Artemisinin-chitosan multifunctional microcapsule as well as preparation method and application thereof

Abstract

The invention provides an artemisinin-chitosan multifunctional microcapsule as well as a preparation method and application thereof. The preparation method comprises the following steps: mixing artemisinin and Span80 with degraded chitosan and Tween 80 to obtain an emulsion; adjusting the pH value to 9-11, and carrying out a single condensation reaction; after dilution, rapidly cooling with an ice-water bath, and adding glutaraldehyde for low-temperature cross-linking curing; and after the reaction is finished, carrying out suction filtration at room temperature, washing and drying to obtain the microcapsule. Based on the synergistic effect of chitosan and artemisinin, a low-temperature composite crosslinking technology is developed, and efficient encapsulation and controllable release of artemisinin in the microcapsule are achieved; the problem that artemisinin is prone to thermal degradation is solved by optimizing the core-wall ratio, pH regulation and control and low-temperature cross-linking curing, and meanwhile, the long-acting slow release performance of the microcapsule in a complex oral environment is remarkably improved by utilizing a dual stabilization mechanism of chitosan single condensation reaction and glutaraldehyde cross-linking. The product has higher active matter loading capacity and release efficiency, and has long-acting application in the scenes of oral cavity bacteria (spots) resistance (inhibition), gingival problem alleviation, hemostasis and the like.

Description

Technical Field

[0001] This application relates to the field of oral care technology, and in particular to an artemisinin-chitosan multifunctional microcapsule, its preparation method, and its application. Background Technology

[0002] The oral cavity, as a vital physiological passage directly connecting the human body to the outside world, plays a crucial role in eating, chewing, and communication, while also serving as the first line of defense against invading pathogens. In recent years, with increasing emphasis on oral health, research on oral care materials has gradually become a hot topic in the field of biomedical engineering. Among these, the development of delivery systems for functional components targeting antibacterial (anti-plaque), anti-inflammatory, and tissue repair-promoting effects has attracted particular attention, as this directly relates to the effectiveness and stability of these active ingredients in the complex oral environment. In the development of oral care materials, traditional functional ingredient delivery carriers, such as liposomes and polymer microspheres, have shown potential in early research and applications due to their certain sustained-release capabilities. Liposomes, as vesicle structures composed of a phospholipid bilayer, possess good biocompatibility and targeting properties, capable of encapsulating both water-soluble and lipid-soluble active ingredients, and have wide applications in active ingredient delivery. However, their limitations become apparent in the unique and complex environment of the oral cavity. The oral cavity experiences continuous saliva flow, with a saliva secretion rate of approximately 0.5-2 ml per minute. This dynamic fluid environment constantly carries away free active ingredient carriers, making liposomes susceptible to degradation by enzymes such as phospholipases in saliva, resulting in burst release—the release of a large amount of active ingredient in a short period, failing to achieve a long-term, stable release of active ingredients. Simultaneously, the pH value in the oral cavity fluctuates with factors such as diet and saliva secretion, typically changing between 5.0 and 7.5. The membrane structure of liposomes may undergo phase transitions or rupture in acidic or alkaline environments, further affecting their stability and active ingredient encapsulation efficiency. Polymer microspheres are micron-sized particles prepared by synthesizing polymer materials. The release rate of active ingredients can be controlled by adjusting the composition and structure of the polymer. However, they face the challenge of enzymatic degradation in the oral environment. The oral cavity contains various enzymes, such as proteases and amylases, which may degrade the backbone material of polymer microspheres, leading to microsphere structural damage and uncontrolled release of active ingredients. Furthermore, the surface properties of polymer microspheres may be altered by the adsorption of salivary proteins, affecting their adhesion to the oral mucosa and thus reducing the residence time of the active ingredient at the site of action. For example, although polylactic acid-glycolic acid copolymer (PLGA) microspheres have good biodegradability, their degradation rate is accelerated by esterases in salivary fluid, making it difficult to achieve precise sustained release of the active ingredient. Summary of the Invention

[0003] This application is made in view of the above-mentioned issues, and its purpose is to provide a multifunctional microcapsule of artemisinin-chitosan that is convenient to store and transport, has good microcapsule stability, achieves efficient encapsulation and controllable release of artemisinin in the microcapsule, has a very good release efficiency of active ingredients, and meets the needs of long-term antibacterial (antimicrobial) effects in the oral cavity.

[0004] The first aspect of this application provides a method for preparing artemisinin-chitosan multifunctional microcapsules, comprising the following steps: 1) Weigh a certain amount of artemisinin and Span80 (sorbitan monooleate), stir evenly to obtain mixture A; separately weigh degraded chitosan and Tween80 (polyoxyethylene sorbitan monooleate), add to distilled water and stir evenly to obtain mixture B; 2) Pour mixture A and mixture B into a three-necked flask at a mass ratio of 3:1, and stir for 30 min at 30-60℃ and 400 r / min to obtain a mixed emulsion; 3) Keep the temperature at 30-60℃, add NaOH solution dropwise to the emulsion while stirring at low speed, adjust the pH value to 9-11, and allow the coagulation reaction to proceed for 10-15 minutes to obtain the initial coagulated body; 4) The initial aggregate is quickly cooled with an ice-water bath, and an appropriate amount of glutaraldehyde is added. The aggregate is then cross-linked and cured at low temperature for about 1 hour under stirring at 200~300 r / min.

[0005] 5) After the reaction is complete, filter, wash and dry at room temperature to obtain microcapsules.

[0006] In any embodiment, the mass ratio of artemisinin to Span80 (sorbitan monooleate) is 10-20:1, preferably 15:1.

[0007] In any embodiment, the mass ratio of the degraded chitosan to Tween80 (polyoxyethylene sorbitan monooleate) is 4-6:1, preferably 5:1.

[0008] In any embodiment, the low-temperature crosslinking reaction temperature is 0-5°C.

[0009] In any embodiment, the mass ratio of the glutaraldehyde crosslinking agent to chitosan is 1:10 to 1:50.

[0010] Core material to wall material ratio: Artemisinin to chitosan mass ratio 3:1, to ensure high active loading and sustained release balance.

[0011] The dual cross-linking system: the synergistic effect of chitosan mono-aggregation (alkaline conditions) and glutaraldehyde covalent cross-linking (low-temperature curing) forms a dense and pH-responsive capsule wall structure.

[0012] Anti-degradation design: Low-temperature operation throughout (≤50 ℃) combined with the Span80 / Tween80 emulsification system to avoid the oxidative inactivation of artemisinin.

[0013] The absorbance of the prepared microcapsules in the UV spectrum was 0.25, demonstrating excellent release efficiency of the active ingredient; the HPLC peak width was narrower, and the sustained-release rate after 72 hours was >80%, meeting the requirements for long-lasting antibacterial (anti-plaque) effects in oral cavity. Simultaneously, the sample exhibited high encapsulation efficiency, with a coverage rate reaching 99.63%.

[0014] This application controls the release efficiency of the active ingredient by adjusting the cross-linking agent ratio (glutaraldehyde to chitosan). Glutaraldehyde reacts with the amino groups of chitosan via a Schiff base reaction, forming a cross-linked network. If the cross-linking agent ratio is too low, the capsule wall structure is loose, with high porosity, leading to excessively rapid release of the active ingredient, resulting in a low concentration of the active ingredient in the solution and reduced absorbance (0.25). If the cross-linking agent ratio is too high, the capsule wall becomes too dense, hindering the release of the active ingredient and potentially increasing absorbance. In this method, the amount of glutaraldehyde used is 0.05 g (1 g chitosan), a suitable ratio that balances the release rate and capsule wall strength, achieving efficient release.

[0015] Controlling the emulsifier ratio (Span80 to Tween80 ratio) and stirring conditions ensures a sustained-release rate of >80% after 72 hours. The combination of Span80 (lipophilic) and Tween80 (hydrophilic) forms a stable emulsion, controlling droplet size. A stirring speed of 400 rpm ensures uniform droplet dispersion and prevents aggregation. A core-to-wall ratio of 3:1: sufficient wall material (1g chitosan) encapsulates the core material (3g artemisinin), ensuring long-term sustained-release capability. Droplet size uniformity directly affects microcapsule particle size uniformity, thus reducing HPLC peak width variation. In this method, both Span80 and Tween80 are used at a ratio of 1:1 (0.2g each), optimizing emulsification. Combined with stirring at 400 rpm, this achieves uniform particle size distribution. The 3:1 core-to-wall ratio, combined with glutaraldehyde cross-linking, results in a sustained-release rate of over 80% after 72 hours, meeting the long-term antibacterial (anti-plaque) requirements of the oral cavity.

[0016] Achieving a high encapsulation rate involves precise control of mixing uniformity, pH adjustment, and the core-to-wall ratio. Stirring conditions (50℃, 400 rpm): promote thorough mixing of the core and wall materials, reducing unencapsulated core material. pH adjustment (to 9-11): chitosan undergoes monoaggregation under alkaline conditions, forming complete capsule walls and preventing core material leakage. Core-to-wall ratio of 3:1: even with a high core material ratio, the wall material can still completely encapsulate the contents, avoiding a decrease in encapsulation rate due to insufficient wall material. This method achieves a high encapsulation rate of 99.63% through precise pH control and stirring, ensuring efficient utilization of the active ingredient.

[0017] A second aspect of this application also provides an artemisinin-chitosan multifunctional microcapsule, obtained using the above-described preparation method.

[0018] A third aspect of this application provides an application of artemisinin-chitosan multifunctional microcapsules, wherein the microcapsules prepared according to the above method or the microcapsules used are applied in oral care products, particularly in toothpaste products.

[0019] The beneficial effects of this invention are as follows: Based on the synergistic effect of the natural polymer chitosan and artemisinin, this application develops a low-temperature composite cross-linking technology to achieve efficient encapsulation and controlled release of artemisinin in microcapsules. By optimizing the core-to-wall ratio, pH control, and low-temperature cross-linking curing, the problem of artemisinin's easy thermal degradation is solved. Simultaneously, utilizing the dual stabilization mechanism of chitosan mono-coagulation reaction and glutaraldehyde cross-linking, the long-lasting sustained-release performance of the microcapsules under complex oral environments (such as saliva rinsing and pH fluctuations) is significantly improved. This product has a higher active ingredient loading and release efficiency, enabling long-term application in oral antibacterial (anti-plaque) and hemostatic scenarios. Attached Figure Description

[0020] Figure 1 This is an appearance characterization image of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 2 This is an electron microscope image of the surface structure of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 3 This is a particle size distribution diagram of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 4 This is a Zeta potential detection diagram of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 5 Infrared spectrum of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule of this application; Figure 6 This is an XRD pattern of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 7 XPS full spectrum of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule of this application; Figure 8 XPS C1s spectrum of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule of this application; Figure 9 XPS O1s spectrum of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule of this application; Figure 10 XPS N1s spectrum of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule of this application; Figure 11This is a DSC test image of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 12 This is a DTG test image of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 13 This is a TGA test image of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 14 This is an HPLC chromatogram of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application; Figure 15 This is a UV test image of a low-temperature ion-crosslinked artemisinin-sodium alginate microcapsule according to this application. Detailed Implementation

[0021] The following detailed description, with appropriate reference to the accompanying drawings, discloses embodiments of an artemisinin-chitosan multifunctional microcapsule, its preparation method, and its application. However, unnecessary details may be omitted. For example, detailed descriptions of well-known facts and repetitive descriptions of essentially identical structures may be omitted. This is to avoid unnecessarily lengthy descriptions and to facilitate understanding by those skilled in the art.

[0022] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of the particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that the ranges 60-110 and 80-120 will also be understood.

[0023] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0024] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0025] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0026] Artemisinin, a natural sesquiterpene lactone compound extracted from the traditional Chinese medicine Artemisia annua, has had its pharmacological activities continuously explored since its discovery. Studies have shown that artemisinin has broad-spectrum antibacterial (plaque-inhibiting) effects, significantly inhibiting common oral pathogens such as Streptococcus mutans (plaque) and Porphyromonas gingivalis (plaque), with a minimum inhibitory concentration (MIC) as low as 5-10 μg / mL. In terms of anti-inflammation, artemisinin can inhibit the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), reducing the inflammatory response of the oral mucosa. Furthermore, artemisinin has been shown to promote the proliferation and differentiation of fibroblasts, accelerating the repair process of oral tissues, and has potential application value in the treatment of oral ulcers, periodontal tissue damage, and other diseases. However, the direct application of artemisinin in oral care faces multiple challenges. First, its water solubility is extremely poor, with a solubility of only about 1.2 mg / L in water. This makes it difficult to dissolve directly in commonly used aqueous oral care formulations, limiting its application in solution or gel products. Second, artemisinin has low photothermal stability and decomposes easily at high temperatures. For example, after being placed at 60°C for 2 hours, its active ingredient content decreases by more than 30%. Conventional pharmaceutical preparation processes, such as electrostatic spray drying and hot melt extrusion, often require high processing temperatures, which can lead to the loss of artemisinin activity and compromise the effectiveness of the formulation. Furthermore, various metabolic enzymes present in the oral environment, such as the cytochrome P450 enzyme system, accelerate the metabolic degradation of artemisinin, resulting in a short half-life in the oral cavity, typically less than 1 hour, making it difficult to maintain an effective concentration of active ingredient. Currently, research on artemisinin both domestically and internationally mainly focuses on its antimalarial and antitumor applications. The design of active ingredient delivery systems largely considers the characteristics of the in vivo circulatory system, such as targeting the liver and tumor tissues. However, the development of delivery systems specifically tailored to the unique environment of the oral cavity remains a gap. Conventional microencapsulation processes, such as electrostatic spray drying, require atomizing and drying the solution in a high-temperature gas stream. This process typically involves temperatures exceeding 100°C, severely damaging the molecular structure of artemisinin and leading to its inactivation. Even with improved low-temperature preparation methods, such as freeze-drying, it is difficult to overcome the problems of rapid metabolism and insufficient mucosal adhesion of artemisinin in the oral cavity. The oral cavity's dynamic environment is uniquely complex, involving not only saliva rinsing, pH fluctuations, and enzymatic processes, but also the physiological characteristics of the oral mucosa. The oral mucosa surface is covered by a mucus layer, within which mucin molecules form a network structure, placing higher demands on the adhesion of active ingredient carriers. Existing delivery systems lack specific designs for oral mucosal adhesion, resulting in active ingredient carriers being easily removed by saliva, having short retention times on the mucosal surface, and insufficient absorption of active ingredients. Furthermore, environmental parameters vary across different parts of the oral cavity. For example, the pH value at the buccal mucosa is relatively stable, while the pH value near dental plaque drops sharply to below 5.0 after eating due to bacterial (plaque) fermentation and acid production. This necessitates delivery systems with pH-responsive release characteristics, enabling the release of active ingredients within specific microenvironments for precise treatment. From the perspective of clinical needs in oral care, current treatments for diseases such as periodontitis and oral ulcers still rely on topical medications. However, the efficacy of existing formulations is not ideal, mainly because the active ingredient delivery systems cannot adapt to the oral environment, resulting in low bioavailability of the active ingredients. For example, periodontitis patients require the continuous release of active ingredients within the periodontal pockets to kill pathogens, but traditional gel formulations only remain in the periodontal pockets for a few hours, which cannot meet the needs of long-term treatment. Therefore, developing a delivery system with good mucosal adhesion, responsiveness to changes in the oral environment (such as pH and enzyme concentration), and the ability to stably encapsulate and precisely release functional components such as artemisinin has significant scientific and clinical application value. Against the backdrop of advancements in materials science and pharmaceutics, the design concepts of novel delivery systems are constantly being updated. For example, smart responsive materials and nanocomposite materials offer new insights into solving the challenges of artemisinin application in oral care. Smart responsive materials can achieve controlled release of active ingredients based on changes in the oral environment (such as pH, temperature, and ionic strength). For instance, pH-sensitive polymers expand or degrade in acidic environments, releasing active ingredients, enabling precise release of active ingredients targeting the acidic environment near dental plaque. Nanocomposite materials can improve the encapsulation rate and stability of artemisinin through surface modification of nanoparticles, while also enhancing adhesion to the oral mucosa. However, the application of these novel materials and technologies in oral care is still in the exploratory stage, requiring specialized design and optimization tailored to the characteristics of artemisinin and the requirements of the oral environment. To address these challenges, this invention develops an artemisinin microcapsule (A2) based on a chitosan-glutaraldehyde low-temperature crosslinking process, solving these problems through material pretreatment, process co-design, and a smart responsive structure. Through experiments and characterization, we can see that the innovative design of the A2 microcapsule brings significant performance advantages. The encapsulation efficiency, calculated using the UV-Vis method, reached 99.63% (out of a 3000 mg original artemisinin feed, only 10.75 mg was unencapsulated), surpassing the traditional system's limitation of 30-40%. SEM revealed a dense composite membrane (pore size <1 μm) forming on the microcapsule surface, effectively preventing active ingredient leakage. XRD confirmed that artemisinin was dispersed amorphously within the capsule wall, improving bioavailability. Simultaneously, the capsule wall swelled in the acidic environment of dental plaque (pH <5.0), accelerating the release of activity, while in the neutral salivary environment, it was released slowly (HPLC showed a sustained-release rate >80% after 72 hours). A UV absorbance peak of 0.25 at 280 nm demonstrated higher active ingredient loading and release efficiency. Furthermore, the concentrated particle size distribution (main peak at 80 nm, PDI <0.2) enhanced mucosal adhesion, and the near-neutral zeta potential (0 mV) reduced salivary protein adsorption, prolonging oral retention time. Furthermore, this delivery system possesses triple effects of antibacterial (anti-plaque), anti-inflammatory, and tissue repair promotion. Through optimization of material biocompatibility and regulation of release kinetics (UV and HPLC combined analysis shows that A2 is superior to traditional systems in both long-acting sustained-release and targeted release performance), it systematically solves key problems such as low encapsulation rate, poor stability, and uncontrollable release of artemisinin in the oral environment. It provides a breakthrough solution for the efficient treatment of oral diseases such as periodontitis and oral ulcers, and has significant scientific value and clinical application prospects.

[0027] The main control factors in this application are: the crosslinking agent ratio, with the molar ratio of glutaraldehyde to chitosan amino groups as the core, which directly affects the crosslinking density of the capsule wall; the emulsifier ratio, the balance between Span80 (lipophilic) and Tween80 (hydrophilic) determines the emulsion stability and particle size uniformity; the core-to-wall ratio, the mass ratio of core material (active material) to wall material (chitosan), which affects the encapsulation rate and release kinetics; the type of chitosan, the degree of degradation affects swelling and release rate, and carboxymethylation can enhance water solubility; and raw material replacement, the replacement of active material or wall material requires re-optimization of process parameters (such as crosslinking degree and pH), otherwise the performance will decline.

[0028] In one embodiment of this application, a method for preparing artemisinin-chitosan multifunctional microcapsules is provided, comprising the following steps: 1) Weigh a certain amount of artemisinin and Span80 (sorbitan monooleate), stir evenly to obtain mixture A; separately weigh degraded chitosan and Tween80 (polyoxyethylene sorbitan monooleate), add to distilled water and stir evenly to obtain mixture B; 2) Pour mixture A and mixture B into a three-necked flask at a mass ratio of 3:1, and stir for 30 min at 30℃~60℃ and 400 r / min to obtain a mixed emulsion; The volume ratio of mixture A to mixture B has a significant impact on the properties of the mixture system: Regarding the impact on emulsion stability, if the aqueous phase volume is too large and the oil phase (artemisinin and Span80 system) volume is too small, the distance between oil droplets in the emulsion may be too large, making the emulsion prone to stratification and reducing stability. Conversely, if the oil phase volume is too large, the aqueous phase may not be sufficient to fully disperse and stabilize the oil droplets, causing them to easily aggregate into large oil clumps, which also leads to emulsion instability. Generally, the volume ratio of the oil phase to the aqueous phase is commonly between 1:10 and 1:2. This application further adjusts the ratio according to the properties of artemisinin, the type and concentration of surfactant, and the required emulsion properties to achieve the optimal dispersion and stabilization effect, obtaining the required porosity and core-to-wall ratio to meet the requirements of sustained release and pH selectivity.

[0029] The volume ratio affects the encapsulation efficiency and drug loading of the active ingredient. If the aqueous phase volume is too small, the amount of chitosan will be insufficient, potentially failing to completely encapsulate the artemisinin particles and reducing the encapsulation efficiency. Conversely, if the oil phase volume is too small, while it can improve the encapsulation efficiency, the drug loading will be limited, failing to meet the dosage requirements for practical applications. Therefore, it is necessary to optimize the volume ratio of the oil and aqueous phases experimentally to obtain higher encapsulation efficiency and drug loading.

[0030] The reason for controlling the temperature of the mixing reaction is that temperature (30℃~60℃) is a decisive condition for ensuring the formation of microcapsules and the stability of active ingredients.

[0031] Low temperatures (<30℃) can lead to failure. At low temperatures (e.g., 20℃), the chitosan molecular chains undergo enhanced hydrogen bonding, resulting in a significant increase in solution viscosity. This leads to a deterioration in the interfacial compatibility between chitosan and mixture A (artemisinin / Span80 organic phase). Insufficient molecular diffusion kinetics cause a sharp drop in emulsification efficiency (even with stirring at 400 r / min). Span80 / Tween80 cannot effectively reduce the oil-water interfacial tension, inevitably leading to phase separation or uneven particle size distribution, resulting in microcapsule encapsulation efficiency below the acceptable threshold.

[0032] Excessively high temperatures (>60℃) can lead to substance decomposition and mixing failure. Artemisinin is heat-sensitive; the peroxy bridge structure begins to break at temperatures above 60℃, with 150℃ being only an extreme example. In practice, HPLC can detect an attenuation of artemisinin characteristic peaks of >20% at 65℃. The emulsion system collapses; the hydrophilic polyoxyethylene chains of Tween 80 undergo dehydration and shrinkage at temperatures above 60℃, and the sudden change in HLB value leads to phase inversion in the O / W emulsion (cloud point effect). At the same time, the hydrolysis of ester bonds in Span 80 is accelerated, and the micelle structure disintegrates. Chitosan loses its function, and the molecular chains are excessively stretched at high temperatures, weakening its ability to encapsulate artemisinin through electrostatic interactions. Furthermore, increased thermal motion promotes the leakage of active ingredients.

[0033] 3) While maintaining the temperature, add NaOH solution dropwise to the emulsion with low-speed stirring, adjust the pH value to 9-11, and allow the coagulation reaction to proceed for 10-15 minutes to obtain the initial coagulated body; In the reaction system of this application, artemisinin and Span80 form one phase (oil phase or hydrophobic phase), while degraded chitosan, Tween80, and distilled water form another phase (aqueous phase). The mixing of the two phases is achieved through the following designed mechanism: Span80 (sorbitan monooleate) is a nonionic surfactant with a long hydrophobic carbon chain and hydrophilic hydroxyl groups in its molecular structure, but its hydrophilicity is relatively weak, classifying it as a lipophilic surfactant. In artemisinin systems, Span80 adsorbs onto the surface of artemisinin particles, with the hydrophobic groups facing the artemisinin and the hydrophilic groups facing outwards. This reduces the surface tension between artemisinin particles to some extent, preventing particle aggregation and facilitating dispersion of artemisinin in the aqueous phase. Tween80 (polyoxyethylene sorbitan monooleate) is also a nonionic surfactant. Compared to Span80, it incorporates polyoxyethylene chains in its molecular structure, significantly enhancing its hydrophilicity. In the aqueous phase, Tween80 forms micelles, whose hydrophobic cores can encapsulate hydrophobic substances. When mixed with a system containing artemisinin and Span80, the Tween80 micelles can further solubilize artemisinin, improving its solubility and stability in the aqueous phase.

[0034] The degraded chitosan used is a natural polymer with good biocompatibility and biodegradability. In the aqueous phase, the amino groups on the degraded chitosan molecular chains can be protonated, giving the chitosan a positive charge. When mixed with an oil phase containing artemisinin, the positively charged chitosan molecules can combine with artemisinin particles or their adsorbed surfactant molecules through electrostatic interactions, resulting in a chitosan coating layer on the surface of the artemisinin particles. This coating layer not only further improves the stability of artemisinin but also controls the release rate, achieving a sustained-release effect of the active ingredient.

[0035] In the preparation of this application, the molecular weight of chitosan is typically controlled between 20,000 and 50,000 Daltons. Excessively high molecular weight leads to reduced microcapsule permeability. High molecular weight chitosan chains are longer, resulting in more binding sites with artemisinin, forming a dense membrane that hinders drug diffusion and slows drug release. Excessive cross-linking also leads to decreased swelling and a slower drug release rate. Conversely, excessively low molecular weight chitosan results in insufficient microcapsule strength. Low molecular weight chitosan chains are shorter, have fewer binding sites with artemisinin, and exhibit low membrane strength, making them prone to rupture.

[0036] When mixed, artemisinin, being hydrophobic, and the aqueous phase, being hydrophilic, form an emulsion due to the combined action of Span80 and Tween80. Span80 primarily reduces the tension at the oil-water interface, allowing artemisinin to disperse better in water, forming tiny oil droplets; Tween80 further stabilizes the emulsion, preventing droplet aggregation and stratification. The presence of chitosan also enhances emulsion stability by forming a protective film on the surface of the oil droplets, preventing collisions and coalescence between them.

[0037] The concentration of NaOH solution is 2%-7%. A lower concentration can provide a sufficient alkaline environment while avoiding excessive degradation of chitosan or destruction of the artemisinin structure. The single-cohesion reaction is the process by which chitosan and artemisinin (or its derivatives) form a complex through charge interaction under alkaline conditions. At pH 9-11, the amino (-NH2) moiety of chitosan is deprotonated, forming a positively charged complex. NH 3+ (Actually, under alkaline conditions) NH2 is in equilibrium with the -OH groups in the solution, but exhibits an overall positive charge, while artemisinin or its derivatives may carry negatively charged groups (such as carboxyl groups, phenolic hydroxyl groups, etc.). The two form a complex through electrostatic interactions. Furthermore, alkaline conditions can control the reaction rate and product stability.

[0038] The initial aggregate was an emulsion of artemisinin-degraded chitosan complex.

[0039] 4) The initial aggregate is quickly cooled with an ice-water bath, and an appropriate amount of glutaraldehyde is added. The aggregate is then cross-linked and cured at low temperature for about 1 hour under stirring at 200~300 r / min.

[0040] 5) After the reaction is complete, filter, wash and dry at room temperature to obtain microcapsules.

[0041] This application involves mixing artemisinin with the lipophilic surfactant Span80 to form a stable oil phase, while simultaneously dissolving degraded chitosan and the hydrophilic surfactant Tween80 in the aqueous phase. The two phases are then mixed in proportion and mechanically stirred to prepare an emulsion. Finally, under alkaline conditions (pH 9-11), the electrostatic interaction between chitosan and artemisinin is utilized to achieve mono-aggregate composite, thereby constructing an active ingredient carrier structure and obtaining artemisinin and chitosan microcapsules.

[0042] Span80 (sorbitan monooleate) is an important nonionic surfactant with excellent emulsifying, dispersing, and solubilizing abilities. As an emulsifier, it reduces the interfacial tension between oil and water, allowing artemisinin (the oil-soluble component) to mix uniformly with the aqueous phase, forming a stable emulsion or microemulsion; solution A is an emulsion. Tween80, through its emulsifying effect, uniformly disperses degraded chitosan in distilled water, improving the stability of the emulsion; solution B is an emulsion.

[0043] Chitosan requires degradation treatment to enhance its water solubility and reactivity. Artemisinin is premixed with the hydrophobic emulsifier Span80 to improve its dispersion stability in the subsequent aqueous phase.

[0044] The collaborative process design begins with primary emulsification. An artemisinin-Span80 mixture and a chitosan-Tween80 aqueous solution (core-to-wall ratio 3:1) are stirred at 50 °C and 400 r / min for 30 minutes to form a stable oil / water (O / W) emulsion. The Span80 / Tween80 blend inhibits Ostwald curing of droplets. Next, a single-cohesion reaction occurs. A 2% NaOH solution is added dropwise to adjust the pH to 9-11, and the mixture is maintained at 50 °C for 10-15 minutes. The alkaline conditions promote the deacetylation of chitosan and its self-assembly into primary capsule walls. Finally, low-temperature cross-linking and curing are performed: the emulsion is rapidly transferred to a 0-5 °C ice-water bath, 0.05 g of glutaraldehyde is added, and the mixture is stirred at 200-300 r / min for 1 hour for cross-linking. The low-temperature environment prevents the thermal decomposition of artemisinin, and the glutaraldehyde covalently cross-links with the amino groups of chitosan to form a dense capsule wall.

[0045] The synergistic mechanism primarily involves dual cross-linking: a single coagulation reaction forms a pH-responsive primary network, while glutaraldehyde covalent cross-linking enhances the mechanical strength of the capsule wall at low temperatures. Together, these two mechanisms improve encapsulation efficiency (99.63%) and enhance resistance to enzymatic degradation. Next is emulsification-low temperature synergy: the Span80 / Tween80 compound stabilizes the emulsion droplet structure, and low-temperature solidification locks in the dispersion of the active ingredient, solving the encapsulation difficulties caused by the hydrophobicity of artemisinin.

[0046] The core-to-wall ratio of the microcapsules is 3:1. This requires controlling the mass ratio of artemisinin (core material) to chitosan (wall material) to be 3:1, while Span80:Tween80 = 1:1, the mass ratio of artemisinin to Span80 to be 10-20:1, and the mass ratio of degraded chitosan to Tween80 to be 4-6:1.

[0047] In any embodiment, the mass ratio of artemisinin to Span80 (sorbitan monooleate) is 10-20:1.

[0048] If the ratio of artemisinin to Span80 is too low, the excess aqueous phase will lead to emulsion collapse. Emulsion type reversal. When the proportion of the aqueous phase (mixture B) is too high, the system reverses from the designed W / O (water-in-oil) type to the O / W (oil-in-water) type. Span80 (HLB=4.3), as a lipophilic emulsifier, cannot effectively cover the increased water-oil interface, and Tween80 (HLB=15.0) dominates the formation of the O / W emulsion, resulting in the exposure of hydrophobic artemisinin to the aqueous phase. Microcapsule structure disintegration: Chitosan, as a hydrophilic polymer, cannot encapsulate the oil phase core in the O / W system. Artemisinin precipitates due to lack of protection, forming a turbid suspension instead of homogeneous microcapsules, and the encapsulation efficiency drops sharply to <50%. Stability degradation: Excessive dilution of chitosan concentration with the aqueous phase results in insufficient capsule wall thickness (<50 nm), decreased mechanical strength of the microcapsules, and aggregation and precipitation during storage.

[0049] Excessive mass ratio leads to an overabundance of oil phase, causing dispersion failure. Insufficient emulsifier coverage: The critical micelle concentration (CMC) of Span80 in the oil phase is exceeded, resulting in insufficient emulsifier molecules per unit area and ineffective reduction of oil-water interfacial tension (>10 mN / m). Even with stirring at 400 r / min, oil droplet aggregation (particle size >10 μm) still occurs, far exceeding the target microcapsule size (1-2 μm). Dramatically increased mass transfer resistance: The high-viscosity oil phase hinders the diffusion of chitosan molecules to the interface, leading to incomplete capsule wall formation (surface porosity >30%) and an increase in artemisinin leakage rate to >40% within the initial 24 h. Loss of function: The low concentration of chitosan in the oil phase (<0.1 wt%) prevents the formation of continuous capsule walls, resulting in loss of sustained-release function; simultaneously, excessive artemisinin crystallization reduces bioavailability.

[0050] Overall, a mass ratio of artemisinin to Span80 deviating from 15:1 will disrupt the above balance and have a certain impact on the system. When the ratio is <10:1, the aqueous phase reverses the emulsion type, leading to encapsulation failure; when the ratio is >20:1, the oil phase exceeds the emulsification limit, causing aggregation and leakage.

[0051] In any embodiment, the mass ratio of the degraded chitosan to Tween80 (polyoxyethylene sorbitan monooleate) is 4-6:1.

[0052] If the ratio is >6:1 (insufficient Tween80), the surfactant concentration is below the critical micelle concentration (CMC). Chitosan aggregates due to hydrogen bonding, forming aggregates >500 nm that block the capsule wall pores. At the same time, the interfacial tension >45 mN / m causes emulsion coalescence (particle size >8 μm), resulting in a burst release effect >60%. If the ratio is <4:1 (excessive Tween80), the excess micelles plunder artemisinin, leading to a decrease in binding rate. They also insert into the chitosan network, causing the capsule wall to become loose (porosity >35%). The zeta potential drops to +15 mV, causing a 7-day aggregation rate >30%.

[0053] When the optimal ratio is 5:1, chitosan expands into an active conformation with a kinetic diameter of ≈120 nm, synergistically with Span80 to suppress the interfacial tension to <5 mN / m, achieving zero-order sustained-release kinetics (R0). 2 >0.98), becoming the core hub for controlling the triple functions of "dissolution-interface-slow release".

[0054] In any embodiment, the low-temperature crosslinking reaction temperature is 0-5°C.

[0055] Temperature is a crucial factor in ensuring microcapsule formation and the stability of the active ingredients. Excessive temperature leads to instability in the solution system, preventing the formation of artemisinin-chitosan microcapsules. The cross-linking reaction of this application was achieved under ice-water bath conditions.

[0056] In any embodiment, the mass ratio of the glutaraldehyde crosslinking agent to chitosan is 1:10 to 1:50.

[0057] Glutaraldehyde, as a cross-linking agent, can react with amino groups and other groups in chitosan molecules to form a cross-linked structure. This allows chitosan to form a more stable three-dimensional network structure, encapsulating core substances such as artemisinin, achieving microencapsulation, and enhancing the stability and mechanical strength of the microcapsules. Too high a concentration leads to a dense structure but increased brittleness and slower release; too low a concentration leads to a loose structure, excessively rapid release, and poor stability.

[0058] The effects and impacts of the relevant parameter design in this application are shown in the table below:

[0059] When there is insufficient wall material (core-to-wall ratio > 3:1), the molecules in the capsule wall are not fully cross-linked, forming a honeycomb or empty capsule structure, leading to decreased mechanical strength and increased rupture rate (12%). Simultaneously, the core material is prone to leakage or incomplete encapsulation, reducing the coverage rate to below 88%. Conversely, when there is excessive wall material (core-to-wall ratio < 3:1), the capsule wall develops a porous structure due to excessive cross-linking or rapid curing, increasing porosity and resulting in excessively high oil loading, accelerating core material diffusion. Furthermore, high-concentration wall material is prone to uneven capsule wall thickness due to uneven stirring or temperature runaway, creating localized thinness and "weak points," ultimately leading to an accelerated release rate. Experiments show that at a core-to-wall ratio of 3:1, the capsule wall is uniform and dense, achieving a coverage rate of 99.63% and a 72-hour sustained-release rate > 80%, exhibiting optimal performance.

[0060] The traditional understanding that "thick walls are less prone to breakage and release slowly" has limitations. The release rate is not solely determined by wall thickness, but is influenced by both the physicochemical properties of the capsule wall (such as porosity and crystallinity) and process conditions (drying method, pH, and temperature). For example, a uniform thin-walled capsule with low porosity (such as ethyl cellulose) may release more slowly than a thick-walled capsule with high porosity (such as gelatin); freeze-drying accelerates release due to increased surface area, while oven drying is slower. A core-to-wall ratio of 3:1, by balancing the wall material concentration with process parameters (such as a stirring speed of 400 r / min and a temperature of 60℃), achieves an optimal solution for the density and functionality of the capsule wall structure, breaking through the single-dimensional understanding of traditional wall thickness.

[0061] A second aspect of this application also provides an artemisinin-chitosan multifunctional microcapsule, obtained using the above-described preparation method.

[0062] A third aspect of this application provides an application of artemisinin-chitosan multifunctional microcapsules, wherein the microcapsules prepared according to the above method or the microcapsules described above are used in oral care products.

[0063] In oral care applications, the wall material (chitosan) of artemisinin microcapsules typically possesses mechanical strength to resist the physical friction during brushing. For example, chitosan microcapsules maintained their integrity for over 2 minutes in simulated oral friction experiments, sufficient to cover the typical brushing time (1-3 minutes). Normal brushing pressure is approximately 150-200 g / cm². 2 This is far lower than the high-pressure conditions used in the laboratory to destroy microcapsules (typically >500 g / cm³). 2 Therefore, brushing friction does not directly cause microcapsules to rupture. Toothpaste often contains binders (such as sodium carboxymethyl cellulose and xanthan gum) to enhance the retention time of active ingredients in the oral cavity. For example, adding 0.5%-1% sodium carboxymethyl cellulose can extend the retention time of artemisinin in the oral cavity to more than 30 minutes, far exceeding the 5-10 minutes of ordinary toothpaste.

[0064] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0065] Example 1 Weigh 3 g of artemisinin and 0.2 g of Span80 (sorbitan monooleate) (15:1), and mix thoroughly. Separately weigh 1 g of degraded chitosan and 0.2 g of Tween80 (polyoxyethylene sorbitan monooleate) (5:1), add 100 mL of distilled water, and mix thoroughly. Pour the two mixtures [m(artemisinin):m(chitosan) = 3:1, i.e., core-to-wall ratio 3:1] into a three-necked flask and stir for 30 min at 50 ℃ and 400 r / min. Under controlled temperature of 50 ℃ and low-speed stirring, add 2% NaOH solution dropwise to the emulsion to adjust the pH (to pH = 9-11) to induce chitosan mono-aggregation reaction for 10-15 min. The above solution was diluted and rapidly cooled in an ice-water bath. An appropriate amount (0.05 g) of glutaraldehyde (in a 1:20 ratio with chitosan) was added, and the mixture was cross-linked and cured at a low temperature (0-5 °C) for approximately 1 h under stirring at 200-300 r / min. After the reaction was complete, the mixture was filtered, washed, and dried at room temperature to obtain the microcapsule product.

[0066] Example 2 This embodiment differs from Embodiment 1 in that 4g of artemisinin, 1.3g of degraded chitosan, and 0.27g of Tween80 are weighed out; all other conditions and steps are the same as in Embodiment 1. (The mass ratio of artemisinin to Span80 is 20:1.) Example 3 This embodiment differs from Embodiment 1 in that 3.6g of artemisinin, 0.24g of Span80, and 1.2g of degraded chitosan are weighed out, while other conditions and steps are the same as in Embodiment 1. (The mass ratio of chitosan to Tween80 is 6:1.) Example 4 The difference between this embodiment and Embodiment 1 is that the reaction temperature in step 2) is 40°C, while the other conditions and steps are the same as in Embodiment 1.

[0067] Example 5 This embodiment differs from Embodiment 1 in that 0.04 g of glutaraldehyde is added; all other conditions and steps are the same as in Embodiment 1. (Glutaraldehyde crosslinking agent to chitosan mass ratio 1:25) Comparative Example 1 The difference between this comparative example and Example 1 is that no Span80 and Tween80 emulsifiers were added; the other steps and conditions were the same as in Example 1.

[0068] Comparative Example 2 The difference between this comparative example and Example 1 is that the pH value was adjusted to 7.0 (neutral) to carry out the single coagulation reaction (pH 9-11 in Example 1), while the other steps and conditions were the same as in Example 1.

[0069] Comparative Example 3 The difference between this comparative example and Example 1 is that the crosslinking curing temperature is changed to 25°C (room temperature) (Example 1 uses a 0-5°C ice bath), while the other steps and conditions are the same as in Example 1.

[0070] Comparative Example 4 The difference between this comparative example and Example 1 is that formaldehyde is used instead of glutaraldehyde as the crosslinking agent, while the other steps and conditions are the same as in Example 1.

[0071] Comparative Example 5 The difference between this comparative example and Example 1 is that the core-to-wall ratio is adjusted to 5:1 (artemisinin 1g: chitosan 1g) (Example 1 is 3:1), while the other steps and conditions are the same as in Example 1.

[0072] Comparative Example 6 The difference between this comparative example and Example 1 is that the core-to-wall ratio is adjusted to 4:1 (artemisinin 4g: chitosan 1g) (Example 1 is 3:1), while the other steps and conditions are the same as in Example 1.

[0073] Comparative Example 7 The difference between this comparative example and Example 1 is that undegraded chitosan (molecular weight > 200 kDa) was used instead of degraded chitosan; the other steps and conditions were the same as in Example 1.

[0074] The microcapsules obtained in Examples 1-5 and Comparative Examples 1-7 were subjected to performance tests. The test results are shown in Table 1 below.

[0075]

[0076] The artemisinin microcapsules obtained in Example 1 were characterized as follows: Experimental instruments XPS (X-ray photoelectron spectroscopy) was performed on a Kratos Axis Ultra DLD using an Al Kα X-ray (1486.6 eV) monochromatic source, and the binding energy was calibrated using the C 1s peak (284.8 eV).

[0077] Infrared spectra were measured on a Bruker Tensor 27 (ATR fully automated sampler, spectral analysis at 400-4000 cm⁻¹).

[0078] Thermogravimetric analysis (TGA) was performed on a NETZSH TG 209C (TASC 414 / 4 controller) thermal analyzer at a heating rate of 10 °C / min (30-800 °C).

[0079] Differential scanning calorimetry (DSC) was performed on a NETZSH DSC 214 thermal analyzer under nitrogen protection at a heating rate of 10 °C / min (30-300 °C).

[0080] Scanning electron microscopy (SEM) was performed on a JEOL JSM-6700F SEM at 20.0 kV without gold sputtering.

[0081] X-ray powder diffraction (XRD) was performed on a Philips X'Pert Pro diffractometer using Cu-Kα rays (λ = 1.5418 Å) at a scan rate of 0.05 o / s.

[0082] Experimental characterization of artemisinin microcapsules: The image shows the overall morphology of the artemisinin-chitosan microcapsules. From... Figure 1 As can be seen from the sample appearance image, the sample appears as a white powder that is easy to store, transport and disperse, with no obvious agglomeration on the surface, indicating that the emulsification and cross-linking steps in the preparation process effectively controlled the particle morphology.

[0083] SEM images (scanning electron microscope images) reveal the microscopic morphology of the microcapsules. Figure 2The results show that the microcapsule surface possesses a dense composite membrane structure, which effectively prevents artemisinin leakage and improves microcapsule stability. Simultaneously, the microcapsule interior may exhibit a porous structure with pore sizes below a few micrometers. This structure not only increases the internal surface area, facilitating artemisinin encapsulation, but also promotes substrate and product diffusion, thereby increasing the reaction rate. These results also indicate that chitosan monocondensation and glutaraldehyde cross-linking enhance the capsule wall density. Similar studies suggest that under pH 9-11 conditions, the degree of deacetylation of chitosan increases, promoting molecular chain cross-linking and forming a complete capsule wall structure.

[0084] The particle size distribution map shows the distribution of particle size in the microcapsule sample. From Figure 3 As can be seen, the microcapsules exhibit a relatively uniform particle size distribution, ranging from 70 to 105 nm, with a moderate average particle size. This uniform particle size distribution helps improve the encapsulation efficiency and release performance of the microcapsules, ensuring uniform release of artemisinin at the target site. The particle size distribution curve shows a main peak at 80 nm and a low polydispersity index (PDI), indicating good dispersibility of the system. While a core-to-wall ratio of 3:1 may result in a thinner capsule wall, the synergistic emulsification effect of Span80 / Tween80 effectively stabilizes the emulsion droplets and inhibits Ostwald ripening, thus achieving a narrow distribution.

[0085] Zeta potential diagrams reflect the surface charge properties of microcapsule particles. Figure 4 zeta potential Figure 4 This graph reflects the surface charge characteristics of artemisinin microcapsules and the influence of the preparation process. The main peaks in the graph are close to 0 mV, indicating that the surface charge of the microcapsules is nearly neutral under these conditions, with an isoelectric point of approximately 0 mV. Near the isoelectric point, the electrostatic repulsion between particles is minimal, making aggregation more likely. During the preparation process, adjusting the pH to 9-11 may have altered the charge state of chitosan, while the cross-linking effect of glutaraldehyde also affected the charge distribution on the microcapsule surface, resulting in a more uniform charge distribution concentrated near the isoelectric point. In summary, this graph indicates that the surface charge of artemisinin microcapsules is nearly neutral under these preparation conditions, and attention should be paid to their stability in solution.

[0086] Infrared spectra revealed the vibrational modes of chemical bonds and functional groups in the microcapsule samples. Figure 5 The infrared spectrum reflects the chemical composition of artemisinin microcapsules and the influence of the preparation process. The characteristic peak of artemisinin appears at 3672 cm⁻¹. -1 2979 cm -1 and 2358 cm -1 The corresponding vibrational absorptions are located near the peroxy and ester groups in the molecule; the characteristic peak of chitosan is located at 3672 cm⁻¹. -1 1396 cm -1 and 1059 cm-1 The vibrations of its hydroxyl and amino groups are evident at this location. During the preparation process, artemisinin and chitosan may form microcapsules through interactions such as hydrogen bonding, leading to changes in the position or intensity of characteristic peaks. Furthermore, the 4342 cm⁻¹ peak in the spectrum... -1 1239 cm -1 676 cm -1 The peaks may originate from excipients such as Span80 and Tween80 introduced during preparation, or from novel substances generated by the interaction between artemisinin and chitosan. In summary, this spectrum confirms the successful preparation of artemisinin microcapsules and reveals their chemical composition and possible interactions.

[0087] The XRD pattern (X-ray diffraction pattern) shows the crystal structure of the microcapsule sample. Figure 6 The XRD pattern reflects the crystal structure characteristics of the artemisinin microcapsules. The diffraction peaks are mainly concentrated in the 10-25° and 40-50° regions at 2θ, indicating the presence of specific interplanar spacings and possible lattice structures within the microcapsules. The peak width and intensity provide information about crystallinity and particle size. During preparation, the interaction between artemisinin and chitosan, as well as the cross-linking reaction (using glutaraldehyde), may have altered the crystal structure of artemisinin; this structural change is reflected in the changes in the position, intensity, and shape of the diffraction peaks in the XRD pattern. Furthermore, additives used or impurities present during preparation may also affect the XRD pattern. In summary, this pattern indicates that the preparation process of the artemisinin microcapsules significantly influences its crystal structure.

[0088] DSC (Differential Scanning Calorimetry) spectra show the changes in the thermal properties of microcapsule samples during heating or cooling. Figure 11 The heat flow curves displayed reflect the thermal stability, melting point, and other properties of the microcapsules. DSC analysis can confirm whether chemical or physical changes occurred during the preparation process, providing important evidence for evaluating the microcapsule's performance. This DSC plot reflects the thermal behavior of artemisinin microcapsules. A significant endothermic peak appears near 200℃, indicating an endothermic transition at this temperature, possibly related to a phase transition or decomposition process. No significant exothermic peaks were observed, indicating no significant exothermic reaction occurred during preparation. Considering the preparation method, the cross-linking reaction (using glutaraldehyde) is carried out at low temperatures, and the chitosan monocondensation reaction and pH adjustment steps typically do not involve significant exothermic or endothermic reactions. Therefore, the DSC plot primarily reflects the endothermic behavior of the artemisinin microcapsules during heating.

[0089] Microcapsule encapsulation rate calculation: Sample concentration calculation: C A2 = = = = 0.003808 mol / L CA2 = 0.003808 mol / L × 282.34 g / mol = 1.075 mg / mL Quality of unencapsulated artemisinin: Unencapsulated mA2 = CV = 1.075 mg / mL × 10ml = 10.75 mg. Packaging efficiency calculation: A2 packaging efficiency = × 100% = × 100% = 99.63% This application develops a low-temperature composite cross-linking technology based on the synergistic effect of chitosan, a natural polymer material, and artemisinin, to achieve efficient encapsulation and controlled release of artemisinin in microcapsules. By controlling the chitosan mono-coagulation reaction (pH 9-11, 50 ℃) combined with low-temperature cross-linking of glutaraldehyde (0-5 ℃, ice-water bath cooling), a core-to-wall ratio of 3:1 (artemisinin:chitosan), an addition of 0.05 g of glutaraldehyde as the cross-linking agent, a stirring rate of 200–300 r / min, and an overall operating temperature ≤50℃ (0-5℃ for key cross-linking steps), the artemisinin activity retention rate is >99%. This solves the problem of active ingredient inactivation caused by traditional high-temperature processes and addresses the challenge of artemisinin's easy thermal degradation (avoiding the high-temperature defects of traditional electrostatic spray drying). Simultaneously, utilizing the dual stabilizing mechanism of chitosan mono-coagulation reaction and glutaraldehyde cross-linking, the long-term sustained-release performance of microcapsules under complex oral environments (such as saliva rinsing and pH fluctuations) is significantly improved. UV data showed that A2 had a peak absorbance of approximately 0.25 at key wavelengths (around 280 nm), indicating that A2 has a higher active ingredient loading and release efficiency. HPLC data also supported the long-term application of A2 in oral antibacterial (anti-plaque) and hemostatic applications. Furthermore, the peak area (1 / 2) of A2 further verified that its release rate and purity were superior to traditional embedding methods.

[0090] It should be noted that this application is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments with the same structure and effect as the technical concept within the scope of this application are included in the technical scope of this application. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, without departing from the spirit of this application, are also included in the scope of this application.

Claims

1. A method for preparing artemisinin-chitosan multifunctional microcapsules, characterized in that, Includes the following steps: 1) Weigh a certain amount of artemisinin and Span80, stir them evenly to obtain mixture A; separately weigh degraded chitosan and Tween80, add them to distilled water and stir evenly to obtain mixture B; 2) Mixture A and mixture B are poured into a three-necked flask at a mass ratio of 3:1 and stirred at a certain temperature to obtain a mixed emulsion; 3) While maintaining the temperature, add NaOH solution dropwise to the mixed emulsion with low-speed stirring to adjust the pH value to 9-11, and obtain the initial aggregate through single coagulation reaction; 4) The initial aggregate is quickly cooled with an ice-water bath, and an appropriate amount of glutaraldehyde is added. The aggregate is then cross-linked and cured at low temperature with stirring. 5) After the reaction is complete, filter, wash and dry at room temperature to obtain microcapsules.

2. The method for preparing artemisinin-chitosan multifunctional microcapsules according to claim 1, characterized in that, The mass ratio of artemisinin to Span80 is 10-20:

1.

3. The method for preparing artemisinin-chitosan multifunctional microcapsules according to claim 1, characterized in that, The mass ratio of the degraded chitosan to Tween80 is 4-6:

1.

4. The method for preparing artemisinin-chitosan multifunctional microcapsules according to claim 1, characterized in that, The reaction temperature in step 2) is 30-60℃.

5. The method for preparing artemisinin-chitosan multifunctional microcapsules according to claim 1, characterized in that, The low-temperature crosslinking reaction temperature is 0-5℃.

6. The method for preparing artemisinin-chitosan multifunctional microcapsules according to claim 1, characterized in that, The mass ratio of the glutaraldehyde crosslinking agent to chitosan is 1:10 - 1:

50.

7. An artemisinin-chitosan multifunctional microcapsule, obtained by the preparation method according to any one of claims 1-6.

8. An application of an artemisinin-chitosan multifunctional microcapsule, wherein the microcapsule obtained by the preparation method according to any one of claims 1-6 or the microcapsule of claim 7 is applied to an oral care product.

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