Intelligent feedback drug delivery system for oral environment and preparation method thereof

Abstract

The invention relates to a charge reversal microcapsule based on an acidic microenvironment and a preparation method thereof. The charge reversal microcapsule is especially suitable for local drug delivery of oral inflammation. The microcapsule is formed by compounding sodium alginate (ALG) and epsilon-polylysine (PLL) through a self-assembly method, and is loaded with a drug. The outer layer of the microcapsule is coated with methacryloyl sulphobetaine (SBMA), and the surface charge of the microcapsule can be reversed along with the change of the pH of the environment. In an acidic environment, the SBMA shows positive electricity, so that the combination between the SBMA and the core of the microcapsule is weakened, and the release of the medicine is triggered. In order to further accurately control the drug release, the microcapsule is wrapped by dual-responsive gel (pH and temperature dual-response), so that the controllable release of the drug at the oral inflammation part is ensured. The microcapsule system disclosed by the invention has excellent biocompatibility and targeting property, can be used for treating local acidic microenvironment related diseases such as oral inflammation, and provides an efficient and controllable drug delivery mode.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of oral treatment, in particular to an intelligent feedback drug delivery system for antibacterial treatment in oral environment and a preparation method thereof. The system is suitable for antibacterial treatment of oral diseases such as gingivitis, periodontal disease, dental caries, etc., and can adjust drug release according to changes in the acidic environment of the oral cavity BACKGROUND

[0002] Oral inflammation (such as gingivitis, periodontitis, etc.) is usually accompanied by the formation of a local acidic environment with a pH range of 5.0-6.5. This acidic environment leads to inaccurate drug release from traditional drug delivery systems, often resulting in excessive drug release or short-lasting drug efficacy. Therefore, it is particularly important to develop an intelligent drug delivery system that can precisely regulate drug release in a specific acidic microenvironment. Although there are a variety of materials systems on the market for oral wound repair or filling, they still have certain deficiencies in actual application, especially in terms of antibacterial effect, environmental responsiveness, and long-term stability.

[0003] For example, patent CN112190770B (degradable tooth extraction wound filling composition and preparation method and application thereof) discloses a composition containing calcium stearate, alginic acid / chitosan complex, bioactive glass, tocopherol acetate, etc., for filling the wound after tooth extraction. Although this scheme can effectively provide filling and repair support for the wound, the excessive use of mineral powders may cause oral discomfort, and the biocompatibility of the material is poor. In addition, the antibacterial release and environmental responsiveness of the material have not been fully optimized, which may affect its long-term therapeutic effect. Patent CN114539361B (gel for hemostasis and promotion of new bone regeneration in alveolar fossa after tooth extraction) proposes a scheme for constructing a gel structure using L-type fiber supramolecules and calcium ion solution, focusing on hemostasis and bone regeneration functions. Although the gel can effectively promote bone regeneration, it does not design for the acidic microenvironment of the oral cavity, drug-loaded antibacterial release, and response mechanism, limiting its application in the oral environment and failing to achieve higher-order drug delivery functions.

[0004] In addition, there are also some membrane materials, gels, hydrogels, etc. carriers for oral wound repair on the market. Patent CN103007338A (temperature-sensitive hydrogel or solvent-sensitive gel) introduces a material that changes its release and adhesion by changing the temperature or solvent to change the gel form. Although this technology has certain environmental responsiveness, its antibacterial property and stability are poor, especially in complex oral environments, which can easily lead to bacterial growth or unstable treatment effect.

[0005] Patent CN105031747A (absorbable tooth extraction wound care composition) proposes a mixture of absorbable biopolymer material and mineral powder for tooth extraction wound repair. Although this composition can effectively promote the initial wound healing, but due to the excessive mineral composition, it may lead to too long setting time. In addition, the high concentration of minerals may cause oral discomfort or irritation, affecting the comfort of patients, and even interfering with the normal healing process of the surrounding tissue of the wound.

[0006] Patent CN105688288A (collagen-based composite oral repair membrane material) introduces a composite membrane material formed by collagen cross-linking modification and self-assembly, which can be used for wound repair. Although the repair film has good biocompatibility and certain repair function, its preparation process is complex and the cost is high, which limits its wide application.

[0007] Patent CN103920192A (bioactive factor-loaded temperature-sensitive composite gel carrier) proposes a composite gel carrier, which promotes bone regeneration through the synergistic effect of adiponectin, calcium ions and calcined bone powder and other bioactive factors. Although the gel has certain bioactive factor release function, it fails to optimize for the particularity of oral environment, and the main defect is the insufficient antibacterial property.

[0008] Patent CN201580084926 (oral antibacterial gel and its preparation method) introduces an oral antibacterial gel, the formula of which includes deionized water, peroxide urine and oat anti-allergic agent, which can disinfect and keep the mouth fresh. Although the gel has certain antibacterial effect, but its antibacterial property and drug release property still have great deficiencies, and with the degradation of the gel, the antibacterial effect will weaken rapidly, which is difficult to continuously and effectively inhibit the growth of bacteria in the oral cavity.

[0009] Patent CN201611254353A (hydrogel for treating pediatric oral ulcers) proposes a hydrogel for pediatric oral ulcers, which contains mussel soft tissue extract, honey and vitamin ingredients. The hydrogel can promote the healing of oral ulcers, but lacks antibacterial function and cannot effectively inhibit the growth of bacteria in the oral cavity, affecting the healing of ulcers.

[0010] Patent CN103457107A (bifunctional layer oral repair membrane) proposes a composite membrane material containing a loose porous layer and a dense antibacterial layer. The membrane can be used for the protection of oral wounds, but its effect is limited, and it fails to dynamically adjust the drug release according to the changes of oral environment.

[0011] Patent CN103007338A (Application of Temperature-Sensitive Hydrogels) proposes a hydrogel whose gel morphology can be adjusted by temperature changes, which can be used for the treatment of oral trauma. Although it has a certain degree of environmental responsiveness, it lacks long-lasting antibacterial properties and sustained drug release capabilities, and its stability in the complex oral environment is insufficient, affecting the effectiveness of practical applications.

[0012] In summary, while existing technologies have made some progress in oral wound repair and drug delivery, many problems remain unresolved, particularly in areas such as "intelligent feedback, environmental response, antibacterial release, and stable wound retention." Therefore, there is an urgent need to develop a new drug delivery system that can precisely trigger drug release in the acidic environment of oral inflammation, while also possessing higher biocompatibility and targeting capabilities. Summary of the Invention:

[0013] To address the problems existing in the prior art, the technical problem to be solved by this invention is: how to prepare a microencapsulation system (SBMA-ALG-PLL) that responds to the oral microenvironment using sodium alginate (ALG), ε-polylysine (PLL), methacrylyl sulfobetaine (SBMA), and the target drug as raw materials; and simultaneously, to rapidly prepare an in-situ adhesive, sprayable oral antibacterial dressing using CMC and N-acetylcysteine ​​(NAC) as raw materials, which ultimately encapsulates SBMA-ALG-PLL, thereby achieving controllable drug delivery in the inflammatory environment of the oral cavity.

[0014] The technical solution adopted by the present invention to solve its technical problem is as follows: The present invention provides a moist antibacterial dressing, which, by weight percentage, comprises the following components:

[0015] Water: 25wt%-75wt%

[0016] Glycerin: 10wt%-60wt%

[0017] CMC-NAC: 0.5wt%-5wt%

[0018] OCMC: 5wt%-15wt%

[0019] SBMA-ALG-PLL: 1-10wt%

[0020] Specifically, the preparation method of the acid-resistant wet adhesive dressing is as follows:

[0021] (1) Preparation of CMC-NAC

[0022] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.05M-0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.15M-0.35M EDC solution. Take N-hydroxysuccinimide (NHS) and prepare a 0.15M-0.35M solution for use with EDC. ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0023] (2) Preparation of OCMC

[0024] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0025] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0026] ① Prepare a 5-10 wt% sodium alginate solution by adding 5-10 g of sodium alginate to deionized water. Prepare a 5-10 wt% ε-polylysine solution by adding 5-10 g of ε-polylysine to deionized water. Mix the sodium alginate (ALG) solution and the ε-polylysine (PLL) solution at a volume ratio of 1:2, add the desired drug (such as an anti-inflammatory or antibacterial drug), and ensure that the drug is uniformly loaded in the composite nanoparticles by blending. The drug loading should be controlled at 10-20 wt% to ensure that the drug is uniformly distributed within the particles; ② Stir the reaction at room temperature for 0.5 h; ③ Dissolve 2-5 g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution to prepare a 2-5% SBMA solution; ④ Mix the prepared SBMA solution with the prepared positively charged ALGP-PLL nanoparticle solution at a mass ratio of 1:10 to 1:20, and stir the reaction at room temperature for 12 h.

[0027] (4) Preparation of OCMCN-SAP gel

[0028] ① Prepare 10 mL of OCMC glycerol aqueous solution with a concentration of 5-15 wt% at room temperature, where the glycerol:water (V / V) ratio is 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1-10 wt%. This solution is named Solution A. ② Prepare 10 mL of CMC-NAC glycerol aqueous solution with a concentration of 0.5-5 wt% at room temperature, where the glycerol:water (V / V) ratio is 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered. Attached image description:

[0029] Figure 1 The image shows the zeta potential data of the ALG-PLL and SBMA-ALG-PLL microcapsules prepared in Example 8 of this invention. Figure 2 SEM image (a) and optical microscope image (b) of the SBMA-ALG-PLL microcapsules prepared in Example 8 of this invention. Figure 3 A standard curve was constructed to show the UV absorption spectra corresponding to different concentrations of vancomycin hydrochloride. Figure 4 The images show the drug release of the OCMCN-SAP gel prepared in Example 8 of this invention in PBS (pH 7.0) and PBS (pH 5) environments, with 40 μg / mL of vancomycin hydrochloride added. Figure 5 The antibacterial effect (plate count method) of the OCMCN-SAP gel prepared in Example 8 of this invention in PBS (pH 7.0) and PBS (pH 5) environments is shown. Detailed implementation method:

[0030] Example 1

[0031] (1) Preparation of CMC-NAC

[0032] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.05M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.15M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.15M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0033] (2) Preparation of OCMC

[0034] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0035] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0036] Prepare a 5wt% sodium alginate solution by adding 5g of sodium alginate to deionized water. Prepare a 5wt% ε-polylysine solution by adding 5g of ε-polylysine to deionized water. Mix the sodium alginate (ALG) solution and the ε-polylysine (PLL) solution at a volume ratio of 1:2, add vancomycin hydrochloride, and ensure uniform drug loading in the composite nanoparticles by blending. The drug loading is controlled at 10-20wt% to ensure uniform drug distribution within the particles; ② Stir the reaction at room temperature for 0.5h; ③ Dissolve 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution to prepare a 2% SBMA solution; ④ Mix the prepared SBMA solution with the prepared positively charged ALGP-PLL nanoparticle solution at a mass ratio of 1:10 and stir the reaction at room temperature for 12h.

[0037] (4) Preparation of OCMCN-SAP gel

[0038] ① Prepare 10 mL of a 5 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0039] Example 2

[0040] (1) Preparation of CMC-NAC

[0041] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.1M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.25M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.25M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0042] (2) Preparation of OCMC

[0043] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0044] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0045] Prepare a 5wt% sodium alginate solution by adding 5g of sodium alginate to deionized water. Prepare a 5wt% ε-polylysine solution by adding 5g of ε-polylysine to deionized water. Mix the sodium alginate (ALG) solution and the ε-polylysine (PLL) solution at a volume ratio of 1:2, add vancomycin hydrochloride, and ensure uniform drug loading in the composite nanoparticles by blending. The drug loading is controlled at 10-20wt% to ensure uniform drug distribution within the particles; ② Stir the reaction at room temperature for 0.5h; ③ Dissolve 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution to prepare a 2% SBMA solution; ④ Mix the prepared SBMA solution with the prepared positively charged ALGP-PLL nanoparticle solution at a mass ratio of 1:10 and stir the reaction at room temperature for 12h.

[0046] (4) Preparation of OCMCN-SAP gel

[0047] ① Prepare 10 mL of a 5 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0048] Example 3

[0049] (1) Preparation of CMC-NAC

[0050] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0051] (2) Preparation of OCMC

[0052] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0053] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0054] Prepare a 5wt% sodium alginate solution by adding 5g of sodium alginate to deionized water. Prepare a 5wt% ε-polylysine solution by adding 5g of ε-polylysine to deionized water. Mix the sodium alginate (ALG) solution and the ε-polylysine (PLL) solution at a volume ratio of 1:2, add vancomycin hydrochloride, and ensure uniform drug loading in the composite nanoparticles by blending. The drug loading is controlled at 10-20wt% to ensure uniform drug distribution within the particles; ② Stir the reaction at room temperature for 0.5h; ③ Dissolve 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution to prepare a 2% SBMA solution; ④ Mix the prepared SBMA solution with the prepared positively charged ALGP-PLL nanoparticle solution at a mass ratio of 1:10 and stir the reaction at room temperature for 12h.

[0055] (4) Preparation of OCMCN-SAP gel

[0056] ① Prepare 10 mL of a 5 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0057] Example 4

[0058] (1) Preparation of CMC-NAC

[0059] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0060] (2) Preparation of OCMC

[0061] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0062] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0063] Sodium alginate (10g) was added to deionized water to prepare a 10wt% sodium alginate solution. ε-polylysine (10g) was added to deionized water to prepare a 10wt% ε-polylysine solution. Sodium alginate (ALG) solution and ε-polylysine (PLL) solution were mixed at a 1:2 volume ratio, and vancomycin hydrochloride was added. The drug was uniformly loaded into the composite nanoparticles through a blending method. The drug loading was controlled at 10-20wt% to ensure uniform distribution of the drug within the particles. The reaction was stirred at room temperature for 0.5h. A 2% SBMA solution was prepared by dissolving 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution. The prepared SBMA solution was mixed with the prepared positively charged ALGP-PLL nanoparticle solution at a 1:10 mass ratio and stirred at room temperature for 12h.

[0064] (4) Preparation of OCMCN-SAP gel

[0065] ① Prepare 10 mL of a 5 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0066] Example 5

[0067] (1) Preparation of CMC-NAC

[0068] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0069] (2) Preparation of OCMC

[0070] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0071] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0072] Sodium alginate (10g) was added to deionized water to prepare a 10wt% sodium alginate solution. ε-polylysine (10g) was added to deionized water to prepare a 10wt% ε-polylysine solution. Sodium alginate (ALG) solution and ε-polylysine (PLL) solution were mixed at a 1:2 volume ratio, and vancomycin hydrochloride was added. The drug was uniformly loaded into the composite nanoparticles through a blending method. The drug loading was controlled at 10-20wt% to ensure uniform distribution of the drug within the particles. The reaction was stirred at room temperature for 0.5h. A 2% SBMA solution was prepared by dissolving 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution. The prepared SBMA solution was mixed with the prepared positively charged ALGP-PLL nanoparticle solution at a 1:10 mass ratio and stirred at room temperature for 12h.

[0073] (4) Preparation of OCMCN-SAP gel

[0074] ① Prepare 10 mL of a 10 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 5 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0075] Example 6

[0076] (1) Preparation of CMC-NAC

[0077] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0078] (2) Preparation of OCMC

[0079] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0080] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0081] Sodium alginate (10g) was added to deionized water to prepare a 10wt% sodium alginate solution. ε-polylysine (10g) was added to deionized water to prepare a 10wt% ε-polylysine solution. Sodium alginate (ALG) solution and ε-polylysine (PLL) solution were mixed at a 1:2 volume ratio, and vancomycin hydrochloride was added. The drug was uniformly loaded into the composite nanoparticles through a blending method. The drug loading was controlled at 10-20wt% to ensure uniform distribution of the drug within the particles. The reaction was stirred at room temperature for 0.5h. A 2% SBMA solution was prepared by dissolving 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution. The prepared SBMA solution was mixed with the prepared positively charged ALGP-PLL nanoparticle solution at a 1:10 mass ratio and stirred at room temperature for 12h.

[0082] (4) Preparation of OCMCN-SAP gel

[0083] ① Prepare 10 mL of a 15 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, maintaining the SBMA-ALG-PLL concentration at 10 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0084] Example 7

[0085] (1) Preparation of CMC-NAC

[0086] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0087] (2) Preparation of OCMC

[0088] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0089] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0090] Sodium alginate (10g) was added to deionized water to prepare a 10wt% sodium alginate solution. ε-polylysine (10g) was added to deionized water to prepare a 10wt% ε-polylysine solution. Sodium alginate (ALG) solution and ε-polylysine (PLL) solution were mixed at a 1:2 volume ratio, and vancomycin hydrochloride was added. The drug was uniformly loaded into the composite nanoparticles through a blending method. The drug loading was controlled at 10-20wt% to ensure uniform distribution of the drug within the particles. The reaction was stirred at room temperature for 0.5h. A 2% SBMA solution was prepared by dissolving 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution. The prepared SBMA solution was mixed with the prepared positively charged ALGP-PLL nanoparticle solution at a 1:15 mass ratio and stirred at room temperature for 12h.

[0091] (4) Preparation of OCMCN-SAP gel

[0092] ① Prepare 10 mL of a 15 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, maintaining the SBMA-ALG-PLL concentration at 10 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0093] Example 8

[0094] (1) Preparation of CMC-NAC

[0095] ① Dissolve 2g of CMC in 100mL of PBS buffer to prepare a 2wt% CMC solution; ② Take 30mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.2M NAC solution; ③ Take 30mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.35M EDC solution, and take N-hydroxysuccinimide (NHS) to prepare a 0.35M solution for use with EDC; ④ Mix 30mL of NAC solution and 30mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1M) or NaOH (1M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC.

[0096] (2) Preparation of OCMC

[0097] ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC.

[0098] (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules

[0099] Sodium alginate (10g) was added to deionized water to prepare a 10wt% sodium alginate solution. ε-polylysine (10g) was added to deionized water to prepare a 10wt% ε-polylysine solution. Sodium alginate (ALG) solution and ε-polylysine (PLL) solution were mixed at a 1:2 volume ratio, and vancomycin hydrochloride was added. The drug was uniformly loaded into the composite nanoparticles through a blending method. The drug loading was controlled at 10-20wt% to ensure uniform distribution of the drug within the particles. The reaction was stirred at room temperature for 0.5h. A 2% SBMA solution was prepared by dissolving 2g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution. The prepared SBMA solution was mixed with the prepared positively charged ALGP-PLL nanoparticle solution at a 1:20 mass ratio and stirred at room temperature for 12h.

[0100] (4) Preparation of OCMCN-SAP gel ① Prepare 10 mL of a 15 wt% OCMC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 10 wt%. This solution is named Solution A. ② Prepare 10 mL of a 0.5-5 wt% CMC-NAC glycerol aqueous solution at room temperature, with a glycerol:water (V / V) ratio of 5:95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

[0101] \ Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 UV absorbance A (281 nm) 0.1385 0.1364 0.1343 0.1321 0.1300 0.1279 0.1257 0.1235 External phase concentration C (pg / mL) 36.00 35.44 34.86 34.28 33.72 33.16 32.56 32.00 Encapsulation efficiency EE (%) 10.0 11.4 12.9 14.3 15.7 17.1 18.6 20.0 Table 1. Encapsulation efficiency of vancomycin hydrochloride in the SBMA-ALG-PLL microcapsules prepared in Examples 1-8 of this invention.

Claims

1. A microcapsule based on charge reversal in an acidic microenvironment, characterized in that, The nanoparticles include: a core structure: a composite nanoparticle formed by electrostatic self-assembly of sodium alginate (ALG) and ε-polylysine (PLL), wherein the composite nanoparticles are loaded with a drug; and an outer coating material: methacryloxysulfobetaine (SBMA), wherein the surface zeta potential of the SBMA can be reversibly regulated from negative to positive or decrease in charge with changes in the ambient pH value. Specifically, when the ambient pH value drops to acidic conditions (pH 5.0-6.5), the charge of SBMA reverses or weakens, thereby reducing its binding with the core nanoparticles, causing the nanoparticles to become structurally loose or the outer layer to desorb, triggering the release of the drug.

2. A method for preparing the charge-reversal microcapsules according to claim 1, characterized in that, Includes the following steps: Sodium alginate (ALG) is dissolved in water to form a negatively charged solution; ε-polylysine (PLL) was dissolved in water to form a positively charged solution, which was then slowly added to the ALG solution to form composite nanoparticles by utilizing the electrostatic interaction between the two, while simultaneously loading the drug; a methacryloyl sulfobetaine (SBMA) solution was prepared and its pH was adjusted to the desired range so that the zeta potential of SBMA was adjustable; SBMA solution is mixed with nanoparticles, and an outer coating material is formed through electrostatic adsorption, hydrogen bonding, or interfacial recombination, thereby obtaining nanoparticles capable of charge reversal in an acidic environment. The specific preparation steps are as follows: (1) Preparation of CMC-NAC ① Dissolve 2g of CMC in 100mL of PBS buffer solution to prepare a 2wt% CMC solution; ② Take 30 mL of deionized water and add N-acetylcysteine ​​(NAC) to prepare a 0.05 M to 0.2 M NAC solution; ③ Take 30 mL of deionized water and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare a 0.15 M to 0.35 M EDC solution. Take N-hydroxysuccinimide (NHS) and prepare a 0.15 M to 0.35 M solution for use with EDC. ④ Mix 30 mL of NAC solution and 30 mL of EDC solution to obtain the reaction solution. Adjust the pH to 6.0 using HCl (1 M) or NaOH (1 M). Stir the reaction in the dark for 1 hour to activate the thiol groups in the NAC molecules with EDC; ⑤ Slowly add the activated NAC solution to the CMC solution. The reaction was continued for 24 hours at room temperature, pH 6.0, in the dark, to ensure that NAC was successfully grafted onto CMC molecules via amidation. After the reaction was complete, the product was purified by membrane dialysis, and the resulting product was freeze-dried and stored to obtain CMC-NAC. (2) Preparation of OCMC ① Dissolve 5.0 g of CMC in 100 mL of deionized water; ② Adjust the pH of the solution to 3.0 using 2 M sulfuric acid (H₂SO₄); ③ Add 50 mL of NaIO₄ solution (0.11 g / mL) to the CMC solution, and react the reaction mixture at room temperature in the dark for 5 hours; ④ Terminate the reaction by adding excess ethylene glycol. Purify the mixture by dialyzing in distilled water (molecular weight range: 8000-14000) for 3 days. Freeze-dry the obtained product to obtain OCMC. (3) Preparation of SBMA-ALG-PLL charge reversal microcapsules ① Prepare a 5-10 wt% sodium alginate solution by adding 5-10 g of sodium alginate to deionized water. Prepare a 5-10 wt% ε-polylysine solution by adding 5-10 g of ε-polylysine to deionized water. Mix the sodium alginate (ALG) solution and the ε-polylysine (PLL) solution at a volume ratio of 1:2, add the desired drug (such as an anti-inflammatory or antibacterial drug), and ensure that the drug is uniformly loaded in the composite nanoparticles by blending. The drug loading should be controlled at 10-20 wt% to ensure that the drug is uniformly distributed within the particles; ② Stir the reaction at room temperature for 0.5 h; ③ Dissolve 2-5 g of methacryloyl sulfobetaine (SBMA) in PBS buffer solution to prepare a 2-5% SBMA solution; ④ Mix the prepared SBMA solution with the prepared positively charged ALGP-PLL nanoparticle solution at a mass ratio of 1:10 to 1:20, and stir the reaction at room temperature for 12 h. (4) Preparation of OCMCN-SAP gel ① Prepare 10 mL of OCMC glycerol aqueous solution with a concentration of 5-15 wt% at room temperature, where the glycerol:water (V / V) ratio is 5:

95. Disperse SBMA-ALG-PLL charge-reversal microcapsules uniformly in the OCMC glycerol aqueous solution, controlling the SBMA-ALG-PLL concentration to 1-10 wt%. This solution is named Solution A. ② Prepare 10 mL of CMC-NAC glycerol aqueous solution with a concentration of 0.5-5 wt% at room temperature, where the glycerol:water (V / V) ratio is 5:

95. This solution is named Solution B. When using, spray Solution A onto the plaque on the teeth, then spray Solution B. The two solutions quickly form a gel upon contact. Spray Solution A and Solution B in a 1:1 ratio. The specific dosage should be based on the size of the plaque to be covered.

3. The microcapsule according to claim 1, wherein, The SBMA exhibits positive or reduced charge in an acidic environment (pH 5.0-6.5), thereby enhancing the drug release rate of the nanoparticles.

4. The dressing according to claim 3, wherein, The OCMC and CMC-NAC two-component system can be sprayed in situ and adhered to the oral cavity environment.

5. The microcapsule according to claim 2 or 3, wherein, The drug loading is 10-20 wt% (the ratio of drug to total nanoparticle mass), and the drug release rate can be further controlled by adjusting the pH of the SBMA solution or the composition of the gel.

6. Use of the charge-reversal microcapsules of claim 1 in the treatment of oral inflammation, wherein the oral inflammation includes gingivitis, periodontitis, oral mucosal ulcers or other oral diseases accompanied by an acidic microenvironment.

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