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

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

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

technical field

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.

Background technique

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.

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.

SUMMARY OF THE INVENTION

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.

As a preferred technical solution of the present invention, the pH of the hydrogel is 3.5-5.5.

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.

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).

As a preferred technical solution of the present invention, the concentration of hydrogen peroxide is 1-30 mM.

As a preferred technical solution of the present invention, the content of horseradish peroxidase is 1-50 U/mL.

As a preferred technical solution of the present invention, the alcohol substance accounts for 5-25% of the total volume of the hydrogel.

As a preferred technical solution of the present invention, the volume ratio of dihydric alcohol to trihydric alcohol is 1:(1.2-4.3).

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,

A combination of any one or more of them, wherein n, m, and p are each independently 35 to 75.

As a kind of preferred technical scheme of the present invention, trihydric alcohol is selected from glycerol and/or trimethylolpropane.

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.

Compared with the prior art, the hydrogel of slow-release chlorine dioxide provided by the present invention has the following beneficial effects:

(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) 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) 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) 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.

Description of drawings

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.

Figure 1: Schematic diagram of the hydrogel formation of tyramine-grafted polyglutamic acid and cysteamine-grafted hyaluronic acid;

Fig. 2: the nuclear magnetic spectrogram before and after the grafting of hyaluronic acid in Example 2;

Figure 3: Schematic diagram of the internal structure of I3 hydrogel;

FIG. 4 is a schematic view of the partially enlarged structure of FIG. 3 .

Detailed ways

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.

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.

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.

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.

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).

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.

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).

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.

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.

Preferably, the content of the chlorine dioxide solution is 70-90 wt % of the hydrogel.

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.

The concentration of the hydrogen peroxide in the present invention is 1-30 mM; preferably 5-20 mM; more preferably 7-15 mM.

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.

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%.

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,

The combination of any one or more of them, wherein, n, m, and p are independently 35 to 75; Typically, the diol is PEG4000.

Described trihydric alcohol is selected from glycerol and/or trimethylolpropane; Preferably, trihydric alcohol is glycerol.

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.

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.

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.

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.

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).

Example 1

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%.

Example 2

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.

Example 3

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;

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;

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.

Table 1

Example 4

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.

Example 5

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.

Example 6

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.

performance evaluation

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.

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. 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. 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.

Table 1

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. 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 . The sustained-release chlorine dioxide hydrogel according to claim 1 , wherein the pH of the hydrogel is 3.5 to 5.5. 3 . 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. 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. The hydrogel of slow-release chlorine dioxide according to claim 1 or 2, wherein the concentration of hydrogen peroxide is 1-30 mM. 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 . 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 . 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 . 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,

A combination of any one or more of them, wherein n, m, and p are each independently 35 to 75. 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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