WO2019001472A1 - Branched polyglycol epoxy derivative cross-linked sodium hyaluronate gel, preparation therefor, and application thereof - Google Patents

Abstract

A branched polyglycol epoxy derivative cross-linked sodium hyaluronate gel, preparation therefor, and an application thereof. A cross-linking agent used in the prepared cross-linked sodium hyaluronate gel is a polyglycol epoxy derivative. There is a plurality of ether bonds present in the molecules of the polyglycol epoxy derivative, such that more hydrogen bonds are present in the gel system, thereby enhancing the stability of the gel. Moreover, due to the special spatial structure of the branched polyglycol derivative, the winding spatial structure of the prepared gel is more complex, such that the prepared gel is more stable. Because the related branched polyglycol epoxy derivative is a single molecular weight compound, the prepared gel product has good batch stability.

Description

分枝型多元甘醇环氧衍生物交联透明质酸钠凝胶及其制备和应用Branched polyglycol epoxy derivative cross-linked sodium hyaluronate gel and preparation and application thereof技术领域Technical field

本发明涉及透明质酸钠凝胶技术领域，具体涉及一种分枝型多元甘醇环氧衍生物交联透明质酸钠凝胶及其制备和应用。The invention relates to the technical field of sodium hyaluronate gel, in particular to a branched multi-glycol epoxy derivative cross-linked sodium hyaluronate gel, and preparation and application thereof.

背景技术Background technique

透明质酸(hyalouronic acid，HA)是由葡萄糖醛酸和乙酰氨基葡糖双糖单位重复组成的一种直链高分子粘性多糖。透明质酸是人体内本身具有的内源性物质，具有良好的生物相容性；具有高粘弹性和非牛顿流变学特性；无毒、无免疫源性、无刺激性，具有很高的安全性，以及可通过注射透明质酸酶降解消除等特点，被广泛用作美容中的软组织填充剂。即将透明质酸注射至皮肤内，以增加软组织体积，可达到除皱或塑形等目的。但是由于透明质酸本身以液体形式存在，在体内透明质酸酶和自由基的作用下非常容易被分解，因此难以达到塑性效果且填充效果持续时间短。Hyalouronic acid (HA) is a linear polymer viscous polysaccharide composed of glucuronic acid and acetylglucosamine disaccharide units. Hyaluronic acid is an endogenous substance in the human body, with good biocompatibility; high viscoelasticity and non-Newtonian rheological properties; non-toxic, non-immunogenic, non-irritating, high It is widely used as a soft tissue filler in beauty because of its safety and its ability to be eliminated by injection of hyaluronidase. Hyaluronic acid is injected into the skin to increase the volume of soft tissue, which can achieve the purpose of wrinkle removal or shaping. However, since hyaluronic acid itself exists in a liquid form, it is easily decomposed by the action of hyaluronidase and free radicals in the body, so that it is difficult to achieve a plastic effect and the filling effect has a short duration.

为了克服这一缺陷，技术人员将交联技术运用于透明质酸，即通过交联剂将透明质酸分子连接起来形成相对稳定的网状结构，使其不再容易被分解、填充维持的时间变长。经过交联修饰后透明酸钠凝胶具有粘弹性能好、不溶于水、机械强度高、降解时间长的优点，同时，交联程度的不同带来了不同的物理特性，使其能够更好地满足美容填充需求。In order to overcome this drawback, the skilled person applies cross-linking technology to hyaluronic acid, that is, the hyaluronic acid molecules are connected by a crosslinking agent to form a relatively stable network structure, so that it is no longer easy to be decomposed and filled for maintenance time. lengthen. After cross-linking modification, the transparent sodium gel has the advantages of good viscoelasticity, insoluble in water, high mechanical strength and long degradation time. At the same time, the different degree of crosslinking brings different physical properties, which makes it better. Meet the beauty filling needs.

目前市售的透明质酸钠凝胶产品中使用的交联剂主要有：BDDE(丁二醇二缩水甘油醚)和DVS(二乙烯基砜)。如法国高德美公司(Galderma)Restylane瑞蓝系列、美国艾尔健公司(Allergan)Juvederm乔雅登系列、法国维法西公司(Laboratoires Vivacy)Stylage系列、台湾科妍生物海德密丝(Hya-Dermis)系列均采用BDDE交联制备透明质酸钠凝胶，而美国基因酶公司(Genzyme)Hylaform系列、德国阿杜德姆公司(Adoderm)Varioderm系列、瑞士泰奥赛恩公司(Teoxane)Teosyal系列均采用DVS作为交联剂制备透明质酸钠凝胶。两种交联剂制备的凝胶具有截然不同的物理性能：DVS交联产品质地硬，交联活性高；BDDE交联产品质地柔软，反应较为温和，膨胀率大。但值得注意的是，上述交联剂均具有毒性或潜在致癌隐患，且交联后的空间网状结构对未反应的交联剂具有包裹作用，去除难度较大。The crosslinking agents currently used in commercially available sodium hyaluronate gel products are mainly BDDE (butanediol diglycidyl ether) and DVS (divinyl sulfone). Such as the French Golderma Restylane series, the Allergan Juvederm series, the Laboratoires Vivacy Stylage series, the Taiwanese bio-Hya-Dermis series Both of them use BDDE cross-linking to prepare sodium hyaluronate gel, while the Genzyme Hylaform series, the German Adoderm Varioderm series, and the Teoxane Teosyal series all use DVS. The crosslinker prepares a sodium hyaluronate gel. The gel prepared by the two cross-linking agents has distinct physical properties: the DVS cross-linked product has a hard texture and high cross-linking activity; the BDDE cross-linked product has a soft texture, a mild reaction and a large expansion ratio. However, it is worth noting that the above cross-linking agents have toxicity or potential carcinogenic potential, and the cross-linked spatial network structure has a wrapping effect on the unreacted cross-linking agent, and the removal is difficult.

专利申请CN201611246123.9中公开了一种高效低毒的多元甘醇环氧衍生物交联剂

(n＝4、5、6、7、8、9、10、11、12……200)，用该交联剂制备的 透明质酸钠凝胶具有优良的性能。但为进一步提高凝胶的体内稳定性，本发明设计了一种分枝型多元甘醇环氧衍生物，其作为交联剂制备透明质酸钠凝胶除具有凝胶柔软、黏弹性好、毒性低、产品均一性等优点外，该凝胶具有更佳的稳定性。A highly efficient and low toxicity polyglycol epoxy derivative crosslinker is disclosed in the patent application CN201611246123.9.

(n = 4, 5, 6, 7, 8, 9, 10, 11, 12, ... 200), the sodium hyaluronate gel prepared using the crosslinking agent has excellent properties. However, in order to further improve the in vivo stability of the gel, the present invention designs a branched polyglycol epoxy derivative which is used as a crosslinking agent to prepare a sodium hyaluronate gel, which has a soft gel and good viscoelasticity. The gel has better stability in addition to its low toxicity and product uniformity.

发明内容Summary of the invention

为克服现有技术的不足，本发明提供一种结构新颖的分枝型多元甘醇环氧衍生物及交联的透明质酸凝胶及其制备和应用。In order to overcome the deficiencies of the prior art, the present invention provides a novel branched-type polyglycol epoxy derivative and a crosslinked hyaluronic acid gel, and a preparation and application thereof.

本发明一方面提供一种分枝型多元甘醇环氧衍生物，其具有如下结构：In one aspect, the present invention provides a branched polyglycol epoxy derivative having the following structure:

其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof,

X₁和X₂为连接基团，独立地选自：-(CH₂)_i-、-(CH₂)_iO-、-(CH₂)_iCO-、-(CH₂)_iNH-、-(CH₂)_iNHCO(CH₂)_j-、-(CH₂)_iCONH(CH₂)_j-、-(CH₂)_iOCO(CH₂)_j-、-(CH₂)_iCOO(CH₂)_j-、

中一种或两种以上的组合，i和j独立地选自0-10的整数，X₁ and X₂ are a linking group independently selected from the group consisting of: -(CH₂ )_i -, -(CH₂ )_i O-, -(CH₂ )_i CO-, -(CH₂ )_i NH-, -(CH₂ )_i NHCO(CH₂ )_j -, -(CH₂ )_i CONH(CH₂ )_j -, -(CH₂ )_i OCO(CH₂ )_j -, -(CH₂ )_i COO( CH₂ )_j -,

One or a combination of two or more, i and j are independently selected from an integer of 0-10,

PEG具有如下结构：-(CH₂CH₂O)_m-，m为4-200的整数，PEG has the following structure: -(CH₂ CH₂ O)_m -, m is an integer from 4 to 200,

n为3-24的整数，n is an integer from 3 to 24,

所述分枝型多元甘醇环氧衍生物为单一分子量的化合物。The branched polyglycol epoxy derivative is a compound of a single molecular weight.

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

其中，B具有如下结构：

Among them, B has the following structure:

r为1-5的整数(具体可为1、2、3、4或5)，r is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),

a、b、c和d为整数，独立地选自0和1。a, b, c and d are integers, independently selected from 0 and 1.

在本发明的另一个实施例中，所述A具有如下结构：In another embodiment of the invention, the A has the following structure:

其中，B具有如下结构：

Among them, B has the following structure:

s为1-5的整数(具体可为1、2、3、4或5)，s is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),

e、f和g为整数，独立地选自0和1。e, f and g are integers independently selected from 0 and 1.

在本发明的一个实施例中，式Ⅱ中，所述r为1、2或3。In one embodiment of the invention, in Formula II, the r is 1, 2 or 3.

在本发明的一个实施例中，式Ⅱ中，所述a、b、c和d均为0。In one embodiment of the invention, in formula II, said a, b, c and d are both zero.

在本发明的另一个实施例中，式Ⅱ中，所述a、b、c和d均为1。In another embodiment of the invention, in formula II, said a, b, c and d are both 1.

在本发明的一个实施例中，式Ⅲ中，所述s为1、2或3。In one embodiment of the invention, in Formula III, the s is 1, 2 or 3.

在本发明的一个实施例中，式Ⅲ中，所述e、f和g均为0。In one embodiment of the invention, in Formula III, the e, f, and g are both zero.

在本发明的另一个实施例中，式Ⅲ中，所述e、f和g均为1。In another embodiment of the invention, in formula III, said e, f and g are both 1.

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

在本发明的一个实施例中，所述n为3-16的整数，具体可为3、4、5、6、7、8、10、12、14或16。In one embodiment of the invention, n is an integer from 3 to 16, specifically 3, 4, 5, 6, 7, 8, 10, 12, 14, or 16.

在本发明的一个实施例中，所述X₁中，所述i和j独立地选自0-10的整数，具体可为0、1、2、3、4、5、6、7、8、9或10，优选为0、1、2或3。In an embodiment of the present invention, in X₁ , the i and j are independently selected from an integer of 0-10, and specifically may be 0, 1, 2, 3, 4, 5, 6, 7, 8 9, 9 or 10, preferably 0, 1, 2 or 3.

在本发明的一个实施例中，所述X₂中，所述i和j独立地选自0-10的整数，具体可为0、1、2、3、4、5、6、7、8、9或10，优选为0、1、2或3。In an embodiment of the present invention, in X₂ , the i and j are independently selected from an integer of 0-10, and specifically may be 0, 1, 2, 3, 4, 5, 6, 7, 8 9, 9 or 10, preferably 0, 1, 2 or 3.

在本发明的一个实施例中，所述X₁选自：-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CONH-、-CH₂CH₂CONH-、-CH₂CONHCH₂-、-CH₂CONHCH₂CH₂-、-CH₂CH₂CONHCH₂CH₂-、-CH₂CH₂NHCOCH₂-和-CH₂CH₂NHCOCH₂CH₂-中一种或两种以上的组合。In one embodiment of the present invention, the X₁ is selected_{from: -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CONH -, - CH 2 CH 2 CONH- And one of -CH₂ CONHCH₂ -, -CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ NHCOCH₂ - and -CH₂ CH₂ NHCOCH₂ CH₂ - Or a combination of two or more.

在本发明的一个优选实施例中，所述X₁为-CH₂CH₂CONH-。In a preferred embodiment of the invention, said X₁ is -CH₂ CH₂ CONH-.

在本发明的一个实施例中，所述X₂选自：-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CONH-、-CH₂CH₂CONH-、-CH₂CONHCH₂-、-CH₂CONHCH₂CH₂-、-CH₂CH₂CONHCH₂CH₂-、-CH₂CH₂NHCOCH₂-和-CH₂CH₂NHCOCH₂CH₂-中一种或两种以上的组合。In one embodiment of the present invention, the X₂ is selected_{from: -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CONH -, - CH 2 CH 2 CONH- And one of -CH₂ CONHCH₂ -, -CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ NHCOCH₂ - and -CH₂ CH₂ NHCOCH₂ CH₂ - Or a combination of two or more.

在本发明的一个优选实施例中，所述X₂为-CH₂-。In a preferred embodiment of the invention, said X₂ is -CH₂ -.

本发明所述的分枝型多元甘醇环氧衍生物中，m为4-200的整数，如4-100的整数(具体可为4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50、60、70、80、90或100)、100-200的整数(具体可为100、110、120、130、140、150、160、170、180、190或200)，优选为4-100的整数。In the branched polyhydric alcohol epoxy derivative of the present invention, m is an integer of 4 to 200, such as an integer of 4 to 100 (specifically, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100), An integer of 100-200 (specifically 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200), preferably an integer from 4 to 100.

在本发明的一个优选实施例中，所述m为4、12或24。In a preferred embodiment of the invention, the m is 4, 12 or 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-1中，m为4。In one embodiment of the invention, in Formula I-1, m is 4.

在本发明的一个实施例中，式Ⅰ-1中，m为12。In one embodiment of the invention, in Formula I-1, m is 12.

在本发明的一个实施例中，式Ⅰ-1中，m为24。In one embodiment of the invention, in Formula I-1, m is 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-2中，m为4。In one embodiment of the invention, in Formula I-2, m is 4.

在本发明的一个实施例中，式Ⅰ-2中，m为12。In one embodiment of the invention, in Formula I-2, m is 12.

在本发明的一个实施例中，式Ⅰ-2中，m为24。In one embodiment of the invention, in Formula I-2, m is 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-3中，m为4。In one embodiment of the invention, in Formula I-3, m is 4.

在本发明的一个实施例中，式Ⅰ-3中，m为12。In one embodiment of the invention, in Formula I-3, m is 12.

在本发明的一个实施例中，式Ⅰ-3中，m为24。In one embodiment of the invention, in Formula I-3, m is 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-4中，m为4。In one embodiment of the invention, in Formula I-4, m is 4.

在本发明的一个实施例中，式Ⅰ-4中，m为12。In one embodiment of the invention, in Formula I-4, m is 12.

在本发明的一个实施例中，式Ⅰ-4中，m为24。In one embodiment of the invention, in Formula I-4, m is 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-5中，m为4。In one embodiment of the invention, in Formula I-5, m is 4.

在本发明的一个实施例中，式Ⅰ-5中，m为12。In one embodiment of the invention, in Formula I-5, m is 12.

在本发明的一个实施例中，式Ⅰ-5中，m为24。In one embodiment of the invention, in Formula I-5, m is 24.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物具有如下结构：In one embodiment of the invention, the branched polyglycol epoxy derivative has the following structure:

在本发明的一个实施例中，式Ⅰ-6中，m为4。In one embodiment of the invention, in Formula I-6, m is 4.

在本发明的一个实施例中，式Ⅰ-6中，m为12。In one embodiment of the invention, in Formula I-6, m is 12.

在本发明的一个实施例中，式Ⅰ-6中，m为24。In one embodiment of the invention, in Formula I-6, m is 24.

本发明另一方面提供一种上述分枝型多元甘醇环氧衍生物的制备方法，所述方法包括在溶剂中，使用催化剂催化

与分枝型多元甘醇

反应的步 骤，According to another aspect of the present invention, there is provided a process for producing the above branched polyglycol epoxy derivative, which comprises catalyzing a catalyst in a solvent

Branched polyglycol

Reaction step,

其中，所述A、X₁、X₂、PEG和n具有本发明上述定义，Wherein A, X₁ , X₂ , PEG and n have the above definitions of the invention,

-X为离去基团，-X is the leaving group,

所述的催化剂为碱催化剂，包括有机碱或无机碱。The catalyst is a base catalyst comprising an organic base or an inorganic base.

在本发的一个实施例中，所述的溶剂包括但不限于：1，4-二氧六环、四氢呋喃、甲苯、丙酮、乙酸乙酯、乙腈、N,N-二甲基甲酰胺、二甲基亚砜或水。In one embodiment of the present invention, the solvent includes, but is not limited to, 1,4-dioxane, tetrahydrofuran, toluene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, and Methyl sulfoxide or water.

在本发的一个实施例中，所述碱催化剂选自但不限于：吡啶、三乙胺、碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、醇钠和醇钾中的一种或多种。In one embodiment of the present invention, the base catalyst is selected from, but not limited to, pyridine, triethylamine, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, One or more of sodium alkoxide and potassium alkoxide.

在本发的一个实施例中，所述离去基团选自：

(-OTs)、

(-OMs)、

(-OBs)、

(-OTf)、-F、-I、-Br和-Cl中的一种。In one embodiment of the invention, the leaving group is selected from the group consisting of

(-OTs),

(-OMs),

(-OBs),

One of (-OTf), -F, -I, -Br, and -Cl.

在本发的一个实施例中，所述分枝型多元甘醇中单羟基与

的摩尔比为1：2-4。In one embodiment of the present invention, the monohydroxy group of the branched polyglycol is

The molar ratio is 1:2-4.

在本发的一个实施例中，所述制备方法还包括纯化步骤；具体地，所述的纯化步骤选自：旋蒸、洗涤、萃取、分子蒸馏和柱分离中的一种或多种的组合。In an embodiment of the present invention, the preparation method further comprises a purification step; specifically, the purification step is selected from the group consisting of: one or more of a combination of rotary distillation, washing, extraction, molecular distillation, and column separation. .

在本发明的一个优选实施例中，所述制备方法包括如下具体步骤：向反应容器中加入上述分枝型多元甘醇、溶剂和催化剂，搅拌，向上述混合物中滴加卤化或磺酸酯化的环氧丙烷，控制反应温度不超过35℃，反应完成后过滤，洗涤滤渣，并收集滤液并纯化，得到所述多元甘醇环氧衍生物。In a preferred embodiment of the present invention, the preparation method comprises the following steps: adding the above-mentioned branched polyglycol, a solvent and a catalyst to a reaction vessel, stirring, and dropwise adding a halogenated or sulfonated ester to the above mixture. The propylene oxide is controlled to have a reaction temperature of not more than 35 ° C. After the reaction is completed, it is filtered, the filter residue is washed, and the filtrate is collected and purified to obtain the polyglycol epoxy derivative.

上述反应通式如下：The above reaction formula is as follows:

采用上述制备方法合成的分枝型多元甘醇环氧衍生物纯度较高，其纯度HPLC检测大于99％。该低毒性、高反应活性、超亲水性多元甘醇环氧衍生物交联剂可用于天然高分子如天然多糖和蛋白质、合成高分子如聚乙二醇和聚乙烯醇等高分子聚合物的交联。The branched multi-glycol epoxy derivative synthesized by the above preparation method has high purity, and its purity is more than 99% by HPLC. The low-toxicity, high-reactivity, super-hydrophilic polyglycol epoxy derivative cross-linking agent can be used for natural polymers such as natural polysaccharides and proteins, synthetic polymers such as polyethylene glycol and polyvinyl alcohol. Cross-linking.

本发明另一方面还提供一种交联剂，所述交联剂包括本发明上述分枝型多元甘醇环氧衍生物。Another aspect of the present invention also provides a crosslinking agent comprising the above branched polyvalent glycol epoxy derivative of the present invention.

本发明另一方面还提供一种本发明上述分枝型多元甘醇环氧衍生物交联的高分子聚合物。所 述高分子聚合物可为天然高分子和/或合成高分子。Another aspect of the present invention provides a high molecular polymer crosslinked by the above branched polyglycol epoxy derivative of the present invention. The high molecular polymer may be a natural polymer and/or a synthetic polymer.

具体地，所述的天然高分子选自：甲壳素及甲壳素衍生物(如羧甲基甲壳素和羧乙基甲壳素)、壳聚糖及壳聚糖衍生物(如羧甲基壳聚糖和羧乙基壳聚糖等)、卡拉胶及羧甲基卡拉胶、纤维素衍生物(如羧甲基纤维素、羟丙基纤维素和羟丙基甲基纤维素等)、淀粉及淀粉衍生物(如羧甲基淀粉等)、海藻酸钠、瓜尔胶及羧甲基瓜尔胶、胶原蛋白和透明质酸及透明质酸盐(如透明质酸钠、透明质酸钾、透明质酸钙、透明质酸镁、透明质酸锌、透明质酸钴和透明质酸四丁铵等)中的一种或多种。Specifically, the natural polymer is selected from the group consisting of: chitin and chitin derivatives (such as carboxymethyl chitin and carboxyethyl chitin), chitosan and chitosan derivatives (such as carboxymethyl shell poly Sugar and carboxyethyl chitosan, etc.), carrageenan and carboxymethyl carrageenan, cellulose derivatives (such as carboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose), starch and Starch derivatives (such as carboxymethyl starch, etc.), sodium alginate, guar gum and carboxymethyl guar, collagen and hyaluronic acid and hyaluronate (such as sodium hyaluronate, potassium hyaluronate, One or more of calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate.

具体地，所述的合成高分子选自：聚乙烯吡咯烷酮、聚乙二醇、聚环氧乙烷、聚乙烯醇、聚醋酸乙烯脂、聚乳酸、聚乙醇酸、聚丙烯酸、聚丙烯酰胺、聚四氢呋喃、聚环氧丁烷、聚氧杂环丁烷、聚马来酸酐、聚羟乙基丙烯酸甲酯、聚丙二醇、聚己内酯、及其衍生物中的一种或多种。Specifically, the synthetic polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl acetate, polylactic acid, polyglycolic acid, polyacrylic acid, polyacrylamide, One or more of polytetrahydrofuran, polybutylene oxide, polyoxetane, polymaleic anhydride, polyhydroxyethyl methacrylate, polypropylene glycol, polycaprolactone, and derivatives thereof.

在本发明的一个优选实施例中，所述天然高分子为透明质酸或透明质酸盐；具体地，所述的透明质酸盐选自：透明质酸钠、透明质酸钾、透明质酸钙、透明质酸镁、透明质酸锌、透明质酸钴和透明质酸四丁铵中的一种或两种以上的混合物。In a preferred embodiment of the present invention, the natural polymer is hyaluronic acid or hyaluronate; specifically, the hyaluronate is selected from the group consisting of sodium hyaluronate, potassium hyaluronate, and hyaluronic acid. One or a mixture of two or more of calcium acid, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate.

在本发明的一个更优选实施例中，所述透明质酸盐为透明质酸钠。In a more preferred embodiment of the invention, the hyaluronate is sodium hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述透明质酸钠的分子量为5万-300万道尔顿，具体可为5-100万道尔顿(如5、10、20、30、40、50、60、70、80、90或100万道尔顿)或100-300万道尔顿(如100、150、200、250或300万道尔顿)。In one embodiment of the invention, the sodium hyaluronate has a molecular weight of 50,000 to 3 million Daltons, specifically 5 to 1 million Daltons (eg, 5, 10, 20, 30, 40, 50). , 60, 70, 80, 90 or 1 million Daltons) or 1 to 3 million Daltons (eg 100, 150, 200, 250 or 3 million Daltons).

本发明另一方面还提供一种凝胶，所述凝胶包含本发明上述交联高分子聚合物。Another aspect of the present invention also provides a gel comprising the above crosslinked high molecular polymer of the present invention.

在本发明的一个优选实施例中，所述凝胶中，所述高分子聚合物为透明质酸或透明质酸盐；具体地，所述的透明质酸盐选自：透明质酸钠、透明质酸钾、透明质酸钙、透明质酸镁、透明质酸锌、透明质酸钴和透明质酸四丁铵中的一种或多种的混合物。In a preferred embodiment of the present invention, in the gel, the high molecular polymer is hyaluronic acid or a hyaluronate; specifically, the hyaluronate is selected from the group consisting of sodium hyaluronate, A mixture of one or more of potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述凝胶中，所述透明质酸钠的分子量为5万-300万道尔顿。In one embodiment of the invention, the sodium hyaluronate has a molecular weight of from 50,000 to 3 million Daltons in the gel.

本发明另一方面提供一种上述分枝型多元甘醇环氧衍生物交联的高分子聚合物的制备方法，包括高分子聚合物与上述分枝型多元甘醇环氧衍生物在碱性条件下交联反应的步骤。Another aspect of the present invention provides a method for preparing a polymer of a crosslinked polyglycol epoxy derivative crosslinked, comprising a high molecular polymer and the above branched polyglycol epoxy derivative in an alkaline state The step of crosslinking reaction under conditions.

在本发明的一个实施例中，所述交联反应在碱性溶液中进行。In one embodiment of the invention, the crosslinking reaction is carried out in an alkaline solution.

在本发明的一个实施例中，所述的碱性溶液选自：氢氧化钠、氢氧化钾和碳酸钠溶液中的一种或多种。In one embodiment of the invention, the alkaline solution is selected from one or more of the group consisting of sodium hydroxide, potassium hydroxide, and sodium carbonate solution.

在本发明的一个优选实施例中，所述碱性溶液为质量浓度为0.1-10％的氢氧化钠水溶液。In a preferred embodiment of the invention, the alkaline solution is an aqueous sodium hydroxide solution having a mass concentration of 0.1-10%.

在本发明的一个实施例中，所述交联高分子聚合物为交联透明质酸钠，所述制备方法包括将 所述分枝型多元甘醇环氧衍生物溶于碱性溶液中，加入透明质酸钠粉末中，搅拌反应的步骤。In one embodiment of the present invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate, and the preparation method comprises dissolving the branched polyglycol epoxy derivative in an alkaline solution. The step of stirring the reaction is carried out by adding sodium hyaluronate powder.

在本发明的一个实施例中，所述分枝型多元甘醇环氧衍生物与透明质酸中聚合物单元的摩尔比为0.01-1:1，具体可为0.01:1、0.05:1、0.1:1、0.15:1、0.2:1、0.25:1、0.3:1、0.4:1、0.5:1、0.6:1、0.7:1、0.8:1、0.9:1或1.0:1，优选为0.1-0.5:1。In one embodiment of the present invention, the molar ratio of the branched polyglycol epoxy derivative to the polymer unit in the hyaluronic acid is 0.01-1:1, specifically 0.01:1, 0.05:1. 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1.0:1, preferably 0.1-0.5:1.

在本发明的一个实施例中，所述透明质酸钠与碱性溶液的质量比为1:5-30，具体可为1:5、1:10、1:15、1:20、1:25或1:30。In one embodiment of the present invention, the mass ratio of the sodium hyaluronate to the alkaline solution is 1:5-30, specifically 1:5, 1:10, 1:15, 1:20, 1: 25 or 1:30.

在本发明的一个实施例中，所述反应温度为35-45℃，具体可为35、36、38、40、42、44或45℃，优选为40℃。In one embodiment of the invention, the reaction temperature is 35-45 ° C, specifically 35, 36, 38, 40, 42, 44 or 45 ° C, preferably 40 ° C.

在本发明的一个实施例中，所述透明质酸钠的分子量为5万-300万道尔顿，具体可为5-100万道尔顿(如5、10、20、30、40、50、60、70、80、90或100万道尔顿)或100-300万道尔顿(如100、150、200、250或300万道尔顿)。In one embodiment of the invention, the sodium hyaluronate has a molecular weight of 50,000 to 3 million Daltons, specifically 5 to 1 million Daltons (eg, 5, 10, 20, 30, 40, 50). , 60, 70, 80, 90 or 1 million Daltons) or 1 to 3 million Daltons (eg 100, 150, 200, 250 or 3 million Daltons).

在本发明的一个实施例中，所述的制备方法还包括交联剂去除步骤；具体地，所述交联剂去除的步骤包括依次将上述交联反应产物pH值调中性、溶胀的步骤。In an embodiment of the present invention, the preparation method further includes a crosslinking agent removing step; specifically, the step of removing the crosslinking agent comprises the steps of sequentially adjusting the pH of the crosslinking reaction product to be neutral and swelling. .

在本发明的一个实施例中，所述将交联反应产物pH值调中性为加酸调pH值至中性，优选的，所述酸为盐酸，更优选为浓度为0.1N-2N盐酸。In one embodiment of the present invention, the pH of the cross-linking reaction product is adjusted to be acid to adjust the pH to neutral. Preferably, the acid is hydrochloric acid, more preferably the concentration is 0.1N-2N hydrochloric acid. .

在本发明的一个实施例中，所述溶胀包括加入适量PBS缓冲液使交联反应产物溶胀。In one embodiment of the invention, the swelling comprises adding an appropriate amount of PBS buffer to swell the crosslinking reaction product.

在本发明的一个实施例中，所述的交联剂去除步骤还包括透析步骤。In one embodiment of the invention, the crosslinker removal step further comprises a dialysis step.

本发明还提供一种上述凝胶的制备方法，其包括上述交联高分子聚合物的制备方法的步骤。The present invention also provides a method for producing the above gel, which comprises the steps of the method for preparing the above crosslinked high molecular polymer.

在本发明的一个实施例中，所述制备方法还包括筛分、灌装和灭菌的步骤。In one embodiment of the invention, the method of preparation further includes the steps of sieving, filling, and sterilizing.

在本发明的一个实施例中，所述的灭菌条件为121℃-125℃蒸汽中灭菌8-25分钟。In one embodiment of the invention, the sterilization conditions are sterilized in steam from 121 ° C to 125 ° C for 8-25 minutes.

在本发明的一个优选实施例中，上述凝胶的制备方法包括如下具体步骤：In a preferred embodiment of the invention, the method of preparing the gel comprises the following specific steps:

步骤一：将分枝型多元甘醇环氧衍生物溶于碱性溶液中，加入透明质酸钠粉末中，35-45℃，优选为40℃搅拌反应形成交联透明质酸钠凝胶；Step 1: dissolving the branched polyglycol epoxy derivative in an alkaline solution, adding sodium hyaluronate powder, stirring at 35-45 ° C, preferably 40 ° C to form a crosslinked sodium hyaluronate gel;

步骤二：加酸将凝胶调节为中性；Step 2: Add acid to adjust the gel to neutral;

步骤三：加入适量PBS缓冲液使凝胶溶胀；Step 3: adding an appropriate amount of PBS buffer to swell the gel;

步骤四：反复透析多次，去除凝胶中残留的小分子交联剂；Step 4: Repeat the dialysis multiple times to remove the residual small molecule cross-linking agent in the gel;

步骤五：用标准筛筛分；Step 5: Screening with a standard sieve;

步骤六：将步骤六中收集的凝胶颗粒灌装于事先灭菌的一次性注射器中，在121℃-125℃蒸汽中灭菌8-25分钟，即可得到注射用修饰透明质酸钠凝胶。Step 6: The gel particles collected in the step 6 are filled in a pre-sterilized disposable syringe, and sterilized in steam at 121 ° C - 125 ° C for 8-25 minutes to obtain a modified sodium hyaluronate for injection. gum.

本发明另一方面提供一种上述分枝型多元甘醇衍生物在制备上述交联剂、交联高分子聚合物和凝胶中的应用。Another aspect of the present invention provides the use of the above branched polyhydric alcohol derivative in the preparation of the above crosslinking agent, crosslinked high molecular polymer and gel.

在本发明的一个实施例中，所述交联高分子聚合物为交联透明质酸或交联透明质酸盐。In one embodiment of the invention, the crosslinked high molecular polymer is crosslinked hyaluronic acid or crosslinked hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述凝胶为包含交联透明质酸钠的凝胶。In one embodiment of the invention, the gel is a gel comprising crosslinked sodium hyaluronate.

本发明另一方面提供一种上述交联剂在制备交联高分子聚合物或凝胶中的应用。Another aspect of the present invention provides the use of the above crosslinking agent in the preparation of a crosslinked polymer or gel.

在本发明的一个实施例中，所述交联高分子聚合物为交联透明质酸或交联透明质酸盐。In one embodiment of the invention, the crosslinked high molecular polymer is crosslinked hyaluronic acid or crosslinked hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述凝胶为包含交联透明质酸钠的凝胶。In one embodiment of the invention, the gel is a gel comprising crosslinked sodium hyaluronate.

本发明另一方面提供一种上述交联高分子聚合物或上述凝胶在制备用于药物、医疗美容、化妆品或保健食品用途的产品中的应用。Another aspect of the present invention provides the use of the above crosslinked high molecular polymer or the above gel in the preparation of a product for pharmaceutical, medical cosmetic, cosmetic or health food use.

在本发明的一个实施例中，所述交联高分子聚合物为交联透明质酸或交联透明质酸盐。In one embodiment of the invention, the crosslinked high molecular polymer is crosslinked hyaluronic acid or crosslinked hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述凝胶为包含交联透明质酸钠的凝胶。In one embodiment of the invention, the gel is a gel comprising crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述的医疗美容用途的产品为软组织填充剂。In one embodiment of the invention, the product for medical cosmetic use is a soft tissue filler.

在本发明的一个实施例中，所述的药物用途的产品包括术后防粘连剂、药物载体和预防和/或治疗疾病的药物。In one embodiment of the invention, the pharmaceutical use product comprises a post-operative anti-adhesion agent, a pharmaceutical carrier, and a medicament for preventing and/or treating a disease.

本发明另一方面提供一种软组织填充剂，其包括上述交联高分子聚合物或凝胶。Another aspect of the present invention provides a soft tissue filler comprising the above crosslinked high molecular polymer or gel.

在本发明的一个实施例中，所述交联高分子聚合物为交联透明质酸或交联透明质酸盐。In one embodiment of the invention, the crosslinked high molecular polymer is crosslinked hyaluronic acid or crosslinked hyaluronate.

在本发明的一个优选实施例中，所述交联高分子聚合物为交联透明质酸钠。In a preferred embodiment of the invention, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.

在本发明的一个实施例中，所述凝胶为包含交联透明质酸钠的凝胶。In one embodiment of the invention, the gel is a gel comprising crosslinked sodium hyaluronate.

本发明采用新型交联剂制备交联透明质酸钠的有益效果包括：本发明制备的交联透明质酸钠凝胶中所用的交联剂为多元甘醇环氧衍生物，由于其分子中存在多个醚键，使得凝胶体系中存在较多氢键，使得凝胶稳定性增强；同时，由于分枝型多元甘醇环氧衍生物的空间结构的特殊性，所制得的凝胶空间的缠绕结构更加复杂，所制得的凝胶更加稳定。另外，由于本发明中所涉及的分枝型多元甘醇环氧衍生物为单一分子量的化合物，其所制得的凝胶产品批次稳定性较好。The beneficial effects of the invention for preparing cross-linked sodium hyaluronate by using a novel cross-linking agent include: the cross-linking agent used in the cross-linked sodium hyaluronate gel prepared by the invention is a polyglycol epoxy derivative, due to its molecular The presence of a plurality of ether linkages results in the presence of more hydrogen bonds in the gel system, resulting in enhanced gel stability; and, at the same time, due to the particularity of the spatial structure of the branched polyglycol epoxy derivative, the resulting gel The winding structure of the space is more complicated, and the gel produced is more stable. Further, since the branched polyglycol epoxy derivative involved in the present invention is a single molecular weight compound, the gel product obtained has good batch stability.

本发明整合了交联透明质酸钠成胶除杂工艺，可制备出低毒、少残留、挤推力小、塑形性好、耐酶性好、体内保留时间长的注射用修饰透明质酸钠凝胶；本发明分枝型多元甘醇环氧衍生物交联的透明质酸钠结构更为紧密，所制备的交联透明质酸钠凝胶稳定性能更加优越。The invention integrates the cross-linked sodium hyaluronate into a glue removing and removing process, and can prepare the modified hyaluronic acid for injection with low toxicity, less residue, small pushing force, good shape, good enzyme resistance and long retention time in the body. The sodium gel; the sodium hyaluronate crosslinked by the branched polyglycol epoxy derivative of the invention has a more compact structure, and the prepared crosslinked sodium hyaluronate gel has superior stability.

具体实施方式Detailed ways

下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技 术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be described clearly and completely in conjunction with the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

实施例1：合成四臂十二甘醇四缩水甘油醚(Ia)Example 1: Synthesis of four-armed dodecaethylene glycol tetraglycidyl ether (Ia)

合成如下结构的四臂十二甘醇四缩水甘油醚：The four-armed dodeca Glycol tetraglycidyl ether having the following structure was synthesized:

向三口瓶中加入四臂十二甘醇

四氢呋喃(THF，100mL)和氢氧化钾(0.8mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，1.2mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品四甘醇二缩水甘油醚。Add four arms of 12 Glycol to a three-neck bottle

Tetrahydrofuran (THF, 100 mL) and potassium hydroxide (0.8 mol) were stirred in a water bath, and then epichlorohydrin (ECH, 1.2 mol) was added dropwise to the reaction system, and the reaction temperature was controlled to not exceed 35 ° C, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain a pure tetraethylene glycol diglycidyl ether.

¹H-NMR(DMSO-d₆)：2.26-2.30(m，8H)，2.54-2.55(m，4H)，2.72-2.73(m，4H)，3.09-3.10(m，4H)，3.17-3.28(m，20H)，3.35-3.64(m，192H)，3.70-3.71(m，4H)，7.88-7.92(t，4H)；¹ H-NMR (DMSO-d₆ ): 2.26-2.30 (m, 8H), 2.54-2.55 (m, 4H), 2.72-2.73 (m, 4H), 3.09-3.10 (m, 4H), 3.17-3.28 (m, 20H), 3.35-3.64 (m, 192H), 3.70-3.71 (m, 4H), 7.88-7.92 (t, 4H);

MALDI-TOF(2780.3，M+Na)。MALDI-TOF (2780.3, M+Na).

实施例2：合成四臂二十四甘醇四缩水甘油醚(Ib)Example 2: Synthesis of four-armed tetraethylene glycol tetraglycidyl ether (Ib)

合成如下结构的四臂二十四甘醇四缩水甘油醚：The four-armed tetraethylene glycol tetraglycidyl ether having the following structure was synthesized:

向三口瓶中加入四臂二十四甘醇

四氢呋喃(THF，100mL)和氢氧化钾(0.8mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，1.2mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品二十四甘醇四缩水甘油醚。Add four arms of 24 Glycol to a three-neck bottle

Tetrahydrofuran (THF, 100 mL) and potassium hydroxide (0.8 mol) were stirred in a water bath, and then epichlorohydrin (ECH, 1.2 mol) was added dropwise to the reaction system, and the reaction temperature was controlled to not exceed 35 ° C, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure tetraethylene glycol tetraglycidyl ether.

¹H-NMR(DMSO-d₆)：2.26-2.30(m，8H)，2.54-2.55(m，4H)，2.72-2.73(m，4H)，3.09-3.10(m，4H)，3.17-3.28(m，20H)，3.35-3.64(m，384H)，3.70-3.71(m，4H)，7.88-7.92(t，4H)；¹ H-NMR (DMSO-d₆ ): 2.26-2.30 (m, 8H), 2.54-2.55 (m, 4H), 2.72-2.73 (m, 4H), 3.09-3.10 (m, 4H), 3.17-3.28 (m, 20H), 3.35-3.64 (m, 384H), 3.70-3.71 (m, 4H), 7.88-7.92 (t, 4H);

MALDI-TOF(4665.9，M+Na)。MALDI-TOF (4665.9, M+Na).

实施例3：合成八臂四甘醇八缩水甘油醚(Ic)Example 3: Synthesis of eight-arm tetraethylene glycol octahydroglycidyl ether (Ic)

合成如下结构的八臂四甘醇八缩水甘油醚：The eight-arm tetraethylene glycol octahydroglycidyl ether having the following structure was synthesized:

向三口瓶中加入八臂四甘醇

四氢呋喃(THF，100mL)和氢氧化钾(1.6mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，2.4mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品八臂四甘醇八缩水甘油醚。Adding eight-arm tetraethylene glycol to a three-necked bottle

Tetrahydrofuran (THF, 100 mL) and potassium hydroxide (1.6 mol) were stirred in a water bath, and then epichlorohydrin (ECH, 2.4 mol) was added dropwise to the reaction system, and the reaction temperature was controlled to not exceed 35 ° C, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure eight-arm tetraethylene glycol octahydroglycidyl ether.

¹H-NMR(DMSO-d₆)：2.27-2.33(m，16H)，2.54-2.55(m，8H)，2.72-2.73(m，8H)，3.09-3.10(m，8H)，3.16-3.26(m，24H)，3.28-3.44(m，24H)，3.48-3.50(m，116H)，3.55-3.60(m，8H)，3.66-3.71(m，16H)，7.87-7.90(t，8H)；¹ H-NMR (DMSO-d₆ ): 2.27-2.33 (m, 16H), 2.54-2.55 (m, 8H), 2.72-2.73 (m, 8H), 3.09-3.10 (m, 8H), 3.16-3.26 (m, 24H), 3.28-3.44 (m, 24H), 3.48-3.50 (m, 116H), 3.55-3.60 (m, 8H), 3.66-3.71 (m, 16H), 7.87-7.90 (t, 8H) ;

MALDI-TOF(2880.8，M+Na)。MALDI-TOF (2880.8, M+Na).

实施例4：合成八臂十二甘醇八缩水甘油醚(Id)Example 4: Synthesis of eight-arm dodeca Glycol octahydroglycidyl ether (Id)

合成如下结构的八臂十二甘醇八缩水甘油醚：The eight-arm dodeca Glycol octahydroglycidyl ether having the following structure was synthesized:

向三口瓶中加入八臂十二甘醇

四氢呋喃(THF，100mL)和氢氧化钾(1.6mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，2.4mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品八臂十二甘醇八缩水甘油醚。Adding eight-armed dodecadiol to a three-necked bottle

Tetrahydrofuran (THF, 100 mL) and potassium hydroxide (1.6 mol) were stirred in a water bath, and then epichlorohydrin (ECH, 2.4 mol) was added dropwise to the reaction system, and the reaction temperature was controlled to not exceed 35 ° C, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure eight-arm dodecafuryl octahydroglycidyl ether.

¹H-NMR(DMSO-d₆)：2.28-2.33(m，16H)，2.54-2.55(m，8H)，2.72-2.73(m，8H)，3.09-3.10(m，8H)，3.16-3.27(m，24H)，3.29-3.44(m，24H)，3.47-3.50(m，372H)，3.55-3.60(m，8H)，3.66-3.71(m，16H)，7.87-7.90(t，8H)；¹ H-NMR (DMSO-d₆ ): 2.28-2.33 (m, 16H), 2.54-2.55 (m, 8H), 2.72-2.73 (m, 8H), 3.09-3.10 (m, 8H), 3.16-3. (m, 24H), 3.29-3.44 (m, 24H), 3.47-3.50 (m, 372H), 3.55-3.60 (m, 8H), 3.66-3.71 (m, 16H), 7.87-7.90 (t, 8H) ;

MALDI-TOF(5698.4，M+Na)。MALDI-TOF (5698.4, M+Na).

实施例5：四臂十二甘醇四缩水甘油醚交联透明质酸钠凝胶(IIa)Example 5: Four-armed dodecaethylene glycol tetraglycidyl ether cross-linked sodium hyaluronate gel (IIa)

将交联剂四臂十二甘醇四缩水甘油醚(0.2mol，实施例1制备)溶于NaOH溶液中加入透明质酸钠粉末(聚合物单元1mol)，40℃搅拌反应形成交联透明质酸钠凝胶；其次向凝胶中加入适量盐酸调节pH为7.0，再加入适量PBS缓冲液凝胶溶胀；然后用标准药典筛将凝胶过筛，收集凝胶颗粒，最后，凝胶经反复透析后，用标准药典筛筛分、灌装、蒸汽灭菌后即得注射用修饰透明质酸钠凝胶。The cross-linking agent four-armed dodeca Glycol tetraglycidyl ether (0.2 mol, prepared in Example 1) was dissolved in a NaOH solution, and sodium hyaluronate powder (polymer unit 1 mol) was added, and stirred at 40 ° C to form a crosslinked transparent substance. Sodium gel; secondly, add appropriate amount of hydrochloric acid to the gel to adjust the pH to 7.0, and then add appropriate amount of PBS buffer gel to swell; then sieve the gel with standard Pharmacopoeia sieve to collect gel particles, and finally, the gel is repeated. After dialysis, the modified sodium hyaluronate gel for injection is obtained by sieving, filling, and steam sterilization with a standard Pharmacopoeia sieve.

实施例6：四臂二十四甘醇四缩水甘油醚交联透明质酸钠凝胶(IIb)Example 6: Four-armed tetraethylene glycol tetraglycidyl ether cross-linked sodium hyaluronate gel (IIb)

将交联剂四臂二十四甘醇四缩水甘油醚(0.2mol，实施例2制备)溶于NaOH溶液中加入透明质酸 钠粉末(聚合物单元1mol)，40℃搅拌反应形成交联透明质酸钠凝胶；其次向凝胶中加入适量盐酸调节pH为7.0，再加入适量PBS缓冲液凝胶溶胀；然后用标准药典筛将凝胶过筛，收集凝胶颗粒，最后，凝胶经反复透析后，用标准药典筛筛分、灌装、蒸汽灭菌后即得注射用修饰透明质酸钠凝胶。The cross-linking agent four-armed tetraethylene glycol tetraglycidyl ether (0.2 mol, prepared in Example 2) was dissolved in a NaOH solution, sodium hyaluronate powder (polymer unit 1 mol) was added, and the reaction was stirred at 40 ° C to form a cross-linked transparent Sodium carbonate gel; secondly, add appropriate amount of hydrochloric acid to the gel to adjust the pH to 7.0, and then add appropriate amount of PBS buffer gel to swell; then sieve the gel with standard Pharmacopoeia sieve to collect gel particles, and finally, gel After repeated dialysis, the modified sodium hyaluronate gel for injection is obtained after screening, filling and steam sterilization with a standard pharmacopeia sieve.

实施例7：八臂四甘醇八缩水甘油醚交联透明质酸钠凝胶(IIc)Example 7: Eight-arm tetraethylene glycol octahydroglyceryl ether cross-linked sodium hyaluronate gel (IIc)

将交联剂八臂四甘醇八缩水甘油醚(0.2mol，实施例3制备)溶于NaOH溶液中加入透明质酸钠粉末(聚合物单元1mol)，40℃搅拌反应形成交联透明质酸钠凝胶；其次向凝胶中加入适量盐酸调节pH为7.0，再加入适量PBS缓冲液凝胶溶胀；然后用标准药典筛将凝胶过筛，收集凝胶颗粒，最后，凝胶经反复透析后，用标准药典筛筛分、灌装、蒸汽灭菌后即得注射用修饰透明质酸钠凝胶。The cross-linking agent octatetraethylene glycol octahydroglycidyl ether (0.2 mol, prepared in Example 3) was dissolved in a NaOH solution, and sodium hyaluronate powder (polymer unit 1 mol) was added, and the mixture was stirred at 40 ° C to form a crosslinked hyaluronic acid. Sodium gel; secondly, add appropriate amount of hydrochloric acid to the gel to adjust the pH to 7.0, and then add appropriate amount of PBS buffer gel to swell; then sieve the gel with standard Pharmacopoeia sieve to collect gel particles, and finally, the gel is repeatedly dialyzed. After that, the modified sodium hyaluronate gel for injection is obtained by sieving, filling and steam sterilization with a standard Pharmacopoeia sieve.

实施例8：八臂十二甘醇八缩水甘油醚交联透明质酸钠凝胶(IId)Example 8: Eight-armed dodecaethylene glycol octahydroglyceryl ether cross-linked sodium hyaluronate gel (IId)

将交联剂八臂十二甘醇八缩水甘油醚(0.2mol，实施例4制备)溶于NaOH溶液中加入透明质酸钠粉末(聚合物单元1mol)，40℃搅拌反应形成交联透明质酸钠凝胶；其次向凝胶中加入适量盐酸调节pH为7.0，再加入适量PBS缓冲液凝胶溶胀；然后用标准药典筛将凝胶过筛，收集凝胶颗粒，最后，凝胶经反复透析后，用标准药典筛筛分、灌装、蒸汽灭菌后即得注射用修饰透明质酸钠凝胶。The cross-linking agent octa-dodecyl octadecyl diglycidyl ether (0.2 mol, prepared in Example 4) was dissolved in a NaOH solution, and sodium hyaluronate powder (polymer unit 1 mol) was added, and stirred at 40 ° C to form a crosslinked transparent substance. Sodium gel; secondly, add appropriate amount of hydrochloric acid to the gel to adjust the pH to 7.0, and then add appropriate amount of PBS buffer gel to swell; then sieve the gel with standard Pharmacopoeia sieve to collect gel particles, and finally, the gel is repeated. After dialysis, the modified sodium hyaluronate gel for injection is obtained by sieving, filling, and steam sterilization with a standard Pharmacopoeia sieve.

实施例9：体外稳定性实验Example 9: In vitro stability test

采用透明质酸酶溶液降解交联的透明质酸钠凝胶，来考察凝胶的体外稳定性。The in vitro stability of the gel was investigated by degrading the crosslinked sodium hyaluronate gel using a hyaluronidase solution.

实验方法：experimental method:

取交联的透明质酸钠凝胶0.5g，加入300U/ml的透明质酸酶溶液2mL，37℃保温降解40小时，加PBS至5mL，取1ml加无水乙醇4mL，10000r/min离心15min，取上清液2mL用PBS定容至5mL，作为甲液；另取交联的透明质酸钠凝胶0.5g，加0.5mol/L硫酸溶液10mL，沸水浴水解15min，加水稀释至100mL，作为乙液。分别取甲液和乙液各1mL，用改良咔唑显色法测葡萄糖醛酸含量。凝胶的体外抗酶降解性用系数R表示，R＝1-0.625A/B，其中A为甲液的葡萄糖醛酸含量，B为乙液的葡萄糖醛酸含量。R值越高，说明其体外抗酶降解性能越好，交联的凝胶越稳定。检测结果如表1所示。Take 0.5 g of cross-linked sodium hyaluronate gel, add 2 mL of 300 U/ml hyaluronidase solution, heat-degrade at 37 ° C for 40 hours, add PBS to 5 mL, take 1 ml of absolute ethanol 4 mL, centrifuge at 10000 r / min for 15 min. Take 2 mL of the supernatant and make up to 5 mL with PBS as a liquid solution. Take 0.5 g of cross-linked sodium hyaluronate gel, add 10 mL of 0.5 mol/L sulfuric acid solution, hydrolyze for 15 min in boiling water bath, and dilute to 100 mL with water. As the liquid B. Take 1 mL of each of the liquid A and the liquid B, respectively, and measure the glucuronic acid content by the modified carbazole colorimetric method. The in vitro anti-enzymatic degradation of the gel is represented by a coefficient R, R = 1 - 0.625 A / B, where A is the glucuronic acid content of the liquid A, and B is the glucuronic acid content of the liquid B. The higher the R value, the better the anti-enzymatic degradation performance in vitro, and the more stable the crosslinked gel. The test results are shown in Table 1.

表1 交联透明质酸钠凝胶的体外酶解稳定性检测结果Table 1 In vitro enzymatic stability test results of cross-linked sodium hyaluronate gel

供试组Test group	IIaIIa	IIbIIb	IIcIIc	IIdIId	BDDE-HABDDE-HA
抗酶降解系数Anti-enzymatic degradation coefficient	91％91%	88％88%	81％81%	89％89%	71％71%

实验结果表明，本发明的分枝型多元甘醇环氧衍生物交联的透明质酸钠凝胶体外稳定性较传统交联剂BDDE交联的透明质酸钠凝胶好。The experimental results show that the sodium hyaluronate gel crosslinked by the branched polyglycol epoxy derivative of the present invention has better stability in vitro than the conventional crosslinker BDDE crosslinked sodium hyaluronate gel.

以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., which are within the spirit and principles of the present invention, should be included in the scope of the present invention. within.

Claims (17)

1. 一种分枝型多元甘醇环氧衍生物，其具有如下结构：A branched polyglycol epoxy derivative having the following structure:

   

   

   其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof,

   X₁和X₂为连接基团，独立地选自：-(CH₂)_i-、-(CH₂)_iO-、-(CH₂)_iCO-、-(CH₂)_iNH-、-(CH₂)_iNHCO(CH₂)_j-、-(CH₂)_iCONH(CH₂)_j-、-(CH₂)_iOCO(CH₂)_j-、-(CH₂)_iCOO(CH₂)_j-、

   

   

   中一种或两种以上的组合，i和j独立地选自0-10的整数，X₁ and X₂ are a linking group independently selected from the group consisting of: -(CH₂ )_i -, -(CH₂ )_i O-, -(CH₂ )_i CO-, -(CH₂ )_i NH-, -(CH₂ )_i NHCO(CH₂ )_j -, -(CH₂ )_i CONH(CH₂ )_j -, -(CH₂ )_i OCO(CH₂ )_j -, -(CH₂ )_i COO( CH₂ )_j -,

   

   

   One or a combination of two or more, i and j are independently selected from an integer of 0-10,

   PEG具有如下结构：-(CH₂CH₂O)_m-，m为4-200的整数，PEG has the following structure: -(CH₂ CH₂ O)_m -, m is an integer from 4 to 200,

   n为3-24的整数，n is an integer from 3 to 24,

   所述分枝型多元甘醇环氧衍生物为单一分子量的化合物。The branched polyglycol epoxy derivative is a compound of a single molecular weight.
2. 如权利要求1所述的衍生物，其特征在于，所述A具有如下结构：The derivative according to claim 1, wherein said A has the following structure:

   

   

   

   

   其中，B具有如下结构：

   

   Among them, B has the following structure:

   

   r为1-5的整数，优选为1、2或3，r is an integer from 1 to 5, preferably 1, 2 or 3,

   a、b、c和d为整数，独立地选自0和1，a, b, c and d are integers, independently selected from 0 and 1,

   s为1-5的整数，优选为1、2或3，s is an integer from 1 to 5, preferably 1, 2 or 3.

   e、f和g为整数，独立地选自0和1；e, f and g are integers, independently selected from 0 and 1;

   优选地，所述a、b、c和d均为0，或，所述a、b、c和d均为1；Preferably, the a, b, c and d are both 0, or the a, b, c and d are both 1;

   优选地，所述e、f和g均为0，或，所述e、f和g均为1。Preferably, the e, f and g are both 0, or the e, f and g are both 1.
3. 如权利要求1或2所述的衍生物，其特征在于，所述A选自如下结构：The derivative according to claim 1 or 2, wherein the A is selected from the following structures:

   

   

   

   
4. 如权利要求1-3任一项所述的衍生物，其特征在于，所述X₁选自：-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CONH-、-CH₂CH₂CONH-、-CH₂CONHCH₂-、-CH₂CONHCH₂CH₂-、-CH₂CH₂CONHCH₂CH₂-、-CH₂CH₂NHCOCH₂-和-CH₂CH₂NHCOCH₂CH₂-中一种或两种以上的组合；和/或，The derivative according to any one of claims 1 to 3, wherein the X_{1 is} selected from the group consisting of: -CH₂ -, -CH₂ CH₂ -, -CH₂ CH₂ CH₂ -, -CH₂ CONH-, -CH₂ CH₂ CONH-, -CH₂ CONHCH₂ -, -CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ NHCOCH₂ - and -CH₂ One or a combination of two or more of CH₂ NHCOCH₂ CH₂ -; and/or,

   所述X₂选自：-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CONH-、-CH₂CH₂CONH-、-CH₂CONHCH₂-、-CH₂CONHCH₂CH₂-、-CH₂CH₂CONHCH₂CH₂-、-CH₂CH₂NHCOCH₂-和-CH₂CH₂NHCOCH₂CH₂-中一种或两种以上的组合；和/或，The X_{2 is} selected from the group consisting of: -CH₂ -, -CH₂ CH₂ -, -CH₂ CH₂ CH₂ -, -CH₂ CONH-, -CH₂ CH₂ CONH-, -CH₂ CONHCH₂ -, - CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ CONHCH₂ CH₂ -, -CH₂ CH₂ NHCOCH₂ - and -CH₂ CH₂ NHCOCH₂ CH₂ - one or a combination of two or more; and / or,

   所述m为4-100的整数。The m is an integer from 4 to 100.
5. 如权利要求1-4任一项所述的衍生物，其特征在于，所述X₁为-CH₂CH₂CONH-；和/或，所述X₂为-CH₂-。The derivative according to any one of claims 1 to 4, wherein X₁ is -CH₂ CH₂ CONH-; and/or X₂ is -CH₂ -.
6. 如权利要求5所述的衍生物，其特征在于，所述分枝型多元甘醇环氧衍生物具有 如下结构：The derivative according to claim 5, wherein the branched polyglycol epoxy derivative has the following structure:

   

   

   

   

   优选地，所述m为4、12或24。Preferably, the m is 4, 12 or 24.
7. 一种权利要求1-6任一项所述的分枝型多元甘醇环氧衍生物的制备方法，所述方法包括在溶剂中，使用催化剂催化

   

   与分枝型多元甘醇

   

   反应的步骤，A process for the preparation of a branched polyglycol epoxy derivative according to any one of claims 1 to 6, which comprises catalyzing a catalyst in a solvent

   

   Branched polyglycol

   

   Reaction step,

   其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof,

   X₁和X₂分别为连接基团，独立地选自：-(CH₂)_i-、-(CH₂)_iO-、-(CH₂)_iCO-、-(CH₂)_iNH-、-(CH₂)_iNHCO(CH₂)_j-、-(CH₂)_iCONH(CH₂)_j-、-(CH₂)_iOCO(CH₂)_j-、-(CH₂)_iCOO(CH₂)_j-、

   

   

   中一种或两种以上的组合，i和j独立地选自0-10的整数，X₁ and X₂ are each a linking group, and are independently selected from: -(CH₂ )_i -, -(CH₂ )_i O-, -(CH₂ )_i CO-, -(CH₂ )_i NH- , -(CH₂ )_i NHCO(CH₂ )_j -, -(CH₂ )_i CONH(CH₂ )_j -, -(CH₂ )_i OCO(CH₂ )_j -, -(CH₂ )_i COO (CH₂ )_j -,

   

   

   One or a combination of two or more, i and j are independently selected from an integer of 0-10,

   -X为离去基团，-X is the leaving group,

   PEG具有如下结构：-(CH₂CH₂O)_m-，m为4-200的整数，PEG has the following structure: -(CH₂ CH₂ O)_m -, m is an integer from 4 to 200,

   n为3-24的整数，n is an integer from 3 to 24,

   所述的催化剂为碱催化剂。The catalyst is a base catalyst.
8. 一种交联剂，所述交联剂包括权利要求1-6任一项所述的分枝型多元甘醇环氧衍生物。A crosslinking agent comprising the branched polyglycol epoxy derivative according to any one of claims 1 to 6.
9. 一种权利要求1-6任一项所述的分枝型多元甘醇环氧衍生物交联的高分子聚合物。A high molecular polymer crosslinked by a branched polyglycol epoxy derivative according to any one of claims 1 to 6.
10. 如权利要求9所述的交联的高分子聚合物，其特征在于，所述高分子聚合物为天然高分子和/或合成高分子；The crosslinked polymer according to claim 9, wherein the high molecular polymer is a natural polymer and/or a synthetic polymer;

    所述的高分子选自：甲壳素及甲壳素衍生物、壳聚糖及壳聚糖衍生物、卡拉胶及羧甲基卡拉胶、纤维素衍生物、淀粉及淀粉衍生物、海藻酸钠、瓜尔胶及羧甲基瓜尔胶、胶原蛋白和透明质酸及透明质酸盐中的一种或多种；和/或，The polymer is selected from the group consisting of chitin and chitin derivatives, chitosan and chitosan derivatives, carrageenan and carboxymethyl carrageenan, cellulose derivatives, starch and starch derivatives, sodium alginate, One or more of guar gum and carboxymethyl guar gum, collagen and hyaluronic acid and hyaluronate; and/or

    所述的合成高分子选自：聚乙烯吡咯烷酮、聚乙二醇、聚环氧乙烷、聚乙烯醇、聚醋酸乙烯脂、聚乳酸、聚乙醇酸、聚丙烯酸、聚丙烯酰胺、聚四氢呋喃、聚环氧丁烷、聚氧杂环丁烷、聚马来酸酐、聚羟乙基丙烯酸甲酯、聚丙二醇、聚己内酯、及其衍生物中的一种或多种。The synthetic polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl acetate, polylactic acid, polyglycolic acid, polyacrylic acid, polyacrylamide, polytetrahydrofuran, One or more of polybutylene oxide, polyoxetane, polymaleic anhydride, polyhydroxyethyl methacrylate, polypropylene glycol, polycaprolactone, and derivatives thereof.
11. 如权利要求9或10所述的交联的高分子聚合物，其特征在于，所述交联高分子聚合物为交联透明质酸钠。The crosslinked polymer according to claim 9 or 10, wherein the crosslinked polymer is crosslinked sodium hyaluronate.
12. 一种权利要求9-11任一项所述的交联高分子聚合物的制备方法，包括高分子聚合物与权利要求1-6任一项所述的分枝型多元甘醇环氧衍生物在在碱性条件下交联反应的步骤。A method for producing a crosslinked high molecular polymer according to any one of claims 9 to 11, comprising a high molecular polymer and the branched polyglycol epoxy derivative according to any one of claims 1 to 6. The step of crosslinking the reaction under alkaline conditions.
13. 如权利要求12所述的制备方法，其特征在于，所述交联高分子聚合物为交联透明质酸钠；The preparation method according to claim 12, wherein the crosslinked high molecular polymer is crosslinked sodium hyaluronate;

    优选地，所述权利要求1-6任一项所述的分枝型多元甘醇环氧衍生物与透明质酸中聚合物单元的摩尔比为0.01-1:1；和/或，所述反应温度为35-45℃；和/或，所述透明质酸钠的分子量为5万-300万道尔顿。Preferably, the molar ratio of the branched polyhydric alcohol epoxy derivative according to any one of claims 1 to 6 to the polymer unit in hyaluronic acid is 0.01 to 1:1; and/or, The reaction temperature is 35-45 ° C; and/or the sodium hyaluronate has a molecular weight of 50,000 to 3 million Daltons.
14. 一种凝胶，所述凝胶包括权利要求9-11任一项所述的交联高分子聚合物；A gel comprising the crosslinked high molecular polymer of any one of claims 9-11;

    优选地，所述交联高分子聚合物为交联透明质酸钠。Preferably, the crosslinked high molecular polymer is crosslinked sodium hyaluronate.
15. 一种权利要求1-6任一项所述的分枝型多元甘醇衍生物在制备权利要求8所述的交联剂、权利要求9-11任一项所述的交联高分子聚合物或权利要求14所述的凝胶中的应用；The branched polyhydric alcohol derivative according to any one of claims 1 to 6, wherein the crosslinking agent according to claim 8 or the crosslinked high molecular polymer according to any one of claims 9 to 11 Or the use in the gel of claim 14;

    优选地，所述的交联高分子聚合物为交联透明质酸钠；和/或，所述凝胶为包含交联透明质酸钠的凝胶。Preferably, the crosslinked high molecular polymer is crosslinked sodium hyaluronate; and/or the gel is a gel comprising crosslinked sodium hyaluronate.
16. 一种权利要求9-11任一项所述的交联高分子聚合物或权利要求14所述的凝胶在制备用于药物、医疗美容、化妆品或保健食品用途的产品中的应用；Use of the crosslinked high molecular polymer according to any one of claims 9 to 11 or the gel according to claim 14 for the preparation of a product for use in medicine, medical cosmetic, cosmetic or health food use;

    优选地，所述的交联高分子聚合物为交联透明质酸钠；和/或，所述凝胶为包含交联透明质酸钠的凝胶；Preferably, the crosslinked high molecular polymer is crosslinked sodium hyaluronate; and/or the gel is a gel comprising crosslinked sodium hyaluronate;

    更优选地，所述的医疗美容用途的产品为软组织填充剂；和/或，所述的药物用途的产品包括术后防粘连剂、药物载体和预防和/或治疗疾病的药物。More preferably, the product for medical cosmetic use is a soft tissue filler; and/or the product for pharmaceutical use includes a post-operative anti-adhesion agent, a drug carrier, and a drug for preventing and/or treating a disease.
17. 一种软组织填充剂，其包括权利要求9-11任一项所述的交联高分子聚合物或权利要求14所述的凝胶；A soft tissue filler comprising the crosslinked high molecular polymer of any one of claims 9-11 or the gel of claim 14;

    优选地，所述的交联高分子聚合物为交联透明质酸钠；和/或，所述凝胶为包含交联透明质酸钠的凝胶。Preferably, the crosslinked high molecular polymer is crosslinked sodium hyaluronate; and/or the gel is a gel comprising crosslinked sodium hyaluronate.