Oral mucosa repair medicine and preparation method thereof

Abstract

The present invention relates to a repair drug for oral mucosa and a preparation method thereof, and belongs to the field of medical technology. The drug includes barnacle peptide, salivaricin, resveratrol, a biphasic adhesive matrix, hydroxyapatite, vitamin B group and other components. Gooseneck barnacles are enzymatically hydrolyzed by pepsin and lumbrokinase in sequence to obtain barnacle peptide. The biphasic adhesive matrix includes an aqueous phase matrix, an oil phase matrix and lecithin; the aqueous phase matrix contains chondroitin sulfate-chitosan quaternary ammonium salt complex and sodium alginate and other components; the oil phase matrix includes sesame oil, beeswax, polylactic acid-glycolic acid copolymer and other components. The present invention adopts a special method to prepare barnacle peptide and salivaricin, and the use of them in combination with resveratrol can achieve multi-target and multi-pathway promotion of oral mucosa repair; the chondroitin sulfate-chitosan quaternary ammonium salt complex is prepared by electrostatic and physical encapsulation, and the biphasic adhesive matrix is ​​prepared in combination with other components, which has good biocompatibility, strong adhesion, and can well prolong the action time of sustained-release drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a medicine for repairing oral mucosa and a preparation method thereof. Background Art

[0002] The oral mucosa serves as a vital barrier against external irritants, playing a critical role in maintaining oral health and normal physiological function. However, various factors can lead to damage to the oral mucosa, causing ulcers, inflammation, and other conditions. These conditions not only cause discomfort such as pain and difficulty eating, but can also affect communication and quality of life. In severe cases, they can even lead to the spread of infection, impacting overall health. Therefore, the research and development of oral mucosal repair drugs is of great importance. Trauma is a common cause of oral mucosal damage. Physical trauma, such as surgery, accidental bites, and burns, as well as chemical trauma, such as contact with corrosive substances, can damage the integrity of the oral mucosa. Furthermore, long-term wear of ill-fitting dentures can cause continuous friction and pressure on the oral mucosa, leading to traumatic ulcers. Infectious factors, such as invasion by pathogens like viruses, bacteria, and fungi, can also cause damage to the oral mucosa. For example, oral herpes, caused by the herpes simplex virus, and oral thrush, caused by Candida albicans, not only damage the mucosal tissue but also disrupt the normal microbial balance in the mouth, making repair more difficult. With the accelerating pace of life and increasing mental stress, immune-related diseases such as recurrent aphthous ulcers and pemphigus are becoming increasingly common among oral mucosal diseases. These diseases, caused by autoimmune system disorders, lead to recurrent ulcers and erosions in the oral mucosa. Traditional treatments are difficult to cure and are prone to recurring attacks, causing long-term pain for patients.

[0003] At present, commonly used oral mucosal repair drugs mainly include local pastes, patches, sprays and other dosage forms. Although these drugs can relieve symptoms to a certain extent, they still have many limitations. For example, traditional paste drugs have poor adhesion in the oral cavity and are easily washed away by saliva, making it difficult to maintain effective drug concentrations at the site of injury, affecting the repair effect; although patch drugs can adhere to the mucosa well, they have problems such as loose adhesion and strong local irritation; spray drugs are easy to use, but the drug is unevenly distributed on the mucosal surface and has a short duration of action. In addition, existing repair drugs lack the coordinated regulation of multiple complex mechanisms in the oral mucosal repair process, and it is difficult to meet the clinical demand for efficient and rapid repair of oral mucosa.

[0004] Therefore, the development of new oral mucosal repair drugs that overcome the shortcomings of existing drugs and have good biocompatibility and adhesion and can promote oral mucosal repair through multiple targets and multiple pathways has become an urgent problem to be solved in the current oral medicine field. Summary of the Invention

[0005] The existing oral mucosal repair drugs have poor adhesion, making it difficult to maintain effective drug concentrations at the site of injury, affecting the repair effect; the repair drugs lack the coordinated regulation of multiple complex mechanisms in the oral mucosal repair process, making it difficult to meet the clinical demand for efficient and rapid repair of oral mucosa. The present invention provides an oral mucosal repair drug and a preparation method thereof, wherein a special enzymatic hydrolysis method is used to prepare barnacle peptides, and a special fermentation extraction method is used to prepare salivaricin. The barnacle peptides, salivaricin and resveratrol are used in combination in a certain proportion to achieve multi-target and multi-pathway promotion of oral mucosal repair; electrostatic and physical encapsulation are used to prepare chondroitin sulfate-chitosan quaternary ammonium salt complexes, which are combined with other ingredients to prepare a biphasic adhesive matrix, which has good biocompatibility, strong adhesion, and can well prolong the action time of sustained-release drugs and improve mucosal repair performance. The specific technical scheme is as follows:

[0006] An oral mucosal repair drug is prepared from the following raw materials in parts by weight: 2 to 5 parts of barnacle peptide, 1 to 3 parts of salivaricin, 0.5 to 2 parts of resveratrol, 70 to 85 parts of a biphasic adhesive matrix, 5 to 10 parts of hydroxyapatite, 0.5 to 3 parts of B vitamins, and the balance is deionized water, with a water content of 4 to 8% by weight.

[0007] The barnacle peptide contains a product with a range of 1kDa to 3kDa obtained by enzymatic hydrolysis of gooseneck barnacle soft matter with pepsin and lumbrokinase in sequence;

[0008] The mass ratio of the components of the biphasic adhesion matrix is: aqueous matrix: oil matrix: lecithin = (7-8): (4-5): (0.3-0.5); the mass ratio of the components of the aqueous matrix is: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate = (1-1.5): (18-22): (0.5-0.8); the mass ratio of the components of the oil matrix is: sesame oil: beeswax: polylactic acid-glycolic acid copolymer: dimethicone = (90-100): (3-5): (8-10): (0.3-0.6);

[0009] The composite mass ratio of chondroitin sulfate to chitosan quaternary ammonium salt in the chondroitin sulfate-chitosan quaternary ammonium salt complex is (1.5-2.0): (0.18-0.25).

[0010] Among the above-mentioned drugs, the preparation method of barnacle peptide includes: crushing the gooseneck barnacle soft body to obtain a crushed material, adding a hydrochloric acid aqueous solution, adding 1% to 2% of the weight of pepsin of the crushed material, enzymatically hydrolyzing at 35°C to 40°C for 1h to 2h, adjusting the pH to 7 to 8, adding 1.5% to 3% of the weight of lumbrokinase of the crushed material, enzymatically hydrolyzing at 35°C to 40°C for 1.5h to 2h, inactivating the enzyme, centrifuging to obtain the supernatant, ultrafiltration using an ultrafiltration membrane to obtain a retentate between 1kDa and 3kDa, and freeze-drying to obtain barnacle peptide.

[0011] In the above-mentioned preparation method of barnacle peptide, the amount of hydrochloric acid aqueous solution is 8 to 10 times the amount of the crushed substance; the pH value of the hydrochloric acid aqueous solution is 1.5 to 2.5; the enzyme is inactivated at 85°C to 90°C for 10 to 15 minutes; and the centrifugation is performed at 4000 r / min to 5000 r / min for 10 to 15 minutes.

[0012] In the above-mentioned drug, the preparation method of salivaricin includes: adding 2wt% to 3wt% of activated salivaricin, 1wt% to 1.5wt% of celery juice, 0.5wt% to 1wt% of bitter melon juice and 0.1wt% to 0.2wt% of glucose oxidase to MRS culture medium, anaerobic culturing at 36°C to 38°C for 48h to 72h to obtain a bacterial liquid, centrifuging at 6000r / min to 8000r / min for 15min to 20min, collecting the supernatant, adding 50wt% to 60wt% ammonium sulfate by weight of the supernatant, standing at 4°C to 6°C for 12h to 18h to precipitate the lactobacillus, centrifuging at 8000r / min to 10000r / min for 20min to 30min, collecting the precipitate, dialyzing it in flowing deionized water for 12h to 24h using a dialysis bag with a molecular weight cutoff of 1kDa, and freeze-drying to obtain salivaricin.

[0013] In the above-mentioned drug, the preparation method of the chondroitin sulfate-chitosan quaternary ammonium salt complex comprises: by weight: dissolving 1.5 to 2.0 parts of chondroitin sulfate in 80 to 100 parts of phosphate buffer at pH 5.3 to 5.6 to form solution A; dissolving 0.18 to 0.25 parts of chitosan quaternary ammonium salt in 50 to 60 parts of phosphate buffer at pH 5.3 to 5.6, and then adding 0.5 to 1.0 parts of polyethylene glycol and 0.3 to 0.5 parts of chloride sodium, and stirred evenly to form solution B; while stirring, solution B was added dropwise into solution A; after the addition was completed, stirring was continued to react, and electrostatic bonding occurred fully to obtain a reaction solution, which was allowed to stand at a low temperature to promote molecular chain contraction and entanglement, thereby physically embedding the electrostatically bonded chitosan quaternary ammonium salt molecules in the chondroitin sulfate network structure; dialyzing was carried out in flowing deionized water for 12 h to 24 h using a dialysis bag with a molecular weight cut-off of 1 kDa, and freeze-drying was performed to obtain a chondroitin sulfate-chitosan quaternary ammonium salt complex.

[0014] In the preparation method of the above-mentioned chondroitin sulfate-chitosan quaternary ammonium salt complex, the stirring speed is 200r / min~250r / min; the dropping speed is 1mL / min~2mL / min; the reaction time is 1h~1.5h; and the low-temperature standing is 2h~3h at a low temperature of 4℃~6℃.

[0015] In the above-mentioned medicines, the B vitamins are a mixture of VB1, VB2, VB6 and VB12.

[0016] The preparation method of the above-mentioned oral mucosal repair medicine comprises the following steps:

[0017] S1: Prepare the aqueous matrix by homogenizing the following mass ratios: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate: deionized water = (1-1.5): (18-22): (0.5-0.8): (80-90);

[0018] S2: According to the mass ratio of sesame oil: beeswax: polylactic acid-glycolic acid copolymer: dimethicone = (90-100): (3-5): (8-10): (0.3-0.6), beeswax is dissolved in sesame oil to obtain beeswax-modified sesame oil, and then polylactic acid-glycolic acid copolymer and dimethicone are added, and ultrasonic emulsification is performed to obtain an oil phase matrix;

[0019] S3: Compounding is performed according to the mass ratio of aqueous matrix: oil matrix: lecithin = (7-8): (4-5): (0.3-0.5) to prepare a biphasic adhesion matrix;

[0020] S4: Add barnacle peptide, salivaricin, resveratrol, and B vitamins to the biphasic adhesive matrix according to their mass proportions, mix well, and finally add hydroxyapatite, mix well, and evaporate to obtain a viscous drug.

[0021] In S2 of the above-mentioned drug preparation method, the temperature of ultrasonic emulsification is 55° C. to 65° C., the power of ultrasonic emulsification is 300W to 350W, and the frequency of ultrasonic emulsification is 30kHz to 40kHz.

[0022] In S3 of the above-mentioned drug preparation method, the compounding is carried out by stirring uniformly at 300 r / min to 500 r / min.

[0023] In S4 of the above-mentioned drug preparation method, the evaporation is performed at 40° C. to 50° C. under negative pressure until the water content reaches 4 wt % to 8 wt %.

[0024] The present invention provides an oral mucosal repair drug and a preparation method thereof, which have the following beneficial effects:

[0025] 1. To prepare barnacle peptides, pepsin initially hydrolyzes proteins from the gooseneck barnacle soft tissue under acidic conditions, breaking them down into specific peptide fragments. Lumbrokinase then further hydrolyzes them under neutral conditions to yield small molecule peptides with specific efficacy. During the cell repair process, these peptides activate relevant signaling pathways within the cell, promote the expression of genes associated with cell proliferation, accelerate the cell cycle, and thus promote cell proliferation. Furthermore, these peptides possess antioxidant and antibacterial activities. Barnacle peptides possess excellent biocompatibility, can promote the proliferation and repair of oral mucosal cells, and participate in various physiological mechanisms involved in oral mucosal repair.

[0026] Second, during the preparation of Lactobacillus salivarius, celery juice and bitter melon juice provide additional nutrients and growth factors to Lactobacillus salivarius, promoting its growth and production while also imparting some additional biological activity to Lactobacillus salivarius. Glucose oxidase helps maintain the redox state in the culture medium, promoting Lactobacillus salivarius' metabolic activity and increasing Lactobacillus salivarius production. Lactobacillus salivarius can modulate cellular immune responses, inhibit inflammatory reactions, reduce inflammatory damage to cells, and create a favorable environment for cell repair. Lactobacillus salivarius has antibacterial properties, inhibiting harmful microorganisms in the mouth, maintaining oral microbial balance, reducing infection, and promoting the repair of the oral mucosa.

[0027] In the preparation of the biphasic adhesive matrix, the chondroitin sulfate-chitosan quaternary ammonium salt complex exhibits excellent biocompatibility and adhesion, interacting with biomolecules on the oral mucosal surface to achieve strong drug adhesion. Poloxamer 407 modifies the matrix's rheological properties, rendering it liquid at room temperature for easy mixing and application, and transforming into a gel at body temperature, which facilitates drug retention on the oral mucosal surface. Sodium alginate increases the matrix's viscosity and stability, helping to form a uniform matrix structure and improving drug adhesion and sustained-release properties. Beeswax, dissolved in sesame oil to form beeswax-modified sesame oil, serves as the primary component of the oil phase and provides a hydrophobic environment, facilitating sustained-release and protecting the drug ingredients. Poly(lactic-co-glycolic acid) copolymer exhibits excellent biodegradability and biocompatibility, modulating the physical properties of the oil phase matrix, controlling the drug release rate, and helping to enhance the cohesiveness of the biphasic adhesive matrix. Simethicone reduces the surface tension of the oil phase matrix, enabling better mixing with the aqueous phase matrix and promoting uniform drug distribution on the oral mucosal surface. Lecithin acts as an emulsifier, promoting the emulsification of the aqueous and oily matrixes, forming a stable biphasic structure and enhancing the matrix's stability and adhesion. The biphasic adhesive matrix, formulated with the various components in a specific ratio, exhibits excellent biocompatibility and adhesion, forming a stable drug carrier on the oral mucosal surface, enabling slow drug release and prolonging its action at the site of injury.

[0028] In the preparation of the chondroitin sulfate-chitosan quaternary ammonium salt complex, chondroitin sulfate is hydrophilic and bioactive, and can form a complex with chitosan quaternary ammonium salt through electrostatic bonding, providing the complex with good biocompatibility and bioactivity. Chitosan quaternary ammonium salt has antibacterial and cationic properties, and can electrostatically bond with the anionic groups of chondroitin sulfate, while also improving the adhesion and antibacterial properties of the complex. Polyethylene glycol increases the viscosity of the solution, facilitating intermolecular interactions and increasing the entanglement and flexibility of the molecular chains. Sodium chloride adjusts the ionic strength of the solution, promoting electrostatic bonding and allowing the complex to form a tighter network structure. The chondroitin sulfate-chitosan quaternary ammonium salt complex combines the advantages of chondroitin sulfate and chitosan quaternary ammonium salt, possessing good biocompatibility, adhesion, and antibacterial properties. It can play a variety of roles in oral mucosal repair, including promoting cell adhesion and proliferation and inhibiting bacterial growth.

[0029] 5. Resveratrol: It has anti-inflammatory and antioxidant properties, reducing inflammation in the oral mucosa, protecting oral mucosal cells from oxidative damage, and promoting oral mucosal repair. Hydroxyapatite enhances the mechanical properties of the drug while promoting the attachment and growth of oral mucosal cells, contributing to the repair process. B vitamins: They participate in cellular metabolism, promoting the growth and repair of oral mucosal cells, and maintaining the normal physiological functions of the oral mucosa. DETAILED DESCRIPTION

[0030] The present invention will be further described below with reference to specific implementation cases, but the present invention is not limited to these embodiments.

[0031] Example 1: A drug for repairing oral mucosa is prepared from the following raw materials in parts by mass: 2 parts of barnacle peptide, 1 part of salivaricin, 0.5 part of resveratrol, 70 parts of a biphasic adhesive matrix, 5 parts of hydroxyapatite, 0.5 part of B vitamins, and the balance is deionized water with a water content of 4wt%; the B vitamins are a mixture of VB1, VB2, VB6, and VB12 in equal mass ratios.

[0032] Among them, the preparation method of barnacle peptide includes: crushing the gooseneck barnacle soft body to obtain a crushed material, adding a pH1.5 hydrochloric acid aqueous solution 8 times the mass of the crushed material, adding 1% of the mass of pepsin to the crushed material, enzymatically hydrolyzing at 35°C for 1 hour, adjusting the pH to 7, adding 1.5% of the mass of lumbrokinase to the crushed material, enzymatically hydrolyzing at 35°C for 1.5 hours, inactivating the enzyme at 85°C for 10 minutes, centrifuging at 4000r / min for 10 minutes, taking the supernatant, ultrafiltration using an ultrafiltration membrane to obtain a retentate between 1kDa and 3kDa, freeze-drying, and obtaining barnacle peptide.

[0033] The preparation method of salivaricin includes: adding 2wt% activated salivaricin, 1wt% celery juice, 0.5wt% bitter melon juice and 0.1wt% glucose oxidase to MRS culture medium, anaerobic culturing at 36°C for 48 hours to obtain a bacterial liquid, centrifuging at 6000r / min for 15 minutes, collecting the supernatant, adding 50wt% ammonium sulfate by mass of the supernatant, standing at 4°C for 12 hours to precipitate the bacteria, centrifuging at 8000r / min for 20 minutes, collecting the precipitate, dialyzing in flowing deionized water for 12 hours using a dialysis bag with a molecular weight cutoff of 1kDa, and freeze-drying to obtain salivaricin.

[0034] The preparation method of the above-mentioned oral mucosal repair medicine comprises the following steps:

[0035] S1: Prepare the aqueous matrix by homogenizing the following mass ratios: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate: deionized water = 1:18:0.5:80;

[0036] S2: Beeswax was dissolved in sesame oil to obtain beeswax-modified sesame oil in a mass ratio of sesame oil: beeswax: poly(lactic acid-co-glycolic acid) copolymer: dimethicone = 90:3:8:0.3. Poly(lactic acid-co-glycolic acid) copolymer and dimethicone were then added and ultrasonic emulsification was performed at 55°C, 300W, and 30kHz to obtain an oily matrix.

[0037] S3: According to the mass ratio of aqueous matrix: oil matrix: lecithin = 7:4:0.3, stir at 300 r / min to mix evenly to prepare a dual-phase adhesive matrix;

[0038] S4: Add barnacle peptide, salivaricin, resveratrol, and B vitamins to the biphasic adhesive matrix according to their mass fractions, mix them evenly, and finally add hydroxyapatite, mix them evenly, and evaporate them at 40°C under negative pressure to a water content of 4wt% to obtain a viscous drug.

[0039] The composite mass ratio of chondroitin sulfate to chitosan quaternary ammonium salt in the chondroitin sulfate-chitosan quaternary ammonium salt complex is 1.5:0.18; the preparation method comprises: dissolving 1.5 parts of chondroitin sulfate in 80 parts of pH 5.3 phosphate buffer to form solution A; dissolving 0.18 parts of chitosan quaternary ammonium salt in 50 parts of pH 5.3 phosphate buffer, then adding 0.5 parts of polyethylene glycol and 0.3 parts of sodium chloride, stirring at 200 r / min, to form solution B; Under stirring at 0 r / min, solution B was added dropwise to solution A at a speed of 1 mL / min. After the addition was completed, the stirring was continued at 200 r / min for 1 hour to allow sufficient electrostatic bonding to occur, thereby obtaining a reaction solution. The reaction solution was allowed to stand at a low temperature of 4°C for 2 hours to promote molecular chain contraction and entanglement, thereby physically embedding the electrostatically bonded chitosan quaternary ammonium salt molecules in the chondroitin sulfate network structure. A dialysis bag with a molecular weight cutoff of 1 kDa was used for dialysis in flowing deionized water for 12 hours, and the solution was freeze-dried to obtain a chondroitin sulfate-chitosan quaternary ammonium salt complex.

[0040] Example 2: A drug for repairing oral mucosa is made from the following raw materials in parts by mass: 3 parts of barnacle peptide, 2 parts of salivaricin, 1.2 parts of resveratrol, 78 parts of biphasic adhesive matrix, 7.5 parts of hydroxyapatite, 1.5 parts of B vitamins, and the balance is deionized water with a water content of 5wt%; the B vitamins are a mixture of VB1, VB2, VB6 and VB12 in a mass ratio of 1:1:2:2.

[0041] Among them, the preparation method of barnacle peptide includes: crushing the gooseneck barnacle soft body to obtain a crushed material, adding a pH2 hydrochloric acid aqueous solution 9 times the mass of the crushed material, adding pepsin 1.5% of the mass of the crushed material, enzymatically hydrolyzing at 37°C for 1.5 hours, adjusting the pH to 7.5, adding 2% of the mass of the crushed material, enzymatically hydrolyzing at 37°C for 1.5 hours, inactivating the enzyme at 88°C for 12 minutes, centrifuging at 4500r / min for 12 minutes, taking the supernatant, ultrafiltration using an ultrafiltration membrane to obtain a retentate between 1kDa and 3kDa, freeze-drying, and obtaining barnacle peptide.

[0042] The preparation method of salivaricin includes: adding 2.5wt% activated salivaricin, 1.2wt% celery juice, 0.8wt% bitter melon juice and 0.15wt% glucose oxidase to MRS culture medium, anaerobic culturing at 37°C for 60h to obtain a bacterial solution, centrifuging at 7000r / min for 18min, collecting the supernatant, adding 55wt% ammonium sulfate by weight of the supernatant, standing at 5°C for 15h to precipitate the bacteria, centrifuging at 9000r / min for 25min, collecting the precipitate, dialyzing in flowing deionized water for 18h using a dialysis bag with a molecular weight cutoff of 1kDa, and freeze-drying to obtain salivaricin.

[0043] The preparation method of the above-mentioned oral mucosal repair medicine comprises the following steps:

[0044] S1: Prepare the aqueous matrix by homogenizing the following mass ratios: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate: deionized water = 1.2:20:0.7:85;

[0045] S2: Beeswax was dissolved in sesame oil to obtain beeswax-modified sesame oil in a mass ratio of sesame oil: beeswax: poly(lactic acid-co-glycolic acid) copolymer: dimethicone = 95:4:9:0.5. Poly(lactic acid-co-glycolic acid) copolymer and dimethicone were then added and ultrasonic emulsification was performed at 60°C, 350W, and 30kHz to obtain an oily matrix.

[0046] S3: According to the mass ratio of aqueous matrix: oil matrix: lecithin = 7.5:4.5:0.4, stir at 400 r / min to mix evenly to prepare a biphasic adhesive matrix;

[0047] S4: Add barnacle peptide, salivaricin, resveratrol, and B vitamins to the biphasic adhesive matrix according to their mass fractions, mix them evenly, and finally add hydroxyapatite, mix them evenly, and evaporate them at 45°C under negative pressure to a water content of 5wt% to obtain a viscous drug.

[0048] The composite mass ratio of chondroitin sulfate to chitosan quaternary ammonium salt in the chondroitin sulfate-chitosan quaternary ammonium salt complex is 1.7:0.21; the preparation method comprises: dissolving 1.7 parts of chondroitin sulfate in 90 parts of phosphate buffer at pH 5.5 to form solution A; dissolving 0.21 parts of chitosan quaternary ammonium salt in 55 parts of phosphate buffer at pH 5.5, then adding 0.8 parts of polyethylene glycol and 0.4 parts of sodium chloride, stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B; stirring at 250r / min to form solution B. / min, solution B was added dropwise to solution A at a rate of 1.5 mL / min. After the addition was completed, the stirring was continued at 250 r / min for 1 h to fully cause electrostatic bonding to obtain a reaction solution, which was allowed to stand at a low temperature of 5°C for 2.5 h to promote the contraction and entanglement of the molecular chains, thereby physically embedding the electrostatically bonded chitosan quaternary ammonium salt molecules in the chondroitin sulfate network structure; a dialysis bag with a molecular weight cutoff of 1 kDa was used for dialysis in flowing deionized water for 18 h, and the solution was freeze-dried to obtain a chondroitin sulfate-chitosan quaternary ammonium salt complex.

[0049] Example 3: A drug for repairing oral mucosa is made from the following raw materials in parts by mass: 5 parts of barnacle peptide, 3 parts of salivaricin, 2 parts of resveratrol, 85 parts of biphasic adhesive matrix, 10 parts of hydroxyapatite, 3 parts of B vitamins, and the balance is deionized water with a water content of 8wt%; the B vitamins are a mixture of VB1, VB2, VB6 and VB12 in a mass ratio of 1:3:1:2.

[0050] Among them, the preparation method of barnacle peptide includes: crushing the gooseneck barnacle soft body to obtain a crushed material, adding a pH2.5 hydrochloric acid aqueous solution 10 times the mass of the crushed material, adding 2% of the mass of pepsin to the crushed material, enzymatically hydrolyzing at 40°C for 2 hours, adjusting the pH to 8, adding 3% of the mass of lumbrokinase to the crushed material, enzymatically hydrolyzing at 40°C for 2 hours, inactivating the enzyme at 90°C for 15 minutes, centrifuging at 5000r / min for 15 minutes, taking the supernatant, ultrafiltration using an ultrafiltration membrane to obtain a retentate between 1kDa and 3kDa, freeze-drying, and obtaining barnacle peptide.

[0051] The preparation method of salivaricin includes: adding 3wt% activated salivaricin, 1.5wt% celery juice, 1wt% bitter melon juice and 0.2wt% glucose oxidase to MRS culture medium, anaerobic culturing at 38°C for 72h to obtain a bacterial liquid, centrifuging at 8000r / min for 20min, collecting the supernatant, adding 60wt% ammonium sulfate by mass of the supernatant, standing at 6°C for 18h to precipitate the lactobacillus, centrifuging at 10000r / min for 30min, collecting the precipitate, dialyzing in flowing deionized water for 24h using a dialysis bag with a molecular weight cutoff of 1kDa, and freeze-drying to obtain salivaricin.

[0052] The preparation method of the above-mentioned oral mucosal repair medicine comprises the following steps:

[0053] S1: Prepare the aqueous matrix by homogenizing the following mass ratios: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate: deionized water = 1.5:22:0.8:90;

[0054] S2: Beeswax was dissolved in sesame oil in a mass ratio of sesame oil: beeswax: poly(lactic acid-co-glycolic acid): dimethicone = 100:5:10:0.6 to obtain beeswax-modified sesame oil. Poly(lactic acid-co-glycolic acid) and dimethicone were then added and ultrasonic emulsification was performed at 65°C, 350W, and 40kHz to obtain an oily matrix.

[0055] S3: According to the mass ratio of aqueous matrix: oil matrix: lecithin = 8:5:0.5, stir at 500 r / min to mix evenly to prepare a dual-phase adhesive matrix;

[0056] S4: Add barnacle peptide, salivaricin, resveratrol, and vitamin B complex into the biphasic adhesive matrix according to their mass fractions, mix well, and finally add hydroxyapatite, mix well, and evaporate under negative pressure at 50°C to a water content of 8wt% to obtain a viscous drug.

[0057] The composite mass ratio of chondroitin sulfate to chitosan quaternary ammonium salt in the chondroitin sulfate-chitosan quaternary ammonium salt complex is 2.0:0.25; the preparation method comprises: dissolving 2.0 parts of chondroitin sulfate in 100 parts of pH 5.6 phosphate buffer to form solution A; dissolving 0.25 parts of chitosan quaternary ammonium salt in 60 parts of pH 5.6 phosphate buffer, then adding 1.0 parts of polyethylene glycol and 0.5 parts of sodium chloride, stirring at 250r / min to form solution B; Under stirring at 0 r / min, solution B was added dropwise to solution A at a speed of 2 mL / min. After the addition was completed, the stirring was continued at 250 r / min for 1.5 h to allow sufficient electrostatic binding to occur, thereby obtaining a reaction solution. The reaction solution was allowed to stand at a low temperature of 6°C for 3 h to promote molecular chain contraction and entanglement, thereby physically embedding the electrostatically bound chitosan quaternary ammonium salt molecules in the chondroitin sulfate network structure. A dialysis bag with a molecular weight cutoff of 1 kDa was used for dialysis in flowing deionized water for 24 h, and the solution was freeze-dried to obtain a chondroitin sulfate-chitosan quaternary ammonium salt complex.

[0058] Sources of raw materials in the above examples: The enzymatic activity of pepsin is 1000 NFu / mg, from Shaanxi Guanchen Biotechnology Co., Ltd. The enzymatic activity of lumbrokinase is 20,000 IU / mg, from Lanli Biotechnology (Xi'an) Co., Ltd. The bacterial activity of Lactobacillus salivarius is 10 billion CFU / g, from Xi'an Miaoguo Biotechnology Co., Ltd. The enzymatic activity of glucose oxidase is U / g, from Zhejiang Fuxuan Biotechnology Co., Ltd. The purity of resveratrol is 98%, from Shanxi Qixin Biotechnology Co., Ltd. The particle size of hydroxyapatite is less than 80 μm, from Lanli Biotechnology (Xi'an) Co., Ltd. Chondroitin sulfate is derived from shark bone, from Shaanxi Taike Biotechnology Co., Ltd. Chitosan quaternary ammonium salt is hydroxypropyltrimethylammonium chloride chitosan, with a purity of 99%, from Xi'an Hols Peptide Bioengineering Co., Ltd. Polyethylene glycol is pharmaceutical grade polyethylene glycol 6000, from Guangzhou Cancheng Chemical Technology Co., Ltd. Poloxamer 407 is pharmaceutical grade imported from BASF, from Shaanxi Zhengyi Pharmaceutical Excipients Co., Ltd. Sodium alginate is food grade, from Fujian Rongsen Biotechnology Co., Ltd. Beeswax is pharmaceutical grade, melting point 60°C, from Shanghai Gaoming Chemical Co., Ltd. Poly(lactic-co-glycolic acid) copolymer is pharmaceutical grade, model PLG50-04, from Wuhan Kemik Biopharmaceutical Technology Co., Ltd. Dimethicone is pharmaceutical grade, model 750cs, from Shaanxi Zhengyi Pharmaceutical Excipients Co., Ltd. Lecithin is soybean lecithin, from Nanjing Yishengyuan Biotechnology Co., Ltd.

[0059] Comparative Example 1

[0060] In the preparation of barnacle peptides, lumbrokinase was not used for enzymatic hydrolysis; other parameters and methods were the same as in Example 1.

[0061] Comparative Example 2

[0062] In the preparation of barnacle peptides, lumbrokinase was replaced by papain (enzyme activity 100,000 U / g); other parameters and methods were the same as in Example 1.

[0063] Comparative Example 3

[0064] In the preparation of barnacle peptides, pepsin was not used for enzymatic hydrolysis; other parameters and methods were the same as in Example 1.

[0065] Comparative Example 4

[0066] In the preparation of barnacle peptides, pepsin was replaced by trypsin (enzyme activity 4000 U / g), and pH 1.5 hydrochloric acid aqueous solution was replaced by pH 8.0 sodium hydroxide aqueous solution; other parameters and methods were the same as in Example 1.

[0067] Comparative Example 5

[0068] In the preparation of salivaricin, 1 wt % celery juice and 0.5 wt % bitter melon juice were not added; other parameters and methods were the same as in Example 1.

[0069] Comparative Example 6

[0070] The chondroitin sulfate-chitosan quaternary ammonium salt complex is directly replaced by chondroitin sulfate and chitosan quaternary ammonium salt (without electrostatic binding or embedding binding); other parameters and methods are the same as in Example 1.

[0071] Comparative Example 7

[0072] In the preparation of the chondroitin sulfate-chitosan quaternary ammonium salt complex, polyethylene glycol was not added; other parameters and methods were the same as in Example 1.

[0073] Comparative Example 8

[0074] In the preparation of the chondroitin sulfate-chitosan quaternary ammonium salt complex, polyethylene glycol and sodium chloride were not added; other parameters and methods were the same as in Example 1.

[0075] Comparative Example 9

[0076] In the preparation of the chondroitin sulfate-chitosan quaternary ammonium salt complex, low-temperature standing was not performed; other parameters and methods were the same as in Example 1.

[0077] Comparative Example 10

[0078] No chondroitin sulfate-chitosan quaternary ammonium salt complex was added to the aqueous matrix; other parameters and methods were the same as in Example 1.

[0079] Comparative Example 11

[0080] No polylactic acid-glycolic acid copolymer was added to the oil phase matrix; other parameters and methods were the same as in Example 1.

[0081] 1. Adhesion time detection

[0082] Artificial simulated saliva was prepared by dissolving 10.5g NaCl, 2.5g Na2HPO4, and 0.2g KH2PO4 in 1000mL of water. A 1.5cm diameter pig colon mucosa was used to simulate oral mucosa. After soaking in the artificial simulated saliva for 2 hours, the mucosa was fixed on a glass slide, keeping the mucosal surface flat. The repair drug (repair drugs from Examples 1 to 3 and Comparative Examples 6 to 11, respectively) was evenly applied to the mucosa to form a 1mm thick coating. The coating was allowed to stand for 3 minutes, then immersed in a beaker filled with 50mL of artificial simulated saliva in a 37°C water bath. The time it took for the repair drug to completely detach from the pig colon mucosa was recorded every 5 minutes (i.e., the adhesion time).

[0083] Table 1 Adhesion time test results (average value of 3 parallel samples)

[0084]

[0085] It can be seen from the above results that the repair drugs of Examples 1 to 3 have a good adhesion effect, wherein the chondroitin sulfate-chitosan quaternary ammonium salt complex forms a stable structure through electrostatic binding and physical embedding, chondroitin sulfate has a negative charge, and chitosan quaternary ammonium salt has a positive charge. The two are combined with each other by electrostatic attraction in a phosphate buffer of a specific pH; the addition of polyethylene glycol and sodium chloride, polyethylene glycol increases the entanglement and flexibility of the molecular chain, and sodium chloride adjusts the ionic strength, promotes the interaction between molecules, and makes the complex form a tighter network structure. Poloxamer 407 reduces the interfacial tension, allowing the matrix to spread better on the mucosal surface; sodium alginate has good film-forming properties and viscosity, and cooperates with the chondroitin sulfate-chitosan quaternary ammonium salt complex to form a continuous and firm adhesion layer on the mucosal surface, enhancing the intermolecular force and prolonging the adhesion time.

[0086] Comparative Example 6 does not perform electrostatic bonding and physical embedding of chondroitin sulfate and chitosan quaternary ammonium salt, and the two components exist in a simple mixed form. In a simulated saliva environment, due to the lack of stable binding force, they are easily dispersed under the action of water molecules and cannot form an effective adhesion network structure. Compared with the embodiment of forming a complex, its binding force with the mucosal surface is greatly weakened, and the drug will be washed off by simulated saliva in a short time, resulting in a significantly shortened adhesion time.

[0087] Comparative Example 7 Polyethylene glycol plays a role in solubilizing, thickening and promoting intermolecular entanglement in the preparation of the composite. After the absence of polyethylene glycol, the degree of entanglement between chondroitin sulfate and chitosan quaternary ammonium salt molecules is reduced, the structure of the composite becomes loose, and the stability decreases. This unstable composite is easily destroyed in the simulated saliva, resulting in the drug falling off the mucosal surface at a faster rate. Therefore, the adhesion time is shorter than that of the embodiment, but due to the presence of electrostatic binding, its adhesion performance is better than that of the simple mixed comparative example 6.

[0088] Comparative Example 8 lacks both polyethylene glycol and sodium chloride. Sodium chloride regulates ionic strength during complex preparation, affecting intermolecular electrostatic interactions and promoting complex formation. The simultaneous absence of both severely disrupts complex formation, weakening intermolecular entanglement and binding forces while preventing effective regulation and stabilization of electrostatic interactions. This results in an extremely unstable complex structure, which readily disintegrates in simulated saliva, reducing drug adhesion and resulting in a shorter duration than Comparative Example 7, which lacks only polyethylene glycol.

[0089] Comparative Example 9 The low temperature standing step is crucial for the formation of the complex. Under low temperature conditions, molecular motion slows down, which is conducive to molecular chain contraction and entanglement, so that the electrostatically bound chitosan quaternary ammonium salt molecules are better physically embedded in the chondroitin sulfate network structure to form a tighter and more stable complex. Without low temperature standing, the structure of the complex is not tight enough, and the intermolecular binding is not strong enough. Under the immersion and flushing of simulated saliva, the complex is easily loosened, and the time for the drug to fall off from the mucosal surface is advanced, resulting in a shortened adhesion time. However, due to the presence of electrostatic binding and partial molecular entanglement, its adhesion time is longer than that of Comparative Examples 6 to 8.

[0090] In Comparative Example 10, the chondroitin sulfate-chitosan quaternary ammonium salt complex in the aqueous matrix is ​​the adhesive component of the biphasic adhesive matrix. Without this complex, the adhesive properties of the aqueous matrix are essentially lost, and relying solely on poloxamer 407 and sodium alginate is unable to form an effective adhesion layer. Poloxamer 407 primarily acts to emulsify and reduce interfacial tension. While sodium alginate has a certain degree of viscosity, it lacks the synergistic effect of the complex and is unable to form a strong adhesion structure on the mucosal surface. The drug has little adhesion in simulated saliva, resulting in a shortened adhesion time.

[0091] Comparative Example 11 polylactic acid-glycolic acid copolymer is an important component of oily matrix, has good film-forming property and adhesiveness, can strengthen the stability of oily matrix and the bonding force with aqueous matrix.Do not add polylactic acid-glycolic acid copolymer, the structure and performance of oily matrix change, its stability descends, and is not tightly combined with aqueous matrix, causes the overall performance of dual-phase adhesion matrix to be affected.Though other compositions still can provide certain adhesive force, can't reach the adhesion effect of dual-phase matrix among the embodiment, the adhesion time of medicine on mucosal surface is shortened.

[0092] 2. In vitro mucosal cell repair ability test

[0093] For accurate testing, the sample of the repair drug only contains the active ingredients of barnacle peptide, salivaricin and resveratrol. The active ingredient samples of the repair drug of Examples 1 to 3 and Comparative Examples 1 to 5 were prepared respectively. Human immortalized oral keratinocytes (HOK cells) were placed in DMEM culture medium containing 10% fetal bovine serum and 1% double antibody (penicillin-streptomycin) and cultured in a 37°C, 5% CO2 incubator until the logarithmic growth phase. HOK cells with good growth were taken and digested with 0.25% trypsin, and the cell density was adjusted to 1×10 5 Cells were seeded in 24-well plates at a concentration of 1 mL / well. After 24 hours of culture and cell attachment, the culture medium was discarded, the cells were washed twice with PBS, and medium containing 1 mM H₂O₂ was added for 2 hours to establish an oxidative damage model. The H₂O₂-containing medium was discarded from the 24-well plates, the cells were washed three times with PBS, and medium containing 100 μg / mL of the repair drug sample was added at a concentration of 1 mL / well. Each well was plated in triplicate. After 24 hours of drug treatment, 20 μL of CCK-8 solution was added to each well. The cells were incubated for an additional 4 hours, and the absorbance (OD) was measured at 450 nm using a microplate reader. Cell culture supernatants were collected and centrifuged at 1200 rpm for 10 minutes. The centrifuge was then used to assay the inflammatory cytokines IL-6 and IL-8 using ELISA kits.

[0094] Table 2 In vitro mucosal cell repair ability test results (average value)

[0095]

[0096] The above results demonstrate that the repair drugs of Examples 1 to 3 possess excellent cell damage repair capabilities and promote anti-inflammatory effects. Barnacle peptides contain multiple active peptide segments. During the cell repair process, they activate relevant signaling pathways within cells, promote the expression of cell proliferation-related genes, accelerate cell cycle progression, and thus promote cell proliferation. Furthermore, they possess antioxidant activity, scavenging excess reactive oxygen species (ROS) produced by H₂O₂ in cells, reducing ROS damage to cellular DNA, proteins, and lipids, protecting cell structure and function, and improving cell survival. Salivaricin modulates cellular immune responses, inhibits inflammatory reactions, reduces inflammatory damage to cells, and creates a favorable environment for cell repair. Resveratrol activates the Nrf2 signaling pathway, upregulating the expression of antioxidant enzymes and enhancing cellular antioxidant capacity. It also inhibits the NF-κB signaling pathway and reduces the production of inflammatory factors. In the H₂O₂-induced oxidative damage model, elevated intracellular oxidative stress levels activate inflammatory signaling pathways such as NF-κB, leading to the massive synthesis and secretion of inflammatory factors such as IL-6 and IL-8. The combination of barnacle peptide, salivaricin, and resveratrol in the examples can inhibit activation of the NF-κB signaling pathway and reduce the transcription and expression of inflammatory factor genes. Barnacle peptide blocks upstream signaling by binding to related receptors; salivaricin regulates immune cell function and reduces the release of inflammatory mediators; and resveratrol inhibits the activity of IκB kinase (IKK), preventing the phosphorylation and activation of NF-κB, preventing it from entering the cell nucleus and initiating transcription of inflammatory factor genes.

[0097] In comparative example 1, lumbrokinase is not used for enzymatic hydrolysis in the preparation of barnacle peptides. Pepsin can only perform preliminary decomposition of the gooseneck barnacle soft body and cannot fully break specific peptide bonds, resulting in the inability to completely release peptide segments with repair activity. The generated barnacle peptides have low activity and cannot effectively activate the repair signal pathway in the cell. After the cells are damaged by H2O2 oxidation, their proliferation and repair capabilities are insufficient, a large number of cells die, and the number of surviving cells decreases, so the OD value decreases. At the same time, due to the lack of effective repair and anti-inflammatory active ingredients, the inflammatory signal pathway in the cell continues to be activated, NF-κB enters the cell nucleus in large quantities, and initiates the transcription of inflammatory factor genes such as IL-6 and IL-8, resulting in the secretion of large amounts of inflammatory factors, and their content is significantly increased.

[0098] Comparative Example 2: The enzymatic cleavage site and mechanism of action of papain are different from those of lumbrokinase. Its enzymatic hydrolysis of gooseneck barnacles is not as expected, and the structure and activity of the resulting barnacle peptides are changed. These abnormal barnacle peptides cannot effectively bind to the corresponding receptors or signaling molecules in the cells and cannot exert efficient pro-repair and anti-inflammatory functions. Under oxidative damage, the cells suffer more damage, the repair process is hindered, and the cell survival rate is reduced. The inflammatory response is not controlled, the cells remain in an inflammatory state, and the secretion of inflammatory factors such as IL-6 and IL-8 increases.

[0099] Comparative Example 3 does not use pepsin for enzymatic hydrolysis, and only relies on the subsequent lumbrokinase to effectively decompose the gooseneck barnacle raw material. Pepsin preliminarily hydrolyzes the protein in the raw material in an acidic environment, providing a suitable substrate structure for the further action of lumbrokinase. Without the action of pepsin, lumbrokinase is difficult to function and can hardly generate active barnacle peptides. After being oxidatively damaged by H2O2, the cells completely lose the repair support of barnacle peptides, and the cells are severely damaged. The inflammatory response is severe, the inflammatory signaling pathways in the cells are overactivated, and IL-6 and IL-8 are released in large quantities, and their content reaches a high level.

[0100] In comparative example 4, pepsin was replaced by trypsin, and the reaction pH value was changed from acidic to alkaline. After changing the reaction environment, it was impossible to perform effective preliminary decomposition of the gooseneck barnacle raw material like pepsin. At the same time, different enzymatic cleavage methods resulted in the generation of barnacle peptides that were not only small in amount, but also severely damaged in structure and activity, and could not play normal repair and anti-inflammatory functions. In this case, the cells almost lost their repair ability, and under H2O2 oxidative damage, their survival rate was extremely low, and the OD value was the lowest. The inflammatory response was completely out of control, and inflammatory factors such as IL-6 and IL-8 were synthesized and secreted in large quantities, and their content reached the highest level.

[0101] Comparative Example 5 Celery juice and bitter melon juice contain special ingredients that promote the growth and metabolism of Lactobacillus salivarius. These ingredients can regulate the metabolic pathways of Lactobacillus salivarius and promote the synthesis and secretion of Lactobacillus salivarius. Without adding celery juice and bitter melon juice, the growth of Lactobacillus salivarius is affected to a certain extent, and the output, purity, and activity of Lactobacillus salivarius are reduced, and its antibacterial and anti-inflammatory effects are weakened. Although barnacle peptides and resveratrol can still play a certain role, the repair and anti-inflammatory effects of the overall medicine decline, and the repair ability of cells after oxidative damage is not as good as in Example, and the number of surviving cells decreases, and OD value is lower. Inflammatory factor secretion increases to some extent, and IL-6 and IL-8 contents are higher than in Example but lower than Comparative Example 1 to Comparative Example 4, because there are other active ingredients that partially maintain anti-inflammatory function.

[0102] 3. Antibacterial effect detection

[0103] After activation of Staphylococcus aureus (DSM45902), Helicobacter pylori (ATCC43504), and Candida albicans (ATCC10231), the bacterial solution concentration was adjusted to 1×10 8 CFU / mL. Take 0.1mL of bacterial suspension and evenly spread it on the surface of the corresponding solid culture medium. Use a microporator to make a 6mm diameter hole in the culture medium. Pipette 20μL of the repair drug solution (the full-ingredient repair drug in Examples 1 to 3 and Comparative Examples 1 to 5 is diluted with physiological saline to a concentration of 500mg / mL) into the hole. After 48 hours of incubation in an acclimatized environment, measure the diameter of the inhibition zone. Three replicates are required for each group.

[0104] Table 3 Antibacterial effect test results (average value)

[0105]

[0106] From the above results, it can be seen that the repair drugs of Examples 1 to 3 have good antibacterial effects.

[0107] Comparative Examples 1 to 5: Mainly affect the preparation process of barnacle peptide and salivaricin, resulting in changes in active ingredients or reduced content. In Comparative Example 1, the activity of barnacle peptide was reduced due to the lack of lumbrokinase enzymatic hydrolysis; in Comparative Example 2, papain replaced lumbrokinase, resulting in abnormal structure of barnacle peptide; in Comparative Example 3, the lack of pepsin resulted in the ineffective production of barnacle peptide; in Comparative Example 4, trypsin and pH changes almost lost the activity of barnacle peptide; in Comparative Example 5, the lack of celery juice and bitter melon juice resulted in decreased production, purity, and activity of salivaricin. These changes in active ingredients weakened the inhibitory effect of the drug on pathogens. In the absence of effective inhibition, the growth of Staphylococcus aureus, Helicobacter pylori, and Candida albicans was less restricted, and the diameter of the inhibition zone was significantly smaller than that of the embodiment.

Claims

1. A repairing drug for oral mucosa, characterized in that: The drug is prepared from the following raw materials in parts by weight: 2 to 5 parts of barnacle peptide, 1 to 3 parts of salivaricin, 0.5 to 2 parts of resveratrol, 70 to 85 parts of biphasic adhesive matrix, 5 to 10 parts of hydroxyapatite, 0.5 to 3 parts of B vitamins, and the balance is deionized water, with a water content of 4wt% to 8wt%. The barnacle peptide contains a product with a size of 1 kDa to 3 kDa obtained by enzymatically hydrolyzing gooseneck barnacle soft matter with pepsin and lumbrokinase in sequence; The mass ratio of the components of the dual-phase adhesion matrix is: aqueous matrix: oil matrix: lecithin = (7-8): (4-5): (0.3-0.5); the mass ratio of the components of the aqueous matrix is: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate = (1-1.5): (18-22): (0.5-0.8); the mass ratio of the components of the oil matrix is: sesame oil: beeswax: polylactic acid-glycolic acid copolymer: dimethicone = (90-100): (3-5): (8-10): (0.3-0.6); The composite mass ratio of chondroitin sulfate to chitosan quaternary ammonium salt in the chondroitin sulfate-chitosan quaternary ammonium salt complex is (1.5-2.0): (0.18-0.25); the preparation method of the chondroitin sulfate-chitosan quaternary ammonium salt complex comprises: dissolving 1.5-2.0 parts of chondroitin sulfate in 80-100 parts of phosphate buffer with a pH of 5.3-5.6 to form solution A; dissolving 0.18-0.25 parts of chitosan quaternary ammonium salt in 50-60 parts of phosphate buffer with a pH of 5.3-5.6; and Then, 0.5 to 1.0 parts of polyethylene glycol and 0.3 to 0.5 parts of sodium chloride are added and stirred evenly to form solution B; solution B is added dropwise into solution A under stirring; after the dropwise addition is completed, stirring is continued for reaction to fully cause electrostatic bonding to obtain a reaction liquid; the reaction liquid is allowed to stand at a low temperature to promote molecular chain contraction and entanglement, and the electrostatically bonded chitosan quaternary ammonium salt molecules are physically embedded in the chondroitin sulfate network structure; a dialysis bag with a molecular weight cutoff of 1 kDa is used for dialysis in flowing deionized water for 12 to 24 hours, and the mixture is freeze-dried to obtain a chondroitin sulfate-chitosan quaternary ammonium salt complex.

2. The oral mucosa repair drug according to claim 1, characterized in that: The preparation method of the barnacle peptide includes: crushing the gooseneck barnacle soft body to obtain a crushed material, adding a hydrochloric acid aqueous solution, adding 1% to 2% of the weight of the crushed material pepsin, enzymatically hydrolyzing at 35°C to 40°C for 1 hour to 2 hours, adjusting the pH to 7 to 8, adding 1.5% to 3% of the weight of the crushed material lumbrokinase, enzymatically hydrolyzing at 35°C to 40°C for 1.5 hours to 2 hours, inactivating the enzyme, centrifuging to obtain a supernatant, ultrafiltration using an ultrafiltration membrane to obtain a retentate between 1 kDa and 3 kDa, and freeze-drying to obtain the barnacle peptide.

3. The oral mucosa repair drug according to claim 2, characterized in that: The amount of the hydrochloric acid aqueous solution is 8 to 10 times the amount of the pulverized material; the pH value of the hydrochloric acid aqueous solution is 1.5 to 2.5; the enzyme is inactivated at 85 to 90° C. for 10 to 15 minutes; and the centrifugation is performed at 4000 to 5000 r / min for 10 to 15 minutes.

4. The oral mucosa repair drug according to claim 1, characterized in that: The preparation method of salivaricin comprises the following steps: adding 2wt% to 3wt% of activated Lactobacillus salivarius, 1wt% to 1.5wt% of celery juice, 0.5wt% to 1wt% of bitter melon juice and 0.1wt% to 0.2wt% of glucose oxidase to an MRS culture medium, anaerobic culturing at 36°C to 38°C for 48h to 72h to obtain a bacterial liquid, centrifuging at 6000r / min to 8000r / min for 15min to 20min, collecting a supernatant, adding 50wt% to 60wt% of ammonium sulfate by weight of the supernatant, standing at 4°C to 6°C for 12h to 18h to precipitate the lactobacillus, centrifuging at 8000r / min to 10000r / min for 20min to 30min, collecting a precipitate, dialyzing the precipitate in flowing deionized water for 12h to 24h using a dialysis bag with a molecular weight cutoff of 1kDa, and freeze-drying to obtain salivaricin.

5. The oral mucosa repair medicine according to claim 1, characterized in that: In the preparation method of the chondroitin sulfate-chitosan quaternary ammonium salt complex, the stirring speed is 200r / min-250r / min; the dropping speed is 1mL / min-2mL / min; the reaction time is 1h-1.5h; and the low-temperature standing is 2h-3h at a low temperature of 4°C-6°C.

6. The oral mucosa repair medicine according to claim 1, characterized in that: The B vitamins are a mixture of VB1, VB2, VB6 and VB12.

7. The method for preparing the oral mucosal repair drug according to claim 1, characterized in that: The steps include: S1: Prepare the aqueous matrix by homogenizing the following mass ratios: chondroitin sulfate-chitosan quaternary ammonium salt complex: poloxamer 407: sodium alginate: deionized water = (1-1.5): (18-22): (0.5-0.8): (80-90); S2: According to the mass ratio of sesame oil: beeswax: polylactic acid-glycolic acid copolymer: dimethicone = (90-100): (3-5): (8-10): (0.3-0.6), beeswax is dissolved in sesame oil to obtain beeswax-modified sesame oil, and then polylactic acid-glycolic acid copolymer and dimethicone are added, and ultrasonic emulsification is performed to obtain an oil phase matrix; S3: Compounding is performed according to the mass ratio of aqueous matrix: oil matrix: lecithin = (7-8): (4-5): (0.3-0.5) to prepare a biphasic adhesion matrix; S4: Add barnacle peptide, salivaricin, resveratrol, and B vitamins to the biphasic adhesive matrix according to their mass proportions, mix well, and finally add hydroxyapatite, mix well, and evaporate to obtain a viscous drug.

8. The method for preparing a repairing drug for oral mucosa according to claim 7, characterized in that: In S2, the temperature of the ultrasonic emulsification is 55° C. to 65° C., the power of the ultrasonic emulsification is 300W to 350W, and the frequency of the ultrasonic emulsification is 30kHz to 40kHz.

9. The method for preparing a repairing drug for oral mucosa according to claim 7, characterized in that: In S3, the compounding is carried out by stirring uniformly at 300 r / min to 500 r / min; and in S4, the evaporation is carried out by evaporating at 40° C. to 50° C. under negative pressure to a water content of 4 wt % to 8 wt %.

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