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 PDFInfo
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- 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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- 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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Abstract
Description
更に、外科手術後の癒着防止用として、また皮膚科領域、眼科領域においても医薬品としての効果が知られており、実用化されているものもある。微生物発酵法により製造されるヒアルロン酸ナトリウムは、例えばある種のストレプトコッカス属を用いて培養し、得られた培養液を希釈し、種々の精製工程を経て、粉末状で取得される。
即ち、高分子量のヒアルロン酸ナトリウムの溶解を短時間で効率よく行うことが難しいこと、該溶液の粘度が非常に高いため取り扱いにくいこと、更に熱等に不安定でろ過あるいは滅菌が難しいこと等である。従って、高分子量のヒアルロン酸ナトリウム注射液を大量に製造する方法については、明らかにされていなかった。
また、本発明の目的は、高分子量のヒアルロン酸類を、凝集を可及的に抑制しながら注射用溶解液に十分に分散させ、清澄な溶解液を得ることができるヒアルロン酸類の溶解方法を提供することにある。
更に、本発明の目的は、高分子量のヒアルロン酸類を、その分子量を可及的に低下させることなく注射用溶解液に溶解させることができるヒアルロン酸類の溶解方法を提供することにある。
即ち、
(1)タービン型、ディスパー型、ディスパータービン型、アンカー型、パドルブレード付鋸羽翼から選ばれた撹拌翼を備えた撹拌槽を用いて、注射用水、生理食塩水、及び緩衝生理食塩水から選ばれた一種の注射用溶解液に、ヒアルロン酸及び/又はその塩を溶解させるヒアルロン酸及び/又はその塩の溶解方法;
(2)撹拌翼の軸が容器中央又は偏心させた位置にある撹拌槽を用いる(1)記載のヒアルロン酸及び/又はその塩の溶解方法;
(3)撹拌翼が、1段又は多段である撹拌槽を用いる(2)記載のヒアルロン酸及び/又はその塩の溶解方法;
(4)撹拌翼の回転数が100~5000rpmである撹拌槽を用いる(3)記載のヒアルロン酸及び/又はその塩の溶解方法;
(5)撹拌槽及びラインの内面材質がテフロン、テフロンライニング又はテフロンコーティングである(4)記載のヒアルロン酸及び/又はその塩の溶解方法;
(6)ヒアルロン酸及び/又はその塩が、平均分子量150万~400万である(1)~(5)の何れかに記載のヒアルロン酸及び/又はその塩の溶解方法;
(7)ヒアルロン酸及び/又はその塩が、ストレプトコッカス・エキFM-100又はストレプトコッカス・エキFM-300を用いて、発酵法により製造されるものである(1)~(6)の何れかに記載のヒアルロン酸及び/又はその塩の溶解方法。
即ち、
(8)大ピッチドタービン翼又はディスパータービン翼の撹拌翼を備えた撹拌槽を用いて、注射用水、生理食塩水、及び緩衝生理食塩水から選ばれた一種の注射用溶解液に、ヒアルロン酸及び/又はその塩を溶解させるヒアルロン酸及び/又はその塩の溶解方法;
(9)撹拌槽が略縦型円筒状であり、撹拌翼が槽中心から径方向外方に偏心させた位置に軸を位置させて配設される(8)記載のヒアルロン酸及び/又はその塩の溶解方法;
(10)撹拌翼の軸の偏心位置が、中心線を1:2に分ける位置である(9)記載のヒアルロン酸及び/又はその塩の溶解方法;
(11)撹拌槽が、撹拌翼径/槽内径の比が0.3~0.5となる撹拌翼を備える(8)~(10)の何れか一項に記載のヒアルロン酸及び/又はその塩の溶解方法;
(12)撹拌翼を1500~1800rpmの回転数で作動させる(8)~(11)の何れか一項に記載の溶解方法;
(13)撹拌時間を45分以上とする(8)~(12)の何れか一項に記載の溶解方法;
(14)撹拌槽及び撹拌槽に接続されるラインの少なくとも内面がステンレス鋼製で電解研磨仕上げされている(8)~(13)の何れかに記載の溶解方法;
(15)ヒアルロン酸及び/又はその塩が、平均分子量150万~400万である(8)~(14)の何れかに記載の溶解方法;
(16)ヒアルロン酸及び/又はその塩の濃度が0.75~1.25w/v%となるように溶解する(8)~(15)の何れか一項に記載の溶解方法;
(17)ヒアルロン酸及び/又はその塩が、ストレプトコッカス・エキFM-100又はストレプトコッカス・エキFM-300を用いて、発酵法により製造されるものである(8)~(16)の何れか一項に記載の溶解方法。
本発明に用いられるヒアルロン酸類は、遊離の形のヒアルロン酸、ヒアルロン酸の塩、又は遊離のヒアルロン酸とヒアルロン酸の塩との混合物を包含する。ヒアルロン酸の塩としては、例えば、ナトリウム塩、カリウム塩、カルシウム塩、リチウム塩等が挙げられるが、ナトリウム塩が最も一般的に用いられる。更に本発明で使用するヒアルロン酸類含有液は、動物組織から抽出したものでも、また発酵法で製造したものでもよいが、発酵法で製造したものを使用するのが好ましい。
また、撹拌翼を配設する位置(撹拌翼の軸の位置)は、通例に従い、槽本体の略中央位置とできるが、撹拌翼の軸を槽本体の半径方向外方に偏心させて設置すると、ヒアルロン酸類の溶解速度が速くなるので好ましいことが分かった。例えば、偏心位置は、槽本体の中心線上の槽直径を1:2に分ける位置、1:3に分ける位置、1:4に分ける位置、1:5に分ける位置等とできるが、なかでも1:2に分ける位置が好ましいことが分かった。
また、同様に、撹拌時間も、短いと、撹拌効果が十分ではなく、溶解性、分散性が悪くなる一方、長すぎると、分子量が低下してしまう等の不具合が生じる。例示的には、45分以上で、100分程度まで、特に60分程度までが好ましい。
また、撹拌翼は、上記のように、撹拌翼の種類、大きさ、設置位置、回転数等々を適切に設計すれば、一段で足りるが、多段にすることを排除するものではない。
ヒアルロン酸類溶液は、高粘度であるが、その脱泡のために、真空ポンプ等の通常の減圧手段を用い、5~20kPa absまで減圧するのが好ましい。温度を上げたり、溶液の撹拌を併用して行うとさらに効果が上がる。
あるいは、テフロン(登録商標)の代わりにステンレス鋼、特にSUS316Lを用いることも好ましく、その場合、内面を電解研磨仕上げすると、テフロン(登録商標)と同等以上の性能が得られる。
これらの工程について簡単に説明すると、ヒアルロン酸類溶液の滅菌は、異物除去の前、又はバイアル等の容器に充填した後で行う。
異物ろ過はろ過処理により行われる。ろ過で使用されるろ過膜は孔径0.2~50μmが好ましい。孔径がその範囲より小さい場合は、前工程で得られた滅菌液が非常に高粘度液のため膜を通液させるのが困難であり、また孔径がその範囲より大きい場合は、異物ろ過が不完全になり、注射液中に目視で判別できる不溶性異物が混在するので好ましくない。
ストレプトコッカス・エキFM-100(微工研菌寄第9027号)を用いて発酵法で得られた分子量237万のヒアルロン酸ナトリウム1580gを20Lのバタフライ弁のついた気密容器に充填した。内面がテフロンコーティングされているステンレス鋼製の容量200Lの撹拌槽にディスパータービン型の撹拌羽根を取付け、pH7.3の2mMリン酸ナトリウム緩衝液を含む生理食塩液(注射用溶解液)149Lを撹拌槽に仕込んだ。
前述のヒアルロン酸ナトリウムを充填した気密容器を撹拌槽の原末投入口に逆さに取付け、バタフライ弁を開き、ヒアルロン酸ナトリウムを撹拌槽中に投入した。図1~2にディスパータービン型撹拌羽根(ディゾルバー翼径275mm、12枚羽根とピッチドパドル翼6枚羽根からなる)の平面図を示す。
1800rpmで撹拌を50分間行い、ヒアルロン酸ナトリウムを完全に溶解した。液中の気泡を除去するため、撹拌槽内圧力を20分間、真空度15kPa absに維持し、気泡を除去した後、常圧に戻した。この溶液のヒアルロン酸ナトリウム濃度をカルバゾール硫酸法により測定したところ、1.00%となった。この液の極限粘度を第十五改正日本薬局方に従って測定すると、33.8dL/gであり、分子量に換算すると237万であった。
冷却部は、出口温度が40℃以下になるように、冷却部外管の水を調節した。冷却部出口圧力が0.33MPaになるように圧力調節弁で制御し、冷却したヒアルロン酸ナトリウム溶解液を孔径5μmのポリ塩化ビニリデン製のろ過膜からなる日本ミリポア社製ミリディスク40を用いて流量60L/hrでろ過した。
ろ過液を、30分間、144rpmで攪拌混合した。次いで、その液をダイアフラム型の充填ポンプを有する充填部、ゴム栓の打栓、巻締め機構を有するバイアル充填密封機で、バイアル瓶に2.85Lずつ充填した。ゴム栓はブチルゴム(大協精工社製)を打栓した。
製品の品質試験を第十五改正日本薬局方、製剤総則・注射剤の項に従って不溶性異物検査を行ったところ、合格率は99.9%以上であった。
撹拌槽における撹拌機の構成を種々変更して最適な撹拌翼、撹拌条件を求めるべく、溶解試験を行った。溶解試験では、生理食塩水149Lを仕込んだ槽内径550mmの撹拌槽に、ヒアルロン酸ナトリウム(極限粘度35.0dL/g)1580gを投入し、撹拌機を作動させてこれを溶解させた。溶解試験の結果は、ヒアルロン酸ナトリウムの分散性、溶解の可否、分子量低下について、以下に記載の各基準に従って評価する。
ヒアルロン酸類の挙動を目視で確認し、次の判定基準に従って、評価する。
○:槽内全体にヒアルロン酸類が分散している状態
△:ヒアルロン酸類が槽底付近で分散しており、槽全体には分散していない状態
×:大半のヒアルロン酸類が槽底にあり、分散が殆ど認められない状態
次の判定基準a~cを総合的に判定し、全ての基準を満たせば○、一つ満たさなければ△、全てを満たさない場合には×とする。
a:ヒアルロン酸類溶解中に、目視レベルで凝集物(ままこ)が認められないこと
b:ヒアルロン酸類溶解液が無色透明であること
c:撹拌槽の壁面に目視レベルで未溶解のヒアルロン酸類が認められないこと
Δ分子量(=(溶解前極限粘度-溶解後極限粘度)/溶解前極限粘度)について、以下の判定基準に従って、判定する。
○:Δ分子量≦0.03
△:0.03<Δ分子量≦0.15
×:0.15<Δ分子量
撹拌翼として、大ピッチドタービン翼、二段ピッチドタービン翼、ピッチドタービン翼とパドルの併用、ディスパータービン翼、マックスブレンド翼、ディゾルバー翼を用意して、撹拌槽に取り付け、撹拌回転数1800rpmで溶解試験を行った。結果を以下の表1に示す。
図5は撹拌槽4に大ピッチドタービン翼5を配設した状態を示すもので、(a)は概略側断面図、(b)は(a)におけるb-b矢視図であり、図中、H=754mm、h=522mm、D=550mm、d=180mmである(d/D=0.33)。尚、撹拌翼の形状に関する当該試験では、大ピッチドタービン翼5を撹拌槽4の偏心位置(e=90mm)に取り付けた。この偏心位置は後記する偏心(1:2)に相当する。
図6は二段ピッチドタービン翼6を撹拌槽4に配設した状態を示すもので、(a)は概略側断面図、(b)は(a)におけるb-b矢視図、(c)は(a)におけるc-c矢視図であり、図中、H=754mm、h1=290mm、h2=232mm、D=550mm、d1(上)=155mm、d2(下)=180mmである(d1/D=0.28(上);d2/D=0.33(下))。この試験においても、二段ピッチドタービン翼6は偏心位置(e=90mm)に取り付けた。
図7はピッチドタービン翼とパドルの併用翼7を撹拌槽4に配設した状態を示すもので、(a)は概略側断面図、(b)は(a)におけるb-b矢視図、(c)は(a)におけるc-c矢視図であり、図中、H=754mm、h1=283mm、h2=85mm(パドル高)、h3=154mm、D=550mm、d1(パドル径)=155mm、d2(タービン翼径)=180mmである(d1/D=0.28(パドル);d2/D=0.33(タービン翼))。この試験においても、併用翼7は偏心位置(e=90mm)に取り付けた。
図8はディスパータービン翼8を撹拌槽4に配設した状態を示すもので、(a)は概略側断面図、(b)は(a)におけるb-b矢視図であり、図中、H=754mm、h=522mm、D=550mm、d=180mmである(d/D=0.33)。この試験においても、ディスパータービン翼8は偏心位置(e=90mm)に取り付けた。
図9はマックスブレンド翼9を撹拌槽4に配設した状態を示すもので、(a)は概略側断面図、(b)は(a)におけるb-b矢視図であり、図中、H=677mm、h(翼高さ)=450mm、D=550mm、d=290mmである(d/D=0.53)。
図10はディゾルバー翼10を撹拌槽4に配設した状態を示すもので、(a)は概略側断面図、(b)はディゾルバー翼10の平面図であり、図中、H=677mm、e=137.5mm、D=550mm、d=250mmである(d/D=0.53)。
撹拌翼の形状について溶解試験の結果が優れていた大ピッチドタービン翼とディスパータービン翼の各々に対して、撹拌翼を、偏心1:2、偏心1:3、偏心1:5の位置に取り付け、溶解における撹拌翼の位置の影響を調べた。結果を次の表2に示す。
これまでの試験で優れていたディスパータービン翼を、性能的に優れていた偏心1:2の位置に設置して、撹拌回転数を1000rpmから2500rpmの範囲で種々変動させて溶解試験を行った。結果を次の表3に示す。
これまでの試験で優れていたディスパータービン翼のサイズを、撹拌翼径/槽内径の比で0.1から1の範囲で変更し、性能的に優れていた偏心1:2の位置、撹拌回転数1800rpmで、溶解試験を実施した。結果を次の表4に示す。
2 軸穴
3 ピッチドパドル翼
4 撹拌槽
5 大ピッチドタービン翼
6 二段ピッチドタービン翼
7 ピッチドタービン翼とパドルの併用翼
8 ディスパータービン翼
9 マックスブレンド翼
10 ディゾルバー翼
Claims (7)
- タービン型、ディスパー型、ディスパータービン型、アンカー型、パドルブレード付鋸羽翼から選ばれた撹拌翼を備えた撹拌槽を用いて、注射用水、生理食塩水、及び緩衝生理食塩水から選ばれた一種の注射用溶解液に、ヒアルロン酸及び/又はその塩を溶解させるヒアルロン酸及び/又はその塩の溶解方法。
- 撹拌翼の軸が容器中央又は偏心させた位置にある撹拌槽を用いる請求項1記載のヒアルロン酸及び/又はその塩の溶解方法。
- 撹拌翼が、1段又は多段である撹拌槽を用いる請求項2記載のヒアルロン酸及び/又はその塩の溶解方法。
- 撹拌翼の回転数が100~5000rpmである撹拌槽を用いる請求項3記載のヒアルロン酸及び/又はその塩の溶解方法。
- 撹拌槽及びラインの内面材質がテフロン、テフロンライニング又はテフロンコーティングである請求項4記載のヒアルロン酸及び/又はその塩の溶解方法。
- ヒアルロン酸及び/又はその塩が、平均分子量150万~400万である請求項1から5の何れか一項に記載のヒアルロン酸及び/又はその塩の溶解方法。
- ヒアルロン酸及び/又はその塩が、ストレプトコッカス・エキFM-100又はストレプトコッカス・エキFM-300を用いて、発酵法により製造されるものである請求項1から6の何れか一項に記載のヒァルロン酸及び/又はその塩の溶解方法。
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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 |
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TW100109193A TW201138758A (en) | 2010-03-17 | 2011-03-17 | Method for dissolving hyaluronic acid and/or a salt thereof |
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JP (1) | JP5603925B2 (ja) |
KR (1) | KR101650222B1 (ja) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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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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JPS63123392A (ja) * | 1986-11-14 | 1988-05-27 | Denki Kagaku Kogyo Kk | ヒアルロン酸の製造方法 |
JPH02234689A (ja) * | 1989-03-09 | 1990-09-17 | Denki Kagaku Kogyo Kk | ヒアルロン酸の製造方法 |
JPH04158796A (ja) * | 1990-10-23 | 1992-06-01 | Chisso Corp | ヒアルロン酸ナトリウム水溶液の製造法 |
JPH08188534A (ja) * | 1995-01-05 | 1996-07-23 | Denki Kagaku Kogyo Kk | ヒアルロン酸ナトリウム溶液注射剤 |
JPH10306103A (ja) * | 1997-05-08 | 1998-11-17 | Nissho Corp | ヒアルロン酸ナトリウム注射液 |
JP2009256464A (ja) * | 2008-04-16 | 2009-11-05 | Mitsubishi Rayon Co Ltd | 粉末ヒアルロン酸およびその塩の製造方法 |
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JP3779200B2 (ja) * | 2001-11-28 | 2006-05-24 | 電気化学工業株式会社 | ヒアルロン酸及び/又はその塩の水溶液の安定化組成物 |
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2010
- 2010-03-17 CN CN201080065518.3A patent/CN102812051B/zh active Active
- 2010-03-17 WO PCT/JP2010/054591 patent/WO2011114469A1/ja active Application Filing
- 2010-03-17 JP JP2012505376A patent/JP5603925B2/ja not_active Expired - Fee Related
- 2010-03-17 KR KR1020127026919A patent/KR101650222B1/ko active IP Right Grant
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2011
- 2011-03-17 TW TW100109193A patent/TW201138758A/zh unknown
Patent Citations (6)
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JPS63123392A (ja) * | 1986-11-14 | 1988-05-27 | Denki Kagaku Kogyo Kk | ヒアルロン酸の製造方法 |
JPH02234689A (ja) * | 1989-03-09 | 1990-09-17 | Denki Kagaku Kogyo Kk | ヒアルロン酸の製造方法 |
JPH04158796A (ja) * | 1990-10-23 | 1992-06-01 | Chisso Corp | ヒアルロン酸ナトリウム水溶液の製造法 |
JPH08188534A (ja) * | 1995-01-05 | 1996-07-23 | Denki Kagaku Kogyo Kk | ヒアルロン酸ナトリウム溶液注射剤 |
JPH10306103A (ja) * | 1997-05-08 | 1998-11-17 | Nissho Corp | ヒアルロン酸ナトリウム注射液 |
JP2009256464A (ja) * | 2008-04-16 | 2009-11-05 | Mitsubishi Rayon Co Ltd | 粉末ヒアルロン酸およびその塩の製造方法 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013189983A1 (de) * | 2012-06-21 | 2013-12-27 | Haas Food Equipment Gmbh | Mischapparat |
CN104394695A (zh) * | 2012-06-21 | 2015-03-04 | 哈斯食品设备有限责任公司 | 混合装置 |
US9814245B2 (en) | 2012-06-21 | 2017-11-14 | Haas Food Equipment Gmbh | Mixing apparatus |
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 |
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 |
Also Published As
Publication number | Publication date |
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TW201138758A (en) | 2011-11-16 |
JPWO2011114469A1 (ja) | 2013-06-27 |
JP5603925B2 (ja) | 2014-10-08 |
KR101650222B1 (ko) | 2016-08-22 |
CN102812051B (zh) | 2015-08-26 |
KR20130056221A (ko) | 2013-05-29 |
CN102812051A (zh) | 2012-12-05 |
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