Resorcinol derivative phospholipid complex dispersion as well as preparation method and application thereof

Abstract

The invention provides a resorcinol derivative phospholipid complex dispersion as well as a preparation method and application thereof, and belongs to the technical field of cosmetics. A resorcinol derivative, an antioxidant, lecithin, sodium surfactin and water are used as raw materials, a strongly hydrophobic phospholipid compound is formed through interaction between hydrophilic ends of the lecithin and strong molecules of phenolic hydroxyl groups of the resorcinol derivative, then a hydrophilic cyclopeptide layer is modified on the surface of the phospholipid compound through the sodium surfactin surfactin, and the hydrophobic phospholipid compound is prepared. The dispersity of the phospholipid complex in water is improved, the stability of the resorcinol derivative can be effectively improved, and the problem of high-temperature discoloration is avoided. The particle size of the resorcinol derivative phospholipid complex dispersion provided by the invention is less than 200nm, and the resorcinol derivative phospholipid complex dispersion has good hydrophilicity and better transdermal permeation absorption effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of cosmetics, in particular to a resorcinol derivative phospholipid complex dispersion, a preparation method and application thereof. BACKGROUND

[0002] Skin pigmentation (such as spots, uneven skin tone) is a common problem that plagues consumers around the world, driving the continued development of the whitening and spot-removing cosmetics market. Traditional whitening agents such as hydroquinone (p-benzenediol) have a significant effect, but have been banned in many countries from use in the cosmetics field due to potential cytotoxicity and side effects (such as permanent white spots, exogenous ochronosis, etc.). Resorcinol derivative whitening agents have emerged as a high-efficiency and relatively safe alternative in this context, becoming a "star" ingredient and research hotspot in the field of contemporary whitening cosmetics. Over the past decade, a series of resorcinol derivatives have been proven to have excellent whitening efficacy, with some even approaching the clinical effects of hydroquinone, but with significantly improved safety, gradually gaining recognition and application in major global cosmetics markets. Although resorcinol derivative whitening agents have gained market recognition for their whitening function, they are prone to discoloration in product applications and can cause skin irritation and other reactions when used at high concentrations.

[0003] To address the above problems, there are currently technical solutions that use cyclodextrin inclusion to form cyclodextrin inclusion complexes, solving the water solubility problem of resorcinol whitening agents, but still having the problem of discoloration. Patent 201910788257.0 reports a compound resorcinol liposome, which uses several resorcinol whitening agents mixed with water-soluble whitening agents such as niacinamide, arbutin, and trans-aminic acid to form an oil phase that is then emulsified to form a liposome. According to the patent disclosure, the water-soluble whitening agents niacinamide, arbutin, and trans-aminic acid cannot be dissolved with the resorcinol whitening agents to form an oil phase, and the emulsion prepared has a significant discoloration.

[0004] Phospholipid complex (Phytosome) is a relatively stable compound or complex formed by charge migration of drug and phospholipid molecules. It can change the physicochemical properties of the parent drug, improve the bioavailability, and has simple preparation method and low cost. In recent years, its application in drug preparation is gradually increasing, especially in the research of phospholipid complex of traditional Chinese medicine. The oxygen atom in the hydroxyl group of the phosphorus atom in the phospholipid structure has a strong electron tendency, and the nitrogen atom has a strong electron loss tendency, so under certain conditions, it can generate a complex with a drug molecule of a certain structure. For example, in the structure of scutellarein, the oxygen of the carboxyl group and the oxygen of the phenolic hydroxyl group both have negative electricity, and can form a complex with the positively charged quaternary amine nitrogen in lecithin through dipole-dipole interaction force; puerarin and lecithin are combined to form a phospholipid complex through the van der Waals force between the polar sites. After the drug forms a complex with the phospholipid, the physicochemical properties, biological activity and the like will change to a great extent, such as the fat solubility is significantly enhanced, the melting point spectrum characteristics and the like will also change obviously. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a resorcinol derivative phospholipid complex dispersion, which improves the color stability and transdermal bioavailability of resorcinol derivatives.

[0006] In order to achieve the above purpose, the present application provides the following technical scheme.

[0007] A resorcinol derivative phospholipid complex dispersion, by mass percentage, comprising 1-10% resorcinol derivative, 0.1%-0.5% antioxidant, 2%-15% lecithin, 0.1%-2% sodium subtilipetide, and the balance is water; the lecithin is soybean lecithin or hydrogenated soybean lecithin, and the content of phosphatidylcholine therein is greater than 70%;

[0008] The lecithin is soybean lecithin or hydrogenated soybean lecithin, and the content of phosphatidylcholine in the lecithin is greater than 70%.

[0009] The mass ratio of the lecithin to the resorcinol derivative is greater than or equal to 1.

[0010] The resorcinol derivative is any two of phenylethyl resorcinol, 4-butyl resorcinol and 4-hexyl resorcinol.

[0011] Preferably, the resorcinol derivative phospholipid complex dispersion further comprises 3-15% oil ester by mass fraction, and the oil is at least one of solid oil with a melting point of 40-80℃ or liquid oil which is liquid at room temperature.

[0012] More preferably, the solid oil is at least one of glyceryl monostearate, glyceryl monolaurate, glyceryl tristearate, glyceryl distearate, glyceryl tripalmitate, glyceryl tribehenate.

[0013] More preferably, the liquid oil is at least one of caprylic / capric triglyceride, jojoba oil, squalane, phytol, cocoyl caprylate / caprate, soybean oil, sunflower seed oil, macadamia oil, meadowfoam seed oil, argan oil, triolein.

[0014] Preferably, the antioxidant is one of tocopherol, dimethylmethoxy chromanol, carnosic acid.

[0015] Another object of the present application is to provide a preparation method of a resorcinol derivative phospholipid complex dispersion, comprising the following steps:

[0016] S1, mixing resorcinol derivative, antioxidant and lecithin, dissolving to form a transparent ethanol solution, removing the solvent under vacuum at 35-60℃ to form a resorcinol derivative phospholipid complex;

[0017] S2, adding sodium subtilisin lipopeptide to water, dissolving to form a transparent aqueous solution at 35-60℃;

[0018] S3, adding the resorcinol derivative phospholipid complex of step S1 to the aqueous solution of step S2, stirring and emulsifying at 35-60℃, and forming a milky white resorcinol derivative phospholipid complex dispersion by high-pressure homogenization.

[0019] Preferably, step S1 further comprises adding the resorcinol derivative phospholipid complex to oil, stirring and dissolving uniformly to form an oil solution at 40-80℃.

[0020] The present application also provides a resorcinol derivative phospholipid complex dispersion for use in cosmetics.

[0021] Compared with the prior art, the present application has the following beneficial effects:

[0022] (1) The resorcinol derivative phospholipid complex dispersion provided by the present application forms a complex by lecithin and resorcinol derivative, the hydrophilic segment of lecithin and the phenolic hydroxyl end of resorcinol derivative are connected by strong intermolecular hydrogen bonds, and the lipophilic end of lecithin is around resorcinol derivative, so that resorcinol derivative has stronger lipophilicity. The formation of the complex shields the phenolic hydroxyl group in resorcinol derivative and passivates the activity of the phenolic hydroxyl group, so that resorcinol derivative has good stability and effectively avoids discoloration at high temperature.

[0023] (2) The resorcinol derivative phospholipid complex dispersion provided by the present application forms a cyclic peptide molecular membrane layer on the hydrophobic surface of the resorcinol derivative phospholipid complex through a specific amphiphilic cyclic peptide modifier, i.e., surfactin sodium, and finally forms a cyclic peptide liposome structure with an inner lecithin layer and an outer cyclic peptide modification layer, which is different from the existing liposome structure (both inner and outer layers have lecithin molecular layers). The hydrophilic end of the outer cyclic peptide molecular layer is a cyclic peptide structure, and the cyclic peptide molecular layer has a strong intermolecular interaction, thereby forming a more compact hydrophilic protective layer, forming a uniformly dispersed liquid with a particle size of less than 200 nm, and having better hydrophilicity and transdermal penetration and absorption.

[0024] (3) The resorcinol derivative mainly inhibits the activity of tyrosinase or reduces the production of tyrosinase in different ways, prevents tyrosinase from catalyzing tyrosine into an intermediate of melanin synthesis, thereby reducing the synthesis of melanin and playing a whitening effect. Phenylethyl resorcinol mainly inhibits melanin synthesis by non-competitive inhibition of tyrosinase activity, butyl resorcinol inhibits melanin synthesis by competitive inhibition of tyrosinase activity, and hexyl resorcinol inhibits melanin synthesis by competitive inhibition of tyrosinase activity. By compounding phenylethyl resorcinol with butyl resorcinol and hexyl resorcinol, the mechanism of action in the process of inhibiting melanin synthesis is complementary and synergistic, thereby increasing the inhibitory effect on melanin synthesis. DETAILED DESCRIPTION

[0025] The present application provides a resorcinol derivative phospholipid complex dispersion, which is composed of the following raw materials in percentage by mass: 1-10% resorcinol derivative, 0.1%-0.5% antioxidant, 2%-15% lecithin, 0.1%-2% surfactin sodium, 0-15% oil ester, and the balance being water; wherein the mass ratio of lecithin to resorcinol derivative is greater than or equal to 1; the lecithin is soybean lecithin or hydrogenated soybean lecithin, and the content of phosphatidylcholine therein is greater than 70%.

[0026] Further, the resorcinol derivative phospholipid complex dispersion is composed of the following raw materials in percentage by mass: 1-10% resorcinol derivative, 0.1%-0.5% antioxidant, 2%-15% lecithin, 0.1%-2% surfactin sodium, 3-15% oil ester, and the balance being water.

[0027] The oil in the present application is at least one of a solid oil with a melting point of 40-80℃ or a liquid oil that is liquid at room temperature.

[0028] In specific embodiments of the present application, the solid oil is at least one of glyceryl monostearate, glyceryl monolaurate, glyceryl tristearate, glyceryl distearate, glyceryl tripalmitate, glyceryl tribehenate; and the liquid oil is at least one of caprylic / capric triglyceride, jojoba oil, squalane, phytol, coco-caprylate / caprate, sunflower seed oil, soybean oil, macadamia nut oil, meadowfoam seed oil, argan oil, triolein.

[0029] In specific embodiments of the present application, the resorcinol derivative is any two of phenylethyl resorcinol, 4-butyl resorcinol, and 4-hexyl resorcinol; and the mass ratio of the two resorcinol derivatives is 1:1.

[0030] The antioxidant is tocopherol. In specific embodiments of the present application, the antioxidant is DELTA tocopherol.

[0031] In specific embodiments of the present application:

[0032] When the oil ester content in the raw material is 0, the preparation method of the resorcinol derivative phospholipid complex dispersion is as follows:

[0033] S1, the resorcinol derivative, the antioxidant, and the lecithin are mixed, ethanol (the volume-to-mass ratio of ethanol to the raw material is 3-4:1) is added to dissolve to form a transparent ethanol solution, and the solvent is removed under vacuum at 35-60°C to form a resorcinol derivative phospholipid complex;

[0034] S2, the iturin sodium is added to water, and dissolved to form a transparent aqueous solution at 35-60°C;

[0035] S3, the resorcinol derivative phospholipid complex of step S1 is added to the aqueous solution of step S2, stirred and emulsified at 35-60°C, and a milky white resorcinol derivative phospholipid complex dispersion is formed by high-pressure homogenization.

[0036] When the oil ester content in the raw material is 3-15%, the preparation method of the resorcinol derivative phospholipid complex dispersion is as follows:

[0037] S1, the resorcinol derivative, the antioxidant, and the lecithin are mixed, ethanol (the volume-to-mass ratio of ethanol to the raw material is 3-4:1) is added to dissolve to form a transparent ethanol solution, and the solvent is removed under vacuum at 35-60°C to form a resorcinol derivative phospholipid complex;

[0038] S2, then the resorcinol derivative phospholipid complex is added to the oil, and stirred and dissolved uniformly to form an oil solution at 40-80°C;

[0039] S3, add the surfactin sodium into water, and dissolve to form a transparent aqueous solution at 35-60°C;

[0040] S4, add the oil solution of step S1 into the aqueous solution of step S2, and emulsify under stirring at 35-60°C to form a milky white resorcinol derivative phospholipid complex dispersion by high pressure homogenization.

[0041] In the specific embodiments of the present application, the high pressure homogenization uses a high pressure homogenizer or a microjet high pressure homogenizer, wherein the homogenization method of the high pressure homogenizer is 1000 bar pressure high pressure homogenization for 5 times.

[0042] The present application is further illustrated below in conjunction with examples and comparative examples. The experimental methods used in the following examples and comparative examples of the present application are all conventional experiments unless otherwise specified, and the materials, reagents, etc. used are all conventionally purchased through commercial channels unless otherwise specified.

[0043] Example 1

[0044] A preparation method of a resorcinol derivative phospholipid complex dispersion, the steps being as follows:

[0045] S1, dissolve 2.5 g of phenylethyl resorcinol, 2.5 g of 4-butyl resorcinol, 0.2 g of tocopherol, and 6 g of soybean lecithin (phosphatidylcholine content 71.2%) in about 45 ml of ethanol to form a transparent ethanol solution, and remove ethanol by vacuum rotary evaporation at 50°C to form a resorcinol derivative phospholipid complex;

[0046] S2, add 0.2 g of surfactin sodium into the remaining 88.3 g of water, and dissolve to be transparent at 50°C;

[0047] S3, add the resorcinol derivative phospholipid complex of step S1 into the aqueous solution of step S2, and emulsify under stirring at 50°C to form a milky white resorcinol derivative phospholipid complex dispersion by a high pressure homogenizer, 1000 bar pressure high pressure homogenization for 5 times.

[0048] Examples 2-5

[0049] A resorcinol derivative phospholipid complex dispersion raw material composition is shown in Table 1, and the raw material content in the formula table is g, and the total weight is 100 g.

[0050] A preparation method of the resorcinol derivative phospholipid complex dispersion, the steps being as follows:

[0051] S1, dissolve the resorcinol derivative, tocopherol, and lecithin in 4 times the volume of ethanol to form a transparent ethanol solution, and remove ethanol by vacuum rotary evaporation at 50°C to form a resorcinol derivative phospholipid complex;

[0052] S2, the oil is stirred and dissolved uniformly at 75°C, and the resorcinol derivative phospholipid complex obtained in step S1 is added and stirred and dissolved uniformly;

[0053] S3, the bacitracin sodium is added to the remaining water and dissolved and made transparent at 65°C.

[0054] S4, the resorcinol derivative phospholipid oil solution of step S2 is added to the aqueous solution of step S3, and emulsified by stirring at 65°C, and passed through a high-pressure homogenizer at 1000 bar for 5 times to form a milky white resorcinol derivative phospholipid complex dispersion.

[0055] Table 1

[0056]

[0057] Example 6

[0058] S1, 1 g of phenethyl resorcinol, 1 g of 4-butyl resorcinol, 0.1 g of chenopodium acid, and 2 g of soybean lecithin (phosphatidylcholine content 90.4%) are dissolved in 16 ml of ethanol to form a transparent ethanol solution, and the ethanol is removed by vacuum rotary evaporation at 50°C to form a phenethyl resorcinol lecithin complex;

[0059] S2, 0.1 g of bacitracin sodium is added to the remaining 95.8 g of water and dissolved and made transparent at 65°C.

[0060] S3, the phenethyl resorcinol phospholipid complex of step S1 is added to the aqueous solution of step S2, and emulsified by stirring at 65°C, and passed through a high-pressure homogenizer at 1000 bar for 5 times to form a milky white phenethyl resorcinol phospholipid complex dispersion.

[0061] Example 7

[0062] S1, 5 g of phenethyl resorcinol, 5 g of 4-hexyl resorcinol, 0.3 g of chenopodium acid, and 10 g of soybean lecithin (phosphatidylcholine content 71.2%) are dissolved in 80 ml of ethanol to form a transparent ethanol solution, and the ethanol is removed by vacuum rotary evaporation at 50°C to form a phenethyl resorcinol lecithin complex;

[0063] S2, 2 g of bacitracin sodium is added to 77.7 g of water and dissolved and made transparent at 65°C.

[0064] S3, add the phenethyl hydroquinone phospholipid complex of step S1 into the aqueous solution of step S2, emulsify under stirring at 65℃, pass through a high pressure homogenizer, 5 times at 1000 bar pressure, to form a milky white phenethyl hydroquinone phospholipid complex dispersion.

[0065] Example 8

[0066] S1, dissolve 3g phenethyl hydroquinone, 3g 4-butyl hydroquinone, 0.1g tocopherol, 6g hydrogenated soybean lecithin (phosphatidylcholine content 71.2%) in 50ml ethanol to form a transparent ethanol solution, remove ethanol by vacuum rotary evaporation at 50℃ to form a phenethyl hydroquinone lecithin complex;

[0067] S2, add the phenethyl hydroquinone phospholipid complex formed in step S1 into 5g squalane under stirring at 70℃ to form a phenethyl hydroquinone phospholipid complex oil solution

[0068] S3, add 0.5g surfactin sodium into 82.4g water, dissolve transparently at 70℃.

[0069] S4, add the phenethyl hydroquinone phospholipid complex oil solution of step S2 into the aqueous solution of step S3, emulsify under stirring at 70℃, pass through a high pressure homogenizer, 5 times at 1000 bar pressure, to form a milky white phenethyl hydroquinone phospholipid complex dispersion.

[0070] Example 9

[0071] S1, dissolve 2.5g phenethyl hydroquinone, 2.5g 4-hexyl hydroquinone, 0.3g dimethyl methoxy chromanol, 5g soybean lecithin (phosphatidylcholine content 71.2%) in 40ml ethanol to form a transparent ethanol solution, remove ethanol by vacuum rotary evaporation at 50℃ to form a phenethyl hydroquinone lecithin complex;

[0072] S2, add the phenethyl hydroquinone phospholipid complex formed in step S1 into 5g coconut alcohol-octanoate / decanoate under stirring at 60℃ to form a phenethyl hydroquinone phospholipid complex oil solution

[0073] S3, add 0.2g surfactin sodium into 84.5g water, dissolve transparently at 60℃.

[0074] S4, add the phenethyl hydroquinone phospholipid complex oil solution of step S2 into the aqueous solution of step S3, emulsify under stirring at 60℃, pass through a high pressure homogenizer, 5 times at 1000 bar pressure, to form a milky white phenethyl hydroquinone phospholipid complex dispersion.

[0075] Example 10

[0076] S1, 2.5g phenethyl resorcinol, 2.5g 4-butyl resorcinol, 0.2g tocopherol, 5g soybean lecithin (phosphatidylcholine content 71.2%) were dissolved in 40ml ethanol to form a transparent ethanol solution, and the ethanol was removed by vacuum rotary evaporation at 50°C to form a phenethyl resorcinol lecithin complex;

[0077] S2, the phenethyl resorcinol lecithin complex formed in S1 was stirred and added to 5g white pool seed oil at 60°C to form a phenethyl resorcinol lecithin complex oil solution

[0078] S3, 0.2g sodium subtilipetrolide was added to 84.6g water and dissolved transparently at 60°C.

[0079] S4, the phenethyl resorcinol lecithin complex oil solution of step S2 was added to the aqueous solution of step S3, and emulsified by stirring at 60°C. The emulsion was passed through a high-pressure homogenizer 5 times at a pressure of 1000bar to form a milky white phenethyl resorcinol lecithin complex dispersion.

[0080] Example 11

[0081] S1, 2.5g phenethyl resorcinol, 2.5g 4-butyl resorcinol, 0.2g tocopherol, 5g soybean lecithin (phosphatidylcholine content 71.2%) were dissolved in 40ml ethanol to form a transparent ethanol solution, and the ethanol was removed by vacuum rotary evaporation at 50°C to form a phenethyl resorcinol lecithin complex;

[0082] S2, the phenethyl resorcinol lecithin complex formed in S1 was stirred and added to 5g blueberry oil at 60°C to form a phenethyl resorcinol lecithin complex oil solution

[0083] S3, 0.2g sodium subtilipetrolide was added to 84.6g water and dissolved transparently at 60°C.

[0084] S4, the phenethyl resorcinol lecithin complex oil solution of step S2 was added to the aqueous solution of step S3, and emulsified by stirring at 60°C. The emulsion was passed through a high-pressure homogenizer 5 times at a pressure of 1000bar to form a milky white phenethyl resorcinol lecithin complex dispersion.

[0085] Comparative Example 1

[0086] The difference from Example 1 is that lecithin is removed. The preparation steps are as follows: S1, dissolve benzene ethyl resorcinol, 4-butyl resorcinol, and tocopherol into an oil phase under stirring at 75°C; S2, add subtilisin to the remaining water and dissolve it into a transparent solution at 75°C; S3, add the benzene ethyl resorcinol oil phase of step S1 to the aqueous solution of step S2, emulsify under stirring at 75°C, pass it through a high-pressure homogenizer at 1000 bar for 5 times, and form a milky white benzene ethyl resorcinol nanoemulsion.

[0087] Comparative Example 2

[0088] The difference from Example 1 is that the mass of lecithin is changed to 2.5 g, and the rest remains unchanged, to form a milky white benzene ethyl resorcinol lecithin complex dispersion.

[0089] Comparative Example 3

[0090] The difference from Example 1 is that lecithin is replaced by phosphatidylcholine with a specification of 50% lecithin, and a milky white benzene ethyl resorcinol phospholipid complex dispersion is formed.

[0091] Comparative Example 4

[0092] The difference from Example 1 is that subtilisin sodium is removed. This method cannot be emulsified into a uniform solution, and a large amount of sticky phospholipid oil appears on the inner wall of the beaker, which cannot be emulsified and stops emulsification, i.e., water and oil are layered. It is shown that resorcinol derivatives form an oleophilic phospholipid complex with lecithin, and lecithin cannot play an emulsifying role.

[0093] Comparative Example 5

[0094] The difference from Example 1 is that polyglycerol 10-laurate is used instead of subtilisin sodium, and the rest is the same. During step S3 stirring emulsification, a small amount of sticky phospholipid oil appears on the inner wall of the beaker, but it can be partially emulsified. It is shown that after replacing subtilisin sodium, the emulsifying ability of sucrose stearate is not sufficient to completely emulsify benzene ethyl resorcinol phospholipid complex.

[0095] Comparative Example 6

[0096] The difference from Example 1 is that sucrose stearate is used instead of subtilisin sodium, and the rest is the same. During step S3 stirring emulsification, a small amount of sticky phospholipid oil appears on the inner wall of the beaker, but it can be partially emulsified. It is shown that after replacing subtilisin sodium, the emulsifying ability of sucrose stearate is not sufficient to completely emulsify benzene ethyl resorcinol phospholipid complex.

[0097] Comparative Example 7

[0098] The difference from Example 2 is that the mass of lecithin is changed to 2.5 g, and the rest remains unchanged, forming a milky white resorcinol derivative phospholipid complex dispersion.

[0099] Comparative Example 8

[0100] The difference from Example 2 is that lecithin is replaced by phosphatidylcholine with 50% lecithin specification, forming a milky white resorcinol derivative phospholipid complex dispersion.

[0101] Comparative Example 9

[0102] The difference from Example 2 is that the sodium iturin is removed, and the rest is the same. This method cannot be emulsified into a uniform solution, and a large amount of sticky phospholipid oil appears on the inner wall of the beaker, which cannot be emulsified, and the emulsification stops, i.e., water and oil are layered. It shows that benzylephdroresorcinol and 4-hexylresorcinol form a complex with lecithin, and lecithin cannot exert its emulsifying performance.

[0103] Comparative Example 10

[0104] The difference from Example 5 is that the sodium iturin is removed, and the rest is the same.

[0105] It cannot be emulsified into a uniform solution, and a large amount of sticky phospholipid oil appears on the inner wall of the beaker, which cannot be emulsified, and the emulsification stops, i.e., water and oil are layered. It shows that benzylephdroresorcinol and 4-hexylresorcinol form a complex with lecithin, and lecithin cannot exert its emulsifying performance.

[0106] Comparative Example 11

[0107] The difference from Example 2 is that polyglycerol 10-laurate is used instead of sodium iturin, and the rest is the same. When stirring and emulsifying in step S4, a small amount of sticky phospholipid oil appears on the inner wall of the beaker, but it can be partially emulsified.

[0108] Comparative Example 12

[0109] The difference from Example 2 is that sucrose stearate is used instead of sodium iturin, and the rest is the same. When stirring and emulsifying in step S4, a small amount of sticky phospholipid oil appears on the inner wall of the beaker, but it can be partially emulsified.

[0110] Comparative Example 13

[0111] Referring to CN110420125A Example 5, a compound resorcinol liposome is prepared from raw materials in the following mass percentages: phenylethyl resorcinol 3%; 4-n-butyl resorcinol 3%; 4-hexyl resorcinol 3%; nicotinamide 1%; arbutin alpha 1%; tramline acid 1%; neoglycerol 8.5%; soybean lecithin (phosphatidylcholine content 71.2%) 3.2%; magnesium aluminum silicate 1.5%; dibenzoylmethane 1.5%; and the balance is water.

[0112] Referring to the preparation method of CN110420125A Example 1, nicotinamide and tramline acid cannot be dissolved in the oil phase. Therefore, the following steps are followed:

[0113] The neoglycerol, lecithin, phenylethyl resorcinol, 4-n-butyl resorcinol, and 4-hexyl resorcinol are heated to 80°C and stirred to obtain a liquid oil phase;

[0114] The nicotinamide, arbutin alpha, tramline acid, and magnesium aluminum silicate are added to water and stirred uniformly, and heated to 80°C to form an aqueous phase;

[0115] The oil phase is added to the aqueous phase and stirred at 2000 rpm to form a light yellow suspension, which is then passed through a high-pressure homogenizer 1000 bar for 5 times to obtain a white compound resorcinol liposome suspension.

[0116] Comparative Example 14

[0117] A resorcinol derivative phospholipid complex dispersion differs from Example 1 in that,

[0118] The resorcinol derivatives are phenylethyl resorcinol 1.7 g, 4-butyl resorcinol 1.7 g, and 4-hexyl resorcinol 1.7 g, and the rest are the same.

[0119] Comparative Example 15

[0120] A resorcinol derivative phospholipid complex dispersion differs from Example 1 in that the 4-butyl resorcinol is removed, and the mass of phenylethyl resorcinol is changed to 5 g, and the rest are the same.

[0121] Comparative Example 16

[0122] A resorcinol derivative phospholipid complex dispersion differs from Example 1 in that the phenylethyl resorcinol is removed, and the mass of 4-butyl resorcinol is changed to 5 g, and the rest are the same.

[0123] Comparative Example 17

[0124] A resorcinol derivative phospholipid complex dispersion differs from Example 5 in that the phenylethyl resorcinol is removed, and the mass of 4-hexyl resorcinol is changed to 5 g, and the rest are the same.

[0125] Example 1: Inhibitory effect of resorcinol derivatives on melanin synthesis

[0126] Melanin is mainly produced by melanocytes in the basal cell layer of the epidermis, and is a water-insoluble, alkali-soluble biological pigment synthesized and secreted by the cells themselves. The production of melanin is regulated by multiple factors, among which external stimuli (especially ultraviolet irradiation), inflammatory reactions and α-MSH agonists can trigger or affect the synthesis process of melanin. In this experiment, the melanin content was detected by NaOH lysis method in mouse melanoma cells under the action of samples.

[0127] The cells were plated in 6-well plates (10 W / well), and after reaching the logarithmic growth phase, the 1640 culture medium was discarded. 2 ml of sample group (4 μg / ml, 5 μM α-MSH 1640 culture medium), 2 ml of model control group (5 μM α-MSH 1640 culture medium), and 2 ml of normal control group (1640 culture medium) were added.

[0128] The sample groups were benzyl resorcinol / 4-butyl resorcinol complex, benzyl resorcinol / 4-hexyl resorcinol complex (4-hexyl resorcinol was 0, 9.1, 16.7, 33.3, 50, 66.7, 83.3, 90.9 and 100%, respectively)

[0129] After the administration was completed, the well plate was placed in the incubator for 48 h, the cells were collected, 0.5 ml of 1 M NaOH solution (containing 10% DMSO) was added, and it was placed in a 60°C water bath for 1 h. After the melanin was fully dissolved, the supernatant was transferred to a 96-well plate, and the absorbance A at 405 nm was measured by an enzyme marker. The calculation method of melanin content D is shown in formula (1), and the calculation method of inhibition rate is shown in formula (2).

[0130] (1)

[0131] (2)

[0132] The results of the inhibitory effect of resorcinol derivatives on melanin synthesis are shown in Table 2.

[0133] Table 2

[0134]

[0135] As shown in Table 2, at the same concentration, the melanin inhibition rates of benzeneethyl resorcinol, 4-butyl resorcinol and 4-hexyl resorcinol alone are not high, less than 50%, while the benzeneethyl resorcinol / 4-butyl resorcinol combination and the benzeneethyl resorcinol / 4-hexyl resorcinol combination at the same concentration can significantly improve the melanin inhibition rate, reaching more than 80%, especially when the mass ratio of the benzeneethyl resorcinol / 4-butyl resorcinol combination and the benzeneethyl resorcinol / 4-hexyl resorcinol combination is 1:1, a better synergistic melanin inhibition effect is achieved.

[0136] Test Example 2: Inhibition of melanin synthesis by examples

[0137] The cells were plated in 6-well plates (10 W / well), and after reaching the logarithmic growth phase, the 1640 culture medium was discarded. 2 ml of the sample group (total concentration of resorcinol derivatives 2 μg / ml, 5 μM α-MSH in 1640 culture medium), 2 ml of the model control group (5 μM α-MSH in 1640 culture medium), and 2 ml of the normal control group (1640 culture medium) were added.

[0138] The sample groups were Example 1, Example 2, Example 3, Example 5, Example 6, Example 7, Example 8, Example 9, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 14, Comparative Example 15, Comparative Example 16, Comparative Example 17, benzeneethyl resorcinol / 4-butyl resorcinol combination (mass ratio 1:1), benzeneethyl resorcinol / 4-hexyl resorcinol combination (mass ratio 1:1), and 4-butyl resorcinol / 4-hexyl resorcinol combination (mass ratio 1:1).

[0139] After the administration was completed, the well plates were placed in an incubator for 48 h, the cells were collected, 0.5 ml of NaOH solution (containing 10% DMSO) with a concentration of 1 M was added, and it was placed in a 60°C water bath for 1 h. After the melanin was fully dissolved, the supernatant was transferred to a 96-well plate, and the absorbance A at 405 nm was measured by an enzyme marker. The calculation method of melanin content D and inhibition rate is referred to Test Example 1.

[0140] The results of the inhibition of melanin synthesis by different examples and comparative examples are shown in Table 3

[0141] Table 3

[0142] Sample group Melanin inhibition rate Example 1 58.1 Example 2 60.8 Example 3 39.6 Example 5 54.2 Example 6 59.3 Example 7 58.7 Example 8 57.9 Example 9 52.4 Comparative Example 1 50.6 Comparative Example 2 53.4 Comparative Example 3 52.7 Comparative Example 14 46.3 Comparative Example 15 27.1 Comparative Example 16 32.4 Comparative Example 17 29.5 Phenylethyl resorcinol / 4-butyl resorcinol combination (mass ratio 1:1) 35.6 Phenylethyl resorcinol / 4-hexyl resorcinol combination (mass ratio 1:1) 34.2 4-Butyl resorcinol / 4-hexyl resorcinol combination (mass ratio 1:1) 21.7

[0143] From Table 3, it can be seen that after the phospholipid complexing technology of the examples is implemented, the melanin inhibition rates of the phenylethyl resorcinol / 4-butyl resorcinol composition, the phenylethyl resorcinol / 4-hexyl resorcinol composition, and the 4-butyl resorcinol / 4-hexyl resorcinol composition are all significantly improved, indicating that after being wrapped by phospholipid complexing, the bioavailability of the active substances to cells is increased. It can also be seen that the 4-butyl resorcinol / 4-hexyl resorcinol composition has a better synergistic effect than the phenylethyl resorcinol / 4-butyl resorcinol composition and the phenylethyl resorcinol / 4-hexyl resorcinol composition.

[0144] Test Example 3: Stability change investigation

[0145] The resorcinol whitening active substances are greatly affected by heat. In this stability investigation, the sample of the examples and the sample of the comparative examples are placed in transparent PET sample bottles and observed for 4 weeks in a 45°C stability investigation box to observe the changes in color and particle size.

[0146] The particle size test is performed by diluting the sample to be tested 100 times with ultrapure water, placing it on a laser particle size instrument, and detecting the particle size. The color and particle size results are shown in Table 4.

[0147] Table 4

[0148]

[0149] From Table 4, by comparing the high-temperature stability of Comparative Example 1, Comparative Example 2, and Comparative Example 3 with Example 1, and comparing Comparative Example 7 and Comparative Example 8 with Example 2, it can be seen that the formation of a complex of lecithin and resorcinol derivatives has a positive effect on alleviating color changes, and the content of lecithin and the change in the PC content of lecithin also have different effects on the high-temperature stability of the color of resorcinol derivatives.

[0150] Test Example 4: Human patch test

[0151] In this test, the examples are added to a cosmetic formulation to prepare an emulsion. The formulations of the test examples are shown in Table 5, and the preparation method is as follows: 1. Dissolve the A phase at 60°C to form a uniform clear solution; 2. Dissolve and disperse the B phase at 60°C (if the B phase does not contain soy lecithin, the B phase can be directly heated to 60°C); 3. Add the B phase to the A phase and shear emulsify at 3000 rpm for 5 min, then cool to 40°C; 4. Heat the C phase at 200 rpm, stir and cool for 30 min, then fill and prepare for use. (If there is no C phase, after step 3, cool and fill for use).

[0152] Table 5

[0153]

[0154] Human patch test test method:

[0155] The test samples are Nos. 1-5 (denoted as Test Example 4-1, 4-2, 4-3, 4-4, 4-5, respectively) in Test Example 4, the negative control is a blank control, and the test population is 10 men and 20 women aged 21-50 years old. In a closed patch test, 0.04 g of the test sample is placed in the patch tester, and a low-sensitization adhesive tape is applied to the inner side of the forearm of the test subject, with a 1 cm gap between the samples. After 24 hours, the test sample is removed, and the skin reaction is observed at 0.5, 24, and 48 hours after removal, respectively. The results are recorded according to the skin reaction grading standard in the “Cosmetic Safety Technology Specification” (2015 edition), as shown in Table 6.

[0156] Table 6

[0157]

[0158] From the results of the human patch test, it can be seen that the phospholipid complex technology treatment of Examples 2 and 5 can correspondingly reduce the risk of irritation.

[0159] The resorcinol derivative phospholipid complex dispersion prepared in Examples 2 and 5 of the present application uses phenylethyl resorcinol and 4-butyl resorcinol and 4-hexyl resorcinol, respectively, compounded at an optimal mass ratio of 1:1, which enhances the synergistic whitening effect of the complex resorcinol derivative. At the same time, due to the action of the phospholipid complex, the resorcinol derivative can be slowly released from the complex, reducing the irritation of the resorcinol derivative.

[0160] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, which should also be considered within the scope of protection of the present application.

Claims

1. A dispersion of a resorcinol derivative phospholipid complex, characterized in that, 1-10% resorcinol derivatives, 0.1%-0.5% antioxidant, 2%-15% lecithin, 0.1%-2% sodium iturin, and the balance water, by mass percentage; the lecithin is soybean lecithin or hydrogenated soybean lecithin, and the content of phosphatidylcholine in the lecithin is greater than 70%; The mass ratio of the lecithin to the resorcinol derivative is greater than or equal to 1; The resorcinol derivative is any two of phenylethyl resorcinol, 4-butyl resorcinol, and 4-hexyl resorcinol.

2. The resorcinol derivative phospholipid complex dispersion according to claim 1, characterized by, The resorcinol derivative phospholipid complex dispersion further comprises 3-15% oil ester, by mass fraction; the oil ester is at least one of solid oil ester having a melting point of 40-80 ℃ or liquid oil ester being liquid at room temperature.

3. The resorcinol derivative phospholipid complex dispersion according to claim 2, characterized by, The solid oil ester is at least one of glycerol monostearate, glycerol monolaurate, glycerol tristearate, glycerol distearate, glycerol tripalmitate, and glycerol tribehenate.

4. The resorcinol derivative phospholipid complex dispersion according to claim 2, characterized by, The liquid oil ester is at least one of caprylic / capric triglyceride, jojoba oil, squalane, phytol, cocoyl caprylate / caprate, soybean oil, sunflower seed oil, macadamia nut oil, meadowfoam seed oil, argan oil, triolein, and the like.

5. The resorcinol derivative phospholipid complex dispersion according to claim 1, wherein The antioxidant is one of tocopherol, dimethylmethoxy chromanol, and cannabiscide.

6. The method for producing a resorcinol derivative phospholipid complex dispersion according to claim 1, characterized by, The method comprises the following steps: S1. mixing the resorcinol derivative, the antioxidant, and the lecithin, dissolving them in ethanol to form a transparent ethanol solution, and removing the solvent under vacuum at 35-60 ℃ to form a resorcinol derivative phospholipid complex; S2. adding the sodium iturin to water, dissolving it at 35-60 ℃ to form a transparent aqueous solution; S3. adding the resorcinol derivative phospholipid complex of step S1 to the aqueous solution of step S2, stirring and emulsifying at 35-60 ℃, and forming a milky white resorcinol derivative phospholipid complex dispersion by high-pressure homogenization.

7. The method of producing a dispersion of a phospholipid complex of a ro- diol derivative according to claim 6, characterized in that, Step S1 further comprises adding the resorcinol derivative phospholipid complex to oil ester, stirring and dissolving uniformly at 40-80 ℃ to form an oil solution.

8. Use of the resorcinol derivative phospholipid complex dispersion of any one of claims 1-5 or prepared by the method of any one of claims 6-7 in cosmetics.

Images