A triple supramolecular composition with mild brushing acid and anti-inflammatory soothing effects, and a method for its preparation and use

Abstract

This invention discloses a triple supramolecular composition with mild exfoliation and anti-inflammatory soothing effects, its preparation method, and its applications. The composition uses a ternary deep eutectic solvent (DES) consisting of salicylic acid, 4-tert-butylcyclohexanol, and bisabolol as its core, which is encapsulated by poloxamer 407 to form drug-loaded micelles, and then compounded with small-molecule sodium hyaluronate. This invention achieves homogeneous and stable co-fusion of the active ingredients through intermolecular hydrogen bonding, significantly improving the solubility and stability of salicylic acid. The composition exhibits good storage stability at both low and room temperatures, with a cumulative release rate of approximately 75% of salicylic acid after 12 hours, and significantly higher transdermal and skin retention rates after 24 hours compared to the control group. It shows an inhibition rate of over 89% against TNF-α, a stinging relief rate of over 87% within 5 minutes, and no skin irritation. This invention can be widely used in the preparation of cosmetics or skincare products for skin exfoliation, anti-inflammation, soothing, and repair, and is particularly suitable for sensitive skin, acne-prone skin, and other skin types requiring gentle exfoliation.

Description

Technical Field

[0001] This invention relates to a triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects, its preparation method, and its application, belonging to the field of biomedical technology. Background Technology

[0002] With the refinement of skincare concepts, chemical exfoliation, as a highly effective method of keratin management, has been widely used to improve skin problems such as acne, enlarged pores, and uneven skin tone. Salicylic acid (SA), a classic lipid-soluble exfoliating ingredient, has become one of the core active ingredients in clinical and at-home skincare products due to its unique keratin-dissolving, anti-inflammatory, antibacterial, and sebum-regulating effects. It can penetrate deep into the pilosebaceous duct, unclogging pores, inhibiting the proliferation of Propionibacterium acnes, and assisting in the repair of the skin barrier function by regulating keratinocyte differentiation, demonstrating a clear improvement effect on inflammatory skin problems such as acne and rosacea.

[0003] However, the application of salicylic acid has long faced key technological bottlenecks, and existing solutions struggle to achieve a balance between efficacy, gentleness, and stability. Firstly, the lipid-soluble nature of salicylic acid results in low solubility in water-based formulations, directly impacting ingredient stability and bioavailability. It also easily leads to issues such as low-temperature precipitation and storage stratification, severely limiting product shelf life and user experience. Secondly, salicylic acid inherently irritates the skin. Even clinically recommended low-concentration (0.5%-2%) products may experience localized high concentrations due to instantaneous release, triggering contact dermatitis symptoms such as erythema, stinging, dryness, and peeling. This risk of irritation is significantly increased, especially for sensitive or inflamed skin. Furthermore, the safety of high-concentration salicylic acid for home use is even more difficult to guarantee; thirdly, existing products lack a synergistic mechanism of immediate soothing, mid-term anti-inflammatory, and deep repair. Even when compounded with anti-inflammatory ingredients, they are mostly simple physical mixtures with poor compatibility and asynchronous effects between ingredients, failing to effectively block the vicious cycle of irritation-inflammation-barrier damage, making it difficult to achieve good acid-removing and soothing effects; fourthly, although traditional solubilization or carrier technologies (such as liposomes and nanoemulsions) can partially improve solubility and transdermal efficiency, they generally have problems such as limited encapsulation rate, uncontrollable release rate, and a single transdermal mechanism. They cannot avoid the irritation risk of rapid release of salicylic acid, nor can they improve the precise action efficiency of active ingredients through layered delivery.

[0004] The link between skin inflammation and barrier damage has been clearly established: chronic inflammation caused by acne, acid peels, and other irritants promotes the secretion of matrix metalloproteinases, degrading collagen and hyaluronic acid, leading to problems such as enlarged pores and sagging skin. Furthermore, skin in an inflammatory state is more sensitive to external stimuli, creating a vicious cycle. Therefore, an ideal acid peel product not only needs to address the solubility, stability, and irritation issues of salicylic acid, but also needs to achieve simultaneous and synergistic effects in keratin conditioning, immediate soothing, mid-term anti-inflammatory treatment, and deep repair, enabling controlled release and precise transdermal absorption of active ingredients.

[0005] Deep eutectic solvents (DES), as a novel green solvent system, can achieve molecular-level homogeneous mixing of poorly soluble active ingredients through the synergistic effect of hydrogen bond acceptors and donors, providing a new pathway to improve ingredient compatibility and stability. DES have found successful applications in various fields, and given their green, environmentally friendly, safe, and non-toxic nature, they also show promising prospects in the cosmetics industry.

[0006] Currently, there are studies applying deep eutectic technology to the modification of salicylic acid. For example, Chinese patent CN202311779841.2 discloses a deep eutectic solvent for salicylic acid and its preparation method. This method utilizes salicylic acid, L-carnitine, and polyols, and prepares the deep eutectic solvent for salicylic acid through specific processes (such as oil bath, ultrasound, and microwave). This technology significantly improves the solubility of salicylic acid in water by forming a deep eutectic system and reduces its irritation to some extent when used directly. However, in practical applications, especially when caring for sensitive skin, rosacea, or acne-prone skin with significant inflammation, simply addressing the solubility and basic irritation of salicylic acid is still insufficient. On the one hand, while the aforementioned technologies improve the physicochemical properties of salicylic acid, the introduced adjuvants (such as L-carnitine) primarily function as solubilizers, lacking immediate inhibitory capabilities for skin nerve sensitivity (such as burning and stinging sensations). On the other hand, their anti-inflammatory effects rely solely on salicylic acid itself, resulting in a relatively singular efficacy dimension when addressing the complex inflammatory microenvironment of the skin, making it difficult to achieve the synergistic effect of "simultaneous acid application, soothing, and anti-inflammation." Furthermore, existing deep eutectic systems have limited retention time on the skin, leading to rapid release of active ingredients and short-lasting effects, and lack immediate moisturizing and repairing functions for damaged skin barriers. Therefore, there is an urgent need for a multifunctional supramolecular composition that can maintain the high solubility and low irritation of salicylic acid while endowing it with active soothing and desensitizing capabilities, synergistic anti-inflammatory effects, and long-lasting moisturizing and repairing abilities to meet the comprehensive care needs of problem skin (especially sensitive acne-prone skin). Summary of the Invention

[0007] The purpose of this invention is to provide a triple supramolecular composition with mild exfoliation and anti-inflammatory soothing effects. This composition forms a novel deep eutectic solvent as its core, which is encapsulated by poloxamer 407 to form drug-loaded micelles and incorporating small-molecule sodium hyaluronate, creating a multi-layered delivery system. This fundamentally reduces the irritation of salicylic acid, achieving intelligent synergy of immediate soothing, medium-term anti-inflammatory effects, and long-term keratin conditioning, while significantly improving transdermal efficiency and stability.

[0008] To achieve the above-mentioned technical objectives, the present invention adopts the following technical solution: A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is formed by using a ternary deep eutectic solvent composed of salicylic acid, 4-tert-butylcyclohexanol and bisabolol as the core, encapsulating the core with poloxamer 407 to form drug-loaded micelles, and finally compounding with small molecule sodium hyaluronate.

[0009] Preferably, the molar ratio of salicylic acid, 4-tert-butylcyclohexanol and bisabolol in the ternary deep eutectic solvent is 1:(1-4); the molar ratio of 4-tert-butylcyclohexanol to bisabolol is (0.5-2):1.

[0010] Preferably, the mass ratio of poloxamer 407 to the ternary deep eutectic solvent core is (5-20):1.

[0011] Preferably, the molecular weight of the small molecule sodium hyaluronate is ≤10 kDa, and its mass concentration in the final triple supramolecular composition is 0.5%-3%.

[0012] This invention also provides a method for preparing the above-described triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects, which includes the following steps: (1) Preparation of ternary deep eutectic solvent DES core: Mix the prescribed amounts of salicylic acid, 4-tert-butylcyclohexanol and bisabolol, stir and react at 60-80℃ for 2-6 hours until a homogeneous and transparent liquid is formed, cool to room temperature, and obtain ternary DES core; (2) Encapsulation of DES core by poloxamer 407: The DES core prepared in step (1) is slowly added to the prescribed amount of poloxamer 407 aqueous solution and magnetically stirred at 2-8℃ for 4-12 hours to form a drug-loaded micelle dispersion. (3) Composite small molecule sodium hyaluronate: Add the prescribed amount of small molecule sodium hyaluronate to the drug-loaded micelle dispersion obtained in step (2), and stir at room temperature for 1-2 hours until uniformly dispersed to obtain the final triple supramolecular composition.

[0013] Preferably, the stirring speed in step (1) is 300-500 rpm.

[0014] Preferably, the stirring speed in step (2) is 100-150 rpm.

[0015] Preferably, the mass concentration of poloxamer 407 in the aqueous solution of poloxamer 407 in step (2) is 10-30%.

[0016] Preferably, the stirring speed in step (3) is 300-500 rpm.

[0017] The present invention also provides the application of the above-mentioned triple supramolecular composition with mild exfoliation and anti-inflammatory soothing effects in the preparation of cosmetics or skin care products for skin keratinization management, anti-inflammation, soothing and repair.

[0018] Deep eutectic solvents (DES) are low-melting-point mixtures formed by hydrogen bond acceptors and donors in a certain stoichiometric ratio through hydrogen bonding. Their melting points are much lower than those of any single component, and they possess advantages such as being environmentally friendly and highly designable. Poloxamer 407, as a high-performance amphiphilic triblock copolymer (PEO-PPO-PEO), exhibits unique reversible thermo-gelation behavior in aqueous media: at low temperatures (typically 4-10℃), the polymer chains are fully hydrated with water molecules, forming a free-flowing, transparent solution; however, when the temperature rises to the surface temperature of human skin (approximately 32-37℃), its hydrophobic polypropylene glycol (PPO) blocks become entangled due to dehydration, spontaneously assembling to form a nanoscale micelle structure with PPO as the core and hydrophilic polyethylene glycol (PEO) as the shell. This thermosensitive phase change property makes it an ideal "smart" delivery carrier: on the one hand, the micelle system can remain stable when stored at room temperature, and after application, it can quickly form a gel reservoir or micelle assembly in situ under the action of body temperature, effectively encapsulating hydrophobic active ingredients (such as salicylic acid and bisabolol) to prevent their oxidation or crystallization, and significantly improving the physical stability of the multi-component system; on the other hand, through the solubilization and sustained-release effect of the micelle core, it can regulate the transdermal release rate of lipophilic active ingredients, avoiding the irritation caused by the rapid and large influx of acidic ingredients into the skin in traditional dosage forms, and achieving the goal of long-lasting sustained release and stable onset of action.

[0019] The small-molecule sodium hyaluronate (oligomeric hyaluronic acid) introduced in the formula not only inherits the excellent moisturizing ability inherent in hyaluronic acid, forming a hydrophilic film on the skin surface to maintain the hydration microenvironment, but also exhibits unique biological functions due to its significantly reduced molecular weight: it can quickly penetrate into the stratum corneum, reversibly opening some drug penetration channels by increasing the fluidity of intercellular lipids, thus acting as a penetration enhancer. This pretreatment effect of leading hydration and opening channels clears obstacles and paves pathways for the transdermal absorption of subsequent active ingredients (especially the active ingredients encapsulated in poloxamer micelles), improving their bioavailability; on the other hand, the immediate replenishment of moisture helps buffer the dryness and irritation of acidic ingredients in the initial stage of penetration, improving the product's gentleness from both physical and sensory perspectives. This invention organically combines the controlled-release carrier function of poloxamer with the penetration-enhancing and soothing pretreatment functions of small-molecule hyaluronic acid, and the two work synergistically to form a hierarchical delivery system of pretreatment-carrier transport-intelligent release.

[0020] Compared with existing technologies, the beneficial effects of this invention are as follows: This invention successfully prepares a triple supramolecular composition that combines gentle acid exfoliation with anti-inflammatory and soothing effects. This composition forms a uniform and stable DES solvent through intermolecular forces, achieving molecular-level uniform mixing of the three active ingredients. Poloxamer 407 micelles act as smart switches, encapsulating the DES core to achieve controlled sustained release of salicylic acid, avoiding instantaneous high-concentration irritation. Simultaneously, 4-tert-butylcyclohexanol can immediately block weak irritation signals that may be generated during the sustained release process, while bisabolol exerts a medium-term anti-inflammatory and repairing effect. Small-molecule sodium hyaluronate, as a penetration enhancer, pre-hydrates and softens the stratum corneum, forming a layered penetration enhancement system with the micelle carrier, significantly improving the transdermal efficiency of the active ingredients. Ultimately, it achieves an intelligent effect of simultaneous action, soothing, and repair, and solves the problems of low-temperature precipitation and storage instability of hydrophobic active ingredients. Attached Figure Description

[0021] Figure 1 The cumulative release curves of salicylic acid in different embodiments and comparative examples of the present invention are shown. Figure 2 The results of the cumulative permeation of salicylic acid over 24 hours in different embodiments and comparative examples in Test Example 3 of this invention; Figure 3 The results of salicylic acid retention in the skin layer in different embodiments and comparative examples in Test Example 3 of this invention; Figure 4 The results show the inhibition rates of the inflammatory factor TNF-α in different embodiments and comparative examples in Test Example 5 of this invention. Detailed Implementation

[0022] The technical solution of the present invention will be further described below with reference to specific embodiments, but it is not limited thereto.

[0023] Example 1 A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is prepared by the following steps: (1) Preparation of ternary DES core: Weigh 0.1 mol salicylic acid (SA), 0.05 mol 4-tert-butylcyclohexanol (TBCH) and 0.05 mol bisabolol (BIS). Place the above components in a reaction vessel and stir at 300 rpm at 70 °C for 4 hours until a homogeneous and transparent liquid is formed. Cool to room temperature to obtain the ternary DES core; (2) Poloxamer encapsulation: Weigh 10 g of poloxamer 407, dissolve it in 90 g of ultrapure water to prepare a 10 wt% solution, and store it in a 4℃ refrigerator for later use; take 2 g of the DES core prepared in step (1), slowly add it to 100 g of the above-mentioned cold-stored poloxamer 407 aqueous solution (the mass ratio of DES core to poloxamer 407 is 1:5), and magnetically stir at 100 rpm for 8 hours at 4℃ to form a drug-loaded micelle dispersion; (3) Composite small molecule sodium hyaluronate: Add 1.5 g of small molecule sodium hyaluronate (molecular weight ≤10 kDa) to the drug-loaded micelle dispersion obtained in step (2), and continue stirring at 300 rpm for 1.5 hours at room temperature until uniformly dispersed to obtain the final triple supramolecular composition.

[0024] Example 2 A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is prepared by the following steps: (1) Preparation of ternary DES core: Weigh 0.1 mol salicylic acid, 0.1 mol 4-tert-butylcyclohexanol and 0.1 mol bisabolol. Place the above components in a reaction vessel and stir at 400 rpm at 70 °C for 4 hours until a homogeneous and transparent liquid is formed. Cool to room temperature to obtain the ternary DES core.

[0025] (2) Poloxamer encapsulation: Weigh 15 g of poloxamer 407, dissolve it in 85 g of ultrapure water to prepare a 15 wt% solution, and store it in a 4℃ refrigerator for later use; take 1.5 g of the DES core prepared in step (1), slowly add it to 100 g of the above-mentioned cold-stored poloxamer 407 aqueous solution, and magnetically stir at 130 rpm for 8 hours at 4℃ to form a drug-loaded micelle dispersion.

[0026] (3) Composite small molecule sodium hyaluronate: Add 1.5 g of small molecule sodium hyaluronate (molecular weight ≤10 kDa) to the drug-loaded micelle dispersion obtained in step (2), and continue stirring at 400 rpm for 1.5 hours at room temperature until uniformly dispersed to obtain the final triple supramolecular composition.

[0027] Example 3 A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is prepared by the following steps: (1) Preparation of ternary DES core: Weigh 0.1 mol salicylic acid, 0.2 mol 4-tert-butylcyclohexanol and 0.1 mol bisabolol. Place the above components in a reaction vessel and stir at 500 rpm at 70°C for 4 hours until a homogeneous and transparent liquid is formed. Cool to room temperature to obtain the ternary DES core.

[0028] (2) Poloxamer encapsulation: Weigh 20 g of poloxamer 407, dissolve it in 80 g of ultrapure water to prepare a 20 wt% solution, and store it in a 4℃ refrigerator for later use; take 1 g of the DES core prepared in step (1), slowly add it to 100 g of the above-mentioned cold-stored poloxamer 407 aqueous solution, and magnetically stir at 150 rpm for 8 hours at 4℃ to form a drug-loaded micelle dispersion.

[0029] (3) Composite small molecule sodium hyaluronate: Add 1.5 g of small molecule sodium hyaluronate (molecular weight ≤10 kDa) to the drug-loaded micelle dispersion obtained in step (2), and continue to stir at 500 rpm for 1.5 hours at room temperature until uniformly dispersed to obtain the final triple supramolecular composition.

[0030] Example 4 A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is prepared by the following steps: (1) Preparation of ternary DES core: Weigh 0.1 mol salicylic acid, 0.15 mol 4-tert-butylcyclohexanol and 0.15 mol bisabolol. Place the above components in a reaction vessel and stir at 450 rpm at 75°C for 3.5 hours until a homogeneous and transparent liquid is formed. Cool to room temperature to obtain the ternary DES core.

[0031] (2) Poloxamer encapsulation: Weigh 30 g of poloxamer 407, dissolve it in 70 g of ultrapure water to prepare a 30 wt% solution, and store it in a refrigerator at 4℃ for later use; take 2 g of the DES core prepared in step (1), slowly add it to 100 g of the above-mentioned cold-stored poloxamer 407 aqueous solution, and magnetically stir at 140 rpm for 6 hours at 6℃ to form a drug-loaded micelle dispersion.

[0032] (3) Composite small molecule sodium hyaluronate: Add 3.03 g of small molecule sodium hyaluronate (molecular weight ≤10 kDa) to the drug-loaded micelle dispersion obtained in step (2), and continue to stir at 450 rpm for 1.5 hours at room temperature until uniformly dispersed to obtain the final triple supramolecular composition.

[0033] Comparative Example 1 This comparative example provides a simple mixed composition, which is prepared by dissolving salicylic acid, 4-tert-butylcyclohexanol, and bisabolol directly in a small amount of propylene glycol at the molar ratio of Example 2 (0.1:0.1:0.1), and then adding an equal amount of small molecule sodium hyaluronate aqueous solution as in Example 2, stirring and mixing evenly to obtain the final product.

[0034] Comparative Example 2 This comparative example provides a composition without poloxamer encapsulation, prepared by the following method: a ternary DES core is prepared according to step (1) of Example 2. Sodium hyaluronate of small molecule is dissolved in ultrapure water to prepare a solution of the same concentration as in Example 2. The DES core is then directly mixed with this solution and stirred until homogenized to obtain the final product.

[0035] Comparative Example 3 This comparative example provides a composition without compounded small molecule hyaluronic acid, which is prepared by: preparing a drug-loaded micelle dispersion according to steps (1) and (2) of Example 2, but without adding small molecule sodium hyaluronate, and directly using it as the final composition.

[0036] Comparative Example 4 A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects is provided, which uses medium molecular weight sodium hyaluronate with a molecular weight of 20kDa instead of small molecular weight sodium hyaluronate. The remaining components, proportions, and preparation methods are the same as in Example 2.

[0037] Performance testing Test Example 1 Appearance and low temperature stability The samples prepared in Examples 1-3 and Comparative Examples 1-3 were sealed and stored at 4℃, 25℃, 40℃ and -4℃ for 90 days, respectively. On the 90th day, the samples were taken out and brought back to room temperature to observe their state. The appearance was observed to see if there were any phenomena such as layering, turbidity, or crystal precipitation. At the same time, the retention rate of salicylic acid in the products stored at 25℃ was detected by high performance liquid chromatography (HPLC). The results are shown in Table 1.

[0038] Table 1. Results of composition stability test As shown in Table 1 above, the triple supramolecular compositions prepared in Examples 1-4 of this invention maintained a uniform and transparent state after being sealed and stored for 90 days at four temperatures: 4℃, 25℃, 40℃, and -4℃. No abnormal phenomena such as layering, turbidity, or crystal precipitation were observed. Furthermore, the salicylic acid content retention rate was above 97% at 25℃, demonstrating excellent high-temperature, low-temperature, and room-temperature storage stability, which was significantly better than that of the comparative examples. Comparative Example 1 did not form a ternary deep eutectic solvent, resulting in poor compatibility among its components. It exhibited stratification and crystallization under low temperature (-4℃), low-temperature refrigeration (4℃), and high temperature (40℃) conditions. At 25℃, the salicylic acid retention rate was only 64.8%, indicating extremely poor stability and failing to meet the requirements for conventional cosmetic storage. Comparative Example 2 involved a system where the ternary DES core was prepared but not encapsulated with poloxamer 407 and directly mixed with a small-molecule sodium hyaluronate aqueous solution. Because the DES core is hydrophobic, its dispersibility was poor after direct mixing with the aqueous phase, leading to oil-water stratification and crystallization at all test temperatures. Comparative Example 3 lacked the hydrophilic film-forming and dispersing aids of small-molecule sodium hyaluronate, resulting in poor gelation. The dispersion exhibited oil-water separation and crystallization issues at various temperatures. At 25°C, the salicylic acid content retention rate was 72.3%, indicating that small molecule sodium hyaluronate has an important synergistic effect on improving the overall dispersion stability of the composition. Comparative Example 4 is a composition using 20kDa medium molecule sodium hyaluronate instead of small molecule sodium hyaluronate. Since the change in the molecular weight of sodium hyaluronate did not affect the formation of the ternary DES core or the encapsulation effect of poloxamer 407, it remained uniform and transparent at all test temperatures, with a salicylic acid content retention rate of 98.1%. Its appearance and content stability were comparable to the example, but subsequent functional tests confirmed that its penetration-promoting, soothing, and repairing effects were far lower than those of the example product.

[0039] Test Example 2 In vitro release experiment The in vitro release behavior of salicylic acid in Examples 1-4, Comparative Examples 1-4, and free salicylic acid solutions was investigated using the Franz diffusion cell method with phosphate buffer solution at pH 5.8 as the receiving medium.

[0040] Experimental Methods: A 0.45 μm, hydrophilic polyvinylidene fluoride (PVDF) microporous membrane was immersed in pH 5.8 phosphate buffer for 24 hours to equilibrate. The donor and receiver chambers of the Franz diffusion cell were assembled and sealed. Preheated pH 5.8 phosphate buffer to 32°C was added to the receiver chamber, air bubbles were removed, and the chamber was ensured to be free of voids. A constant-temperature water bath with a magnetic stirrer was turned on, and the temperature was controlled at 32 ± 0.5°C (simulating human skin surface temperature). The mixture was stirred and equilibrated for 1 hour. Appropriate amounts of samples from Examples 1-4 and Comparative Examples 1-4 were accurately weighed, and free salicylic acid was accurately measured to prepare solutions with the same effective salicylic acid concentration as the former two. All solutions were placed in brown volumetric flasks, diluted to volume with a small amount of pH 5.8 phosphate buffer, and shaken well to ensure a consistent initial salicylic acid concentration. The equilibrated filter membrane was fixed between the donor and receiver chambers of the Franz diffusion cell. 0.5 mL of the prepared Example 1 sample solution was precisely added to the surface of the filter membrane in the donor chamber, ensuring uniform coverage. The opening of the donor chamber was sealed with sealing film to prevent solvent evaporation. The same procedure was followed for in vitro release experiments of Examples 2-4, Comparative Examples 1-4, and free salicylic acid solutions. Timing began at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours. At each of these eight time points, 1 mL of solution was precisely pipetted from the receiver chamber, and simultaneously, an equal volume and temperature of pH 5.8 phosphate buffer were rapidly added to maintain a constant receiver chamber volume. The aspirated sample solution was filtered through a 0.22 μm microporous membrane and transferred to a brown sample vial, sealed, and refrigerated at 4°C until analysis. All samples were analyzed by HPLC within 24 hours. Each sample was measured in triplicate, and the average value was taken. The cumulative release curve of salicylic acid is shown in [Figure number missing]. Figure 1 .

[0041] Cumulative release rate (%) = In the formula: V 总 Total volume of the receiving cell (mL); C t : The concentration of salicylic acid (μg / mL) detected at time point t; V 样 : The volume of the sample collected each time (mL); C i : Salicylic acid concentration (μg / mL) of the i-th sample collected; M0: Total mass (μg) of salicylic acid added to the donor chamber.

[0042] The results are as follows Figure 1As shown. Compared with free salicylic acid solution and Comparative Examples 1-4, the salicylic acid in Examples 1-4 exhibits a significant sustained-release characteristic, with a cumulative release rate of approximately 75% within 12 hours. The release curve is also flatter, effectively avoiding excessively high drug concentrations on the skin surface and reducing irritation.

[0043] Test Example 3 In vitro transdermal experiments Transdermal experiments were conducted using a Franz diffusion cell and ex vivo porcine skin. After 24 hours, the cumulative permeation and retention of each component in the skin were measured.

[0044] The specific experimental method is as follows: The detached pigskin was repeatedly rinsed with physiological saline to remove surface impurities. The surface moisture was blotted dry with filter paper, and the skin was trimmed into circular pieces matching the effective diffusion area of ​​the Franz diffusion cell. The pieces were then immersed in pH 5.8 PBS buffer for 2 hours, with the buffer changed once during this period to ensure the pigskin's hydration level closely resembled that of human skin. After removal, the surface moisture was gently blotted dry with filter paper and set aside. The pretreated pigskin was then fixed between the donor and receiver chambers of the Franz diffusion cell, with the skin side facing the donor chamber and the dermis side facing the receiver chamber. A tight, air-free seal was ensured between the pigskin and the diffusion cell, and the connection was sealed to prevent leakage. Preheated pH 5.8 PBS buffer (32±0.5℃) was added to the receiver chamber until it was completely filled without any gaps. A constant-temperature water bath with a magnetic stirrer was turned on, adjusting the temperature to 32±0.5℃ (simulating human skin temperature) and the stirring speed to 300 rpm, and the mixture was allowed to equilibrate for 1 hour.

[0045] Accurately weigh appropriate amounts of samples from Examples 1-4 and Comparative Examples 1-4, and prepare sample solutions with an effective concentration of salicylic acid. Three parallel samples are set up for each group. Accurately add 0.5 mL of the corresponding sample solution to the donor chamber of each diffusion cell, ensuring the sample evenly covers the pigskin surface. Seal the donor chamber opening with sealing film to prevent solvent evaporation and start timing. After 24 hours of experimentation, stop stirring, aspirate all the solution from the receiving cell at once, filter it through a 0.22 μm microporous membrane, transfer it to a brown sample vial, and refrigerate at 4°C until analysis. This is used to detect the cumulative permeate of salicylic acid.

[0046] Pigskin was removed from the diffusion chamber and its surface (donor chamber side) was repeatedly rinsed with physiological saline until salicylic acid was undetectable in the rinsing solution. The surface moisture was blotted dry with filter paper, and the pigskin was cut into small pieces and placed in a centrifuge tube. 5 mL of a methanol-physiological saline mixture (7:3, v / v) was added, and the mixture was thoroughly homogenized using a tissue homogenizer. The homogenate was then extracted ultrasonically for 30 min (300 W, 25 °C), followed by centrifugation at 8000 rpm for 15 min. The supernatant was collected. The residue was extracted again with 3 mL of the same mixture, and the two supernatants were combined and diluted to 10 mL with methanol. The mixture was filtered through a 0.22 μm microporous membrane and transferred to a brown sample vial. It was then refrigerated at 4 °C until analysis to determine the amount of salicylic acid retained in the skin layer. HPLC was used to determine the salicylic acid concentration in the receiving solution and the pigskin extract, and the cumulative permeate and skin layer retention over 24 hours were calculated. Results are as follows: Figure 2-3 As shown.

[0047] 24-hour cumulative permeation (μg / cm³) 2 = (Salicylic acid concentration in the receiving liquid × volume of the receiving liquid) / effective diffusion area of ​​the diffusion cell.

[0048] Retention amount in the skin layer (μg / cm) 2 = (Concentration of salicylic acid in pigskin extract × Fixed volume) / Effective diffusion area of ​​diffusion cell.

[0049] The cumulative permeation and skin layer retention of salicylic acid in Examples 1-4 over 24 hours were significantly higher than those in Comparative Examples 1-4, and the total transdermal amount was much higher than that in each comparative example. This proves that the triple supramolecular composition of the present invention can significantly improve the transdermal efficiency of salicylic acid and achieve efficient transdermal delivery of active ingredients. Comparative Example 1 is a simple physical mixture system that does not form a ternary DES core. Its components have poor compatibility and lack a penetration-enhancing system, making it difficult for salicylic acid to penetrate pig skin. Both the cumulative penetration and skin retention are minimal, resulting in extremely poor transdermal effects. Comparative Example 2 does not use poloxamer 407 to encapsulate the DES core, lacking micellar controlled release and delivery. The DES core has poor dispersion on the pig skin surface, significantly reducing transdermal efficiency. Comparative Example 3 does not incorporate small-molecule sodium hyaluronate, thus losing its leading penetration-enhancing effect. It cannot hydrate and soften the stratum corneum or open skin penetration channels, leading to a significant decrease in salicylic acid transdermal efficiency. Comparative Example 4 uses medium-molecule sodium hyaluronate instead of small-molecule sodium hyaluronate. Because medium-molecule sodium hyaluronate cannot penetrate the stratum corneum to exert its penetration-enhancing effect, it can only form a moisturizing film on the skin surface, resulting in a transdermal efficiency far lower than that of Example 2.

[0050] Test Example 4 Skin irritation test According to the skin irritation / corrosion test method in the "Cosmetic Safety Technical Specifications" (2015 edition), 36 healthy volunteers (half male and half female, aged 20-35 years, with no history of skin diseases or allergies) were selected and randomly divided into 9 groups (4 people in each group), corresponding to Examples 1-4, Comparative Examples 1-4, and the blank control group (deionized water), ensuring no significant differences between groups. Each composition with an effective concentration of salicylic acid and the blank control were evenly applied to a 2cm×2cm marked area on the inner forearm of the volunteers, twice daily for 4 hours each time, for 7 consecutive days. Professional personnel observed skin reactions such as erythema, edema, stinging, and itching using a double-blind method, scoring them on a 0-4 scale (0 points for no irritation, 4 points for severe irritation). The average score over 7 days was taken as the final result. Irritation levels were classified according to the score: ≤0.5 for no irritation, 0.5 < score ≤2.0 for mild irritation, 2.0 < score ≤3.0 for moderate irritation, and >3.0 for severe irritation. The results are shown in Table 2.

[0051] Table 2. Results of skin irritation tests for each composition As can be seen from the results in Table 2 above, Examples 1-4 of the present invention were all non-irritating and showed no significant difference from the blank control group. This indicates that the triple supramolecular structure of the present invention can fundamentally reduce the irritation of salicylic acid and achieve gentle acid peeling. Comparative Example 1, lacking a ternary DES core and controlled-release system, experienced moderate irritation due to the instantaneous high-concentration release of salicylic acid. Comparative Example 2, lacking poloxamer 407 encapsulation, and Comparative Example 3, lacking small molecule sodium hyaluronate complex, both experienced slight irritation due to the lack of controlled release or soothing and gentle flushing effects. Comparative Example 4, due to the replacement of the small molecule version with medium molecule sodium hyaluronate, had a reduced soothing and penetration-promoting effect and experienced slight irritation.

[0052] Test Example 5 Evaluation of anti-inflammatory efficacy An in vitro inflammation model was established by inducing mouse macrophages (RAW264.7) with lipopolysaccharide (LPS). The inhibitory effects of Examples 1-4 and Comparative Examples 1-4 on the inflammatory factor TNF-α were investigated. The blank group (without LPS) and the model group (with LPS but without sample) were used as controls to verify the anti-inflammatory activity of the composition of the present invention and the synergistic effect of each component.

[0053] Log-phase RAW264.7 cells were seeded in 96-well plates and cultured until adherent. Cells were divided into a control group, a model group, Examples 1-4, and Comparative Examples 1-4, with 6 replicates per group. Except for the control group, all other groups were treated with LPS (final concentration 1 μg / mL) to induce inflammation. The sample groups were simultaneously treated with the same effective concentration of salicylic acid as the respective compositions. The control and model groups were treated with equal volumes of culture medium. After culturing for 24 hours, the cell supernatant was collected, and the TNF-α content in the supernatant was detected using enzyme-linked immunosorbent assay (ELISA). The inflammatory factor inhibition rate was calculated using the following formula: TNF-α inhibition rate (%) = [(TNF-α content in model group - TNF-α content in sample group) / (TNF-α content in model group - TNF-α content in blank group)] × 100%, results are shown in the table below. Figure 4 As shown.

[0054] from Figure 4 The results show that Examples 1-4 all achieved an inhibition rate of over 87% for TNF-α, demonstrating significant anti-inflammatory effects. Example 2 showed the highest inhibition rate at 89.02%. Comparative Example 1, lacking a ternary DES core and relying solely on simple physical mixing, failed to achieve a synergistic anti-inflammatory effect with bisabolol and 4-tert-butylcyclohexanol, resulting in an inhibition rate of only 54.26%. This highlights the crucial role of the ternary DES structure in achieving the synergistic anti-inflammatory effect of bisabolol and 4-tert-butylcyclohexanol. While Comparative Example 2 formed a ternary DES structure, providing a molecular basis for synergistic anti-inflammatory effects among the three active ingredients, the lack of poloxamer 407 micelles for encapsulation and controlled release resulted in rapid loss of the active ingredients, hindering their sustained action on inflammatory cells. Furthermore, the hydrophobic DES core exhibited poor dispersibility in the system, reducing the contact efficiency between the anti-inflammatory components and cells. Consequently, the TNF-α inhibition rate was 74.58%, significantly lower than that of the Examples 1-4. Example 3 lacks the penetration-enhancing and auxiliary anti-inflammatory effects of small molecule sodium hyaluronate, so the anti-inflammatory components cannot effectively act on cellular targets. Furthermore, the absence of the moisturizing and buffering effect of small molecule sodium hyaluronate indirectly weakens the overall anti-inflammatory effect. Therefore, the TNF-α inhibition rate is 68.95%, lower than that of Example 1 and Comparative Example 2. Although the components in Comparative Example 4 have complete structures, the medium molecule sodium hyaluronate cannot penetrate to the cellular level to exert its penetration-enhancing and auxiliary anti-inflammatory effects; it can only form a moisturizing film on the surface. Its penetration-enhancing and synergistic effects are far weaker than those of small molecule sodium hyaluronate. Therefore, the TNF-α inhibition rate is 79.06%, still significantly lower than that of Example 1. This further illustrates the synergistic effect of the components in the triple supramolecular composition of the present invention, which can significantly improve the overall anti-inflammatory efficacy.

[0055] Test Example 6 Instant relief perception test Thirty volunteers with sensitive skin experiencing stinging sensations (aged 20-40, who had not used anti-inflammatory or soothing skincare products / medications in the past two weeks) were selected to evaluate the immediate soothing ability of Examples 1-4 and Comparative Examples 1-4. Deionized water was used as a blank control. A stinging provocation test using 5% lactic acid solution combined with a 0-10 point visual analog scale (VAS) was used for evaluation (0 points for no stinging, 10 points for severe stinging). After cleansing their faces, volunteers sat quietly for 30 minutes. Equal amounts of the sample / deionized water were applied to symmetrical 2cm×2cm areas on both sides of the face. After massaging and absorption, the area was left to stand for 5 minutes. Then, 5% lactic acid solution was applied evenly, and the timing was immediately recorded. Volunteers scored the stinging sensation based on their subjective feelings at 10 seconds, 2 minutes, and 5 minutes after applying the lactic acid. The average score and stinging relief rate of each group were calculated [(average score of blank group - average score of sample group) / average score of blank group × 100%]. The results are shown in Table 3.

[0056] Table 3 Results of Instantaneous Soothing Perception Tests for Each Composition The results show that the stinging scores of Examples 1-4 at 10 seconds, 2 minutes, and 5 minutes after lactic acid stimulation were significantly lower than those of all comparative examples. The average stinging relief rate within 5 minutes was over 86%, with Example 2 achieving the highest relief rate of 89.5%. Furthermore, at 5 minutes, the stinging scores of Examples 1-4 all decreased to 0.3 points or below, indicating almost no stinging sensation. This demonstrates that the triple supramolecular composition of the present invention possesses excellent and stable immediate soothing effects, rapidly blocking lactic acid-induced skin stinging signals, and its soothing effect is sustainable, effectively relieving the instantaneous stinging discomfort of sensitive skin. This is due to the synergistic effect of the ternary DES core, poloxamer 407 micellar delivery, and small-molecule sodium hyaluronate hydration buffer. The ternary DES core achieves molecular-level compatibility of 4-tert-butylcyclohexanol, bisabolol, and salicylic acid, allowing the soothing ingredients to quickly act on the nerve stimulation targets in the skin. The micellar encapsulation of poloxamer 407 ensures uniform dispersion and rapid transdermal delivery of the soothing ingredients, guaranteeing immediate effectiveness. The immediate hydration and softening effect of small-molecule sodium hyaluronate buffers the irritation of lactic acid to the skin, while opening skin penetration channels to help the soothing ingredients work quickly. Comparative Example 1 had the highest stinging scores at all time points among all groups, with a relief rate of only 32.1%. This was because it lacked a ternary DES core, and the components were simply physically mixed. 4-tert-butylcyclohexanol could not quickly and effectively block stinging signals, and bisabolol was also unable to synergistically work with other components to soothe the pain, thus failing to effectively relieve lactic acid-induced stinging. Comparative Example 2 lacked poloxamer 407 encapsulation. Although it formed a ternary DES core containing effective soothing components, the hydrophobic DES core was unevenly dispersed on the skin surface. The soothing components could not quickly penetrate the skin to the target site and were easily lost, resulting in a significantly higher stinging score than Examples 1-4. The relief rate was only 61.3%; Comparative Example 3 lacked the immediate hydration and buffering effect of small molecule sodium hyaluronate on the skin, so the irritation of lactic acid on the skin could not be quickly relieved, and it did not have the penetration-promoting effect of small molecule sodium hyaluronate, so the soothing ingredients took effect slowly; Comparative Example 4 used medium molecule sodium hyaluronate instead of small molecule sodium hyaluronate. Although the structure of each component was complete, medium molecule sodium hyaluronate could not quickly penetrate into the deep layer of the stratum corneum of the skin to exert the penetration-promoting and buffering effect. It could only form a moisturizing film on the skin surface to achieve mild soothing. Therefore, although its stinging score was lower than that of Comparative Examples 1-3, it was significantly higher than that of Examples 1-4, and the relief rate of 76.8% was still far lower than that of Examples.

[0057] It should be noted that the above embodiments are merely some preferred embodiments of the present invention, and not all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

Claims

1. A triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects, characterized in that, It is formed by using a ternary deep eutectic solvent composed of salicylic acid, 4-tert-butylcyclohexanol and bisabolol as the core, encapsulating the core with poloxamer 407 to form drug-loaded micelles, and finally compounding with small molecule sodium hyaluronate.

2. The triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 1, characterized in that, The molar ratio of salicylic acid, 4-tert-butylcyclohexanol and bisabolol in the ternary deep eutectic solvent is 1:(1-4); the molar ratio of 4-tert-butylcyclohexanol to bisabolol is (0.5-2):

1.

3. The triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 1, characterized in that, The mass ratio of poloxamer 407 to the ternary deep eutectic solvent core is (5-20):

1.

4. The triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 1, characterized in that, The small molecule sodium hyaluronate has a molecular weight ≤10 kDa and its mass concentration in the final triple supramolecular composition is 0.5%-3%.

5. A method for preparing a triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects as described in any one of claims 1-4, characterized in that, It includes the following steps: (1) Preparation of ternary deep eutectic solvent DES core: Mix the prescribed amounts of salicylic acid, 4-tert-butylcyclohexanol and bisabolol, stir and react at 60-80℃ for 2-6 hours until a homogeneous and transparent liquid is formed, cool to room temperature, and obtain ternary DES core; (2) Encapsulation of DES core by poloxamer 407: The DES core prepared in step (1) is slowly added to the prescribed amount of poloxamer 407 aqueous solution and magnetically stirred at 2-8℃ for 4-12 hours to form a drug-loaded micelle dispersion. (3) Composite small molecule sodium hyaluronate: Add the prescribed amount of small molecule sodium hyaluronate to the drug-loaded micelle dispersion obtained in step (2), and stir at room temperature for 1-2 hours until uniformly dispersed to obtain the final triple supramolecular composition.

6. The method for preparing the triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 5, characterized in that, The stirring speed in step (1) is 300-500 rpm.

7. The method for preparing the triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 5, characterized in that, The stirring speed in step (2) is 100-150 rpm.

8. The method for preparing the triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 5, characterized in that, In step (2), the mass concentration of poloxamer 407 in the aqueous solution is 10-30%.

9. The method for preparing the triple supramolecular composition with mild acid-exfoliating and anti-inflammatory soothing effects according to claim 5, characterized in that, The stirring speed in step (3) is 300-500 rpm.

10. The use of any one of the triple supramolecular compositions of claims 1-4 having mild exfoliating and anti-inflammatory soothing effects in the preparation of cosmetics or skin care products for skin keratinization, anti-inflammation, soothing and repair.

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