4-butylresorcinol composite liposome preparation and preparation method thereof

Abstract

The invention relates to a 4-butylresorcinol composite liposome preparation, which is prepared from the following raw materials in percentage by mass: 0.1 to 10 percent of 4-butylresorcinol, 0.2 to 1.6 percent of antioxidant, 0.2 to 1 percent of stabilizer, 0.3 to 2.5 percent of carrier, 0.1 to 0.8 percent of film-forming agent, 21 to 80 percent of auxiliary agent and the balance of water, the antioxidant is prepared from dipotassium glycyrrhizinate, litsea cubeba extract and tocopherol; the stabilizer is composed of dextrin and oxidized pullulan; the film-forming agent is a sodium hyaluronate cross-linked polymer solution. The preparation is good in stability, the permeation amount after 24 hours is greater than or equal to 100.0 mu g / cm < 2 >, and the inhibition rate gt on tyrosinase; 86%.

Description

Technical Field

[0001] This application relates to the field of efficacy carrier technology, and in particular to a 4-butylresorcinol complex liposome formulation and its preparation method. Background Technology

[0002] With the improvement of people's living standards and their pursuit of beauty, skin whitening has become one of the important research directions in the global beauty and skincare field. Skin color is mainly determined by the content and distribution of melanin. Excessive melanin production can lead to problems such as dull skin and age spots, affecting the appearance of the skin. Therefore, developing effective whitening agents to inhibit melanin production and promote its metabolism has become a focus of attention for many researchers and cosmetic companies.

[0003] 4-Butylresorcinol is a highly effective skin-whitening ingredient, but its photosensitivity, chemical instability, low water solubility, and certain irritant properties limit its application in cosmetics or pharmaceuticals. Traditional liposomes suffer from problems such as rapid leakage of active ingredients and poor stability, and single stabilization technologies (such as surface modification or freeze-drying) are insufficient to meet the requirements for stability and chemical protection. Summary of the Invention

[0004] This invention develops a 4-butylresorcinol complex liposome formulation, which, compared with traditional liposomes, can maximize the stability of the active ingredient, increase the penetration rate of the active ingredient in subsequent applications, and reduce the skin irritation caused by 4-butylresorcinol.

[0005] In a first aspect of this application, a 4-butylresorcinol complex liposome formulation is provided, comprising the following raw materials in weight percentages: 0.1-10% 4-butylresorcinol, 0.2-1.6% antioxidant, 0.2-1% stabilizer, 0.3-2.5% carrier, 0.1-0.8% film-forming agent, 21-80% adjuvant, and the balance being water; based on the total mass of the 4-butylresorcinol complex liposome formulation, the antioxidant is composed of 0.05-0.3% dipotassium glycyrrhizate, 0.05-0.3% Litsea cubeba extract, and 0.1-1% tocopherol; the stabilizer is composed of 0.1-0.5% dextrin and 0.1-0.5% oxypullanose; and the film-forming agent is a sodium hyaluronate cross-linked polymer solution.

[0006] By adopting the above technical solution, this application provides a 4-butylresorcinol complex liposome formulation with good stability and a permeation rate ≥100.0 μg / cm³ after 24 hours. 2The inhibition rate of tyrosinase is >86%. This may be because, on the one hand, dextrin provides physical stability through its branched structure, and pullulan, a modified polysaccharide, has good stability. The synergistic effect of the two ensures the stability of the 4-butylresorcinol complex liposome formulation during long-term storage and use. On the other hand, dipotassium glycyrrhizate has both antioxidant and anti-inflammatory effects, reducing skin damage caused by inflammation by inhibiting inflammatory responses. Litsea cubeba extract contains alkaloids and terpenoids, which, through their antioxidant effects, can protect the chemically stable phase of 4-butylresorcinol, thus better inhibiting tyrosinase. The synergistic effect of the two can effectively reduce skin inflammation and improve the whitening effect. Furthermore, the sodium hyaluronate cross-linked polymer solution can form a pH-responsive outer membrane, intelligently releasing active ingredients in the weakly acidic environment of the skin, which can also more effectively inhibit tyrosinase and improve the whitening effect.

[0007] Preferably, the mass percentage of 4-butylresorcinol is 4.5%-6.5%.

[0008] Preferably, the antioxidant has a mass percentage of 0.8-1.0%.

[0009] Furthermore, the sodium hyaluronate cross-linked polymer solution consists of 3% sodium hyaluronate cross-linked polymer by mass, 92% water by mass, and 5% 1,2-glutaraldehyde by mass.

[0010] Preferably, the mass percentage of the sodium hyaluronate cross-linked polymer solution is 0.3-0.6%.

[0011] Optionally, the mass ratio of dipotassium glycyrrhizate to Litsea cubeba extract is 1:(0.167-6).

[0012] By adopting the above technical solution and controlling the dosage of dipotassium glycyrrhizate and Litsea cubeba extract according to the above mass ratio, the chemical phase stability of the 4-butylresorcinol complex liposome preparation can be guaranteed when the mass ratio of dipotassium glycyrrhizate and Litsea cubeba extract is 1:(0.167-6).

[0013] Optionally, the mass ratio of the dextrin to the oxidized pullulan is 1:(0.2-5).

[0014] By adopting the above technical solution and controlling the amount of dextrin and pullulan polysaccharide according to the above mass ratio, the structural phase stability of the 4-butylresorcinol complex liposome preparation can be guaranteed when the mass ratio of dextrin and pullulan polysaccharide is 1:(0.2-5).

[0015] Optionally, the mass ratio of the carrier to the stabilizer is (1-9):1.

[0016] By adopting the above technical solution and adjusting the dosage of carrier and stabilizer according to the above mass ratio, when the mass ratio of carrier and stabilizer is (1-9):1, the carrier and stabilizer can jointly protect the structural phase stability of the 4-butylresorcinol complex liposome formulation.

[0017] Optionally, the carrier is hydrogenated lecithin.

[0018] Preferably, the hydrogenated lecithin has a mass percentage of 1-1.8%.

[0019] Furthermore, the mass ratio of hydrogenated lecithin, dextrin, and oxidized pullulan is (1-1.8):(0.1-0.5):(0.1-0.5).

[0020] Optionally, the additives include lipid additives and aqueous additives, wherein the lipid additive is caprylic / capric triglyceride.

[0021] Optionally, based on the total mass of the 4-butylresorcinol complex liposome formulation, the mass percentage of the caprylic / capric triglyceride is 1-20%; and the mass percentage of the glycerol is 20-60%.

[0022] Preferably, the mass percentage of the caprylic / capric triglyceride is 9.5-11.5%; and the mass percentage of the glycerol is 35-45%.

[0023] Optionally, the oxidized pullulan includes the following preparation steps: b1: Add water to pullulan and stir in the dark until completely dissolved to obtain a pullulan solution; b2: Keep the reaction system away from light, add sodium periodate to pullulan polysaccharide solution, and continue the reaction for 12-36 hours to obtain the first reaction solution; b3: Add ethylene glycol to the first reaction solution and stir for 1-3 hours to obtain the second reaction solution; b4: The second reaction solution was placed into a dialysis bag and dialyzed to obtain an oxidized pullulan polysaccharide solution; b5: Take out the oxidized pullulan polysaccharide solution from the dialysis bag, add ethanol to the solution, let it stand for 0.5-1.5 hours, filter, wash, collect the precipitate, dry, and obtain oxidized pullulan polysaccharide. The mass ratio of sodium periodate in step b2 to pullulan in step b1 is (0.4-0.6):1; The volume-to-mass ratio of ethylene glycol in step b3 to pullulan in step b1 is 0.8-1.2 mL: 1 g.

[0024] Furthermore, the ethanol mentioned in step b5 is anhydrous ethanol.

[0025] In a second aspect, this application provides a method for preparing a 4-butylresorcinol complex liposome formulation as described in the first aspect of this application, comprising the following preparation steps: S1: Disperse hydrogenated lecithin, dextrin, and oxidized pullulan polysaccharide in glycerol, stir evenly, heat to 50-70℃, add dipotassium glycyrrhizate, Litsea cubeba extract, sodium hyaluronate cross-linked polymer solution, and water to obtain phase A; S2: Mix 4-butylresorcinol and octanoic acid / decanoic acid triglyceride, heat to 40-50℃, add tocopherol, mix well, and obtain phase B; S3: Add phase B to phase A and emulsify to obtain a crude emulsion; S4: Homogenize the crude emulsion to obtain the 4-butylresorcinol complex liposome formulation.

[0026] Furthermore, the hydrogenated lecithin in step S1 has a mass percentage of 1.0-1.8%.

[0027] Furthermore, in step S3, the shear emulsification rate of phase A and phase B is 8000-12000 rpm, and the homogenization time is 3-7 min; in step S4, the pressure of the high-pressure microjet is 15000-25000 psi.

[0028] In a third aspect of this application, this application provides the use of a 4-butylresorcinol complex liposome formulation as described in the first aspect of this application in the preparation of skin care products for inhibiting tyrosinase activity.

[0029] In summary, the present invention has at least one of the following beneficial technical effects: 1. This application provides a 4-butylresorcinol complex liposome formulation with good stability and a permeation rate ≥100.0 μg / cm³ after 24 hours. 2 The inhibition rate of tyrosinase is >86%. On one hand, dextrin provides physical stability through its branched structure, and pullulan, a modified polysaccharide, exhibits good stability. The synergistic effect of these two components ensures the stability of the 4-butylresorcinol complex liposome formulation during long-term storage and use. On the other hand, dipotassium glycyrrhizate possesses both antioxidant and anti-inflammatory properties, reducing skin damage caused by inflammation by inhibiting inflammatory responses. Litsea cubeba extract contains alkaloids and terpenoids, which, through their antioxidant effects, protect the chemically stable phase of 4-butylresorcinol, thereby better inhibiting tyrosinase. The synergistic effect of these two components effectively reduces skin inflammation and enhances the whitening effect. Furthermore, the sodium hyaluronate cross-linked polymer solution forms a pH-responsive outer membrane, intelligently releasing active ingredients in the weakly acidic environment of the skin, further inhibiting tyrosinase and improving the whitening effect.

[0030] 2. This application provides the use of a 4-butylresorcinol complex liposome formulation in the preparation of anti-tyrosinase skincare products. It exhibits an inhibition rate of >86% against tyrosinase, thus enhancing whitening effects. Detailed Implementation

[0031] The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Specific conditions not specified in the examples shall be carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0032] Artemisia annua extract was purchased from Changsha Hepu Biotechnology Co., Ltd.; pullulan was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (P121048); sodium hyaluronate cross-linked polymer solution was purchased from Renheng Zhiyan Biotechnology (Shandong) Co., Ltd., and the sodium hyaluronate cross-linked polymer solution consisted of 3% sodium hyaluronate cross-linked polymer, 92% water, and 5% 1,2-glutaraldehyde. Dextrin was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (D104350).

[0033] Preparation Example 1 The preparation methods of Litsea cubeba extract include: a1: Weigh 5.0 kg of Litsea cubeba root, crush it, and obtain Litsea cubeba powder; a2: Put the pepper powder into an extraction tank and reflux it three times with 75% ethanol (solvent). Each time, the amount of solvent used is 10 times that of the pepper powder (i.e., 50.0 kg). Each extraction time is 2 hours. After combining the extracts, concentrate them to dryness and then further dry them to obtain the total extract of pepper. a3: The total extract of Litsea cubeba was dissolved in water and loaded onto AB-8 macroporous adsorption resin. The eluent fraction was collected with 30% ethanol, concentrated and dried to obtain Litsea cubeba extract.

[0034] Preparation Example 2 Methods for preparing oxidized pullulan include: b1: Weigh 100.0g pullulan, add 2L of deionized water, and stir continuously in a 40℃ water bath for about 3 hours under light-protected conditions until completely dissolved to obtain pullulan solution; b2: Keep the reaction system away from light, stabilize the temperature at 35℃, slowly add 50g of sodium periodate (NaIO4) solid to the pullulan polysaccharide solution while stirring, and continue the reaction for 24h to obtain the first reaction solution; b3: Slowly add 100 mL of ethylene glycol to the first reaction solution and stir for 2 hours to obtain the second reaction solution; b4: Put the second reaction solution into a dialysis bag and dialyze with deionized water, changing the water 4 times a day until no blue color appears in the dialysate when tested with starch-KI test paper, and obtain the oxidized pullulan polysaccharide solution; b5: Take out the oxidized pullulan polysaccharide solution from the dialysis bag, slowly add 3 times the volume of anhydrous ethanol to the solution, let it stand for 1 hour, filter it, wash it 3 times with anhydrous ethanol and collect the precipitate. b6: The precipitate was placed in a freeze dryer and freeze-dried at -50°C for 36 hours to obtain oxidized pullulan.

[0035] The Litsea cubeba extract used in the following examples was derived from Preparation Example 1, and the oxidized pullulan polysaccharide was derived from Preparation Example 2.

[0036] Example 1 A 4-butylresorcinol complex liposome formulation comprises the following raw materials in weight percentages: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water; wherein the antioxidant is composed of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol; the stabilizer is composed of 0.3% dextrin and 0.3% oxypullanin; the carrier is hydrogenated lecithin; the film-forming agent is a sodium hyaluronate cross-linked polymer solution; and the adjuvant is composed of 10.5% lipid adjuvant and 40% aqueous adjuvant, wherein the lipid adjuvant is caprylic / capric triglyceride, and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0037] The mass ratio of dipotassium glycyrrhizate to Litsea cubeba extract was 1:1; the mass ratio of dextrin to oxidized pullulan was 1:1.

[0038] Preparation method: S1: A phase preparation: Hydrogenated lecithin, dextrin, and oxidized pullulan were dispersed in glycerol and stirred until homogeneous. The mixture was then heated to 60°C and stirred for 15 minutes to allow it to fully dissolve or swell. A sodium hyaluronate crosspolymer solution, Litsea cubeba extract, dipotassium glycyrrhizate, and water were added, and the mixture was stirred for another 15 minutes while maintaining the temperature to obtain a homogeneous and transparent phase A. The phase A was then cooled to 50°C for later use. S2: B phase preparation: Mix 4-butylresorcinol and octanoic acid / decanoic acid triglycerides, heat to 45°C, and stir until completely dissolved to obtain phase B1; add phase B2 (tocopherol) to phase B1, mix evenly to obtain clear phase B, and keep at 45°C for later use. S3: Primary emulsification: At 45°C, phase B was slowly added to phase A, and the mixture was sheared and emulsified for 5 minutes using a high-speed shear machine (10000 rpm) to obtain a crude emulsion. S4: High-pressure homogenization: The crude emulsion was cooled to 25°C and homogenized repeatedly three times under high pressure microfluidic jet at 20,000 psi to obtain a 4-butylresorcinol complex liposome formulation.

[0039] Example 2 Example 2 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of dipotassium glycyrrhizate and Litsea cubeba extract remains unchanged, and the mass ratio of dipotassium glycyrrhizate and Litsea cubeba extract is 1:6.

[0040] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.05% dipotassium glycyrrhizate, 0.3% Litsea cubeba extract, and 0.55% tocopherol by mass percentage. The stabilizer consists of 0.3% dextrin and 0.3% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, where the lipid adjuvant is caprylic / capric triglyceride and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0041] The preparation method is the same as in Example 1.

[0042] Example 3 Example 3 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of dipotassium glycyrrhizate and Litsea cubeba extract remains unchanged, and the mass ratio of dipotassium glycyrrhizate and Litsea cubeba extract is 1:0.167.

[0043] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.3% dipotassium glycyrrhizate, 0.05% Litsea cubeba extract, and 0.55% tocopherol by mass percentage. The stabilizer consists of 0.3% dextrin and 0.3% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, the lipid adjuvant being caprylic / capric triglyceride and the aqueous adjuvant being glycerol. The balance is water. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0044] The preparation method is the same as in Example 1.

[0045] Example 4 Example 4 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of dextrin and pullulan remains unchanged, and the mass ratio of dextrin to pullulan is 1:5.

[0046] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass. The stabilizer consists of 0.1% dextrin and 0.5% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, where the lipid adjuvant is caprylic / capric triglyceride and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0047] The preparation method is the same as in Example 1.

[0048] Example 5 Example 5 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of dextrin and pullulan remains unchanged, and the mass ratio of dextrin to pullulan is 1:0.2.

[0049] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol. The stabilizer consists of 0.5% dextrin and 0.1% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, where the lipid adjuvant is caprylic / capric triglyceride and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0050] Example 6 Example 6 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of hydrogenated lecithin, dextrin and oxidized pullulan remains unchanged, and the mass ratio of hydrogenated lecithin, dextrin and oxidized pullulan is 1.8:0.1:0.1.

[0051] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.2% stabilizer, 1.8% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass. The stabilizer consists of 0.1% dextrin and 0.1% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, where the lipid adjuvant is caprylic / capric triglyceride and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0052] The preparation method is the same as in Example 1.

[0053] Example 7 Example 7 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the total mass of hydrogenated lecithin, dextrin and oxidized pullulan remains unchanged, and the mass ratio of hydrogenated lecithin, dextrin and oxidized pullulan is 1.0:0.5:0.5.

[0054] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation varies. This embodiment includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 1.0% stabilizer, 1.0% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass. The stabilizer consists of 0.5% dextrin and 0.5% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, where the lipid adjuvant is caprylic / capric triglyceride and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0055] The preparation method is the same as in Example 1.

[0056] Comparative Example 1 Comparative Example 1 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that dipotassium glycyrrhizate is replaced by Litsea cubeba extract.

[0057] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.35% by mass of Litsea cubeba extract and 0.55% by mass of tocopherol; the stabilizer consists of 0.3% by mass of dextrin and 0.3% by mass of oxidized pullulan; the carrier is hydrogenated lecithin; the film-forming agent is a sodium hyaluronate cross-linked polymer solution; and the adjuvant consists of 10.5% by mass of lipid adjuvant and 40% by mass of aqueous adjuvant, with the lipid adjuvant being caprylic / capric triglyceride and the aqueous adjuvant being glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0058] The preparation method is the same as in Example 1.

[0059] Comparative Example 2 Comparative Example 2 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the extract of Litsea cubeba is replaced by dipotassium glycyrrhizate.

[0060] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.35% dipotassium glycyrrhizate and 0.55% tocopherol by mass percentage; the stabilizer consists of 0.3% dextrin and 0.3% oxidized pullulan by mass percentage; the carrier is hydrogenated lecithin; the film-forming agent is a sodium hyaluronate cross-linked polymer solution; and the adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, with the lipid adjuvant being caprylic / capric triglyceride and the aqueous adjuvant being glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0061] The preparation method is the same as in Example 1.

[0062] Comparative Example 3 Comparative Example 3 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that dextrin is replaced by pullulan oxidase.

[0063] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvants, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass percentage. The stabilizer is oxidized pullulan polysaccharide. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvants consist of 10.5% lipid adjuvants and 40% aqueous adjuvants; the lipid adjuvant is caprylic / capric triglyceride, and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0064] The preparation method is the same as in Example 1.

[0065] Comparative Example 4 Comparative Example 4 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that oxypullanose is replaced by dextrin.

[0066] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvants, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass percentage. The stabilizer is dextrin. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvants consist of 10.5% lipid adjuvants and 40% aqueous adjuvants; the lipid adjuvant is caprylic / capric triglyceride, and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0067] The preparation method is the same as in Example 1.

[0068] Comparative Example 5 Comparative Example 5 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that the Litsea cubeba extract is replaced with Artemisia annua extract.

[0069] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% artemisia annua extract, and 0.55% tocopherol by mass percentage. The stabilizer consists of 0.3% dextrin and 0.3% oxidized pullulan. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, with the lipid adjuvant being caprylic / capric triglyceride and the aqueous adjuvant being glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0070] The preparation method is the same as in Example 1.

[0071] Comparative Example 6 Comparative Example 6 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that pullulan is replaced by pullulan in equal mass.

[0072] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 0.45% film-forming agent, 50.5% adjuvant, and the balance being water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass. The stabilizer consists of 0.3% dextrin and 0.3% pullulan by mass. The carrier is hydrogenated lecithin. The film-forming agent is a sodium hyaluronate cross-linked polymer solution. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant, with the lipid adjuvant being caprylic / capric triglyceride and the aqueous adjuvant being glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0073] The preparation method is the same as in Example 1.

[0074] Comparative Example 7 Comparative Example 7 provides a 4-butylresorcinol complex liposome formulation, which differs from Example 1 in that it does not contain a sodium hyaluronate cross-linked polymer solution.

[0075] Specifically, the raw material composition of the 4-butylresorcinol complex liposome formulation differs. This comparative example includes the following raw materials by mass percentage: 5.05% 4-butylresorcinol, 0.9% antioxidant, 0.6% stabilizer, 1.4% carrier, 50.5% adjuvant, and the balance water. The antioxidant consists of 0.175% dipotassium glycyrrhizate, 0.175% Litsea cubeba extract, and 0.55% tocopherol by mass percentage. The stabilizer consists of 0.3% dextrin and 0.3% oxidized pullulan. The carrier is hydrogenated lecithin. The adjuvant consists of 10.5% lipid adjuvant and 40% aqueous adjuvant; the lipid adjuvant is caprylic / capric triglyceride, and the aqueous adjuvant is glycerol. All mass percentages are calculated based on the total mass of the 4-butylresorcinol complex liposome formulation.

[0076] The preparation method is the same as in Example 1.

[0077] Experimental Example 1: Stability Study of 4-Butylresorcinol Complex Liposome Formulation Examples 1-7 and Comparative Examples 1-7 were placed in centrifuge tubes at 45°C in the dark, and the stratification of the 4-butylresorcinol complex liposome formulations prepared from Examples 1-7 and Comparative Examples 1-7 was observed at different time points (30 days and 120 days) to characterize the stability of the 4-butylresorcinol complex liposome formulations. The results are shown in Table 1: Table 1 Based on Examples 1-3 and Table 1, it can be seen that keeping the total mass of dipotassium glycyrrhizate and Litsea cubeba extract constant, and adjusting the mass ratio of dipotassium glycyrrhizate and Litsea cubeba extract, has little effect on the stability of the 4-butylresorcinol complex liposome formulation.

[0078] Based on Examples 1, 4-5, and Table 1, it can be seen that by keeping the total mass of dextrin and oxidized pullulan unchanged and adjusting the mass ratio of dextrin and oxidized pullulan within a reasonable range, the 4-butylresorcinol complex liposome formulation can remain stable.

[0079] Based on Examples 1, 6-7 and Table 1, it can be seen that by keeping the total mass of hydrogenated lecithin, dextrin and oxidized pullulan unchanged, and by adjusting the mass ratio of hydrogenated lecithin, dextrin and oxidized pullulan, the addition of too much or too little hydrogenated lecithin may cause the 4-butylresorcinol complex liposome preparation to separate into layers and make it impossible to preserve for a long time.

[0080] Based on Example 1, Comparative Examples 1-2 and Table 1, it can be seen that replacing dipotassium glycyrrhizate and Litsea cubeba extract with each other by equal mass has little effect on the stability of the 4-butylresorcinol complex liposome formulation.

[0081] Based on Example 1, Comparative Examples 3-4 and Table 1, it can be seen that replacing dextrin and oxidized pullulan with each other by equal mass may disrupt the synergistic effect of dextrin and oxidized pullulan, thereby damaging the structural stability of the 4-butylresorcinol complex liposome formulation, resulting in the inability of the 4-butylresorcinol complex liposome formulation to be stored for a long time and the appearance of stratification.

[0082] Based on Example 1, Comparative Example 5, and Table 1, it can be seen that replacing the Litsea cubeba extract with Artemisia annua extract by mass has little impact on the stability of the 4-butylresorcinol complex liposome formulation.

[0083] Based on Example 1, Comparative Example 6, and Table 1, it can be seen that replacing pullulan with an equal mass of oxidized pullulan may be because the system lacks oxidized pullulan, thus losing the synergistic effect of dextrin and oxidized pullulan, resulting in the 4-butylresorcinol complex liposome formulation not being able to be stored for a long time and exhibiting stratification.

[0084] Based on Example 1, Comparative Example 7, and Table 1, it can be seen that when the sodium hyaluronate cross-linked polymer solution is missing from the system, the 4-butylresorcinol complex liposome formulation cannot be stored for a long time and exhibits stratification.

[0085] Example 2: In vitro inhibition rate of 4-butylresorcinol complex liposome formulation against tyrosinase was determined using 10 mL test tubes to set up sample tubes (T1), sample background (T2), enzyme reaction tubes (C1), and solvent background (C2). For each sample and each test concentration, three parallel tubes were set up for the sample tubes (T1) and enzyme reaction tubes (C1). The contents of each tube are shown in Table 2. The concentration of phosphate buffer was 0.01 mol / L, pH = 6.8, the concentration of tyrosinase solution was 100 U / mL, and the levodopa solution was a 1.5 g / L levodopa solution prepared with 0.01 mol / L, pH = 6.8 phosphate buffer. The 4-butylresorcinol complex liposome formulations prepared in Example 17 and Comparative Examples 1-7 were used as samples. The samples were added according to Table 2, thoroughly mixed, and incubated in a 37°C water bath for 10 min. Add 2 mL of 1.5 g / L levodopa solution prepared with 0.01 mol / L phosphate buffer (pH 6.8) to each tube sequentially. Control the reaction time for each tube to 5 min. Immediately transfer the reaction solution from each tube to a cuvette and measure the absorbance at 475 nm. Calculate the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome formulation using the following formula. For tubes T1 and C1, set up three parallel tubes, and take the average value for the calculation: Inhibition rate = [1-(A T1 -A T2 ) / (A C1 -A C2 )]×100%; Table 2 The experimental results are shown in Table 3: Table 3 serial number Tyrosinase inhibition rate % Example 1 95.2 Example 2 86.7 Example 3 88.3 Example 4 91.2 Example 5 92.4 Example 6 87.5 Example 7 88.6 Comparative Example 1 68.7 Comparative Example 2 71.3 Comparative Example 3 75.9 Comparative Example 4 77.2 Comparative Example 5 72.1 Comparative Example 6 78.4 Comparative Example 7 64.2 Based on Examples 1-3 and Table 3, it can be seen that in Example 1, the mass ratio of dipotassium glycyrrhizate to Litsea cubeba extract was 1:1. The 4-butylresorcinol complex liposome preparation prepared in Example 1 showed the best tyrosinase inhibition rate, which was superior to that in Examples 2-3. Therefore, adjusting the mass ratio of dipotassium glycyrrhizate to Litsea cubeba extract can affect the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome preparation.

[0086] Based on Examples 1, 4-5, and Table 3, it can be seen that in Example 1, the mass ratio of dextrin to oxidized pullulan was 1:1. The 4-butylresorcinol complex liposome preparation prepared in Example 1 showed the best inhibition rate against tyrosinase, superior to that in Examples 4-5. Therefore, adjusting the mass ratio of dextrin to oxidized pullulan can affect the inhibition rate of the 4-butylresorcinol complex liposome preparation against tyrosinase.

[0087] Based on Examples 1, 6-7, and Table 3, the 4-butylresorcinol complex liposome formulation prepared in Example 1 exhibits the best tyrosinase inhibition rate, superior to that in Examples 6-7. Therefore, adjusting the mass ratio of hydrogenated lecithin, dextrin, and oxidized pullulan can affect the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome formulation.

[0088] Based on Example 1, Comparative Examples 1-2, and Table 3, it can be seen that when dipotassium glycyrrhizate and Litsea cubeba extract were interchanged in equal quantities in Comparative Examples 1-2, the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome preparation prepared in Comparative Examples 1-2 was significantly reduced. This may be because the synergistic effect of dipotassium glycyrrhizate and Litsea cubeba extract was disrupted, and the chemical stability of the 4-butylresorcinol complex liposome preparation was also affected. Furthermore, the oxidative degradation of 4-butylresorcinol was accelerated, leading to a significant decrease in the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome preparation.

[0089] Based on Example 1, Comparative Examples 3-4, and Table 3, it can be seen that when dextrin and oxidized pullulan were substituted for each other in equal quantities in Comparative Examples 3-4, the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome preparation prepared in Comparative Examples 3-4 was significantly reduced. This may be because the synergistic effect of dextrin and oxidized pullulan was disrupted, and the structural stability of the 4-butylresorcinol complex liposome preparation was also affected, resulting in a significant decrease in the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome preparation.

[0090] Based on Example 1, Comparative Example 5, and Table 3, it can be seen that when the same amount of Litsea cubeba extract was replaced with Artemisia annua extract in Comparative Example 5, the 4-butylresorcinol complex liposome preparation prepared in Comparative Example 5 showed a significant decrease in the inhibition rate of tyrosinase.

[0091] Based on Example 1, Comparative Example 6, and Table 3, it can be seen that when pullulan was replaced with pullulan in Comparative Example 6, the 4-butylresorcinol complex liposome preparation prepared in Comparative Example 6 showed a significant decrease in the inhibition rate of tyrosinase.

[0092] Based on Example 1, Comparative Example 7, and Table 3, it can be seen that without the addition of sodium hyaluronate cross-linked polymer solution in Comparative Example 7, the 4-butylresorcinol complex liposome formulation prepared in Comparative Example 7 exhibited a significantly lower tyrosinase inhibition rate. This may be because the sodium hyaluronate cross-linked polymer solution can form a pH-responsive outer membrane, intelligently releasing the active ingredient in the weakly acidic environment of the skin. When the sodium hyaluronate cross-linked polymer solution is absent from the system, the active ingredient cannot be effectively released, leading to a significant decrease in the tyrosinase inhibition rate of the 4-butylresorcinol complex liposome formulation.

[0093] Experimental Example 3: In vitro transdermal test of 4-butylresorcinol complex liposome formulation The effect of the 4-butylresorcinol complex liposome formulations prepared in Example 1 and Comparative Examples 1-2 on transdermal absorption (permeation enhancement) capacity was evaluated using a transdermal absorption (permeation enhancement) test.

[0094] In vitro transdermal assays were performed using a vertical diffusion cell. Nude mouse skin (abdominal skin, with subcutaneous fat and blood vessels removed) was used as the model. The skin was pre-washed with 10 mL of physiological saline and its integrity was checked to ensure there was no damage. The receiving solution was phosphate-buffered saline (PBS). The skin patch was fixed between the supply and receiving cells, with the skin layer facing upwards, and equilibrated for 20 min. Experimental groups 1-3 (corresponding to Example 1 and Comparative Examples 1-2, respectively) of equal mass were added to the supply cell, and the receiving solution was collected after 24 h. The content of 4-butylresorcinol in the receiving solution was determined by high-performance liquid chromatography (HPLC, Shimadzu, Japan), and the permeation rate per unit area was calculated. The results are shown in Table 4. Three parallel experiments were set up, and the average value was used for calculation.

[0095] The formula for calculating the per-unit area transmittance on a leather patch is as follows: Q n =VC n / A Among them, Q n The unit area permeation of 4-butylresorcinol at time t (μg / cm²) 2 ), A is the permeation area, C n t represents the measured concentration of 4-butylresorcinol in the receiving solution at time t, and V represents the total volume of the receiving solution.

[0096] Table 4 serial number <![CDATA[Permeation amount per unit area after 24 h (μg / cm 2 )]]> Example 1 115.26 Comparative Example 1 66.85 Comparative Example 2 62.24 Based on Example 1, Comparative Examples 1-2 and Table 4, it can be seen that substituting the mass of dipotassium glycyrrhizate and Litsea cubeba extract may disrupt the synergistic effect of dipotassium glycyrrhizate and Litsea cubeba extract, thereby disrupting the chemically stable phase of the 4-butylresorcinol complex liposome formulation, resulting in a significant decrease in the cumulative penetration rate of the 4-butylresorcinol complex liposome formulation.

[0097] The above are all preferred embodiments of this application and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made to the products, methods and principles of this application should be covered within the scope of protection of this application.

Claims

1. A 4-butylresorcinol complex liposome formulation, characterized in that, The raw materials include the following percentages by weight: 0.1-10% 4-butylresorcinol, 0.2-1.6% antioxidant, 0.2-1% stabilizer, 0.3-2.5% carrier, 0.1-0.8% film-forming agent, 21-80% additives, and the balance being water; Based on the total mass of the 4-butylresorcinol complex liposome formulation, the antioxidant is composed of 0.05-0.3% by mass of dipotassium glycyrrhizate, 0.05-0.3% by mass of Litsea cubeba extract, and 0.1-1% by mass of tocopherol. The stabilizer consists of 0.1-0.5% dextrin and 0.1-0.5% pullulan by mass. The film-forming agent is a sodium hyaluronate cross-linked polymer solution.

2. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The mass ratio of dipotassium glycyrrhizate to Litsea cubeba extract is 1:(0.167-6).

3. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The mass ratio of dextrin to oxidized pullulan is 1:(0.2-5).

4. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The mass ratio of the carrier to the stabilizer is (1-9):

1.

5. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The carrier is hydrogenated lecithin.

6. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The additives include lipid additives and aqueous additives. The lipid additive is caprylic / capric triglyceride, and the aqueous additive is glycerol.

7. The 4-butylresorcinol complex liposome formulation according to claim 6, characterized in that, Based on the total mass of the 4-butylresorcinol complex liposome formulation, the mass percentage of the caprylic / capric triglyceride is 1-20%; and the mass percentage of the glycerol is 20-60%.

8. The 4-butylresorcinol complex liposome formulation according to claim 1, characterized in that, The oxidized pullulan polysaccharide includes the following preparation steps: b1: Add water to pullulan and stir in the dark until completely dissolved to obtain a pullulan solution; b2: Keep the reaction system away from light, add sodium periodate to pullulan polysaccharide solution, and continue the reaction for 12-36 hours to obtain the first reaction solution; b3: Add ethylene glycol to the first reaction solution and stir to obtain the second reaction solution; b4: The second reaction solution was placed into a dialysis bag and dialyzed to obtain an oxidized pullulan polysaccharide solution; b5: Take out the oxidized pullulan polysaccharide solution from the dialysis bag, add ethanol to the solution, let it stand, filter, wash, collect the precipitate, dry, and obtain oxidized pullulan polysaccharide. The mass ratio of sodium periodate in step b2 to pullulan in step b1 is (0.4-0.6):1; The volume-to-mass ratio of ethylene glycol in step b3 to pullulan in step b1 is 0.8-1.2 mL: 1 g.

9. A method for preparing a 4-butylresorcinol complex liposome formulation according to any one of claims 1-8, characterized in that, The preparation steps include the following: S1: Disperse hydrogenated lecithin, dextrin, and oxidized pullulan polysaccharide in glycerol, stir evenly, heat to 50-70℃, add dipotassium glycyrrhizate, Litsea cubeba extract, sodium hyaluronate cross-linked polymer solution, and water to obtain phase A; S2: Mix 4-butylresorcinol and octanoic acid / decanoic acid triglyceride, heat to 40-50℃, add tocopherol, mix well, and obtain phase B; S3: Add phase B to phase A and emulsify to obtain a crude emulsion; S4: Homogenize the crude emulsion to obtain the 4-butylresorcinol complex liposome formulation.

10. The use of the 4-butylresorcinol complex liposome formulation according to claims 1-8 in the preparation of skin care products for inhibiting tyrosinase activity and / or promoting penetration.

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