High-concentration water-soluble salicylic acid supramolecular system and application thereof

Abstract

The invention discloses a high-concentration water-soluble salicylic acid supramolecular system and application thereof, and belongs to the technical field of supramolecules. The invention provides a water-soluble salicylic acid supramolecular system, and aims to solve the problem that in the prior art, the requirements of high drug loading capacity (gt; 30%), low irritation (soothing), continuous skin penetration and the like are difficult to synergistically meet. The invention aims to introduce a supramolecular technology to develop supramolecular salicylic acid which is high in drug loading capacity (more than or equal to 30wt%), is stable and uniform liquid at the low temperature of-5 DEG C, is low in irritation and has long-acting skin penetration and controlled release, so that the supramolecular salicylic acid has breakthrough significance in treatment of skin diseases and also has a good application prospect. The invention also finds that the supramolecular system can more effectively deliver salicylic acid to adipose tissues to enhance the metabolic regulation effect of salicylic acid, thereby providing an innovative solution for local weight loss.

Description

TECHNICAL FIELD

[0001] The present application relates to a high-concentration water-soluble salicylic acid supramolecular system and its application, belonging to the field of supramolecular technology. BACKGROUND

[0002] Salicylic acid (o-hydroxybenzoic acid) as a multifunctional organic acid plays an important role in medicine, skin care and cosmetics. It is widely used in the treatment of skin problems such as acne, psoriasis, seborrheic dermatitis, etc. by promoting keratin metabolism, reducing inflammation, inhibiting microorganisms and regulating sebum secretion, and is also a common ingredient for cosmetic peeling.

[0003] In recent years, the application scenarios of salicylic acid have been continuously expanded, for example, in scalp care, 2% salicylic acid shampoo can remove keratin blockage in hair follicles to help improve androgenetic alopecia; in sunscreen products (concentration ≤3%), it has dual functions of absorbing UVB and regulating keratin metabolism; and in wound care, 5% salicylic acid gel can accelerate the healing of chronic ulcers by inhibiting biofilm formation, and clinical studies have shown that it can shorten the repair time by about 28%.

[0004] Although the liposolubility of salicylic acid helps it penetrate the keratin layer of the skin, its water solubility is extremely low (about 0.2 g / L at 20℃), which seriously restricts the design of preparations and efficacy. Traditional solubilization methods rely on organic solvents such as ethanol and propylene glycol, but these ingredients are highly irritating and can damage the skin barrier. Insufficient solubility also leads to uneven distribution of salicylic acid in the skin, reduced bioavailability, and the need for patients to increase the frequency of use, thereby increasing the risk of adverse reactions such as erythema and desquamation, which is particularly pronounced in the treatment of acute skin diseases.

[0005] On the other hand, high-concentration salicylic acid (such as 30% supramolecular peeling) has shown more than 80% efficiency in treating moderate to severe acne due to its strong keratolytic effect. However, the contradiction between high concentration and low solubility makes existing products generally highly irritating and short-acting, limiting their wider clinical application.

[0006] In view of the water solubility problem of salicylic acid, the existing technical approaches can be summarized as follows: Patent CN105106108A discloses a carrier inclusion technology using β-cyclodextrin or liposomes for embedding, but the drug loading is mostly below 15%; Patent CN106726690A discloses a nano-powder technology that relies on particle size reduction to improve solubility, but it is also prone to flocculation due to a Zeta potential below 20 mV, and the preparation cost is relatively high; Patents CN116585207A, CN116322617A and CN115429711A disclose microemulsion / micellar systems that rely on 10 30% of surfactants (such as Tween 80) help to increase solubility, but there is a potential risk of skin sensitization; patents CN105147596A and CN105106108A complex salicylic acid with gel, although the combination of salicylic acid and poloxamer, but still use ethanol Propylene glycol mixed solvent dissolves salicylic acid, and the skin irritation is obvious; and its preparation process is complicated, and starch nanocrystals, poloxamer suspension, alpha Cyclodextrin aqueous solution and low molecular weight fish collagen aqueous solution and other supramolecular systems, combined with ultrasonic dispersion, freeze-drying and other complex processes, have high requirements for equipment and operators.

[0007] It can be seen that the prior art still cannot achieve multiple goals such as high drug loading (30%), low irritation, long-term penetration and controlled release. Therefore, it is urgent to develop a method for improving the water solubility of salicylic acid, which not only meets the dual needs of health and beauty, but also opens up a new way for the development of salicylic acid in the fields of medicine and skin care products, and has very high practical value and economic value. SUMMARY

[0008] To solve the above problems, the present application provides a high-concentration water-soluble salicylic acid system based on supramolecular technology, which aims to solve the problem that the prior art cannot simultaneously meet the requirements of high drug loading (>30%), low irritation (relief) and sustained skin penetration. The present application aims to develop a high drug loading (can achieve ≥30 wt%) and low temperature-5℃ stable homogeneous liquid, low irritation, and long-term skin penetration and controlled release of supramolecular salicylic acid, which not only has a breakthrough significance in the treatment of skin diseases, but also finds that the supramolecular system can deliver salicylic acid more effectively to adipose tissue, enhance its metabolic regulation, and thus provide an innovative solution for local weight loss.

[0009] The first object of the present application is to provide a method for preparing a water-soluble salicylic acid supramolecular system, comprising the following preparation method: (1) heating and stirring salicylic acid and ethylenediaminetetraacetic acid; (2) adding a third molecule, heating and stirring to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the third molecule is 25-45:5-15:40-70. The third molecule is any one or two of methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropandiol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropyl ethylenediamine.

[0010] In one embodiment, the third molecule is any one of methylsilanetriol, diglycerol, tetrahydroxypropyl ethylenediamine or aminopropandiol; Optionally, the tertiary molecule is obtained by mixing dipropylene glycol and tromethamine in a mass ratio of 1~2:3~4; Optionally, the tertiary molecule is obtained by mixing diglycerides and tetrahydroxypropylethylenediamine in a mass ratio of 1~2:1~2; Optionally, the tertiary molecule is obtained by mixing aminomethylpropanol and aminomethylpropanediol in a mass ratio of 3-4:1-2.

[0011] In one embodiment, a water-soluble salicylic acid supramolecular system is prepared under nitrogen or argon atmosphere.

[0012] In one embodiment, the heating and stirring in step (1) is carried out at 95~125℃ and 200~600rpm for 1~3h; Optionally, stir at 100~125℃ and 300~550rpm for 1~2.5 h; Optionally, stir at 110~120℃ and 350~500rpm for 1.5~2 hours.

[0013] In one embodiment, the heating and stirring in step (2) is carried out at 60~90℃ and 200~400 rpm for 3~16 hours.

[0014] Optionally, stir at 60~85℃ and 200~350rpm for 4~14 hours; Optionally, stir at 70~80℃ and 250~300rpm for 5~11 hours.

[0015] A second objective of this invention is to provide a water-soluble salicylic acid supramolecular system prepared by any of the methods described above.

[0016] In one embodiment, the salicylic acid supramolecular system can have a salicylic acid mass concentration of up to 45 wt%. The system is miscible with water in any proportion and is compatible with conventional pH adjusters (such as citric acid and sodium lactate), soothing and anti-allergic ingredients (such as Centella asiatica extract), moisturizers (such as glycerin and sodium hyaluronate), antioxidants (vitamin E and disodium EDTA), thickeners / emulsifiers (such as carbomer and xanthan gum), and preservative systems (such as phenoxyethanol and ethylhexylglycerin), etc., without causing salicylic acid to precipitate.

[0017] A third objective of this invention is to provide a pharmaceutical product containing the above-described water-soluble salicylic acid supramolecular system.

[0018] A fourth objective of this invention is to provide a daily chemical product containing the above-described water-soluble salicylic acid supramolecular system. Optionally, the daily chemical product is a toiletries or cosmetic; Optionally, the daily chemical products include serums and gels; Optionally, the components of the essence include, but are not limited to: salicylic acid molecular system, sodium citrate, centella asiatica extract, sodium hyaluronate, disodium EDTA, xanthan gum, phenoxyethanol, and water; Optionally, the components of the gel include, but are not limited to, salicylic acid supramolecular systems, dextran, and water.

[0019] The fifth objective of this invention is to provide a method for simultaneously improving the properties of salicylic acid, wherein the properties include one or more of the following: solubility, stability, transdermal permeability, soothing and repairing effects, exfoliating effects, antibacterial effects, anti-inflammatory effects, and lipogenesis inhibition effects, and to prepare a water-soluble salicylic acid supramolecular system, comprising the steps of: (1) Heat and stir salicylic acid and ethylenediaminetetraacetic acid; (2) Add the third molecule and mix, heat and stir to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the tertiary molecule is 25~45:5~15:40~70; The third molecule is any one or two of the following: methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropylene glycol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropylethylenediamine.

[0020] In one embodiment, the third molecule is any one of methylsilanetriol, diglyceride, tetrahydroxypropylethylenediamine, or aminopropylene glycol. Optionally, the tertiary molecule is obtained by mixing dipropylene glycol and tromethamine in a mass ratio of 1~2:3~4; Optionally, the tertiary molecule is obtained by mixing diglycerides and tetrahydroxypropylethylenediamine in a mass ratio of 1~2:1~2; Optionally, the tertiary molecule is obtained by mixing aminomethylpropanol and aminomethylpropanediol in a mass ratio of 3-4:1-2.

[0021] In one embodiment, the heating and stirring in step (1) is carried out at 95~125℃ and 200~600rpm for 1~3h; Optionally, stir at 100~125℃ and 300~550rpm for 1~2.5 h; Optionally, stir at 110~120℃ and 350~500rpm for 1.5~2 hours.

[0022] In one embodiment, the heating and stirring in step (2) is carried out at 60~90℃ and 200~400 rpm for 3~16 hours.

[0023] Optionally, stir at 60~85℃ and 200~350rpm for 4~14 hours; Optionally, stir at 70~80℃ and 250~300rpm for 5~11 hours.

[0024] The sixth object of the present invention is to provide the application of any of the above-described methods or the above-described water-soluble salicylic acid supramolecular system in the preparation of daily chemical products and pharmaceuticals.

[0025] In one embodiment, the water-soluble salicylic acid supramolecular system can effectively treat acne, pimples, and characteristic dermatitis, while promoting keratin metabolism and possessing anti-inflammatory, antibacterial, and soothing effects, and can thus be applied in cosmetics, medical aesthetics, pharmaceuticals and other fields.

[0026] Beneficial effects of the present invention (1) In this invention, ethylenediaminetetraacetic acid, a third molecule and salicylic acid are used to form a supramolecular self-recognition system through hydrogen bonds. The mass concentration of salicylic acid in the system can be as high as 45 wt%. The system can be gradually diluted with water and is miscible with water, so that salicylic acid can simultaneously meet the different field requirements of high drug loading (>30%) and low drug loading.

[0027] (2) In this invention, ethylenediaminetetraacetic acid and a tertiary molecule are selected as the compatibility molecules of salicylic acid to form a supramolecular system, which helps to stabilize the system. At the same time, the formation of hydrogen bonds reduces the irritation of salicylic acid.

[0028] (3) In this invention, ethylenediaminetetraacetic acid and a third molecule are selected as the compatibility molecules of salicylic acid to form a supramolecular system, which helps the skin penetration of salicylic acid while maintaining the continuous skin penetration and controlled release of salicylic acid for 24 hours.

[0029] (4) In this invention, ethylenediaminetetraacetic acid and a third molecule are selected as the compatibility molecules of salicylic acid to form a supramolecular system. The system is in liquid state, which effectively reduces the melting point of salicylic acid and breaks through the limitations of traditional solid salicylic acid. At -5℃ (below the freezing point), salicylic acid still maintains an active liquid state, and the icy sensation reaches the skin directly. At the same time, it adds more design possibilities for subsequent formulation applications.

[0030] (5) In this invention, ethylenediaminetetraacetic acid and a tertiary molecule are selected as compatibility molecules for salicylic acid to form a supramolecular system. Its aqueous solution is compatible with soluble functional molecules, which improves the compatibility of salicylic acid.

[0031] (6) The present invention provides a green and environmentally friendly preparation process for a high-concentration water-soluble salicylic acid system based on supramolecular technology. It has good atom economy, avoids the use and emission of toxic and harmful substances, is simple to operate, does not require separation and purification, and is easy to scale up for production.

[0032] (7) The present invention provides a high-concentration water-soluble salicylic acid system based on supramolecular technology. In addition to its traditional effects in acne treatment, anti-inflammation, whitening, and hair loss prevention, it has outstanding effects in local fat reduction and reducing milia, thus broadening the application scope of salicylic acid. Attached Figure Description

[0033] Figure 1 This is the infrared spectrum of the supramolecular salicylic acid system in Example 1.

[0034] Figure 2 The results are for transdermal treatment of the supramolecular salicylic acid system in Examples 7 and 10.

[0035] Figure 3 The effects of the water-soluble salicylic acid supramolecular system and monomeric salicylic acid on TNF-α, IL-1α and IL-8 in Example 3.

[0036] Figure 4 This is the effect of Example 1 on the activity of ATGL and LPL. Detailed Implementation

[0037] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explanation of the present invention and are not intended to limit the present invention.

[0038] Supramolecular technology utilizes hydrogen bonds, π-π stacking, van der Waals forces, and other non-covalent interactions between two or more different molecules to screen for matching molecules that recognize each other and assemble into an organic whole. By utilizing these intermolecular forces, a single molecule can not only maintain its original efficacy but also improve its solubility, bioavailability, stability, and other properties. It can even achieve synergistic effects through the selection of compatible molecules.

[0039] The present invention aims to provide a method for preparing a water-soluble salicylic acid supramolecular system, comprising the following steps: (1) Heat and stir salicylic acid and ethylenediaminetetraacetic acid; (2) Add the third molecule and mix, heat and stir to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the tertiary molecule is 25~45:5~15:40~70; The third molecule is any one or two of the following: methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropylene glycol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropylethylenediamine.

[0040] The water-soluble salicylic acid supramolecular system comprises 25-45 wt% salicylic acid (CAS: 69-72-7), 5-15 wt% ethylenediaminetetraacetic acid (CAS: 60-00-4), and 40-70 wt% tertiary molecules; The tertiary molecule can be one or a mixture of two of the following: methylsilanetriol (CAS: 6284-40-8), dipropylene glycol (CAS: 25265-71-8), diglycerides (CAS: 627-82-7), tromethamine (CAS: 74103-07-4), aminopropylene glycol (CAS: 616-30-8), aminomethylpropanol (CAS: 124-68-5), aminomethylpropanediol (CAS: 115-69-5), and tetrahydroxypropylethylenediamine (CAS: 102-60-3). When it is a mixture of two, such as methylsilanetriol to dipropylene glycol in a mass ratio of 1~4:1~4.

[0041] In this invention, the content of salicylic acid in the raw material components can be 25 wt%, 35 wt%, 40 wt%, and 45 wt%, the content of ethylenediaminetetraacetic acid can be 5 wt%, 8 wt%, 12 wt%, and 15 wt%, the content of the tertiary molecule can be 40 wt%, 48 wt%, 62 wt%, and 70 wt%, and the mass ratio of methylsilanetriol to dipropylene glycol can be 1:2, 1:3, 2:3, 2:2, and 3:4.

[0042] The high-concentration water-soluble salicylic acid system based on supramolecular technology is prepared by the following method: (1) Heat and stir salicylic acid and ethylenediaminetetraacetic acid; (2) Add the third molecule and mix, heat and stir to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the tertiary molecule is 25~45:5~15:40~70; The third molecule is one or two of the following: methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropylene glycol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropylethylenediamine.

[0043] In this invention, the preparation atmosphere is nitrogen or argon; specifically, in the embodiments of this invention, it can be nitrogen and argon. In this invention, the stirring temperature in step (1) is 95-125°C, specifically 95, 105, 115, or 125°C; In this invention, the stirring time in step (1) is 1 to 3 hours, specifically 1, 1.5, 2.5, or 3 hours; In this invention, the stirring rate in step (1) is 200~600 rpm, specifically 200, 350, 450, 600 rpm; In this invention, the stirring temperature in step (2) is 60-90°C, specifically 60, 70, 80, or 90°C; In this invention, the stirring time in step (2) is 3 to 16 hours, specifically 3, 8, 12, or 16 hours; In this invention, the stirring rate in step (2) is 200~400 rpm, specifically 200, 250, 350, or 400 rpm.

[0044] In this invention, the mass concentration of salicylic acid in the system can be as high as 45 wt%, and it is miscible with water in any proportion. In the embodiments of this invention, the final mass fraction of salicylic acid after dilution can be 35 wt%, 30 wt%, 20 wt%, 10 wt%, 5 wt%, 2 wt%, 1 wt%, or 0.5 wt%.

[0045] In this invention, the high-concentration water-soluble salicylic acid system based on supramolecular technology has good compatibility and is compatible with conventional pH adjusters (such as citric acid and sodium lactate), soothing and anti-allergic ingredients (such as Centella asiatica extract), moisturizers (such as glycerin and sodium hyaluronate), antioxidants (vitamin E and disodium EDTA), thickeners / emulsifiers (such as carbomer and xanthan gum), and preservative systems (such as phenoxyethanol and ethylhexylglycerin), etc., which means that it will not cause salicylic acid to precipitate.

[0046] The aforementioned high-concentration water-soluble salicylic acid system based on supramolecular technology can effectively treat acne, pimples, and characteristic dermatitis, while promoting keratin metabolism and possessing anti-inflammatory, antibacterial, and soothing effects, thus making it applicable to cosmetics, medical aesthetics, and pharmaceutical fields.

[0047] The aforementioned high-concentration water-soluble salicylic acid system based on supramolecular technology has fat-reducing effects and can be further used in skin care products or medical aesthetics.

[0048] To further illustrate the present invention, the following detailed description of a high-concentration water-soluble salicylic acid system based on supramolecular technology and its applications is provided by the present invention in conjunction with embodiments.

[0049] Raw materials used in the examples: CAS: 60-00-4 (Ethylenediaminetetraacetic acid) Salicylic acid CAS: 69-72-7; Dipropylene glycol CAS: 25265-71-8; Methylsilanetriol CAS: 10519-96-7.

[0050] Test method: 1. Fourier transform infrared spectroscopy test parameters: Machine specifications: FTS6000; Machine manufacturer: Bio-ard, USA; Experimental parameters: Scanning range 500~4000 cm⁻¹ -1 The resolution is 4 cm. -1 .

[0051] 2. In vitro percutaneous permeation experiment: Immediately after slaughtering the pig, both ears were removed to avoid scalding and damaging the skin tissue with boiling water. The pig ears were cleaned, dried, and the surface hair was shaved off. They were then cut into strips approximately 3cm wide. Skin was harvested using a skin grafting scalpel, and the skin surface was examined. Skin with breaks, wounds, or bruises was discarded to minimize the impact of skin problems on the experimental results. The skin was then cut into approximately 2cm x 2cm pieces and stored at -20℃ for no more than two weeks.

[0052] The thawed pig ear skin was carefully placed between the two chambers of a Franz diffusion cell, ensuring that the hairy, keratinized side faced the diffusion cell and the other side faced the receiving cell with the magnetic stir bar. The pig ear skin was then pressed tightly against the edges of the two chambers and clamped together with stainless steel clamps to prevent leakage of the receiving solution. Freshly prepared receiving solution was then slowly poured into the receiving cell, expelling any air bubbles to ensure full contact between the pig ear skin and the receiving solution, thus ensuring an effective diffusion area. The transdermal diffusion apparatus was preheated to 37°C, and the assembled diffusion cell was placed within it. A constant temperature circulating water bath of 37°C and magnetic stirring at 300 rpm were set. Equal amounts of the hydrogels from Examples 2 and 10, the serum, and the commercially available salicylic acid gel were evenly applied and sealed with plastic wrap. After the experiment began, 0.5 ml samples were collected at 2 h, 4 h, 6 h, 12 h, and 24 h. After each sampling, the sample was promptly replaced with an equal volume of fresh receiving solution (a) to maintain a constant volume.

[0053] The sample taken from the percutaneous penetration experiment was filtered through a 0.45μm microporous filter, and its concentration was determined and recorded by high performance liquid chromatography. The cumulative drug penetration amount was calculated according to the following formula.

[0054]

[0055] Where Q is the cumulative transdermal penetration of the drug per unit area (µg / cm²). -2 V is the volume of the receiving cell (7 mL); A is the diffusion area (1.77 cm²). 2 Cn represents the drug concentration (µg / mL) measured at the nth sampling point. -1 Vi is the sampling volume (0.55 mL).

[0056] 3. Evaluation of soothing and repairing effects: Individuals aged 20-45 years were selected, provided they had no serious systemic diseases, no immunodeficiency or autoimmune diseases, no active allergic diseases, no history of severe allergies to cosmetics, and had not used hormonal drugs or immunosuppressants in the past month. Those whose skin test sites had no scars, pigmentation, atrophy, port-wine stains, or other blemishes that would affect the test results, had not participated in other clinical trials, used the test substance as required, had complete documentation, and signed informed consent forms before the test.

[0057] Thirty qualified volunteers were selected, and the inner arm was chosen as the test site. No products (cosmetics or topical medications) were allowed on the test site for three days before the test. The participants were required to clean the test site with water and wipe it dry with a tissue.

[0058] Subjects sat quietly for 30 minutes in a constant temperature and humidity environment (temperature (21±1) ℃, humidity (40-60) %), and two circular areas with a diameter of 18 mm were marked on the corresponding positions of the inner sides of the left and right forearms. During this period, subjects were not allowed to drink water or beverages. The test sites were exposed and placed in the test position, remaining relaxed. Baseline values ​​of the two areas were first measured, and then a 1% sodium dodecyl sulfate (SLS) solution was used to induce erythema on the inner sides of both forearms for 24 hours. The right side was designated as the experimental group. The sample from Example 3 was applied to the test area on the right hand, while the left hand area served as the control group. From day 1 to day 10, the subjects in the experimental group used the test product on the right hand area in the morning and evening, while the subjects in the left hand area served as the control group and did not use any product. To conduct soothing and repair experimental data testing: Skin parameters, including transepidermal water loss (TEWL) and skin red pigment content, were measured on the left and right hands at 1, 5, and 10 days after using the test sample. Testing of the same subject must be performed using the same instrument by the same tester, and the test probe should be cleaned between measurements.

[0059] 4. Exfoliation effect test: The stratum corneum of human skin was tested using the German CK Visioscan (VC20) skin texture scanner: The initial value test, product usage test, efficacy test, and statistical analysis were all conducted on the sample in accordance with the physicochemical testing methods in Chapter 4 of the "Cosmetic Safety Technical Specifications". (1) Subjects and testing conditions: In a constant temperature test environment with a temperature of (21±1)℃ and a humidity of (40~60)%, 30 volunteers with more stratum corneum on their elbows were selected. Inclusion criteria: 1. Age 20-45 years, all indoor workers (excluding pregnant or lactating women); 2. No serious systemic diseases, no immunodeficiency or autoimmune diseases; 3. No active allergic diseases; 4. No highly sensitive constitution; 5. No use of hormone drugs or immunosuppressants in the past month; 6. No participation in other clinical trials at the current or recent three months. Termination and exclusion criteria: 1. Volunteers request to terminate the trial for their own reasons; 2. Volunteers experience adverse reactions that prevent them from continuing the trial; 3. Volunteers have poor compliance, such as using other skincare products that may affect the trial during the test.

[0060] (2) Data testing: Thirty volunteers were selected, and the test was conducted according to a randomized, double-blind principle. The skin around the left or right elbow with more stratum corneum was randomly selected as the test area. The test area was located and the location mark was kept in place at all times. During the test, no other shower gels or cosmetics or other products that could affect the test results were used on the test area. Volunteers in the experimental group applied the diluted sample of Example 4 to the same location for 14 consecutive days, once in the morning and once in the evening. Volunteers in the control group could not use other cosmetics or bath products with exfoliating effects during the test.

[0061] The number of exfoliated stratum corneum cells (SEsc) was measured in volunteers of both the control and experimental groups on days 0, 7, and 14. The test area was kept dry for one hour before each test. During the test, subjects were required to sit quietly for at least 20 minutes in a constant temperature and humidity environment (20-22°C, 40%-60% relative humidity). The SEsc value of the fixed area was measured by the measurement personnel, and three measurements were taken for each area, with the average value recorded. The lower the SEsc value, the less stratum corneum was present in the test area, and the better the exfoliation effect.

[0062] 5. Anti-inflammatory test (1) Cell viability test The cell line used in the experiment was HaCaT immortalized human epidermal cells, purchased from Beijing Beina Chuanglian Biotechnology Research Institute. After receiving the cells, they were thawed, cultured, and cryopreserved. Cells up to the fifth passage were cryopreserved; the cells used in this experiment were cells from the fifth passage or later.

[0063] HaCaT cell suspension was seeded into 96-well cell culture plates and cultured overnight. A zero-base group, a blank control group (BC), and a sample group were then established. In the sample group, six concentration gradients were set up for the supramolecular salicylic acid system of Example 6, with six replicate wells for each concentration gradient. In the blank control group, 100 μL of culture medium containing 10% FBS was added to each well. In the sample group, 100 μL of culture medium containing samples at different dilutions was added to each well, with sample concentrations of 1%, 0.32%, 0.1%, 0.03%, 0.01%, and 0.003%. The zero-base group was not seeded with cells; only 100 μL of cell culture medium was added. The 96-well plates were then placed in a CO2 incubator for incubation. After incubation, the supernatant was discarded, and MTT-containing culture medium was added to each well. The plates were then incubated in a CO2 incubator in the dark for 3 hours. After culturing, discard the supernatant, add 100 μL of DMSO to each well, measure the absorbance A at 570 nm using a microplate reader, and calculate cell viability using the following formula (2-2): (2-2) (2) Effects of NADES on the expression of inflammatory factors To test the effect of the supramolecular salicylic acid system of Example 6 on the expression of inflammatory factors, cell suspensions were seeded into 12-well cell culture plates and cultured overnight. A blank control group (BC), a model control group (M), a positive control group (PC), and a sample group were set up. The blank control group used normal culture medium, the model control group used culture medium containing LPS (1 μg / mL), and the positive control group used culture medium containing LPS and dexamethasone. The sample group was divided into two groups: the first group contained different concentrations of the supramolecular salicylic acid system of Example 6, and the second group contained salicylic acid monomers, ensuring that both groups had the same mass fraction of salicylic acid. After the incubation period, the supernatant was collected and transferred to an ultra-low temperature freezer at -80°C. The levels of TNF-α, IL-1α, and IL-8 were detected according to the ELISA kit instructions.

[0064] 6. Fat Loss Test (1) Cell culture Cell seeding: 3T3-L1 adipocytes were seeded at 10×10⁻⁶ cells / cm². 4 Cells / well were seeded at a density of 24-well plates and incubated at 37°C and 5% CO2 for 24 hours until adherence.

[0065] (2) Drug treatment grouping Blank control group: only culture medium (DMEM) was added.

[0066] Experimental group: culture medium (DMEM) containing different concentrations of supramolecular salicylic acid from Example 7.

[0067] Positive control group: culture medium (DMEM) containing caffeine (0.19 mg / mL) was added.

[0068] Each group should repeat the cell experiment at least 3 times.

[0069] Treatment method: After the adipocytes are differentiated and matured, they are treated with culture medium containing different concentrations of the product for 24-48 hours.

[0070] (3) Sample collection and testing Cell samples: Collect processed adipocytes, lyse them, extract total protein, and store at -80℃ for later use.

[0071] Activity detection: Detect the activity of ATGL and LPL according to the kit instructions, with 3 replicates for each sample.

[0072] Example 1 The preparation of a water-soluble salicylic acid supramolecular system includes the following steps: mixing salicylic acid (45 wt% of the total system) and ethylenediaminetetraacetic acid (15 wt% of the total system), stirring at 125°C and 350 rpm (referred to as R1 in the following examples) for 1 h (referred to as t1 in the following examples); then adding a third molecule (methylsilanetriol - abbreviated as MSDS, accounting for 40 wt% of the total system), cooling to 90°C (referred to as T2 in the following examples), and stirring at 250 rpm (referred to as R2 in the following examples) for 3 h (referred to as t2 in the following examples) to obtain a water-soluble salicylic acid supramolecular system. The entire mixing process was carried out under nitrogen protection.

[0073] Examples 2 to 7 Based on Example 1, the mixing temperature, time, third molecule, and proportion were changed to prepare a water-soluble salicylic acid supramolecular system with the specific parameters shown in Table 1.

[0074] Table 1 Parameters of Examples 1-7

[0075] Comparative Example 1 Based on Example 1, without adding ethylenediaminetetraacetic acid (i.e., salicylic acid accounts for 60 wt% of the total system), the remaining steps are the same as in Example 1.

[0076] Comparative Example 2 Based on Example 1, without adding methylsilanetriol (the mass ratio of salicylic acid and ethylenediaminetetraacetic acid remained the same as in Example 1), the remaining steps were the same as in Example 1.

[0077] Comparative Example 3 Based on Example 2, ethylenediamine was used instead of ethylenediaminetetraacetic acid, and the remaining steps were the same as in Example 1.

[0078] Comparative Example 4 Based on Example 2, succinic acid was used instead of ethylenediaminetetraacetic acid, and the remaining steps were the same as in Example 1.

[0079] Comparative Example 5 Based on Example 3, propylene glycol was used instead of tetrahydroxypropyl ethylenediamine, and the remaining steps were the same as in Example 1.

[0080] Comparative Example 6 Based on Example 3, glycerol was used instead of tetrahydroxypropyl ethylenediamine alcohol, and the remaining steps were the same as in Example 1.

[0081] Comparative Example 7 Based on Example 4, the amount of ethylenediaminetetraacetic acid added was changed to 16 wt%, and aminopropylene glycol was 49 wt%. The remaining steps were the same as in Example 1.

[0082] Comparative Example 8 Based on Example 4, the amount of ethylenediaminetetraacetic acid added was changed to 4 wt%, the amount of aminopropylene glycol was changed to 61 wt%, and the remaining steps were the same as in Example 1.

[0083] Comparative Example 9: Direct Mixing Based on Example 5, a water-soluble salicylic acid supramolecular system was prepared, including the following steps: A mixture of salicylic acid, ethylenediaminetetraacetic acid, dipropylene glycol, and tromethamine was directly mixed and stirred at 125°C and 350 rpm for 3 h to obtain a salicylic acid system.

[0084] Comparative Example 10: Changing the mixing order Based on Example 1, a water-soluble salicylic acid supramolecular system was prepared, including the steps of mixing salicylic acid (45 wt% of the total system) and a tertiary molecule (40 wt% of the total system) at 125 °C and 350 rpm for 1 h; then adding ethylenediaminetetraacetic acid (15 wt% of the total system), cooling to 90 °C, and stirring at 250 rpm for 3 h to obtain the salicylic acid system. The entire mixing process was carried out under nitrogen protection.

[0085] Example 8: Characterization of the water-soluble salicylic acid supramolecular system The water-soluble salicylic acid supramolecular system prepared in Example 1 was characterized using Fourier transform infrared spectroscopy, and the results are as follows: Figure 1 As shown.

[0086] It is evident that both salicylic acid and water-soluble salicylic acid supramolecular systems have a molecular weight of 1650 cm⁻¹. -1 The presence of a peak at 3400 cm⁻¹ represents the stretching vibration of the carbonyl (C=O) group. -1 The peaks around the 20th position correspond to the stretching of the hydroxyl (OH) group.

[0087] The results showed that in the water-soluble salicylic acid supramolecular system of Example 1, 1732 cm⁻¹ -1 The emergence of new peaks around the 0.5°C is due to the increase in electron cloud density in the carbonyl oxygen, indicating that a large number of hydrogen bonds have formed in the water-soluble salicylic acid supramolecular system, thus confirming the formation of the supramolecular system.

[0088] Example 9: Stability testing of water-soluble salicylic acid supramolecular system The products prepared in Examples 1-7 and Comparative Examples 1-10 were tested for stability, and the results are shown in Table 2.

[0089] Table 2 Stability Testing

[0090] The water-soluble salicylic acid supramolecular systems prepared in Examples 1-7 were diluted with deionized water to a final mass fraction of 35 wt%, 30 wt%, 20 wt%, 10 wt%, 5 wt%, 2 wt%, 1 wt%, and 0.5 wt% to obtain homogeneous, transparent liquid systems. All systems could be stored at -5℃, 25℃, and 45℃ for at least 6 months. After being cycled 15 times at -15℃ and 40℃, the final system could still maintain a stable, homogeneous liquid state without phase separation or precipitation of solids.

[0091] Example 10: Application of water-soluble salicylic acid supramolecular system in the preparation of cosmetics 1. Using the water-soluble salicylic acid supramolecular system prepared in Example 6, cosmetics were prepared as follows: (1) Salicylic acid (2 wt%) acne-clearing and balancing serum: Water-soluble salicylic acid supramolecular system: 4.5 wt%; Centella asiatica extract: 2 wt%; Sodium hyaluronate (2W Da): 0.1 wt%; Xanthan gum: 0.2 wt%; Phenoxyethanol: 0.5 wt%; Deionized water to 100%; The salicylic acid acne-reducing and balancing essence was prepared by mixing and homogenizing.

[0092] (2) High-concentration salicylic acid (30 wt%) oil-controlling and skin-renewing gel: Water-soluble salicylic acid supramolecular system 67 wt%; β-glucan 5 wt%; deionized water to 100%; The oil-controlling and skin-renewing gel was prepared by mixing and homogenizing.

[0093] 2. Testing transdermal permeability The skin penetration results were tested using the acne-removing balancing essence, oil-controlling skin-renewing gel prepared in step 1, a 67% aqueous solution (i.e., salicylic acid content of 30%) of the system obtained in Example 7, and a commercially available 30wt% salicylic acid gel.

[0094] The results are as follows Figure 2 As shown, the 67% aqueous solution of the system obtained in Example 7 and the skin-renewing gel in Example 10 exhibited good, slowly increasing penetration effects at the same 30 wt% salicylic acid content, achieving long-lasting controlled release within 24 hours. Furthermore, compared to commercially available 30 wt% salicylic acid gels, the salicylic acid release at any given time point was higher, indicating that the water-soluble salicylic acid supramolecular system of this invention has better transdermal efficacy and bioavailability.

[0095] Effective transdermal absorption and bioavailability are important indicators for evaluating drug efficacy; good transdermal absorption and bioavailability indicate better efficacy. The transdermal absorption of the serum in Example 10 is also as described above. Figure 2 As shown, even in a low-concentration salicylic acid (2 wt%) system formulation, the water-soluble salicylic acid supramolecular system of the present invention can still achieve long-term sustained controlled release.

[0096] 3. Evaluation of soothing and repairing effects The water-soluble salicylic acid supramolecular system prepared in Example 5 was diluted with water to a final salicylic acid content of 2wt% and used as the experimental group for evaluation of its soothing and repairing efficacy. The structure is shown in Table 3.

[0097] Table 3 Evaluation of Soothing and Repairing Efficacy

[0098] The results showed that the water-soluble salicylic acid supramolecular system obtained in Example 5 exhibited significant differences in epidermal water loss and skin hemoglobin levels (P<0.05). After 10 days, the skin largely recovered, with test results approaching the initial values. The blank control group showed slight recovery after 10 days, but the condition remained more severe and recovery was slow compared to the initial values. This indicates that the water-soluble salicylic acid supramolecular system of this invention can repair the skin barrier, improve skin erythema, and has a soothing and repairing effect on damaged skin.

[0099] 4. Exfoliating effect The water-soluble salicylic acid supramolecular system obtained in Example 4 was diluted with water to a final salicylic acid content of 1 wt% and used as the experimental group for exfoliation efficacy testing. The results are shown in Table 4.

[0100] Table 4. Exfoliation Efficacy

[0101] The results showed that, compared with the blank control group and the simple 1% salicylic acid aqueous solution, the number of keratinocytes exfoliated (SEsc) in volunteers using the water-soluble salicylic acid supramolecular system obtained in Example 4 was reduced. After 14 days, the number of keratinocytes exfoliated (SEsc) decreased by 27.8%, which indicates that the water-soluble salicylic acid supramolecular system of Example 4 has a good effect on keratinocyte exfoliation, that is, it can better promote keratinocyte metabolism.

[0102] 5. Anti-inflammatory effects Excessive secretion of three inflammatory factors, TNF-α, IL-1α, and IL-8, can lead to inflammatory lesions in acne. Example 3 investigated the effects of a water-soluble salicylic acid supramolecular system and an equal amount of salicylic acid monomer (by mass of salicylic acid) on cellular levels of TNF-α, IL-1α, and IL-8.

[0103] The results are as follows Figure 3 As shown, the results indicate that, compared to the model group, although both the water-soluble salicylic acid supramolecular system and the salicylic acid monomer in Example 3 significantly reduced the secretion of these three inflammatory factors, the water-soluble salicylic acid supramolecular system in Example 3 exhibited a stronger anti-inflammatory effect at the same salicylic acid content. The results demonstrate that the supramolecular system played a synergistic role, enhancing the anti-inflammatory activity of salicylic acid.

[0104] 7. Fat-inhibiting effect Triglyceride lipase (ATGL) is a key lipase that is primarily responsible for hydrolyzing triglycerides (TAG) in adipose tissue into diglycerides (DAG) and free fatty acids (FFA), playing an important role in weight loss and metabolic regulation.

[0105] The water-soluble salicylic acid supramolecular system prepared in Example 1 was used to test the ATGL activity, and the results are as follows: Figure 4 Figure A shows the results. The results indicate that, using the ATGL activity of the control group (KB) as a standard, this demonstrates the normal enzyme activity state unaffected by external factors. Group A represents the ATGL activity of a single component, salicylic acid (0.2 mg / mL), and Group B represents the ATGL activity of a mixture of ethylenediaminetetraacetic acid (0.275 mg / mL) and methylsilanetriol (0.025 mg / mL). As shown in the figure, neither single-component salicylic acid nor the ethylenediaminetetraacetic acid / methylsilanetriol combination can promote ATGL activity. Group C represents the ATGL activity of the water-soluble salicylic acid supramolecular system of Example 1 (added with salicylic acid at a concentration of 0.2 mg / mL). After supramolecular formation, the system promotes ATGL activity. Group D is the positive control group. Although the activity of the water-soluble salicylic acid supramolecular system is not as high as that of the positive control group D, it still indicates that it can increase ATGL activity, proving that the water-soluble salicylic acid supramolecular system of this invention has a fat-reducing effect.

[0106] In muscle tissue, lipoprotein lipase (LPL) promotes fatty acid oxidation for energy. Increased LPL activity in skeletal muscle can improve fat burning efficiency and insulin sensitivity, thereby reducing fat accumulation.

[0107] The LPL activity results of the water-soluble salicylic acid supramolecular system prepared in Example 1 are as follows: Figure 4 Figure B shows the LPL activity of a single component, salicylic acid (0.2 mg / mL). Group A shows the LPL activity of a mixture of ethylenediaminetetraacetic acid (0.275 mg / mL) and methylsilanetriol (0.025 mg / mL). As can be seen from the figure, neither single-component salicylic acid nor the ethylenediaminetetraacetic acid / methylsilanetriol combination can promote LPL activity. Figure C shows the LPL results of the water-soluble salicylic acid supramolecular system of Example 1 (added with 0.2 mg / mL salicylic acid). After supramolecular formation, the system promotes LPL activity. Group D is the positive control group. The activity of the water-soluble salicylic acid supramolecular system is higher than that of the positive control group D, indicating that it can increase LPL activity, proving that the water-soluble salicylic acid supramolecular system of this invention has a good fat-reducing effect.

[0108] 8. Comparative Performance Testing The salicylic acid systems prepared by comparative examples 1 to 8 were tested for their properties, and the results are shown in Table 5.

[0109] Table 5 Comparative Performance Testing

[0110] Note: The a-test method and reagent concentration are the same as those in the above tests. Transdermal water loss and skin redness changes are data from day 10.

[0111] The results showed that, under the same reagent concentration, the transdermal performance of the systems obtained in the comparative example decreased, the reduction in the number of stratum corneum exfoliations was reduced after 14 days, the effect of promoting keratin metabolism was worse, and the repair of the skin barrier and improvement of skin erythema were not as good as the corresponding embodiments of the present invention in terms of soothing and repairing effects on damaged skin.

[0112] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A method for preparing a water-soluble salicylic acid supramolecular system, characterized in that, The preparation methods include the following: (1) Heat and stir salicylic acid and ethylenediaminetetraacetic acid; (2) Add the third molecule and mix, heat and stir to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the tertiary molecule is 25~45:5~15:40~70; The third molecule is any one or two of the following: methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropylene glycol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropylethylenediamine.

2. The method according to claim 1, characterized in that, The third molecule is any one of methylsilanetriol, diglycerol, tetrahydroxypropylethylenediamine, or aminopropylene glycol. Optionally, the tertiary molecule is obtained by mixing dipropylene glycol and tromethamine in a mass ratio of 1~2:3~4; Optionally, the tertiary molecule is obtained by mixing diglycerides and tetrahydroxypropylethylenediamine in a mass ratio of 1~2:1~2; Optionally, the tertiary molecule is obtained by mixing aminomethylpropanol and aminomethylpropanediol in a mass ratio of 3-4:1-2.

3. The method according to claim 1, characterized in that, Water-soluble salicylic acid supramolecular systems were prepared under nitrogen or argon atmospheres.

4. The method according to claim 1, characterized in that, In step (1), the heating and stirring are carried out at 95~125℃ and 200~600 rpm for 1~3 hours.

5. The method according to claim 1, characterized in that, In step (2), the heating and stirring are carried out at 60~90℃ and 200~400 rpm for 3~16 h.

6. The water-soluble salicylic acid supramolecular system prepared by the method according to any one of claims 1 to 5.

7. A medicine, characterized in that, The drug contains the water-soluble salicylic acid supramolecular system as described in claim 6.

8. A daily chemical product, characterized in that, The daily chemical product contains the water-soluble salicylic acid supramolecular system as described in claim 6; Optionally, the daily chemical product is a toiletries or cosmetic; Optionally, the daily chemical products include serums and gels; Optionally, the components of the essence include, but are not limited to: salicylic acid supramolecular system, sodium citrate, centella asiatica extract, sodium hyaluronate, disodium EDTA, xanthan gum, phenoxyethanol, and water; Optionally, the components of the gel include, but are not limited to, salicylic acid supramolecular systems, dextran, and water.

9. A method for simultaneously improving the properties of salicylic acid, said properties including one or more of solubility, stability, transdermal permeability, soothing and repairing effects, exfoliating effects, antibacterial effects, anti-inflammatory effects, and lipogenesis inhibition effects, characterized in that... The preparation of a water-soluble salicylic acid supramolecular system includes the following steps: (1) Heat and stir salicylic acid and ethylenediaminetetraacetic acid; (2) Add the third molecule and mix, then heat and ultrasonically stir to prepare a water-soluble salicylic acid supramolecular system; The mass ratio of salicylic acid, ethylenediaminetetraacetic acid and the tertiary molecule is 25~45:5~15:40~70; The third molecule is one or two of the following: methylsilanetriol, dipropylene glycol, diglycerol, tromethamine, aminopropylene glycol, aminomethylpropanol, aminomethylpropanediol, and tetrahydroxypropylethylenediamine.

10. The application of the method according to any one of claims 1 to 5 or the water-soluble salicylic acid supramolecular system according to claim 6 in the preparation of daily chemical products and pharmaceuticals.

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