A salicylic acid deep eutectic solvent and its preparation method and application

Abstract

The present invention discloses a salicylic acid deep eutectic solvent and a preparation method and application thereof. The salicylic acid deep eutectic solvent is formed by combining salicylic acid, L-carnitine and an optional polyol under intermolecular forces, so that the molecular polarity in the salicylic acid deep eutectic solvent is changed, the hydrogen bond-related effect with water and the van der Waals force-related effect are enhanced, the water solubility of salicylic acid is increased, and the transdermal permeability of L-carnitine and salicylic acid is improved. The prepared skin care products and toiletries do not need to add too many auxiliary materials, have good skin feel, and are mild and non-irritating. The preparation method provided by the present invention combines a variety of deep eutectic solvent preparation methods in the preparation process, the reaction conditions are mild, the time is short, it is conducive to industrial production, and the reaction is thorough, and the available range of multiple substances can be increased at the same time.

Description

Technical Field

[0001] The invention relates to the technical fields of chemistry such as medicine, cosmetics and cleaning compounds, and in particular to a salicylic acid deep eutectic solvent and a preparation method and application thereof. Background Art

[0002] Deep Eutectic Solvent (DES) is a binary or ternary eutectic solvent composed of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) in a certain stoichiometric ratio. The components in DES are bound together by weak non-covalent interactions such as hydrogen bonds and ionic bonds. At the same time, as an analog of ionic liquids, DES has the advantages of easy preparation, high solubility, good thermal stability, non-volatility, non-toxicity, high ionic conductivity, low vapor pressure, flame retardancy, and thermal / chemical stability. Deep eutectic solvents have been well applied in many fields. In view of their green, environmentally friendly, safe and non-toxic nature, they also have good application prospects in the field of cosmetics.

[0003] Salicylic acid, also known as salicylic acid, was first extracted from willow bark, sweet birch bark and white pearl tree, and has the same source as mandelic acid; salicylic acid, also known as β-hydroxy acid (BHA), is a natural lipophilic active ingredient that can penetrate pores, dissolve dead skin cells, regulate keratin, unclog pores, and enhance skin cell vitality. The latest clinical studies also show that salicylic acid and benzoyl peroxide are equally effective in treating acne. Salicylic acid has excellent biological activity, but it is almost insoluble in water. Its solubility in water at 20°C is 2g / L. It tends to crystallize and precipitate in non-buffered, low pH solutions. Low water solubility and recrystallization not only reduce the effective bioavailability of the active ingredient, but also irritate the skin. In actual applications, a large amount of alcohol is added to dissolve it, and then a large amount of surfactant is added to dissolve salicylic acid in water. High content of alcohol and surfactant will increase the irritation to the skin and limit its addition amount. At the same time, some related salicylic acid modification methods such as chemical modification, liposomalization, microencapsulation and other methods have improved the solubility and irritation problems of salicylic acid to a certain extent. However, these methods will make the product sticky and not refreshing to a certain extent, and some polymer materials have certain allergenicity, and have not fundamentally solved the problem.

[0004] In view of the excellent biological activity of salicylic acid, its poor water solubility, weak permeability, strong biological irritation, poor bioapplicability, etc. limit its use in medicine, cosmetics, and toiletries. We believe that the existing technology still needs to be improved and developed. Summary of the invention

[0005] In order to overcome the shortcomings of the prior art and to solve the problems of poor solubility, strong irritation and low permeability when the existing salicylic acid is used as a monomer, one of the purposes of the present invention is to provide a salicylic acid deep eutectic solvent, which has good permeability, cell and biocompatibility, good solubility and low irritation, and is used in cosmetics and toiletries to have the characteristics of exfoliation, acne removal, oil control, moisturizing, high bioavailability, stable properties, etc.

[0006] A second object of the present invention is to provide a method for preparing the salicylic acid deep eutectic solvent.

[0007] The third object of the present invention is to provide a use of the salicylic acid deep eutectic solvent in the preparation of acne prevention and treatment products, skin care compositions and washing and care compositions.

[0008] One of the purposes of the present invention is achieved by the following technical solution:

[0009] A salicylic acid deep eutectic solvent, the general chemical structure of which is:

[0010]

[0011] in, is L-carnitine; is salicylic acid;

[0012] The molar ratio of L-carnitine to salicylic acid is (1-4):(1-2).

[0013] Furthermore, the salicylic acid deep eutectic solvent further includes a polyol, and its general chemical structure is:

[0014]

[0015] Among them, R(OH) n It is a polyol, n≥2.

[0016] Furthermore, in the above-mentioned salicylic acid deep eutectic solvent, the polyol is selected from one or more of propylene glycol, butylene glycol, pentylene glycol, glycerol, and glycerol glucoside.

[0017] The general structural formula of the above polyol is C n H 2n+2-x (OH) x (x≥2), the molecular formula of glycerol glucoside is C9H 18 O8.

[0018] In the above structure, the present invention combines multiple monomers such as natural extract salicylic acid, L-carnitine and optional polyols through intermolecular forces to obtain a salicylic acid deep eutectic solvent, which can not only improve the solubility of the monomer itself and reduce irritation, but also promote the permeability of the monomer, thereby improving bioavailability. The salicylic acid deep eutectic solvent retains the characteristics of multiple substances such as salicylic acid, carnitine, polyols, etc. to the greatest extent, so that it has higher solubility, cosmetics and toiletries formula applicability and biological efficacy; it is used in cosmetics and toiletries and has the characteristics of exfoliation, acne removal, oil control, moisturizing, dandruff removal, refreshing and non-greasy, high bioavailability, stable properties, etc.

[0019] Carnitine in the above structure is a vitamin-like nutrient, also known as vitamin BT. Carnitine has good moisturizing effect, mainly due to its water absorption ability. It has hydration ability on human skin, and a lower dosage can also make the skin moist and smooth. Carnitine is a hydroxy acid, which has the ability to exfoliate, has a certain ability to accelerate the metabolism of epidermal cells, accelerate the shedding of dead skin cells, and promote skin regeneration, thereby achieving the effect of making the skin smooth and brightening the skin tone; however, there are certain defects when carnitine is used in cosmetic formulas, such as poor permeability and difficulty in being absorbed by the skin.

[0020] Polyols such as propylene glycol are slightly sweet, colorless, odorless, viscous and hygroscopic straight-chain fatty alcohol liquids. Propylene glycol is often used as a wetting agent and solvent, and is also the main ingredient of advanced antifreeze. The mechanism of its moisturizing effect is the same as that of glycerin.

[0021] Glyceryl glucoside has excellent moisturizing ability. Literature has shown that 2-α-configuration glyceryl glucoside (2-αGG) can significantly increase the expression of aquaporin AQP3, and AQP3 protein plays an important role in the water retention function of skin epithelial cells. At the same time, studies have shown that glyceryl glucoside has good skin permeability and can effectively reduce water loss. In addition, 2-αGG has a variety of physiological activities, such as activating and promoting cell regeneration; enhancing cell vitality and accelerating cell metabolism; enhancing cell antioxidant capacity; and promoting collagen synthesis.

[0022] Furthermore, in the above-mentioned salicylic acid deep eutectic solvent, the molar ratio of L-carnitine, polyol and salicylic acid is (1-4):(0-4):(1-2), wherein the content of polyol is not 0; preparing the salicylic acid deep eutectic solvent according to this molar ratio can make the reaction proceed fully and improve the reaction yield.

[0023] Furthermore, in the above-mentioned salicylic acid deep eutectic solvent, the molar ratio of salicylic acid, L-carnitine and polyol (such as propylene glycol) is 1:2:1. The use of the above-mentioned specific molar ratio is more conducive to the reaction of salicylic acid, polyol and L-carnitine to form a deep eutectic solvent with a specific structure.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. Salicylic acid, L-carnitine and optional polyols combine under intermolecular forces to form a salicylic acid deep eutectic solvent, which greatly improves the water solubility of salicylic acid and increases the solubility of salicylic acid in water. The chemical structure of the salicylic acid deep eutectic solvent provided by the present invention is When R(OH) n When it is propylene glycol, its structural formula is: In the above chemical structure, propylene glycol can be replaced by one of other polyols such as glycerol glucoside or a mixture of any ratio thereof. In the present invention, salicylic acid and L-carnitine are organically combined under the action of ionic bonds; and the polyol contains abundant hydroxyl groups, which can form hydrogen bonds with L-carnitine and salicylic acid, so that the melting point of the deep eutectic solvent is lowered and it is liquid at room temperature. After the salicylic acid deep eutectic solvent is formed, the protons on the carboxyl groups of the natural extract salicylic acid are shifted, and the electron cloud distribution in multiple monomers changes, so that the molecular polarity in the natural salicylic acid deep eutectic solvent is changed, and the hydrogen bond-related effects and van der Waals-related effects with water are enhanced, which increases the solubility of the natural salicylic acid deep eutectic solvent in water, thereby increasing the water solubility of salicylic acid.

[0026] 2. Improve the discomfort caused by traditional and modern processes to promote the solubility of salicylic acid in water, optimize skin feel, and reduce irritation. Salicylic acid has excellent biological activity, but salicylic acid is almost insoluble in water, and its solubility in water at 20°C is 2g / L. In practical applications, it will be dissolved by adding a large amount of alcohol, and then a large amount of surfactant will be added to dissolve salicylic acid in water. High content of alcohol and surfactant will increase the irritation to the skin, limiting the amount of addition. At the same time, some related salicylic acid modification methods such as chemical modification, liposomalization, microencapsulation, etc. have improved the solubility and irritation problems of salicylic acid to a certain extent, but these methods will make the product sticky and not refreshing to a certain extent. The salicylic acid deep eutectic solvent provided by the present invention does not need to add a large amount of alcohol, surfactant, or polymer base when preparing related products, and the ingredients are streamlined, refreshing and non-greasy, and the skin feel is good.

[0027] 3. Increase the transdermal permeability of L-carnitine and salicylic acid, and promote their application in toiletries. After salicylic acid, L-carnitine and optional polyols of the present invention are combined to form a salicylic acid deep eutectic solvent, the charge distribution in the salicylic acid deep eutectic solvent changes, making its potential closer to the isoelectric point of the skin, making it easier to open the skin's barrier membrane and promote skin absorption. The increase in the water solubility of the salicylic acid deep eutectic solvent can also enhance the hydration inside and outside the skin's surface cells, thereby increasing transdermal permeability. Salicylic acid has good biological activity, which can penetrate pores, dissolve dead skin cells, regulate keratin, unclog pores, and enhance cell vitality, but its low solubility in water and poor permeability limit its application in toiletries. The present invention increases the solubility of salicylic acid in water, which can promote the application of salicylic acid in toiletries to a certain extent.

[0028] 4. The salicylic acid deep eutectic solvent of the present invention improves the low solubility, low permeability and high bioirritation of salicylic acid to a certain extent. While increasing the available range of substances, the salicylic acid deep eutectic solvent also has the advantages of multiple substances such as salicylic acid, L-carnitine, and polyols; and the salicylic acid deep eutectic solvent has good permeability, cell and biocompatibility, good solubility and no irritation, and is applied to skin care products and toiletries, and has the characteristics of exfoliation, acne removal, oil control, moisturizing, high bioavailability, stable properties, etc.

[0029] The second object of the present invention is achieved by adopting the following technical solution:

[0030] A method for preparing a salicylic acid deep eutectic solvent comprises the following preparation steps:

[0031] A1) weighing L-carnitine and salicylic acid, mixing them uniformly at room temperature, placing them in a reaction kettle, and stirring them in an oil bath to obtain an L-carnitine salicylic acid mixed solution;

[0032] A2) Under the protection of inert gas, the mixed solution prepared in A1 is subjected to ultrasonic reaction;

[0033] A3) maintaining inert gas protection, subjecting the mixed solution obtained in A2 to microwave reaction;

[0034] A4) vacuum drying the mixture obtained in A3 to obtain the salicylic acid deep eutectic solvent.

[0035] Furthermore, the preparation method of the above-mentioned salicylic acid deep eutectic solvent comprises the following steps:

[0036] S1) weighing L-carnitine and part of the polyol and mixing them uniformly at room temperature to obtain an L-carnitine polyol dispersion solution;

[0037] S2) weighing salicylic acid and remaining polyol and mixing them uniformly at room temperature to obtain a salicylic acid polyol dispersion solution;

[0038] S3) mixing the L-carnitine polyol dispersion solution obtained in S1 and the salicylic acid polyol dispersion solution obtained in S2 at room temperature, stirring in an oil bath, to obtain a mixed solution;

[0039] S4) Under the protection of inert gas, subjecting the mixed solution prepared in S3 to ultrasonic reaction;

[0040] S5) maintaining inert gas protection, subjecting the mixed solution obtained in S4 to microwave reaction;

[0041] S6) vacuum drying the mixture obtained in S5 to obtain the salicylic acid deep eutectic solvent.

[0042] Furthermore, in the above-mentioned preparation method, the inert gas is one or more of nitrogen, helium, neon and argon. Stirring, ultrasonic and microwave reaction of the reactants under the inert gas can improve the purity of the obtained salicylic acid deep eutectic solvent and avoid oxidation to destroy biological activity.

[0043] Furthermore, in the above-mentioned preparation method, the temperature of the oil bath is 60-100°C (such as 60°C, 70°C, 80°C, 90°C, 100°C), and the stirring time is 12-24h (such as 12h, 18h, 24h); stirring under the condition of oil bath heating can provide the required temperature for the reaction, allowing salicylic acid, carnitine, and propylene glycol to combine through intermolecular forces to form a salicylic acid deep eutectic solvent.

[0044] Furthermore, in the above-mentioned preparation method, the ultrasonic input power of the ultrasonic reaction is 260-300 W, the ultrasonic frequency is 40-60 kHz, the ultrasonic temperature is 40-80° C., and the ultrasonic reaction time is 3-6 h; ultrasonic treatment can accelerate the reaction rate between salicylic acid, L-carnitine and the optional polyol.

[0045] Furthermore, in the above-mentioned preparation method, the microwave power of the microwave reaction is 30-50W, and the microwave reaction time is 20-35min; under this microwave power and reaction time, the reaction is complete, the salicylic acid and the polyol are fully contacted, and the reaction proceeds smoothly.

[0046] Furthermore, in the above-mentioned preparation method, the vacuum drying time is 48 hours.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The preparation method of the salicylic acid deep eutectic solvent of the present invention combines different deep eutectic solvent preparation methods such as oil bath, ultrasound, microwave, etc. during the preparation process, which can make the reaction fully proceed and improve the reaction yield, so that L-carnitine and salicylic acid can be combined through ion bonds, and optionally combined with polyols through hydrogen bonds to form a salicylic acid deep eutectic solvent, thereby increasing the water solubility and transdermal permeability of the monomer. The prepared salicylic acid deep eutectic solvent has stable properties and, compared with traditional salicylic acid products, has better solubility, skin care product formulation applicability and biological efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The diagram is a sample diagram of the salicylic acid deep eutectic solvent prepared in Example 1 and the salicylic acid deep eutectic solvent prepared in Example 5, wherein the left side is the salicylic acid deep eutectic solvent prepared in Example 1, and the right side is the salicylic acid deep eutectic solvent prepared in Example 5;

[0050] Figure 2 The sample structure characterization spectrum of the salicylic acid deep eutectic solvent prepared in Example 1 ( 1 HNMR);

[0051] Figure 3 The sample structure characterization spectrum of the salicylic acid deep eutectic solvent prepared in Example 5 ( 1 HNMR);

[0052] Figure 4 FTIR spectrum of salicylic acid, L-carnitine, propylene glycol and the salicylic acid deep eutectic solvent prepared in Example 1;

[0053] Figure 5 FTIR spectrum of salicylic acid, L-carnitine and the salicylic acid deep eutectic solvent prepared in Example 5;

[0054] Figure 6 This is a test result diagram of the average water content of the stratum corneum of the salicylic acid deep eutectic solvent aqueous solution prepared in Experimental Example 1 in Performance Test Example (III);

[0055] Figure 7 This is a graph showing the cell counting results of the exfoliation test of the salicylic acid deep eutectic solvent aqueous solution prepared in Experimental Example 1 and Experimental Example 4 and the L-carnitine propylene glycol salicylic acid mixed solution of Comparative Example 3 in Performance Test Example (V);

[0056] Figure 8 This is a comparison chart of the average cleansing oil rate and the average immediate oil control rate over 6 hours of the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos in Comparative Examples 5 and 6 used by the subjects in Performance Test Example (IX);

[0057] Fig. 9The oil control rate results of the subjects in Performance Test Example (IX) after using the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days;

[0058] Fig.10 The results of the ASFS score change rate after the subjects in Performance Test Example (IX) used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days;

[0059] Fig.11 The graph of the change rate of the number of dandruff after the subjects in Performance Test Example (IX) used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days;

[0060] Fig.12 This is a graph showing the change in dandruff area after the subjects in Performance Test Example (IX) used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days. DETAILED DESCRIPTION

[0061] The following examples are further given to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention.

[0062] Example 1

[0063] S1) taking 2 mol of L-carnitine and 0.5 mol of propylene glycol, mixing them uniformly at room temperature to obtain an L-carnitine propylene glycol dispersion;

[0064] S2) taking 1 mol of salicylic acid and 0.5 mol of propylene glycol, and mixing them uniformly at room temperature to obtain a salicylic acid propylene glycol dispersion;

[0065] S3) mixing the L-carnitine propylene glycol dispersion prepared in S1 and the salicylic acid propylene glycol dispersion prepared in S2, placing in a reaction kettle, and stirring in an oil bath at 80° C. for 12 h under the protection of an argon atmosphere to obtain a mixed solution;

[0066] S4) subjecting the mixed solution obtained in S3 to ultrasonic reaction, with an ultrasonic input power of 300 W, an ultrasonic frequency of 50 kHz, a temperature of 50° C., and an ultrasonic reaction for 4 h. As the reaction proceeds, argon is slowly added to ensure that the temperature and pressure in the reactor are maintained within a corresponding range to ensure argon atmosphere protection;

[0067] S5) maintaining argon atmosphere protection, subjecting the mixed solution obtained in S4 to microwave reaction, with a microwave power of 50 W and a microwave reaction time of 25 min to ensure complete reaction;

[0068] S6) Dry the mixture obtained in S5 in a vacuum drying oven for 48 hours to obtain a salicylic acid deep eutectic solvent having an appearance as shown in Figure 1 The bottle on the left shows a clear and transparent liquid.

[0069] Example 2

[0070] S1) taking 4 mol of L-carnitine and 0.5 mol of butanediol, mixing them uniformly at room temperature to obtain an L-carnitine butanediol dispersion;

[0071] S2) taking 2 mol of salicylic acid and 0.5 mol of butylene glycol, mixing them uniformly at room temperature to obtain a salicylic acid butylene glycol dispersion;

[0072] S3) mixing the L-carnitine butanediol dispersion prepared in S1 and the salicylic acid butanediol dispersion prepared in S2 evenly, placing in a reaction kettle, and stirring in an oil bath at 60° C. for 18 h under the protection of an argon atmosphere to obtain a mixed solution;

[0073] S4) subjecting the mixed solution obtained in S3 to ultrasonic reaction, with an ultrasonic input power of 260 W, an ultrasonic frequency of 40 kHz, a temperature of 60° C., and an ultrasonic reaction for 3 h. As the reaction proceeds, argon is slowly added to ensure that the temperature and pressure in the reactor are maintained within a corresponding range to ensure argon atmosphere protection;

[0074] S5) maintaining argon atmosphere protection, subjecting the mixed solution obtained in S4 to microwave reaction, with a microwave power of 40 W and a microwave reaction time of 20 min to ensure complete reaction;

[0075] S6) Drying the mixture obtained in S5 in a vacuum drying oven for 48 hours to obtain a salicylic acid deep eutectic solvent.

[0076] Example 3

[0077] S1) taking 1 mol of L-carnitine and 2 mol of glycerol, mixing them uniformly at room temperature to obtain an L-carnitine glycerol dispersion;

[0078] S2) taking 1 mol of salicylic acid and 2 mol of glycerol, mixing them uniformly at room temperature to obtain a salicylic acid-glycerol dispersion;

[0079] S3) mixing the L-carnitine glycerol dispersion prepared in S1 and the salicylic acid glycerol dispersion prepared in S2 evenly, placing in a reaction kettle, and stirring in an oil bath at 70° C. for 24 h under the protection of an argon atmosphere to obtain a mixed solution;

[0080] S4) subjecting the mixed solution obtained in S3 to ultrasonic reaction, with an ultrasonic input power of 300 W, an ultrasonic frequency of 60 kHz, a temperature of 40° C., and an ultrasonic reaction for 4 h. As the reaction proceeds, argon is slowly added to ensure that the temperature and pressure in the reactor are maintained within a corresponding range to ensure argon atmosphere protection;

[0081] S5) maintaining argon atmosphere protection, subjecting the mixed solution obtained in S4 to microwave reaction, with a microwave power of 60 W and a microwave reaction time of 35 min to ensure complete reaction;

[0082] S6) Drying the mixture obtained in S5 in a vacuum drying oven for 48 hours to obtain a salicylic acid deep eutectic solvent.

[0083] Example 4

[0084] S1) taking 4 mol of L-carnitine and 1 mol of glycerol glucoside, mixing them uniformly at room temperature to obtain an L-carnitine glycerol glucoside dispersion;

[0085] S2) taking 2 mol of salicylic acid and 1 mol of glyceryl glucoside, mixing them uniformly at room temperature to obtain a salicylic acid glyceryl glucoside dispersion;

[0086] S3) mixing the L-carnitine glycerol glucoside dispersion prepared in S1 and the salicylic acid glycerol glucoside dispersion prepared in S2, placing in a reaction kettle, and stirring in an oil bath at 80° C. for 12 h under the protection of an argon atmosphere to obtain a mixed solution;

[0087] S4) subjecting the mixed solution obtained in S3 to ultrasonic reaction, with an ultrasonic input power of 300 W, an ultrasonic frequency of 50 kHz, a temperature of 50° C., and an ultrasonic reaction for 4 h. As the reaction proceeds, argon is slowly added to ensure that the temperature and pressure in the reactor are maintained within a corresponding range to ensure argon atmosphere protection;

[0088] S5) maintaining argon atmosphere protection, subjecting the mixed solution obtained in S4 to microwave reaction, with a microwave power of 50 W and a microwave reaction time of 25 min to ensure complete reaction;

[0089] S6) Drying the mixture obtained in S5 in a vacuum drying oven for 48 hours to obtain a salicylic acid deep eutectic solvent.

[0090] Example 5

[0091] A1) 2 mol of L-carnitine and 1 mol of salicylic acid were mixed at room temperature, placed in a reaction kettle, and stirred for 12 h in an oil bath at 80° C. under argon atmosphere to obtain an L-carnitine salicylic acid mixed solution;

[0092] A2) subjecting the L-carnitine salicylic acid mixed solution prepared in A1 to ultrasonic reaction, with an ultrasonic input power of 300 W, an ultrasonic frequency of 50 kHz, a temperature of 50° C., and an ultrasonic reaction for 4 h. As the reaction proceeds, argon gas is slowly added to ensure that the temperature and pressure in the autoclave are maintained within the corresponding range to ensure argon atmosphere protection;

[0093] A3) Maintaining argon atmosphere protection, subjecting the mixed solution obtained in A2 to microwave reaction at a microwave power of 50 W for 25 min to ensure complete reaction;

[0094] A4) Dry the mixture obtained in A3 in a vacuum drying oven for 48 hours to obtain a salicylic acid deep eutectic solvent having an appearance as shown in Figure 1 The bottle on the right shows a clear and transparent liquid.

[0095] To facilitate subsequent testing, the salicylic acid deep eutectic solvent prepared in Example was prepared into an aqueous solution and numbered as follows:

[0096] Experimental Example 1

[0097] The salicylic acid deep eutectic solvent prepared in Example 1 was added to deionized water, with the volume ratio of the salicylic acid deep eutectic solvent to deionized water being 95:5, to prepare a salicylic acid deep eutectic solvent aqueous solution.

[0098] Experimental Example 2

[0099] The salicylic acid deep eutectic solvent prepared in Example 1 was added to deionized water, with the volume ratio of the salicylic acid deep eutectic solvent to deionized water being 80:20, to prepare a salicylic acid deep eutectic solvent aqueous solution.

[0100] Experimental Example 3

[0101] The salicylic acid deep eutectic solvent prepared in Example 4 was added to deionized water, with the volume ratio of the salicylic acid deep eutectic solvent to deionized water being 95:5, to prepare a salicylic acid deep eutectic solvent aqueous solution.

[0102] Experimental Example 4

[0103] The salicylic acid deep eutectic solvent prepared in Example 5 was added to deionized water, with the volume ratio of the salicylic acid deep eutectic solvent to deionized water being 95:5, to prepare a salicylic acid deep eutectic solvent aqueous solution.

[0104] Comparative Example 1

[0105] Salicylic acid in an amount equimolar to the salicylic acid deep eutectic solvent in Experimental Example 1 was added to deionized water, and the pH was adjusted to prepare a salicylic acid aqueous solution.

[0106] Comparative Example 2

[0107] An L-carnitine aqueous solution was prepared by adding an equimolar amount of L-carnitine to the salicylic acid deep eutectic solvent in Experimental Example 1 into deionized water.

[0108] Comparative Example 3

[0109] L-carnitine, propylene glycol and salicylic acid in an equal molar amount to the salicylic acid deep eutectic solvent in Experimental Example 1 were added to deionized water and mixed evenly to prepare a mixed solution of L-carnitine, propylene glycol and salicylic acid.

[0110] Comparative Example 4

[0111] L-carnitine, glycerol glucoside and salicylic acid in an equal molar amount to the salicylic acid deep eutectic solvent in Experimental Example 3 were added to deionized water and mixed evenly to prepare a mixed solution of L-carnitine, glycerol glucoside and salicylic acid.

[0112] Comparative Example 5

[0113] A brand of shampoo containing salicylic acid is provided.

[0114] Comparative Example 6

[0115] Provide a brand of shampoo containing L-carnitine.

[0116] Structural characterization:

[0117] (I) Nuclear magnetic resonance spectroscopy

[0118] The structures of the natural salicylic acid deep eutectic solvents obtained in Example 1 and Example 5 were characterized using a nuclear magnetic resonance spectrometer (600 Hz), and the specific test parameters were: 1 H NMR, temperature 25 ° C, structural analysis using MestReNova. The results are as follows Figure 2 , 3 shown.

[0119] Specifically, the NMR test results of the salicylic acid deep eutectic solvent obtained in Example 1 are as follows: Figure 2 As shown: 1 HNMR (600MHz, Methanol-d4) δ7.83 (dd, J=7.7, 1.8Hz, 1H), 7.29 (ddd, J=8.2, 7.2, 1.8Hz, 1H), 6.93–6.62 (m, 2H), 4.57–4.45 (m, 2H), 3.66 (t, J=6.4Hz, 4H), 3.44–3.37 (m, 4H), 3.21 (s, 18H), 2.52–2.27 (m, 4H), 1.75 (p, J=6.4Hz, 2H). The chemical signals indicated that the ratio of salicylic acid: L-carnitine: 1,3-propylene glycol was 1:2:1, and the structure was correct.

[0120] The NMR test results of the salicylic acid deep eutectic solvent obtained in Example 5 are as follows: Figure 3 As shown: 1H NMR (600 MHz, Methanol-d4) δ7.83 (dd, J = 7.8, 1.8 Hz, 1H), 7.29 (ddd, J = 8.8, 7.1, 1.8 Hz, 1H), 6.79 (ddd, J = 14.9, 7.9, 1.2 Hz, 2H), 4.50 (tddt, J = 7.7, 5.0, 2.5, 1.3 Hz, 2H), 3.44–3.36 (m, 4H), 3.22 (s, 18H), 2.49–2.36 (m, 4H). The chemical signals indicated that the ratio of L-carnitine: salicylic acid was 2:1 and the structure was correct.

[0121] (II) Infrared test

[0122] The salicylic acid deep eutectic solvent prepared in Example 1 was subjected to infrared testing and comparison with salicylic acid, L-carnitine and propylene glycol. The results are as follows: Figure 4 As shown. It can be seen that the salicylic acid deep eutectic solvent has a wave number of 1100cm -1 、1600cm -1 、2800cm -1 There are characteristic peaks similar to those of salicylic acid at a wave number of 1400 cm -1 、1480cm -1 、1600cm -1 There are characteristic peaks similar to those of L-carnitine at wave number 1000 cm -1 、2950cm -1 The same characteristic peaks as those of propylene glycol exist at 3000-3500 cm -1 There is a broad deep eutectic solvent characteristic peak at , indicating that a deep eutectic solvent of salicylic acid containing polyols has been formed.

[0123] The salicylic acid deep eutectic solvent prepared in Example 5 was subjected to infrared testing and comparison with salicylic acid and L-carnitine. The results are as follows: Figure 5 As shown. It can be seen that the salicylic acid deep eutectic solvent has a wave number of 1100cm -1 、1600cm -1 、2800cm -1 There are characteristic peaks similar to those of salicylic acid at a wave number of 1400 cm -1 、1480cm -1 、1600cm -1 The same characteristic peaks as those of L-carnitine exist at 3000-3500 cm -1 There is a broad hydrogen bonding characteristic peak at , indicating that a deep eutectic solvent of salicylic acid without polyols has been formed.

[0124] Performance Test:

[0125] (I) Sample water solubility test

[0126] The salicylic acid deep eutectic solvents of Examples 1 to 5 prepared under the conditions of the present invention, salicylic acid monomer compounds and commercially available cyclodextrin-encapsulated salicylic acid were tested for water solubility at a test temperature of 20° C. The test results are shown in Table 1 below.

[0127] Table 1. Sample solubility test table

[0128]

[0129] It can be seen from the data in the above table that salicylic acid monomer is almost insoluble in water, and its solubility in water at 20°C is 0.2g / 100ml. The water solubility of the salicylic acid deep eutectic solvents prepared under the conditions of the present invention is better than that of monomeric salicylic acid. The salicylic acid deep eutectic solvents prepared in Examples 1 to 5 are miscible with water in any proportion.

[0130] (II) Transdermal effect test

[0131] The transdermal effect test was conducted on Experimental Examples 1 to 4 and Comparative Examples 1, 3, and 4. The specific test method is as follows:

[0132] (1) The samples provided in Experimental Examples 1 to 4 and Comparative Examples 1, 3, and 4 were used for the following penetration test.

[0133] (2) The dorsal skin of GF Kunming mice was used, and the subcutaneous fat layer and connective tissue were carefully peeled off, rinsed with saline, and placed in saline for later use.

[0134] (3) The Franz cell method was used for transdermal experiments. The exposed mouse skin area in the diffusion cell of the Franz diffusion device was 1.13 cm 2 , the volume of the receiving chamber is 15mL.

[0135] (4) Take 1.0 mL of the test solution and apply it to the skin surface. Add 15 mL of the receiving solution containing 10% ethanol and commercially available PBS buffer solution (pH ≈ 7.4) into the receiving cell. Place the cell in a constant temperature water bath at 32 ± 0.5 °C and stir at a speed of 350 rad / min.

[0136] (5) Subcutaneous permeability test: 2 mL of receiving solution was collected at different time points, and triplicate samples were collected at each time point. 2 mL of receiving solution was immediately added to the receiving chamber after sampling. The receiving solutions collected at different time points were filtered through a 0.22 μm microporous filter membrane, and the concentration of the receiving solution was measured by liquid phase detection.

[0137] The test results are shown in Table 2 below.

[0138] Table 2 Transdermal effect test results

[0139]

[0140] Under the same experimental conditions, the permeation per unit area of ​​the samples provided in Experimental Examples 1 to 4 and Comparative Examples 1, 3, and 4 all increased over time. From the permeation per unit area, it can be seen that the permeation effect of salicylic acid at 24 hours is salicylic acid (3192.96 μg / cm 2 )>Salicylic acid monomer aqueous solution (644.86μg / cm 2 The results show that the permeation amount of salicylic acid in the salicylic acid deep eutectic solvent aqueous solution of Experimental Examples 1 to 4 is better than that of the physical mixed solution of equal molar amount in Comparative Examples 3 and 4 and the corresponding monomer solution of equal molar amount in Comparative Example 1.

[0141] (III) Moisturizing test

[0142] Experimental Example 1 was used for the moisturizing test.

[0143] (1) Before using the sample

[0144] a. Do not use any products (cosmetics, skin care products or topical medications) on the test area 2 to 3 days before the test, and do not come into contact with water 1 to 3 hours before the test day.

[0145] b. Qualified subjects fill out the informed consent form;

[0146] c. Before the test, the subjects need to clean the inner forearms of both hands uniformly by wiping them clean with dry tissue paper;

[0147] d. The subjects rested for 25 minutes in an environment with a temperature of 21±1°C and a relative humidity of 50±10% RH.

[0148] Use a skin moisture content tester (CM85) to collect the moisture content of the skin stratum corneum before using the sample;

[0149] Set the sample area and blank area;

[0150] (2) For single-use samples, apply the sample in a 9-point matrix on the test area with a finger cot. Apply the sample 3 times on the front, back, left, and right sides. Weigh the finger cot and control the application amount to (2.0±0.1) mg / cm 2 , no samples are used in the blank area.

[0151] a. The subjects need to stay in an environment with a temperature of 21±1℃ and a relative humidity of 50±10% RH;

[0152] b. Retest the data of each area of ​​the arm 2h and 4h after application.

[0153] (3) Statistical results (such as Figure 6 (shown)

[0154] a. In the before and after comparison, compared with the baseline value, the change rate of the water content of the stratum corneum of the test area of ​​the subject's arm after a single use of the salicylic acid deep eutectic solvent aqueous solution of Experimental Example 1 for 2h and 4h was 59.63% (P<0.05) and 48.79% (P<0.05), respectively, both of which increased significantly.

[0155] b. In the before and after comparison, compared with the baseline value, the change rate of the water content of the stratum corneum of the skin in the blank area of ​​the subject's arm after a single use of the salicylic acid deep eutectic solvent aqueous solution of Experimental Example 1 for 2h and 4h was 0.13% (P>0.05) and -0.24% (P>0.05), respectively, with no significant difference.

[0156] c. In the inter-group comparison, compared with the blank area, the water content of the stratum corneum of the test area was significantly different 2h and 4h after a single application of salicylic acid (P < 0.01). The above results show that salicylic acid deep eutectic solvent has a significant skin moisturizing effect.

[0157] (IV) Patch test:

[0158] The samples provided in Experimental Example 1 and Comparative Examples 1, 3, and 4 were used for patch testing. The specific testing method is as follows:

[0159] (1) Select qualified patch test equipment and use the closed patch test method. Place 0.020g to 0.025g of the test substance in the patch test equipment and apply it to the curved side of the subject's forearm with a hypoallergenic tape.

[0160] (2) After 24 hours, remove the test substance and observe the skin reaction at 0.5, 24, and 48 hours after removal. Record the results according to the skin reaction grading standard in the Technical Specification for Safety of Cosmetics (2015 edition).

[0161] Tables 3-1 to 3-4 are patch test results statistics. It can be seen from Tables 3-1 to 3-4 that 0 of the 40 people who used the salicylic acid deep eutectic solvent aqueous solution provided in Experimental Example 1 to conduct a human skin occlusive patch test had adverse skin reactions. However, the salicylic acid solutions, L-carnitine propylene glycol salicylic acid aqueous solutions and L-carnitine glycerol glucoside salicylic acid aqueous solutions provided in Comparative Examples 1, 3 and 4 all had some adverse skin reactions.

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] Table 4. Skin occlusion patch test skin reaction grading standard

[0168]

[0169] (V) Exfoliation test

[0170] The samples provided in Experimental Example 1, Experimental Example 4 and Comparative Example 3 were used for exfoliation testing. The specific testing method is as follows:

[0171] 1. After thawing and cleaning the pig skin, fix the skin between the supply chamber and the receiving chamber of the Franz cell diffusion tank, with the stratum corneum facing the supply chamber and the dermis facing the receiving chamber; add 7.0 mL of receiving solution into the receiving chamber, tighten and fix the suckling pig skin, add 1.5 mL of receiving solution (PBS) into the receiving chamber through a sampler, exhaust the air, and make the dermis layer of the skin in close contact with the receiving solution.

[0172] 2. Add the sample to the skin surface in the supply chamber. Add 50 μL of the sample to the pig skin surface (PBS buffer was added to the control group surface as a blank control). Spread the sample evenly from the center of the skin to the edge in a radial pattern. The sample exposure area is 3.14 cm 2 Each sample was repeated 3 times in parallel, and the water bath was kept at a constant temperature of (32±1)℃, and there were no bubbles in the water bath.

[0173] 3. After incubation for 24 hours, put on the finger cot and rub the sample application area. After rubbing for two minutes, add 0.5 mL of cleaning solution (0.1% Triton X-100) to the supply chamber and blow to clean the keratinocytes shed from the skin surface.

[0174] 4. Transfer the cleaning solution to a 1.5 mL centrifuge tube and set aside.

[0175] 5. Cell counting:

[0176] Place a 1.5 mL EP tube containing the cleaning solution on a mini mixer (MIX-2500), adjust to the maximum speed, and oscillate for 2 minutes. Then take 10 μL of the cleaning solution and spot it on the cell counting plate. Use an automatic cell counter to count the cells and measure the keratinocyte density in the cleaning solution. Set two detection wells for each repeat (parallel) and take the average value as the cell density of the group.

[0177] The test groups are shown in Tables 5-1 to 5-3 below.

[0178]

[0179]

[0180]

[0181] Figure 7 The results of the exfoliation test cell counts of the samples provided in Experimental Example 1, Experimental Example 4 and Comparative Example 3 are shown in FIG. Figure 7 It can be seen that compared with the BC group, the number of exfoliated keratinocytes in the PC group increased significantly after treatment, indicating that the positive control of this test is effective; compared with the BC group, the number of exfoliated keratinocytes in the samples of Experimental Examples 1 and 4 increased after treatment with salicylic acid deep eutectic solvent aqueous solution, among which the result of Experimental Example 1 was significant, indicating that the salicylic acid deep eutectic solvent aqueous solution has a good exfoliating effect, and the salicylic acid deep eutectic solvent containing polyols in the structure has a better exfoliating effect; the number of exfoliated keratinocytes in the sample of Comparative Example 3 after treatment with the mixed solution of L-carnitine, propylene glycol and salicylic acid did not increase significantly, indicating that the mixed solution of L-carnitine, propylene glycol and salicylic acid has no obvious exfoliating effect.

[0182] (VI) Propionibacterium acnes detection

[0183] 1. Experimental steps:

[0184] Take 2.5 mL of the sample solution with different dilutions and add it to 2.5 mL of double culture medium. The culture medium required for Propionibacterium acnes is Clostridium enrichment culture medium. 5 cfu / mL~5×10 6 cfu / mL of bacterial solution was inoculated into test tubes containing different dilution solutions and culture media. The same method was used to inoculate the bacterial solution into a culture media test tube without the sample solution as a positive control. In the same way, a test tube without bacterial solution was used as a negative control and cultured in a 37°C incubator (cultured in a 28°C incubator for 64 hours for fungi) and observed for 48 hours.

[0185] 2. Judgment criteria:

[0186] When the positive control tube has bacterial growth (turbidity) and the negative control tube has no bacterial growth (transparent), the concentration of the sample solution corresponding to the highest dilution concentration of the test group with no bacterial growth is the minimum inhibitory concentration (MIC) of the sample. The test results are shown in Table 6 below.

[0187] Table 6 Propionibacterium acnes detection results

[0188]

[0189] The experimental results show that the salicylic acid deep eutectic solvents prepared in Examples 1 and 5 can effectively inhibit Propionibacterium acnes, while the mixed solution and monomer salicylic acid provided in Comparative Example 3 have poor antibacterial effects.

[0190] (VII) Cytotoxicity test

[0191] 1. Human dermal papilla cells were cultured at 1.0×10 4 Cells were seeded into 96-well plates at a density of 100 μL per well and incubated for 24 h.

[0192] 2. After the cells have adhered for 24 hours, discard the culture medium and add 100L of the sample solution to each well to set up a blank group and a negative group.

[0193] 3. After the cells were incubated for 24 hours, 10 μL of MTT solution was added to each well and the cells were cultured in an incubator for 4 hours.

[0194] 4. Discard the culture medium, add 150 μL DMSO to each well, shake for 10 minutes and measure the absorbance at 490 nm (OD 490nm ), and compare with the control samples not treated with the test substance and calculate the results.

[0195]

[0196] Where:

[0197] Relative survival rate - relative OD 490nm , %

[0198] Test OD 490nm ——Average OD of the test substance 490nm

[0199] Neg OD 490nm ——Average OD of negative control 490nm

[0200] When the concentration of the salicylic acid deep eutectic solvent in Example 1 was 0.15463 mg / mL, the relative cell viability value was 91.24%, and there was no significant difference between the cell state and the cell state of the solvent control group under the microscope. Therefore, according to the test results, it was finally determined that the salicylic acid deep eutectic solvent did not show cytotoxicity within the range of 0.15463 mg / mL.

[0201] (VIII) Malassezia detection

[0202] 1. Culture medium Pityrosporum medium (MFM): 60.0 g malt agar, 20.0 g ox bile (dry), 10.0 g Tween 40, 2.5 g glycerol mono-oleate, 1.0 L distilled water, sterilize at 121°C for 15 min.

[0203] 2. Passaging: ① Prepare a test tube containing 5-10 mL of liquid culture medium and 2 plates; ② Open it in the safety cabinet, burn the top with an alcohol lamp, then quickly drip sterile water to break it, and then break it with tweezers; ③ Pipette 0.5 mL of liquid culture medium into the freeze-dried tube, put it back into the liquid test tube after it is fully dissolved, and mix it; ④ Pipette 0.2 mL of bacterial suspension into the plate, spread it evenly, repeat twice to obtain two plates; ⑤ Culture all the liquid test tubes and plates under the above-mentioned culture conditions, and they can be used when the bacteria grow.

[0204] 3. After two subcultures, pick up the colonies with an inoculation loop and place them in an appropriate amount of sterile physiological saline. Pipet and aspirate several times to adjust the turbidity to McFarland No. 1 turbidimetric tube. Spread the plate and count the concentration to (2-4)×10 6 CFU / mL. Dilute the bacterial suspension 10 times with sterile saline, take 100uL and evenly spread it on the plate and dry it. Place 2 Oxford cups evenly on each plate and press them lightly to fit the culture medium. Add 200uL of drug solution to each Oxford cup, set up three parallels for each drug, and set up a propylene glycol control group and a 0.1mg / mL ketoconazole positive control. Culture in an incubator at 32°C for 72h, take pictures, and measure the diameter of the inhibition zone with Image J. Measure each cup 3 times and take the average value.

[0205] 4. The results were determined according to the National Committee for Clinical Trials Standards (NCCLS) standard: the diameter of the inhibition zone <8 mm was insensitive, 8-13 mm was low sensitivity, 13-19 mm was moderate sensitivity, and >19 mm was highly sensitive. The test was considered qualified if the three repeated tests showed antibacterial effects. No inhibition zone was produced in the negative control group, otherwise the test was invalid.

[0206] 5. Experimental results:

[0207] Table 7 Malassezia detection results

[0208]

[0209] The experimental results show that salicylic acid deep eutectic solvent can effectively inhibit Malassezia, and the inhibition effect is better than salicylic acid monomer solution and mixed solution.

[0210] (IX) Oil control and anti-dandruff test

[0211] The sample salicylic acid deep eutectic solvent aqueous solution provided in Experimental Example 1 and the salicylic acid carnitine propylene glycol solution provided in Comparative Example 3 were used to prepare shampoo according to the basic cosmetic formula, which were recorded as Experimental Example 1 shampoo and Comparative Example 3 shampoo, respectively. The oil control and anti-dandruff tests were carried out with the commercially available competitive shampoos of Comparative Examples 5 and 6. The specific test method is:

[0212] 1. Before using the sample

[0213] (1) 30 subjects were not allowed to wash their hair or comb their hair for 48±4 hours.

[0214] (2) Qualified subjects are screened and fill in the informed consent form;

[0215] (3) The subjects rested for 30 minutes in an environment with a temperature of 21±1℃ and a relative humidity of 50±10% RH;

[0216] (4) Use a scalp oil tester and hair ultrasound dermatoscope to collect oil data on the head, score the dandruff on the scalp, scan the dandruff for 60 seconds, and fill out a shampoo trial skin feel evaluation questionnaire;

[0217] (5) Washing hair: Wash half of the hair with clean water as a blank control area, and use the sample once for 60 seconds on the other half of the hair.

[0218] 2. Single use sample immediately or after 6 hours

[0219] (1) The subjects rested for 30 minutes in an environment with a temperature of 21±1℃ and a relative humidity of 50±10% RH;

[0220] (2) Retest the scalp oil data in the blank area and sample area;

[0221] 3. After using the sample for 14 days

[0222] (1) You cannot wash your hair within 48±4 hours before the visit, and the time before each visit should be basically the same. You cannot comb your hair on the day of the visit;

[0223] (2) On the day of the follow-up visit, the scalp dandruff condition was scored, the dandruff was swept for 60 seconds, the scalp oil content was measured, and the shampoo trial skin feel evaluation questionnaire was filled out;

[0224] 4. After using the sample for 28 days

[0225] (1) You cannot wash your hair within 48±4 hours before the visit, and the time before each visit should be basically the same. You cannot comb your hair on the day of the visit;

[0226] (2) On the day of the follow-up visit, the scalp dandruff condition was scored, dandruff was swept for 60 seconds, the scalp oil content was measured, and a shampoo trial skin feel evaluation questionnaire was filled out.

[0227] 5. Sample usage instructions

[0228] Clean and care for your hair and scalp according to normal head care methods. Use once every 2-3 days, 3 times a week, using sufficient amount based on daily care needs.

[0229] 6. Test Results

[0230] Figure 8 The comparison chart shows the average cleansing oil rate and the average immediate oil control rate in 6 hours of the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos in Comparative Example 5 and Comparative Example 6. The cleansing oil rate of the shampoo group in Experimental Example 1 was 98.23% (P<0.01), which was significantly better than the shampoo groups in Comparative Example 3, Comparative Example 5, and Comparative Example 6. The immediate oil control rate in 6 hours of the shampoo group in Experimental Example 1 was 86.34%, which was significantly better than the shampoo groups in Comparative Example 3, Comparative Example 5, and Comparative Example 6.

[0231] Fig. 9 The oil control rate results of the subjects after using the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days, compared with the baseline value, the average oil rate of the shampoo group of Experimental Example 1 was significantly reduced by 47.12% and 73.26% (P<0.01), and the oil rate was significantly reduced compared with the shampoo groups of Comparative Examples 3, 5 and 6, indicating that the shampoo of Experimental Example 1 has a long-lasting oil control effect and is significantly better than the shampoos of Comparative Examples 3, 5 and 6.

[0232] Fig.10 The results of the ASFS score change rate after the subjects used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days, compared with the baseline value, the average sticky scalp dandruff score ASFS of the shampoo group of Experimental Example 1 was significantly reduced by 46.32% (P<0.01) and 70.23% (P<0.001), respectively, and the sticky scalp dandruff score ASFS of the shampoo groups of Comparative Examples 3, 5 and 6 were reduced but significantly less than that of the shampoo of Experimental Example 1, indicating that the shampoo of Experimental Example 1 has the effect of improving dandruff and is better than the shampoos of Comparative Examples 3, 5 and 6.

[0233] Fig.11 The graph shows the change rate of the number of dandruff after the subjects used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days. Compared with the baseline value, the average number of dandruff in the shampoo group of Experimental Example 1 decreased by 12.36% and 48.79% respectively (P<0.01), and the number of dandruff in the shampoo groups of Comparative Examples 3, 5 and 6 also decreased to a certain extent but was significantly less than that of the shampoo of Experimental Example 1, indicating that the shampoo of Experimental Example 1 has the effect of reducing the number of dandruff and is better than the shampoo groups of Comparative Examples 3, 5 and 6.

[0234] Fig.12The graph shows the change rate of dandruff area after the subjects used the shampoos prepared in Experimental Example 1 and Comparative Example 3 and the commercially available shampoos of Comparative Examples 5 and 6 for 14 days and 28 days. Compared with the baseline value, the average dandruff area of ​​the shampoo group in Experimental Example 1 was reduced by 22.78% and 55.84% (P<0.01), respectively. The number of dandruff in the shampoo groups of Comparative Examples 3, 5 and 6 was also reduced to a certain extent but was significantly less than that of the shampoo in Experimental Example 1, indicating that the shampoo in Experimental Example 1 has the effect of reducing the dandruff area and is better than the shampoo groups of Comparative Examples 3, 5 and 6.

[0235] The results of the questionnaire on skin feel after using shampoo are shown in Table 8.

[0236] Table 8. Statistical table of skin feel evaluation of subjects after shampoo trial

[0237]

[0238] As shown in Table 8, the subjects who used the shampoo of Experimental Example 1 did not experience any adverse skin sensation, while the subjects who used the shampoos of Comparative Example 3, Comparative Example 5, and Comparative Example 6 experienced varying degrees of adverse skin sensation.

[0239] The above results indicate that the aqueous solution of salicylic acid deep eutectic solvent has the effect of controlling oil on the scalp, and is significantly better than shampoos prepared with salicylic acid L-carnitine aqueous solution and salicylic acid monomer aqueous solution, a commercially available competitor shampoo containing salicylic acid, and a commercially available competitor shampoo containing carnitine; the aqueous solution of salicylic acid deep eutectic solvent has good oil control and anti-dandruff effects. At the same time, compared with shampoos prepared with salicylic acid L-carnitine aqueous solution and salicylic acid monomer aqueous solution, a commercially available competitor shampoo containing salicylic acid and a commercially available competitor shampoo containing carnitine, the aqueous solution of salicylic acid deep eutectic solvent has a more refreshing and non-greasy, gentle and non-irritating skin feel.

[0240] (X) Clinical trials for the treatment of acne

[0241] The sample provided in Experimental Example 1 was prepared into microneedles according to the preparation requirements of microneedles. The microneedles in Experimental Example 1 and a commercially available acne-removing microneedle were tested for acne treatment. The specific test method is as follows:

[0242] 1. Recruit volunteers

[0243] (1) First, the 40 volunteers recruited were diagnosed with acne grade. Only volunteers with acne grade 2 or above were required. The acne grade table is shown in Table 9.

[0244] Table 9 Acne grading table

[0245]

[0246] (2) Qualified subjects are screened and fill in the informed consent form;

[0247] (3) The subjects rested for 30 minutes in an environment with a temperature of 21±1℃ and a relative humidity of 50±10% RH;

[0248] (4) Use VISIA skin image analyzer to scan the skin on the face. It uses the Mirror medical imaging system to group and test the skin of different age groups, circular facial photography technology and a small magnifying glass tool to quantitatively analyze redness, pores, and UV reflection points, and accurately diagnose subtle skin problems. Provide a clear qualitative analysis report;

[0249] (5) Microneedle treatment: Half of the face was treated with a commercially available acne-removing microneedle as a control area, and the other half of the face was treated with the microneedle of Experimental Example 1.

[0250] 2. After 6 hours of single use of the sample

[0251] (1) The subjects rested for 30 minutes in an environment with a temperature of 21±1℃ and a relative humidity of 50±10% RH;

[0252] (2) Retest the facial skin condition data of the control area and sample area;

[0253] 3. After using the sample for 14 days

[0254] (1) Do not wash your face within 48 ± 4 hours before the visit, and the time before each visit should be basically the same;

[0255] (2) On the day of the follow-up visit, take photos of the facial skin condition, rate the facial condition, and fill out the questionnaire;

[0256] 4. After using the sample for 28 days

[0257] (1) You cannot wash your face within 48±4 hours before the visit, and the time before each visit should be basically the same;

[0258] (2) On the day of the follow-up visit, take photos of the facial skin condition, rate the facial condition, and fill out the questionnaire.

[0259] 5. Precautions after treatment

[0260] (1) Do not squeeze or rub the facial skin, otherwise it will cause damage to the facial skin surface and cause infection.

[0261] (2) Do not use overly hot water to wash your face to avoid oxidative decomposition of injected drugs.

[0262] (3) Keep the wound skin at the injection site clean and hygienic, avoid contact with liquid within six to eight hours after injection, and avoid infection through the needle hole.

[0263] (4) Avoid exposure of facial skin to excessively strong ultraviolet rays.

[0264] (5) Avoid eating spicy food, smoking, drinking, etc.

[0265] 6. Experimental Results

[0266] The questionnaire statistics are shown in Table 10.

[0267]

[0268]

[0269] The results in the above table show that the microneedles prepared with the salicylic acid deep eutectic solvent aqueous solution of the present invention have the efficacy of treating acne, and are significantly better than the microneedles of a certain competitor on the market; the salicylic acid deep eutectic solvent aqueous solution of the present invention has good efficacy in removing acne.

[0270] It should be understood that the application of the present invention is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A salicylic acid deep eutectic solvent, characterized in that: Its chemical structure is: in, is L-carnitine; is salicylic acid; R(OH) n For polyol, n≥2; The molar ratio of the L-carnitine, the polyol and the salicylic acid is 2:1:1; the polyol is selected from one or more of propylene glycol, butylene glycol, pentylene glycol, glycerol and glyceryl glucoside.

2. A method for preparing the salicylic acid deep eutectic solvent according to claim 1, comprising the following steps: S1) weighing L-carnitine and part of the polyol and mixing them uniformly at room temperature to obtain an L-carnitine polyol dispersion solution; S2) weighing salicylic acid and remaining polyol and mixing them uniformly at room temperature to obtain a salicylic acid polyol dispersion solution; S3) mixing the L-carnitine polyol dispersion solution obtained in S1 and the salicylic acid polyol dispersion solution obtained in S2 at room temperature, stirring in an oil bath, to obtain a mixed solution; S4) Under the protection of inert gas, subjecting the mixed solution prepared in S3 to ultrasonic reaction; S5) maintaining inert gas protection, subjecting the mixed solution obtained in S4 to microwave reaction; S6) vacuum drying the mixture obtained in S5 to obtain the salicylic acid deep eutectic solvent.

3. The preparation method according to claim 2, characterized in that: The oil bath temperature is 60-100° C., and the stirring time is 12-24 hours.

4. The preparation method according to claim 2, characterized in that: The ultrasonic power is 260-300W, the frequency is 40-60kHz, the temperature is 40-80°C, and the reaction time is 3-6 hours.

5. The preparation method according to claim 2, characterized in that: The microwave power is 30-50W, and the reaction time is 20-35 minutes.

6. The preparation method according to claim 2, characterized in that: The vacuum drying time is 48 hours.

7. The preparation method according to claim 2, characterized in that: The inert gas is one or more of nitrogen, helium, neon and argon.

8. Use of the salicylic acid deep eutectic solvent according to claim 1 in preparing products for preventing and treating acne.

9. Use of the salicylic acid deep eutectic solvent according to claim 1 in the preparation of skin care products and / or toiletries.

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