pressure ratio of the composition is, for example, 0.9 to 1.2 (ratio to physiological saline).

[0039] (pH of composition) The pH of the composition according to this embodiment is, for example, 6.0 to 8.0, preferably 7.0 to 8.0. The pH of the composition can be adjusted using the above-mentioned pH regulator and / or buffer, if necessary. The pH of the composition can be confirmed using a pH meter.

[0040] The package according to this embodiment can suppress changes in the pH of the composition over time.

[0041] (Intrinsic viscosity of composition) The intrinsic viscosity of the composition according to this embodiment is 11.8 dL / g or more. If the intrinsic viscosity of the composition is less than 11.8 dL / g, it becomes difficult to form and maintain a mucosal protuberance at the tumor site during endoscopic surgery, which is undesirable. The upper limit of the intrinsic viscosity of the composition is, for example, 19.5 dL / g or less. The intrinsic viscosity of the composition is a value measured according to Section 2.53, Viscosity Measurement Method, of the General Tests Methods of the Japanese Pharmacopoeia, 18th Edition.

[0042] The package according to this embodiment can suppress the change in the intrinsic viscosity of the composition over time. The package according to this embodiment can suppress the decrease in intrinsic viscosity (the ratio of the intrinsic viscosity after storage to the intrinsic viscosity at the start of storage) to within -15% after storage (protected from light) at 60°C for 2 weeks.

[0043] (Method of preparing the composition) The method for preparing the composition of this embodiment is not particularly limited, and the composition can be prepared by mixing hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof, and other ingredients as necessary.

[0044] Specifically, ingredients other than hyaluronic acid or its salt and indigo carmine are dissolved in water (e.g., water for injection). If necessary, the pH of the solution is adjusted to 7 to 8 using a pH adjuster and / or buffer. After dissolving hyaluronic acid or its salt in this solution, indigo carmine is dissolved, and water is added as needed to prepare the composition. When preparing the composition, the solution may be heated appropriately to improve solubility depending on the concentration of the ingredients used.

[0045] The composition can be prepared in the atmosphere (air) or in an inert gas atmosphere, such as nitrogen gas.

[0046] The prepared composition is appropriately sterilized. Examples of sterilization methods include filtration sterilization, high-pressure steam sterilization, etc. The composition may be sterilized after being filled into a medical container.

[0047] (Use of the composition) The composition of this embodiment can be used for forming and maintaining a mucosal prominence at a tumor site under endoscopic surgery. Thus, in one embodiment, the composition of this embodiment is for submucosal local injection, preferably for endoscopic mucosal resection and / or endoscopic submucosal dissection. The composition of this embodiment may be diluted appropriately to achieve a desired viscosity depending on the situation.

[0048] (Medical containers) The package of this embodiment comprises a medical container filled with the composition and sealed in an oxygen-barrier container together with an oxygen scavenger, the medical container being a polypropylene syringe. The polypropylene is preferably polypropylene conforming to the Japanese Pharmacopoeia General Test Method - Plastic Pharmaceutical Container Test Method. By sealing the medical container filled with the composition together with an oxygen scavenger in an oxygen-barrier container, the effects of oxygen can be suppressed, further improving storage stability. In particular, the package of this embodiment can more effectively suppress the decrease in the weight-average molecular weight of sodium hyaluronate and the deterioration (decomposition and discoloration) of indigo carmine compared to a syringe made of a cyclic olefin copolymer. Furthermore, since the medical container is a polypropylene syringe, the decrease in viscosity and pH of the composition can be suppressed.

[0049] The water vapor permeability of the medical container according to this embodiment is preferably 0.20% or less. By ensuring that the water vapor permeability of the medical container is 0.20% or less, the concentration of the composition can be suppressed, and the weight-average molecular weight of hyaluronic acid or its salt, the quantitative value of the indigo carmine content, etc. can be stabilized. In this specification, water vapor permeability is measured according to the General Test Methods for Plastic Pharmaceutical Containers in the 18th Edition of the Japanese Pharmacopoeia.

[0050] The medical container filled with the composition and the oxygen scavenger can be enclosed in an oxygen-barrier container according to a conventional method. The encapsulation 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. Furthermore, the encapsulation can be carried out after replacing the atmosphere inside the oxygen-barrier container with an inert gas.

[0051] The size of the medical container (polypropylene syringe) according to this embodiment is not particularly limited, and can be selected appropriately depending on the amount of the composition to be filled, the intended use, the form of use, and the like.

[0052] In a preferred embodiment, the medical container is a pre-filled syringe made of polypropylene.

[0053] The syringe may have a gasket made of an elastomer. Examples of elastomers include, but are not limited to, natural rubber, isoprene rubber, chlorinated or brominated butyl rubber, chloroprene rubber, nitrile-butadiene rubber, styrene-butadiene rubber, and silicone rubber (especially vulcanized rubbers); thermoplastic elastomers such as styrene elastomers, hydrogenated styrene elastomers, polyvinyl chloride elastomers, olefin elastomers, polyester elastomers, polyamide elastomers, and polyurethane elastomers; and mixtures of styrene elastomers with 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 a single type 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 that it has elastic properties and can be sterilized by gamma rays, electron beams, and high-pressure steam.

[0055] The gasket that constitutes the syringe is preferably 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 the rear end.

[0056] The composition can be filled into a medical 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. Examples of inert gases that can be used include nitrogen gas, argon gas, and carbon dioxide gas.

[0057] The medical container filled with the composition is preferably sterilized. The sterilization method is not particularly limited, and conventionally known methods such as high-pressure steam sterilization can be used. When high-pressure steam sterilization is used as the sterilization method, steam can be used as the sterilization medium for high-pressure steam sterilization. A mixed gas of inert gas and air or air can be used as the pressurized medium for high-pressure steam sterilization. That is, high-pressure steam sterilization may be performed using steam as the sterilization medium and air as the pressurized medium, or using steam as the sterilization medium and an inert gas as the pressurized medium, or using steam as the sterilization medium and a mixed gas of air and an inert gas as the pressurized medium.

[0058] Inert gases used in high-pressure steam sterilization include nitrogen gas, argon gas, and carbon dioxide gas, with nitrogen gas being preferred because it is available at low cost.

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

[0060] The method for producing the medical container is not particularly limited, and any known method can be appropriately selected, such as injection molding, extrusion molding, blow molding, rotational molding, blow molding, transfer molding, press molding, or solution casting.

[0061] (oxygen absorber) There are no particular limitations on the oxygen scavenger, as long as it does not pose problems such as toxicity in use and can efficiently absorb oxygen to reduce the amount of oxygen in the atmosphere.

[0062] In a preferred embodiment, the oxygen absorption capacity of the oxygen scavenger is 15 mL or more. The upper limit of the oxygen absorption capacity of the oxygen scavenger is not particularly limited and may be, for example, 200 mL or less. The oxygen absorption capacity can be measured by a known method. When a commercially available oxygen scavenger is used, the oxygen absorption capacity may be the catalog value.

[0063] 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.

[0064] The oxygen absorber may be one that absorbs oxygen and carbon dioxide gas at the same time, or one that absorbs oxygen and releases carbon dioxide gas.

[0065] 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 kneaded with an oxygen absorber, 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.

[0066] Commercially available oxygen absorbers include Ageless (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.), Moduran (manufactured by Nippon Kayaku Food Techno Co., Ltd.), Secur (registered trademark) (manufactured by Nisso Fine Co., Ltd.), and Vitalon (registered trademark).

[0067] (Oxygen barrier container) The oxygen barrier container is not particularly limited as long as it is a container that can enclose the medical container and is non-toxic. The oxygen barrier container may be a soft container or a hard container. In addition, the oxygen barrier container may have a light-shielding ability.

[0068] In a preferred embodiment, the oxygen permeability of the oxygen barrier container (oxygen permeability of the material forming the oxygen barrier container) is 8.0 cm or less when measured at 23°C and 50% RH, from the viewpoint of further demonstrating the effects of the present invention. 3 / m 2 ·day·atm or less, and more preferably 5.0cm 3 / m 2 ·day·atm or less, and more preferably 3.0cm 3 / m 2 ·day·atm or less, and particularly preferably 2.0 cm 3 / m 2 The oxygen permeability can be measured in accordance with JIS K 7126-2:2006 under conditions of 23°C and 50% RH using an oxygen permeability measuring device (OX-TRAN (registered trademark) MODEL2 / 22 manufactured by MOCON).

[0069] In a preferred embodiment, the oxygen permeability (cm 3 / m 2 The ratio of the oxygen absorption capacity (mL) of the oxygen scavenger to the oxygen absorbed by the oxygen scavenger (mL) is 25 or more.

[0070] The material for forming the oxygen barrier container is not particularly limited as long as it has a certain degree of strength and hardness and 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.

[0071] Examples of materials for the substrate of metallized films, metallized sheets, inorganic vapor-deposited films and inorganic vapor-deposited sheets include polyolefin resins such as polypropylene and polyethylene, polyamide, polyvinyl chloride, polyester, and polystyrene / polypropylene resin.

[0072] The material forming the oxygen barrier container may be a laminate. At least one layer of the laminate contains the above-mentioned material having oxygen barrier properties. The materials of the other layers constituting the laminate are not particularly limited.

[0073] When oxygen barrier containers are formed from films or sheets, the packaging container is often formed by folding the film or sheet and heat-sealing the periphery, so it is preferable that the part that will become the innermost surface when folded is formed from at least a heat-sealable adhesive resin layer (for example, polyolefin resins such as polypropylene and polyethylene, polystyrene / polypropylene resin, ethylene-vinyl acetate resin, ethylene-acrylic acid resin, polyvinyl chloride resin, or various thermoplastic elastomers).

[0074] Specific examples of materials for oxygen barrier containers include, but are not limited to: · Multilayer film or sheet made of polypropylene (PP) / silica-deposited polyethylene terephthalate (PET) / polypropylene (PP) laminated in this order; · Multilayer film or sheet made by laminating biaxially oriented polyamide (OPA) / polyethylene (PE) / aluminized PET / polyethylene (PE) in this order; Multilayer film or sheet made of OPA / PE / aluminized PET / PE laminated in this order; Multilayer film or sheet made by laminating OPA / PE / aluminum foil / PE / PE in this order; Multilayer film or sheet made by laminating OPA / PE / aluminum foil / PE / PET / PE in this order; Multilayer film or sheet made of PET / PE / aluminized PET / PE / ethylene-vinyl acetate copolymer (EVA) / PE laminated in this order; Multilayer film or sheet made of polyvinylidene chloride / PE / aluminized PET / PE laminated in this order; · Multilayer film or sheet made by laminating PET / aluminized ethylene-vinyl alcohol copolymer (EVOH) / PE in this order; · Multilayer film or sheet made of biaxially oriented nylon (ONY) / EVOH / PE laminated in this order; Multilayer film or sheet made by laminating PET / aluminized EVOH / a blend of the above resins in that order Multilayer film or sheet made by laminating PP / EVOH / PP in this order Examples include:

[0075] Examples of the oxygen barrier container include blister containers, bags, tubes, etc. When the oxygen barrier container is a blister container, a combination of a top film (for example, a multilayer film of PET / aluminum-deposited EVOH / a blend of the above resin) and a bottom film (for example, a multilayer film of PP / EVOH / PP) can be used.

[0076] The method for producing the oxygen barrier container is not particularly limited, and any known method can be appropriately selected depending on the type of material from which the oxygen barrier container is made, the shape, etc.

[0077] <Stabilization method> Another aspect of the present invention is a method for stabilizing a composition comprising hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof, the method comprising: The method includes enclosing a medical container filled with the composition in an oxygen barrier container together with an oxygen scavenger, The weight average molecular weight of the hyaluronic acid or its salt is 600,000 or more, the concentration of the hyaluronic acid or a salt thereof in the composition is 0.1 to 0.5 w / v %, The concentration of the indigo carmine in the composition is 0.0002 to 0.012 w / v%, the content of the L-methionine in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, the content of the citric acid or a salt thereof in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof; The intrinsic viscosity of the composition is 11.8 dL / g or more, This is a stabilization method, wherein the medical container is a syringe made of polypropylene.

[0078] In this embodiment, stabilizing the composition means suppressing a decrease in the weight-average molecular weight of sodium hyaluronate and the content of indigo carmine, suppressing a decrease in the intrinsic viscosity of the composition, and suppressing a decrease in the pH of the composition.

[0079] The specific explanation of the stabilization method has been given above, so a detailed explanation will be omitted here. [Example]

[0080] The effects of the present invention will be explained 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.

[0081] <Reference Examples 1 and 2> Sodium chloride and sodium hydrogen phosphate hydrate were added to an appropriate amount of water for injection cooled to room temperature and dissolved in the amounts listed in Table 1 below, and then sodium dihydrogen phosphate hydrate was used to adjust the pH to 7-8. Sodium hyaluronate with a weight-average molecular weight of approximately 1,000,000 was added little by little to this solution and dissolved, and then the total volume was adjusted to 2,000 mL with water for injection to prepare a composition. 20 mL of this composition was filled into a medical container (syringe) listed in Table 2, sealed, and then sterilized by high-pressure steam (121°C, 4 minutes). A butyl rubber gasket was used as the gasket that constituted the syringe.

[0082] <Reference example 3> In Reference Example 3, a commercially available hyaluronic acid preparation filled in a glass vial was used.

[0083] [Table 1]

[0084] [Table 2]

[0085] The medical containers (syringes) of Reference Examples 1 to 3 were stored at 60°C for 3 weeks. The intrinsic viscosity of the composition, the weight-average molecular weight of sodium hyaluronate, and the pH of the composition were measured or calculated at the start (after sterilization), 1 week, 2 weeks, and 3 weeks. The intrinsic viscosity of the composition was measured according to Section 2.53, Viscosity Measurement, of the Japanese Pharmacopoeia, 18th Edition, General Tests. The weight-average molecular weight was calculated using the intrinsic viscosity value according to Laurent's formula. The pH was measured using a pH meter (manufactured by DKK-TOA Corporation) according to Section 2.54, pH Measurement, of the Japanese Pharmacopoeia, 18th Edition, General Tests. The percentage change in intrinsic viscosity and weight-average molecular weight, with the initial values ​​(after sterilization) taken as 100%, is also shown (Tables 3 and 4).

[0086] [Table 3]

[0087] [Table 4]

[0088] [Table 5]

[0089] As shown in Tables 3 and 4, in the medical containers of Reference Examples 1 and 2, the intrinsic viscosity of the composition and the weight-average molecular weight of sodium hyaluronate decrease less than in the glass vial of Reference Example 3. Also, as shown in Table 5, it was found that the pH changes over time of the compositions in the medical containers of Reference Examples 1 and 2 and the hyaluronic acid preparation in the glass vial of Reference Example 3 are comparable.

[0090] <Example 1 and Comparative Example 1> It is known that the stability of indigo carmine decreases under the influence of oxygen. However, when a composition containing hyaluronic acid or its salt and indigo carmine is filled into a medical container (syringe), the effect of the material forming the syringe on stability is unknown. When comparing a syringe made of polypropylene with a syringe made of cyclic olefin copolymer, the polypropylene syringe is more easily permeable to oxygen inside the syringe than the cyclic olefin copolymer syringe. Below, we investigated the effect of the material forming the syringe on stability.

[0091] Under a nitrogen atmosphere, L-methionine, sodium citrate hydrate, sodium chloride, and trisodium phosphate hydrate were dissolved in an appropriate amount of water for injection in the amounts listed in Table 6 below, and then the pH was adjusted to 7-8 using sodium dihydrogen phosphate hydrate. Sodium hyaluronate with a weight-average molecular weight of approximately 1,000,000 was added in small amounts to this solution and dissolved, followed by indigo carmine and water for injection to a total volume of 2500 mL to prepare a composition. 20 mL of this composition was filled into a medical container (syringe) listed in Table 7, sealed, and then autoclaved (121°C, 4 minutes) using nitrogen gas as the pressure medium. The sterilized syringe and a deoxidizer ("Ageless®", Mitsubishi Gas Chemical Company, Inc.) with an oxygen absorption capacity of 50 mL were then sealed in an oxygen barrier container (a bag made of aluminum vapor-deposited film) to prepare a package. The oxygen barrier container had an oxygen permeability of 2.0 cm when measured at 23°C and 50% RH. 3 / m 2 ·day·atm Materials made from the following materials were used.

[0092] [Table 6]

[0093] [Table 7]

[0094] The packaging of Example 1 and Comparative Example 1 is stored at 60 ℃ for 2 weeks (protected from light), and the intrinsic viscosity of the composition, the weight-average molecular weight of sodium hyaluronate and the pH of the composition are measured or calculated at the beginning (after sterilization), 1 week and 2 weeks later.The intrinsic viscosity is measured according to the viscosity measurement method of Section 2.53 of the Japanese Pharmacopoeia General Test Method, 18th Edition.The weight-average molecular weight is calculated by the Laurent formula using the intrinsic viscosity value.The change rate (%) of the intrinsic viscosity and weight-average molecular weight at the beginning (after sterilization) is also shown (Table 8 and Table 9), assuming that the intrinsic viscosity and weight-average molecular weight are 100%.

[0095] [Table 8]

[0096] [Table 9]

[0097] The packages of Example 1 and Comparative Example 1 were stored (protected from light) at 60°C for 2 weeks, and the indigo carmine concentration (content) was measured at a wavelength of 254 nm at the start (after sterilization), and after 1 week and 2 weeks, based on the literature of Bailey JE (J. Assoc. Off. Anal Chem, 63, 565 (1980)). The percentage change (%) when the content at the start (after sterilization) is set to 100% is also shown (Table 10).

[0098] [Table 10]

[0099] The packages of Example 1 and Comparative Example 1 were stored at 60°C for 2 weeks (protected from light), and the pH of the compositions was measured at the start (after sterilization), and after 1 week and 2 weeks (Table 11).

[0100] [Table 11]

[0101] It has been found that when indigo carmine is added, the intrinsic viscosity of the composition and the weight-average molecular weight of sodium hyaluronate change at different rates depending on the medical container.It has been found that the intrinsic viscosity of the composition and the weight-average molecular weight of sodium hyaluronate decrease in Example 1, which is stored in a syringe made of polypropylene, are suppressed compared to Comparative Example 1, which is stored in a syringe made of cyclic olefin copolymer.

[0102] Furthermore, it was found that the content of indigo carmine was maintained in Example 1, but was significantly reduced in Comparative Example 1.

[0103] Furthermore, it was found that the pH of the composition in Example 1 was less likely to decrease than that in Comparative Example 1.

Claims

1. A package in which a medical container filled with a composition containing hyaluronic acid or a salt thereof, indigo carmine, L-methionine, and citric acid or a salt thereof is sealed in an oxygen barrier container together with an oxygen scavenger, The weight average molecular weight of the hyaluronic acid or its salt is 600,000 or more, the concentration of the hyaluronic acid or its salt in the composition is 0.1 to 0.5 w / v %, the concentration of the indigo carmine in the composition is 0.0002 to 0.012 w / v %, the content of the L-methionine in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, the content of the citric acid or a salt thereof in the composition is 0.25 to 50 parts by mass per 100 parts by mass of the hyaluronic acid or a salt thereof, The intrinsic viscosity of the composition is 11.8 dL / g or more; A package in which the medical container is a syringe made of polypropylene.

2. The oxygen barrier container has an oxygen permeability of 8.0 cm when measured at 23°C and 50% RH. ３ / m ２ 2. The package of claim 1, wherein the temperature is 0.5°C or less.

3. The package according to claim 1, wherein the oxygen absorber has an oxygen absorption capacity of 15 mL or more.

4. The oxygen barrier container has an oxygen permeability (cm ３ / m ２ 2. The package according to claim 1, wherein the ratio of the oxygen absorption amount (mL) of the oxygen absorber to the oxygen absorber's oxygen per day (day atm) is 25 or more.

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