WO2011114469A1 - ヒアルロン酸及び／又はその塩の溶解方法 - Google Patents

ヒアルロン酸及び／又はその塩の溶解方法 Download PDF

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Publication number
WO2011114469A1
WO2011114469A1 PCT/JP2010/054591 JP2010054591W WO2011114469A1 WO 2011114469 A1 WO2011114469 A1 WO 2011114469A1 JP 2010054591 W JP2010054591 W JP 2010054591W WO 2011114469 A1 WO2011114469 A1 WO 2011114469A1
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Prior art keywords
hyaluronic acid
salt
blade
stirring
dissolving
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PCT/JP2010/054591
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English (en)
French (fr)
Japanese (ja)
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丈士 萩原
裕司 服部
博光 星加
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電気化学工業株式会社
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Priority to KR1020127026919A priority Critical patent/KR101650222B1/ko
Priority to PCT/JP2010/054591 priority patent/WO2011114469A1/ja
Priority to CN201080065518.3A priority patent/CN102812051B/zh
Priority to JP2012505376A priority patent/JP5603925B2/ja
Priority to TW100109193A priority patent/TW201138758A/zh
Publication of WO2011114469A1 publication Critical patent/WO2011114469A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/09—Stirrers characterised by the mounting of the stirrers with respect to the receptacle
    • B01F27/093—Stirrers characterised by the mounting of the stirrers with respect to the receptacle eccentrically arranged
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/11—Stirrers characterised by the configuration of the stirrers
    • B01F27/112—Stirrers characterised by the configuration of the stirrers with arms, paddles, vanes or blades
    • B01F27/1125—Stirrers characterised by the configuration of the stirrers with arms, paddles, vanes or blades with vanes or blades extending parallel or oblique to the stirrer axis
    • B01F27/11251—Stirrers characterised by the configuration of the stirrers with arms, paddles, vanes or blades with vanes or blades extending parallel or oblique to the stirrer axis having holes in the surface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/11—Stirrers characterised by the configuration of the stirrers
    • B01F27/115—Stirrers characterised by the configuration of the stirrers comprising discs or disc-like elements essentially perpendicular to the stirrer shaft axis
    • B01F27/1152—Stirrers characterised by the configuration of the stirrers comprising discs or disc-like elements essentially perpendicular to the stirrer shaft axis with separate elements other than discs fixed on the discs, e.g. vanes fixed on the discs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/11—Stirrers characterised by the configuration of the stirrers
    • B01F27/13—Openwork frame or cage stirrers not provided for in other groups of this subclass
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/808—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with stirrers driven from the bottom of the receptacle
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/81—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis the stirrers having central axial inflow and substantially radial outflow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/90—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with paddles or arms 
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/91—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with propellers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/05—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media from solid polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/04—Apparatus for enzymology or microbiology with gas introduction means
    • C12M1/06—Apparatus for enzymology or microbiology with gas introduction means with agitator, e.g. impeller
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention relates to a technique for producing an injection solution of hyaluronic acid and / or a salt thereof (hereinafter also collectively referred to as hyaluronic acid) suitable for a pharmaceutical product from a solution containing hyaluronic acid and / or a salt thereof.
  • hyaluronic acid hyaluronic acid
  • Hyaluronic acid is a high molecular weight polysaccharide that is said to have a molecular weight of up to 5 million, which is formed by repeatedly linking disaccharide units in which N-acetyl-D-glucosamine and D-glucuronic acid are linked.
  • the glucuronic acid is separated and purified as sodium hyaluronate in the form of sodium salt.
  • Sodium hyaluronate with a molecular weight of about 2 million is known to exhibit superior effects in the treatment of knee osteoarthritis, shoulder periarthritis, rheumatoid arthritis, etc., as a pharmaceutical compared with a molecular weight of about 800,000. (Pharmacology and Treatment Vol. 22 No.
  • sodium hyaluronate can be purified and obtained with a high molecular weight, but there are various difficult problems when mass-producing sodium hyaluronate injection solutions. That is, it is difficult to efficiently dissolve high molecular weight sodium hyaluronate in a short time, it is difficult to handle because the viscosity of the solution is very high, and it is unstable to heat, etc., and filtration or sterilization is difficult. is there. Accordingly, a method for producing a large amount of high molecular weight sodium hyaluronate injection has not been clarified.
  • the present inventor researched a method for obtaining high-purity pharmaceutical grade hyaluronic acid by efficiently separating and removing foreign substances from the hyaluronic acid-containing liquid in producing a large amount of hyaluronic acid-containing liquid as an injection solution.
  • hyaluronic acids were dissolved in an injection solution, using a general stirring tank under normal conditions, the hyaluronic acids were not sufficiently dissolved and aggregates were formed. It has been found that the stirring and dissolving step becomes a bottleneck because the molecular weight of hyaluronic acid is reduced during the dissolution.
  • This invention was made
  • Another object of the present invention is to provide a method for dissolving hyaluronic acids that can sufficiently disperse high molecular weight hyaluronic acids in an injectable solution while suppressing aggregation as much as possible to obtain a clear solution. There is to do.
  • an object of the present invention is to provide a method for dissolving hyaluronic acids, which can dissolve high molecular weight hyaluronic acids in an injectable solution without reducing the molecular weight as much as possible.
  • the following method is provided. That is, (1) Select from water for injection, physiological saline, and buffered physiological saline using a stirring tank equipped with a stirring blade selected from turbine type, disper type, disper turbine type, anchor type and saw blade with paddle blade A method for dissolving hyaluronic acid and / or a salt thereof in which hyaluronic acid and / or a salt thereof is dissolved in the one kind of injectable dissolution solution; (2) The method for dissolving hyaluronic acid and / or a salt thereof according to (1), wherein a stirring tank in which the axis of the stirring blade is in the center of the container or in an eccentric position is used; (3) The method for dissolving hyaluronic acid and / or a salt thereof according to (2), wherein the stirring blade is a single-stage or multi-stage stirring tank; (4) The method for dissolving hyaluronic acid and / or a salt thereof according to (3), where
  • the following method is provided. That is, (8) Hyaluronic acid in a kind of injection solution selected from water for injection, physiological saline, and buffered physiological saline using a stirring tank equipped with a large pitched turbine blade or a stirring blade of a disper turbine blade And / or a method for dissolving hyaluronic acid and / or a salt thereof for dissolving the salt; (9)
  • the agitation tank has a substantially vertical cylindrical shape, and the agitation blade is disposed with the shaft positioned at a position eccentrically outward in the radial direction from the center of the tank, and / or the hyaluronic acid according to (8) Salt dissolution method;
  • the stirring tank includes a stirring blade having a stirring blade diameter / tank
  • high molecular weight hyaluronic acids can be sufficiently dispersed in a solution for injection while suppressing aggregation and molecular weight reduction as much as possible, and it is possible to produce injection solutions on a large scale. It becomes.
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of another disper turbine type
  • FIG. 1 shows the example of
  • FIG. 2 shows a state in which a two-stage pitched turbine blade is disposed in a stirring tank, (a) is a schematic side sectional view, (b) is a view taken along the line bb in (a), and (c) is (a).
  • FIG. FIG. 2 shows a state in which pitched turbine blades and paddle blades are disposed in a stirring tank, where (a) is a schematic side sectional view, (b) is a view taken along line bb in (a), and (c) is It is a cc arrow line view in (a).
  • FIG. 2 shows a state in which a disper turbine blade is disposed in a stirring tank, in which (a) is a schematic sectional side view, and (b) is a view taken along the line bb in (a).
  • FIG. 2 shows a state in which Maxblend blades are arranged in a stirring tank, where (a) is a schematic side sectional view, and (b) is a view taken along the line bb in (a).
  • wing to the stirring tank is shown, (a) is a schematic sectional side view, (b) is a top view of a dissolver blade.
  • the hyaluronic acids used in the present invention include free forms of hyaluronic acid, hyaluronic acid salts, or a mixture of free hyaluronic acid and hyaluronic acid salts.
  • Examples of the salt of hyaluronic acid include sodium salt, potassium salt, calcium salt, lithium salt and the like, and sodium salt is most commonly used.
  • the hyaluronic acid-containing liquid used in the present invention may be extracted from animal tissue or manufactured by a fermentation method, but it is preferable to use a solution manufactured by a fermentation method.
  • Hyaluronic acids by fermentation can be obtained by known methods using microorganisms such as bacteria having the ability to produce hyaluronic acid such as Streptococcus.
  • a strain used in the fermentation method a microorganism having the ability to produce hyaluronic acid isolated from the natural world, or Streptococcus ex FM-100 described in JP-A No. 63-123392 (Mikkenkenbyo No. 9027) is used.
  • a mutant strain that stably produces hyaluronic acid at a high yield such as Streptococcus equi FM-300 (Mikkenkenbyo No. 2319) described in JP-A-2-23489. Mutant strains are preferably used.
  • the hyaluronic acids produced by the above fermentation method and usable in the present invention have a high molecular weight and generally have an average molecular weight of 1.5 to 4 million. This is because when the average molecular weight is less than 1,500,000, the efficacy as a pharmaceutical agent is lowered, while it is difficult to obtain a compound having an average molecular weight of more than 4,000,000 by the above method. However, this does not mean that the dissolution method according to the present invention cannot be used to dissolve low molecular weight hyaluronic acid.
  • physiological saline and buffered physiological saline can be used as an injectable solution used in the step of dissolving hyaluronic acid, and pH adjustment including a buffer such as acid, alkali, and phosphate is particularly possible.
  • a buffer such as acid, alkali, and phosphate
  • those approved by the Japanese Pharmacopoeia General Preparations for Injection, including drugs, etc. can be used.
  • the amount of hyaluronic acid added in the dissolution step is set so that the hyaluronic acid concentration is 0.75 to 1.25 w / v%.
  • the hyaluronic acid concentration is 0.75 w / v% or less, the hyaluronic acid solution has a low viscosity and is easy to produce.
  • it is 1.25 w / v% or more, it is difficult to prepare a large amount from the solubility of hyaluronic acids. Therefore, a hyaluronic acid concentration of 0.75 to 1.25 w / v%, which becomes a highly viscous solution, corresponds to the production conditions targeted by the dissolution method of the present invention.
  • the hyaluronic acid to be dissolved is filled in an airtight container with a valve, and then charged into a stirring tank by a charging chute through the valve.
  • the angle of the charging chute is preferably a steep slope of 50 ° or more.
  • a butterfly valve is preferably used as the valve. By switching the valve, hyaluronic acid can be aseptically charged into the agitation tank without touching the outside air.
  • the material of the airtight container with a valve is preferably stainless steel, the inner surface thereof coated with Teflon, or the inner surface thereof subjected to electrolytic polishing finish, from the viewpoint of cleanability, ease of handling, and the like.
  • the agitation tank used for the dissolution is a general substantially vertical cylindrical tank body with a vertical axis agitation device, and the agitation device is arranged inside the tank body with the axis line in the vertical direction.
  • a stirrer equipped with a stirring blade selected from a turbine type, a disper type, a disper turbine type, an anchor type, and a saw blade with a paddle blade can be used as the stirring device. Then, it was found that those having turbine type, disper type, and disper turbine type agitating blades were preferable, and in particular, large pitched turbine blades and disper turbine blades were preferable.
  • the position where the stirring blade is disposed (the position of the shaft of the stirring blade) can be approximately the center position of the tank body, as usual, but if the shaft of the stirring blade is installed eccentrically outward in the radial direction of the tank body It was found preferable because the dissolution rate of hyaluronic acids is increased.
  • the eccentric position can be a position where the tank diameter on the center line of the tank body is divided by 1: 2, a position divided by 1: 3, a position divided by 1: 4, a position divided by 1: 5, etc. : It turned out that the position divided into 2 is preferable.
  • the rotation speed of the stirring blade is generally 100 to 5000 rpm, for example, 800 to 2000 rpm.
  • the large pitched turbine blade and the disper turbine blade are preferable among the stirring blades, and the rotation speed is 1500 to 1800 rpm. Was found to be preferable. If the rotational speed is too small, the dispersibility of hyaluronic acids in a solution for injection becomes poor. On the contrary, even if the rotational speed is increased, the stirring blade does not rotate because the molecular weight of the hyaluronic acid is too high. In addition, it is often effective to warm simultaneously with stirring during dissolution, but in the case of hyaluronic acids, troublesome physical property changes such as molecular weight reduction can occur due to heating.
  • stirring when the stirring is not sufficient, it is conceivable to increase the stirring time. However, when the stirring time is extended, physical property changes such as a decrease in molecular weight may occur. However, in addition to adjusting the stirring blade shape, position, other operating conditions, etc., by setting the rotation speed within the above range, it can dissolve in a short time under mild conditions without heating. it can.
  • the stirring blade preferably has a stirring blade diameter (d) / tank inner diameter (D) ratio (d / D) of 0.3 to 0.5. This is because when the ratio is less than 0.3, the stirring effect is not sufficient and the solubility and dispersibility are deteriorated. On the other hand, when the ratio exceeds 0.5, problems such as a decrease in molecular weight occur. Similarly, if the stirring time is short, the stirring effect is not sufficient, and the solubility and dispersibility deteriorate. On the other hand, if the stirring time is too long, problems such as a decrease in molecular weight occur.
  • it is preferably 45 minutes or longer, up to about 100 minutes, particularly up to about 60 minutes. Further, as described above, if the type, size, installation position, number of rotations, and the like of the stirring blade are appropriately designed as described above, one step is sufficient, but this does not exclude the fact that the stirring blade is multi-staged.
  • the dissolving operation it is preferable to depressurize the inside of the stirring vessel as appropriate. This is to remove hyaluronic acids and bubbles in the liquid, but is also effective to increase the dissolution rate.
  • the hyaluronic acid solution has a high viscosity, but it is preferable to reduce the pressure to 5 to 20 kPa abs using a normal pressure reducing means such as a vacuum pump for defoaming. When the temperature is increased or the solution is stirred together, the effect is further improved.
  • the material of the inner surface of the stirring tank for dissolution may be stainless steel, glass, Teflon (registered trademark), etc. due to the corrosion resistance to saline solution, the cleanability of the inner surface after dissolution, etc., but the hyaluronic acid solution adheres to the material surface.
  • Teflon (registered trademark), Teflon (registered trademark) lining or Teflon (registered trademark) coating is preferable. This is because Teflon (registered trademark) has less adherence of a hyaluronic acid solution compared to other materials, and is suitable for discharging the solution from the stirring tank or washing the stirring tank.
  • the hyaluronic acid solution is sterilized before removing foreign substances or after filling a container such as a vial.
  • Foreign matter filtration is performed by filtration.
  • the filtration membrane used for filtration preferably has a pore size of 0.2 to 50 ⁇ m. If the pore size is smaller than that range, the sterilizing solution obtained in the previous step is very viscous and difficult to pass through the membrane. If the pore size is larger than this range, foreign matter filtration is not possible. This is not preferable because it becomes complete and insoluble foreign matter that can be visually discerned is mixed in the injection solution.
  • the material of the filtration membrane can be selected from polytetrafluoroethylene, polyester, Teflon (registered trademark), polypropylene, polyvinylidene fluoride, nylon and the like, but polyvinylidene fluoride, polypropylene or nylon is preferable.
  • As the shape of the filtration membrane any of a flat membrane, a filter cartridge, and a disposable filter can be used. However, when processing in a large amount, a filter cartridge or a disposable filter is preferable.
  • Specific examples of the filtration membrane that can be used in the present invention include Millipak and Durapore Millidisk manufactured by Nihon Millipore.
  • the pH of the hyaluronic acid-containing liquid is 2 to 10, and the temperature is 5 to 100 ° C., and arbitrary conditions are selected.
  • the flow rate and pressure at the time of liquid flow are set in consideration of pressure resistance according to the type of filter, but care must be taken because foreign matter may flow out of the filter when pressure is applied.
  • a flow rate of 50 to 300 L / hr and a processing pressure of 0.01 to 0.50 MPa are preferable.
  • the filtrate can be diluted with a solution for injection to adjust the concentration.
  • a filling machine comprising a portion for filling the container with the hyaluronic acid solution and a sealing portion for sealing the container with a rubber stopper or filling the container after the filling is used.
  • a container for injection solution to be filled a general ampoule, vial, Duffer Jocto type or prefilled syringe is used.
  • Example 1 1580 g of sodium hyaluronate having a molecular weight of 2.37 million obtained by fermentation using Streptococcus ex FM-100 (Microtechnical Laboratories No. 9027) was filled into an airtight container equipped with a 20 L butterfly valve. A disperser turbine type stirring blade is attached to a 200 L stirring tank made of stainless steel whose inner surface is coated with Teflon, and 149 L of physiological saline (solution for injection) containing 2 mM sodium phosphate buffer at pH 7.3 is stirred. The tank was charged.
  • FIGS. 1 and 2 are plan views of a disperser turbine type stirring blade (dissolver blade diameter 275 mm, consisting of 12 blades and 6 pitched paddle blades). Stirring was performed at 1800 rpm for 50 minutes to completely dissolve sodium hyaluronate. In order to remove bubbles in the liquid, the pressure in the stirring tank was maintained at a vacuum degree of 15 kPa abs for 20 minutes, and after the bubbles were removed, the pressure was returned to normal pressure.
  • This solution was continuously sterilized with a kids cooker continuous sterilizer manufactured by Kikkoman.
  • This apparatus consisted of a double tube, the inner tube had an inner diameter of 23 mm, a fixed stirrer was incorporated, and the heating unit volume was 3.4 L, the holding unit volume was 0.6 L, and the cooling unit volume was 2.6 L.
  • the hot water in the heating unit outer tube was adjusted so that the temperature of the holding unit was 135 ° C., and the metering pump at the heating unit inlet was controlled so that the residence time in the holding unit was 34 seconds.
  • the cooling unit adjusted the water in the cooling unit outer tube so that the outlet temperature was 40 ° C. or lower.
  • the pressure of the cooling section outlet pressure is controlled by a pressure control valve so that the pressure is 0.33 MPa, and the cooled sodium hyaluronate solution is flowed using a Millidisk 40 manufactured by Nihon Millipore, which is made of a polyvinylidene chloride filter membrane having a pore size of 5 ⁇ m Filtration was performed at 60 L / hr. The filtrate was stirred and mixed at 144 rpm for 30 minutes. Next, 2.85 L of the liquid was filled into each vial by a vial filling and sealing machine having a filling part having a diaphragm type filling pump, a stopper for a rubber stopper, and a tightening mechanism.
  • the rubber stopper was stoppered with butyl rubber (Daikyo Seiko Co., Ltd.).
  • the pass rate was 99.9% or more.
  • a disper turbine type agitating blade as shown in FIGS. 3 and 4 (having a blade diameter of 243 mm, 12 blades, a blade diameter of 170 mm, and 4 blades) ) was performed under the same conditions, and it was confirmed to be effective as well.
  • Example 2 A dissolution test was conducted in order to obtain various optimum stirring blades and stirring conditions by variously changing the configuration of the stirrer in the stirring tank.
  • 1580 g of sodium hyaluronate (intrinsic viscosity 35.0 dL / g) was charged into a stirring tank having an inner diameter of 550 mm charged with 149 L of physiological saline, and this was dissolved by operating the stirrer.
  • dispersibility of sodium hyaluronate, dissolution possibility, and molecular weight reduction are evaluated according to the criteria described below.
  • FIG. 6 shows a state in which the two-stage pitched turbine blade 6 is disposed in the stirring tank 4.
  • FIG. 6 (a) is a schematic side sectional view
  • FIG. 7 shows a state where the pitched turbine blade and the paddle combined blade 7 are disposed in the stirring tank 4.
  • FIG. 7A is a schematic sectional side view
  • FIG. 7B is a view taken along the line bb in FIG.
  • FIG. 8 shows a state in which the disper turbine blades 8 are arranged in the stirring tank 4.
  • FIG. 8 (a) is a schematic side sectional view
  • FIG. 8 shows a state in which the disper turbine blades 8 are arranged in the stirring tank 4.
  • FIG. 8 (a) is a schematic side sectional view
  • FIGS. 10A and 10B show a state in which the dissolver blade 10 is disposed in the stirring tank 4.
  • FIG. 10A is a schematic side sectional view
  • the large pitched turbine blade and the disperse turbine blade were excellent in all items of dispersibility of sodium hyaluronate, possibility of dissolution, and molecular weight reduction.
  • the two-stage pitched turbine blade is inferior in dispersibility of sodium hyaluronate and also has a decrease in molecular weight, and the combined use of the remaining pitched turbine blade and paddle is either dispersible or dissolvable.
  • the molecular weight drop was also observed, and the degree of molecular weight drop was particularly large in the Max Blend blade.

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PCT/JP2010/054591 2010-03-17 2010-03-17 ヒアルロン酸及び／又はその塩の溶解方法 WO2011114469A1 (ja)

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PCT/JP2010/054591 WO2011114469A1 (ja) 2010-03-17 2010-03-17 ヒアルロン酸及び／又はその塩の溶解方法
CN201080065518.3A CN102812051B (zh) 2010-03-17 2010-03-17 透明质酸和/或其盐的溶解方法
JP2012505376A JP5603925B2 (ja) 2010-03-17 2010-03-17 ヒアルロン酸及び／又はその塩の溶解方法
TW100109193A TW201138758A (en) 2010-03-17 2011-03-17 Method for dissolving hyaluronic acid and/or a salt thereof

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WO2013189983A1 (de) * 2012-06-21 2013-12-27 Haas Food Equipment Gmbh Mischapparat
CN111215015A (zh) * 2019-12-26 2020-06-02 浙江长城搅拌设备股份有限公司 粘稠流体混合和气体分散专用搅拌装置

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CN102489193B (zh) * 2011-11-28 2014-06-18 上海景峰制药有限公司 一种玻璃酸钠配液过程的溶解方法
CN103537217B (zh) * 2013-10-24 2015-12-02 浙江金磊高温材料股份有限公司 一种用于物料搅拌机上的搅拌装置
CN106309472B (zh) * 2015-07-03 2019-01-04 北京泰克美高新技术有限公司 透明质酸或其盐在制备治疗视神经萎缩的药物中的用途

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WO2013189983A1 (de) * 2012-06-21 2013-12-27 Haas Food Equipment Gmbh Mischapparat
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CN111215015B (zh) * 2019-12-26 2022-07-12 浙江长城搅拌设备股份有限公司 粘稠流体混合和气体分散专用搅拌装置

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