WO2008037171A1 - Procédé de préparation d'un gel d'acide hyaluronique en deux stades de réticulation - Google Patents

Procédé de préparation d'un gel d'acide hyaluronique en deux stades de réticulation Download PDF

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Publication number
WO2008037171A1
WO2008037171A1 PCT/CN2007/002466 CN2007002466W WO2008037171A1 WO 2008037171 A1 WO2008037171 A1 WO 2008037171A1 CN 2007002466 W CN2007002466 W CN 2007002466W WO 2008037171 A1 WO2008037171 A1 WO 2008037171A1
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WIPO (PCT)
Prior art keywords
hyaluronic acid
gel
concentration
acid gel
preparing
Prior art date
Application number
PCT/CN2007/002466
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English (en)
Chinese (zh)
Inventor
Min Liu
Original Assignee
Beijing Pro-Medical Biotech Research Institute
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Application filed by Beijing Pro-Medical Biotech Research Institute filed Critical Beijing Pro-Medical Biotech Research Institute
Publication of WO2008037171A1 publication Critical patent/WO2008037171A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C08J3/244—Stepwise homogeneous crosslinking of one polymer with one crosslinking system, e.g. partial curing
    • 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 hyaluronic acid gel and a process for the preparation thereof, and more particularly to a hyaluronic acid gel having a long retention time and its passage A method of preparing the hyaluronic acid gel by secondary crosslinking.
  • Hyaluronic acid is a linear polymer polysaccharide in which ⁇ -DN acetylglucosamine and ⁇ -D-glucuronic acid are bonded to each other, and is widely distributed in mammalian connective tissues, cockscombs, and streptococcus.
  • hyaluronic acid gel prepared from hyaluronic acid as a filler is transplanted or injected into the body to show good body compatibility, and it has the functions of anti-wrinkle, breast enhancement and filling. , and has no side effects on the human body, and is widely used in medical and beauty industries.
  • This patent is to overcome the shortcomings of the above-mentioned hyaluronic acid gel storage time, and the secondary cross-linking process effectively increases the steric hindrance, so that the prepared hyaluronic acid gel is attacked by hyaluronidase. Difficult to enter, greatly improve the retention time of hyaluronic acid gel.
  • the hyaluronic acid gel of the present invention has a retention time of 2 to 50 times that of the prior art hyaluronic acid gel.
  • One object of the present invention is to provide a hyaluronic acid gel which has a long storage time and a good liner effect and a preparation method thereof, and the storage time of the prepared hyaluronic acid gel is obtained by secondary crosslinking. 2 to 50 times that of a cross-linked hyaluronic acid gel.
  • Another object of the present invention is to provide a medical material of hyaluronic acid gel.
  • a method for preparing a hyaluronic acid gel comprising the steps of:
  • the sodium hyaluronate is dissolved in a sodium hydroxide solution having a concentration of 0.3% to 0.9%, the concentration of hyaluronic acid is 6%-10%, preferably 6%-8%, and the weight of sodium hyaluronate is 0.5-2.8 wt. % glycidyl ether type crosslinking agent, preferably 1-2.5 wt.%, more preferably 1-2 wt.%, reaction temperature 40-60 ° C, preferably 45-55 ° C, reaction time 1-10 hours, placed cool down;
  • the reactant of the step (1) is added to the same weight and the same concentration of the sodium hydroxide solution in the primary crosslinking reaction;
  • the reactant of the step (2) is added to the same or different glycidyl ether type crosslinking agent as (1), and the amount thereof is 3-7 wt.%, preferably 3.75-6.25 t%, more preferably the weight of the sodium hyaluronate. 3-5 wt.% b Stir well to make the solution uniform. Heating is started, the reaction time is 1-5 hours, the reaction temperature is 40-60 ° C, preferably 50-60 ° C, more preferably 50-53 ° C, gel formation;
  • the gel of the step (3) is immersed in a NaCl solution having a concentration of 0.8-1%, and neutralized with a HC1 solution to a pH of 6.5-7.5.
  • the soaking in the step (4) is to soak the gel to a content of hyaluronic acid of 1 to 3 wt%, preferably 1 to 2% w, based on the total weight of the gel.
  • the preparation method further comprises the step of pulverizing when the gel is soaked to a content of hyaluronic acid of 1 to 3 wt.% of the total weight of the gel, more preferably when the gel is soaked to a content of hyaluronic acid as a total gel.
  • a pulverization step is carried out, wherein the glycidyl ether type crosslinking agent is ethylene glycol diglycidyl ether and/or 1,4-butanediol glycidyl ether. .
  • the mass concentration of the NaCl solution described in the step (4) is 0.8-1%; and the mass concentration of the HC1 is 0.3-0.9%.
  • a hyaluronic acid gel prepared by the above preparation method.
  • a medical material comprising a wrinkle pad material, which is formed by immersing and immersing the hyaluronic acid gel after the above-mentioned hyaluronic acid gel.
  • the soaking is immersed in a NaCi solution, and the neutralization is performed by HCL.
  • the solution was neutralized to a pH of 6.5-7.5.
  • the mass concentration of the NaCl solution is 0.8-1%%; and the mass concentration of the HC1 is 0.3-0.9%.
  • the content of hyaluronic acid after soaking the hyaluronic acid gel is 1-3 wt% of the total weight of the gel. / 0 .
  • the hyaluronic acid gel of the present invention is completed by secondary crosslinking, and the amount of the crosslinking agent can be remarkably reduced, and the residue of the crosslinking agent can be reduced, and the residue of the crosslinking agent can be minimized to the injection site.
  • the influence of the human body effectively preventing the damage of the cross-linking agent to the human body.
  • the preservation time of the hyaluronic acid gel is effectively improved, which improves the retention at the injectable site, increases the retention time, and improves the gel quality.
  • the hyaluronic acid gel of the present invention can be used as a cushioning material for wrinkles for use in the medical or cosmetic industry.
  • BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below with reference to examples:
  • Example 1 8 g of sodium hyaluronate was dissolved in 100 g of a sodium hydroxide solution having a concentration of 0.8%, and the concentration of hyaluronic acid was about 8%, and 1.4- 0.08 g of butanediol glycidyl ether was heated at 45 ° C for 3 hours. Place and add the above-mentioned sodium hydroxide solution of the same weight and the same concentration. Then, 0.5 g of 1.4-butylene glycol glycidyl ether was further added, stirred well, and heated at a temperature of 50 ° C for 2.5 hours to prepare a hyaluronic acid gel.
  • the hyaluronic acid gel prepared above was immersed in a 0.9% NaCl solution and neutralized to a pH of 6.5 with a 0.3% HCl solution, and the gel was soaked to a hyaluronic acid content of 1%.
  • the pulverization into the corresponding granules is an ideal crease liner material.
  • the hyaluronic acid gel was subjected to hyaluronidase degradation experiments and compared with primary crosslinked gel particles using the same hyaluronic acid and a crosslinking agent, and as a result, the secondary crosslinked gel particles were degraded. 20.92 times for one cross-linking.
  • Example 2 8 g of sodium hyaluronate was dissolved in 120 g of a sodium hydroxide solution having a concentration of 0.6%, and the concentration of hyaluronic acid was about 6.7%.
  • 0.2 g of ethylene glycol glycidyl ether was added thereto, and the mixture was heated at 50 ° C for 2 hours. Place and add the above-mentioned sodium hydroxide solution of the same weight and the same concentration. Then, 0.3 g of an ethylene glycol glycidyl ether crosslinking agent was further added, and the mixture was thoroughly stirred, and heated at 53 ° C for 1.5 hours to prepare a hyaluronic acid gel.
  • the hyaluronic acid gel prepared above was immersed in a 0.8% NaCl solution, and neutralized to a pH of 7, with a concentration of 0.6% of the HC1 solution, soaked to a hyaluronic acid content of 2%.
  • the pulverization into the corresponding granules is an ideal crease liner material.
  • the hyaluronic acid gel was subjected to hyaluronidase degradation experiments and compared with primary crosslinked gel particles using the same hyaluronic acid and a crosslinking agent, and as a result, the secondary crosslinked gel particles were degraded. 46.65 times as much as one cross-linking.
  • Example 3 8 g of sodium hyaluronate was dissolved in 90 g of a sodium hydroxide solution having a concentration of 0.3%, and the concentration of hyaluronic acid was about 8.9%, and 0.15 g of 1.4-butylene glycol glycidyl ether was added. Heat at 55 ° C for 2 hours and place. Then add the same weight, the same concentration of sodium hydroxide solution, stir well, then add 0.43g ethylene glycol glycidyl ether crosslinker, stir well, react at temperature 55 ° C for 1.5 hours, to produce hyaluronic acid gel.
  • the hyaluronic acid gel prepared above was immersed in a NaCl solution having a concentration of 1%, and neutralized to a pH of 7.5 with a 0.9% HC1 solution, and the gel was soaked to a hyaluronic acid content of 3%.
  • the powder is broken into the corresponding particles, which is the ideal wrinkle pad material.
  • the hyaluronic acid gel was subjected to hyaluronidase degradation experiments and compared with primary crosslinked gel particles using the same hyaluronic acid and a crosslinking agent, and as a result, the secondary crosslinked gel particles were degraded. 10.88 times for one cross-linking.
  • this example only uses ethylene glycol glycidyl ether crosslinker and 1.4-butanediol shrinkage.
  • the specific process of the technical solution of the present invention is described by taking glyceryl ether as an example.
  • any glycidyl ether type crosslinking agent can realize the technical solution according to the art.
  • the preparation method of the hyaluronic acid is universal for any glycidyl ether type crosslinking agent, and the use of any glycidyl ether as a crosslinking agent can obviously obtain the contents of the present invention. Strong support.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Materials For Medical Uses (AREA)
  • Cosmetics (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne un procédé de préparation d'un gel d'acide hyaluronique comprenant les étapes suivantes : (1) réticulation du hyaluronate de sodium avec de l'éther de diglycidyle dans une solution de NaOH, (2) addition du produit de (1) à la solution de NaOH de même masse et concentration que la solution de NaOH de (1), (3) de nouveau, réticulation par addition d'éther de diglycidyle au produit de (2), d'où formation d'un gel, (4) trempage du gel de (3) dans une solution de NaCl et ajustement de la solution au pH 6,5-7,5. Un gel d'acide hyaluronique est préparé suivant le procédé précité. Un produit médical est formé par le gel d'acide hyaluronique précité.
PCT/CN2007/002466 2006-09-29 2007-08-15 Procédé de préparation d'un gel d'acide hyaluronique en deux stades de réticulation WO2008037171A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610152600.5 2006-09-29
CNA2006101526005A CN101153061A (zh) 2006-09-29 2006-09-29 一种透明质酸及其二次交联形成凝胶的方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110964215A (zh) * 2019-12-26 2020-04-07 华熙生物科技股份有限公司 一种注射用左旋聚乳酸和交联透明质酸复合凝胶的制备方法及所得产品
EP2649101B1 (fr) 2010-12-06 2021-06-02 Teoxane Procédé de préparation d'un gel réticulé

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US8691957B2 (en) * 2007-09-28 2014-04-08 Shiseido Company, Ltd. Swellable crosslinked hyaluronan powder and method for producing the same
CN101724164B (zh) * 2008-10-31 2011-12-14 科妍生物科技股份有限公司 交联透明质酸的制造方法
CN101829365B (zh) * 2010-04-13 2013-04-17 杭州市第一人民医院 一种巩膜外加压生物复合材料及制备方法
CN102757570A (zh) * 2011-04-25 2012-10-31 颜先琴 一种透明质酸钠凝胶的制备方法
CN103146003A (zh) * 2013-03-06 2013-06-12 上海其胜生物制剂有限公司 一种低温二次交联透明质酸钠凝胶的制备方法
CN110003360A (zh) * 2013-06-28 2019-07-12 盖尔德玛公司 用于制备交联的透明质酸产物的方法
CN104771331B (zh) * 2015-03-12 2017-12-12 华熙福瑞达生物医药有限公司 一种透明质酸弹性体及其应用
CN107540763B (zh) * 2016-06-24 2020-08-11 宁夏妙朗生物科技有限公司 一种利用生物交联剂制备注射型长效透明质酸凝胶的方法
CN106397795B (zh) * 2016-08-31 2018-12-21 陕西佰傲再生医学有限公司 一种混合透明质酸凝胶及其制备方法
CN108837186A (zh) * 2018-06-21 2018-11-20 东莞市联洲知识产权运营管理有限公司 一种表面涂覆有抗菌涂层的医用材料的制备方法
CN113087935B (zh) * 2021-05-19 2022-05-27 青岛琛蓝海洋生物工程有限公司 一种抵抗透明质酸酶水解的复合透明质酸钠凝胶及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4716224A (en) * 1984-05-04 1987-12-29 Seikagaku Kogyo Co. Ltd. Crosslinked hyaluronic acid and its use
CN1342171A (zh) * 1999-02-03 2002-03-27 维特罗莱夫英国有限公司 多重交联的透明质酸衍生物的生产方法
US20040127698A1 (en) * 2002-12-31 2004-07-01 Industrial Technology Research Institute Method for producing double-crosslinked hyaluronate material

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4716224A (en) * 1984-05-04 1987-12-29 Seikagaku Kogyo Co. Ltd. Crosslinked hyaluronic acid and its use
CN1342171A (zh) * 1999-02-03 2002-03-27 维特罗莱夫英国有限公司 多重交联的透明质酸衍生物的生产方法
US20040127698A1 (en) * 2002-12-31 2004-07-01 Industrial Technology Research Institute Method for producing double-crosslinked hyaluronate material

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2649101B1 (fr) 2010-12-06 2021-06-02 Teoxane Procédé de préparation d'un gel réticulé
CN110964215A (zh) * 2019-12-26 2020-04-07 华熙生物科技股份有限公司 一种注射用左旋聚乳酸和交联透明质酸复合凝胶的制备方法及所得产品
CN110964215B (zh) * 2019-12-26 2022-03-29 华熙生物科技股份有限公司 一种注射用左旋聚乳酸和交联透明质酸复合凝胶的制备方法及所得产品

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