WO2006051950A1 - 架橋ヒアルロン酸ゲルの製造方法 - Google Patents
架橋ヒアルロン酸ゲルの製造方法 Download PDFInfo
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- WO2006051950A1 WO2006051950A1 PCT/JP2005/020864 JP2005020864W WO2006051950A1 WO 2006051950 A1 WO2006051950 A1 WO 2006051950A1 JP 2005020864 W JP2005020864 W JP 2005020864W WO 2006051950 A1 WO2006051950 A1 WO 2006051950A1
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- hyaluronic acid
- gel
- acid gel
- mixture
- crosslinked hyaluronic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- 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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- 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
- C08J3/075—Macromolecular gels
-
- 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
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
-
- 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
- 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 method for producing a crosslinked hyaluronic acid gel, and more particularly to a method for producing a crosslinked hyaluronic acid gel having a low cross-linking ratio and excellent viscoelasticity more easily.
- Cross-linked hyaluronic acid gel obtained by cross-linking hyaluronic acid has excellent biocompatibility, and also has biodegradability in which degradation progresses over time in the body and eventually disappears.
- Conventionally, utilizing such properties of crosslinked hyaluronic acid gel research and development on application to anti-adhesion agents, bone repair agents, sustained drug release compositions, and tissue augmenting substances have been actively conducted. .
- a spreader injection in the field of beauty formation is known.
- a crosslinked hyaluronic acid gel is generally prepared by stirring and mixing hyaluronic acid and a crosslinking agent in an aqueous solution, and chemically bonding the hyaluronic acid polymer chains between the crosslinking agents.
- a crosslinked hyaluronan gel is administered in vivo, after the gel is decomposed in the living body, the remaining crosslinking agent component is recognized as a foreign substance by the living body, causing an inflammatory reaction.
- adverse effects such as For this reason, for the purpose of maintaining biocompatibility, it is desirable to prepare a crosslinked hyaluronic acid gel with the lowest possible crosslinking rate.
- Japanese Patent No. 3094074 reports a method for producing a crosslinked hyaluronic acid gel having a relatively low crosslinking rate and excellent viscoelasticity.
- hyaluronic acid and a crosslinking agent are mixed in an aqueous solution to initiate a crosslinking reaction, and water is added before gelling occurs to form a mixed solution.
- Dilution is one step that hinders the progress of the cross-linking reaction, and volatilizes water from this mixed solution to cause the cross-linking reaction to proceed again.
- the reaction control is difficult o
- Patent Document 1 Patent No. 3094074
- the present invention has been made in view of the above-described problems of the prior art, and an object of the present invention is to easily produce a crosslinked hyaluronic acid gel having a low crosslinking rate and exhibiting excellent viscoelasticity.
- An object of the present invention is to provide a novel manufacturing method that can be used.
- the amount of crosslinking agent added can be increased by setting the hyaluronic acid in the mixture to be subjected to the crosslinking reaction to a high concentration condition of iowZv% or more. It was clearly demonstrated that a crosslinked hyaluronic acid gel having excellent viscoelasticity can be obtained even when the amount is decreased.
- general hyaluronic acid 10W / V
- aqueous solution of hyaluronic acid having a high concentration is in the form of a solid powder or a gel having a very high viscosity that cannot be called a solution.
- the present inventors usually react crosslinked hyaluronic acid under extremely high concentration conditions that are not used by those skilled in the art, so that crosslinked hyaluronic acid exhibiting excellent viscoelasticity despite a low crosslinking rate. The inventors found that a gel can be easily produced, and completed the present invention. It was
- a method for producing a crosslinked hyaluronic acid gel according to the present invention is characterized by stirring and mixing a mixture containing hyaluronic acid iowZv% or more, a crosslinking agent, and water under acid or alkaline conditions. Is.
- the storage elastic modulus G ′ (frequency 1 Hz) of the mixture before being subjected to a crosslinking reaction is 15000 Pa or more.
- the method for producing the crosslinked hyaluronic acid gel it is preferable to stir and mix the hyaluronic acid polymer chain in the mixture without physically breaking. In addition, the rack Then, it is preferable to stir and mix the mixture with a rotating and revolving mixer. In the method for producing the crosslinked hyaluronic acid gel, it is preferable to stir and mix the mixture with a bread dough kneading apparatus or a moistening apparatus. In the method for producing the crosslinked hyaluronic acid gel, it is preferable to stir and mix the mixture by squeezing with a human hand.
- the concentration of the crosslinking agent in the mixture is 0.02 to: LWZV%.
- the concentration of the crosslinking agent in the mixture is 0.02 to 2 WZW% with respect to the hyaluronic acid constituent unit.
- the crosslinking agent is selected from the group strength of divinyl sulfone, 1,4 butanediol'diglycidyl ether, and ethylene glycol'diglycidyl ether.
- FIG. 1 is an overall view of a rotating / revolving mixer used in an embodiment of the present invention.
- FIG. 2 is an overall view of a bread dough kneading apparatus used in one embodiment of the present invention.
- FIG. 3 is a measurement result of viscoelasticity of a crosslinked hyaluronic acid gel (hyaluronic acid 41 W / V%, divinylsulfone crosslinking rate per structural unit of hyaluronic acid 0.8%) obtained in Example 11 of the present invention.
- FIG. 4 Viscoelasticity measurement results of a commercially available crosslinked hyaluronic acid gel (Restylane: Q MED).
- FIG. 5 Cross-linked hyaluronic acid gel obtained according to Example 12 of the present invention (hyaluronic acid 33 W / V%, 1,4 butanediol 'diglycidyl ether crosslinking rate 1% with respect to hyaluronic acid structural unit) It is a viscoelasticity measurement result.
- FIG. 6 Viscoelasticity measurement results of the crosslinked hyaluronic acid gel obtained according to Example 13 of the present invention (hyaluronic acid 26 W / V%, divinylsulfone crosslinking rate 0.8% with respect to hyaluronic acid structural unit). is there.
- FIG. 7 Cross-linked hyaluronic acid gel obtained according to Example 14 of the present invention (hyaluronic acid 26 W / V%, 1,4 butanediol diglycidyl ether cross-linking ratio 1% with respect to hyaluronic acid constituent unit). It is a viscoelasticity measurement result.
- FIG. 8 Cross-linked hyaluronic acid gel obtained according to Example 15 of the present invention (hyaluronic acid 13 W / V%, 1,4 butanediol diglycidyl ether cross-linking ratio to hyaluronic acid structural unit 2.8% ) Viscoelasticity measurement results.
- the method for producing a crosslinked hyaluronic acid gel useful in the present invention is characterized by stirring and mixing a mixture containing 10 WZV% or more of hyaluronic acid, a crosslinking agent, and water under acid or alkaline conditions.
- a crosslinked hyaluronic acid gel having excellent viscoelasticity despite a low crosslinking rate can be easily produced.
- crosslinking rate represents the number of crosslinking agents per hyaluronic acid structural unit.
- a crosslinking rate of 100% indicates that one crosslinking agent is bound to one hyaluronic acid structural unit.
- Hyaluronic acid used in the present invention is a linear polymer in which N-acetyl-D-darcosamine residues and D-glucuronic acid residues are alternately bonded as shown in the following general formula. Any material can be used without particular limitation.
- Hyaluronic acid is, for example, isolated and extracted from chicken crowns and other animal tissues,
- 'It can be obtained by fermentation using microorganisms such as Coccus.
- a hyaluronic acid metal salt such as hyaluronic acid sodium salt or hyaluronic acid potassium salt, or a hydroxyl group or a carboxyl group of hyaluronic acid is etherified or esterified.
- a hyaluronic acid derivative obtained by amidation, acetalization, or ketalization may be used.
- hyaluronic acid of the present invention Commercially available products can also be used as the hyaluronic acid of the present invention.
- examples of commercially available hyaluronic acid include Neohyaguchi 12 (manufactured by Shiseido Co., Ltd.) and hyaluronic acid (manufactured by Kibunsha Co., Ltd.).
- the mixture used for the crosslinking reaction contains 10 to 20 WZV% of the hyaluronic acid.
- hyaluronic acid having a molecular weight of 100,000 or more which is generally used, is used to form a high-concentration hyaluronic acid aqueous solution of iowZv% or more as described above, a solid powder or Exhibits a very viscous gel and storage modulus at a frequency of 1 Hz G 'becomes 15000Pa or more.
- the reaction is preferably carried out in a state where the mixture used for the crosslinking reaction exhibits such a solid powder form or a high-viscosity gel form.
- the storage elastic modulus G ′ (frequency 1 Hz) of the mixture before being subjected to the crosslinking reaction is 15000 Pa or more.
- the molecular weight of hyaluronic acid used in the present invention is not particularly limited, but it is preferable that the molecular weight is 100,000 or more, and the molecular weight is about 500,000 to 3,000,000. Usually, most of the hyaluronic acid generally used has a molecular weight of 100,000 or more, but there is also a specially reduced hyaluronic acid with a molecular weight of about 10,000. In the present invention, when such a low molecular weight hyaluronic acid having a molecular weight of about 10,000 is used, even if the hyaluronic acid concentration is set to 10 WZ V% or more, the hyaluronic acid may be uniformly dispersed in water. When the crosslinking rate is lowered, it becomes soft and the desired viscoelasticity may not be obtained.
- any crosslinking agent may be used as long as it can bridge the polymer chains of the hyaluronic acid by chemical bonds.
- a cross-linking agent for hyaluronic acid a polyfunctional compound having two or more functional groups capable of forming a covalent bond by reacting with a reactive functional group such as a carboxyl group, a hydroxyl group, and a acetoamide group of the hyaluronic acid molecule is used. be able to.
- crosslinking agent used in the present invention examples include 1,3 butadiene diepoxide, 1, 2, 7, 8 diepoxy kutan, 1,5 hexagen jepoxide, and other alkyl diepoxy compounds, ethylene
- examples thereof include diglycidyl ethers such as glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, and bisphenol A diglycidyl ether, divinyl sulfone, and epichlorohydrin.
- divinyl sulfone, 1,4 butanediol 'diglycidyl ether, and ethylene glycol diglycidyl ether can be preferably used.
- the blending amount of the crosslinking agent in the mixture subjected to the crosslinking reaction is not particularly limited, but from the viewpoint of biocompatibility of the resulting crosslinked hyaluronic acid gel, it is as much as possible. It is preferable to carry out the crosslinking reaction with a small amount of a crosslinking agent.
- the concentration of the crosslinking agent is preferably 0.02 to: LWZV%, and more preferably 0.05 to 0.5 WZV%.
- the concentration of the cross-linking agent in the mixture is preferably 0.02 to 2 WZW% with respect to the hyaluronic acid structural unit. According to the present invention, a crosslinked hyaluronic acid gel having excellent viscoelasticity can be produced even when the concentration of the crosslinking agent is 1 WZV% or less in the mixture.
- the crosslinking reaction is carried out with a crosslinking agent concentration of 0.066 W / V% and a hyaluronic acid concentration of 14 WZV%, Assuming that it has reacted with the reactive group of S hyaluronic acid, the crosslinking rate of the resulting crosslinked hyaluronic acid gel is usually about 1.67% or less per hyaluronic acid structural unit. In other words, one crosslinker is bound per 64 hyaluronic acid building blocks.
- a mixture containing 1 OWZV% or more of the hyaluronic acid, the crosslinking agent, and water is stirred and mixed under acid or alkaline conditions.
- the hyaluronic acid polymer chains are cross-linked by chemical bonding to produce a cross-linked hyaluronic acid gel.
- acids such as hydrochloric acid and sulfuric acid, bases such as sodium hydroxide and potassium hydroxide, or phosphates are used.
- an appropriate buffer such as quaternary ammonia salt
- components that are usually used in medicines, cosmetics, etc. in advance in the mixture subjected to the crosslinking reaction affect the purpose and effect of the present invention. You may mix
- components that can be incorporated include ascorbic acid and its derivatives, humectants such as glycerin, retinol and its derivatives, salicyl.
- examples include anti-inflammatory agents such as acids.
- the method of stirring and mixing the mixture is not particularly limited, but the stirring and mixing may be performed without physically breaking the hyaluronic acid polymer chain in the mixture.
- Hyaluronic acid has a very high water swellability, for example about 10 W
- aqueous solution of hyaluronic acid of about Zv% exhibits a very high viscosity gel.
- a generally used rotary type stirring and mixing apparatus such as a propeller mixer or a disperser, it adheres to the stirring blades or the wall of the apparatus, and the entire system is uniformly stirred and mixed. Is difficult. If the stirring blade is forcibly rotated using such a stirring and mixing device, the molecular chain of the hyaluronic acid polymer is physically cut by the sharp stirring blade. Therefore, the target crosslinked hyaluronic acid gel (crosslinked gel having a three-dimensional network structure) cannot be obtained.
- the method for producing a crosslinked hyaluronic acid gel of the present invention for example, stirring and mixing using a rotation and revolution type mixing device, stirring and mixing using a bread dough kneading device (or a mochi-kushi device), Or, by mixing the hyaluronic acid polymer chain in the mixture without physically breaking it, such as stirring and mixing by human hands, the condition of the hyaluronic acid concentration is extremely high at 10 wZv% or more. However, it is possible to easily form a uniform bridge structure.
- a rotation / revolution type mixing device is used as a method of stirring and mixing the mixture in the present invention. Stirring and mixing can be used.
- the rotation-revolution mixer used in the present invention is known to those skilled in the art.
- the mixing devices described in JP-A-11-226376 and JP-A-2000-271465 can be used in the present invention.
- FIG. 1 shows a rotating / revolving mixer according to an embodiment of the present invention.
- a rotation-revolution mixing apparatus 10 includes a container body 14 for storing a sample, a container lid 12 thereof, a container holder 16 for fixing and holding the container body 14, and a container holder 16.
- a rotation mechanism 20 that rotates the rotation mechanism 18 along the rotation axis 18, a support portion 22 that supports the rotation mechanism 20, and a revolution mechanism 26 that rotates the support portion 22 along the rotation axis 24.
- a mixture body 30 containing hyaluronic acid 10 WZV% or more, a bridging agent and water is accommodated in the container body 14 of the rotating / revolving mixer 10, the container lid 12 is fitted, and the container holder 16 is mounted.
- the container holder 16 is rotated along the rotation axis 18 by the rotation mechanism 20, and the support portion 22 that supports the rotation mechanism 20 is rotated along the rotation axis 24 by the revolution mechanism 26. It is done.
- the mixture 30 accommodated in the container holder 16 rotates along the rotation axis 18 and revolves along the revolution axis 24.
- the mixture 30 containing hyaluronic acid 10 WZV% or more, the crosslinking agent and water is supplied to the rotation-revolution mixer 10 having the rotation mechanism 20 and the rotation mechanism 26, and revolves while rotating and stirred.
- the mixture 30 is a solid powder or a gel with very high viscosity, but the entire system that does not physically break the molecular chain of the hyaluronic acid polymer is stirred and mixed uniformly. Therefore, a uniform cross-linked structure can be easily formed between hyaluronic acid molecules.
- the container holder 16 is rotated and revolved simultaneously by the rotation mechanism 20 and the revolution mechanism 26.
- the rotation speed can be freely set.
- the rotation speed of the container holder 16 varies depending on the properties and capacity of the prepared crosslinked hyaluronic acid gel and the scale of the container holder 16 and the rotating / revolving mixer 10, but in general, the rotation speed is 60 to: L000 rotation Z minutes, revolution speed is about 300-3000 rotation Z minutes.
- the time for stirring and mixing the mixture 30 with the rotation-revolution mixer 10 is the same as in the case of the rotation speed described above. Usually, it is 10 seconds to 30 minutes.
- stirring and mixing using a bread dough kneader can be used as a method of stirring and mixing the mixture in the present invention.
- the bread dough kneading apparatus used in the present invention is known to those skilled in the art, and various commercially available apparatuses can be used in the present invention.
- FIG. 2 shows an apparatus for kneading bread dough according to one embodiment of the present invention.
- a bread dough kneading apparatus 40 includes a container main body 44 that accommodates a sample, a container lid 42, a bread dough kneading blade 46 in the container main body 44, and a container main body 44. And a rotating mechanism 50 that rotates along the shaft 48.
- the dough kneading blade 46 is designed according to the purpose of kneading the bread dough, unlike a sharp stirring blade for a normal mixer or food processor.
- ordinary bread dough forms a cross-linked structure of dartene by kneading and obtains a unique viscoelasticity.
- stirring and mixing are performed without physically breaking the molecular chain of dartene. It is necessary (the same is true in the case of mochi which obtains viscoelasticity by entanglement of amylopectin).
- a bread dough kneading blade 46 is attached to the container body 44 of the bread dough kneading device 40, and the container body 44 contains a mixture 60 containing hyaluronic acid 10 WZV% or more, a crosslinking agent and water, and a container lid 42 is fitted. .
- the dough kneading blade 46 in the container body 44 is connected to the rotating mechanism 50. Therefore, it is rotated along the rotation axis 48. Then, the mixture 60 contained in the container body 44 is stirred and mixed by the rotation of the bread dough kneading blades 46.
- the bread dough kneading blade 46 is originally designed so that stirring and mixing can be performed without physically breaking the molecular chain of dartene in the dough. Therefore, also in the above production example, the entire system without physically breaking the molecular chain of the hyaluronic acid polymer in the mixture 60 is uniformly stirred and mixed.
- the mixture 60 containing hyaluronic acid 10WZV% or more, the crosslinking agent and water is supplied to the pan dough kneading device 40, and the mixture is stirred and mixed by rotation of the bread dough kneading blade 46.
- 60 is in the form of a solid powder or a gel with a very high viscosity, the entire system without physically breaking the hyaluronic acid polymer molecular chain is uniformly stirred and mixed.
- a uniform cross-linked structure can be formed between hyaluronic acid molecules.
- the rotational speed of the bread dough kneading blade 46 can be freely set.
- the properties and capacity of the prepared crosslinked hyaluronic acid gel, the shape of the bread dough kneading blade 46, and the container body 44 and the dough kneading Forces that vary depending on the scale of the device 40 In general, the rotational speed is about 1000 to 2000 revolutions Z minutes.
- the time for stirring and mixing the mixture 60 by the bread dough kneading device 40 is also similar to the case of the rotation speed described above, such as the properties and capacity of the prepared crosslinked hyaluronan gel, the shape of the blade, the scale of the device, etc. Although it depends on the conditions, it is usually about 2 to 6 minutes.
- stirring and mixing by a mochi-kushi device can be used in the same manner as the bread dough kneading device.
- the mochi device used in the present invention is known to those skilled in the art, and various commercially available devices can be used in the present invention.
- stirring and mixing the mixture as a method of stirring and mixing the mixture, stirring and mixing by human hand can be used.
- the time for mixing the mixture by human hand-kneading is usually different depending on conditions such as the properties and volume of the prepared crosslinked hyaluronan gel and the size of the bag. ⁇ About 10 minutes.
- the cross-linking rate is low, such as 2% or less per unit of structural unit of carboxylic acid.
- the cross-linked hyaluronic acid gel at a frequency of 1 Hz of the crosslinked hyaluronic acid gel that has reached the equilibrium of swelling in physiological saline can be easily obtained by cross-linking hyaluronic acid gel having a very excellent viscoelasticity of lOOPa or more, more preferably lOOOPa or more. It can be manufactured.
- the crosslinked hyaluronic acid gel obtained by the production method of the present invention can be used as it is or in pharmaceuticals, cosmetics and the like by blending it in an appropriate formulation.
- the crosslinked hyaluronic acid gel obtained by the production method of the present invention has a high enzyme digestion resistance (hyal-mouth-dase resistance) and can maintain a gel structure for a long time in a living body, for example, It is expected to be particularly suitably applied as a joint injection agent, intraocular vitreous replacement agent, and ophthalmic surgery adjuvant.
- Hyaluronic acid is currently used as a joint injection for the purpose of improving symptoms such as knee osteoarthritis, shoulder periarthritis, and knee joint pain in rheumatoid arthritis.
- the obtained crosslinked hyaluronic acid gel has a high resistance to enzyme digestion, it can be expected that the effect of symptom improvement will be maintained for a long period of time by using it as a joint injection.
- silicone oil is now widely used as an intraocular vitreous replacement for restoring the detached retina.
- hyaluronic acid which is an in vivo component, is considered suitable.
- hyaluronic acid is easily decomposed by enzymes in the eye, so at present, vitreous replacement As a product, hyaluronic acid is not sold. Since the crosslinked hyaluronic acid gel obtained by the present invention has high resistance to enzymatic digestion, it can be expected to have an effect of staying in the eye for a long period of time, attaching the retina to the choroid, and repositioning the retina when used as a vitreous substitute. . In recent years, cataract surgery has been performed safely and easily by using hyaluronic acid as an ophthalmic surgery aid.
- the crosslinked hyaluronic acid gel obtained by the present invention is a crosslinked gel, it is a very small fine particle and exhibits a viscoelasticity equivalent to that of a highly viscoelastic hyaluronic acid solution. For this reason, it can be expected to be used as an adjuvant during ophthalmic surgery as well as a commercially available hyaluronic acid ophthalmic surgery adjuvant.
- all commercially available hyaluronic acid preparations are sterile filtered, but the crosslinked hyaluronic acid gel obtained by the present invention can perform high-pressure steam sterilization, thus minimizing the risk of microbial contamination of the final product. It is possible to limit.
- Example 1 Hyaluronic acid 41 W / V%, divinylsulfone crosslinking rate 0.8%
- the swollen crosslinked hyaluronan gel is crushed with a sample mill (SK-M2 type: manufactured by Kyoritsu Riko Co., Ltd.), and the desired crosslinked hyaluronan gel slurry is obtained.
- SK-M2 type manufactured by Kyoritsu Riko Co., Ltd.
- the desired crosslinked hyaluronan gel slurry is obtained.
- Comparative Example 1 1 Commercial cross-linked hyaluronic acid gel (Restylane: G) -MED Park. Cross-linking rate: 1%
- the crosslinked hyaluronic acid gel slurry obtained in Example 11 above reached a swelling equilibrium in physiological saline even though the crosslinking rate was as low as 0.8%.
- the storage elastic modulus G ′ was about 20000 Pa and the loss elastic modulus G ′ ′ was about 5000 Pa in the frequency range of 0.1 to: LOHz, indicating excellent viscoelasticity.
- the hyaluronic acid concentration in the mixture used for the crosslinking reaction is remarkably high at 41 WZV%, so that the hyaluronic acid molecular chains are sterically constrained by a small amount of crosslinking agent and the network structure is strong. This is thought to be because of the stability.
- the cross-linked hyaluronic acid gel slurry of Comparative Example 11 has a crosslinking rate of about 1% and swells in physiological saline. It was found that the storage elastic modulus G ′ when the equilibrium was reached was about 1000 Pa, and the loss elastic modulus G ′ ′ was about 200 Pa. From this The cross-linked hyaluronic acid gel slurry obtained in Example 1-1 above has excellent viscoelasticity sufficient for practical use as a stretch-stretching injecting agent even though the cross-linking rate is low. Wow.
- Example 1-1 a crosslinked hyaluronic acid gel showing a low cross-linking rate and excellent viscoelasticity by performing a crosslinking reaction under a very high hyaluronic acid concentration condition of 41 WZV%. It has been proved that it can be manufactured more easily.
- Example 11 the present inventors tried the same test as in Example 11 above by appropriately changing the type of the crosslinking agent and the hyaluronic acid concentration condition used for the crosslinking reaction, and the viscoelasticity of the obtained crosslinked hyaluronic acid gel slurry was determined. The relationship was examined.
- Example 1 2 33 W / V% hyaluronic acid.
- the obtained gel is allowed to stand in saline until the swelling equilibrium is reached for 1 week, and the swollen crosslinked hyaluronic acid gel is crushed with a sample mill (SK-M2 type: manufactured by Kyoritsu Riko Co., Ltd.) to obtain the desired crosslinked hyaluron.
- An acid gel slurry was obtained.
- the obtained crosslinked hyaluronan gel slurry was measured for storage elastic modulus G and loss elastic modulus G ′ ′ in the same manner as in Example 1-1.
- the crosslinking rate of the obtained crosslinked hyaluronic gel is 1% per unit of hyaluronic acid structural unit.
- Figure 5 shows the measurement results.
- the crosslinked hyaluronic acid gel of Example 12 obtained using 1,4 butanediol diglycidyl ether as a crosslinking agent and under a condition of a hyaluronic acid concentration of 33 WZV% has a crosslinking rate.
- the storage elastic modulus G ′ is about 1500 Pa and the loss elastic modulus G ′ ′ is about 1500 Pa in the frequency range of 0.1 to LOHz. 300-400 Pa. Therefore, even when a crosslinking agent different from Example 1-1 is used, a crosslinked hyaluronic acid gel having a low crosslinking rate and excellent viscoelasticity can be obtained by performing a crosslinking reaction under a high concentration condition of hyaluronic acid. I was able to obtain it.
- Example 1 3 26 W / V% hyaluronic acid, divinyl sulfone crosslinking rate 0.8%
- the product is allowed to stand for 1 week in physiological saline until the swelling equilibrium is reached, and the swollen crosslinked hyaluronic acid gel is crushed with a sample mill (SK — M2 type: manufactured by Kyoritsu Riko Co., Ltd.) to obtain the desired crosslinked hyaluronic acid.
- a gel slurry was obtained.
- the storage elastic modulus G ′ and the loss elastic modulus G ′ ′ were measured in the same manner as in Example 1-1.
- Example 1 4 26 W / V% hyaluronic acid, 1.4 Butanediol diglycidyl ether Purified water 3000 ⁇ L, 2% NaOH aqueous solution 333 ⁇ L, and 1,4 butanediol 'diglycidyl ether 5 ⁇ L was added, and further, hyaluronic acid (Bio-Hiaguchi 12: manufactured by Shiseido Co., Ltd.) 1. Og was added. This mixture (storage modulus G ′ at a frequency of 1 Hz: 60000 Pa) was stirred and mixed at room temperature for 5 minutes with a rotation-revolution mixer (AR-250: manufactured by THINKY), and then allowed to stand at room temperature for 24 hours. .
- a rotation-revolution mixer AR-250: manufactured by THINKY
- the obtained gel is allowed to stand in physiological saline for 1 week until the swelling equilibrium is reached, and the swollen crosslinked hyaluronan gel is crushed with a sample mill (SK-M2 type: manufactured by Kyoritsu Riko Co., Ltd.) to obtain the desired crosslinking.
- a hyaluronic acid gel slurry was obtained. Obtained rack For the bridge hyaluronic acid gel slurry, the storage elastic modulus G and the loss elastic modulus G ′ ′ were measured in the same manner as in Example 1-1.
- the crosslinking rate of the obtained crosslinked hyaluronic gel is about 1% per unit of hyaluronic acid structural unit.
- Figure 7 shows the measurement results.
- Example 1-5 13 WZV% hyaluronic acid, 1.4 Butanediol diglycidyl ether crosslinking rate 2.8%
- the obtained gel is allowed to stand in physiological saline for 1 week until the swelling equilibrium is reached, and the swollen crosslinked hyaluronan gel is crushed with a sample mill (SK-M2 type: manufactured by Kyoritsu Riko Co., Ltd.) to obtain the desired crosslinking.
- a hyaluronic acid gel slurry was obtained.
- the obtained bridge hyaluronic acid gel slurry was measured for the storage elastic modulus G and the loss elastic modulus G ′ ′ in the same manner as in Example 1-1.
- the crosslinked hyaluronic acid gel of Example 15 obtained using 1,4 butanediol 'diglycidyl ether as a crosslinking agent and under a condition of a hyaluronic acid concentration of 13 WZV% has a crosslinking rate of 2
- the storage elastic modulus G ′ when the swelling equilibrium was reached with physiological saline was about 150 Pa
- the loss elastic modulus G ′ ′ was about 20 Pa. From these results, by carrying out the crosslinking reaction under high concentration conditions of hyaluronic acid, 0. It became clear that a crosslinked hyaluronan gel having excellent viscoelasticity was obtained despite a low crosslinking rate of about 8 to 2.8%.
- the product is allowed to stand in physiological saline until the swelling equilibrium is reached for 1 week.
- the swollen crosslinked hyaluronan gel is crushed with a sample mill (SK-M2 type: manufactured by Kyoritsu Riko Co., Ltd.), and the desired crosslinked hyaluronan gel slurry is obtained.
- SK-M2 type manufactured by Kyoritsu Riko Co., Ltd.
- the obtained crosslinked hyaluronan gel slurry was measured for storage elastic modulus G ′ using a rheometer (Rheolyst AR1000-N: manufactured by TA Instruments) at 25 ° C. and a frequency of 1 Hz. The results are shown in Table 1 below.
- Comparative example 2-2 5.0 Unmeasurable (partial gel) Comparative example 2-3 3.0 Unmeasurable (partial gel) Comparative example 2-4 2.0 Unmeasurable (very small part of Tachibana) Gel) Comparative Example 2—5 1.0 Unmeasurable (Partial drawing gel)
- the present inventors tried a cross-linking reaction with a high concentration of hyaluronic acid and a small amount of a cross-linking agent using a commercially available bread dough kneader, and measured the viscoelasticity of the obtained cross-linked hyaluronic acid gel. did.
- the product was sealed in a sealable polyethylene bag and allowed to stand at room temperature for 18 hours to obtain 200 g of a crosslinked hyaluronan gel.
- About 7.2 g of this cross-linked hyaluronic acid gel was allowed to stand in physiological saline until it reached swelling equilibrium for 1 week to obtain a swollen gel.
- this swollen gel was crushed with a mill to form a slurry, and this was filled with about 1 mL in a small syringe and subjected to high-pressure steam sterilization.
- the storage elastic modulus G ′ was measured using a rheometer (Rheolyst AR1000—N: TA Instruments) at 25 ° C. and a frequency of 1 Hz, and it was 577 Pa. It was.
- the present inventors tried a cross-linking reaction with a high concentration of hyaluronic acid and a small amount of a cross-linking agent by stirring and mixing with human hands, and measured the viscoelasticity of the obtained cross-linked hyaluronic acid gel. did.
- Example 4 4- 2. Comparative Example 4 1
- the bag was quickly sealed, and the mixture in the bag was mixed well with two fingers of both hands. After mixing for about 5 minutes, the bag was shaken to collect the gel-like mixture at the bottom of the bag, which was formed into a rod shape. The bag was allowed to stand in a clean bench for 4 hours, and then the bag was broken to remove the product to obtain a crosslinked hyaluronic acid gel. This cross-linked hyaluronic acid gel was allowed to stand in physiological saline until a swelling equilibrium was reached for 1 week to obtain a swollen gel.
- the present inventors considered the application of the crosslinked hyaluronan gel slurry used by injecting into a living body like, for example, a stretch-stretching injection, and performed enzymatic digestion of the crosslinked hyaluronan gel slurry obtained by the present invention. The tolerance was examined.
- test products were used as test products.
- a control product was prepared under the same conditions except that it did not contain hyaluronan-dase.
- Each tube was placed in a 37 ° C constant temperature bath and subjected to an enzyme reaction for 16 hours.
- the final enzyme activity of the test product after addition of the enzyme solution was 201 unitZmL.
- each tube was inverted, the liquid sample was absorbed with a paper towel, and the weight of the sample remaining at the bottom of the tube was measured.
- Figure 9 shows the results of measuring the sample weights of the test and control products in each sample as a percentage of the theoretical remaining sample.
- the theoretical residual sample percentage (%) is obtained by subtracting the liquefied sample weight from the theoretical initial sample weight (lg) and subtracting the residual sample weight from the theoretical initial sample weight (lg). It is a representation. As shown in Fig. 9, in the control product to which the additive solution containing no enzyme (0.112 mL) was added, although the weight of the additive solution increased, there was a 1.2% hyaluronic acid aqueous solution or The liquid of the cross-linked hyaluronic acid gel was not seen at all. On the other hand, it was found that about 80% of the test product to which the enzyme was added was liquid in the 1.2% hyaluronic acid aqueous solution.
- the crosslinked hyaluronic acid gels 1 to 5 obtained by the production method of the present invention the liquefaction of the gel was only 35% to 25%. For this reason, it is considered that the crosslinked hyaluronic acid gel slurry obtained by the present invention can maintain a gel structure for a long period of time even in a living body where enzyme digestion resistance (hyal mouth-dase resistance) is high.
Abstract
Description
Claims
Priority Applications (4)
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EP05806183A EP1818344A4 (en) | 2004-11-15 | 2005-11-14 | METHOD FOR SYNTHESIZING RETICULATED HYALURONIC ACID GEL |
JP2006545019A JP4875988B2 (ja) | 2004-11-15 | 2005-11-14 | 架橋ヒアルロン酸ゲルの製造方法 |
CN2005800387600A CN101056891B (zh) | 2004-11-15 | 2005-11-14 | 交联透明质酸凝胶的制备方法 |
KR1020077006232A KR101239037B1 (ko) | 2004-11-15 | 2005-11-14 | 가교 히알루론산 겔의 제조 방법 |
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JP (1) | JP4875988B2 (ja) |
KR (1) | KR101239037B1 (ja) |
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JP2010077434A (ja) * | 2008-09-23 | 2010-04-08 | Scivision Biotech Inc | 架橋ヒアルロン酸の製造方法 |
JP2010130920A (ja) * | 2008-12-03 | 2010-06-17 | Shiseido Co Ltd | ヒアルロン酸酵素複合体ゲル |
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WO2014061332A1 (ja) | 2012-10-17 | 2014-04-24 | コスメディ製薬株式会社 | ヒアルロン酸ゲル及びその製造方法 |
US9855206B2 (en) | 2012-10-17 | 2018-01-02 | Cosmed Pharmaceutical Co., Ltd. | Hyaluronic acid gel and manufacturing method thereof |
KR20150070159A (ko) | 2012-10-17 | 2015-06-24 | 코스메드 파마소티컬 씨오 쩜 엘티디 | 히알루론산 겔 및 그의 제조 방법 |
JP2016524016A (ja) * | 2013-06-28 | 2016-08-12 | ガルデルマ エス.エー. | 成形された架橋ヒアルロン酸生成物を製造するための方法 |
US10077321B2 (en) | 2013-06-28 | 2018-09-18 | Galderma S.A. | Method for manufacturing a shaped crosslinked hyaluronic acid product |
US10982016B2 (en) | 2013-06-28 | 2021-04-20 | Galderma Holding SA | Method for manufacturing a shaped cross-linked hyaluronic acid product |
US11702484B2 (en) | 2013-06-28 | 2023-07-18 | Galderma Holding SA | Method for manufacturing a shaped cross-linked hyaluronic acid product |
KR20160028408A (ko) | 2013-07-03 | 2016-03-11 | 가부시키가이샤 리타파마 | 수용성 히알루론산 겔 및 그의 제조 방법 |
WO2015002091A1 (ja) | 2013-07-03 | 2015-01-08 | 株式会社リタファーマ | 水溶性ヒアルロン酸ゲル及びその製造方法 |
CN104004208A (zh) * | 2014-04-16 | 2014-08-27 | 常州药物研究所有限公司 | 交联透明质酸钠生物膜及其制备方法 |
JP2021021082A (ja) * | 2016-01-29 | 2021-02-18 | ハンミ ファーマシューティカルズ カンパニー リミテッド | 複合ヒアルロン酸架橋物及びその製造方法 |
US11180576B2 (en) | 2016-01-29 | 2021-11-23 | Hanmi Pharm. Co., Ltd. | Combination of cross-linked hyaluronic acids and method of preparing the same |
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CN101056891A (zh) | 2007-10-17 |
KR101239037B1 (ko) | 2013-03-04 |
CN101056891B (zh) | 2010-05-26 |
JP4875988B2 (ja) | 2012-02-15 |
EP1818344A4 (en) | 2012-04-18 |
JPWO2006051950A1 (ja) | 2008-05-29 |
KR20070083570A (ko) | 2007-08-24 |
EP1818344A1 (en) | 2007-08-15 |
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