Process method for producing vascular hardener
By combining modified ethylene-vinyl alcohol copolymer and hyaluronic acid, a sclerosing agent with higher biocompatibility and stability was prepared, which solved the problem of unstable treatment effect in the existing technology, and achieved more precise and lasting vascular occlusion effect and safety, while reducing production costs.
Patent Information
- Application Number
- CN202511118792.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-11
- Publication Date
- 2025-11-07
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
Existing sclerosing agents for treating hemangiomas have drawbacks such as unstable treatment effects, easy recurrence, easy scarring, skin necrosis, and nerve paralysis. In addition, the treatment process puts a dual burden on patients, both physically and financially.
A sclerosing agent composed of 10%–15% w/v modified ethylene-vinyl alcohol copolymer, 10%–15% w/v anhydrous ethanol, 5%–10% w/v modified hyaluronic acid, 1%–5% w/v glycerol, 1%–2% w/v sodium polyglucosamine carboxylate, and 0.9% sodium chloride aqueous solution is prepared through specific process steps, including dissolution, ultrasonic dispersion, and filtration sterilization, to enhance biocompatibility and stability, and promote vascular fibrosis and hemostasis.
It improves the biocompatibility and stability of sclerosing agents, prolongs the duration of action, reduces inflammatory response, enhances sclerosing effect, reduces production costs, and ensures the safety and precision of treatment.
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medical vascular sclerosing agents, in particular to a process for producing a vascular sclerosing agent. BACKGROUND
[0002] A vascular sclerosing agent is a medical preparation that causes abnormal blood vessels to close through chemical stimulation. After being injected into diseased blood vessels, it causes endothelial damage, promotes the formation of thrombus and fibrosis in the blood vessels, and ultimately causes the blood vessels to occlude. Currently, vascular sclerosing agents mainly include anhydrous alcohol, 5% sodium morrhuate, 10% ethoxylated sclerosing alcohol, etc. Vascular sclerosing agents are mainly used in the treatment of some vascular diseases, such as vascular malformations, varicose veins, and internal hemorrhoids, etc. Among them, 3% sodium morrhuate is generally used for treating venous malformations, and 5% sodium morrhuate is generally used for treating hemangiomas.
[0003] However, some studies have shown that there are many disadvantages in treating hemangiomas with some sclerosing agents, such as skin necrosis, nerve palsy, fever, allergic reactions, brain poisoning, interstitial pneumonia, and pulmonary softening after treatment, as well as unstable treatment effect, easy recurrence, and easy scarring, etc. The occurrence of such situations harms the patients and also requires re-treatment, which brings double pressure on the patients' body and economy. SUMMARY
[0004] In view of the problems in the background art, the present application provides a vascular sclerosing agent with a simple production method and stable treatment effect, which is achieved by the following technical scheme:
[0005] The vascular sclerosing agent is composed of 10%-15% w / v modified ethylene-vinyl alcohol copolymer, 10%-15% w / v anhydrous ethanol, 5%-10% w / v modified hyaluronic acid, 1%-5% w / v glycerol, 1%-2% w / v chitosan sodium carboxylate, and the rest is 0.9% sodium chloride aqueous solution;
[0006] The process for producing the vascular sclerosing agent comprises the following steps:
[0007] S1: Dissolve the modified ethylene-vinyl alcohol copolymer in 0.9% sodium chloride aqueous solution, heat to 60℃, and slowly stir and disperse;
[0008] S2: Then slowly add glycerol and chitosan sodium carboxylate to the solution in sequence using a dropping funnel under stirring;
[0009] S3: Add the modified hyaluronic acid to the anhydrous ethanol, and ultrasonically disperse for 30-40 min at 35-45 kHz and 250-350 W;
[0010] S4: adding the modified hyaluronic acid ethanol solution into the mixed solution in S2, and continuing to ultrasonic for 1-2 hours to obtain a blood vessel sclerosing agent;
[0011] S5: filtering and sterilizing the prepared blood vessel sclerosing agent.
[0012] Specifically, the dropping speed in S2 is 4 s / drop.
[0013] Specifically, the pore size of the membrane filter for filtering and sterilizing in S5 is 0.45 μm or 0.22 μm.
[0014] The preparation method of the modified ethylene-vinyl alcohol copolymer comprises the following steps:
[0015] Step (1): dissolving 2 g of ethylene-vinyl acetate copolymer in 10 ml of toluene, ultrasonic for 5-10 minutes at 45 kHz, 250 W and 80℃, then adding 10 ml of sodium hydroxide methanol solution, mixing for 1-2 hours, then filtering, washing the residue with 30 ml of methanol for three times, and then drying in a vacuum drying box at 60℃ for 12-24 hours to obtain ethylene-vinyl alcohol copolymer;
[0016] Step (2): dissolving the dried ethylene-vinyl alcohol copolymer in 5 ml of 80℃ N-methyl pyrrolidone, adding the solution into 20 ml of distilled water under stirring, filtering after the addition is completed, washing the residue with 30 ml of distilled water for three times, and then drying in a vacuum drying box at 60℃ for 12-15 hours;
[0017] Step (3): slowly dropping the residue after step (2) into an excess amount of succinyl chloride solution under ice bath, reacting for 0.5-1 hour, washing with 30 ml of toluene for three times, concentrating, adding the concentrated solution into 5 ml of DCM, adding EDCI, HOBT and DIPEA under nitrogen protection, reacting for 0.5 hours, then adding 500 mg of phenylalanine, continuing to react for 5-6 hours under stirring at room temperature, filtering after the reaction is completed, washing the residue with toluene for three times, and then drying the residue in a vacuum drying box at 60℃ for 12-15 hours to obtain the modified ethylene-vinyl alcohol copolymer.
[0018] Specifically, the sodium hydroxide methanol solution is a 1 mol / L NaOH methanol solution.
[0019] The preparation method of the modified sodium hyaluronate comprises the following steps:
[0020] Step (a): dissolving hyaluronic acid in distilled water, ultrasonic for 30 minutes, adding an appropriate amount of base to adjust the pH value of the solution to 7.5-8.5 to configure a hyaluronic acid alkaline aqueous solution;
[0021] Step (b): 5g of octadecyl succinic anhydride is dissolved in a small amount of dimethyl sulfoxide, then slowly added dropwise into the hyaluronic acid alkaline aqueous solution under stirring, the reaction mixture is stirred at room temperature, the reaction is carried out for 12-24 hours, after the reaction is completed, 0.5% hydrochloric acid aqueous solution is added dropwise to adjust the pH to 5-7, and the reaction is terminated after stirring for 10-15 minutes;
[0022] Step (c): the reaction product is washed with 30ml of petroleum ether for three times, and concentrated to obtain a yellow oil, which is the modified hyaluronic acid.
[0023] Specifically, the alkali is 0.1mol / L sodium hydroxide solution, and the dilute hydrochloric acid is 0.5% hydrochloric acid aqueous solution.
[0024] Specifically, the concentration of the hyaluronic acid alkaline aqueous solution prepared in step (a) is 1mg / ml.
[0025] Compared with the prior art, the beneficial effects of the present application are that:
[0026] The vascular sclerosing agent described in the present application enhances the biocompatibility by modifying the ethylene-vinyl alcohol copolymer, helps the vascular sclerosing agent to stay in the local blood vessel, and prolongs the action time. The modification of hyaluronic acid improves the stability of the vascular sclerosing agent, forms a physical barrier in the blood vessel, promotes the fibrosis of the blood vessel wall, and at the same time may reduce the inflammatory reaction, assisting the hardening process. Polyaminoglucose carboxylate sodium, a chitosan derivative, has biological adhesion and hemostatic effect. It helps the vascular sclerosing agent to adhere to the inner wall of the blood vessel, enhances the hardening effect, and at the same time promotes local blood coagulation and accelerates blood vessel occlusion.
[0027] Secondly, the addition of glycerol in the vascular sclerosing agent can adjust the viscosity of the solution, prevent the degradation of the components, and at the same time its lubricity helps to reduce local irritation, improve the tolerance of patients, and ensure the smooth progress of the injection process. Using 0.9% sodium chloride aqueous solution as the solvent can maintain isotonic environment, reduce tissue irritation during injection, and ensure the stability and safety of the vascular sclerosing agent.
[0028] More importantly, the vascular sclerosing agent described in the present application achieves more precise and durable blood vessel occlusion effect through the synergy of multiple components. In addition, the production process is simple, the raw materials are cheap and easy to obtain, and the production cost is reduced, which can benefit more patients. DETAILED DESCRIPTION
[0029] The technical solutions of the present application will be described in detail below with reference to the embodiments. The following embodiments are only used to more clearly illustrate the technical solutions of the present application, and therefore only serve as examples, but cannot limit the protection scope of the present application.
[0030] It should be noted that the experimental methods used in the examples are conventional methods unless otherwise specified; the materials, reagents, etc. used are commercially available unless otherwise specified.
[0031] In the present application, unless otherwise specified, the numerical range "a~b" represents a shorthand notation for any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0~5" represents that all real numbers between "0~5" have been listed herein, and "0~5" is only a shorthand notation for these numerical combinations.
[0032] In the present application, unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined with each other to form new technical solutions.
[0033] In the present application, unless otherwise specified, all steps mentioned herein can be performed in sequence or randomly, but preferably in sequence; for example, the method comprises steps (1) and (2), which means that the method can comprise steps (1) and (2) performed in sequence, or steps (2) and (1) performed in sequence; for example, the method can further comprise step (3), which means that step (3) can be added to the method in any order; for example, the method can comprise steps (1), (2) and (3), or steps (1), (3) and (2), or steps (3), (1) and (2), etc.
[0034] In the present application, unless otherwise specified, the specific values and specific substances in the examples herein can be combined with other features described in the description section; for example, if the description mentions that the reaction temperature is 10~100℃, and the example mentions that the reaction temperature is 20℃, then it can be considered that the range of 10~20℃ or the range of 20~100℃ has been specifically disclosed herein, and this range can be combined with other features described in the description section to form new technical solutions.
[0035] Example 1
[0036] Preparation of modified ethylene-vinyl alcohol copolymer
[0037] Dissolve 2 g of ethylene-vinyl acetate copolymer in 10 ml of toluene, ultrasonic at 45 kHz, 250 W, 80℃ for 5 minutes, then add 10 ml of 1 mol / L sodium hydroxide methanol solution, mix for 12 hours, then filter, wash the residue with 30 ml of methanol three times, then put it in a vacuum drying oven at 60℃ for 12 hours to obtain ethylene-vinyl alcohol copolymer;
[0038] The dried ethylene-vinyl alcohol copolymer was dissolved in 5 ml of 80°C N-methyl pyrrolidone, the solution was added dropwise into 20 ml of distilled water under vigorous stirring, after the dropwise addition was completed, the filtrate was filtered with a 200 mesh filter paper, the filter residue was washed with 30 ml of distilled water for three times, and was dried in a 60°C vacuum drying oven for 12 hours;
[0039] The dried filter residue was slowly added dropwise into an excess of succinyl chloride solution under ice bath, after 0.5 hours of reaction, it was washed with 30 ml of toluene for three times, was concentrated, the concentrated solution was added into 5 ml of DCM, EDCI, HOBT and DIPEA were added, and after 0.5 hours of reaction under nitrogen protection, 500 mg of phenylalanine was added, and the reaction was continuously carried out under stirring at room temperature for 5-6 hours, after the reaction was completed, it was filtered, the filter residue was washed with toluene for three times, and the filter residue was dried in a 60°C vacuum drying oven for 12-15 hours to obtain a modified ethylene-vinyl alcohol copolymer.
[0040] Preparation of modified sodium hyaluronate
[0041] 500 mg of hyaluronic acid was dissolved in 500 ml of distilled water, was ultrasonically dissolved for 30 minutes, 0.1 mol / L sodium hydroxide solution was added to adjust the pH value of the solution to 7.5-8.5, and was configured into a 1 mg / ml hyaluronic acid alkaline aqueous solution;
[0042] 5 g of octadecyl succinic anhydride was dissolved in a small amount of dimethyl sulfoxide, and then was slowly added dropwise into the hyaluronic acid alkaline aqueous solution under stirring, the reaction mixture was stirred at room temperature, and was reacted for 12 hours, after the reaction was completed, 0.5% hydrochloric acid was added dropwise to adjust the pH to 5-7, and was stirred for 10 minutes to terminate the reaction;
[0043] The reaction product was washed with 30 ml of petroleum ether for three times, was concentrated to obtain a yellow oil, which was the modified hyaluronic acid.
[0044] Preparation of a vascular sclerosing agent
[0045] S1: 20 mg of the modified ethylene-vinyl alcohol copolymer was dissolved in 200 ml of 0.9% sodium chloride aqueous solution, was heated to 60°C, and was dispersed under slow stirring;
[0046] S2: then 2 g of glycerol and 2 g of sodium polyglucosamine carboxylate were slowly added dropwise into the solution in sequence at 4 s / drop under stirring using a dropping funnel;
[0047] S3: 10 mg of the modified hyaluronic acid was added into 20 ml of anhydrous ethanol, and was ultrasonically dispersed for 30 min at 35-45 kHz and 250-350 W;
[0048] S4: the anhydrous ethanol solution of the modified hyaluronic acid was added into the mixed solution in S2, and was continuously ultrasonically dispersed for 1 hour to obtain a vascular sclerosing agent;
[0049] S5: The prepared blood vessel sclerosing agent is filtered with a pore size of 0.45 μm membrane filter to remove bacteria, and product 1 is obtained.
[0050] Example 2
[0051] Preparation of modified ethylene-vinyl alcohol copolymer
[0052] Dissolve 2 g of ethylene-vinyl acetate copolymer in 10 ml of toluene, and ultrasonically treat for 10 minutes at 45 kHz, 250 W and 80°C. Then add 10 ml of 1 mol / L sodium hydroxide methanol solution, mix for 2 hours, and then filter. Wash the residue with 30 ml of methanol three times, and then place in a vacuum drying oven at 60°C for 24 hours to obtain ethylene-vinyl alcohol copolymer.
[0053] Dissolve the dried ethylene-vinyl alcohol copolymer in 5 ml of 80°C N-methyl pyrrolidone, and drop the solution into 20 ml of distilled water under vigorous stirring. After the dropwise addition is completed, filter with a 200 mesh filter paper, wash the residue with 30 ml of distilled water three times, and place in a vacuum drying oven at 60°C for 15 hours.
[0054] Slowly drop the dried residue into an excess of succinyl chloride solution under ice bath, and react for 1 hour. Then wash three times with 30 ml of toluene, concentrate, and add the concentrated solution to 5 ml of DCM. Add EDCI, HOBT and DIPEA, and react for 0.5 hours under nitrogen protection. Then add 500 mg of phenylalanine, continue to react for 6 hours under stirring at room temperature. After the reaction is completed, filter, wash the residue with toluene three times, and place the residue in a vacuum drying oven at 60°C for 15 hours to obtain the modified ethylene-vinyl alcohol copolymer.
[0055] Preparation of modified sodium hyaluronate
[0056] Dissolve the hyaluronic acid in distilled water, and ultrasonically treat for 30 minutes. Add 0.1 mol / L sodium hydroxide solution to adjust the pH of the solution to 7.5-8.5, and configure into a 1 mg / ml hyaluronic acid alkaline aqueous solution.
[0057] Dissolve 5 g of octadecyl succinic anhydride in a small amount of dimethyl sulfoxide, and then slowly drop into the hyaluronic acid alkaline aqueous solution under stirring. Stir the reaction mixture at room temperature, and react for 12-24 hours. After the reaction is completed, add 0.5% hydrochloric acid to adjust the pH to 5-7, and stir for 10-15 minutes to terminate the reaction.
[0058] Wash the reaction product with 30 ml of petroleum ether three times, and concentrate to obtain a yellow oil, which is the modified hyaluronic acid.
[0059] Preparation of blood vessel sclerosing agent
[0060] Preparation of sclerosing agents
[0061] S1: Dissolve 20 mg of modified ethylene-vinyl alcohol copolymer in 200 ml of 0.9% sodium chloride aqueous solution, heat to 60 °C, and disperse by slow stirring;
[0062] S2: Then, with stirring, slowly add 2g of glycerol and 2g of sodium polyglucosamine carboxylate to the solution dropwise at a rate of 4s / drop using a dropping funnel;
[0063] S3: Add 10mg of modified hyaluronic acid to 20ml of anhydrous ethanol and ultrasonically disperse it for 30min at 35-45kHz and 250-350W.
[0064] S4: Add the anhydrous ethanol solution of modified hyaluronic acid to the mixed solution in S2, and continue sonication for 1 hour to obtain a sclerosing agent;
[0065] S5: The prepared sclerosing agent is filtered and sterilized using a membrane filter with a pore size of 0.45μm to obtain product 2.
[0066] Example 3
[0067] The preparation methods for the modified ethylene-vinyl alcohol copolymer and modified sodium hyaluronate in this embodiment are the same as those in Example 1.
[0068] Preparation of sclerosing agents
[0069] S1: Dissolve 10 mg of modified ethylene-vinyl alcohol copolymer in 100 ml of 0.9% sodium chloride aqueous solution, heat to 60 °C, and disperse by slow stirring;
[0070] S2: Then, with stirring, slowly add 1 mg of glycerol and 1 mg of sodium polyglucosamine carboxylate to the solution dropwise at a rate of 4 seconds per drop using a dropping funnel;
[0071] S3: Add 7 mg of modified hyaluronic acid to 15 ml of anhydrous ethanol and ultrasonically disperse at 35-45 kHz and 250-350 W for 40 min.
[0072] S4: Add the anhydrous ethanol solution of modified hyaluronic acid to the mixed solution in S2 and continue for more than 2 hours to obtain an arteriosclerosis agent;
[0073] S5: The prepared sclerosing agent is filtered and sterilized using a membrane filter with a pore size of 0.22μm to obtain product 3.
[0074] Example 4
[0075] The difference between this example and Example 1 is that the vascular sclerosing agent is composed of 12 mg modified ethylene-vinyl alcohol copolymer, 13 ml absolute ethanol, 7 mg modified hyaluronic acid, 4 mg glycerol, 2 mg sodium polyglucosamine carboxylate, and the rest is 0.9% sodium chloride aqueous solution; the rest of the preparation method is the same as Example 1, and product 4 is obtained.
[0076] Comparative Example 1
[0077] The difference between this comparative example and Example 1 is that hyaluronic acid is used instead of modified hyaluronic acid, and the rest of the preparation method is the same as Example 1.
[0078] Comparative Example 2
[0079] The difference between this comparative example and Example 1 is that ethylene-vinyl alcohol copolymer is used instead of modified ethylene-vinyl alcohol copolymer, and the rest of the preparation method is the same as Example 1.
[0080] Performance test
[0081] Foam stability experiment
[0082] Two disposable syringes are connected through a medical tee, and the product prepared in the above examples and indoor air are drawn into a 10 ml disposable syringe at a ratio of 1:3, and mixed by rapidly injecting 40-50 times between the two syringes. A stable foam is prepared, and all the foam is injected into one syringe at the last time. The syringe containing all the foam is removed from the tee and inverted vertically on the horizontal table top. At this moment, the time is started and the change of the foam is observed. The amount of liquid separated from the bottom of the syringe is half the volume of the original mixed liquid, and each group of experiments is repeated ten times to calculate the average value.
[0083] Table 1 Foam stability experiment results
[0084] No. Average time (min) Example 1 7.75 Example 2 6.89 Example 3 7.23 Example 4 7.08 Comparative Example 1 1.54 Comparative Example 2 2.43
[0085] Foam blood replacement capacity experiment
[0086] Tessari method is used to prepare the foam. After the foam is prepared, the bottom tee is opened, 3 mL of foam is injected into the simulated blood vessel, and the farthest distance reached by the foam and the time used before retreating 4 cm are recorded.
[0087] Table 2 Foam blood replacement capacity experiment results
[0088] No. Farthest distance (cm) Back-off time (min) Example 1 40.7 2.01 Example 2 39.8 2.31 Example 3 39.4 2.01 Example 4 40.1 1.98 Comparative Example 1 20.1 0.21 Comparative Example 2 22.7 0.22
[0089] From the above experimental results, it can be seen that the vascular sclerosing agent prepared by modifying ethylene-vinyl alcohol copolymer and hyaluronic acid has a foam residence time of 6.89-7.75 min, a farthest distance in the simulated blood vessel of 39.4-40.7 cm, and a time of 1.98-2.31 min before retreating 4 cm, which is much better than the comparative examples.
[0090] In summary, the above is only a preferred example of the present application, and does not limit the present application in any form; any skilled person in the art without departing from the technical solution of the present application, using the disclosed technical content to make some changes, modifications and equivalent changes, are considered equivalent examples of the present application; at the same time, any equivalent changes, modifications and evolution of the above examples according to the essence of the present application, still belong to the protection scope of the technical solution of the present application.
Claims
1. A process for the production of a vascular sclerosing agent, characterized in that, The blood vessel sclerosing agent is composed of 10-15% w / v modified ethylene-vinyl alcohol copolymer, 10-15% w / v anhydrous ethanol, 5-10% w / v modified hyaluronic acid, 1-5% w / v glycerol, 1-2% w / v sodium polyglucosamine carboxylate, and the rest is 0.9% sodium chloride aqueous solution; The process method for producing the blood vessel sclerosing agent comprises the following steps: S1: dissolve the modified ethylene-vinyl alcohol copolymer in 0.9% sodium chloride aqueous solution, heat to 60°C, and slowly stir and disperse; S2: then slowly add glycerol and sodium polyglucosamine carboxylate to the solution in turn under stirring using a dropping funnel; S3: add the modified hyaluronic acid to anhydrous ethanol, and ultrasonically disperse for 30-40 min under 35-45 kHz and 250-350 W; S4: add the anhydrous ethanol solution of the modified hyaluronic acid to the mixed solution in S2, and continue to ultrasonically for 1-2 hours to obtain the blood vessel sclerosing agent; S5: filter and sterilize the prepared blood vessel sclerosing agent.
2. A process for the production of a vascular sclerosing agent according to claim 1, characterized in that, The dropping rate in S2 is 4 s / drop.
3. A process for the production of a vascular sclerosing agent according to claim 1, characterized in that, The pore size of the membrane filter for filtering and sterilizing in S5 is 0.45 μm or 0.22 μm.
4. The process for producing a vascular sclerosing agent according to claim 1, wherein The preparation method of the modified ethylene-vinyl alcohol copolymer comprises the following steps: Step (1): dissolve 2 g of ethylene-vinyl acetate copolymer in 10 ml of toluene, ultrasonically for 5-10 min under 45 kHz, 250 W and 80°C, then add 10 ml of sodium hydroxide methanol solution, mix for 1-2 hours, filter, wash the residue with 30 ml of methanol for three times, and then dry in a vacuum drying box at 60°C for 12-24 hours to obtain ethylene-vinyl alcohol copolymer; Step (2): dissolve the dried ethylene-vinyl alcohol copolymer in 5 ml of 80°C N-methyl pyrrolidone, add the solution to 20 ml of distilled water under vigorous stirring, after the addition is completed, filter with a 200 mesh filter paper, wash the residue with 30 ml of distilled water for three times, and dry in a vacuum drying box at 60°C for 12-15 hours; Step (3): slowly drop the residue after drying in step (2) into an excess amount of succinyl chloride solution under ice bath, react for 0.5-1 hour, wash with 30 ml of toluene for three times, concentrate, add the concentrated solution to 5 ml of DCM, add EDCI, HOBT and DIPEA under nitrogen protection, react for 0.5 hour, then add 500 mg of phenylalanine, continue to react for 5-6 hours under stirring at room temperature, after the reaction is completed, filter, wash the residue with toluene for three times, and dry the residue in a vacuum drying box at 60°C for 12-15 hours to obtain the modified ethylene-vinyl alcohol copolymer.
5. A process for the production of a vascular sclerosing agent according to claim 4, characterized in that, The sodium hydroxide methanol solution is 1 mol / L NaOH methanol solution.
6. The process as claimed in claim 1, wherein, The preparation method of the modified sodium hyaluronic acid comprises the following steps: Step (a): dissolve hyaluronic acid in distilled water, ultrasonically for 30 min, add an appropriate amount of base to adjust the pH value of the solution to 7.5-8.5, and configure into a hyaluronic acid alkaline aqueous solution; Step (b): 5g of octadecyl succinic anhydride is dissolved in a small amount of dimethyl sulfoxide, then slowly drop into the hyaluronic acid alkaline aqueous solution under stirring, the reaction mixture is stirred at room temperature, the reaction is carried out for 12-24 hours, after the reaction is completed, add diluted hydrochloric acid to adjust the pH to 5-7, stir for 10-15 minutes, and terminate the reaction; Step (c): the reaction product is washed with 30ml of petroleum ether for three times, and concentrated to obtain yellow oil, which is the modified hyaluronic acid.
7. A process for the production of a vascular sclerosing agent according to claim 6, characterized in that, The base is 0.1mol / L sodium hydroxide solution, and the diluted hydrochloric acid is 0.5% hydrochloric acid aqueous solution.
8. A process for the production of a vascular sclerosing agent according to claim 6, characterized in that, The concentration of the hyaluronic acid alkaline aqueous solution prepared in step (a) is 1mg / ml.