A TPGS deep eutectic solvent, self-microemulsion and preparation method and application thereof

Abstract

The present invention relates to a TPGS low eutectic solvent, a self-microemulsion and a preparation method and application thereof, and belongs to the technical field of daily chemical products. The TPGS low eutectic solvent of the present invention is prepared from polyethylene glycol 1000 vitamin E succinate and a ligand; the molar ratio of the polyethylene glycol 1000 vitamin E succinate to the ligand is (1-10): (1-10); the ligand includes phenylethyl resorcinol, 4-butyl resorcinol, peptidomide or phloretin. The self-microemulsion prepared by combining the TPGS low eutectic solvent with an emulsifier and auxiliary components realizes the stable encapsulation of the low eutectic solvent, enables the whitening component to penetrate efficiently in the skin, realizes the effect of efficient whitening, and reduces the irritation of the whitening active component, thereby improving safety. The particle size of the obtained self-microemulsion is nanometer, the skin feels fresh, the whitening effect is better than that of single use, synergistic synergy, and higher stability.

Description

Technical Field

[0001] The invention relates to the technical field of daily chemical products, and in particular to a TPGS low eutectic solvent, a self-microemulsification, and a preparation method and application thereof. Background Art

[0002] D-α-tocopheryl polyethylene glycol 1000succinate (TPGS) is a surfactant with low toxicity and irritation. It is synthesized by esterification of hydrophilic polyethylene glycol and hydrophobic α-tocopherol succinate (vitamin E derivative). Therefore, it contains a hydrophobic alkyl tail and a hydrophilic polar head and has amphiphilic properties. Due to its unique amphiphilic structure, it can be used as an excellent solubilizer, stabilizer and emulsifier for hydrophobic substances.

[0003] A deep eutectic solvent is a stable mixture of two or more chemical substances that is in liquid state at room temperature through physical interaction. It is mainly formed through the non-covalent bonding of functional groups between compounds, and has the functions of enhancing the solubility of active substances, enhancing permeability and transdermal effects, and improving the efficacy of active substances. It is widely used in the fields of cosmetics, health products, food, etc.

[0004] Self-microemulsion is a nano-scale phospholipid sphere with a special structure. It has a hydrophilic end that can dissolve in water and a hydrophobic end that can dissolve in oil. Therefore, whether in aqueous or oily substances, self-microemulsion has good permeability and solubility. The particle size of self-microemulsion is 10nm~1000nm, which is a transparent dispersion system of two immiscible solutions. Because the particles of self-microemulsion are small and the interfacial tension is small, it is easy to penetrate into the skin, usually up to 10 -2 mN / m~10 -6 mN / m, so it has very strong emulsification and solubilization ability, which improves the stability and efficacy of the active ingredients, and can especially significantly improve the transdermal penetration performance.

[0005] Whitening cosmetics are very popular in the market, and the application of efficient and guaranteed whitening raw materials is attracting more and more attention. At the same time, the application of stable and safe raw materials has also become the focus of people's attention. Phenylethyl resorcinol (abbreviated as 377), 4-butyl resorcinol (abbreviated as 577), Thiamidol, Phloretin, etc. are recognized raw materials with whitening effects on the market, and they all have their own limitations. For example, they are difficult to dissolve in water, easily oxidized, have poor photostability, are easy to change color under light, are extremely unstable, have poor transdermal absorption, and are easy to agglomerate. Increasing its water solubility and photostability, reducing irritation, improving the safety of use, ensuring that the raw materials are effectively absorbed and ensuring physical and chemical stability, and extending the service life of the product are the directions of whitening cosmetic research efforts. Summary of the invention

[0006] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a TPGS low eutectic solvent, a self-microemulsion and a preparation method and application thereof. The self-microemulsion has the characteristics of small particle size, good solubility, high stability and good whitening effect.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides a TPGS low eutectic solvent, which is prepared from polyethylene glycol 1000 vitamin E succinate (TPGS) and a ligand; the molar ratio of polyethylene glycol 1000 vitamin E succinate (TPGS) to the ligand is (1~10): (1~10); the ligand includes phenylethylresorcinol, 4-butylresorcinol, peptidomide or phloretin.

[0009] The present invention selects a specific whitening active ingredient as a ligand, and forms a stable mixture (stable low eutectic solvent) in a liquid state at room temperature through physical interaction with TPGS having a unique amphiphilic structure, thereby improving the stability of the whitening active ingredient. At the same time, the molar ratio of TPGS to the specific ligand of the present invention will affect the preparation of the low eutectic solvent. If the molar ratio of TPGS to the ligand is too small or too large, the non-covalent bond between the two will not be sufficient to reach a steady state and the low eutectic solvent cannot be prepared.

[0010] As a preferred embodiment of the TPGS deep eutectic solvent of the present invention, the molar ratio of polyethylene glycol 1000 vitamin E succinate (TPGS) to the ligand is (1-2): (1-2). Under this condition, the obtained TPGS deep eutectic solvent is clear and transparent, and has better stability.

[0011] In a second aspect, the present invention provides a method for preparing the above-mentioned TPGS low eutectic solvent, comprising mixing polyethylene glycol 1000 vitamin E succinate (TPGS) and a ligand according to a molar ratio, reacting them fully, and cooling them to room temperature to obtain the TPGS low eutectic solvent.

[0012] As a preferred embodiment of the preparation method of the present invention, the reaction temperature of the sufficient reaction is 60-80° C., and the reaction time of the sufficient reaction is 30 min-2 h.

[0013] After the TPGS and the ligand are mixed, the low eutectic solvent can be better prepared at the reaction temperature and reaction time. If the temperature is too high or the time is too long, the activity of the components will be affected.

[0014] In a third aspect, the present invention provides the use of the above-mentioned TPGS deep eutectic solvent in the preparation of self-microemulsion.

[0015] The present invention prepares a self-microemulsion from a TPGS low eutectic solvent, and utilizes the free dispersion property of the self-microemulsion in water to achieve high solubility of the whitening active ingredient, improve the permeability of the whitening active ingredient in the skin, and further improve the efficacy of the whitening active ingredient.

[0016] In a fourth aspect, the present invention provides a self-microemulsion, comprising, by weight percentage: 10% to 30% of the TPGS low eutectic solvent, 10.5% to 44.5% of the emulsifier, and 34.5% to 59.5% of auxiliary ingredients; the auxiliary ingredients include at least one of 1,2-propylene glycol, 1,2-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,2-hexanediol, dipropylene glycol, glycerol, phenoxyethanol, ethylhexylglycerol, p-hydroxyacetophenone, and deionized water.

[0017] The present invention combines the TPGS low eutectic solvent with an emulsifier and auxiliary components to form a self-microemulsion that is hydrophilic on the outside and hydrophobic on the inside, and can spontaneously form nanoparticles in water to encapsulate the active ingredients and protect them from interference from external humidity, oxygen, ultraviolet rays, etc., thereby improving stability. The particle size of the formed nanoparticles is usually 50-150nm, has good solubility, and is easier to penetrate the epidermis, dermis and subcutaneous tissue of the skin for penetration.

[0018] As a preferred embodiment of the self-microemulsion of the present invention, the self-microemulsion comprises, by weight percentage: 30% of the TPGS low eutectic solvent, 35.5% of the emulsifier, and 34.5% of the auxiliary components.

[0019] As a preferred embodiment of the self-microemulsion of the present invention, the auxiliary component includes at least one of 1,2-propylene glycol, 1,2-butylene glycol, 1,2-pentanediol, 1,3-pentanediol and dipropylene glycol.

[0020] As a preferred embodiment of the self-microemulsion of the present invention, the emulsifier includes lecithin, soybean lecithin, hydrogenated lecithin, hydrogenated soybean lecithin (HSPC), Tween 80, polyoxyethylene hydrogenated castor oil, polyglyceryl-3 methyl glucose distearate, PEG-40 hydrogenated castor oil, stearyl alcohol polyether-2, inulin lauryl carbamate, behenyl alcohol, polysorbate-60, PEG-15 glyceryl laurate, sorbitan polyether-30 tetraoleate, spermaceti At least one of alcohol polyether-25, alkyl glucoside, sodium stearoyl glutamate, sodium cocoyl glutamate, polyglyceryl-10 stearate, polyglyceryl-10 myristate, polyglyceryl-10 laurate, sodium myristoyl glutamate, sodium lauroyl glutamate, sodium stearoyl glycinate, sodium cocoyl glycinate, sodium palmitoyl glycinate, sodium lauroyl glycinate, sodium stearate, oleic acid, sodium palmitate, sodium myristate, lauric acid, sodium laurate and potassium laurate.

[0021] As a preferred embodiment of the self-microemulsification of the present invention, the emulsifier includes at least one of lecithin, soybean lecithin, hydrogenated lecithin, hydrogenated soybean lecithin (HSPC), Tween 80, polyoxyethylene hydrogenated castor oil, PEG 40 hydrogenated castor oil, and sorbitan polyether-30 tetraoleate.

[0022] In a fifth aspect, the present invention provides a method for preparing the self-microemulsion, comprising mixing a TPGS low eutectic solvent with an emulsifier and auxiliary components, and stirring at 40-60° C. for 1-2 hours to obtain the self-microemulsion.

[0023] As a preferred embodiment of the preparation method of the present invention, the stirring temperature is 50° C., and the stirring time is 1 hour.

[0024] In a sixth aspect, the present invention provides the use of the self-microemulsion in preparing whitening products.

[0025] In a seventh aspect, the present invention provides a whitening preparation comprising the self-microemulsion and auxiliary materials.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention provides a new low eutectic solvent-TPGS low eutectic solvent, which has the characteristics of high stability. The TPGS low eutectic solvent can spontaneously form nanoparticles when added to the aqueous phase. TPGS itself has the function of a surfactant, and there is no need to add a surfactant. The product is stable, has good transdermal permeability and good absorption. At the same time, the TPGS low eutectic solvent of the present invention encapsulates the whitening active ingredient inside the TPGS, thereby improving the solubility and stability of the active ingredient. The self-microemulsion of the present invention realizes the stable encapsulation of the low eutectic solvent, so that the whitening ingredients can be efficiently penetrated in the skin, and the effect of efficient whitening is achieved, while reducing the irritation of the whitening active ingredient and improving safety. The particle size of the obtained self-microemulsion is nanometer, the skin feels refreshing, the whitening effect is better than that of single use, synergistically enhancing, and the stability is higher. On the one hand, the penetration-promoting effect of the low eutectic solvent further enhances the whitening effect. On the other hand, the self-microemulsion of the present invention is more stable, safe and non-irritating while achieving efficient whitening. Meanwhile, the self-microemulsion of the present invention does not contain organic solvent, thus avoiding allergenicity, and the obtained self-microemulsion has small toxic and side effects; the preparation method of the self-microemulsion has mild conditions, simple production, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The appearance of the TPGS-phenethylresorcinol deep eutectic solvent (TPGS-phenethylresorcinol DES) prepared by mixing TPGS and the ligand phenethylresorcinol in a molar ratio of 1:2 in Example 1 of the present invention;

[0029] Figure 2 The appearance of the TPGS-peptide amine methyl ether deep eutectic solvent (TPGS-peptide amine methyl ether DES) prepared by mixing TPGS and the ligand peptide amine methyl ether in a molar ratio of 2:1 in Example 1 of the present invention;

[0030] Figure 3 The appearance of the TPGS-4-butylresorcinol deep eutectic solvent (TPGS-4-butylresorcinol DES) prepared by using TPGS and the ligand 4-butylresorcinol in a molar ratio of 1:2 in Example 1 of the present invention;

[0031] Figure 4 The appearance of the TPGS-phloretin deep eutectic solvent (TPGS-phloretin DES) prepared by mixing TPGS and the ligand phloretin in a molar ratio of 1:2 in Example 1 of the present invention;

[0032] Figure 5 The differential scanning calorimetry (DSC) spectrum of the TPGS-phenethylresorcinol deep eutectic solvent (TPGS-377) prepared by mixing TPGS and the ligand phenethylresorcinol in a molar ratio of 1:2 in Test Example 1 of the present invention;

[0033] Figure 6The differential scanning calorimetry (DSC) spectrum of the TPGS-peptide amine methyl ether deep eutectic solvent (TPGS-peptide amine methyl ether) prepared by mixing TPGS and the ligand peptide amine methyl ether in a molar ratio of 2:1 in Test Example 1 of the present invention;

[0034] Figure 7 The differential scanning calorimetry (DSC) spectrum of the TPGS-4-butylresorcinol deep eutectic solvent (TPGS-577) prepared by mixing TPGS and the ligand 4-butylresorcinol in a molar ratio of 1:2 in Test Example 1 of the present invention;

[0035] Figure 8 The infrared spectrum of the TPGS-phenethylresorcinol deep eutectic solvent (TPGS-377) prepared by mixing TPGS and the ligand phenethylresorcinol in a molar ratio of 1:2 in Test Example 2 of the present invention;

[0036] Fig. 9 The infrared spectrum of the TPGS-peptide amine methyl ether deep eutectic solvent (TPGS-peptide amine methyl ether) prepared by TPGS and the ligand peptide amine methyl ether in the test example 2 of the present invention according to the molar ratio of 2:1;

[0037] Fig.10 The infrared spectrum of the TPGS-4-butylresorcinol deep eutectic solvent (TPGS-577) prepared by mixing TPGS and the ligand 4-butylresorcinol in a molar ratio of 1:2 in Test Example 2 of the present invention;

[0038] Fig.11 is a particle size distribution diagram of the self-microemulsion 1 in Test Example 3 of the present invention;

[0039] Fig.12 This is the particle size distribution diagram of the self-microemulsion 6 in Test Example 3 of the present invention;

[0040] Fig.13 This is the particle size distribution diagram of the self-microemulsion of comparative example 1 in test example 3 of the present invention;

[0041] Fig.14 The particle size results of the self-microemulsions 1 and 6 in Test Example 3 of the present invention and Comparative Examples 1 and 2 after being placed at room temperature and 45°C for different time periods (one week, one month, two months, and three months);

[0042] Fig.15 The results are the ratios of the whitening active ingredient content of the self-microemulsion 1 in Test Example 4 of the present invention and the self-microemulsion of Comparative Example 1 after being placed at different temperatures (-15°C, 25°C, 45°C) for one week, one month, two months, and three months to that before placement. DETAILED DESCRIPTION

[0043] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0044] Unless otherwise specified, other materials, reagents, etc. used in the examples can be obtained from commercial sources.

[0045] Example 1

[0046] 1. Effect of different ligands on the preparation of TPGS deep eutectic solvent (TPGS-DES)

[0047] DES was prepared by combining polyethylene glycol 1000 vitamin E succinate (TPGS) with different ligands, including oleic acid, idebenone, coenzyme Q-10, phenylethyl resorcinol, 4-butyl resorcinol, hydroxypinacolone retinoic acid ester, peptidylcholine, vitamin C, tocopherol, tetrahydrocurcumin, madecassoside, phloretin, etc.

[0048] TPGS and the ligand were mixed in a molar ratio of 1:1, placed in a sealed water bath at 60°C, heated and stirred for 30 min, and cooled to room temperature.

[0049] The effects of TPGS combined with different ligands on the preparation of TPGS-DES are shown in Table 1.

[0050] Table 1

[0051]

[0052] The results in Table 1 show that the whitening ingredients phenylethylresorcinol, peptidomide, 4-butylresorcinol, and phloretin as ligands of TPGS can form TPGS-DES, indicating that only specific whitening ingredients as ligands of TPGS can form TPGS-DES.

[0053] 2. Effect of TPGS to ligand molar ratio on the preparation of TPGS-DES

[0054] TPGS and ligand (phenylethyl resorcinol) were mixed in different molar ratios, placed in a sealed water bath at 60°C, heated and stirred for 30 minutes, cooled to room temperature, and the appearance of the obtained product was observed.

[0055] The results of the products prepared according to different molar ratios of TPGS and ligand are shown in Table 2 below.

[0056] Table 2

[0057]

[0058] The results in Table 2 show that when the molar ratio of TPGS to the ligand phenethyl resorcinol is in the range of (1-10): (1-10), TPGS deep eutectic solvent (TPGS-DES) can be formed. When the molar ratio exceeds this range, such as 1:11 or 11:1, TPGS-DES cannot be formed. When the molar ratio of TPGS to the ligand phenethyl resorcinol is in the range of (1-2): (1-2), the formed TPGS-DES is clear and more stable.

[0059] TPGS was reacted with the ligands peptidomide, 4-butylresorcinol and phloretin in different molar ratios. The results showed that when the molar ratio of TPGS to the ligands peptidomide, 4-butylresorcinol and phloretin was in the range of (1~10):(1~10), TPGS deep eutectic solvent (TPGS-DES) could be formed. When the molar ratio was in the range of (1~2):(1~2), the formed TPGS-DES was more stable.

[0060] The appearance of the TPGS-phenethylresorcinol deep eutectic solvent (TPGS-phenethylresorcinol DES) prepared by TPGS and the ligand phenethylresorcinol in a molar ratio of 1:2 is as follows Figure 1 The results showed that TPGS-phenylethylresorcinol DES was a yellow, clear, transparent, mobile liquid.

[0061] The appearance of the TPGS-peptide amine methyl ether (TPGS-peptide amine methyl ether DES) prepared by the molar ratio of TPGS to the ligand peptide amine methyl ether is as follows: Figure 2 The results showed that TPGS-peptide aminomethyl DES was a brown, clear, transparent, mobile liquid.

[0062] The appearance of the TPGS-4-butylresorcinol deep eutectic solvent (TPGS-4-butylresorcinol DES) prepared by using TPGS and ligand 4-butylresorcinol in a molar ratio of 1:2 is as follows: Figure 3 The results showed that TPGS-4-butylresorcinol DES was a yellow, clear, transparent, mobile liquid.

[0063] The appearance of the TPGS-phloretin deep eutectic solvent (TPGS-phloretin DES) prepared by mixing TPGS and the ligand phloretin in a molar ratio of 1:2 is as follows: Figure 4 The results showed that TPGS-phloretin DES was a reddish brown, clear, and transparent mobile liquid.

[0064] Example 2

[0065] TPGS and phenethyl resorcinol were mixed in a molar ratio of 1:2, placed in a sealed water bath at 60°C, heated and stirred for 120 minutes, and cooled to room temperature to obtain a TPGS-phenethyl resorcinol low eutectic solvent (TPGS-phenethyl resorcinol DES).

[0066] Example 3

[0067] TPGS and phenethyl resorcinol were mixed in a molar ratio of 1:2, placed in a sealed water bath at 80°C, heated and stirred for 30 minutes, and cooled to room temperature to obtain a TPGS-phenethyl resorcinol low eutectic solvent (TPGS-phenethyl resorcinol DES).

[0068] Test Example 1

[0069] 1. The melting points of the TPGS deep eutectic solvents prepared in Examples 1 to 3 and the melting points of TPGS and each ligand monomer were measured using a differential scanning calorimeter.

[0070] The measurement results show that the melting point of the TPGS low eutectic solvent is lower than that of TPGS and the corresponding ligand monomer, indicating that the present invention successfully prepares the deep eutectic solvent (DES).

[0071] The differential scanning calorimetry (DSC) spectrum of TPGS-phenethylresorcinol deep eutectic solvent (TPGS-377) prepared by mixing TPGS and ligand phenethylresorcinol in a molar ratio of 1:2 is shown in the figure below: Figure 5 As shown; the differential scanning calorimetry (DSC) spectrum of the TPGS-peptide amine methyl ether low eutectic solvent (TPGS-peptide amine methyl ether) prepared by TPGS and the ligand peptide amine methyl ether at a molar ratio of 2:1 is shown Figure 6 As shown; the differential scanning calorimetry (DSC) spectrum of TPGS-4-butylresorcinol deep eutectic solvent (TPGS-577) prepared by mixing TPGS and ligand 4-butylresorcinol in a molar ratio of 1:2 is shown Figure 7 shown.

[0072] Test Example 2

[0073] The infrared spectra of the TPGS deep eutectic solvents (TPGS-DES) prepared in Examples 1, 2, and 3 and the infrared spectra of TPGS and each ligand monomer were measured using a Fourier transform infrared spectrometer (IRSpirit, Shimadzu Corporation, Tokyo, Japan).

[0074] The measurement results show that the transmittance of TPGS-DES prepared in Examples 1, 2, and 3 at different wavelengths is lower than the transmittance of TPGS and the corresponding ligand monomers at different wavelengths, indicating that the present invention successfully prepares a deep eutectic solvent (DES).

[0075] The infrared spectrum of TPGS-phenethylresorcinol deep eutectic solvent (TPGS-377) prepared by mixing TPGS and ligand phenethylresorcinol in a molar ratio of 1:2 is shown in Figure 8 As shown; the infrared spectrum of TPGS-peptide amine mitrol low eutectic solvent (TPGS-peptide amine mitrol) prepared by TPGS and ligand peptide amine mitrol according to the molar ratio of 2:1 is shown Fig. 9 As shown; the infrared spectrum of TPGS-4-butylresorcinol low eutectic solvent (TPGS-577) prepared by TPGS and ligand 4-butylresorcinol in a molar ratio of 1:2 is shown Fig.10 shown.

[0076] Example 4

[0077] The self-microemulsion of the present invention comprises the following components in weight percentage: 10% to 30% of the TPGS low eutectic solvent prepared in the embodiment, 10.5% to 44.5% of the emulsifier, and 34.5% to 59.5% of the auxiliary components; the emulsifier comprises lecithin, soybean lecithin, hydrogenated lecithin, hydrogenated soybean lecithin (HSPC), Tween 80, polyoxyethylene hydrogenated castor oil, polyglycerol-3 methyl glucose distearate, PEG-40 hydrogenated castor oil, stearyl alcohol polyether-2, inulin lauryl carbamate, behenyl alcohol, polysorbate-60, PEG-15 glyceryl laurate, sorbitol polyether-30 tetraoleate, cetearyl alcohol polyether-25, alkyl glucoside, hard At least one of sodium acyl glutamate, sodium cocoyl glutamate, polyglyceryl-10 stearate, polyglyceryl-10 myristate, polyglyceryl-10 laurate, sodium myristoyl glutamate, sodium lauroyl glutamate, sodium stearoyl glycinate, sodium cocoyl glycinate, sodium palmitoyl glycinate, sodium lauroyl glycinate, sodium stearate, oleic acid, sodium palmitate, sodium myristate, lauric acid, sodium laurate, and potassium laurate; the auxiliary ingredients include at least one of 1,2-propylene glycol, 1,2-butylene glycol, 1,2-pentanediol, 1,3-pentanediol, 1,2-hexanediol, dipropylene glycol, glycerin, phenoxyethanol, ethylhexylglycerin, p-hydroxyacetophenone, and deionized water.

[0078] TPGS and ligand were mixed in a container at a molar ratio of 1:2, placed in a sealed water bath at 65°C, heated and stirred for 30 minutes, and cooled to room temperature to prepare a TPGS low eutectic solvent (TPGS-DES); the prepared TPGS-DES was mixed with an emulsifier and auxiliary components, stirred at 50°C for 1 hour, and prepared microemulsions 1-18;

[0079] Preparation method of self-microemulsion 19:

[0080] TPGS and ligand were mixed in a molar ratio of 1:2 and placed in a container, which was sealed and heated and stirred at 65°C water bath for 30 minutes, and then cooled to room temperature to prepare TPGS low eutectic solvent (TPGS-DES); the prepared TPGS-DES was mixed with an emulsifier and auxiliary components, and stirred at 40°C for 2 hours.

[0081] Preparation method of self-microemulsion 20:

[0082] TPGS and ligand were mixed in a molar ratio of 1:2 and placed in a container, which was sealed and heated and stirred at 65°C for 30 minutes, and then cooled to room temperature to prepare a TPGS low eutectic solvent (TPGS-DES); the prepared TPGS-DES was mixed with an emulsifier and auxiliary components, and stirred at 60°C for 1 hour.

[0083] Among them, TPGS-DES prepared from TPGS and phenylethylresorcinol is referred to as T-377DES; TPGS-DES prepared from TPGS and 4-butylresorcinol is referred to as T-577DES; TPGS-DES prepared from TPGS and peptide anmido is referred to as T-ThDES; TPGS-DES prepared from TPGS and phloretin is referred to as T-PhDES.

[0084] The components and contents of self-microemulsions 1 to 20 are shown in Tables 3-1 and 3-2 below.

[0085] Table 3-1

[0086]

[0087] Table 3-2

[0088]

[0089] Comparative Example 1

[0090] A self-microemulsion, the components, content and preparation method are the same as those of the self-microemulsion 1, the only difference is that the preparation condition of the self-microemulsion 1, stirring at 50° C. for 1 hour, is replaced by stirring at 50° C. for 0.5 hour.

[0091] Comparative Example 2

[0092] A self-microemulsion, the components, content and preparation method are the same as those of the self-microemulsion 1, the only difference is that the preparation condition of the self-microemulsion 1, stirring at 50° C. for 1 hour, is replaced by stirring at 30° C. for 1 hour.

[0093] Comparative Example 3

[0094] A self-microemulsion, the components, content and preparation method are the same as those of the self-microemulsion 1, the only difference is that 30% of T-377DES in the components is replaced by 25% of TPGS monomer and 5% of phenylethylresorcinol monomer.

[0095] Comparative Example 4

[0096] A self-microemulsion, the components, content and preparation method are the same as those of the self-microemulsion 6, the only difference is that 30% of T-577DES in the components is replaced by 25% of TPGS monomer and 5% of 4-butylresorcinol monomer.

[0097] Test Example 3

[0098] The appearance, particle size and particle size stability of the self-microemulsions 1 to 20 prepared in Example 4 and the self-microemulsions of Comparative Examples 1 to 4 were tested.

[0099] Observe the appearance of the self-microemulsion by visual inspection; measure the particle size and particle size distribution of the self-microemulsion by using a particle size analyzer;

[0100] The microemulsions were placed in room temperature and 45°C environments for 3 months, and the particle sizes of the microemulsions were tested in the first week, the first month, the second month, and the third month.

[0101] 1. The appearance and particle size test results show that the appearance of self-microemulsions 1 to 20 are all yellow uniform liquids; the particle size is 120 to 160 nm; while the appearance of the self-microemulsions of comparative examples 1 to 4 is yellow liquid, and the particle size is 190 to 250 nm. The appearance and particle size results of self-microemulsions 1 to 2, 6 to 7 and comparative examples 1 to 4 are shown in Table 4 below, where the particle size is the average particle size of the self-microemulsion.

[0102] Table 4

[0103]

[0104] The particle size distribution of self-microemulsion 1 is shown in Fig.11 As shown, the particle size distribution diagram of the self-microemulsion 6 is as follows Fig.12 As shown, the particle size distribution diagram of the self-microemulsion of comparative example 1 is as follows Fig.13 shown.

[0105] 2. The microemulsions were placed in room temperature and 45°C for 3 months. The test results showed that the particle size of the self-microemulsions 1 to 20 did not change much, ranging from 140 to 230 nm, and there was no significant change in the particle size; while the particle size of the self-microemulsions of comparative examples 1 to 4 increased significantly, reaching about 900 to 1500 nm. It can be seen that the particle size stability of the self-microemulsions prepared in the embodiments of the present invention is better.

[0106] The particle sizes of the self-microemulsions 1-2, 6-7 and comparative examples 1-4 after being placed in the room temperature and 45°C environment for 3 months are shown in Table 5 below:

[0107] Table 5

[0108]

[0109] The particle size results of self-microemulsion 1, 6 and comparative examples 1 and 2 after being placed at room temperature and 45°C for different time periods (one week, one month, two months, and three months) are as follows: Fig.14 As shown, the results show that the particle size of the self-microemulsions 1 and 6 changes slightly, while the particle size of the self-microemulsions of comparative examples 1 and 2 increases significantly.

[0110] In summary, the self-microemulsion prepared in the embodiment of the present invention has a smaller particle size and better stability.

[0111] Test Example 4

[0112] The content stability of the whitening active ingredient (phenylethylresorcinol or 4-butylresorcinol) of the self-microemulsions 1 to 20 prepared in Example 4 and the self-microemulsions of Comparative Examples 1 to 4 was tested. The content of phenylethylresorcinol or 4-butylresorcinol in the self-microemulsion samples was determined by high performance liquid chromatography.

[0113] Dilute the standard phenethyl resorcinol or 4-butyl resorcinol to a concentration of 1000 ppm; dilute the self-microemulsion sample to be tested to 0.1 μg / ml in the same way.

[0114] HPLC conditions:

[0115] (1) Chromatographic column: Agilent 5 TC-C18 (3.5 μm 4.6 × 150 mm),

[0116] (2) Mobile phase: A water (45%)-B methanol (55%),

[0117] (3) Column temperature: 30°C,

[0118] (4) Flow rate: 1 mL / min,

[0119] (5) Injection volume: 10 μL,

[0120] (6) Wavelength: 280nm,

[0121] (7) Duration: 12 minutes,

[0122] (8) Preparation of standard curve: 800, 400, 200, 100, 50, 25 μg / mL (filtered with 0.45 μm filter membrane),

[0123] (9) Sample preparation: 0.01 g sample + 5 mL ethanol to dissolve.

[0124] The content of whitening active ingredients in each microemulsion was tested before and after being placed at different temperatures (-15℃, 25℃, 45℃) for one week, one month, two months, and three months, and the ratio of the content of whitening active ingredients before and after placement was calculated.

[0125] The test results show that the ratio of the whitening active ingredient content of self-microemulsions 1 to 20 after being placed at different temperatures (-15°C, 25°C, 45°C) for 3 months to that before the placement is between 95% and 85%, while the ratio of the whitening active ingredient content of the self-microemulsions of comparative examples 1 to 4 after being placed at different temperatures (-15°C, 25°C, 45°C) for 3 months to that before the placement is between 80% and 60%, indicating that the self-microemulsions prepared in the embodiments of the present invention have good stability, and the content of the whitening active ingredient in the self-microemulsions is less affected by temperature.

[0126] The ratio of the whitening active ingredient content of the self-microemulsions 1-2, 6-7 and comparative examples 1-2 after being placed at different temperatures (-15°C, 25°C, 45°C) for 3 months to that before being placed is shown in Table 6. The ratio of the whitening active ingredient content of the self-microemulsions 1 and comparative example 1 after being placed at different temperatures (-15°C, 25°C, 45°C) for one week, one month, two months, and three months to that before being placed is shown in Table 6. Fig.15 As shown,

[0127] Table 6

[0128]

[0129] Test Example 5

[0130] The permeability of the self-microemulsions 1 to 20 prepared in Example 4 and the self-microemulsions of Comparative Examples 1 to 4 was tested.

[0131] The test method is as follows: fix the pretreated fresh pig skin with uniform thickness between the diffusion cell and the receiving cell, the receiving liquid surface is in contact with the lower layer of the skin, start the electromagnetic stirrer and the constant temperature water bath, under the conditions of stirring speed of 320rpm and temperature of 32℃, use the self-microemulsions 1-20 and the self-microemulsions of comparative examples 1-4 as test samples, the receiving liquid in the cell is physiological saline, take pig skin samples 2h, 4h, and 6h after the start of the diffusion experiment, cut them into pieces and extract overnight. Determine the intradermal active substance retention of each sample (using phenylethyl resorcinol or 4-butyl resorcinol as the detection object).

[0132] The test results showed that after 2 hours of diffusion, the retention of the whitening active ingredients of microemulsions 1 to 20 in pig skin was 26.74 to 32.25 μg / cm 2 ; Diffusion 4h, retention 42.31~65.21μg / cm 2 ; Diffusion 6h, retention 59.47~86.24μg / cm 2 After diffusion for 2h, the retention of the whitening active ingredients of the liposomes of Comparative Examples 1 to 4 in the pig skin was 6.15 to 12.35 μg / cm 2 ; Diffusion 4h, retention is 14.45~24.78μg / cm 2; Diffusion 6h, retention is 20.85~32.74μg / cm 2 It can be seen that the retention amount of the whitening active ingredient of the self-microemulsion prepared in the embodiment of the present invention in the pig skin is higher, and the penetration-promoting effect of the self-microemulsion is better.

[0133] The retention amounts of the whitening active ingredients of the self-microemulsions 1-2, 6-7 and comparative examples 1-4 in pig skin are shown in Table 7 below:

[0134] Table 7

[0135]

[0136] Compared with the self-microemulsion of comparative example 1, the penetration-enhancing effect of the self-microemulsion 1 was increased by 3.4 times.

[0137] Test Example 6

[0138] The whitening effects of the self-microemulsions 1 to 4 prepared in Example 4 and the self-microemulsions of Comparative Examples 1 to 2 were tested.

[0139] The test method is as follows: randomly select volunteers aged 18 to 35 years old, take the test sample, dilute it with pure water and place it in the spot tester, and apply it to the subject's arm with a low-allergenic tape (blind test, without telling the type of sample solution). The evaluation criteria are shown in Table 8.

[0140] Table 8

[0141]

[0142] The whitening effect test results of the self-microemulsions 1 to 4 and comparative examples 1 to 2 are shown in Table 9 below.

[0143] Table 9

[0144]

[0145] The results in Table 9 show that self-microemulsions 1 to 4 have significant whitening effects, and more than 70% of the volunteers have no irritation; while the self-microemulsions of comparative examples 1 to 2 have no obvious whitening effects, and more than 93% of the volunteers have irritation. This shows that the self-microemulsions prepared in the embodiments of the present invention have better whitening effects.

[0146] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A TPGS deep eutectic solvent, characterized in that: The invention is prepared from polyethylene glycol 1000 vitamin E succinate and a ligand; the molar ratio of the polyethylene glycol 1000 vitamin E succinate to the ligand is (1-10): (1-10); the ligand includes phenylethyl resorcinol, 4-butyl resorcinol, peptidylcholine or phloretin; The preparation method of the TPGS low eutectic solvent comprises: mixing polyethylene glycol 1000 vitamin E succinate and a ligand according to a molar ratio, reacting them fully, and cooling them to room temperature to obtain the TPGS low eutectic solvent; The reaction temperature of the full reaction is 60-80° C., and the reaction time of the full reaction is 30 min-2 h.

2. The TPGS deep eutectic solvent according to claim 1, characterized in that The molar ratio of the polyethylene glycol 1000 vitamin E succinate to the ligand is (1-2): (1-2).

3. The method for preparing the TPGS deep eutectic solvent according to claim 1 or 2, characterized in that: Mixing polyethylene glycol 1000 vitamin E succinate and the ligand according to a molar ratio, reacting sufficiently, and cooling to room temperature to obtain the TPGS low eutectic solvent; The reaction temperature of the full reaction is 60-80° C., and the reaction time of the full reaction is 30 min-2 h.

4. Use of the TPGS deep eutectic solvent according to claim 1 or 2 in preparing a self-microemulsion.

5. A self-microemulsion, characterized in that: Measured in weight percentage, the invention comprises: 10% to 30% of the TPGS low eutectic solvent according to claim 1 or 2, 10.5% to 44.5% of an emulsifier, and 34.5% to 59.5% of auxiliary components; the auxiliary components include at least one of 1,2-propylene glycol, 1,2-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,2-hexanediol, dipropylene glycol, glycerol, phenoxyethanol, ethylhexylglycerol, p-hydroxyacetophenone, and deionized water.

6. The self-microemulsion according to claim 5, characterized in that The emulsifier includes lecithin, soybean lecithin, hydrogenated lecithin, hydrogenated soybean lecithin, Tween 80, polyoxyethylene hydrogenated castor oil, polyglyceryl-3 methyl glucose distearate, PEG-40 hydrogenated castor oil, steareth-2, inulin lauryl carbamate, behenyl alcohol, polysorbate-60, PEG-15 glyceryl laurate, sorbitol polyether-30 tetraoleate, ceteareth-25, alkyl glucoside , sodium stearoyl glutamate, sodium cocoyl glutamate, polyglyceryl-10 stearate, polyglyceryl-10 myristate, polyglyceryl-10 laurate, sodium myristoyl glutamate, sodium lauroyl glutamate, sodium stearoyl glycinate, sodium cocoyl glycinate, sodium palmitoyl glycinate, sodium lauroyl glycinate, sodium stearate, oleic acid, sodium palmitate, sodium myristate, lauric acid, sodium laurate, and at least one of potassium laurate.

7. The method for preparing the self-microemulsion according to claim 5 or 6, characterized in that: The TPGS low eutectic solvent is mixed with the emulsifier and the auxiliary components, and stirred at 40-60° C. for 1-2 hours to obtain the self-microemulsion.

8. Use of the self-microemulsion according to claim 5 or 6 in the preparation of whitening products.

9. A whitening preparation, characterized in that: The method comprises the self-microemulsification according to claim 5 or 6 and auxiliary materials.

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