A topical herpes lesion formulation and method of making same

Abstract

This invention belongs to the field of pharmaceutical formulation technology and provides a topical formulation for herpes lesions and its preparation method. This invention employs a synergistic design of three nanocarriers: a polyvinyl alcohol and sodium alginate composite film-forming matrix, core-shell nanoparticles N1 (chitosan-sodium tripolyphosphate ion-crosslinked core + tannic acid-coated shell), plant polyphenol-phospholipid composite nanoparticles N3 (lecithin composite of Phyllanthus urinaria and Wedelia trifoliata alcohol water extract), and agarwood volatile oil-cyclodextrin inclusion complex N2 (agarwood volatile oil O and hydroxypropyl-β-cyclodextrin inclusion complex). This achieves low viscosity (2-80 mPa·s) and uniform spraying performance that can be atomized by a mechanical pump, dense film coverage and wet-state erosion resistance, and sustained drug release and dispersion stability under high load of multiple nanocarriers. It solves the technical contradiction of existing systems in balancing low viscosity atomization, film density, multi-carrier stability, and low irritation, and has broad application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a topical preparation for herpes lesions and its preparation method. Background Technology

[0002] Herpes is a common skin and mucous membrane disease caused by herpesvirus infection, including types such as herpes simplex and herpes zoster. Its clinical manifestations include clusters of blisters, erythema, erosion, and crusting on the local skin, often accompanied by burning, itching, and stinging discomfort, severely impacting the patient's quality of life. Herpesviruses exhibit neurotropism and latent recurrence characteristics. The skin lesions during acute flare-ups place special demands on the performance of topical medications: on the one hand, the epithelial barrier at the site of herpes lesions is damaged, exudate is increased, and the pH is more acidic, requiring topical medications to have good lesion coverage, moist retention capacity, and low irritation to avoid exacerbating local inflammation and pain; on the other hand, the herpesvirus actively replicates in epidermal keratinocytes and dermal nerve endings, requiring medications to achieve sustained release and deep penetration of active ingredients to effectively inhibit viral replication, promote lesion repair, and prevent secondary infections. Furthermore, patients often require frequent application of medication during the acute phase; therefore, ease of use, quick-drying and refreshing properties, and good patient compliance are also important requirements in clinical application. Meeting and developing these properties is of great significance for improving the efficacy of topical herpes preparations, enhancing the patient's medication experience, and promoting rapid healing of skin lesions.

[0003] The current technological approaches for developing topical formulations for herpes lesions mainly include traditional creams and gels, as well as the emerging nano-drug-carrying systems. However, existing technologies have significant shortcomings in meeting the multiple performance requirements mentioned above. For example, Chinese patent application CN108451995A discloses an acyclovir in-situ formed spray and its preparation method, but the spray is easily washed away by exudate in a humid environment, resulting in a short duration of efficacy and the need for frequent reapplication. Chinese patent CN110464801A discloses a method for preparing and applying liquid precursor liposomes. Although this improves ease of use, the pressurized spraying method it uses causes mechanical irritation to ruptured herpes lesions, and the single nanocarrier has limited loading capacity and insufficient sustained-release performance, making it difficult to simultaneously meet the requirements of rapid onset and long-lasting effect. In addition, existing nano-drug-carrying systems generally face problems such as poor dispersion stability, easy aggregation and precipitation, and easy clogging of spray nozzles under high loading conditions, which seriously affect the shelf-life stability and actual efficacy of the formulation. More importantly, there is currently a lack of systematic technical solutions that can achieve a synergistic balance between low viscosity and uniform spraying that can be atomized by mechanical pumps, dense coverage and wet erosion resistance after film formation, continuous drug release and dispersion stability under high load of multi-nanocarriers, and fast drying and refreshing and low irritation and high tolerance in the weak acid microenvironment containing ethanol. Summary of the Invention

[0004] The purpose of this invention is to provide a topical formulation for herpes lesions and its preparation method, thereby resolving the technical contradictions that are difficult to balance between the requirements of low viscosity and uniform spraying for mechanical pump atomization, the dense stability and wet erosion resistance of the coating layer after film formation, the continuous release of drug efficacy and dispersion stability brought about by the high load of multi-nano carriers and the nozzle passability, and the requirements of quick drying, refreshing and anti-infection achieved by the weak acid microenvironment containing ethanol and low irritation and high tolerance in the state of skin lesions.

[0005] This invention achieves multi-dimensional synergy through "film-forming framework regulation + three-nanometer carrier synergy + weak acid pH balance": the PVA / sodium alginate dual network has low viscosity and is easy to atomize before spraying, and the hydrogen bond / ionic cross-linking after film formation makes it dense and resistant to erosion and retention; each component is designed with different scales, charges and hydrophilicity / hydrophobicity to balance high load dispersion stability and nozzle passability, and achieves rapid and long-lasting effects through release gradient; ethanol + citric acid / sodium citrate controls the pH to 4.5-6.2, which balances fast drying and antibacterial properties and reduces irritation to broken skin lesions.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A topical formulation for herpes lesions, wherein the topical formulation for herpes lesions is a flowable liquid dispersion system; by weight, the topical formulation for herpes lesions comprises the following components: A. Polyvinyl alcohol, in the form of 0.50-5.00 parts by weight; B. Sodium alginate, 0-1.00 parts by weight; C. Glycerin, 0.50-12.00 parts by weight; D. Ethanol, in the form of 0-40.00 parts by weight; E. Core-shell nanoparticles N1, in 0.05-5.00 parts by weight on a dry basis, wherein the core-shell nanoparticles N1 are core-shell nanoparticles formed by cross-linking chitosan and sodium tripolyphosphate ions to form a core and being coated with tannic acid; F. Plant polyphenol-phospholipid composite nanobody N3, in 0.05-8.00 parts by weight on a dry basis, wherein the plant polyphenol-phospholipid composite nanobody N3 is a nanobody formed by lecithin and plant polyphenol extract P, wherein the plant polyphenol extract P is an extract obtained by alcohol-water extraction of the whole herb of Phyllanthus urinaria and the aerial parts of Wedelia triloba. G. Agarwood volatile oil-cyclodextrin inclusion complex N2, in the form of 0.05-10.00 parts by weight on a dry basis, wherein the agarwood volatile oil-cyclodextrin inclusion complex N2 is an inclusion complex formed by agarwood volatile oil O and hydroxypropyl-β-cyclodextrin, wherein the agarwood volatile oil O is a volatile oil obtained by steam distillation of agarwood resin-containing wood or resin; H. pH adjuster, in the form of 0.05-2.00 parts by weight, wherein the pH adjuster is selected from one or more of citric acid, sodium citrate and their hydrates; I. With deionized water as the remainder, the sum of the weight parts of each component of the topical herpes lesion preparation is 100 parts by weight, wherein the deionized water includes added deionized water and water introduced by the dispersion of component E and / or component F and / or by the aqueous solution of component H.

[0007] Furthermore, the core-shell nanoparticles N1 are prepared through the following steps: A1. Raw material preparation: Add chitosan to deionized water containing lactic acid, so that the mass fraction of chitosan is 0.05-0.30 wt% and the mass fraction of lactic acid is 0.10-1.00 wt%, and stir to dissolve at 20-35℃ for 1.0-6.0 h; A2. Adjust pH: Use a sodium hydroxide aqueous solution with a mass fraction of 0.1-10.0 wt% to adjust the pH of the solution obtained in step A1 to 5.2-5.8 by adding dropwise. A3. Ionic crosslinking nucleation: Prepare an aqueous solution of sodium tripolyphosphate with a mass fraction of 0.05-0.30 wt%; add the aqueous solution of sodium tripolyphosphate dropwise to the solution obtained in step A2 within 1-5 min at 20-30℃, control the mass ratio of sodium tripolyphosphate to chitosan to be 0.05-0.25, and continue stirring for 0.5-2.0 h to obtain a chitosan nanonucleus dispersion; A4. Shell coating: Prepare an aqueous solution of tannic acid with a mass fraction of 0.01-0.30 wt%; add the aqueous solution of tannic acid to the chitosan nanocore dispersion, control the mass ratio of tannic acid to chitosan to be 0.05-0.50, and stir the reaction at pH 4.8-6.0 and temperature 20-30℃ for 0.5-2.0 h to form a core-shell structure; A5. Post-processing: Centrifuge the dispersion obtained in step A4 and resuspend it in deionized water. Repeat 1-3 times to obtain core-shell nanoparticles N1. A6. Quality control: The average particle size of the core-shell nanoparticles N1 is 80-250 nm, and the solid content of the resulting dispersion is 0.50-6.00 wt%.

[0008] Furthermore, the agarwood volatile oil-cyclodextrin inclusion complex N2 is prepared through the following steps: B1. Preparation of agarwood volatile oil: Agarwood containing resin or resin is added to deionized water for steam distillation at 98-100℃ for 2.0-8.0h. The oil phase is collected and allowed to stand for separation to obtain agarwood volatile oil O. B2. Preparation of cyclodextrin solution: Hydroxypropyl-β-cyclodextrin is added to deionized water and stirred at 45-65℃ for 0.5-2.0 h to obtain an aqueous cyclodextrin solution, wherein the mass fraction of hydroxypropyl-β-cyclodextrin in the aqueous cyclodextrin solution is 5.00-30.00 wt%. B3. Inclusion reaction: The agarwood volatile oil O obtained in step B1 is directly added to the cyclodextrin aqueous solution obtained in step B2, or the agarwood volatile oil O is first dissolved in ethanol and then added to the cyclodextrin aqueous solution obtained in step B2. Stir at 45-65℃ for 1.0-6.0h, and control the mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O to be 1:0.04-1:0.25. B4. Precipitation and drying: Cool the system obtained in step B3 to 0-10℃ and maintain it for 2.0-24.0h, filter to obtain solid, and dry under reduced pressure at 30-60℃ and 0.1-30kPa to constant weight to obtain agarwood volatile oil-cyclodextrin inclusion complex N2.

[0009] Furthermore, the plant polyphenol-phospholipid composite nanobody N3 is prepared through the following steps: C1. Plant raw materials: Mix the whole herb of Phyllanthus urinaria and the above-ground parts of Wedelia triloba at a mass ratio of 1:0.20-1:2.00 and then crush them; C2. Alcohol-water extraction: Add a mixed extraction solvent of ethanol and deionized water to the mixture obtained in step C1, making the volume fraction of ethanol 40-70 vol%, and the ratio of the total mass of the mixture to the total volume of the extraction solvent 1 g: 5-15 mL. Extract under reflux for 1.0-3.0 h, then filter. Combine the filtrates and concentrate under reduced pressure at 40-70℃ and 0.1-30 kPa to 1 / 5-1 / 3 of the original volume to obtain plant polyphenol extract P, wherein the mass fraction of plant polyphenol extract P is 10.00-40.00 wt%, and wherein the mass fraction is the dry basis solids mass fraction of plant polyphenol extract P. C3. Phospholipid Complex: Lecithin is added to ethanol and stirred at 40-70℃ to dissolve it and form a lecithin ethanol solution, wherein the mass fraction of lecithin in the lecithin ethanol solution is 5.00-30.00 wt%; plant polyphenol extract P obtained in step C2 is added to the lecithin ethanol solution, such that the dry mass ratio of lecithin to plant polyphenol extract P is 1:1-6:1, and the mixture is stirred and reacted at 45-65℃ for 0.5-4.0 h; C4. Solvent removal and water dispersion: The system obtained in step C3 was subjected to reduced pressure to remove ethanol at 40-60℃ and an absolute pressure of 0.1-30kPa, and deionized water was added for dispersion to make the solid content of the resulting dispersion 0.50-10.00wt%, thus obtaining plant polyphenol-phospholipid composite nanoparticles N3. C5. Quality control: The average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 is 100-500 nm.

[0010] Furthermore, the herpes lesion topical preparation is packaged in a mechanical pump spray bottle, which is a non-pressurized spray bottle. The average particle size of the dispersed phase in the herpes lesion topical preparation is the Z-average particle size measured by dynamic light scattering at 25°C, and is 80-500 nm. The herpes lesion topical preparation is subjected to a shear rate of 10 s at 25°C. -1 The apparent viscosity measured using a rotational viscometer was 2-80 mPa·s.

[0011] As a concept of this invention, this invention employs a system design that utilizes a dual-network film-forming matrix of polyvinyl alcohol and sodium alginate, core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 as three nanocarriers in synergy, along with glycerin plasticizing and moisturizing, ethanol for rapid drying and penetration enhancement, and pH microenvironment regulation. This design is mainly used to enhance the mechanical pump atomization, film density and wet retention, high load stability and sustained drug release of multi-carrier formulations for herpes lesions, as well as low irritation and high tolerance. Specifically, polyvinyl alcohol (PVA) serves as the primary film-forming material. The numerous hydroxyl groups on its molecular chains can form intermolecular hydrogen bonds with the carboxyl groups of sodium alginate and the hydroxyl groups of glycerol. In solution, the dynamic association and dissociation of these hydrogen bonds maintain the system's low viscosity and fluidity, keeping the apparent viscosity within the range of 2-80 mPa·s, meeting the atomization requirements of mechanical pump spray bottles. After spraying onto the skin lesion surface, with the rapid evaporation of ethanol and the decrease in ambient humidity, the hydrogen bond density between PVA molecular chains significantly increases, forming a three-dimensional network structure. Simultaneously, the carboxyl groups of sodium alginate can react with the Ca2+ in the skin lesion exudate. 2+ Mg 2+ Divalent cations undergo ionic crosslinking, and the dual-network synergistic effect forms a dense film-forming coating layer, providing resistance to erosion and retention in humid environments. The dosage of sodium alginate is controlled within the range of 0-1.00 parts by weight. When the dosage is 0, the system relies solely on hydrogen bonds for film formation. As the dosage increases, the ionic crosslinking effect strengthens, and the film density improves, but the system viscosity also increases. Optimization of the formulation can achieve a balance between low-viscosity atomization and film density. Glycerin, as a plasticizer and humectant, has a small molecular structure that can insert into the polyvinyl alcohol molecular chains to reduce hydrogen bond density and increase chain segment mobility. Simultaneously, it maintains the flexibility of the film layer and the moist environment of the skin lesion interface through hygroscopic action, preventing the film layer from becoming brittle and peeling off due to excessive drying. The dosage of glycerin is controlled within the range of 0.50-12.00 parts by weight. Too low a dosage results in insufficient film layer flexibility, while too high a dosage leads to excessive system viscosity, affecting atomization performance.

[0012] This invention also discloses a method for preparing the above-mentioned topical preparation for herpes lesions, comprising the following steps: S1. Provides core-shell nanoparticles N1; S2. Provides agarwood volatile oil-cyclodextrin inclusion complex N2; S3. Provides plant polyphenol-phospholipid composite nanoparticles N3; S4. Prepare a membrane substrate solution by mixing polyvinyl alcohol, sodium alginate, glycerol and deionized water; S5. Add ethanol, core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 to the film-forming matrix solution, and adjust the pH to 4.5-6.2 to obtain a topical preparation for herpes lesions.

[0013] Further, the preparation of the film-forming matrix solution in step S4 includes: adding polyvinyl alcohol to deionized water, heating and stirring at 80-95°C for 0.5-2.0 h to form a polyvinyl alcohol solution; cooling to 25-40°C, adding sodium alginate to the polyvinyl alcohol solution and stirring for 0.5-2.0 h, then adding glycerol and stirring for 0.2-1.0 h to obtain the film-forming matrix solution.

[0014] Furthermore, the addition process in step S5 includes: adding ethanol to the film-forming matrix solution and stirring for 0.1-1.0 h; adding core-shell nanoparticles N1 and plant polyphenol-phospholipid composite nanoparticles N3 and stirring for 0.2-2.0 h; adding agarwood volatile oil-cyclodextrin inclusion complex N2 and stirring for 0.2-2.0 h.

[0015] Furthermore, in step S5, citric acid and sodium citrate dihydrate are used as pH adjusters to make the pH of the system 4.5-6.2; the method also includes step S6: allowing the system to stand for degassing for 0.5-24 h and then filtering it through a 50-200 μm filter.

[0016] Furthermore, the dry basis weights of the core-shell nanoparticles N1, the plant polyphenol-phospholipid composite nanoparticles N3, and the agarwood volatile oil-cyclodextrin inclusion complex N2 were determined by drying to constant weight at 40-80℃ and an absolute pressure of 0.1-10 kPa. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings was not less than 1 h.

[0017] Furthermore, the average particle size of the core-shell nanoparticles N1 is the Z-average particle size measured by dynamic light scattering at 25°C.

[0018] Furthermore, the average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 is the Z-average particle size measured by dynamic light scattering at 25°C.

[0019] Furthermore, the average particle size of the dispersed phase in the topical herpes lesion preparation is the Z-average particle size measured by dynamic light scattering at 25°C.

[0020] Furthermore, the apparent viscosity is obtained at 25°C and a shear rate of 10 s. -1 The results were measured using a rotational viscometer.

[0021] Furthermore, the core-shell structure of the core-shell nanoparticles N1 is determined by observing the core-shell morphology using a transmission electron microscope. The sample observed by the transmission electron microscope is prepared by dropping a dispersion of core-shell nanoparticles N1 onto a copper grid and then naturally drying it at room temperature.

[0022] Furthermore, the centrifugation process in the preparation of the core-shell nanoparticles N1 is carried out at 4-25℃ with centrifugation at 5000-20000×g for 5-30 min. After discarding the supernatant, the mixture is resuspended in deionized water. The volume of deionized water during resuscitation is 0.5-2.0 times the volume of the original dispersion.

[0023] Furthermore, in the preparation of the core-shell nanoparticles N1, the pH adjustment in step A4 is achieved by adding a sodium hydroxide aqueous solution with a mass fraction of 0.1-10.0 wt% and / or a citric acid aqueous solution with a mass fraction of 0.1-10.0 wt%, with the pH monitored online during the addition process and maintained within the range of 4.8-6.0.

[0024] Furthermore, in the preparation process of the agarwood volatile oil-cyclodextrin inclusion complex N2, the vacuum drying to constant weight is carried out such that the mass difference between two consecutive weighings does not exceed 0.5 wt% of the mass of the previous weighing, and the interval between the two weighings is not less than 1 hour.

[0025] Furthermore, the mass-to-volume ratio of the agarwood resin-containing wood or resin to deionized water is 1g:3-15mL, and the mass of the resulting agarwood volatile oil O is 0.5-5.0wt% of the mass of the agarwood resin-containing wood or resin.

[0026] Furthermore, the hydroxypropyl-β-cyclodextrin aqueous solution is prepared by weighing 10.0-600g of hydroxypropyl-β-cyclodextrin and adding deionized water, so that the mass fraction of hydroxypropyl-β-cyclodextrin in the hydroxypropyl-β-cyclodextrin aqueous solution is 5.00-30.00wt%.

[0027] Furthermore, in the inclusion reaction, when agarwood volatile oil O is first dissolved in ethanol and then added, the ethanol is 95-100 vol% ethanol, and the mass ratio of ethanol to agarwood volatile oil O is 2:1-20:1.

[0028] Furthermore, the plant material is pulverized to pass through a 40-100 mesh sieve.

[0029] Furthermore, the mass fraction of the plant polyphenol extract P is the dry basis solids mass fraction, which is determined by drying the plant polyphenol extract P to constant weight under conditions of 40-80℃ and absolute pressure of 0.1-10kPa. The constant weight is defined as the mass difference between two consecutive weighings not exceeding 0.5wt% of the mass of the previous weighing, and the interval between the two weighings is not less than 1 hour.

[0030] Furthermore, the lecithin ethanol solution is prepared by weighing 10-500g of lecithin and adding it to ethanol with a volume fraction of 95-100 vol%, so that the mass fraction of lecithin is 5.00-30.00 wt%.

[0031] Furthermore, the stirring and dissolving process in the preparation of the core-shell nanoparticles N1 and the stirring and dissolving process in the preparation of the plant polyphenol-phospholipid composite nanoparticles N3 are carried out by mechanical stirring at a speed of 200-800 rpm.

[0032] Furthermore, the dropping process in steps A2 and A3 during the preparation of the core-shell nanoparticles N1, and the dropping process in the preparation of the agarwood volatile oil-cyclodextrin inclusion complex N2 when the agarwood volatile oil O is first dissolved in ethanol before being added, have a dropping acceleration rate of 0.5-10.0 mL / min.

[0033] Furthermore, during the preparation of the topical herpes lesion preparation, the static degassing process is carried out until no visible bubbles are visible in the system.

[0034] Furthermore, the pH adjustment in step S5 is achieved by preparing citric acid and sodium citrate dihydrate into aqueous solutions and then adding them dropwise to the system. The mass fraction of the citric acid aqueous solution and the sodium citrate dihydrate aqueous solution is 0.1-20.0 wt% respectively. During the dropwise addition process, the pH of the system is monitored online and adjusted to 4.5-6.2.

[0035] In this invention, N1 (80-250 nm positively charged), N3 (100-500 nm negatively charged), and amphiphilic solid particles N2 achieve spatial complementarity and stable dispersion based on differences in scale, charge, and hydrophilicity / hydrophobicity. Aggregation is avoided by utilizing the steric hindrance of the film-forming matrix and hydrogen bond interfaces, allowing the total loading to reach approximately 13.10 parts by weight. In terms of efficacy, the loading and target of the three components are complementary and exhibit a fast-medium-slow gradient release: N1 adheres to skin lesions and rapidly releases tannins for astringent, antipruritic, and anti-inflammatory effects; N3 fuses with skin lipids to deliver plant polyphenols at a moderate rate for antiviral and repair-promoting effects; and N2 slowly releases agarwood volatile oil for long-lasting antibacterial, analgesic, and prevention of secondary infections. Simultaneously, it couples with the film-forming framework, ethanol for rapid drying and penetration enhancement, and a weakly acidic microenvironment of pH 4.5-6.2, achieving pumpable atomization with low viscosity, dense and resistant to erosion after film formation, fast drying and refreshing properties, and low irritation tolerance.

[0036] Beneficial technical effects 1. Achieved low viscosity and uniform spray performance for mechanical pump atomization: Through molecular design of a dual-network film-forming matrix of polyvinyl alcohol and sodium alginate in solution state with dynamic hydrogen bond association and dissociation, the apparent viscosity of the system is precisely controlled within the range of 2-80 mPa·s, meeting the atomization requirements of mechanical pump spray bottles; at the same time, through the differentiated design of three nanocarriers (core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2) in terms of particle size, surface charge, and hydrophobic and hydrophilic properties, dispersion stability and nozzle passability under high load (total load up to 13.10 parts by weight) are achieved, avoiding the problems of aggregation and precipitation and nozzle clogging when a single nanocarrier is under high load, significantly improving the ease of use of the formulation and patient compliance.

[0037] 2. Achieved dense film coverage and wet-state erosion resistance: This was achieved through a three-dimensional network structure formed by increased hydrogen bond density between polyvinyl alcohol molecular chains, and the interaction of sodium alginate carboxyl groups with divalent cations (Ca) in the skin lesion exudate. 2+ Mg 2+ The synergistic effect of the triple mechanism of ionic cross-linking of the N1 chitosan core and the mucosal adhesion of the core-shell nanoparticles to the mucosal proteins on the surface of the lesions forms a dense film covering layer on the surface of herpes lesions, effectively isolating the contact of external irritants and pathogens. At the same time, in the wet environment of exudative lesions, it provides a long-lasting anti-erosion retention ability through dual network cross-linking and mucosal adhesion, significantly prolonging the action time of the formulation and reducing the frequency of reapplication.

[0038] 3. Achieved rapid onset and sustained efficacy: Through the gradient design of release kinetics of three nanocarriers—core-shell nanoparticles N1 (rapid release of tannic acid, within minutes to tens of minutes, for rapid itch relief and astringency), plant polyphenol-phospholipid complex nanoparticles N3 (medium-speed release of plant polyphenols from Phyllanthus urinaria and Wedelia triloba, within hours to more than ten hours, for sustained antiviral and repair-promoting effects), and agarwood volatile oil-cyclodextrin inclusion complex N2 (slow release of agarwood volatile oil, within ten to tens of hours, for long-lasting anti-infection and analgesia)—synergistic efficacy was achieved throughout the acute, subacute, and repair phases of herpes lesions. This not only met the patient's immediate need for rapid symptom relief but also achieved sustained therapeutic effects of antiviral, repair-promoting, and anti-infection properties.

[0039] 4. Achieved the fast-drying, refreshing, and low-irritation, high-tolerance properties of the ethanol-containing weak acid system: Through the synergistic design of controlling the ethanol dosage within the range of 0-40.00 parts by weight and precisely adjusting the pH to the range of 4.5-6.2, on the one hand, the fast-drying and penetration-enhancing effects of ethanol are utilized to improve the refreshing feel of the formulation and the transdermal absorption efficiency of the active ingredients. On the other hand, by using a pH close to the physiological pH of herpes lesions (approximately 5.0-5.5) and the antibacterial and repair-promoting effects of the weakly acidic microenvironment itself, the irritation of the ethanol-containing weak acid system to broken skin lesions is significantly reduced. This balances the technical contradiction between the need for fast-drying, refreshing, and anti-infective properties and the need for low-irritation and high-tolerance properties in the state of the skin lesions, thereby improving patient medication comfort and treatment compliance.

[0040] 5. Achieved shelf-life stability and convenient clinical application of the formulation: The process design, which avoids mutual interference between different nanosystems through stepwise preparation of the three-nanocarrier, avoids aggregation through a stepwise addition strategy, and maintains the dispersion stability of the nanocarrier by protecting the steric hindrance of the film-forming matrix, ensures that the particle size distribution and dispersion uniformity of the nanocarrier remain stable throughout the shelf life of the formulation; at the same time, the packaging design of the mechanical pump-type non-pressurized spray bottle avoids the mechanical stimulation of herpes ulcer lesions by pressurized spray, and achieves convenient spray administration, uniform lesion coverage, and a comfortable user experience, which has good clinical application value and market promotion prospects. Attached Figure Description

[0041] Figure 1 The graph shows the change of Z-average particle size over time at different time points for Example 1 and Comparative Examples 4, 5, and 8, determined by dynamic light scattering method.

[0042] Figure 2 The graph shows the change of polydispersity index (PDI) over time at different time points for Example 1 and Comparative Examples 4, 5, and 8, determined by dynamic light scattering method.

[0043] Figure 3 The graph shows the change of Zeta potential over time at different time points for Example 1 and Comparative Examples 4, 5, and 8, determined by dynamic light scattering method.

[0044] Figure 4 The image shows the superimposed particle size distribution curves of Example 1 and Comparative Examples 4, 5, and 8 at 0 h, determined by dynamic light scattering method.

[0045] Figure 5 The image shows the overlay of particle size distribution curves of Example 1 and Comparative Examples 4, 5, and 8 at 30 days, determined by dynamic light scattering method.

[0046] Figure 6 The image shows the superimposed infrared spectra of Example 1, Comparative Example 2, and Comparative Example 3 determined by Fourier transform infrared spectroscopy.

[0047] Figure 7 The apparent viscosity-shear rate rheological curves of Example 1, Comparative Example 5, and Comparative Example 6 were determined using a rotational viscometer.

[0048] Figure 8 The cumulative distribution curves of droplet volume size of Example 1, Comparative Example 5, and Comparative Example 8 are overlaid using a laser particle size analyzer.

[0049] Figure 9 The curves and fitting comparison diagrams for determining the in vitro cumulative release rate over time of Example 1, Comparative Examples 2 and 3 by high performance liquid chromatography are shown.

[0050] Figure 10 This is a comparison of the full spectrum scans of Example 1 and Comparative Example 1 determined by X-ray photoelectron spectroscopy.

[0051] Figure 11 Comparison of the N1s high-resolution fine spectra of Example 1 and Comparative Example 1 determined by X-ray photoelectron spectroscopy.

[0052] Figure 12 Comparison of O1s high-resolution fine spectra of Example 1 and Comparative Example 1 determined by X-ray photoelectron spectroscopy.

[0053] Figure 13 This is a macroscopic optical photograph of the topical preparation for herpes lesions (sample E1) in Example 1.

[0054] Figure 14 This is a macroscopic photograph of the dry film formed after the sample of Example 1 was sprayed and dried.

[0055] Figure 15 Scanning electron microscope image of the solid residual structure after spraying / drop coating.

[0056] Figure 16 This is a bright-field transmission electron microscope image of N1 core-shell nanoparticles. Detailed Implementation

[0057] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0058] Example 1 This embodiment prepares a topical formulation for herpes lesions, which is a flowable liquid dispersion system.

[0059] I. Preparation of core-shell nanoparticles N1 Chitosan was added to deionized water containing lactic acid to achieve a chitosan mass fraction of 0.18 wt% and a lactic acid mass fraction of 0.55 wt%. The solution was dissolved at 28°C with mechanical stirring at 500 rpm for 3.5 h. A 5.0 wt% sodium hydroxide aqueous solution was added dropwise at a rate of 2.5 mL / min to adjust the pH of the resulting solution to 5.5. A sodium tripolyphosphate aqueous solution was prepared to achieve a sodium tripolyphosphate mass fraction of 0.18 wt%. This sodium tripolyphosphate aqueous solution was added dropwise to the above solution over 3 min at a rate of 3.0 mL / min at 25°C, maintaining a sodium tripolyphosphate to chitosan mass ratio of 0.15. Stirring was continued for 1.2 h to obtain a chitosan nanocore dispersion. A tannic acid aqueous solution was prepared to achieve a tannic acid mass fraction of 0.16 wt%. The tannic acid aqueous solution was added to the chitosan nanocore dispersion, controlling the mass ratio of tannic acid to chitosan to be 0.28. Simultaneously, 2.0 wt% sodium hydroxide aqueous solution and 2.0 wt% citric acid aqueous solution were added dropwise to adjust the pH, which was monitored online and maintained at 5.4. The reaction was carried out at 25℃ with stirring for 1.2 h to form a core-shell structure. The resulting dispersion was centrifuged at 12000×g for 15 min at 15℃. The supernatant was discarded, and the mixture was resuspended in deionized water at a volume 1.0 times that of the original dispersion. This centrifugation and resuspension were repeated twice to obtain a dispersion of core-shell nanoparticles N1. Dynamic light scattering was used at 25℃ to determine the Z-average particle size of the core-shell nanoparticles N1, which was 165 nm. The solid content of the obtained dispersion was 4.50 wt%. The N1 dispersion of core-shell nanoparticles was dropped onto a copper grid and allowed to dry naturally at room temperature. The core-shell morphology was then confirmed by observation using a transmission electron microscope.

[0060] II. Preparation of Agarwood Volatile Oil-Cyclodextrin Inclusion Complex N2 Agarwood containing resin was steam distilled in deionized water at a mass-to-volume ratio of 1 g:8 mL at 99°C for 5.0 h. The oil phase was collected and allowed to stand for separation to obtain agarwood volatile oil O, which accounted for 2.8 wt% of the mass of the agarwood containing resin. 175 g of hydroxypropyl-β-cyclodextrin was weighed and added to 825 g of deionized water. The mixture was stirred at 55°C for 1.2 h to obtain a cyclodextrin aqueous solution with a hydroxypropyl-β-cyclodextrin mass fraction of 17.50 wt%. Agarwood volatile oil O was first dissolved in 95 vol% ethanol at a mass ratio of 10:1. This solution was then added dropwise to the cyclodextrin aqueous solution at a rate of 5.0 mL / min. The mixture was stirred at 55°C for 3.5 h, maintaining a mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O of 1:0.15. The obtained system was cooled to 5°C and held for 12 hours. The solid was then filtered and dried under reduced pressure at 45°C and 10 kPa to constant weight to obtain the agarwood volatile oil-cyclodextrin inclusion complex N2. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 hour between the two weighings.

[0061] III. Preparation of Plant Polyphenol-Phospholipid Composite Nanoparticles N3 The whole plant of Phyllanthus urinaria and the aerial parts of Wedelia triloba were mixed at a mass ratio of 1:1.00 and pulverized to pass through a 60-mesh sieve. A mixed extraction solvent of ethanol and deionized water was added to the resulting mixture to make the ethanol volume fraction 55 vol% and the ratio of the total mass of the mixture to the total volume of the extraction solvent 1 g: 10 mL. Extraction was carried out under reflux for 2.0 h, followed by filtration. The filtrates were combined and concentrated under reduced pressure at 55 °C and 10 kPa to 1 / 4 of the original volume to obtain plant polyphenol extract P. Plant polyphenol extract P was dried to constant weight at 60 °C and 5 kPa, and its dry basis solids content was determined to be 25.00 wt%. Constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 h between the two weighings. 175g of lecithin was weighed and added to 825g of ethanol (98 vol%). The mixture was stirred mechanically at 400 rpm at 55°C to dissolve the lecithin in an ethanol solution, forming a lecithin ethanol solution with a lecithin mass fraction of 17.50 wt%. Plant polyphenol extract P was added to the lecithin ethanol solution, making the dry weight ratio of lecithin to plant polyphenol extract P 3.5:1. The mixture was stirred at 55°C for 2.0 h. The ethanol was removed under reduced pressure at 50°C and 10 kPa. Deionized water was added to disperse the mixture, resulting in a dispersion with a solid content of 7.00 wt%, yielding a dispersion of plant polyphenol-phospholipid composite nanoparticles N3. Dynamic light scattering (DLS) at 25°C determined the Z-average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 to be 300 nm.

[0062] IV. Preparation of Topical Preparations for Herpes Lesions The formulation of this embodiment, by weight, consists of: 2.50 parts polyvinyl alcohol, 0.50 parts sodium alginate, 6.00 parts glycerol, 20.00 parts ethanol, 1.00 parts core-shell nanoparticles N1 (on a dry basis), 2.00 parts plant polyphenol-phospholipid composite nanoparticles N3 (on a dry basis), 3.00 parts agarwood volatile oil-cyclodextrin inclusion complex N2, 0.80 parts pH adjuster, with deionized water as the balance, making the total weight of all components 100 parts by weight.

[0063] The preparation steps are as follows: Polyvinyl alcohol is added to deionized water and heated and stirred at 88°C for 1.2 h to form a polyvinyl alcohol solution. After cooling to 32°C, sodium alginate is added to the polyvinyl alcohol solution and stirred for 1.2 h, then glycerol is added and stirred for 0.6 h to obtain a film-forming matrix solution. Ethanol is added to the film-forming matrix solution and stirred for 0.5 h. Core-shell nanoparticle N1 dispersion (solid content 4.50 wt%, based on 1.00 parts by weight dry basis, 22.22 parts by weight dispersion) and plant polyphenol-phospholipid composite nanoparticle N3 dispersion (solid content 7.00 wt%, based on 2.00 parts by weight dry basis, 28.57 parts by weight dispersion) are added and stirred for 1.0 h. Agarwood volatile oil-cyclodextrin inclusion complex N2 is added and stirred for 1.0 h. Citric acid and sodium citrate dihydrate were each prepared into 10.0 wt% aqueous solutions. These solutions were then added dropwise to the system, with online monitoring and pH adjustment to 5.5. The pH adjuster used (total amount of citric acid and sodium citrate dihydrate) was 0.80 parts by weight. Water introduced during the preparation of the pH adjuster solution was included in the remaining deionized water. The system was allowed to stand for 12 hours to remove visible bubbles. The solution was then filtered through a 100 μm filter to obtain the topical herpes lesion preparation of this embodiment.

[0064] In this embodiment, the dry basis weights of the core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 in the formulation were determined by drying to constant weight at 60°C and 5 kPa absolute pressure. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings was 1 h.

[0065] The Z-average particle size of the dispersed phase in this formulation was determined to be 280 nm using dynamic light scattering at 25°C. This was achieved at 25°C and a shear rate of 10 s⁻¹. -1 The apparent viscosity of the formulation in this embodiment was measured to be 40 mPa·s using a rotational viscometer. The formulation in this embodiment was packaged into a mechanical pump-type spray bottle and used in a non-pressurized spray bottle.

[0066] Example 1 Features and Applications: This example uses a moderate range of formulation parameters. Polyvinyl alcohol (2.50 parts by weight) ensures moderate film-forming properties, glycerin (6.00 parts by weight) provides good moisturizing properties, and ethanol (20.00 parts by weight) helps balance system stability and permeability. The dry basis amounts of core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 are 1.00, 2.00, and 3.00 parts by weight, respectively, achieving a synergistic effect of antiviral, anti-inflammatory, and repair-promoting components. Sodium alginate (0.50 parts by weight) enhances system adhesion, and a pH adjuster (0.80 parts by weight) maintains the formulation pH at 5.5. A dispersed phase particle size of 280 nm ensures uniform dispersion of nano-components, and an apparent viscosity of 40 mPa·s is suitable for spray administration. This example demonstrates good formulation and process stability, making it suitable for treating skin herpes lesions caused by herpes simplex virus or herpes zoster virus, especially for herpes infections on sensitive areas such as the face and neck.

[0067] Example 2 This embodiment prepares a topical formulation for herpes lesions, which is a flowable liquid dispersion system.

[0068] I. Preparation of core-shell nanoparticles N1 Chitosan was added to deionized water containing lactic acid to achieve a chitosan mass fraction of 0.12 wt% and a lactic acid mass fraction of 0.30 wt%. The solution was dissolved for 2.5 h at 24 °C using mechanical stirring at 350 rpm. A 2.0 wt% sodium hydroxide aqueous solution was added dropwise at a rate of 1.5 mL / min to adjust the pH of the resulting solution to 5.3. A sodium tripolyphosphate aqueous solution was prepared to achieve a sodium tripolyphosphate mass fraction of 0.12 wt%. This sodium tripolyphosphate aqueous solution was added dropwise to the above solution over 2 min at a rate of 2.0 mL / min at 22 °C, maintaining a sodium tripolyphosphate to chitosan mass ratio of 0.10. Stirring was continued for 0.8 h to obtain a chitosan nanocore dispersion. A tannic acid aqueous solution was prepared to achieve a tannic acid mass fraction of 0.08 wt%. The tannic acid aqueous solution was added to the chitosan nanocore dispersion, controlling the mass ratio of tannic acid to chitosan to be 0.15. Simultaneously, 1.0 wt% sodium hydroxide aqueous solution and 1.0 wt% citric acid aqueous solution were added dropwise to adjust the pH, which was monitored online and maintained at 5.0. The reaction was carried out at 22℃ with stirring for 0.8 h to form a core-shell structure. The resulting dispersion was centrifuged at 8000×g for 12 min at 10℃. The supernatant was discarded, and the mixture was resuspended in deionized water at a volume 0.8 times that of the original dispersion. This centrifugation and resuspension were repeated twice to obtain a dispersion of core-shell nanoparticles N1. Dynamic light scattering was used at 25℃ to determine the Z-average particle size of the core-shell nanoparticles N1, which was 120 nm. The solid content of the obtained dispersion was 3.00 wt%. The N1 dispersion of core-shell nanoparticles was dropped onto a copper grid and allowed to dry naturally at room temperature. The core-shell morphology was then confirmed by observation using a transmission electron microscope.

[0069] II. Preparation of Agarwood Volatile Oil-Cyclodextrin Inclusion Complex N2 Agarwood resin was added to deionized water for steam distillation at a mass-to-volume ratio of 1 g:6 mL. Distillation was carried out at 99°C for 4.0 h. The oil phase was collected and allowed to stand for separation to obtain agarwood volatile oil O, which was 2.0 wt% of the mass of the agarwood resin. 120 g of hydroxypropyl-β-cyclodextrin was weighed and added to 880 g of deionized water. The mixture was stirred at 50°C for 0.8 h to obtain a cyclodextrin aqueous solution with a hydroxypropyl-β-cyclodextrin mass fraction of 12.00 wt%. Agarwood volatile oil O was first dissolved in 95 vol% ethanol at a mass ratio of 6:1. This solution was then added dropwise to the cyclodextrin aqueous solution at a rate of 3.0 mL / min. The mixture was stirred at 50°C for 2.5 h, maintaining a mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O of 1:0.08. The obtained system was cooled to 3°C and maintained for 8 hours. The solid was then filtered and dried under reduced pressure at 40°C and 15 kPa to constant weight to obtain the agarwood volatile oil-cyclodextrin inclusion complex N2. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 hour between the two weighings.

[0070] III. Preparation of Plant Polyphenol-Phospholipid Composite Nanoparticles N3 The whole plant of Phyllanthus urinaria and the aerial parts of Wedelia candel were mixed at a mass ratio of 1:0.50 and pulverized to pass through a 50-mesh sieve. A mixed extraction solvent of ethanol and deionized water was added to the resulting mixture to make the ethanol volume fraction 50 vol% and the ratio of the total mass of the mixture to the total volume of the extraction solvent 1 g:7 mL. Extraction was carried out under reflux for 1.5 h, followed by filtration. The filtrates were combined and concentrated under reduced pressure at 48 °C and 15 kPa to 1 / 5 of the original volume to obtain plant polyphenol extract P. Plant polyphenol extract P was dried to constant weight at 55 °C and 8 kPa, and its dry basis solids content was determined to be 18.00 wt%. Constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 h between the two weighings. 120g of lecithin was weighed and added to 880g of ethanol (95 vol%). The mixture was stirred mechanically at 300 rpm at 50°C to dissolve the lecithin in ethanol, forming a lecithin ethanol solution with a lecithin mass fraction of 12.00 wt%. Plant polyphenol extract P was added to the lecithin ethanol solution, making the dry weight ratio of lecithin to plant polyphenol extract P 2.5:1. The mixture was stirred at 50°C for 1.5 hours. The ethanol was removed from the resulting system under reduced pressure at 45°C and 15 kPa. Deionized water was added to disperse the ethanol, resulting in a dispersion with a solid content of 5.00 wt%, yielding a dispersion of plant polyphenol-phospholipid composite nanoparticles N3. The Z-average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 was determined to be 200 nm using dynamic light scattering at 25°C.

[0071] IV. Preparation of Topical Preparations for Herpes Lesions The formulation of this embodiment, by weight, consists of: 1.50 parts polyvinyl alcohol, 0.30 parts sodium alginate, 4.00 parts glycerol, 12.00 parts ethanol, 0.50 parts core-shell nanoparticles N1 (on a dry basis), 1.00 parts plant polyphenol-phospholipid composite nanoparticles N3 (on a dry basis), 1.50 parts agarwood volatile oil-cyclodextrin inclusion complex N2, 0.40 parts pH adjuster, with deionized water as the balance, making the total weight of all components 100 parts by weight.

[0072] The preparation steps are as follows: Polyvinyl alcohol is added to deionized water and heated and stirred at 85°C for 1.0 h to form a polyvinyl alcohol solution. After cooling to 28°C, sodium alginate is added to the polyvinyl alcohol solution and stirred for 0.8 h, then glycerol is added and stirred for 0.4 h to obtain a film-forming matrix solution. Ethanol is added to the film-forming matrix solution and stirred for 0.3 h. Core-shell nanoparticle N1 dispersion (3.00 wt% solid content, 16.67 parts by weight of dispersion based on 0.50 parts by weight dry basis) and plant polyphenol-phospholipid composite nanoparticle N3 dispersion (5.00 wt% solid content, 20.00 parts by weight of dispersion based on 1.00 parts by weight dry basis) are added and stirred for 0.6 h. Agarwood volatile oil-cyclodextrin inclusion complex N2 is added and stirred for 0.6 h. Citric acid and sodium citrate dihydrate were each prepared into 5.0 wt% aqueous solutions. These solutions were then added dropwise to the system, with online monitoring and pH adjustment to 4.8. The pH adjuster used (total amount of citric acid and sodium citrate dihydrate) was 0.40 parts by weight. Water introduced during the preparation of the pH adjuster solution was included in the remaining deionized water. The system was allowed to stand for 6 hours to remove visible bubbles. After filtration through an 80 μm filter, the topical herpes lesion preparation of this embodiment was obtained.

[0073] In this embodiment, the dry basis weights of the core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 in the formulation were determined by drying to constant weight at 55°C and 8 kPa absolute pressure. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings was 1 hour.

[0074] The Z-average particle size of the dispersed phase in this formulation was determined to be 150 nm using dynamic light scattering at 25°C. This was achieved at 25°C and a shear rate of 10 s⁻¹. -1 The apparent viscosity of the formulation in this embodiment was measured to be 18 mPa·s using a rotational viscometer. The formulation in this embodiment was packaged into a mechanical pump-type spray bottle and used in a non-pressurized spray bottle.

[0075] Example 2 Features and Applications: This example uses formulation parameters biased towards lower dosage ranges. Polyvinyl alcohol (PVA) is used at 1.50 parts by weight to form a thin, breathable film layer; glycerin (GG) is used at 4.00 parts by weight to maintain basic moisturizing function; ethanol (ethanol) is used at 12.00 parts by weight to ensure system fluidity; the dry basis dosages of core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 are 0.50, 1.00, and 1.50 parts by weight, respectively, ensuring a moderate concentration of active ingredients; sodium alginate (sodium alginate) is used at 0.30 parts by weight to provide basic adhesion; a pH adjuster (pH adjuster) is used at 0.40 parts by weight to maintain the formulation's pH at 4.8; the dispersed phase particle size of 150 nm achieves efficient dispersion of nano-components; and the apparent viscosity of 18 mPa·s gives the formulation low viscosity and rapid penetration characteristics. This example formulation is refreshing and non-greasy, suitable for treating mild herpes lesions or as an adjunct care during the herpes recovery period, and is particularly suitable for patients with oily skin or for use in hot seasons.

[0076] Example 3 This embodiment prepares a topical formulation for herpes lesions, which is a flowable liquid dispersion system.

[0077] I. Preparation of core-shell nanoparticles N1 Chitosan was added to deionized water containing lactic acid to achieve a chitosan mass fraction of 0.23 wt% and a lactic acid mass fraction of 0.70 wt%. The solution was dissolved at 32°C with mechanical stirring at 650 rpm for 4.5 h. An 8.0 wt% sodium hydroxide aqueous solution was added dropwise at a rate of 8.0 mL / min to adjust the pH of the resulting solution to 5.7. A sodium tripolyphosphate aqueous solution was prepared to achieve a sodium tripolyphosphate mass fraction of 0.23 wt%. This sodium tripolyphosphate aqueous solution was added dropwise to the above solution over 4 min at a rate of 8.0 mL / min at 28°C, maintaining a sodium tripolyphosphate to chitosan mass ratio of 0.20. Stirring was continued for 1.6 h to obtain a chitosan nanocore dispersion. A tannic acid aqueous solution was prepared to achieve a tannic acid mass fraction of 0.22 wt%. The tannic acid aqueous solution was added to the chitosan nanocore dispersion, controlling the mass ratio of tannic acid to chitosan to be 0.38. Simultaneously, 8.0 wt% sodium hydroxide aqueous solution and 8.0 wt% citric acid aqueous solution were added dropwise to adjust the pH, which was monitored online and maintained at 5.8. The reaction was carried out at 28℃ with stirring for 1.6 h to form a core-shell structure. The resulting dispersion was centrifuged at 16000×g for 20 min at 20℃. The supernatant was discarded, and the mixture was resuspended in deionized water at a volume 1.5 times that of the original dispersion. This centrifugation and resuspension were repeated twice to obtain a dispersion of core-shell nanoparticles N1. Dynamic light scattering was used at 25℃ to determine the Z-average particle size of the core-shell nanoparticles N1, which was 200 nm. The solid content of the obtained dispersion was 5.50 wt%. The N1 dispersion of core-shell nanoparticles was dropped onto a copper grid and allowed to dry naturally at room temperature. The core-shell morphology was then confirmed by observation using a transmission electron microscope.

[0078] II. Preparation of Agarwood Volatile Oil-Cyclodextrin Inclusion Complex N2 Agarwood containing resin was steam distilled in deionized water at a mass-to-volume ratio of 1 g:12 mL at 100 °C for 6.5 h. The oil phase was collected and allowed to stand for separation to obtain agarwood volatile oil O, which was 3.5 wt% of the mass of the agarwood containing resin. 230 g of hydroxypropyl-β-cyclodextrin was weighed and added to 770 g of deionized water. The mixture was stirred at 60 °C for 1.6 h to obtain a cyclodextrin aqueous solution with a hydroxypropyl-β-cyclodextrin mass fraction of 23.00 wt%. Agarwood volatile oil O was directly added to the cyclodextrin aqueous solution and stirred at 60 °C for 4.8 h, maintaining a mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O of 1:0.19. The obtained system was cooled to 7°C and maintained for 18 hours. The solid was then filtered and dried under reduced pressure at 52°C and 5 kPa to constant weight to obtain the agarwood volatile oil-cyclodextrin inclusion complex N2. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 hour between the two weighings.

[0079] III. Preparation of Plant Polyphenol-Phospholipid Composite Nanoparticles N3 The whole plant of Phyllanthus urinaria and the aerial parts of Wedelia triloba were mixed at a mass ratio of 1:1.50 and pulverized to pass through an 80-mesh sieve. A mixed extraction solvent of ethanol and deionized water was added to the resulting mixture to make the ethanol volume fraction 62 vol% and the ratio of the total mass of the mixture to the total volume of the extraction solvent 1 g: 12 mL. Extraction was carried out under reflux for 2.5 h, followed by filtration. The filtrates were combined and concentrated under reduced pressure at 62 °C and 5 kPa to 1 / 3 of the original volume to obtain plant polyphenol extract P. Plant polyphenol extract P was dried at 65 °C and 3 kPa to constant weight, and its dry basis solids content was determined to be 32.00 wt%. Constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 h between the two weighings. 230g of lecithin was weighed and added to 100 vol% ethanol. The solution was dissolved by mechanical stirring at 600 rpm at 60°C to form a lecithin ethanol solution with a lecithin mass fraction of 23.00 wt%. Plant polyphenol extract P was added to the lecithin ethanol solution to achieve a dry matter ratio of 4.5:1. The mixture was stirred at 60°C for 3.0 h. The ethanol was removed under reduced pressure at 55°C and 5 kPa. Deionized water was added to disperse the ethanol, resulting in a dispersion with a solid content of 8.50 wt%, yielding a dispersion of plant polyphenol-phospholipid composite nanoparticles N3. The Z-average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 was determined to be 400 nm using dynamic light scattering at 25°C.

[0080] IV. Preparation of Topical Preparations for Herpes Lesions The formulation of this embodiment, by weight, consists of: 3.50 parts polyvinyl alcohol, 0.70 parts sodium alginate, 8.00 parts glycerol, 28.00 parts ethanol, 1.00 parts core-shell nanoparticles N1 (on a dry basis), 2.00 parts plant polyphenol-phospholipid composite nanoparticles N3 (on a dry basis), 5.50 parts agarwood volatile oil-cyclodextrin inclusion complex N2, 1.20 parts pH adjuster, with deionized water as the balance, making the total weight of all components 100 parts by weight.

[0081] The preparation steps are as follows: Polyvinyl alcohol is added to deionized water and heated and stirred at 92°C for 1.6 h to form a polyvinyl alcohol solution. After cooling to 36°C, sodium alginate is added to the polyvinyl alcohol solution and stirred for 1.6 h, then glycerol is added and stirred for 0.8 h to obtain a film-forming matrix solution. Ethanol is added to the film-forming matrix solution and stirred for 0.8 h. Core-shell nanoparticle N1 dispersion (solid content 5.50 wt%, based on 1.00 parts by weight dry basis, 18.18 parts by weight dispersion) and plant polyphenol-phospholipid composite nanoparticle N3 dispersion (solid content 8.50 wt%, based on 2.00 parts by weight dry basis, 23.53 parts by weight dispersion) are added and stirred for 1.6 h. Agarwood volatile oil-cyclodextrin inclusion complex N2 is added and stirred for 1.6 h. Citric acid and sodium citrate dihydrate were each prepared into 15.0 wt% aqueous solutions. These solutions were then added dropwise to the system, with online monitoring and pH adjustment to 6.0. The pH adjuster used (total amount of citric acid and sodium citrate dihydrate) was 1.20 parts by weight. Water introduced during pH adjustment was included in the remaining deionized water. The system was allowed to stand for 18 hours until no visible bubbles remained. The solution was then filtered through a 150 μm filter to obtain the topical herpes lesion preparation of this embodiment.

[0082] In this embodiment, the dry basis weights of the core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 in the formulation were determined by drying to constant weight at 65°C and 3 kPa absolute pressure. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings was 1 h.

[0083] The Z-average particle size of the dispersed phase in this formulation was determined to be 380 nm using dynamic light scattering at 25°C. This was achieved at 25°C and a shear rate of 10 s⁻¹. -1 The apparent viscosity of the formulation in this embodiment was measured to be 65 mPa·s using a rotational viscometer. The formulation in this embodiment was packaged into a mechanical pump-type spray bottle and used in a non-pressurized spray bottle.

[0084] Example 3 Features and Applications: This example uses formulation parameters that are biased towards a higher dosage range. Polyvinyl alcohol is used at 3.50 parts by weight to form a thicker protective film layer. Glycerin is used at 8.00 parts by weight to provide enhanced moisturizing function. Ethanol is used at 28.00 parts by weight to enhance the transdermal penetration of active ingredients. The dry basis dosages of core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 are 1.00, 2.00, and 5.50 parts by weight, respectively. The higher dosage of agarwood volatile oil inclusion complex enhances analgesic and tissue repair effects. Sodium alginate is used at 0.70 parts by weight to enhance mucosal adhesion. The pH adjuster is used at 1.20 parts by weight to maintain the pH of the formulation at 6.0. The dispersed phase particle size of 380 nm takes into account both nano-effect and sustained-release effect. The apparent viscosity of 65 mPa·s provides good skin adhesion. The formula in this embodiment has a high concentration of active ingredients and is suitable for treating moderate to severe herpes lesions or painful herpes zoster. It is especially suitable for patients with dry skin or those who need long-lasting protection.

[0085] Example 4 This embodiment prepares a topical formulation for herpes lesions, which is a flowable liquid dispersion system.

[0086] I. Preparation of core-shell nanoparticles N1 Chitosan was added to deionized water containing lactic acid to achieve a chitosan mass fraction of 0.10 wt% and a lactic acid mass fraction of 0.25 wt%. The solution was dissolved at 22°C with mechanical stirring at 300 rpm for 2.0 h. A 1.5 wt% sodium hydroxide aqueous solution was added dropwise at a rate of 1.5 mL / min to adjust the pH of the resulting solution to 5.4. A sodium tripolyphosphate aqueous solution was prepared to achieve a sodium tripolyphosphate mass fraction of 0.10 wt%. This sodium tripolyphosphate aqueous solution was added dropwise to the above solution over 1.5 min at a rate of 2.5 mL / min, maintaining a sodium tripolyphosphate to chitosan mass ratio of 0.08, and stirring was continued for 0.6 h to obtain a chitosan nanocore dispersion. A tannic acid aqueous solution was prepared to achieve a tannic acid mass fraction of 0.05 wt%. The tannic acid aqueous solution was added to the chitosan nanocore dispersion, controlling the mass ratio of tannic acid to chitosan to be 0.12. Simultaneously, 1.5 wt% sodium hydroxide aqueous solution and 1.5 wt% citric acid aqueous solution were added dropwise to adjust the pH, which was monitored online and maintained at 5.2. The reaction was carried out at 22℃ with stirring for 0.6 h to form a core-shell structure. The resulting dispersion was centrifuged at 8000×g for 10 min at 8℃. The supernatant was discarded, and the mixture was resuspended in deionized water at a volume 0.6 times that of the original dispersion. This centrifugation and resuspension were repeated once to obtain a dispersion of core-shell nanoparticles N1. Dynamic light scattering was used at 25℃ to determine the Z-average particle size of the core-shell nanoparticles N1, which was 95 nm. The solid content of the obtained dispersion was 4.00 wt%. The N1 dispersion of core-shell nanoparticles was dropped onto a copper grid and allowed to dry naturally at room temperature. The core-shell morphology was then confirmed by observation using a transmission electron microscope.

[0087] II. Preparation of Agarwood Volatile Oil-Cyclodextrin Inclusion Complex N2 Agarwood containing resin was steam distilled in deionized water at a mass-to-volume ratio of 1 g:10 mL at 100 °C for 7.0 h. The oil phase was collected and allowed to stand before separation to obtain agarwood volatile oil O, which was 3.2 wt% of the mass of the agarwood containing resin. 260 g of hydroxypropyl-β-cyclodextrin was weighed and added to 740 g of deionized water. The mixture was stirred at 62 °C for 1.8 h to obtain a cyclodextrin aqueous solution with a hydroxypropyl-β-cyclodextrin mass fraction of 26.00 wt%. Agarwood volatile oil O was first dissolved in 98 vol% ethanol (ethanol to agarwood volatile oil O mass ratio of 15:1). Then, it was added dropwise to a cyclodextrin aqueous solution at a rate of 7.0 mL / min. The mixture was stirred at 62 °C for 5.5 h, maintaining a mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O of 1:0.22. The resulting system was cooled to 2 °C and maintained for 20 h. The solid was filtered and dried under reduced pressure at 55 °C and 2 kPa to constant weight to obtain the agarwood volatile oil-cyclodextrin inclusion complex N2. Constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with a 1-h interval between the two weighings.

[0088] III. Preparation of Plant Polyphenol-Phospholipid Composite Nanoparticles N3 The whole plant of Phyllanthus urinaria and the aerial parts of Wedelia candel were mixed at a mass ratio of 1:0.80 and pulverized to pass through a 65-mesh sieve. A mixed extraction solvent of ethanol and deionized water was added to the resulting mixture to make the ethanol volume fraction 58 vol% and the ratio of the total mass of the mixture to the total volume of the extraction solvent 1 g:9 mL. Extraction was carried out under reflux for 1.8 h, followed by filtration. The filtrates were combined and concentrated under reduced pressure at 52 °C and 8 kPa to 1 / 4 of the original volume to obtain plant polyphenol extract P. Plant polyphenol extract P was dried to constant weight at 58 °C and 6 kPa, and its dry basis solids content was determined to be 22.00 wt%. Constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, with an interval of 1 h between the two weighings. 150g of lecithin was weighed and added to 850g of ethanol (98 vol%). The mixture was stirred mechanically at 450 rpm at 52°C to dissolve the lecithin in an ethanol solution, forming a lecithin ethanol solution with a lecithin mass fraction of 15.00 wt%. Plant polyphenol extract P was added to the lecithin ethanol solution, making the dry matter ratio of lecithin to plant polyphenol extract P 3.0:1. The mixture was stirred at 52°C for 1.8 h. The ethanol was removed from the resulting system under reduced pressure at 48°C and 8 kPa. Deionized water was added to disperse the mixture, resulting in a dispersion with a solid content of 6.00 wt%, yielding a dispersion of plant polyphenol-phospholipid composite nanoparticles N3. The Z-average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 was determined to be 250 nm using dynamic light scattering at 25°C.

[0089] IV. Preparation of Topical Preparations for Herpes Lesions The formulation of this embodiment, by weight, consists of: 4.30 parts polyvinyl alcohol, 0.40 parts sodium alginate, 7.00 parts glycerol, 15.00 parts ethanol, 0.80 parts core-shell nanoparticles N1 (on a dry basis), 1.50 parts plant polyphenol-phospholipid composite nanoparticles N3 (on a dry basis), 8.50 parts agarwood volatile oil-cyclodextrin inclusion complex N2, 0.60 parts pH adjuster, with deionized water as the balance, making the total weight of all components 100 parts by weight.

[0090] The preparation steps are as follows: Polyvinyl alcohol is added to deionized water and heated and stirred at 90°C for 1.4 h to form a polyvinyl alcohol solution. After cooling to 30°C, sodium alginate is added to the polyvinyl alcohol solution and stirred for 1.0 h, then glycerol is added and stirred for 0.5 h to obtain a film-forming matrix solution. Ethanol is added to the film-forming matrix solution and stirred for 0.4 h. Core-shell nanoparticle N1 dispersion (solid content 4.00 wt%, based on 0.80 parts by weight dry basis, 20.00 parts by weight dispersion) and plant polyphenol-phospholipid composite nanoparticle N3 dispersion (solid content 6.00 wt%, based on 1.50 parts by weight dry basis, 25.00 parts by weight dispersion) are added and stirred for 0.8 h. Agarwood volatile oil-cyclodextrin inclusion complex N2 is added and stirred for 0.8 h. Citric acid and sodium citrate dihydrate were each prepared into 8.0 wt% aqueous solutions. These solutions were then added dropwise to the system, with online monitoring and pH adjustment to 5.2. The pH adjuster used (total amount of citric acid and sodium citrate dihydrate) was 0.60 parts by weight. Water introduced during the preparation of the pH adjuster solution was included in the remaining deionized water. The system was allowed to stand for 8 hours to remove visible bubbles. The solution was then filtered through a 120 μm filter to obtain the topical herpes lesion preparation of this embodiment.

[0091] In this embodiment, the dry basis weights of the core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 in the formulation were determined by drying to constant weight at 58°C and 6 kPa absolute pressure. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings was 1 h.

[0092] The Z-average particle size of the dispersed phase in this formulation was determined to be 220 nm using dynamic light scattering at 25°C. This was achieved at 25°C and a shear rate of 10 s⁻¹. -1 The apparent viscosity of the formulation in this embodiment was measured to be 52 mPa·s using a rotational viscometer. The formulation in this embodiment was packaged into a mechanical pump-type spray bottle and used in a non-pressurized spray bottle.

[0093] Example 4 Features and Applications: In this example, 4.30 parts by weight of polyvinyl alcohol forms a strong and tough protective film layer, 7.00 parts by weight of glycerin provides sufficient moisturizing effect, 15.00 parts by weight of ethanol maintains suitable fluidity, the dry basis amounts of core-shell nanoparticles N1 and plant polyphenol-phospholipid composite nanoparticles N3 are 0.80 and 1.50 parts by weight, respectively, the dry basis amount of agarwood volatile oil-cyclodextrin inclusion complex N2 is 8.50 parts by weight, which significantly enhances the analgesic, antipruritic and nerve repair effects, the sodium alginate is 0.40 parts by weight, which provides basic adhesion function, the pH adjuster is 0.60 parts by weight, which maintains the pH of the formulation at 5.2, the dispersed phase particle size of 220 nm is conducive to the transdermal absorption of the nanocarrier, and the apparent viscosity of 52 mPa·s balances spreadability and adhesion. This embodiment of the formulation highlights the high concentration of agarwood volatile oil inclusion complex, which is suitable for treating postherpetic neuralgia with significant neuralgia, and is especially suitable for elderly patients or cases of long-lasting postherpetic neuralgia.

[0094] Comparative Example 1: Basically the same as Example 1, except that in the preparation of core-shell nanoparticle N1, step A4 shell coating was done by using sodium alginate solution instead of tannic acid aqueous solution, so that the mass fraction of sodium alginate was 0.16wt%, the mass ratio of sodium alginate to chitosan was controlled at 0.28, and the reaction was stirred for 1.2h at pH 5.4 and temperature 25℃. The amount of other components and preparation conditions remained unchanged.

[0095] Comparative Example 2: It is basically the same as Example 1, except that the preparation step of agarwood volatile oil-cyclodextrin inclusion complex N2 is omitted, and 3.00 parts by weight of agarwood volatile oil O is directly added in step S5, while the amount of other components and preparation conditions remain unchanged.

[0096] Comparative Example 3: It is basically the same as Example 1, except that the lecithin complexation process is omitted in step C3 of the preparation of plant polyphenol-phospholipid composite nanobody N3. The plant polyphenol extract P obtained in step C2 is used directly. It is dried to constant weight at 50°C and 10 kPa absolute pressure and then dispersed in deionized water to make the solid content of the dispersion 7.00 wt%. It is used as a plant polyphenol aqueous dispersion. The amount of other components and the preparation conditions remain unchanged.

[0097] Comparative Example 4: It is basically the same as Example 1, except that the amount of core-shell nanoparticle N1 is 0.03 parts by weight, while the amount of other components and preparation conditions remain unchanged.

[0098] Comparative Example 5: It is basically the same as Example 1, except that the amount of core-shell nanoparticle N1 is 6.00 parts by weight, while the amount of other components and preparation conditions remain unchanged.

[0099] Comparative Example 6: Basically the same as Example 1, except that the amount of glycerol used is 0.30 parts by weight, while the amounts of other components and preparation conditions remain unchanged.

[0100] Comparative Example 7: Basically the same as Example 1, except that the amount of ethanol used is 45.00 parts by weight, while the amounts of other components and preparation conditions remain unchanged.

[0101] Comparative Example 8: Basically the same as Example 1, except that in the preparation of core-shell nanoparticles N1, the mass fraction of chitosan in step A1 was adjusted to 0.08 wt%, the mass fraction of sodium tripolyphosphate in step A3 was adjusted to 0.08 wt% and the mass ratio of sodium tripolyphosphate to chitosan was controlled to be 0.05, and the mass fraction of tannic acid in step A4 was adjusted to 0.03 wt% and the mass ratio of tannic acid to chitosan was controlled to be 0.08. Other preparation conditions remained unchanged. The average particle size of the obtained core-shell nanoparticles N1 was 65 nm. The amount of other components and preparation conditions remained unchanged.

[0102] Performance testing: Apparent viscosity and atomization performance testing: The test subject was the topical formulation for herpes lesions prepared in this embodiment. The purpose of the test was to evaluate the rheological properties of the formulation at different shear rates and its correlation with the atomization performance of the mechanical pump. The test principle is based on the shear-thinning behavior of non-Newtonian fluids. The apparent viscosity at different shear rates was measured using a rotational viscometer, and the spray uniformity was verified by actual atomization testing using a mechanical pump. Experimental method: Using a rotational viscometer, under conditions of 25±2℃ and 50±5%RH, the viscosity of the formulation was measured at shear rates of 1, 5, 10, 20, 50, and 100 s. -1 The apparent viscosity was measured at each shear rate and taken after stabilizing for 30 seconds. Simultaneously, the formulation was loaded into a mechanical pump spray bottle and sprayed vertically 10 times from a distance of 20 cm from white paper. The uniformity of droplet distribution and coverage area were statistically analyzed using image analysis. Key parameters: test temperature 25±2℃, sample volume not less than 30 mL, shear rate range 1-100 s. -1 Each group was tested in parallel three times. Data processing: Calculate the average apparent viscosity ± standard deviation, plot the viscosity-shear rate curve, and evaluate the atomization uniformity index.

[0103] Film-forming performance and wet adhesion testing: The test object was the film layer formed on a simulated skin matrix by the topical herpes lesion preparation prepared in this embodiment. The purpose of the test was to evaluate the film-forming speed, film integrity, density, and erosion resistance under wet conditions. The test principle is based on the process of film-forming material spreading on the matrix surface, solvent evaporation, polymer crosslinking to form a continuous film layer, and the mechanical stability of the film layer under water erosion. Experimental method: The preparation was uniformly coated on the surface of the silicone film at a coating amount of 2.0 mg / cm³. 2The surface drying time and actual drying time were measured at 25±2℃ and 60±5%RH relative humidity. The microstructure and density of the film were observed using scanning electron microscopy. The coated silica film was immersed in simulated body fluid at 37℃ and flushed for 1 hour using a peristaltic pump at a flow rate of 10 mL / min. The weight loss rate and adhesion retention rate of the film were then measured. Key parameter: Coating amount 2.0 mg / cm³. 2 The ambient temperature was 25±2℃, the humidity was 60±5%RH, the rinsing temperature was 37℃, the flow rate was 10mL / min, and the rinsing time was 1h. Data processing: The average ± standard deviation of surface drying time, actual drying time, film weight loss rate, and adhesion retention rate were calculated.

[0104] Nanoparticle Dispersion Stability and Sedimentation Rate Testing: The test subject was the herpes lesion topical formulation prepared in this embodiment. The purpose of the test was to evaluate the dispersion uniformity and long-term storage stability of core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 in the formulation system. The test principle is based on the equilibrium relationship between Brownian motion, gravitational sedimentation, and aggregation kinetics of nanoparticles in liquid media. Dynamic light scattering was used to monitor particle size changes, and a Turbiscan stability analyzer was used to detect sedimentation stratification. Experimental methods: Dynamic light scattering was used to measure the Z-mean particle size and polydispersity index (PDI) of the dispersed phase at 0h, 24h, 7d, 14d, and 30d after formulation preparation at 25±2℃. Simultaneously, a Turbiscan stability analyzer was used to vertically scan the sample at 25℃, recording the changes in transmitted and backscattered light intensities at different heights over time, and the stability index (TSI) was calculated. Key parameters: Test temperature 25±2℃, sample volume 15mL, scan interval 24h, scan height 40mm, wavelength 880nm. Data processing: Calculate the mean ± standard deviation of particle size and PDI at each time point, and plot particle size-time curves and TSI-time curves.

[0105] In vitro release kinetics and sustained release performance testing: The test subjects were the core-shell nanoparticle N1-encapsulated components and plant polyphenol-phospholipid composite nanobody N3-encapsulated components in the herpes lesion topical formulation prepared in this embodiment, and the in vitro release behavior of these components was evaluated. The purpose of the test was to evaluate the sustained-release effect and release kinetic characteristics of the nanocarriers on the active ingredients. The test principle was based on the diffusion, dissolution, and degradation release mechanism of the drug from the nanocarrier. A dialysis membrane method was used to simulate the skin barrier, and the cumulative release of characteristic components in the receiving solution was detected by HPLC or UV-Vis. Experimental method: The formulation was placed in a dialysis bag (molecular weight cutoff 12000-14000 Da) and placed in a release medium containing 0.5% Tween-80 PBS buffer at pH 6.5, a temperature of 32±1℃, and a rotation speed of 100 rpm. 3 mL samples were taken at time points of 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h, and an equal volume of fresh medium was added. The total polyphenol content and the content of volatile oil characteristic components in the receiving solution were determined by HPLC. Key parameters: dialysis bag molecular weight cutoff 12000-14000 Da, receiving liquid volume 200 mL, temperature 32±1℃, rotation speed 100 rpm, sample volume 5.0 g. Data processing: Calculate cumulative release rate and fit zero-order, first-order, Higuchi, and Korsmeyer-Peppas release models.

[0106] Nozzle passability and atomized particle size distribution test: The test object was the droplets formed by atomizing the herpes lesion topical formulation prepared in this embodiment through a mechanical pump spray bottle. The purpose of the test was to evaluate the passability of the formulation to the nozzle, atomization efficiency, and droplet particle size distribution characteristics. The test principle is based on the fluid dynamics process of liquid forming droplets through the nozzle under the pressure of a mechanical pump. The dispersed phase particle size and system viscosity directly affect the nozzle clogging risk and atomization quality. Experimental method: The formulation was loaded into a mechanical pump spray bottle and sprayed continuously 100 times at 25±2℃. The number of cloggings and the spray volume per spray were recorded. A laser particle size analyzer was used to collect droplet samples at a distance of 20cm from the nozzle to determine the droplet volume median diameter (Dv50) and particle size distribution span (Span). The morphology and quantity of residues inside the nozzle were observed under a microscope. Key parameters: 100 sprays, test temperature 25±2℃, collection distance 20cm, laser wavelength He-Ne 632.8nm, measurement range 0.1-2000μm. Data processing: Calculate the mean ± standard deviation of single spray volume, Dv50, Span, and clogging frequency to evaluate the nozzle passability level.

[0107] Skin Irritation and Safety Evaluation Test: The test subject was the topical preparation for herpes lesions prepared in this embodiment. The purpose of the test was to evaluate the irritation, tolerance, and safety of the preparation on broken and intact skin. The test principle is based on the potential irritant effects of ethanol, weakly acidic pH, and nano-components in the preparation on the skin barrier. The irritant response was evaluated through an in vitro recombinant human epidermal model and animal skin irritation tests. Experimental Methods: Using the EpiDerm recombinant human epidermal model, 0.1 mL of the preparation was evenly applied to the model surface. After exposure for 30 min, the model was gently rinsed with PBS buffer and cultured for another 42 h. Cell viability was determined by the MTT assay. Simultaneously, healthy New Zealand white rabbits were used. 0.2 g of the preparation was applied to intact skin and artificially created broken skin (0.5 cm × 0.5 cm superficial abrasions), once daily for 7 consecutive days. The Draize scoring method was used to evaluate irritant responses such as erythema and edema. Skin tissue was collected for HE staining and histopathological examination. Key parameters: Exposure dose 0.1-0.2 g, exposure time 30 min-7 d, MTT culture conditions 37℃, 5% CO2. Data processing: Calculate mean ± standard deviation of cell viability, Draize score, and determine the degree of irritation.

[0108] Figure 1 The Z-mean particle size of Example 1 and Comparative Examples 4, 5, and 8 was determined by dynamic light scattering method at 0h, 24h, 7d, and 30d. The basic parameters were test temperature 25℃, time points 0h, 24h, 7d, and 30d, and output Z-mean particle size. The variable parameters were sample type and time. The results showed that the particle size of Example 1 drifted little over time and did not increase abruptly. Comparative Examples 4 and 8 showed a significant increasing trend over time, and Comparative Example 5 was generally larger and continued to shift upward over time. This proves that the nanocarrier design of Example 1 can achieve long-term stability of the dispersed phase particle size and reduce the risk of aggregation.

[0109] Figure 2 The polydispersity index (PDI) of Examples 1 and Comparative Examples 4, 5, and 8 was determined by dynamic light scattering method at 0h, 24h, 7d, and 30d. The basic parameters were test temperature 25℃, time points 0h, 24h, 7d, and 30d, and output PDI. The variable parameters were sample type and time. The results showed that the PDI of Example 1 remained at a low level and changed slowly, while the PDI of Comparative Examples 4 and 8 increased significantly with time, and Comparative Example 5 maintained a high PDI throughout the process. This proves that the system of Example 1 has a narrower distribution, more uniform dispersion, and better shelf-life stability.

[0110] Figure 3The Zeta potential of Example 1 and Comparative Examples 4, 5, and 8 was measured over time at 0h, 24h, 7d, and 30d using dynamic light scattering method. The basic parameters were test temperature 25℃, time points 0h, 24h, 7d, and 30d, and output Zeta potential. The variable parameters were sample type and time. The results showed that the potential of Example 1 remained relatively stable over time. The absolute values ​​of the potentials of Comparative Examples 4 and 8 gradually decreased and were accompanied by particle size instability. The potential level of Comparative Example 5 did not match the rheological state, making the dispersion system more prone to structural fluctuations. This proves that Example 1 can maintain long-term dispersion stability through the synergy of charge and interface interactions.

[0111] Figure 4 The particle size distribution curves of Example 1 and Comparative Examples 4, 5, and 8 at 0 h were overlaid using the dynamic light scattering method. The basic parameters were: test temperature 25℃, output intensity-weighted particle size distribution, and logarithmic scale for particle size axis. The variable parameter was sample type. The results showed that the main peak of Example 1 was concentrated and the tail was short. The distribution of Comparative Example 5 was shifted towards larger particle size. The distributions of Comparative Examples 4 and 8 were wider and showed long tail characteristics that were not conducive to stability. This proves that Example 1 can obtain a more reasonable combination of particle size center and distribution width in the initial state.

[0112] Figure 5 The particle size distribution curves of Example 1 and Comparative Examples 4, 5, and 8 over 30 days were overlaid using dynamic light scattering method. The basic parameters were test temperature 25℃, output intensity-weighted particle size distribution, and logarithmic scale for particle size axis. The variable parameter was sample type. The results showed that the distribution shape and peak position of Example 1 remained stable, while Comparative Examples 4 and 8 showed significant broadening and migration towards the larger particle size side. Comparative Example 5 maintained a large particle size and its distribution further broadened. This proves that Example 1 has stronger anti-aggregation and anti-sedimentation instability capabilities, reflecting the rationality of the formulation structure design.

[0113] Figure 6 Fourier transform infrared spectroscopy was used to determine the values ​​of Example 1, Comparative Example 2, and Comparative Example 3 at 4000 to 400 cm⁻¹. -1 Infrared spectral overlay within the range, with basic parameters being a scan range of 4000 to 400 cm⁻¹. -1 The output transmittance curves as a function of wavenumber, with the variable parameter being the sample type, show that Example 1 exhibits peak position shifts and spectral shape changes relative to the control sample in the hydroxyl stretching vibration region and the carbonyl and phosphate ester related characteristic regions. Meanwhile, Comparative Examples 2 and 3 are closer to the free state characteristics, proving that Example 1 has stronger host-guest inclusion and hydrogen bond intermolecular interactions, thus supporting the rationality of its stability and release behavior.

[0114] Figure 7The shear rates of Example 1, Comparative Examples 5 and 6 at 25°C were measured using a rotational viscometer from 1 to 100 s. -1 Rheological curves showing apparent viscosity versus shear rate within a given range, with the basic parameters being a test temperature of 25°C and shear rates ranging from 1 to 100 s⁻¹. -1 The apparent viscosity was output and displayed using a double logarithmic coordinate system. The variable parameters were sample type and shear rate. The results showed that Example 1 exhibited moderate shear thinning characteristics to balance static stability and easy atomization during spraying. Comparative Example 5 had too high a base viscosity and excessive shear thinning, which increased the atomization burden. Comparative Example 6 had too low viscosity, which resulted in insufficient structural support. This proves that the rheological window of Example 1 is more suitable for the synergistic balance between mechanical pump atomization and film formation requirements.

[0115] Figure 8 The cumulative distribution curves of droplet volume and particle size of Example 1, Comparative Examples 5 and 8 were overlaid using a laser particle size analyzer. The basic parameters were laser particle size analysis, output of cumulative volume fraction as a function of particle size, and reading of Dv10, Dv50, and Dv90 and calculating Span. The variable parameter was sample type. The results showed that the cumulative curve of Example 1 had a steeper transition and a smaller Span, indicating a narrow distribution. The cumulative curve of Comparative Example 5 was flatter, corresponding to a wide distribution and coarse droplets. The cumulative curve of Comparative Example 8 had an abnormal shape, corresponding to bimodality and aggregation behavior. This proves that Example 1 is more reasonable in terms of atomization quality and distribution controllability.

[0116] Figure 9 To determine the cumulative release rate of Example 1 and Comparative Examples 2 and 3 over 0.25 to 24 hours using high-performance liquid chromatography (HPLC), the following curves and fitting comparisons were obtained. The basic parameters were: release via dialysis membrane method, release medium PBS containing 0.5% Tween 80, temperature 32°C, rotation speed 100 rpm, time points from 0.25 to 24 hours, and HPLC quantitative output of cumulative release rate. The variable parameters were sample type and time. The results showed that the release curve of Example 1 was flatter and could be well described by the diffusion model. Comparative Examples 2 and 3 showed rapid release characteristics in the early stage and were closer to explosive release behavior overall, proving that the synergistic structure of the nanocarrier can achieve more controllable and sustained release.

[0117] Figure 10 The image shows a comparison of the full-spectrum scans of Example 1 and Comparative Example 1 determined by X-ray photoelectron spectroscopy. The basic parameters are the scanning binding energy from 0 to 1200 eV and the output intensity curve as a function of binding energy. The variable parameter is the sample type. The results show that there are systematic differences between the two in the proportion of surface element signals and the spectral shape, indicating that changing the shell material will significantly change the surface chemical environment. This proves that the shell construction of Example 1 can form a surface chemical state basis that is more matched with the interface interaction.

[0118] Figure 11The high-resolution fine N1s spectra of Example 1 and Comparative Example 1 were compared by X-ray photoelectron spectroscopy. The basic parameters were the acquisition of the N1s energy region and the comparison of the peak shape contribution of different chemical states. The variable parameter was the sample type. The results showed that Example 1 showed a stronger signal enhancement of free amino-related chemical states, while Comparative Example 1 showed a stronger signal enhancement of protonated amino-related chemical states. This proves that the shell and core surface of Example 1 interact in different ways, thus forming a more favorable distribution of interfacial chemical states.

[0119] Figure 12 The high-resolution fine O1s spectra of Example 1 and Comparative Example 1 were compared by X-ray photoelectron spectroscopy. The basic parameters were the acquisition of the O1s energy region and the analysis of the contributions of different oxygen-containing functional groups. The variable parameter was the sample type. The results showed that Example 1 showed a greater contribution of phenolic hydroxyl-related components on the high binding energy side, while Comparative Example 1 showed a greater contribution of carboxyl or carbonyl-related components. This proves that the shell surface of Example 1 is rich in phenolic hydroxyl characteristics and can provide a more suitable basis for interfacial interactions, thus supporting the rationality of its stability and overall performance.

[0120] Figure 13 The image shows a macroscopic optical photograph of the topical formulation for herpes lesions in Example 1, revealing its translucent, opalescent appearance (light amber to light brown) and flowable liquid state in a transparent container. After degassing and filtration, no visible bubbles or large particles were observed. This demonstrates the effectiveness of the preparation process, ensuring the macroscopic homogeneity of the dispersion and its conformity to the expected physical state.

[0121] Figure 14 This is a macroscopic photograph of the dry film formed after spraying and drying the sample of Example 1 onto a glass slide. It shows a light yellowish-brown, translucent, and uniform film formation, with a color similar to... Figure 13 The liquid samples shown remained consistent. This demonstrates that the formulation exhibits excellent spray film-forming properties, forming a continuous and uniform thin film layer after drying.

[0122] Figure 15 The image is a medium-magnification scanning electron microscope image of the solid residual structure after spraying and drop coating. Under a 50-micrometer scale field of view, it clearly shows a two-phase composite structure consisting of a continuous polymer matrix and micro-nano dispersed phase inlays. It can be seen that the dispersed phase units are randomly and discretely distributed in the film and are effectively wrapped and bridged by the matrix, which confirms that the components in the composite system form a stable spatial stack and physical bonding form according to the design.

[0123] Figure 16These are bright-field transmission electron microscopy (BTEM) images of N1 core-shell nanoparticles, acquired using the mass-thickness contrast principle at an accelerating voltage of 200 kV. The images show a uniform, near-spherical morphology, with particle size distribution concentrated in the 120–180 nm range. A darker outer shell clearly encapsulates a brighter inner core layer, with uniform shell thickness. This uniform shell thickness is attributed to the higher electron density and scattering ability of the aromatic-ring-rich tannic acid shell compared to the chitosan core. This demonstrates the successful construction of a nanocarrier with a well-defined core-shell structure via an ionogelation and interfacial assembly strategy.

[0124] Table 1. Performance comparison data between the examples and comparative examples. As can be seen from the performance of the examples and comparative examples in Table 1, the four examples are significantly superior to the comparative examples in terms of comprehensive performance across multiple dimensions, including apparent viscosity, dispersed phase particle size, film-forming properties, wet stability, cell tolerance, release kinetics, and atomization performance. Comparative Example 1, due to the replacement of the N1 shell of the core-shell nanoparticles with sodium alginate coating, showed a slightly faster release rate, but the film weight loss rate increased significantly to 15%, and the cell survival rate decreased to 85%, indicating that the tannic acid shell plays a crucial role in enhancing nanoparticle stability and reducing irritation. Comparative Examples 2 and 3, due to the absence of the cyclodextrin inclusion structure of agarwood volatile oil and the phospholipid complex structure of plant polyphenols, respectively, resulted in film weight losses as high as 18% and 25%, and cell survival rates decreased to 80% and 75%, respectively, with excessively rapid release rates exceeding 90%. This demonstrates that the nanocarrier structure design of cyclodextrin inclusion and phospholipid complex is crucial for achieving sustained release, reducing volatile oil irritation, and improving polyphenol stability. Comparative Examples 4 and 5 showed that the amount of N1 in the core-shell nanoparticles was lower and higher than the scope of the claims, respectively. The former had a film weight loss rate as high as 35%, a cell survival rate of only 70%, and a cumulative release rate as low as 55%, while the latter experienced a surge in apparent viscosity to 120 mPa·s, an increase in droplet size to 95 μm, and 8 instances of clogging. This indicates that the amount of N1 in the core-shell nanoparticles must be strictly controlled within the range of 0.05-5.00 parts by weight to balance film stability, release efficiency, and atomization performance. Comparative Example 6 showed a surge in film weight loss rate to 45% and a drop in cell survival rate to 60% due to an excessively low amount of glycerin (0.30 parts by weight), demonstrating that glycerin is indispensable as a humectant for maintaining the wet stability of the film and reducing irritation. Comparative Example 7 showed a sharp drop in cell survival rate to 55% due to an excessively high amount of ethanol (45 parts by weight), proving that the amount of ethanol must be controlled within the range of 0-40 parts by weight to balance the needs for quick drying and refreshing sensation with low irritation to the skin. In Comparative Example 8, because the particle size of the core-shell nanoparticles N1 decreased to 65 nm, which is below the lower limit of the range, the film weight loss rate increased to 28% and the number of clogging events increased to 5. This indicates that the nanoparticle size needs to be controlled within the range of 80-250 nm to ensure both dispersion stability and nozzle passability. In summary, the formulation design of the embodiments effectively solves the multiple coupling contradictions between the requirements of low viscosity for mechanical pump atomization, dense and stable film formation and wet erosion resistance, continuous release and dispersion stability under high load of multiple nanocarriers, nozzle passability, and low irritation and high tolerance.

[0125] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A topical preparation for herpes lesions, characterized in that, The topical formulation for herpes lesions is a flowable liquid dispersion system; by weight, the topical formulation for herpes lesions comprises the following components: A. Polyvinyl alcohol, in the form of 0.50-5.00 parts by weight; B. Sodium alginate, 0-1.00 parts by weight; C. Glycerin, 0.50-12.00 parts by weight; D. Ethanol, in the form of 0-40.00 parts by weight; E. Core-shell nanoparticles N1, in 0.05-5.00 parts by weight on a dry basis, wherein the core-shell nanoparticles N1 are core-shell nanoparticles formed by cross-linking chitosan and sodium tripolyphosphate ions to form a core and being coated with tannic acid; F. Plant polyphenol-phospholipid composite nanobody N3, in 0.05-8.00 parts by weight on a dry basis, wherein the plant polyphenol-phospholipid composite nanobody N3 is a nanobody formed by lecithin and plant polyphenol extract P, wherein the plant polyphenol extract P is an extract obtained by alcohol-water extraction of the whole herb of Phyllanthus urinaria and the aerial parts of Wedelia triloba. G. Agarwood volatile oil-cyclodextrin inclusion complex N2, in the form of 0.05-10.00 parts by weight on a dry basis, wherein the agarwood volatile oil-cyclodextrin inclusion complex N2 is an inclusion complex formed by agarwood volatile oil O and hydroxypropyl-β-cyclodextrin, wherein the agarwood volatile oil O is a volatile oil obtained by steam distillation of agarwood resin-containing wood or resin; H. pH adjuster, in the form of 0.05-2.00 parts by weight, wherein the pH adjuster is selected from one or more of citric acid, sodium citrate and their hydrates; I. With deionized water as the remainder, the sum of the weight parts of each component of the topical herpes lesion preparation is 100 parts by weight, wherein the deionized water includes added deionized water and water introduced by the dispersion of component E and / or component F and / or by the aqueous solution of component H.

2. The topical preparation for herpes lesions according to claim 1, characterized in that, The core-shell nanoparticles N1 are prepared through the following steps: A1. Raw material preparation: Add chitosan to deionized water containing lactic acid, so that the mass fraction of chitosan is 0.05-0.30 wt% and the mass fraction of lactic acid is 0.10-1.00 wt%, and stir to dissolve at 20-35℃ for 1.0-6.0 h; A2. Adjust pH: Use a sodium hydroxide aqueous solution with a mass fraction of 0.1-10.0 wt% to adjust the pH of the solution obtained in step A1 to 5.2-5.8 by adding dropwise. A3. Ionic crosslinking nucleation: Prepare an aqueous solution of sodium tripolyphosphate with a mass fraction of 0.05-0.30 wt%; add the aqueous solution of sodium tripolyphosphate dropwise to the solution obtained in step A2 within 1-5 min at 20-30℃, control the mass ratio of sodium tripolyphosphate to chitosan to be 0.05-0.25, and continue stirring for 0.5-2.0 h to obtain a chitosan nanonucleus dispersion; A4. Shell coating: Prepare an aqueous solution of tannic acid with a mass fraction of 0.01-0.30 wt%; add the aqueous solution of tannic acid to the chitosan nanocore dispersion, control the mass ratio of tannic acid to chitosan to be 0.05-0.50, and stir the reaction at pH 4.8-6.0 and temperature 20-30℃ for 0.5-2.0 h to form a core-shell structure; A5. Post-processing: Centrifuge the dispersion obtained in step A4 and resuspend it in deionized water. Repeat 1-3 times to obtain core-shell nanoparticles N1. A6. Quality control: The average particle size of the core-shell nanoparticles N1 is 80-250 nm, and the solid content of the resulting dispersion is 0.50-6.00 wt%.

3. The topical preparation for herpes lesions according to claim 1, characterized in that, The agarwood volatile oil-cyclodextrin inclusion complex N2 was prepared by the following steps: B1. Preparation of agarwood volatile oil: Agarwood containing resin or resin is added to deionized water for steam distillation at 98-100℃ for 2.0-8.0h. The oil phase is collected and allowed to stand for separation to obtain agarwood volatile oil O. B2. Preparation of cyclodextrin solution: Hydroxypropyl-β-cyclodextrin is added to deionized water and stirred at 45-65℃ for 0.5-2.0 h to obtain an aqueous cyclodextrin solution, wherein the mass fraction of hydroxypropyl-β-cyclodextrin in the aqueous cyclodextrin solution is 5.00-30.00 wt%. B3. Inclusion reaction: The agarwood volatile oil O obtained in step B1 is directly added to the cyclodextrin aqueous solution obtained in step B2, or the agarwood volatile oil O is first dissolved in ethanol and then added to the cyclodextrin aqueous solution obtained in step B2. Stir at 45-65℃ for 1.0-6.0h, and control the mass ratio of hydroxypropyl-β-cyclodextrin to agarwood volatile oil O to be 1:0.04-1:0.

25. B4. Precipitation and drying: Cool the system obtained in step B3 to 0-10℃ and maintain it for 2.0-24.0h, filter to obtain solid, and dry under reduced pressure at 30-60℃ and 0.1-30kPa to constant weight to obtain agarwood volatile oil-cyclodextrin inclusion complex N2.

4. The topical preparation for herpes lesions according to claim 1, characterized in that, The plant polyphenol-phospholipid composite nanoparticles N3 are prepared through the following steps: C1. Plant raw materials: Mix the whole herb of Phyllanthus urinaria and the above-ground parts of Wedelia triloba at a mass ratio of 1:0.20-1:2.00 and then crush them; C2. Alcohol-water extraction: Add a mixed extraction solvent of ethanol and deionized water to the mixture obtained in step C1, so that the volume fraction of ethanol is 40-70 vol%, and the ratio of the total mass of the mixture to the total volume of the extraction solvent is 1 g: 5-15 mL. Extract under reflux for 1.0-3.0 h, then filter. Combine the filtrates and concentrate them under reduced pressure at 40-70℃ and 0.1-30 kPa to 1 / 5-1 / 3 of the original volume to obtain plant polyphenol extract P. The mass fraction of plant polyphenol extract P is 10.00-40.00 wt%, where the mass fraction is the dry basis solids mass fraction of plant polyphenol extract P. C3. Phospholipid Complex: Lecithin is added to ethanol and stirred at 40-70℃ to dissolve it and form a lecithin ethanol solution, wherein the mass fraction of lecithin in the lecithin ethanol solution is 5.00-30.00 wt%; plant polyphenol extract P obtained in step C2 is added to the lecithin ethanol solution, such that the dry mass ratio of lecithin to plant polyphenol extract P is 1:1-6:1, and the mixture is stirred and reacted at 45-65℃ for 0.5-4.0 h; C4. Solvent removal and water dispersion: The system obtained in step C3 was subjected to reduced pressure to remove ethanol at 40-60℃ and an absolute pressure of 0.1-30kPa, and deionized water was added for dispersion to make the solid content of the resulting dispersion 0.50-10.00wt%, thus obtaining plant polyphenol-phospholipid composite nanoparticles N3. C5. Quality control: The average particle size of the plant polyphenol-phospholipid composite nanoparticles N3 is 100-500 nm.

5. The topical preparation for herpes lesions according to claim 1, characterized in that, The herpes lesion topical preparation is packaged in a mechanical pump spray bottle, which is a non-pressurized spray bottle. The average particle size of the dispersed phase in the herpes lesion topical preparation is 80-500 nm. The herpes lesion topical preparation is tested at 25°C with a shear rate of 10 s. -1 The apparent viscosity measured using a rotational viscometer was 2-80 mPa·s.

6. A method for preparing a topical formulation for herpes lesions as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Provides core-shell nanoparticles N1; S2. Provides agarwood volatile oil-cyclodextrin inclusion complex N2; S3. Provides plant polyphenol-phospholipid composite nanoparticles N3; S4. Prepare a membrane substrate solution by mixing polyvinyl alcohol, sodium alginate, glycerol and deionized water; S5. Add ethanol, core-shell nanoparticles N1, plant polyphenol-phospholipid composite nanoparticles N3, and agarwood volatile oil-cyclodextrin inclusion complex N2 to the film-forming matrix solution, and adjust the pH to 4.5-6.2 to obtain a topical preparation for herpes lesions.

7. The preparation method according to claim 6, characterized in that, The preparation of the film-forming matrix solution in step S4 includes: adding polyvinyl alcohol to deionized water, heating and stirring at 80-95°C for 0.5-2.0 h to form a polyvinyl alcohol solution; cooling to 25-40°C, adding sodium alginate to the polyvinyl alcohol solution and stirring for 0.5-2.0 h, then adding glycerol and stirring for 0.2-1.0 h to obtain the film-forming matrix solution.

8. The preparation method according to claim 6, characterized in that, The addition process in step S5 includes: adding ethanol to the film-forming matrix solution and stirring for 0.1-1.0 h; adding core-shell nanoparticles N1 and plant polyphenol-phospholipid composite nanoparticles N3 and stirring for 0.2-2.0 h; adding agarwood volatile oil-cyclodextrin inclusion complex N2 and stirring for 0.2-2.0 h.

9. The method according to claim 6, characterized in that, In step S5, citric acid and sodium citrate dihydrate are used as pH adjusters to make the pH of the system 4.5-6.

2. The method also includes step S6: allowing the system to stand for degassing for 0.5-24 h and then filtering it through a 50-200 μm filter.

10. The topical preparation for herpes lesions according to claim 1, characterized in that, The dry basis weights of the core-shell nanoparticles N1, the plant polyphenol-phospholipid composite nanoparticles N3, and the agarwood volatile oil-cyclodextrin inclusion complex N2 were determined by drying to constant weight at 40-80℃ and an absolute pressure of 0.1-10 kPa. The constant weight was defined as the difference between two consecutive weighings not exceeding 0.5 wt% of the previous weighing, and the interval between the two weighings being no less than 1 h.

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