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WO2012118194A1 - Seringue préremplie pour le remplissage d'une seringue ayant un corps en résine par une solution aqueuse contenant de l'acide hyaluronique ou un sel de celui-ci - Google Patents

Seringue préremplie pour le remplissage d'une seringue ayant un corps en résine par une solution aqueuse contenant de l'acide hyaluronique ou un sel de celui-ci Download PDF

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Publication number
WO2012118194A1
WO2012118194A1 PCT/JP2012/055427 JP2012055427W WO2012118194A1 WO 2012118194 A1 WO2012118194 A1 WO 2012118194A1 JP 2012055427 W JP2012055427 W JP 2012055427W WO 2012118194 A1 WO2012118194 A1 WO 2012118194A1
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WO
WIPO (PCT)
Prior art keywords
aqueous solution
hyaluronic acid
salt
solution containing
barrel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2012/055427
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English (en)
Japanese (ja)
Inventor
健司 能見
賢太郎 島田
忠志 守川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Denka Co Ltd
Original Assignee
Denki Kagaku Kogyo KK
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Filing date
Publication date
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Priority to JP2013502425A priority Critical patent/JP5957442B2/ja
Priority to KR1020137026038A priority patent/KR20140145940A/ko
Priority to CN201280011059.XA priority patent/CN103547273A/zh
Publication of WO2012118194A1 publication Critical patent/WO2012118194A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels

Definitions

  • the present invention relates to a prefilled syringe in which a syringe having a resin barrel is filled with an aqueous solution containing hyaluronic acid or a salt thereof.
  • Hyaluronic acid is known as a polysaccharide composed of linked disaccharide units of N-acetylglucosamine and glucuronic acid.
  • Hyaluronic acid is generally used as a raw material for pharmaceuticals, cosmetics, foods and the like.
  • As a production method of hyaluronic acid there are a method of producing with an extract from a chicken crown or the like, and a method of producing by a fermentation method using a microorganism.
  • Patent Document 1 describes that hyaluronic acid was produced by fermentation using Streptococcus tin-epidemicus.
  • Patent Document 2 describes that hyaluronic acid powder was produced by fermentation using Streptococcus equi (ATCC9527).
  • prefilled syringes are stored and distributed in a state filled with a pharmaceutical composition, it may take several years from the filling of the pharmaceutical composition in a production factory to the administration. Therefore, it goes without saying that it is necessary to provide long-term stability, but it is required to be able to visually determine the contamination of impurities during administration and to confirm the safety of the pharmaceutical composition. Therefore, the material constituting the barrel is required to be highly transparent, and in the conventional prefilled syringe, a glass barrel that can ensure transparency is frequently used.
  • Patent Document 3 discloses a prefilled solution in which a sodium hyaluronate aqueous solution is filled in a syringe having a resin barrel, a gasket slidably inserted into the barrel, and a plunger attached to the gasket. A syringe is described.
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide a prefilled syringe capable of stably storing an aqueous solution containing high-purity hyaluronic acid or a salt thereof filled in a resin barrel.
  • the present inventors have surprisingly found that even when a resin barrel such as COP resin is used, an aqueous solution containing hyaluronic acid or a salt thereof in an aqueous solution containing metal thiosulfate, metal thiocyanate, thiourea It has also been found that the viscosity or stability of the sodium hyaluronate aqueous solution is remarkably recovered when thiosemicarbazides, thioketones and sulfides are added.
  • a prefilled syringe in which a syringe having a resin barrel is filled with an aqueous solution containing hyaluronic acid or a salt thereof.
  • the aqueous solution containing the above hyaluronic acid or a salt thereof contains at least one additive selected from the group consisting of metal thiosulfate, metal thiocyanate, thioureas, thiosemicarbazides, thioketones and sulfides. contains.
  • a metal thiosulfate, a metal thiocyanate, a thiourea, a thiosemicarbazide, a thioketone and a sulfide are added to an aqueous solution containing hyaluronic acid or a salt thereof, a COP resin is used.
  • resin barrels such as the first, the viscosity or stability of an aqueous solution containing hyaluronic acid or a salt thereof hardly decreases.
  • the high-purity sodium hyaluronate aqueous solution filled in the resin barrel can be stably stored even when a resin barrel that easily transmits ultraviolet rays is used.
  • a hyaluronic acid composition for filling a syringe having a resin barrel is provided.
  • a metal thiosulfate, a metal thiocyanate, a thiourea, a thiosemicarbazide, a thioketone and a sulfide are added to an aqueous solution containing hyaluronic acid or a salt thereof, COP Even when a resin barrel such as a resin is filled, the viscosity or stability of an aqueous solution containing hyaluronic acid or a salt thereof hardly decreases.
  • the aqueous solution containing hyaluronic acid or a salt thereof is added with one or more selected from the group consisting of metal thiosulfate, metal thiocyanate, thioureas, thiosemicarbazides, thioketones and sulfides. Since it contains a product, the high-purity sodium hyaluronate aqueous solution filled in the resin barrel can be stably stored.
  • FIG. 1 is a schematic view of a prefilled syringe according to an embodiment of the present invention.
  • FIG. 2 is a graph showing changes in the intrinsic viscosity residual rate when sodium hyaluronate powder is added to an aqueous solution containing L-methionine.
  • FIG. 1 is a schematic view of a prefilled syringe which is a preferred embodiment of the present invention.
  • the prefilled syringe 1 according to the present embodiment can basically adopt the configuration of a conventional prefilled syringe as it is, and as shown in FIG. 1, a barrel 20 having a tip opening 21 provided at the tip, and a barrel A syringe 10 having a gasket 24 slidable in a liquid-tight and air-tight manner within the inside 20 and a plunger 25 attached to the rear end of the gasket 24, and a cap member 26 that seals the tip opening 21 of the barrel 20.
  • a silicone film 28 formed by spraying silicone oil is provided on the inner peripheral surface of the barrel 20.
  • the barrel 20 is a cylindrical body, and a distal end opening 21 for attaching an injection needle is provided at the distal end, and a finger is placed at the rear end during a pharmaceutical composition injection operation.
  • a pair of flanges 22 are provided facing each other.
  • a cap member 26 which is a sealing member to be described later is attached to the distal end opening 21 of the barrel 20.
  • an injection needle (not shown) may be directly attached.
  • a screwing portion 23 for attaching the cap member 26 or the injection needle is provided on the outer peripheral surface of the tip opening 21.
  • the barrel 20 is formed of a transparent resin material in order to allow visual inspection of the filled pharmaceutical composition 27.
  • the material for forming the barrel 20 is not particularly limited, but for example, polystyrene, polyamide, polycarbonate, polyvinyl chloride, polyvinylidene chloride, poly- (4-methylpentene-1) in terms of light transmittance, strength, or dimensional accuracy. ), Various resins such as polyvinyl alcohol, acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyester such as polyethylene terephthalate, cyclic polyolefin, and cyclic olefin copolymer.
  • a cyclic olefin polymer (COP) or a cyclic olefin copolymer (COC) having particularly excellent permeability is preferable from the viewpoint of improving the efficiency and accuracy of visual inspection of contents.
  • a resin is a thermoplastic saturated norbornene-based resin composition marketed under the Zeonex (registered trademark) by Nippon Zeon Co., Ltd., and is incompatible with the thermoplastic saturated norbornene-based resin. What disperse
  • the gasket 24 is not particularly limited in material, but is preferably formed of an elastic body such as rubber or a thermoplastic elastomer in order to maintain airtightness. Among them, it is particularly preferable to use butyl rubber having a small dimensional change in autoclave sterilization as a main raw material. As the butyl rubber, halogenated butyl rubber that has been chlorinated or brominated to improve crosslinkability, adhesion, and the like can also be used. However, it is not particularly limited as long as it can be used as a medical instrument and has been conventionally used as a material for forming a syringe gasket. Further, the surface material of the gasket is not particularly limited.
  • a material that has not been surface-treated with a tetrafluoroethylene resin film or an ultrahigh molecular weight polyethylene film is preferable.
  • silicone oil can be applied to the gasket surface.
  • the plunger 25 is sufficient if it has a strength sufficient to withstand the pushing force and bending required for sliding the gasket 24 within the barrel 20, and is made of a hard plastic material such as polyethylene or polypropylene. Although it is mentioned, it is not particularly limited as long as it can be used as a medical instrument and has been conventionally used as a material for forming a plunger.
  • the cap member 26 is in close contact with the tip opening 21 of the barrel 20 and hermetically seals the tip opening 21 and is made of an elastic body or hard resin such as butyl rubber, high-density polyethylene, polypropylene, polystyrene, or polyethylene terephthalate.
  • an elastic body or hard resin such as butyl rubber, high-density polyethylene, polypropylene, polystyrene, or polyethylene terephthalate.
  • a thing can be used, if it can be used as a medical instrument and has been conventionally used as a material for forming a cap member, it is not particularly limited.
  • a female thread portion that is threadedly engaged with the threaded portion 23 formed on the outer peripheral surface of the tip opening 21 of the barrel 20 is formed on the inner peripheral surface of the cap member 26.
  • the silicone oil applied to the inner peripheral surface of the barrel to form the silicone film 28 is basically polydimethylsiloxane, but polydimethylsiloxane having substituted side chains and terminals may be used as long as the lubricity is not impaired. it can. Specific examples include polymethylphenylsiloxane and polymethylhydrogensiloxane. You may mix
  • aqueous solution containing hyaluronic acid or a salt thereof is filled.
  • the syringe 10 having the above-described configuration is particularly suitable for filling a high-viscosity pharmaceutical composition such as an aqueous solution containing hyaluronic acid or a salt thereof.
  • the aqueous solution containing hyaluronic acid or a salt thereof filled in the syringe 10 having the above configuration is selected from the group consisting of metal thiosulfate, metal thiocyanate, thioureas, thiosemicarbazides, thioketones and sulfides.
  • One or more additives is selected from the group consisting of metal thiosulfate, metal thiocyanate, thioureas, thiosemicarbazides, thioketones and sulfides.
  • An aqueous solution containing hyaluronic acid or a salt thereof having such a composition is excellent in physical stability because the intrinsic viscosity residual ratio after storage is high as demonstrated in the examples described later.
  • the viscosity and quality are not easily lowered, and it is suitable, for example, as a pharmaceutical composition prefilled in a syringe as a prefilled syringe.
  • the metal thiosulfate may be, for example, potassium thiosulfate or sodium thiosulfate.
  • the metal thiocyanate may be, for example, potassium thiocyanate or sodium thiocyanate.
  • the thioketones may be, for example, thiopental.
  • the sulfides may be, for example, L-methionine or DL-methionine.
  • the above thioureas are compounds having a structure of RNC ( ⁇ S) —NR, and may be, for example, H 2 NC ( ⁇ S) —NH 2 .
  • the above thiosemicarbazides are compounds having a structure of RNC ( ⁇ S) —NH—NR, and may be, for example, H 2 —NC ( ⁇ S) —NH—NH 2 . From the viewpoint of further improving the stability of an aqueous solution containing hyaluronic acid or a salt thereof, L-methionine or sodium thiosulfate is preferable.
  • the above 5 ppb or less may be, for example, 0.001, 0.01, 0.1, 0.5, 1, 2, 4, or 5 ppb.
  • the content may be equal to or less than the value exemplified here, or may be in the range of any two values. This content is preferably smaller from the viewpoint of improving the stability of an aqueous solution containing hyaluronic acid or a salt thereof.
  • the content of the reducing agent contained in the aqueous solution containing hyaluronic acid or a salt thereof used in the present embodiment is, for example, 5, 10, 30, 50, 100, 150, 300, 500, 800, 1000, 1500, 2000. 5000 or 10000 ⁇ g / mL. Moreover, this content rate may be in the range of any two values exemplified here. From the viewpoint of further improving the stability of the aqueous solution containing hyaluronic acid or a salt thereof, 10 ⁇ g / mL or more is preferable, and 100 ⁇ g / mL or more is more preferable.
  • the content is preferably 2000 ⁇ g / mL or less, more preferably 1500 ⁇ g / mL or less, from the viewpoint of reducing production cost or improving operability.
  • the average molecular weight of sodium hyaluronate or a salt thereof contained in an aqueous solution containing hyaluronic acid or a salt thereof used in the present embodiment is, for example, 500,000, 800,000, 1,000,000, 1.5 million, 1.8 million, 2 million, 2.5 million, It may be 3 million, 5 million, or 8 million. This average molecular weight may be within the range of any two values exemplified here. From the viewpoint of further improving the viscosity of an aqueous solution containing hyaluronic acid or a salt thereof, it is preferably 1 million or more, more preferably 1.5 million or more.
  • An aqueous solution containing high-viscosity hyaluronic acid or a salt thereof is excellent in retention in the affected area when used as an injection for the treatment of arthropathy.
  • the average molecular weight of sodium hyaluronate contained in an aqueous solution containing hyaluronic acid or a salt thereof is calculated by measuring the intrinsic viscosity, and then calculating the Laurent formula (LAURENT et al., Biochim Biophys Acta. 1960 Aug 26; 42: 476-485.) Can be used to calculate.
  • the content of hyaluronic acid or a salt thereof contained in the aqueous solution containing hyaluronic acid or a salt thereof used in the present embodiment is, for example, 0.1, 1, 5, 8, 9, 10, 11, 12, 15, or 20 mg / It may be mL. This content may be within the range of any two values exemplified here. From the viewpoint of therapeutic effect or operability when used for injections and the like, it is preferably in the range of 5 and 15 mg / mL, more preferably in the range of 8 and 12 mg / mL.
  • the pH of the aqueous solution containing hyaluronic acid or a salt thereof used in the present embodiment may be, for example, 5.5, 6, 6.5, 6.8, 7, 7.8, 8, 8.5, or 9. This pH may be within the range of any two values exemplified herein. From the viewpoint of stability, a value in the range of 6.5 and 8 is preferable, and a value in the range of 6.8 and 7.8 is more preferable.
  • the “hyaluronic acid salt” may be, for example, sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, calcium hyaluronate, or ammonium hyaluronate.
  • sodium hyaluronate is preferable from the viewpoint that a desired viscosity or a therapeutic effect on arthropathy can be expected.
  • the chemical name of sodium hyaluronate is, for example, [ ⁇ 3) -2-acetamido-2-deoxy- ⁇ -D-glucopyranosyl- (1 ⁇ 4) - ⁇ -D-sodium glucopyranosyluronate- (1 ⁇ ] n (IUPAC) Can be represented.
  • divalent soluble iron is iron in a soluble state and is divalent. It can also be expressed as Fe 2+ or divalent iron.
  • the pharmaceutical composition prefilled in the syringe is an aqueous solution containing hyaluronic acid or a salt thereof.
  • the pharmaceutical composition contains an aqueous solution containing hyaluronic acid or a salt thereof excellent in stability, the viscosity and quality are hardly lowered even after long-term storage. Further, for example, when it is administered in or around the joint, it can stay in the affected area for a long time or a desired time.
  • an injection in the form of a prefilled syringe is employed from the viewpoint that it can be directly administered to an affected area such as a joint.
  • This pharmaceutical composition is prepared according to the dosage form by using a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, lidocaine hydrochloride, procaine hydrochloride, etc.), a stabilizer (eg, human serum albumin). , Polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.), antioxidants and the like.
  • the pharmaceutical composition may also contain sodium hydrogen phosphate, crystalline sodium dihydrogen phosphate, and sodium chloride as additives.
  • the adjusted pharmaceutical composition can be administered to, for example, humans and mammals (eg, rats, mice, rabbits, dogs, monkeys, sheep, pigs, cows, cats, etc.).
  • the pharmaceutical composition includes a composition used for the purpose of prevention.
  • the administration method of this pharmaceutical composition can be appropriately selected depending on the age, symptoms, affected area, etc. of the subject.
  • 2.5 mL of an adult can be administered into the knee joint cavity 5 times continuously every week.
  • it can be administered at intervals of 2 to 4 weeks.
  • 2.5 mL of an adult once a week for 5 consecutive shoulder joints (shoulder joint cavity, subacromial bursa, or biceps long head tendon) can be administered within the tendon sheath).
  • 2.5 mL of an adult can be administered into the knee joint cavity 5 times continuously every week. It may also be administered in combination with an appropriate chemotherapeutic agent.
  • Examples of the pharmacological action of this pharmaceutical composition include: a) viscoelasticity or lubrication action by hyaluronate binding to the cartilage tissue and covering the surface, b) cartilage matrix stabilization action (degeneration suppression) C) analgesic action by covering the surface of inflammatory cells and synovial cells, or by suppressing the production of analgesic substances, or d) close to arthritis with synovial and cartilage degeneration Examples thereof include inflammatory effects expressed by affecting synovial cells, chondrocytes, or inflammatory cells such as neutrophils and macrophages. By these actions, for example, reduction of pain, improvement of daily life activities and joint range of motion are expected.
  • a sodium hyaluronate aqueous solution was prepared by the following procedure. First, 1 liter of a medium consisting of 5% glucose, 0.2% monopotassium phosphate, 1.0% polypeptone, and 0.5% yeast extract was heat sterilized and then Streptococcus equi FM-100 No. 9027). The culture was carried out for 20 hours at 200 rpm with stirring, at a temperature of 33 ° C., and at pH 8.5 (control by automatic dropping of 20% sodium hydroxide) while aeration of air at 1 vvm. This solution was filtered with a cell filtration device and dialyzed against water for 12 hours to recover the hyaluronic acid solution in the dialysis membrane.
  • the collection container used was an inner surface made of glass in order to prevent iron contamination.
  • Sodium chloride was added to 2.5% here, and ethanol was added twice as much as the hyaluronic acid solution to precipitate sodium hyaluronate.
  • the precipitate was washed 5 times with ethanol, and the impurities were thoroughly washed out and then air-dried at 40 ° C. for 10 hours to obtain Na hyaluronic acid powder.
  • the obtained sodium hyaluronate powder was dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride, and sodium hyaluronate containing 5, 8, 10, 12, 15 mg / mL of hyaluronic acid Na, respectively.
  • An aqueous solution was obtained.
  • the intrinsic viscosity was measured, and the molecular weight of Na hyaluronate was calculated using Laurent's formula.
  • Streptococcus ex FM-100 was cultured according to the procedure described in Example 1, and a sodium hyaluronate aqueous solution was purified by the same procedure as that described in Example 1 of Patent Document 3 (Japanese Patent Laid-Open No. 2008-280430). Specifically, first, 1 liter of a medium consisting of 5% glucose, 0.2% potassium phosphate, 1.0% polypeptone, and 0.5% yeast extract is heat-sterilized, and then Streptococcus ex FM-100 is added. Vaccinated.
  • the culture was carried out for 20 hours at 200 rpm with stirring, at a temperature of 33 ° C., and at pH 8.5 (control by automatic dropping of 20% sodium hydroxide) while aeration of air at 1 vvm.
  • the culture solution is diluted 10 times with ion-exchanged water, and 5 g of activated carbon (Shirakaba RW50-T manufactured by Takeda Pharmaceutical Co., Ltd.) and pearlite (LocaHelp # 409, Mitsui Mining & Smelting Co., Ltd.) are added to the 2.5 L aqueous solution. 30 g was added, treated for 1 hour, and filtered using Nutsche.
  • the obtained sodium hyaluronate powder was dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride, and sodium hyaluronate containing 5, 8, 10, 12, 15 mg / mL of hyaluronic acid Na, respectively.
  • An aqueous solution was obtained.
  • the intrinsic viscosity was measured, and the molecular weight of Na hyaluronate was determined using the Laurent equation.
  • Example 1 (1) Analysis of soluble iron
  • the hyaluronic acid Na powder prepared in Example 1 and Comparative Example 1 was dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride, and the hyaluronic acid Na was dissolved in 5, 8
  • An aqueous sodium hyaluronate solution containing 10, 12, or 15 mg / mL was prepared (No. 1 to 10), respectively.
  • the amount of divalent soluble iron, the amount of divalent and trivalent soluble iron, and the total amount of iron were measured by the following procedures (1-1) to (1-3). did.
  • the total iron amount includes soluble and insoluble iron amounts.
  • the detection limit of the bivalent soluble iron amount, the bivalent and trivalent soluble iron amount, and the total iron amount was 5 ppb.
  • Example 1 From the above results, 1) that the method described in Example 1 can be used, it is possible to prepare an aqueous solution of sodium hyaluronate having a mixed amount of divalent soluble iron of 5 ppb or less, and 2) hyaluronic acid can be obtained by divalent soluble iron. It was found that the intrinsic viscosity after storage of the aqueous acid Na solution was lowered, and 3) trivalent soluble iron did not affect the intrinsic viscosity after storage of the aqueous hyaluronate solution.
  • Example 2 Various additives were dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride as shown in Table 5 (No. 23 to 34). Next, the sodium hyaluronate powder prepared in Example 1 was dissolved in each aqueous solution so as to have a concentration of 10 mg / mL. Furthermore, after storing at 80 ° C. for 24 hours, the intrinsic viscosity and the intrinsic viscosity residual ratio (%) were measured.
  • glycine, L-aspartate Na, and purified sucrose are non-reducing compounds.
  • L-methionine, Na thiosulfate, Na bromide, Na hydrogen sulfite, Na sulfide, Na thioglycolate, glucose, and ascorbic acid are reducing compounds.
  • the stability of the aqueous hyaluronate solution was improved when the aqueous solution prepared by dissolving the sodium hyaluronate powder prepared in Example 1 contained L-methionine or sodium thiosulfate. Further, even if the compound has reducible properties like L-methionine and Na thiosulfate, it is rather stable when it contains sodium bisulfite, sodium sulfide, Na thioglycolate, glucose, and ascorbic acid. The sex was decreasing.
  • Example 3 Various additives were dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride as shown in Table 6 (Nos. 35 to 41). Further, 11.3 ppb (5 ppb as divalent soluble iron) was added to each aqueous solution. Next, the sodium hyaluronate powder prepared in Example 1 was dissolved in each aqueous solution so as to have a concentration of 10 mg / mL. Then, after storing for 24 hours at 80 ° C., the intrinsic viscosity and the intrinsic viscosity residual ratio (%) were measured.
  • the aqueous solution in which the sodium hyaluronate powder prepared in Example 1 was dissolved contained 5 ppb of divalent soluble iron, and the stability of the aqueous hyaluronate solution was lowered. Furthermore, it was found that the decrease in stability was significantly suppressed by L-methionine or Na thiosulfate.
  • Example 4 L-methionine was dissolved in an aqueous solution containing 2 mM phosphate buffer and 0.9% sodium chloride at concentrations shown in Table 7 (No. 42 to 48). Next, the sodium hyaluronate powder prepared in Example 1 was dissolved in each aqueous solution so as to have a concentration of 10 mg / mL. Furthermore, after storing at 80 ° C. for 24 hours, the intrinsic viscosity and the intrinsic viscosity residual ratio (%) were measured.
  • the aqueous solution in which the hyaluronic acid Na powder prepared in Example 1 was dissolved contained 10 ⁇ g / mL or more of L-methionine, and the stability of the aqueous hyaluronic acid solution was improved. Further, the improvement of the stability became moderate when L-methionine was contained at 100 ⁇ g / mL.
  • FIG. 2 shows the results of Table 8 and Table 3 as graphs.
  • FIG. 2 shows that the stability of the aqueous solution of sodium hyaluronate is improved when L-methionine is contained at 1000 ⁇ g / mL in a hyaluronic solution containing a low concentration of divalent soluble iron. This stabilizing effect was particularly remarkable when the divalent soluble iron concentration was 5 ppb or less.
  • the aqueous solution of sodium hyaluronate having a low content of divalent soluble iron had an improved residual intrinsic viscosity after storage. Furthermore, when L-methionine was contained in the sodium hyaluronate aqueous solution, the intrinsic viscosity remaining rate was further improved.
  • This aqueous sodium hyaluronate solution has high stability and is less likely to cause a decrease in viscosity or quality even after long-term storage, and thus is excellent as a raw material for pharmaceutical compositions, for example. Moreover, since it is suitable for long-term storage, the cost can be reduced.
  • Silicone oil (Shin-Etsu Chemical Co., Ltd.) having a kinematic viscosity of 5,000 cSt on the inner peripheral surface of a barrel having a capacity of 5 ml, a cylinder outer diameter of 15.05 mm, a cylinder inner diameter of 12.45 mm, and a total length of 79.0 mm, which is mainly composed of COP resin “KF-96-5000cs” manufactured by the company was sprayed under the following conditions so that the average coating amount was 18 ⁇ g in the range of 12 to 25 ⁇ g per cm 2 .
  • the COP resin a thermoplastic saturated norbornene resin composition commercially available as Zeonex (registered trademark) from Nippon Zeon Co., Ltd. was used.
  • Example 2 the hyaluronic acid aqueous solution of Example 1 was filled with 2.9 ml of the hyaluronic acid aqueous solution added with various additives at the concentrations shown in Table 8, and the gasket was plugged. A prefilled syringe was assembled. The limit after the prefilled syringe is irradiated with light of 1,200,000 Lux ⁇ hr (3000 Lux ⁇ 400 hr) with a D65 lamp for color comparison / inspection (FL20S.D-EDL-D65 manufactured by Toshiba Lighting & Technology Corp.) under the condition of 25 ° C. Viscosity and intrinsic viscosity residual ratio (%) were measured (referred to as Example 2).
  • Comparative Example 2 For comparison, the same experiment was conducted on a prefilled syringe that was filled with 2.9 ml of the hyaluronic acid aqueous solution of Comparative Example 1 and the gasket was plugged (referred to as Comparative Example 2).
  • Comparative Example 3 a common glass syringe was separately prepared, and the same experiment was performed on the sample filled with the hyaluronic acid aqueous solution of Example 1 (referred to as Comparative Example 3).
  • Comparative Example 4 and To do For comparison, a similar experiment was performed on a syringe prepared with a barrel made of COP resin shielded with aluminum foil and filled with the hyaluronic acid aqueous solution of Example 1 (Comparative Example 4 and To do).
  • the amount of light is normally 1.2 million Lux ⁇ hr as described above, and when the amount of light is increased (indicated as “strong”), 2.4 million Lux ⁇ hr (3000 Lux ⁇ 800 hr) of light is irradiated. .
  • the hyaluronic acid aqueous solution when filled in a syringe having a COP resin barrel is likely to be less stable due to the influence of light from the outside than when filled into a glass syringe.
  • the reason is probably that a syringe having a COP resin barrel is more likely to transmit ultraviolet light than a general glass syringe.
  • the stability recovered to the same extent as in the case of the glass syringe.
  • This aqueous hyaluronic acid solution is excellent as a raw material for pharmaceuticals, for example, because it does not easily deteriorate in viscosity or quality even after long-term storage. Moreover, since it is suitable for long-term storage, the cost can be reduced.

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Abstract

L'invention concerne une seringue préremplie qui peut stocker de façon stable une solution aqueuse d'hyaluronate de sodium hautement pure qui remplit l'intérieur d'un corps en résine. L'invention concerne une seringue préremplie qui remplit une seringue ayant un corps en résine par une solution aqueuse contenant de l'acide hyaluronique ou un sel de celui-ci. De plus, la solution aqueuse contenant de l'acide hyaluronique ou un sel de celui-ci contient une teneur en fer soluble divalent non supérieure à 5 ppb et contient au moins un additif choisi dans le groupe consistant en un thiosulfate métallique, un thiocyanate métallique, une thiourée, un thiosemicarbazide, une thiocétone et un sulfure.
PCT/JP2012/055427 2011-03-02 2012-03-02 Seringue préremplie pour le remplissage d'une seringue ayant un corps en résine par une solution aqueuse contenant de l'acide hyaluronique ou un sel de celui-ci Ceased WO2012118194A1 (fr)

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JP2013502425A JP5957442B2 (ja) 2011-03-02 2012-03-02 樹脂製バレルを有するシリンジ内にヒアルロン酸又はその塩を含む水溶液を充填してなるプレフィルドシリンジ
KR1020137026038A KR20140145940A (ko) 2011-03-02 2012-03-02 수지제 배럴을 갖는 시린지 내에 히알루론산 또는 히알루론산염을 포함하는 수용액을 충전하여 형성되는 프리필드시린지
CN201280011059.XA CN103547273A (zh) 2011-03-02 2012-03-02 一种向具有树脂制筒部的注射器内注入含透明质酸或透明质酸盐的水溶液而成的预充式注射器

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019003330A1 (fr) * 2017-06-28 2019-01-03 株式会社 日立ハイテクノロジーズ Récipient de milieu électrophorétique
JP2019147755A (ja) * 2018-02-27 2019-09-05 ロート製薬株式会社 眼科組成物

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104174100B (zh) * 2014-09-03 2017-04-19 金富康 非接触预充式注射器
CN108883235B (zh) * 2016-03-29 2024-04-19 有限会社工机工程 高滑动性注射器
WO2018168587A1 (fr) * 2017-03-13 2018-09-20 ナミックス株式会社 Seringue pré-remplie et méthode de conservation pour résine composite

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02103204A (ja) * 1988-10-12 1990-04-16 Denki Kagaku Kogyo Kk ヒアルロン酸の精製方法
JPH08104642A (ja) * 1994-10-04 1996-04-23 Takada Seiyaku Kk ヒアルロン酸ナトリウム注射液用安定化組成物
JPH10212303A (ja) * 1997-01-31 1998-08-11 Denki Kagaku Kogyo Kk ヒアルロン酸ナトリウム水溶液用安定化組成物
JPH11302197A (ja) * 1998-04-17 1999-11-02 Seikagaku Kogyo Co Ltd ヒアルロン酸安定化組成物
JP2003160464A (ja) * 2001-11-28 2003-06-03 Denki Kagaku Kogyo Kk ヒアルロン酸及び／又はその塩の水溶液の安定化組成物
WO2010064667A1 (fr) * 2008-12-03 2010-06-10 電気化学工業株式会社 Seringue

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1247175B (it) * 1991-04-19 1994-12-12 Fidia Spa Procedimento per la purificazione di acido ialuronico e frazione di acido ialuronico puro per uso oftalmico.
JP2006104461A (ja) * 2004-09-10 2006-04-20 Seikagaku Kogyo Co Ltd グリコサミノグリカン画分中の不純物の除去方法
JPWO2007142285A1 (ja) * 2006-06-07 2009-10-29 協和発酵バイオ株式会社 ヒアルロン酸塩の精製方法
JP2009011315A (ja) * 2007-06-05 2009-01-22 Mitsubishi Rayon Co Ltd ヒアルロン酸の製造方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02103204A (ja) * 1988-10-12 1990-04-16 Denki Kagaku Kogyo Kk ヒアルロン酸の精製方法
JPH08104642A (ja) * 1994-10-04 1996-04-23 Takada Seiyaku Kk ヒアルロン酸ナトリウム注射液用安定化組成物
JPH10212303A (ja) * 1997-01-31 1998-08-11 Denki Kagaku Kogyo Kk ヒアルロン酸ナトリウム水溶液用安定化組成物
JPH11302197A (ja) * 1998-04-17 1999-11-02 Seikagaku Kogyo Co Ltd ヒアルロン酸安定化組成物
JP2003160464A (ja) * 2001-11-28 2003-06-03 Denki Kagaku Kogyo Kk ヒアルロン酸及び／又はその塩の水溶液の安定化組成物
WO2010064667A1 (fr) * 2008-12-03 2010-06-10 電気化学工業株式会社 Seringue

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KENNEDY, J.F. ET AL.: "The degradation of hyaluronic acid by ferrous ions", CARBOHYDRATE RESEARCH, vol. 22, no. 1, 1972, pages 43 - 51 *
PIGMAN, W. ET AL.: "Depolymerization of hyaluronic acid by the ORD reaction", ARTHRITIS RHEUMATISM, vol. 4, 1961, pages 240 - 52 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019003330A1 (fr) * 2017-06-28 2019-01-03 株式会社 日立ハイテクノロジーズ Récipient de milieu électrophorétique
GB2577222A (en) * 2017-06-28 2020-03-18 Hitachi High Tech Corp Electrophoretic medium container
JPWO2019003330A1 (ja) * 2017-06-28 2020-04-16 株式会社日立ハイテク 泳動媒体容器
US11243187B2 (en) 2017-06-28 2022-02-08 Hitachi High-Tech Corporation Electrophoretic medium container
GB2577222B (en) * 2017-06-28 2022-05-25 Hitachi High Tech Corp Electrophoretic medium container
JP2019147755A (ja) * 2018-02-27 2019-09-05 ロート製薬株式会社 眼科組成物
JP2022125363A (ja) * 2018-02-27 2022-08-26 ロート製薬株式会社 眼科組成物
JP7133942B2 (ja) 2018-02-27 2022-09-09 ロート製薬株式会社 眼科組成物

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