Hesperetin product for treating oral ulcer

By combining hesperin with hyaluronic acid hydrogel, gel products for the treatment of oral ulcers were prepared, which solved the problem that drugs in the prior art were difficult to effectively relieve inflammation and pain of oral ulcers, and achieved efficient and safe local treatment effects.

CN120168398APending Publication Date: 2025-06-20WENZHOU MEDICAL UNIV +1
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Patent Information

Application Number
CN202510374824.3
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2025-03-27
Publication Date
2025-06-20

AI Technical Summary

Technical Problem

Prior Art When treating oral ulcers, conventional drugs are difficult to effectively relieve inflammation and pain, and may cause side effects. Long-term or excessive use may lead to oral mucosa atrophy and immunosuppression.

Method used

Hesperin is used as the main ingredient, and semi-flow dynamic gel or double-layer gel patches are prepared by combining with hyaluronic acid hydrogels to adhere to the wounds of oral ulcers. The anti-inflammatory, antioxidant and analgesic effects of hesperin are used to combine the good biocompatibility and adhesion of hyaluronic acid to achieve local treatment.

Benefits of technology

It significantly improves the effect of treating oral ulcers, reduces inflammation and pain, prolongs the drug's residence time in the treatment area, enhances the permeability and local effects of the drug, reduces the risk of side effects, and provides an inexpensive, safe and efficient treatment plan.

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Abstract

The invention provides a hesperetin product for treating oral ulcer, the hesperetin product contains hesperetin, and the hesperetin product is attached to the wound surface of the oral ulcer. The hesperetin product prepared by adopting the technical scheme of the invention can effectively improve the stability and the controllable release property of a therapeutic drug, can enhance the local effect of the drug on an ulcer part and prolong the action time, and is simple and convenient to treat and operate and obvious in treatment effect. The innovative treatment mode is expected to bring a new treatment choice for oral ulcer patients, and a new treatment strategy is provided for healing of oral mucosa ulcer.
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Description

Technical Field

[0001] The invention relates to the technical field of hesperidin, in particular to a hesperidin product for treating oral ulcers. Background Art

[0002] With the improvement of people's living standards, oral ulcers have gradually become a common pathological symptom in clinical practice. It refers to a superficial or deep injury on the surface of the oral mucosa, usually manifested as local ulcers, often accompanied by inflammation, burning pain and erythema of mucosal tissue in the early stage, and thick yellow-white pus membranes on the ulcer surface in the later stage. The causes of injury are varied, including accidental bites, heat, electricity, chemical trauma, autoimmune diseases, nutritional deficiencies, long-term stress, etc., which lead to acute or chronic damage to the oral mucosa and the formation of surface ulcers, usually round or oval. Clinically, drug treatment is generally chosen, such as mouthwash, watermelon frost and other drugs containing analgesic, anti-infective or anti-inflammatory ingredients, and emphasizes that patients maintain good living habits, pay attention to nutritional supplements, and avoid spicy and acidic foods. However, the long-term inflammation and severe pain caused by these ulcers are still the most common and difficult problems encountered in the clinical treatment of ulcer wounds. Inflammation has a wide range of effects on the body, and any mechanism that can subside the inflammation of the ulcer wound will play a role in relieving the pain of oral ulcers. When the ulcer wound is large, conventional drugs are difficult to relieve short-term pain symptoms, and patients will have difficulty eating, talking and other actions, which will also have a negative impact on their mental health, including anxiety and depression. In addition, steroid hormone drugs such as methasone are often used clinically to reduce inflammation and pain, and local anesthetics such as lidocaine gargle are used to relieve pain in the ulcer area. However, these drugs are expensive and may cause unnecessary toxic reactions to the human body. Long-term or excessive use may cause atrophy of the oral mucosa and cause local immunosuppression, increasing the risk of infection. Therefore, how to find a cheap, environmentally friendly drug with few side effects on the human body and high anti-inflammatory and analgesic effects has become a difficult problem that needs to be solved in the current clinical treatment of oral ulcers.

[0003] Hesperetin (3′,5,7-trihydroxy-4-methoxyflavone) belongs to flavonoid plant extracts, mainly derived from citrus fruits (such as satsumas abundantly produced locally in Wenzhou, Zhejiang), and is a cheap growth factor. Regular consumption of foods rich in hesperetin helps prevent cardiovascular, neurodegenerative, and inflammatory diseases, as well as metabolic disorders such as diabetes. Some studies have shown that hesperetin itself has the effects of promoting angiogenesis, anti-inflammation, antioxidant, strengthening immune regulation, and preventing cancer. It can efficiently scavenge peroxynitrite ions to regulate the inflammatory microenvironment and achieve a rapid anti-inflammatory effect, with significant curative effects on inflammation caused by skin and mucosal wounds. Some literature also points out that hesperetin is highly correlated with multiple signal pathway transmissions, such as ERK, MAPK, etc. At the same time, hesperetin also has special osteogenic, lipid-lowering, and analgesic effects, and has great clinical treatment potential and market application prospects in human tissue engineering such as wound repair, nerve regeneration, and bone defect repair. The good biocompatibility of hesperetin provides new ideas for its application in oral preparations. Currently, there is no report on the use of hesperetin for the prevention or treatment of oral ulcers. Summary of the Invention

[0004] The purpose of the present invention is to overcome the drawbacks and deficiencies of the prior art and provide a hesperetin product for treating oral ulcers.

[0005] The technical solution adopted by the present invention is as follows: The present invention provides a hesperetin product for treating oral ulcers. The hesperetin product contains hesperetin, and the hesperetin product adheres to the oral ulcer wound surface.

[0006] The first aspect provided by the present invention is a semi-fluid gel hesperetin gel product, and its preparation method includes the following steps:

[0007] S1. Add sodium hyaluronate powder to deionized water to prepare a viscous sodium hyaluronate solution;

[0008] S2. Dissolve hesperetin powder in DMSO to obtain a hesperetin solution, add the hesperetin solution to the sodium hyaluronate solution, and continue to add EDC and NHS and stir to react to obtain a cross-linked product;

[0009] S3. Store the cross-linked product frozen to form a semi-fluid gel.

[0010] Preferably, in step S1, the mass concentration of the sodium hyaluronate is 3-5%, in step S2, the concentration of the hesperetin solution is 30-50 μM, and the volume ratio of the hesperetin solution to the sodium hyaluronate solution is 1:4-6.

[0011] Preferably, in step S1, the sodium hyaluronate solution is obtained by stirring under the condition of 40-60 °C.

[0012] Preferably, in step S2, the molar ratio of EDC to NHS is 1 - 1.5:1.

[0013] Preferably, in step S3, it is frozen at 3 - 5°C for 24 - 28 h.

[0014] The second aspect of the present invention provides a double - layer gel patch hesperetin gel product, and its preparation method includes the following steps:

[0015] S1. Dissolve hesperetin powder in DMSO to obtain a hesperetin solution with a concentration of 30 - 50 μM.

[0016] S2. Preparation of the first contact layer solution: Take 1 - 3 mL of the hesperetin solution, 0.3 - 0.6 g of polymer, and 0.05 - 0.3 g of photoinitiator, dissolve them in 5 - 20 ml of deionized water, maintain stirring at 50 - 60°C overnight to obtain the first contact layer solution for standby.

[0017] S3. Preparation of the second reinforcement layer solution: Take 0.5 - 2 mL of the hesperetin solution, 0.6 - 1.2 g of polymer, 0.2 - 0.6 g of photoinitiator, and 0.5 - 1.2 g of dexamethasone acetate, dissolve them in 20 - 50 ml of deionized water, maintain stirring at 50 - 60°C overnight, then add 0.05 - 0.5 g of calcium chloride, and continue to stir evenly to obtain the second reinforcement layer solution for standby.

[0018] S4. Inject the first contact layer solution and the second reinforcement layer solution into the mold respectively, and cross - link them into a gel under ultraviolet light irradiation to obtain the hesperetin double - layer gel patch.

[0019] Preferably, the photoinitiator includes Irgacure 2959, and the polymer includes at least one of N - vinylcaprolactam and methacrylated hyaluronic acid.

[0020] Preferably, 0.1 - 0.5 g of co - initiator is further added to the deionized water in step S3, and the co - initiator includes triethanolamine.

[0021] The beneficial effects of the present invention are as follows:

[0022] 1. The present invention innovatively applies hesperetin to the treatment of oral ulcers, and makes a product that can adhere to the oral ulcer wound surface with hesperetin to achieve the treatment purpose.

[0023] 2. In one embodiment of the present invention, hyaluronic acid hydrogel is introduced as a new drug carrier material. As a polysaccharide naturally present in human connective tissues, hyaluronic acid is widely used in the medical and cosmetic fields. Its molecular structure is unique, composed of alternating glucuronic acid and N-acetylglucosamine units that form a three-dimensional network structure. This structure can mimic the extracellular matrix of tissues and has the potential to guide cell behavior during tissue regeneration (such as cartilage and dental pulp regeneration). Such a structure endows hyaluronic acid hydrogel with excellent biocompatibility, drug-loading capacity, and adhesiveness. The biocompatibility of hyaluronic acid hydrogel is an important basis for its non-toxic side effects in the body. Due to its natural presence in human tissues, hyaluronic acid can blend well with the surrounding tissues in the human body, reducing the risk of immune rejection. This means that patients rarely experience allergies or other adverse reactions during gel treatment, ensuring the safety of drug administration. Another advantage of hyaluronic acid hydrogel is its unique three-dimensional structure, which makes it an excellent drug carrier. During the treatment of oral ulcers, due to the special nature of the oral mucosa, most drugs are required to effectively stay on the ulcer surface while avoiding being washed away by the flowing saliva in the mouth. This network structure not only facilitates drug loading and stability but also provides a large surface area, helping to achieve uniform distribution and sustained release of the drug in the material, with good drug-loading performance. Adhesiveness is another remarkable feature of hyaluronic acid hydrogel. According to the special process formula obtained from our experiments, this hydrogel can firmly adhere to the ulcer surface in the human oral environment without easy slippage. This strong adhesiveness not only prolongs the residence time of the drug at the treatment site but also improves the permeability of the drug in the ulcer tissue, thereby enhancing the treatment effect. By loading hesperetin, a drug for treating oral mucosal ulcers, into hyaluronic acid hydrogel, not only can the stability and controlled release of the therapeutic drug be improved, but also the local action of the drug at the ulcer site can be enhanced, prolonging the action time. The treatment operation is simple and the treatment effect is obvious. This innovative treatment method is expected to bring new treatment options for patients with oral ulcers and provide new treatment strategies for the healing of oral mucosal ulcers.

[0024] 3. In another embodiment of the present invention, to improve the mechanical properties of the product, a double-layer gel patch is provided. Through the composite structure of the first contact layer attached to the surface of the oral wound and the second reinforcement layer that enhances the mechanical strength, this gel patch has good oral adhesiveness and better mechanical properties. It can still adhere to the oral cavity wall during oral movement, ensuring its normal function and better application performance. Description of the Drawings

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, obtaining other drawings based on these drawings still belongs to the scope of the present invention.

[0026] Figure 1 UV spectral kurtosis diagram of the semi-fluid gel prepared in Example 1;

[0027] Figure 2 Schematic diagram of the live / dead staining experiment of the biocompatibility of the semi-fluid gel with different hesperetin concentrations prepared in Example 1;

[0028] Figure 3 CCK8 detection statistical chart of the biocompatibility of the semi-fluid gel with different hesperetin concentrations prepared in Example 1;

[0029] Figure 4 Wound recovery rate diagram of the rat oral ulcer model treated with different model groups;

[0030] Figure 5 HE schematic diagram of the rat oral ulcer model treated with different model groups;

[0031] Figure 6 PCR inflammatory factor statistical chart of the rat oral ulcer model treated with different model groups;

[0032] Figure 7 CCK8 detection statistical chart of the biocompatibility of Examples 2 - 3;

[0033] Figure 8 Rheological property test diagrams of (a) the contact layer single-layer gel patch and (b) the reinforcement layer single-layer gel patch prepared in Example 3. Detailed implementation manners

[0034] To make the objectives, technical solutions, and advantages of the present invention clearer, the following will further describe the present invention in detail with reference to the drawings.

[0035] Example 1

[0036] Preparation method of a semi-fluid gel hesperetin product for treating oral ulcers:

[0037] (1) Preparation of hyaluronic acid solution

[0038] Weigh the sodium hyaluronate powder and add it to the pre-measured deionized water to prepare a sodium hyaluronate solution with a mass concentration of 4%. Under the condition of constant temperature at 50 °C, stir it with a constant temperature magnetic stirrer at a speed of 1000 revolutions per minute (rpm) until the sodium hyaluronate can be completely dissolved; seal the relatively viscous aqueous solution of hyaluronic acid and set it aside at room temperature;

[0039] (2) Mixing of hesperetin solution

[0040] Weigh different masses of hesperetin solid powder and dissolve it in DMSO (dimethyl sulfoxide) to obtain hesperetin solutions with different concentrations, and then use a pipette to aspirate 400 μL of the hesperetin solution; add the hesperetin solution to a new test tube containing 2 mL of hyaluronic acid solution for a common reaction;

[0041] (3) Addition and reaction of cross-linking agent

[0042] Weigh and add 40 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 24 g of N-hydroxysuccinimide (NHS) powder to the test tube in sequence, and ensure that they are mixed evenly with each other; add 200 μL of deionized water to the mixture, and continue magnetic stirring at a speed of 1000 rpm at room temperature to ensure the full reaction of EDC and NHS with hyaluronic acid and hesperetin;

[0043] (4) Cryopreservation

[0044] After the stirring is completed, invert the test tube and place it in a 4 °C environment for cryopreservation for different times. This step helps the formation and stabilization of the hydrogel; after the freezing is completed, take out the gel preparation from the 4 °C refrigerator and observe that the gel morphology should be semi-fluid and have a strong adhesion force.

[0045] Among them, six comparison groups with final working concentrations of 0 μM, 10 μM, 20 μM, 40 μM, 80 μM, and 160 μM of the hesperetin solution were set, and freezing times of 24 h, 48 h, and 72 h were set respectively for live-dead cell double staining and CCK-8 biocompatibility detection.

[0046] Steps for live-dead cell double staining: Using the transwell co-culture mode, first spread 100 μL of the gel preparation on the upper chamber of a 24-well plate, and then inoculate L929 cells (at a concentration of 1×10 5 / well) into the lower chamber. Finally, place the upper and lower chambers together in a 37 °C cell culture incubator for co-culture for 24 h. The L929 cells in the lower chamber are stained with a live / dead cell double staining reagent, and observed and photographed under a fluorescence microscope. Live cells show green fluorescence and dead cells show red fluorescence.

[0047] CCK-8 detection steps: Using the transwell co-culture model, first spread 100 μL of the gel preparation on the upper chamber of a 24-well plate, and then inoculate L929 cells (at a concentration of 1×10 5 / well) into the lower chamber. Finally, place the upper and lower chambers together in a 37 °C cell incubator for co-culture for 24 h. Then, add 10% CCK-8 solution to the L929 cells in the lower chamber. After incubation for 2 h, observe the absorbance value at 450 nm using a microplate reader.

[0048] Live / dead cell double staining ( Figure 2 ) and CCK-8 biocompatibility ( Figure 3 ) experimental results show that when the concentration of hesperetin is 40 μM and the freezing time is 24 h, the activity is the best.

[0049] Also, take some of the hesperetin gel reagents prepared from the above-mentioned preferred comparison groups for biocompatibility testing. Attach the entire pig large intestine mucosa with the hesperetin gel reagent to a slide, and slowly drip water into a paper cup until the hesperetin gel reagent peels off. Use the mass of the water dripped into the paper cup to measure the peeling force between the oral ulcer gel and the intestinal mucosa, and the gravity of the dripped water is used as the biocompatibility force of the oral ulcer gel of the present invention. Specifically as follows:

[0050] Use fresh and clean pig large intestine mucosa soaked in artificial simulated saliva (2.38 g of Na2HPO4, 0.19 g of KH2PO4, 0.8 g of NaCl dissolved in 1000 mL of water) to simulate the oral mucosa. Cut a sufficient amount of pig large intestine mucosa, take a 50 mm diameter pig large intestine mucosa and paste it and fix it between the first slide and the second slide, keeping the surface flat. Place the 0.3 g experimental sample of the hesperetin gel reagent to be tested on the slide, moisten it slightly with water to make the pig large intestine mucosa in close contact with the experimental sample of the hesperetin gel reagent, and apply an external force of 200 g for 3 min at the same time; use a water dripping device to drip water into the paper cup, adjust the infusion flow rate of the water dripped into the paper cup to 120 drops per minute until the hesperetin gel reagent and the intestinal mucosa fall off. Weigh the mass of the water dripped into the paper cup. The gravity of the dripped water is the total peeling force of the experimental sample of the hesperetin gel reagent, that is, the biocompatibility force of the experimental sample of the hesperetin gel reagent. Compare the mass of the water dripped into the paper cup from the start to the fall-off process of each experimental sample to distinguish the biocompatibility force of the oral ulcer gel. Each oral ulcer gel experimental sample is measured 3 times and the average value is taken. The statistical results are shown in Table 1.

[0051] Table 1

[0052]

[0053] After testing, it is obtained that when the concentration of the hesperetin solution is 40 μM and the freezing time is 24 h, the activity and biocompatibility are the best.

[0054] The hesperetin gel reagent prepared under these preparation parameters was used to treat the rat oral ulcer model.

[0055] Figures 4 - 6 Among them, CN: model group (group with ulcers formed but not treated); Hes: simple hesperetin drug treatment group (hesperetin solution group); HA: simple hyaluronic acid material group; Hes / HA: hyaluronic acid-loaded hesperetin group (semi-fluid gel hesperetin product group); WF: commercial watermelon frost spray group (clinical treatment control group).

[0056] As Figure 4 shown, the Hes / HA group (purple) had the best promoting effect on the healing of rat oral ulcers. Compared with the clinical drug watermelon frost WF group (orange), there were significant statistical differences. Among them, for the detection of the ulcer area healing rate, the ulcer healing rate UHR (%) = [initial ulcer area (S0) - ulcer area after treatment (S1)] / initial ulcer area (S0) × 100%.

[0057] As Figure 5 shown, after 8 days, the results of HE staining of tissues showed that the Hes / HA group had the best treatment effect, the epithelium of the tongue tissue recovered completely, and the structure was dense; there were certain cavitation structures under the skin in the WF group, and the epithelial tissues in other groups still showed discontinuous defects.

[0058] As Figure 6 shown, after 8 days, the tissues were detected by qPCR, and the results showed that Hes / HA significantly inhibited the expression of the M1-type pro-inflammatory factors iNOS and IL-1β gene levels, and there were significant statistical differences compared with other experimental groups, indicating that hyaluronic acid-loaded hesperetin (Hes / HA) had a significant anti-inflammatory effect.

[0059] Example 2

[0060] A preparation method of a hesperetin double-layer gel patch for treating oral ulcers:

[0061] S1. Dissolve hesperetin powder in DMSO to obtain a hesperetin solution with a concentration of 40 μM.

[0062] S2. Preparation of the first contact layer solution

[0063] Take 2 mL of the hesperetin solution prepared in step S1, 0.3 g of methacrylated hyaluronic acid, 0.1 g of Irgacure 2959, and dissolve them in 15 ml of deionized water. Stir overnight at 50 - 60 °C to obtain the first contact layer solution for standby.

[0064] S3. Preparation of the second reinforcement layer solution

[0065] Take 1 mL of the hesperetin solution prepared in step S1, 0.8 g of methacrylated hyaluronic acid, 0.4 g of Irgacure 2959, and 0.8 g of dexamethasone acetate, dissolve them in 30 ml of deionized water, stir overnight at 50 - 60 °C, then add 0.2 g of calcium chloride, and continue to stir evenly to obtain the second reinforcing layer solution for standby;

[0066] S4. Inject the first contact layer solution and the second reinforcing layer solution into the mold respectively, crosslink them into a gel under ultraviolet light irradiation, and take out the samples after gel formation to obtain the hesperetin double-layer gel patch, the contact layer single-layer gel patch, and the reinforcing layer single-layer gel patch respectively.

[0067] Example 3

[0068] A preparation method of a hesperetin double-layer gel patch for treating oral ulcers:

[0069] S1. Dissolve hesperetin powder in DMSO to obtain a hesperetin solution with a concentration of 40 μM,

[0070] S2. Preparation of the first contact layer solution

[0071] Take 2 mL of the hesperetin solution prepared in step S1, 0.4 g of methacrylated hyaluronic acid, and 0.2 g of Irgacure 2959, dissolve them in 15 ml of deionized water, stir overnight at 50 - 60 °C to obtain the first contact layer solution for standby;

[0072] S3. Preparation of the second reinforcing layer solution

[0073] Take 1 mL of the hesperetin solution prepared in step S1, 0.6 g of methacrylated hyaluronic acid, 0.2 g of N-vinylcaprolactam, 0.4 g of Irgacure 2959, 0.2 g of triethanolamine, and 0.8 g of dexamethasone acetate, dissolve them in 30 ml of deionized water, stir overnight at 50 - 60 °C, then add 0.2 g of calcium chloride, and continue to stir evenly to obtain the second reinforcing layer solution for standby;

[0074] S3. Inject the first contact layer solution and the second reinforcing layer solution into the mold respectively, crosslink them into a gel under ultraviolet light irradiation, and take out the samples after gel formation to obtain the hesperetin double-layer gel patch, the contact layer single-layer gel patch, and the reinforcing layer single-layer gel patch respectively.

[0075] The hesperetin double-layer gel patches prepared in Examples 2 and 3 were subjected to biocompatibility in the same manner as in Example 1, and the results were as Figure 7 shown, and the hesperetin double-layer gel patch showed good biocompatibility.

[0076] The rheological properties of the single-layer gel patch of the contact layer and the single-layer gel patch of the reinforcement layer prepared in Example 3 were tested as follows: Using the sandblasted surface probe of a rheometer, maintaining the test temperature at 37 °C, 29 sampling points were taken to test the modulus under a constant strain of 1% and a frequency sweep mode of 0.01 - 100 Hz. Figure 8 It is the rheological modulus diagram of the single-layer gel patch of the contact layer and the single-layer gel patch of the reinforcement layer. The storage modulus G' is higher than the loss modulus G", indicating that both have a certain elasticity on the surface. The storage modulus G' of the single-layer gel patch of the reinforcement layer is relatively high, indicating its good mechanical properties. In the hesperetin bilayer gel patch of the present invention, the single-layer gel patch of the reinforcement layer can protect the single-layer gel patch of the contact layer.

[0077] The wet adhesion of the hesperetin bilayer gel patch and the single-layer gel patch of the contact layer prepared in Examples 2 and 3 was tested using the same method as in Example 1, and the results are shown in Table 2 below:

[0078] Table 2

[0079]

[0080]

[0081] The patches prepared in Example 2 and Example 3 showed good wet adhesion.

[0082] The above-disclosed are only the preferred embodiments of the present invention. Of course, the scope of the rights of the present invention cannot be limited thereby. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope covered by the present invention.

Claims

1. A hesperidin product for treating oral ulcers, characterized in that: The hesperidin product contains hesperidin, and the hesperidin product is attached to the wound surface of oral ulcer.

2. A hesperidin product for treating oral ulcers according to claim 1, characterized in that: The hesperidin gel product is a semi-fluid dynamic gel, and its preparation method comprises the following steps: S1. Adding sodium hyaluronate powder into deionized water to prepare a viscous sodium hyaluronate solution; S2, dissolving hesperidin powder in DMSO to obtain a hesperidin solution, adding the hesperidin solution to the sodium hyaluronate solution, and continuing to add EDC and NHS and stirring to react to obtain a cross-linked product; S3. The cross-linked product is frozen and stored to form a semi-fluid dynamic gel.

3. The hesperidin product for treating oral ulcers according to claim 2, characterized in that: In step S1, the mass concentration of the hyaluronic acid is 3-5%, in step S2, the concentration of the hesperetin solution is 30-50 μM, and the volume ratio of the hesperetin solution to the hyaluronic acid solution is 1:4-6.

4. The hesperidin product for treating oral ulcers according to claim 2, characterized in that: In step S1, stirring is performed at 40-60° C. to obtain a sodium hyaluronate solution.

5. The hesperidin product for treating oral ulcers according to claim 2, characterized in that: In step S2, the molar ratio of EDC to NHS is 1-1.5:

1.

6. The hesperidin product for treating oral ulcers according to claim 2, characterized in that: In step S3, freeze at 3-5°C for 24-28h.

7. The hesperidin product for treating oral ulcers according to claim 1, characterized in that: The hesperidin gel product is a double-layer gel patch, and its preparation method comprises the following steps: S1. Dissolve hesperidin powder in DMSO to obtain a hesperidin solution with a concentration of 30-50 μM. S2. Preparation of the first contact layer solution: 1-3 mL of hesperidin solution, 0.3-0.6 g of polymer, and 0.05-0.3 g of photoinitiator are dissolved in 5-20 ml of deionized water, and stirred at 50-60° C. overnight to obtain the first contact layer solution for use; S3, preparation of the second reinforcement layer solution: 0.5-2 mL of hesperidin solution, 0.6-1.2 g of polymer, 0.2-0.6 g of photoinitiator, and 0.5-1.2 g of dexamethasone acetate are dissolved in 20-50 ml of deionized water, stirred at 50-60° C. overnight, and then 0.05-0.5 g of calcium chloride is added, and stirring is continued to be uniform to obtain a second reinforcement layer solution for use; S4, injecting the first contact layer solution and the second reinforcement layer solution into the mold respectively, cross-linking into gel under the irradiation of ultraviolet light, and obtaining the hesperidin double-layer gel patch.

8. The hesperidin product for treating oral ulcers according to claim 7, characterized in that: The photoinitiator includes Irgacure 2959, and the polymer includes at least one of N-vinyl caprolactam and methacryloyl hyaluronic acid.

9. The hesperidin product for treating oral ulcers according to claim 7, characterized in that: 0.1-0.5 g of a co-initiator is also added to the deionized water in step S3, and the co-initiator includes triethanolamine.