CN111528220A - A kind of hydrogel of slow-release chlorine dioxide and preparation method thereof - Google Patents

A kind of hydrogel of slow-release chlorine dioxide and preparation method thereof Download PDF

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CN111528220A
CN111528220A CN202010318088.7A CN202010318088A CN111528220A CN 111528220 A CN111528220 A CN 111528220A CN 202010318088 A CN202010318088 A CN 202010318088A CN 111528220 A CN111528220 A CN 111528220A
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chlorine dioxide
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CN111528220B (en
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范治平
程萍
王正平
韩军
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    • AHUMAN NECESSITIES
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Abstract

The invention relates to the technical field related to slow release of chlorine dioxide, and particularly provides a hydrogel for slow release of chlorine dioxide and a preparation method thereof. The invention provides a hydrogel for slowly releasing chlorine dioxide, which is prepared from raw materials including chlorine dioxide, tyramine-grafted polyglutamic acid solution, cysteamine-grafted hyaluronic acid solution, horseradish peroxidase, hydrogen peroxide and alcohol substances; wherein the alcohol substance comprises dihydric alcohol with the relative molecular weight of 2000-5000 and trihydric alcohol with the relative molecular weight of 80-300. According to the invention, tyramine-grafted polyglutamic acid and cysteamine-grafted hyaluronic acid are adopted to form an interpenetrating network structure in a hydrogel system, so that the mechanical strength of the hydrogel is effectively improved; under the synergistic effect of specific dihydric alcohol and trihydric alcohol, a low-temperature-resistant and anti-freezing hydrogel system suitable for the slow release of chlorine dioxide is formed, and the problem that the use condition of a chlorine dioxide solution is limited due to easy icing of the chlorine dioxide solution is avoided.

Description

一种缓释二氧化氯的水凝胶及其制备方法A kind of hydrogel of slow-release chlorine dioxide and preparation method thereof

技术领域technical field

本发明涉及二氧化氯的缓释相关的技术领域,更具体地,本发明提供一种缓 释二氧化氯的水凝胶及其制备方法。The present invention relates to the related technical field of the slow-release of chlorine dioxide, more specifically, the present invention provides a kind of hydrogel of slow-release chlorine dioxide and preparation method thereof.

背景技术Background technique

二氧化氯是一种有效抗病毒化学试剂,二氧化氯具有广谱抗微生物作用, 而且对高等动物细胞无致痛、致畸、致突变作用,还具有消除甲醛的作用,具 有高度的安全性,被世界卫生组织列为Al级广谱、安全、高效消毒剂,被推 崇为第四代消毒剂。但是传统二氧化氯缓释凝胶只适用于温度较高的室温环 境,在低温环境中由于二氧化氯溶液结冰等原因,造成缓释凝胶无法释放抗病 毒的有效物质,低温环境适用性较差,因此合适载体及配方的缺乏使其应用受 到了一定限制。Chlorine dioxide is an effective antiviral chemical reagent. Chlorine dioxide has a broad-spectrum anti-microbial effect, and has no pain, teratogenic and mutagenic effects on higher animal cells. It also has the effect of eliminating formaldehyde and has a high degree of safety. , is listed by the World Health Organization as an Al-level broad-spectrum, safe and efficient disinfectant, and is respected as the fourth-generation disinfectant. However, the traditional chlorine dioxide slow-release gel is only suitable for high-temperature room temperature environment. In low temperature environment, due to the freezing of chlorine dioxide solution and other reasons, the slow-release gel cannot release effective antiviral substances. Therefore, the lack of suitable carriers and formulations limits its application.

缓释抗菌剂的凝胶剂大多采用人工合成高分子材料作为载体,但材料本身合 成步骤较多,环境经济性较差,用于医用领域有潜在生物毒性。并且传统凝胶载 体只适用于室温环境,在低温环境中由于结冰等原因,无法实现药物的缓释,或 缓释效果较差,天然高分子基生物水凝胶的出现为解决这一问题提供了较好方案, 其生物相容性良好,并且可在自然界中降解吸收,与药物结合还可以用于不同临 床病症,表现出广阔的应用前景,但其在使用过程中可能出现力学性能不佳、可 注射性不好等劣势。Most of the gels of slow-release antibacterial agents use synthetic polymer materials as carriers, but the materials themselves have many synthetic steps, poor environmental economy, and potential biological toxicity in the medical field. And the traditional gel carrier is only suitable for room temperature environment. In the low temperature environment, due to freezing and other reasons, the sustained release of drugs cannot be achieved, or the sustained release effect is poor. The emergence of natural polymer-based biohydrogels solves this problem. It provides a better solution, its biocompatibility is good, and it can be degraded and absorbed in nature. It can also be used for different clinical conditions in combination with drugs, showing a broad application prospect, but its mechanical properties may be different during use. Disadvantages such as good injectability and poor injectability.

发明内容SUMMARY OF THE INVENTION

为解决上述技术问题,本发明第一方面提供一种缓释二氧化氯的水凝胶,其 制备原料包括二氧化氯、酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、 辣根过氧化物酶、双氧水以及醇类物质;其中,醇类物质包括相对分子量为 2000~5000的二元醇以及相对分子量为80~300的三元醇。In order to solve the above-mentioned technical problems, the first aspect of the present invention provides a slow-release chlorine dioxide hydrogel, and its preparation raw materials include chlorine dioxide, tyramine-grafted polyglutamic acid solution, cysteamine-grafted transparent Acid solution, horseradish peroxidase, hydrogen peroxide and alcohol substances; wherein, the alcohol substances include dihydric alcohols with relative molecular weights of 2000-5000 and trihydric alcohols with relative molecular weights of 80-300.

作为本发明的一种优选技术方案,水凝胶的pH为3.5~5.5。As a preferred technical solution of the present invention, the pH of the hydrogel is 3.5-5.5.

作为本发明的一种优选技术方案,所述接枝的聚谷氨酸溶液与半胱胺接枝的 透明质酸溶液均是以5wt%的二氧化氯溶液为基底液,将聚谷氨酸溶液与半胱胺接 枝的透明质酸分别配制成溶液。As a preferred technical solution of the present invention, the grafted polyglutamic acid solution and the cysteamine-grafted hyaluronic acid solution both use 5wt% chlorine dioxide solution as the base liquid, and the polyglutamic acid The solution and cysteamine-grafted hyaluronic acid were separately formulated into solutions.

作为本发明的一种优选技术方案,酪胺接枝的聚谷氨酸溶液浓度为 100~300mg/mL;半胱胺接枝的透明质酸溶液的浓度为100~300mg/mL;优选地, 接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液的体积比为1:(0.5~1.5)。As a preferred technical solution of the present invention, the concentration of tyramine-grafted polyglutamic acid solution is 100-300 mg/mL; the concentration of cysteamine-grafted hyaluronic acid solution is 100-300 mg/mL; preferably, The volume ratio of the grafted polyglutamic acid solution to the cysteamine-grafted hyaluronic acid solution is 1:(0.5-1.5).

作为本发明的一种优选技术方案,双氧水的浓度为1~30mM。As a preferred technical solution of the present invention, the concentration of hydrogen peroxide is 1-30 mM.

作为本发明的一种优选技术方案,辣根过氧化物酶的含量为1~50U/mL。As a preferred technical solution of the present invention, the content of horseradish peroxidase is 1-50 U/mL.

作为本发明的一种优选技术方案,醇类物质占水凝胶总体积的5~25%。As a preferred technical solution of the present invention, the alcohol substance accounts for 5-25% of the total volume of the hydrogel.

作为本发明的一种优选技术方案,二元醇与三元醇的体积比为1:(1.2~4.3)。As a preferred technical solution of the present invention, the volume ratio of dihydric alcohol to trihydric alcohol is 1:(1.2-4.3).

作为本发明的一种优选技术方案,二元醇的结构选自HO(CH2CH2O)nH、 HO(CH2CH2CH2CH2O)mH、

Figure BDA0002460237510000021
中的任一种或多种的组合,其中,n、 m、p分别独立为35~75。As a preferred technical solution of the present invention, the structure of the dihydric alcohol is selected from HO(CH 2 CH 2 O) n H, HO(CH 2 CH 2 CH 2 CH 2 O) m H,
Figure BDA0002460237510000021
A combination of any one or more of them, wherein n, m, and p are each independently 35 to 75.

作为本发明的一种优选技术方案,三元醇选自丙三醇和\或三羟甲基丙烷。As a kind of preferred technical scheme of the present invention, trihydric alcohol is selected from glycerol and/or trimethylolpropane.

本发明的第二方面提供一种所述缓释二氧化氯的水凝胶的制备方法,包括步 骤:酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、醇类物质混合,再 加入辣根过氧化物酶与双氧水,调节pH,再于室温下静置,即得所需水凝胶。The second aspect of the present invention provides a method for preparing the hydrogel of slow-release chlorine dioxide, comprising the steps of: tyramine-grafted polyglutamic acid solution, cysteamine-grafted hyaluronic acid solution, alcohol The mixture is mixed with similar substances, and then horseradish peroxidase and hydrogen peroxide are added to adjust the pH, and then stand at room temperature to obtain the desired hydrogel.

与现有技术相比,本发明提供的缓释二氧化氯的水凝胶具有如下的有益效果:Compared with the prior art, the hydrogel of slow-release chlorine dioxide provided by the present invention has the following beneficial effects:

(1)采用了酪胺接枝的聚谷氨酸与半胱胺接枝的透明质酸,在水凝胶体系中 形成互穿网络结构,有效提高了水凝胶的力学强度;(1) the polyglutamic acid of tyramine grafting and the hyaluronic acid of cysteamine grafting are adopted, and the interpenetrating network structure is formed in the hydrogel system, which effectively improves the mechanical strength of the hydrogel;

(2)在特定二元醇与三元醇的协同作用下,形成适合于二氧化氯缓慢释放的 耐低温抗冻的水凝胶体系,避免了由于二氧化氯溶液易结冰而使其使用条件受限 的问题;(2) Under the synergistic effect of specific dihydric alcohol and trihydric alcohol, a low-temperature and anti-freezing hydrogel system suitable for the slow release of chlorine dioxide is formed, which avoids the use of chlorine dioxide solution because it is easy to freeze. conditional issues;

(3)本申请提供的水凝胶体系的各种组分均源自天然来源的天然多糖大分子 或天然聚氨基酸,二者结合制备凝胶,得到环境友好、可降解吸收的材料,解决 了以往载体材料易环境污染,不易回收利用的缺点;(3) The various components of the hydrogel system provided by this application are all derived from natural polysaccharide macromolecules or natural polyamino acids, and the two are combined to prepare gels to obtain environmentally friendly, degradable and absorbable materials, which solve the problem of In the past, carrier materials were prone to environmental pollution and were not easy to be recycled;

(4)本发明所提供的原位交联可降解缓释凝胶含有药物二氧化氯,可以实现 缓释时间更长的、可调节的释药周期,并且释放出来的药物表现出良好的药物活 性;相比现有用药方式,该凝胶制剂复合物可显著延长药效时间。(4) The in-situ cross-linked degradable sustained-release gel provided by the present invention contains the drug chlorine dioxide, which can realize a longer sustained-release time and an adjustable drug-releasing cycle, and the released drug exhibits good drug performance Activity; compared with the existing medication mode, the gel preparation complex can significantly prolong the drug effect time.

附图说明Description of drawings

为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例 或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的 附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造 性劳动的前提下,还可以根据这些附图获得其他的附图。In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only These are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained according to these drawings without creative efforts.

图1:接枝酪胺的聚谷氨酸和接枝半胱胺的透明质酸形成水凝胶的示意图;Figure 1: Schematic diagram of the hydrogel formation of tyramine-grafted polyglutamic acid and cysteamine-grafted hyaluronic acid;

图2:实施例2透明质酸接枝前后的核磁谱图;Fig. 2: the nuclear magnetic spectrogram before and after the grafting of hyaluronic acid in Example 2;

图3:I3水凝胶内部结构示意图;Figure 3: Schematic diagram of the internal structure of I3 hydrogel;

图4:图3的局部放大结构示意图。FIG. 4 is a schematic view of the partially enlarged structure of FIG. 3 .

具体实施方式Detailed ways

除非另有说明、从上下文暗示或属于现有技术的惯例,如果现有技术中披露 的具体术语的定义与本申请中提供的任何定义不一致,则以本申请中提供的术语 定义为准。下面结合具体实施方式对本发明提供技术方案中的技术特征作进一步 清楚、完整的描述,并非对其保护范围的限制。Unless stated otherwise, implied from context, or pertains to common practice in the prior art, to the extent that definitions of specific terms disclosed in the prior art are inconsistent with any definitions provided in this application, the definitions of terms provided in this application shall control. The technical features in the technical solutions provided by the present invention are further clearly and completely described below in conjunction with the specific embodiments, and are not intended to limit the scope of its protection.

本发明中的词语“优选的”、“优选地”、“更优选的”等是指,在某些情况下可 提供某些有益效果的本发明实施方案。然而,在相同的情况下或其他情况下,其 他实施方案也可能是优选的。此外,对一个或多个优选实施方案的表述并不暗示 其他实施方案不可用,也并非旨在将其他实施方案排除在本发明的范围之外。The words "preferred", "preferably", "more preferred" and the like in the present invention refer to embodiments of the invention which, under certain circumstances, may provide certain benefits. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention.

本发明第一方面提供一种缓释二氧化氯的水凝胶,其制备原料包括二氧化氯、 酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、辣根过氧化物酶、双氧 水以及醇类物质;优选地,所述水凝胶的pH为3.5~5.5;更优选为4.5。A first aspect of the present invention provides a slow-release chlorine dioxide hydrogel, and its preparation raw materials include chlorine dioxide, tyramine-grafted polyglutamic acid solution, cysteamine-grafted hyaluronic acid solution, horseradish Peroxidase, hydrogen peroxide and alcohol substances; preferably, the pH of the hydrogel is 3.5-5.5; more preferably, it is 4.5.

本发明所述酪胺接枝的聚谷氨酸(PGA-Ty)是采用水相法将酪胺接枝于聚谷 氨酸分子中;聚谷氨酸(PGA)分子结构上是一类尼龙-4的衍生物,重复单元的 4位碳上接枝有一个羧基。PGA具有的众多性质,如:水溶性、可降解性、可食 用性及对人类和环境的友好性等。The tyramine-grafted polyglutamic acid (PGA-Ty) of the present invention uses an aqueous method to graft tyramine into the polyglutamic acid molecule; the polyglutamic acid (PGA) molecular structure is a kind of nylon Derivatives of -4 with a carboxyl group grafted on the 4th carbon of the repeating unit. PGA has many properties, such as: water solubility, degradability, edibility and friendliness to humans and the environment.

所述酪胺接枝的聚谷氨酸的具体制备过程不做特别限定,可以通过本领域技术人员熟知的方法制备得到,一种实施方式中,所述酪胺接枝的聚谷氨酸的制备方法 为:将聚谷氨酸溶解于蒸馏水中,再加入酪胺盐酸盐;随后EDC和NHS加入到混 合溶液中引发反应,随着反应的进行,用1M的氢氧化钠和盐酸溶液调节体系的pH 稳定于4.8;在室温下搅拌过夜,将体系pH值调回7后,反应溶液被转移到截流 分子量为1000Da的透析袋中,首先在100mM的氯化钠溶液中透析2天,再于水 和乙醇的混合溶液(体积比3:1)中透析1天,最后在纯水中透析1天,透析纯化 的产品溶液最终冻干形成白色絮状样品,4℃冷冻保存,即得所需的酪胺接枝的聚谷 氨酸,所述酪胺盐酸盐与聚谷氨酸的重量比为1:(1~1.2);所述酪胺盐酸盐、EDC、 NHS的重量比为1:(4~5):(2.4~2.9);其具体反应过程与原理如反应式(1)所示。The specific preparation process of the tyramine-grafted polyglutamic acid is not particularly limited, and can be prepared by methods well known to those skilled in the art. In one embodiment, the tyramine-grafted polyglutamic acid has a The preparation method is as follows: dissolving polyglutamic acid in distilled water, then adding tyramine hydrochloride; then adding EDC and NHS to the mixed solution to initiate a reaction, and adjusting with 1M sodium hydroxide and hydrochloric acid solution as the reaction proceeds The pH of the system was stable at 4.8; after stirring overnight at room temperature, the pH value of the system was adjusted back to 7, and the reaction solution was transferred to a dialysis bag with a cut-off molecular weight of 1000 Da, firstly dialyzed in 100 mM sodium chloride solution for 2 days, and then Dialyzed in a mixed solution of water and ethanol (volume ratio 3:1) for 1 day, and finally dialyzed in pure water for 1 day, the dialysis-purified product solution was finally freeze-dried to form a white flocculent sample, which was frozen at 4°C to obtain the result. The desired tyramine-grafted polyglutamic acid, the weight ratio of the tyramine hydrochloride to the polyglutamic acid is 1: (1-1.2); the weight ratio of the tyramine hydrochloride, EDC, NHS It is 1: (4-5): (2.4-2.9); its specific reaction process and principle are shown in reaction formula (1).

Figure BDA0002460237510000041
Figure BDA0002460237510000041

本发明所述半胱胺接枝的透明质酸(HA-CA)是采用水相法将半胱胺接枝于透 明质酸分子中,透明质酸(HA)是一种酸性粘多糖,是由D-葡萄糖醛酸及N-乙酰 葡糖胺组成的双糖单位,透明质酸具有独特的分子结构和优良的生物相容性,在机 体内显示出多种重要的生理功能,如润滑关节,调节血管壁的通透性,调节蛋白质, 水电解质扩散及运转,促进创伤愈合等。The cysteamine-grafted hyaluronic acid (HA-CA) of the present invention adopts the aqueous phase method to graft the cysteamine into the hyaluronic acid molecule, and hyaluronic acid (HA) is an acidic mucopolysaccharide. A disaccharide unit composed of D-glucuronic acid and N-acetylglucosamine, hyaluronic acid has a unique molecular structure and excellent biocompatibility, and exhibits a variety of important physiological functions in the body, such as lubricating joints , regulate the permeability of blood vessel wall, regulate protein, water and electrolyte diffusion and operation, and promote wound healing.

所述半胱胺接枝的透明质酸的具体制备过程不做特别限定,可以通过本领域技术人员熟知的方法制备得到,一种实施方式中,所述半胱胺接枝的透明质酸的具体 制备方法为:称取透明质酸溶于去离子水中,用磁力搅拌器恒温搅拌至完全溶解, 称取半胱胺盐酸盐,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基 琥珀酰亚胺(NHS)溶于的蒸馏水中,室温活化1h,将活化液加入到透明质酸溶液 中,室温搅拌过夜,反应液移入透析袋中蒸馏水透析3天,透析纯化的产品溶液最 终冻干形成白色絮状样品,4℃冷冻保存,即得所需的半胱胺接枝的透明质酸,所述 半胱胺盐酸盐与透明质酸的重量比为1:(1~1.3);所述半胱胺盐酸盐、EDC、NHS 的重量比为1:(1.45~1.75):(1~1.2);其具体反应过程与原理如反应式(2) 所示。The specific preparation process of the cysteamine-grafted hyaluronic acid is not particularly limited, and can be prepared by a method well known to those skilled in the art. In one embodiment, the cysteamine-grafted hyaluronic acid is The specific preparation method is as follows: take hyaluronic acid and dissolve it in deionized water, stir at a constant temperature with a magnetic stirrer until it is completely dissolved, weigh cysteamine hydrochloride, 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were dissolved in distilled water, activated at room temperature for 1 h, the activation solution was added to the hyaluronic acid solution, stirred at room temperature overnight, and the reaction solution was transferred into Distilled water in the dialysis bag was dialyzed for 3 days, the dialysis-purified product solution was finally freeze-dried to form a white flocculent sample, and frozen at 4°C to obtain the desired cysteamine-grafted hyaluronic acid, the cysteamine hydrochloride The weight ratio to hyaluronic acid is 1:(1-1.3); the weight ratio of cysteamine hydrochloride, EDC, NHS is 1:(1.45-1.75):(1-1.2); its specific reaction process And the principle is shown in reaction formula (2).

Figure BDA0002460237510000051
Figure BDA0002460237510000051

在一种实施方式中,接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液的重量比为1:(0.5~1.5);优选地,接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液 的重量比为1:(0.8~1.2);更优选地,接枝的聚谷氨酸溶液与半胱胺接枝的透明 质酸溶液的体积比为1:1。In one embodiment, the weight ratio of the grafted polyglutamic acid solution to the cysteamine-grafted hyaluronic acid solution is 1:(0.5-1.5); The weight ratio of the cysteamine-grafted hyaluronic acid solution is 1:(0.8-1.2); more preferably, the volume ratio of the grafted polyglutamic acid solution to the cysteamine-grafted hyaluronic acid solution is 1 :1.

本发明所述接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液均是以5wt%的二氧化氯溶液为基底液,将聚谷氨酸溶液与半胱胺接枝的透明质酸分别配制成溶液; 酪胺接枝的聚谷氨酸溶液的浓度为30~300mg/mL;优选为40~100mg/mL;进一步优 选为40~70mg/mL;半胱胺接枝的透明质酸溶液的的浓度为100~300mg/mL; 30~300mg/mL;优选为40~100mg/mL;进一步优选为40~70mg/mL;本发明对所述 二氧化氯溶液的购买厂家不做特别限制,一种实施方式中,二氧化氯溶液购自上海 阿达玛斯试剂公司。The grafted polyglutamic acid solution and the cysteamine-grafted hyaluronic acid solution of the present invention both use 5wt% chlorine dioxide solution as the base solution, and the polyglutamic acid solution and cysteamine are grafted. The hyaluronic acid is respectively prepared into solutions; the concentration of the tyramine-grafted polyglutamic acid solution is 30-300 mg/mL; preferably 40-100 mg/mL; more preferably 40-70 mg/mL; cysteamine-grafted The concentration of the hyaluronic acid solution is 100-300 mg/mL; 30-300 mg/mL; preferably 40-100 mg/mL; more preferably 40-70 mg/mL; the present invention has no effect on the purchaser of the chlorine dioxide solution. To make a special limitation, in one embodiment, the chlorine dioxide solution is purchased from Shanghai Adamas Reagent Company.

优选地,二氧化氯溶液的含量为水凝胶的70~90wt%。Preferably, the content of the chlorine dioxide solution is 70-90 wt % of the hydrogel.

所述辣根过氧化物酶的含量为1~50U/mL;优选为5~30U/mL;进一步优选为 5~20U/mL;辣根过氧化物酶(HRP)由于其良好的生物相容性及高度的稳定性, 被广泛应用于酶交联水凝胶体系中,在双氧水存在的条件下,苯酚衍生化的聚合物 可以在辣根过氧化物酶的催化下形成交联网络,而HRP介导的水凝胶通常应用于天 然高分子材料中,例如透明质酸、葡聚糖、明胶、壳聚糖等;合成高分子材料,如 聚(l-谷氨酸)、四臂PPO-PEO也适用酶交联方法,得到相关水凝胶,但由于合成 高分子材料复杂的合成步骤及添加剂的潜在毒性,使其临床应用受到很大的限制。The content of the horseradish peroxidase is 1-50U/mL; preferably 5-30U/mL; more preferably 5-20U/mL; horseradish peroxidase (HRP) due to its good biocompatibility It is widely used in enzymatic cross-linked hydrogel systems due to its high stability and high stability. In the presence of hydrogen peroxide, phenol-derived polymers can form a cross-linked network under the catalysis of horseradish peroxidase, while HRP-mediated hydrogels are usually used in natural polymer materials, such as hyaluronic acid, dextran, gelatin, chitosan, etc.; synthetic polymer materials, such as poly(l-glutamic acid), four-arm PPO -PEO is also suitable for enzymatic cross-linking method to obtain related hydrogels, but its clinical application is greatly limited due to the complex synthesis steps of synthesizing polymer materials and the potential toxicity of additives.

本发明所述双氧水的浓度为1~30mM;优选为5~20mM;进一步优选为7~15mM。The concentration of the hydrogen peroxide in the present invention is 1-30 mM; preferably 5-20 mM; more preferably 7-15 mM.

本发明采用了酪胺接枝的聚谷氨酸与半胱胺接枝的透明质酸,在过氧化氢以及辣根过氧化物酶作用下,体系发生原位交联,即在聚谷氨酸大分子链上引入酚羟基 通过氧化酶催化酚羟基氧化交联和含有巯基的透明质酸通过氧化交联构成互穿网络 水凝胶,其过程如图1所示,在交联过程中出现的两种新共价键:一种是苯环上相 邻两个碳原子之间形成的碳碳键;一种是邻位碳原子与酚氧原子之间的碳氧键。 HA-CA因双氧水的存在,也会影响其自交联过程,最终形成稳定交联的二硫键;形 成的两个网络协同作用提高了水凝胶的力学强度和药物缓释能力;该制备方法既可 克服化学交联剂带来的毒性,又可解决物理交联效果不佳的缺点,自身材料还可实 现无毒无害降解;此外,为减少过氧化氢对体系的影响,本申请的技术方案中采用 较低浓度的过氧化氢。The invention adopts tyramine-grafted polyglutamic acid and cysteamine-grafted hyaluronic acid, and under the action of hydrogen peroxide and horseradish peroxidase, the system undergoes in-situ cross-linking, that is, in polyglutamine The introduction of a phenolic hydroxyl group into the acid macromolecular chain catalyzes the oxidative crosslinking of the phenolic hydroxyl group by oxidase, and the hyaluronic acid containing sulfhydryl groups forms an interpenetrating network hydrogel through oxidative crosslinking. There are two new covalent bonds: one is the carbon-carbon bond formed between two adjacent carbon atoms on the benzene ring; the other is the carbon-oxygen bond between the ortho-position carbon atom and the phenolic oxygen atom. Due to the existence of hydrogen peroxide, HA-CA will also affect its self-crosslinking process, and finally form a stable cross-linked disulfide bond; the synergistic effect of the two networks formed improves the mechanical strength of the hydrogel and the sustained drug release ability; the preparation The method can not only overcome the toxicity brought by the chemical cross-linking agent, but also solve the disadvantage of poor physical cross-linking effect, and the material itself can also achieve non-toxic and harmless degradation; in addition, in order to reduce the influence of hydrogen peroxide on the system, this application A lower concentration of hydrogen peroxide is used in the technical solution.

本发明所述醇类物质包括相对分子量为2000~5000的二元醇以及相对分子量为80~300的三元醇;优选地,醇类物质占水凝胶总体积的5~25%;优选为8~20%; 进一步优选为10~16%;更优选为14%。The alcohol substances of the present invention include dihydric alcohols with a relative molecular weight of 2000-5000 and trihydric alcohols with a relative molecular weight of 80-300; preferably, the alcohol substances account for 5-25% of the total volume of the hydrogel; preferably 8 to 20%; more preferably 10 to 16%; more preferably 14%.

所述二元醇的结构选自HO(CH2CH2O)nH、HO(CH2CH2CH2CH2O)mH、

Figure BDA0002460237510000061
中的任一种或多种的组合,其中,n、m、p分别独立为35~75; 优选地,二元醇为PEG4000、PEG6000、PEG8000中的任一种或多种的组合;更优 选地,二元醇为PEG4000。The structure of the diol is selected from HO(CH 2 CH 2 O) n H, HO(CH 2 CH 2 CH 2 CH 2 O) m H,
Figure BDA0002460237510000061
The combination of any one or more of them, wherein, n, m, and p are independently 35 to 75; Typically, the diol is PEG4000.

所述三元醇选自丙三醇和\或三羟甲基丙烷;优选地,三元醇为甘油。Described trihydric alcohol is selected from glycerol and/or trimethylolpropane; Preferably, trihydric alcohol is glycerol.

本发明所述二元醇与三元醇的体积比为1:(1.2~4.3);优选地,二元醇与三 元醇的体积比为1:(1.7~3.5);进一步优选地,二元醇与三元醇的体积比为1: (2.1~2.9);更优选地,二元醇与三元醇的体积比为1:2.5。The volume ratio of dihydric alcohol to trihydric alcohol in the present invention is 1:(1.2~4.3); preferably, the volume ratio of dihydric alcohol to trihydric alcohol is 1:(1.7~3.5); The volume ratio of hydric alcohol to trihydric alcohol is 1: (2.1-2.9); more preferably, the volume ratio of dihydric alcohol to trihydric alcohol is 1:2.5.

申请人在实验过程中发现采用特定的二元醇与三元醇协同作用下,尤其采用PEG4000与甘油共同作用,并控制PEG4000与甘油的体积比为1:(2.1~2.9),体 系pH在4~5之间;有利于形成适合于二氧化氯缓慢释放的耐低温抗冻的水凝胶体 系,并且其与水凝胶中的其他组分形成的水凝胶体系的可注射性较好,在实际使用 过程中的可操作性较好,这可能是由于通过PEG4000、甘油调节体系有机组分的粘 度以及羟值,从而提高体系中不同组分之间的水合作用,降低水凝胶的结冰温度, 并提高水凝胶体系的可注射性能。During the experiment, the applicant found that under the synergistic effect of specific diols and triols, especially PEG4000 and glycerol were used together, and the volume ratio of PEG4000 and glycerol was controlled to be 1: (2.1 to 2.9), and the pH of the system was 4 ~5; it is beneficial to form a low temperature and antifreeze hydrogel system suitable for the slow release of chlorine dioxide, and the injectability of the hydrogel system formed with other components in the hydrogel is good, The operability in the actual use process is better, which may be due to the adjustment of the viscosity and hydroxyl value of the organic components of the system through PEG4000 and glycerol, thereby improving the hydration between different components in the system and reducing the hydrogel. freezing temperature, and improve the injectability of hydrogel systems.

本发明的第二方面提供一种所述缓释二氧化氯的水凝胶的制备方法,包括步骤:将酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、醇类物质混合,再加入 辣根过氧化物酶与双氧水,调节pH,再于室温下静置,即得所需水凝胶。The second aspect of the present invention provides a preparation method of the hydrogel of slow-release chlorine dioxide, comprising the steps of: a tyramine-grafted polyglutamic acid solution, a cysteamine-grafted hyaluronic acid solution, Alcohol substances are mixed, horseradish peroxidase and hydrogen peroxide are added, pH is adjusted, and the mixture is allowed to stand at room temperature to obtain the desired hydrogel.

优选地,所述缓释二氧化氯的水凝胶的制备方法,包括步骤:将PGA-Ty溶液 和HA-CA溶液加入PBS中,再加入醇类物质充分溶解形成溶液,最后加入HRP, 调节pH,最后加入H2O2快速搅拌形成载药凝胶,于室温下静置过夜,确保交联反 应彻底完成;形成凝胶过程中,凝胶时间采用小瓶倾斜法进行测试,即样品瓶倒置 一分钟之内没有观察到流体流动,则可判定样品达到凝胶状态。Preferably, the preparation method of the slow-release chlorine dioxide hydrogel includes the steps of: adding the PGA-Ty solution and the HA-CA solution into PBS, then adding alcohol substances to fully dissolve to form a solution, and finally adding HRP to adjust pH, and finally add H 2 O 2 to quickly stir to form a drug-loaded gel, and let stand overnight at room temperature to ensure that the cross-linking reaction is completely completed; during the gel formation process, the gel time is tested by the vial tilting method, that is, the sample vial is inverted If no fluid flow is observed within one minute, the sample is judged to have reached a gel state.

所述用于调节pH的试剂为柠檬酸/磷酸二氢钠;优选地,柠檬酸/磷酸二氢钠总 加入量占水凝胶总体积7~9%;进一步优选地,柠檬酸/磷酸二氢钠的重量比为1: (0.8~1.2)。The reagent for adjusting pH is citric acid/sodium dihydrogen phosphate; preferably, the total addition amount of citric acid/sodium dihydrogen phosphate accounts for 7-9% of the total volume of the hydrogel; more preferably, citric acid/sodium dihydrogen phosphate The weight ratio of sodium hydrogen is 1: (0.8~1.2).

实施例1Example 1

本发明的实施例1提供一种酪胺接枝的聚谷氨酸(PGA-Ty),其制备过程为: 将1g聚谷氨酸溶解于50毫升蒸馏水中,再加入1.076g酪胺盐酸盐;随后4.457g EDC 和2.674gNHS加入到混合溶液中引发反应;随着反应的进行,用1M的氢氧化钠和 盐酸溶液调节体系的pH稳定于4.8;在室温下搅拌过夜,将体系pH值调回7后, 反应溶液被转移到截流分子量为1000Da的透析袋中;首先在100mM的氯化钠溶 液中透析2天,再于水和乙醇的混合溶液(体积比3:1)中透析1天,最后在纯水 中透析1天;透析纯化的产品溶液最终冻干形成白色絮状样品,4℃冷冻保存,经测 试收率86%左右。Embodiment 1 of the present invention provides a tyramine-grafted polyglutamic acid (PGA-Ty), the preparation process of which is as follows: Dissolve 1 g of polyglutamic acid in 50 ml of distilled water, and then add 1.076 g of tyramine hydrochloride Then 4.457g EDC and 2.674g NHS were added to the mixed solution to initiate the reaction; as the reaction progressed, the pH of the system was adjusted to 4.8 with 1M sodium hydroxide and hydrochloric acid solution; stirred at room temperature overnight, the pH of the system was adjusted After being adjusted back to 7, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 1000 Da; firstly dialyzed against 100 mM sodium chloride solution for 2 days, and then dialyzed against a mixed solution of water and ethanol (volume ratio 3:1) for 1 1 day, and finally dialyzed in pure water for 1 day; the dialysis-purified product solution was finally freeze-dried to form a white flocculent sample, which was frozen and stored at 4°C, and the tested yield was about 86%.

实施例2Example 2

本发明的实施例2提供一种半胱胺接枝的透明质酸(HA-CA),其制备过程为: 称取透明质酸2g溶于100ml去离子水中,用磁力搅拌器恒温搅拌至完全溶解;称 取半胱胺盐酸盐1.68g,EDC 2.73g和NHS 1.72g溶于100ml的蒸馏水中,室温活 化1h(pH=4.8),将活化液加入到透明质酸溶液中,室温搅拌过夜;反应液移入透 析袋中蒸馏水透析3天,透析纯化的产品溶液最终冻干形成白色絮状样品,4℃冷冻 保存,经测试收率92%左右,其透明质酸接枝前后的核磁谱图如图2所示,在2.6~2.8 之间有峰产生。Embodiment 2 of the present invention provides a cysteamine-grafted hyaluronic acid (HA-CA), the preparation process of which is as follows: Weigh 2 g of hyaluronic acid and dissolve it in 100 ml of deionized water, and stir it at a constant temperature with a magnetic stirrer until complete Dissolve; Weigh cysteamine hydrochloride 1.68g, EDC 2.73g and NHS 1.72g, dissolve in 100ml of distilled water, activate at room temperature for 1h (pH=4.8), add the activation solution to the hyaluronic acid solution, stir at room temperature overnight The reaction solution was moved into a dialysis bag for dialysis with distilled water for 3 days, and the purified product solution was finally freeze-dried to form a white flocculent sample, which was frozen and stored at 4°C. The tested yield was about 92%. The NMR spectra before and after hyaluronic acid grafting As shown in Fig. 2, a peak is generated between 2.6 and 2.8.

实施例3Example 3

本发明的实施例3提供了缓释二氧化氯的水凝胶,其制备原料包括酪胺接枝的 聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、辣根过氧化物酶、双氧水以及醇类物 质;辣根过氧化物酶的含量为10U/mL;双氧水的浓度为10mM;醇类物质占水凝 胶总体积的14%;调节酪胺接枝的聚谷氨酸溶液浓度与半胱胺接枝的透明质酸溶液 的浓度以及酪胺接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液的体积比,形成 不同的缓释二氧化氯的水凝胶,其具体浓度以及体积比如下表1所示;Embodiment 3 of the present invention provides a hydrogel of slow-release chlorine dioxide, and its preparation raw materials include tyramine-grafted polyglutamic acid solution, cysteamine-grafted hyaluronic acid solution, horseradish peroxidase , hydrogen peroxide and alcohol substances; the content of horseradish peroxidase is 10U/mL; the concentration of hydrogen peroxide is 10mM; alcohol substances account for 14% of the total volume of the hydrogel; adjust the tyramine grafted polyglutamic acid solution The concentration of the cysteamine-grafted hyaluronic acid solution and the volume ratio of the tyramine-grafted polyglutamic acid solution to the cysteamine-grafted hyaluronic acid solution to form different slow-release chlorine dioxide waters Gel, its specific concentration and volume ratio are shown in Table 1 below;

所述接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液均是以5wt%的二氧化氯溶液为基底液,将聚谷氨酸溶液与半胱胺接枝的透明质酸分别配制而成;二氧化 氯溶液的含量为水凝胶的80wt%;醇类物质包括二元醇以及三元醇;二元醇与三元 醇的体积比为1:2.5;二元醇为PEG4000;三元醇为甘油;The grafted polyglutamic acid solution and the cysteamine-grafted hyaluronic acid solution are both based on a 5wt% chlorine dioxide solution, and the polyglutamic acid solution and the cysteamine-grafted hyaluronic acid solution are The acid is prepared separately; the content of chlorine dioxide solution is 80wt% of the hydrogel; the alcohols include dihydric alcohol and trihydric alcohol; the volume ratio of dihydric alcohol to trihydric alcohol is 1:2.5; dihydric alcohol It is PEG4000; the trivalent alcohol is glycerol;

所述缓释二氧化氯的水凝胶的制备方法,包括步骤:将PGA-Ty溶液和HA-CA 溶液加入PBS中,再加入醇类物质充分溶解形成溶液,最后加入HRP,调节pH至 4.5,最后加入H2O2快速搅拌形成载药凝胶,于室温下静置过夜,确保交联反应彻 底完成;形成凝胶过程中,凝胶时间采用小瓶倾斜法进行测试,即样品瓶倒置一分 钟之内没有观察到流体流动,则可判定样品达到凝胶状态;用于调节pH的试剂为 柠檬酸/磷酸二氢钠;柠檬酸/磷酸二氢钠的重量比为1:1。The preparation method of the slow-release chlorine dioxide hydrogel includes the steps of: adding PGA-Ty solution and HA-CA solution into PBS, then adding alcohol substances to fully dissolve to form a solution, and finally adding HRP to adjust pH to 4.5 , and finally add H 2 O 2 to quickly stir to form a drug-loaded gel, and let stand overnight at room temperature to ensure that the cross-linking reaction is completely completed; during the gel formation process, the gel time is tested by the vial tilting method, that is, the sample vial is inverted for one If no fluid flow is observed within minutes, it can be determined that the sample has reached a gel state; the reagent used to adjust the pH is citric acid/sodium dihydrogen phosphate; the weight ratio of citric acid/sodium dihydrogen phosphate is 1:1.

表1Table 1

Figure BDA0002460237510000081
Figure BDA0002460237510000081

Figure BDA0002460237510000091
Figure BDA0002460237510000091

实施例4Example 4

本发明的实施例4提供了缓释二氧化氯的水凝胶,其具体实施方式同实施例3 中I3的体系相同,不同之处在于,没有甘油。Example 4 of the present invention provides a slow-release chlorine dioxide hydrogel, the specific implementation of which is the same as the system of I3 in Example 3, except that there is no glycerin.

实施例5Example 5

本发明的实施例5提供了缓释二氧化氯的水凝胶,其具体实施方式同实施例3 中I3的体系相同,不同之处在于,二元醇为PEG6000。Example 5 of the present invention provides a hydrogel of slow-release chlorine dioxide, and its specific implementation is the same as the system of I3 in Example 3, except that the dihydric alcohol is PEG6000.

实施例6Example 6

本发明的实施例6提供了缓释二氧化氯的水凝胶,其具体实施方式同实施例3 中I3的体系相同,不同之处在于,二元醇为PEG8000。Example 6 of the present invention provides a hydrogel of slow-release chlorine dioxide, and its specific implementation is the same as the system of I3 in Example 3, except that the dihydric alcohol is PEG8000.

性能评估performance evaluation

1.水凝胶内部型貌测试:选取实施例3中的水凝胶I3为样品,首先将样品放入-20℃ 冰箱冻成冰,之后放入冻干机冻干得到SEM样品;冻干样品放在SEM载物台表面, 用导电胶带粘结固定并形成导电通路,随后将固定好的样品喷金1分钟,使样品表 面形成致密的镀金薄膜;样品形貌在5KV加速电压下进行观测;需要注意的是,样 品冻干制备过程容易破坏内部形貌,为了真实反映凝胶内部结构形貌,应在样品冻 结成固态时进行脆断。1. Hydrogel internal shape test: select the hydrogel I3 in Example 3 as the sample, first put the sample into a -20°C refrigerator and freeze it into ice, and then put it into a freeze dryer to freeze dry to obtain a SEM sample; freeze dry The sample was placed on the surface of the SEM stage, fixed with conductive tape to form a conductive path, and then the fixed sample was sprayed with gold for 1 minute to form a dense gold-plated film on the surface of the sample; the morphology of the sample was observed under an accelerating voltage of 5KV ; It should be noted that the sample freeze-drying preparation process easily destroys the internal morphology. In order to truly reflect the internal structure and morphology of the gel, brittle fracture should be performed when the sample is frozen into a solid state.

测试结果如图3~图4所示,可以看出水凝胶内部均具有多孔结构,并且孔之间 具有良好的贯穿性;图4是图3结构中的局部放大图。The test results are shown in Figures 3 to 4. It can be seen that the hydrogel has a porous structure inside, and the pores have good penetration; Figure 4 is a partial enlarged view of the structure in Figure 3.

2.水凝胶可注射性表征:将实施例3中的所有样品与实施例4~6所得水凝胶样品进 行可注射性表征,即观察水凝胶是否可以进行可以通过注射的方式使用;每个样品 取100个试样,其可注射性的评价等级与标准为:A级:出现不可注射的样品个数 为0~5个;B级:出现不可注射的样品个数为6~17个;C级:出现不可注射的样品 个数为18~40个;D级:出现不可注射的样品个数为大于等于41;2. Characterization of the injectability of hydrogels: All the samples in Example 3 and the hydrogel samples obtained in Examples 4 to 6 were characterized for their injectability, that is, to observe whether the hydrogels could be used by injection; 100 samples were taken from each sample, and the evaluation grades and standards for injectability were as follows: Grade A: the number of non-injectable samples was 0 to 5; Grade B: the number of non-injectable samples was 6 to 17 Grade C: The number of non-injectable samples is 18-40; Grade D: The number of non-injectable samples is greater than or equal to 41;

3.水凝胶耐低温性表征:将实施例3中的所有样品与实施例4~6所得水凝胶样品进 行耐低温特性表征,所得水凝胶呈圆柱状,样品置于分别置于室温与-10℃2h,再分 别于室温与-10℃下使用万能材料测试仪(WDW-50,济南恒乐兴科仪器有限公司)进 行压缩实验测试,测试仪设置压缩速率为20mm/min,观察压缩百分比为20%时(压 缩百分比由样品压缩形变高度除以样品原有高度计算得到),水凝胶是否破裂。3. Characterization of low temperature resistance of hydrogels: All the samples in Example 3 and the hydrogel samples obtained in Examples 4 to 6 were characterized for low temperature resistance. The obtained hydrogels were cylindrical, and the samples were placed at room temperature respectively. and -10 ℃ for 2 hours, and then use a universal material tester (WDW-50, Jinan Hengle Xingke Instrument Co., Ltd.) at room temperature and -10 ℃ to carry out the compression test. The compression rate of the tester is set to 20mm/min. Observe When the compression percentage is 20% (the compression percentage is calculated by dividing the compression deformation height of the sample by the original height of the sample), whether the hydrogel is broken.

表1Table 1

Figure BDA0002460237510000101
Figure BDA0002460237510000101

以上所述为本发明较佳实施例,对于本领域的普通技术人员而言,根据本发明 的教导,在不脱离本发明的原理与精神的情况下,对实施方式所进行的改变、修改、 替换和变型仍落入本发明的保护范围之内。The above are preferred embodiments of the present invention. For those of ordinary skill in the art, according to the teachings of the present invention, without departing from the principles and spirit of the present invention, changes, modifications, Substitutions and modifications still fall within the scope of the present invention.

Claims (10)

1.一种缓释二氧化氯的水凝胶,其特征在于,其制备原料包括二氧化氯、酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、辣根过氧化物酶、双氧水以及醇类物质;其中,醇类物质包括相对分子量为2000~5000的二元醇以及相对分子量为80~300的三元醇。1. a hydrogel of slow-release chlorine dioxide, is characterized in that, its preparation raw material comprises chlorine dioxide, the polyglutamic acid solution of tyramine grafting, the hyaluronic acid solution of cysteamine grafting, horseradish Peroxidase, hydrogen peroxide and alcohol substances; wherein, the alcohol substances include dihydric alcohols with relative molecular weights of 2000-5000 and trihydric alcohols with relative molecular weights of 80-300. 2.根据权利要求1所述缓释二氧化氯的水凝胶,其特征在于,水凝胶的pH为3.5~5.5。2 . The sustained-release chlorine dioxide hydrogel according to claim 1 , wherein the pH of the hydrogel is 3.5 to 5.5. 3 . 3.根据权利要求1或2所述缓释二氧化氯的水凝胶,其特征在于,所述接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液均是以5wt%的二氧化氯溶液为基底液,将聚谷氨酸溶液与半胱胺接枝的透明质酸分别配制成溶液。3. the hydrogel of slow-release chlorine dioxide according to claim 1 and 2, is characterized in that, the polyglutamic acid solution of described grafting and the hyaluronic acid solution of cysteamine grafting are all at 5wt% The chlorine dioxide solution was used as the base solution, and the polyglutamic acid solution and the cysteamine-grafted hyaluronic acid were respectively prepared into solutions. 4.根据权利要求3所述缓释二氧化氯的水凝胶,其特征在于,酪胺接枝的聚谷氨酸溶液浓度为100~300mg/mL;半胱胺接枝的透明质酸溶液的浓度为100~300mg/mL;优选地,接枝的聚谷氨酸溶液与半胱胺接枝的透明质酸溶液的体积比为1:(0.5~1.5)。4. The hydrogel of slow-release chlorine dioxide according to claim 3, is characterized in that, the polyglutamic acid solution concentration of tyramine grafting is 100~300mg/mL; the hyaluronic acid solution of cysteamine grafting The concentration is 100-300 mg/mL; preferably, the volume ratio of the grafted polyglutamic acid solution to the cysteamine-grafted hyaluronic acid solution is 1:(0.5-1.5). 5.根据权利要求1或2所述缓释二氧化氯的水凝胶,其特征在于,双氧水的浓度为1~30mM。5. The hydrogel of slow-release chlorine dioxide according to claim 1 or 2, wherein the concentration of hydrogen peroxide is 1-30 mM. 6.根据权利要求1或2所述缓释二氧化氯的水凝胶,其特征在于,辣根过氧化物酶的含量为1~50U/mL。6 . The slow-release chlorine dioxide hydrogel according to claim 1 or 2 , wherein the content of horseradish peroxidase is 1-50 U/mL. 7 . 7.根据权利要求1或2所述缓释二氧化氯的水凝胶,其特征在于,醇类物质占水凝胶总体积的5~25%。7 . The slow-release chlorine dioxide hydrogel according to claim 1 or 2 , wherein the alcohol substance accounts for 5-25% of the total volume of the hydrogel. 8 . 8.根据权利要求1~6任一项所述缓释二氧化氯的水凝胶,其特征在于,二元醇与三元醇的体积比为1:(1.2~4.3)。8 . The sustained-release chlorine dioxide hydrogel according to claim 1 , wherein the volume ratio of dihydric alcohol to trihydric alcohol is 1:(1.2˜4.3). 9 . 9.根据权利要求1~6任一项所述缓释二氧化氯的水凝胶,其特征在于,二元醇的结构选自HO(CH2CH2O)nH、HO(CH2CH2CH2CH2O)mH、
Figure FDA0002460237500000011
中的任一种或多种的组合,其中,n、m、p分别独立为35~75。
9 . The slow-release chlorine dioxide hydrogel according to claim 1 , wherein the structure of the dihydric alcohol is selected from the group consisting of HO(CH 2 CH 2 O) n H, HO(CH 2 CH 2 CH 2 CH 2 O) m H,
Figure FDA0002460237500000011
A combination of any one or more of them, wherein n, m, and p are each independently 35 to 75.
10.一种根据权利要求1~9任一项所述缓释二氧化氯的水凝胶的制备方法,其特征在于,包括步骤:酪胺接枝的聚谷氨酸溶液、半胱胺接枝的透明质酸溶液、醇类物质混合,再加入辣根过氧化物酶与双氧水,调节pH,再于室温下静置,即得所需水凝胶制剂。10. A preparation method of the hydrogel of slow-release chlorine dioxide according to any one of claims 1 to 9, characterized in that, comprising the steps of: a polyglutamic acid solution grafted with tyramine, a cysteamine grafted The hyaluronic acid solution of the branch is mixed with alcohol substances, and then horseradish peroxidase and hydrogen peroxide are added to adjust the pH, and then stand at room temperature to obtain the desired hydrogel preparation.
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