CN111920699A

CN111920699A - Whitening and freckle-removing composition, whitening and freckle-removing soluble microneedle patch and preparation method thereof

Info

Publication number: CN111920699A
Application number: CN202010961448.5A
Authority: CN
Inventors: 温新国; 张敏敏; 冯家颖; 陈航平; 陈叶盛; 杨思超
Original assignee: Neworld Pharmaceutical Co ltd; Guangzhou Xinji Weina Biotechnology Co ltd
Current assignee: Neworld Pharmaceutical Co ltd
Priority date: 2020-09-14
Filing date: 2020-09-14
Publication date: 2020-11-13
Anticipated expiration: 2040-09-14
Also published as: CN111920699B

Abstract

The invention relates to a whitening and freckle-removing composition, a whitening and freckle-removing soluble microneedle patch and a preparation method thereof. The whitening and freckle-removing composition consists of oxidized resveratrol, resveratrol and small molecular substances, wherein the small molecular substances consist of the following components in parts by weight: 40-50 parts of alpha-arbutin, 40-50 parts of glutathione and 1-3 parts of soybean isoflavone, wherein the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 1 to 10. The soluble microneedle patch for whitening and removing freckles is prepared from viscous liquid consisting of oxidized resveratrol, resveratrol inclusion liquid, small molecular substances, microneedle framework materials and a first solvent; the inclusion liquid of the oxyresveratrol and the resveratrol is prepared from oxyresveratrol, resveratrol, hydroxypropyl-beta cyclodextrin and a second solvent. The soluble microneedle patch for whitening and removing freckles has excellent mechanical properties and good whitening and freckle removing effects.

Description

Whitening and freckle-removing composition, whitening and freckle-removing soluble microneedle patch and preparation method thereof

Technical Field

The invention belongs to the field of microneedles, and particularly relates to a whitening and freckle-removing composition, a whitening and freckle-removing soluble microneedle patch and a preparation method thereof.

Background

The color spot is a general name of all dark spots formed on the skin by stimulation of various adverse factors of the internal and external world, and is mostly a pigmentation spot which is formed by increasing or eliminating the synthesis of melanin on the surface layer of the skin slowly to become brown or black. The color spots are more frequent on the cheeks and forehead, which seriously affects the beauty of the face. With the improvement of living standard, the pursuit of people for beauty is more strongly expressed, and a common language in China is called ' one white covers three ugly ', which reflects the Chinese consumer's choking and vogue, and also promotes the growth of whitening and freckle-removing products. The existing commercially available whitening and freckle-removing products usually achieve whitening and freckle-removing effects by adding skin whitening agents into the products, and the action mechanism of the skin whitening agents usually takes tyrosinase as a target point to inhibit tyrosinase activity, synthesis and migration, or has cytotoxicity on melanocytes to inhibit pigmentation. However, the skin is a complex tissue structure, and the stratum corneum is the main barrier for the penetration of active ingredients, so that most ingredients, particularly water-soluble ingredients, cannot well penetrate into subcutaneous tissues to play a role. Common effective skin whitening agents have the problems of poor skin permeability and poor stability in water or air, cannot exert the maximum efficacy when added into the traditional cosmetic formulations such as cream, water, milk and the like, and have unobvious whitening and spot-lightening effects.

Disclosure of Invention

Based on the above, the invention firstly provides a whitening and freckle-removing composition, which has good whitening, freckle-removing or freckle-removing effects, can be combined with a specific microneedle auxiliary material to prepare a soluble microneedle patch with good mechanical properties, and has good skin whitening and freckle-removing effects.

The specific technical scheme is as follows:

a whitening and freckle-removing composition comprises oxyresveratrol, resveratrol and small molecular substances, wherein the small molecular substances comprise the following components in parts by weight: 40-50 parts of alpha-arbutin, 40-50 parts of glutathione and 1-3 parts of soybean isoflavone, wherein the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 1 to 10.

In some embodiments, the mass ratio of the oxyresveratrol to the resveratrol is 1.5-2.5: 1.

In some embodiments, the mass ratio of the alpha-arbutin, the glutathione and the soybean isoflavone is 48-50: 2.

In some of these embodiments, the mass ratio of the total mass of the oxyresveratrol and resveratrol to the small molecule substance is 1: 4 to 6.

The invention also provides application of the whitening and freckle-removing composition.

The specific technical scheme is as follows:

the composition is applied to preparing a whitening and freckle-removing skin care product or a whitening and freckle-removing cosmetic.

The invention also provides a soluble microneedle patch for whitening and removing freckles. The microneedle patch has good mechanical strength and good skin whitening and speckle removing effects.

The technical scheme is as follows:

a soluble microneedle patch for whitening skin and removing speckle is prepared from resveratrol oxide, resveratrol clathrate, small molecular substance, microneedle skeleton material and viscous liquid composed of first solvent;

the inclusion liquid of the oxyresveratrol and the resveratrol is prepared from oxyresveratrol, resveratrol, hydroxypropyl-beta cyclodextrin and a second solvent;

the micromolecule substance comprises the following components in parts by weight: 40-50 parts of alpha-arbutin, 40-50 parts of glutathione and 1-3 parts of soybean isoflavone;

the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 1-10;

the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the microneedle skeleton material is 1: 10-90;

the microneedle matrix material is selected from one or more of sodium hyaluronate, hydroxypropyl cellulose, hydroxyethyl cellulose and povidone K30, or the microneedle matrix material is composed of glycerin and one or more of the following materials: sodium hyaluronate, hydroxypropyl cellulose, hydroxyethyl cellulose, povidone.

In some embodiments, the weight percentage of the oxidized resveratrol in the soluble microneedle patch for whitening and removing freckles is 1-3%.

In some embodiments, the weight percentage of the oxidized resveratrol in the soluble microneedle patch for whitening and removing freckles is 1.5-2.2%.

In some embodiments, the oxidized resveratrol in the soluble microneedle patch for whitening and removing freckles is 2% by weight.

In some embodiments, the mass ratio of the oxyresveratrol to the resveratrol is 1.8-2.2: 1.

In some embodiments, the mass ratio of the total mass of the oxidized resveratrol and resveratrol to the microneedle scaffold material is 1: 30 to 50.

In some embodiments, the total mass fraction of the oxyresveratrol and the resveratrol in the inclusion solution of the oxyresveratrol and the resveratrol is 0.2-0.8%, and the total mass fraction of the oxyresveratrol, the resveratrol and the hydroxypropyl-beta cyclodextrin is 3-6%.

In some embodiments, the total mass fraction of the oxyresveratrol and the resveratrol in the inclusion solution of the oxyresveratrol and the resveratrol is 0.4-0.6%, and the total mass fraction of the oxyresveratrol, the resveratrol and the hydroxypropyl-beta cyclodextrin is 3.5-4.5%.

In some embodiments, the preparation method of the inclusion liquid of oxyresveratrol and resveratrol comprises the following steps: under the condition of stirring, adding the mixed solution of oxyresveratrol and resveratrol into the aqueous solution of hydroxypropyl-beta cyclodextrin, and continuously stirring until complete inclusion.

In some embodiments, the mixed solution of oxyresveratrol and resveratrol has a mass fraction of 1-5%, and the solvent is an ethanol aqueous solution with a mass fraction of 50% -70%; the mass fraction of the water solution of the hydroxypropyl-beta cyclodextrin is 3-6%.

In some embodiments, the mixed solution of oxyresveratrol and resveratrol has a mass fraction of 1-2%, and the solvent is an ethanol aqueous solution with a mass fraction of 55-65%; the mass fraction of the water solution of the hydroxypropyl-beta cyclodextrin is 4-6%.

In some of these embodiments, the microneedle scaffold material consists of low molecular weight sodium hyaluronate, high molecular weight sodium hyaluronate, glycerol, and hydroxypropyl cellulose; the molecular weight of the low molecular weight sodium hyaluronate is 4500-5500; the molecular weight of the high molecular weight sodium hyaluronate is 26-30 ten thousand.

In some of these embodiments, the weight percentages of the low molecular weight sodium hyaluronate, high molecular weight sodium hyaluronate, glycerin, and hydroxypropyl cellulose are as follows: 7-10% of low-molecular-weight sodium hyaluronate, 75-80% of high-molecular-weight sodium hyaluronate, 6-8% of glycerol and 6-8% of hydroxypropyl cellulose.

In some of these embodiments, the weight percentages of the low molecular weight sodium hyaluronate, high molecular weight sodium hyaluronate, glycerin, and hydroxypropyl cellulose are as follows: 8.6 percent of low molecular weight sodium hyaluronate, 77.6 percent of high molecular weight sodium hyaluronate, 6.9 percent of glycerol and 6.9 percent of hydroxypropyl cellulose.

In some of these embodiments, the first solvent is an aqueous ethanol solution.

In some embodiments, the first solvent is an ethanol aqueous solution with a mass fraction of 15-25%.

In some of these embodiments, the viscous liquid has a solids content of 6% to 12%.

In some of these embodiments, the viscous liquid has a solids content of 6.9% to 8.1%.

In some embodiments, the needle body of the soluble microneedle patch for whitening and removing freckles is pyramid-like shape or cone-like shape, and the height of the needle body is 300-800 um.

The invention also provides a preparation method of the whitening and freckle removing soluble microneedle patch.

The specific technical scheme is as follows:

a preparation method of a soluble microneedle patch for whitening and removing freckles comprises the following steps:

adding the micromolecular substance into the first solvent, adding the inclusion liquid of the oxyresveratrol and the resveratrol and the microneedle framework material, stirring to dissolve or swell the micromolecular substance uniformly, centrifuging to remove bubbles, and obtaining the viscous liquid; and coating the viscous liquid on a microneedle mould in a vacuum environment, drying, and stripping the microneedle mould to obtain the whitening and freckle removing soluble microneedle patch.

In some embodiments, the rotation speed of the centrifugation is 3000-4000 r/min, and the centrifugation time is 3-5 min.

In some of these embodiments, the pressure of the vacuum environment is between-0.07 MPa and-0.09 MPa.

In some of these embodiments, the thickness of the liquid to which the viscous liquid is applied to the microneedle mold is 1 ± 0.5 mm.

In some embodiments, the drying temperature is room temperature, the humidity is 15-25%, and the drying time is 12-20 h.

In some embodiments, the preparation method of the whitening and freckle removing soluble microneedle patch further comprises the step of packaging the obtained whitening and freckle removing soluble microneedle patch in a clean environment with the temperature of 18-25 ℃ and the humidity of 30-50% RH.

The whitening and freckle-removing composition, the whitening and freckle-removing soluble microneedle patch and the preparation method thereof have the advantages that:

according to the invention, the oxidized resveratrol, the soybean isoflavone, the alpha-arbutin and the glutathione are selected to be compounded in a certain proportion as active ingredients, a microneedle framework material with a specific type and a specific dosage is matched, and the oxidized resveratrol and the resveratrol are firstly included by the hydroxypropyl-beta cyclodextrin and then loaded into microneedles, so that the soluble microneedle patch with good mechanical strength and whitening and freckle removing effects can be prepared, the microneedles are utilized to realize painless transdermal absorption, the absorption and the utilization rate of active ingredients are effectively promoted, and the rapid and lasting whitening and freckle removing effects are realized.

The oxyresveratrol and the resveratrol are included by the hydroxypropyl-beta cyclodextrin and then loaded into the microneedle, so that the stability of the oxyresveratrol and the resveratrol can be effectively improved, and the whitening and freckle removing effects of the oxyresveratrol and the resveratrol are further improved.

The oxyresveratrol and the resveratrol are compounded with the soybean isoflavone, the alpha-arbutin and the glutathione to have the synergistic effect, so that the whitening and freckle removing effects of the active ingredients can be effectively improved.

The further preferable micro-needle framework material is a combination of low-molecular-weight sodium hyaluronate, high-molecular-weight sodium hyaluronate, glycerin and hydroxypropyl cellulose in a certain proportion, and the combination of the materials is preferably used as the micro-needle framework material, so that the mechanical property of the soluble micro-needle patch can be further improved, the skin penetration rate of the micro-needle patch can be further improved, the micro-needle patch can effectively penetrate through a skin stratum corneum barrier, a micro-pore channel is formed on the surface of the skin, and effective components (oxidized resveratrol, soybean isoflavone, alpha-arbutin and glutathione) for whitening and removing freckles are rapidly dissolved in the skin and absorbed by a dermis layer, so that the effects of whitening the skin and removing freckles are better achieved.

The microneedle patch provided by the invention has the advantages that the raw materials for preparing the needle body and the film layer are the same, the balance between the ductility of the film and the hardness of the needle body is realized, the one-step rapid coating is realized, the preparation method is very simple, and the large-scale production is very facilitated.

Drawings

FIG. 1 is a diagram showing the inclusion of oxyresveratrol and an inclusion solution of resveratrol in example 1.

FIG. 2 is a graph showing the stability of oxidized resveratrol and inclusion liquid of resveratrol in example 1.

Fig. 3 is a micrograph of a whitening and freckle-removing soluble microneedle patch loaded with oxidized resveratrol.

FIG. 4 is a micrograph of rat skin stained by trypan blue after being applied with a whitening and freckle-removing soluble microneedle patch loaded with resveratrol oxide.

Detailed Description

Experimental procedures according to the invention, in which no particular conditions are specified in the following examples, are generally carried out under conventional conditions, or under conditions recommended by the manufacturer. The various chemicals used in the examples are commercially available.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.

The "plurality" referred to in the present invention means two or more. "and/or", "and/or" describe the association relationship of the associated object, meaning that there may be three relationships, e.g., a and/or B, may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.

The present invention will be described in further detail with reference to specific examples.

The following examples used the following starting materials:

oxyresveratrol, available from QIANIDDE biomedical technology (Shanghai) Inc.;

resveratrol, purchased from alatin;

alpha-arbutin, available from sanyuan longsheng biotechnology ltd;

glutathione, purchased from sanyuan longsheng biotechnology limited;

soy isoflavones, available from sanyuan longsheng biotechnology limited;

hydroxypropyl-beta cyclodextrin, available from Zibo Qianji Biotech, Inc.;

sodium hyaluronate with molecular weight of 5000, available from western Anmeichuan Biotech limited;

sodium hyaluronate, having a molecular weight of 28 ten thousand, purchased from seian meichuan biotechnology limited;

glycerol, purchased from guangzhou import and export trade ltd;

hydroxypropyl cellulose, available from shanghai ltd, chemical trade in ashland, asian;

polyvinylpyrrolidone, molecular weight 1300kDa, available from Shanghai Co., chemical trade of Ashland.

Example 1

Investigating the stability of the inclusion liquid of oxyresveratrol and resveratrol, and the specific operation method comprises the following steps: weighing oxyresveratrol and resveratrol according to the mass ratio of 2:1, and preparing a series of mixed liquids of oxyresveratrol and resveratrol with the mass fractions of 1%, 2%, 3%, 4% and 5% by using an ethanol water solution with the mass fraction of 60%, wherein the mixed liquids are marked as solutions A1, A2, A3, A4 and A5; taking a certain amount of hydroxypropyl-beta cyclodextrin, preparing an aqueous solution with the mass fraction of 5% by using water, and marking as a solution B. Placing 5 cups of solution B on a magnetic stirrer, and slowly dripping solution A1, solution A2, solution A3, solution A4 and solution A5 according to the amount of 1/3 solution B while stirring to obtain inclusion solutions of oxyresveratrol and resveratrol, wherein the inclusion solutions of oxyresveratrol and resveratrol are respectively 0.25%, 0.5%, 0.75%, 1% and 1.25% in mass fraction of the inclusion compound. After 2h of continued stirring, the final inclusion was observed, as shown in FIG. 1: the inclusion liquid with the inclusion compound mass fractions of 0.25 percent, 0.5 percent and 0.75 percent is clear, which indicates that the oxyresveratrol and the resveratrol are completely included; the inclusion solution with complete inclusion was left at room temperature (25 ℃) overnight, and the stability of the inclusion solution was observed, as shown in FIG. 2: the obtained inclusion liquid of oxyresveratrol and resveratrol has good stability.

Example 2

This embodiment provides a method for preparing a soluble microneedle patch (as shown in fig. 3) carrying 1% of oxidized resveratrol for whitening and removing freckles, in which an inclusion solution of oxidized resveratrol and resveratrol, a small molecular substance, a microneedle framework material and a solvent form a viscous liquid, the viscous liquid is coated on a microneedle mold in a negative pressure environment, and the viscous liquid is dried to obtain the microneedle patch.

The preparation method of the whitening and freckle-removing soluble microneedle patch carrying the oxidized resveratrol comprises the following steps:

(1) preparing oxyresveratrol and resveratrol inclusion liquid: weighing oxyresveratrol and resveratrol according to the mass ratio of 2:1, and preparing a solution A with the mass fraction of 1.5% by using a 60% ethanol water solution; taking a certain amount of hydroxypropyl-beta cyclodextrin, and preparing a solution B with the mass fraction of 5% by using water; under the stirring of a magnetic stirrer, 46.62g of the solution A (containing oxidized resveratrol and resveratrol 0.7g) is slowly dripped into 93.38g of the solution B (containing hydroxypropyl-beta cyclodextrin 4.67g), and finally, an inclusion solution containing oxidized resveratrol and resveratrol with the mass fraction of 0.5% and the total mass fraction of 3.83% is obtained, wherein the inclusion compound refers to oxidized resveratrol and resveratrol.

(2) Preparing viscous liquid: taking soybean isoflavone, alpha-arbutin and glutathione according to the mass ratio of 2:49:49, stirring and mixing to obtain 6.1g of mixed powder, adding 795.9g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the ethanol aqueous solution to obtain 0.76% of solution, continuously adding 140.0g of the oxidized resveratrol prepared in the step (1) and the inclusion liquid of the resveratrol, stirring and mixing uniformly to obtain 1.22% of solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and (3) adding 58g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (with the molecular weight of 5000) and sodium hyaluronate (with the molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, centrifuging (with the rotating speed of 3500r/min and the time of 4min) to remove bubbles, and obtaining viscous liquid with the mass fraction of 6.95%.

(3) Preparing a microneedle patch: and (3) coating the viscous liquid prepared in the step (2) on a microneedle mould in a vacuum environment with the vacuum degree of-0.07 MPa, controlling the coating thickness to be 1mm, taking out, drying for 16h in an environment with the room temperature and the humidity of 20%, and then stripping the microneedle mould to obtain the whitening and freckle removing soluble microneedle patch carrying the oxidized resveratrol, wherein the shape of a needle body of the microneedle patch is similar to a cone, and the height of the needle body is 400 microns.

(4) And (4) packaging the microneedle patch obtained in the step (3) in a clean environment with the temperature of 18-25 ℃ and the humidity of 30-50% RH.

Example 3

The embodiment provides a preparation method of a whitening and freckle-removing soluble microneedle patch carrying 2% oxyresveratrol, which is characterized in that an inclusion solution of oxyresveratrol and resveratrol, a small molecular substance, a microneedle framework material and a solvent form a viscous liquid, the viscous liquid is coated above a microneedle mould in a negative pressure environment, and the viscous liquid is dried to obtain the microneedle patch.

(1) preparing oxyresveratrol and resveratrol inclusion liquid: weighing oxyresveratrol and resveratrol according to the mass ratio of 2:1, and preparing a solution A with the mass fraction of 1.5% by using a 60% ethanol water solution; taking a certain amount of hydroxypropyl-beta cyclodextrin, and preparing a solution B with the mass fraction of 5% by using water; under the stirring of a magnetic stirrer, 99.90g of the solution A (containing oxidized resveratrol and resveratrol 1.5g) is slowly dripped into 200.10g of the solution B (containing hydroxypropyl-beta cyclodextrin 10g) to finally obtain an inclusion solution containing oxidized resveratrol and resveratrol with the mass fraction of 0.5% and the total mass fraction of 3.83%, wherein the inclusion compound refers to the oxidized resveratrol and the resveratrol.

(2) Preparing viscous liquid: taking soybean isoflavone, alpha-arbutin and glutathione according to the mass ratio of 2:49:49, stirring and mixing to obtain 6.10g of mixed powder, adding 635.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the ethanol aqueous solution to obtain 0.95% of solution, continuously adding 300g of the oxidized resveratrol prepared in the step (1) and the resveratrol inclusion liquid, stirring and mixing uniformly to obtain 1.87% of solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and (3) adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (molecular weight of 5000) and sodium hyaluronate (molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, centrifuging (rotating speed is 3500r/min, time is 4min) to remove bubbles, and obtaining viscous liquid with the mass fraction of 7.56%.

Example 4

The embodiment provides a preparation method of a whitening and freckle-removing soluble microneedle patch loaded with 2.6% oxyresveratrol, which is characterized in that an inclusion liquid of the oxyresveratrol and the resveratrol, a small molecular substance, a microneedle framework material and a solvent form a viscous liquid, the viscous liquid is coated above a microneedle mould in a negative pressure environment, and the viscous liquid is dried to obtain the microneedle patch.

(1) preparing oxyresveratrol and resveratrol inclusion liquid: weighing oxyresveratrol and resveratrol according to the mass ratio of 2:1, and preparing a solution A with the mass fraction of 1.5% by using a 60% ethanol water solution; taking a certain amount of hydroxypropyl-beta cyclodextrin, and preparing a solution B with the mass fraction of 5% by using water; under the stirring of a magnetic stirrer, 139.86g of solution A (containing oxidized resveratrol and resveratrol 2.1g) is slowly dripped into 280.14g of solution B (containing hydroxypropyl-beta cyclodextrin 14g), and finally, an inclusion solution containing oxidized resveratrol and resveratrol with the mass fraction of 0.5% and the total mass fraction of 3.83% is obtained, wherein the inclusion compound refers to the oxidized resveratrol and the resveratrol.

(2) Preparing viscous liquid: taking soybean isoflavone, alpha-arbutin and glutathione according to the mass ratio of 2:49:49, stirring and mixing to obtain 6.10g of mixed powder, adding 515.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the mixed powder to obtain 1.17% of solution, continuously adding 420.00g of oxyresveratrol prepared in the step (1) and inclusion liquid of resveratrol, stirring and mixing uniformly to obtain 2.36% of solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and (3) adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (molecular weight of 5000) and sodium hyaluronate (molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, centrifuging (rotating speed is 3500r/min, time is 4min) to remove bubbles, and obtaining viscous liquid with mass fraction of 8.02%.

Example 5

The embodiment provides a preparation method of a whitening and freckle-removing soluble microneedle patch loaded with 2% oxidized resveratrol, which is different from embodiment 3 in that a microneedle framework material is not added with low-molecular-weight sodium hyaluronate.

(2) Preparing viscous liquid: taking soybean isoflavone, alpha-arbutin and glutathione according to the mass ratio of 2:49:49, stirring and mixing to obtain 6.10g of mixed powder, adding 635.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the mixed powder to obtain 0.95% of solution, continuously adding 300.00g of the oxidized resveratrol prepared in the step (1) and the inclusion solution of the resveratrol, stirring and mixing uniformly to obtain 1.87% of solution, and then mixing according to the mass percentage of 6.9%: 6.9%: adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose and sodium hyaluronate (molecular weight is 28 ten thousand) into 86.2%, stirring to enable the mixture to be uniformly swelled, centrifuging (rotating speed is 3500r/min, time is 4min) to remove bubbles, and obtaining viscous liquid with mass fraction of 7.56%.

Example 6

This example provides a method for preparing a soluble microneedle patch carrying 2% oxidized resveratrol for whitening and removing freckles, which is different from example 3 in that a microneedle framework material is different, and low molecular weight sodium hyaluronate is replaced by polyvinylpyrrolidone (molecular weight of 1300 kDa).

(2) Preparing viscous liquid: taking soybean isoflavone, alpha-arbutin and glutathione according to the mass ratio of 2:49:49, stirring and mixing to obtain 6.10g of mixed powder, adding 635.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the mixed powder to obtain 0.95% of solution, continuously adding 300.00g of the oxidized resveratrol prepared in the step (1) and the inclusion solution of the resveratrol, stirring and mixing uniformly to obtain 1.87% of solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose, polyvinylpyrrolidone (with the molecular weight of 1300kDa) and sodium hyaluronate (with the molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, and centrifuging (the rotating speed is 3500r/min and the time is 4min) to remove bubbles to obtain a viscous liquid with the mass fraction of 7.56%.

Comparative example 1

This comparative example provides a method for preparing a whitening and freckle-removing soluble microneedle patch loaded with 2% oxyresveratrol, which is different from example 3 in that no small molecular substance is added.

(2) Preparing viscous liquid: 635.90g of ethanol aqueous solution with the mass fraction of 21% is taken, 300.00g of the oxyresveratrol prepared in the step (1) and the inclusion liquid of the resveratrol are added, and after stirring and mixing are carried out uniformly, the solution with the mass fraction of 1.23% is obtained, and then the solution with the mass fraction of 6.9%: 6.9%: 8.6%: 64.10g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (molecular weight of 5000) and sodium hyaluronate (molecular weight of 28 ten thousand) is added into 77.6%, the mixture is stirred to be uniformly swelled, and air bubbles are removed by centrifugation (rotating speed is 3500r/min and time is 4min) to obtain viscous liquid with the mass fraction of 7.56%.

Comparative example 2

The comparative example provides a preparation method of a whitening and freckle-removing soluble microneedle patch loaded with 2% oxidized resveratrol, which is different from example 3 in that small molecular substances are different and glutathione is not added.

(2) Preparing viscous liquid: taking soybean isoflavone and alpha-arbutin according to the mass ratio of 2:98, stirring and mixing to obtain 6.10g of mixed powder, adding 635.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the mixed powder to obtain 0.95% solution, continuously adding 300.00g of the oxyresveratrol prepared in the step (1) and the inclusion liquid of the resveratrol, stirring and mixing uniformly to obtain 1.87% solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and (3) adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (molecular weight of 5000) and sodium hyaluronate (molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, centrifuging (rotating speed is 3500r/min, time is 4min) to remove bubbles, and obtaining viscous liquid with the mass fraction of 7.56%.

Comparative example 3

The comparative example provides a preparation method of a whitening and freckle-removing soluble microneedle patch carrying 2% oxidized resveratrol, which is different from example 3 in that a small molecular substance is different and no alpha-arbutin is added.

(2) Preparing viscous liquid: taking soybean isoflavone and glutathione according to the mass ratio of 2:98, stirring and mixing to obtain 6.10g of mixed powder, adding 635.90g of ethanol aqueous solution with the mass fraction of 21%, stirring to dissolve the mixed powder to obtain 0.95% solution, continuously adding 300.00g of the oxidized resveratrol prepared in the step (1) and the inclusion liquid of the resveratrol, stirring and mixing uniformly to obtain 1.87% solution, and then mixing according to the mass percentage of 6.9%: 6.9%: 8.6%: and (3) adding 58.00g of a mixture of glycerol, hydroxypropyl cellulose, sodium hyaluronate (molecular weight of 5000) and sodium hyaluronate (molecular weight of 28 ten thousand) into 77.6%, stirring to enable the mixture to be uniformly swelled, centrifuging (rotating speed is 3500r/min, time is 4min) to remove bubbles, and obtaining viscous liquid with the mass fraction of 7.56%.

Example 7

The whitening and freckle-removing soluble microneedle patch with the oxidized resveratrol prepared in the embodiments 2-6 and the comparative examples 1-3 is used for testing the skin puncture rate, and the specific operation method comprises the following steps: cutting the microneedle patch into a certain shape, pressing the microneedle patch on the skin of a rat subjected to unhairing treatment for 30s, taking the microneedle out of the skin, applying 1% trypan blue to the surface of the skin for 2min, wiping off, observing the number of needle holes on the skin under a microscope (shown in figure 4), and dividing by the total number of needle bodies on the microneedle patch applied to the skin to obtain the puncture rate, and performing parallel test for 3 times, wherein the results are shown in table 1.

Table 1 skin penetration test results

As can be seen from the results of table 1: the whitening and freckle-removing soluble microneedle patch prepared in examples 2 to 4 and carrying oxyresveratrol has the best hardness in example 3 and the best penetration rate on rat skin. The hardness of the microneedle is increased and then decreased along with the increase of the addition proportion of the oxidized resveratrol and the resveratrol inclusion compound, and the microneedle has the best hardness when the loading capacity is about 2 percent. The places of the whitening and freckle-removing soluble microneedle patch prepared in examples 5-6, which is different from the place of example 3, are that sodium hyaluronate with low molecular weight is not added and polyvinylpyrrolidone (with a molecular weight of 1300kDa) is used to replace the sodium hyaluronate with low molecular weight, the hardness of the microneedle is obviously reduced compared with that of example 3, so that the puncture rate is reduced, and the addition of a certain amount of sodium hyaluronate with low molecular weight is beneficial to improving the hardness of the microneedle body.

Example 8

The whitening active ingredients and the dosages of the whitening and freckle removing soluble microneedle patch carrying oxyresveratrol prepared in examples 5-6 are the same as those of example 3, but the mechanical properties are obviously poorer than those of example 3, the skin penetration rate of rats is lower than that of example 3, and the active ingredients are dissolved in the skin and absorbed by the dermis layer in smaller amounts than those of example 3, so that the whitening and freckle removing effects of the whitening and freckle removing soluble microneedle patch prepared in examples 5-6 can be expected to be poorer than those of example 3. Based on this, in the present embodiment, only the whitening and freckle removing soluble microneedle patches carrying resveratrol oxide prepared in examples 2 to 4 and comparative examples 1 to 3 were used for evaluation tests of whitening and freckle removing effects. The specific operation method comprises the following steps: selecting 3 women with more spots on the face, washing the face before sleeping every night, using the whitening and freckle-removing soluble microneedle patch carrying the oxidized resveratrol prepared in the embodiments 2-4 and the comparative examples 1-3 at the specified spot for 60d once a day for 15 minutes each time, measuring the color depth of the skin at the spots before 1d and 30d and 60d after use by using a functional spectrophotometer, calculating the color change of 30d and 60d after use relative to 1d before use, namely the color difference delta E, continuously testing for 3 times, and taking an average value. The results are shown in Table 2.

TABLE 2 comparison of color differences Δ E at different times

As can be seen from the results of table 2: the microneedle patch prepared in example 3 of the whitening and freckle removing soluble microneedle patch with oxidized resveratrol prepared in examples 2-4 has the best freckle removing effect, which shows that when other active substance components and the use amount are not changed, the freckle removing effect is increased and then reduced along with the increase of the loading amounts of the oxidized resveratrol and the resveratrol, and the reason for the reduction may be related to the reduction of the mechanical strength of microneedles. Compared with the whitening and freckle-removing soluble microneedle patch prepared in the comparative examples 1-3, which is not added with small molecular substances (alpha-arbutin, glutathione and soybean isoflavone) or is only added with two of the alpha-arbutin, the glutathione and the soybean isoflavone, the freckle removing effect is poor, and the compound of the oxyresveratrol and the resveratrol inclusion compound, the alpha-arbutin, the glutathione and the soybean isoflavone shows that the freckle removing effect is better.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The whitening and freckle-removing composition is characterized by consisting of oxyresveratrol, resveratrol and small molecular substances, wherein the small molecular substances consist of the following components in parts by weight: 40-50 parts of alpha-arbutin, 40-50 parts of glutathione and 1-3 parts of soybean isoflavone, wherein the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 1 to 10.

2. The whitening and freckle-removing composition according to claim 1, wherein the mass ratio of the oxidized resveratrol to the resveratrol is 1.5-2.5: 1; and/or the presence of a gas in the gas,

the mass ratio of the alpha-arbutin to the glutathione to the soybean isoflavone is 48-50: 2; and/or the presence of a gas in the gas,

the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 4 to 6.

3. Use of the whitening and freckle-removing composition according to claim 1 or 2 in preparing a whitening and freckle-removing skin care product or a whitening and freckle-removing cosmetic product.

4. A soluble microneedle patch for whitening and removing freckles is characterized by being prepared from a viscous liquid consisting of an inclusion liquid of oxidized resveratrol and resveratrol, a small molecular substance, a microneedle framework material and a first solvent;

5. The soluble microneedle patch for whitening and removing freckles according to claim 4, wherein the weight percentage of the oxidized resveratrol in the soluble microneedle patch for whitening and removing freckles is 1-3%, preferably 1.5-2.2%, and more preferably 2%.

6. The soluble microneedle patch for whitening and removing freckles according to claim 4, wherein the mass ratio of the oxidized resveratrol to the resveratrol is 1.8-2.2: 1; and/or the presence of a gas in the gas,

the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the small molecular substances is 1: 4-6; and/or the presence of a gas in the gas,

the mass ratio of the total mass of the oxidized resveratrol and the resveratrol to the microneedle skeleton material is 1: 30-50; and/or the presence of a gas in the gas,

the total mass fraction of the oxyresveratrol and the resveratrol in the inclusion liquid of the oxyresveratrol and the resveratrol is 0.2-0.8%, and the total mass fraction of the oxyresveratrol, the resveratrol and the hydroxypropyl-beta cyclodextrin is 3-6%; and/or the presence of a gas in the gas,

the microneedle framework material is composed of low-molecular-weight sodium hyaluronate, high-molecular-weight sodium hyaluronate, glycerol and hydroxypropyl cellulose, wherein the molecular weight of the low-molecular-weight sodium hyaluronate is 4500-5500, and the molecular weight of the high-molecular-weight sodium hyaluronate is 26-30 ten thousand; and/or the presence of a gas in the gas,

the first solvent is ethanol water solution; and/or the presence of a gas in the gas,

the solid content of the viscous liquid is 6-12%.

7. The soluble microneedle patch for whitening and removing freckles according to claim 6, wherein the weight percentages of the low molecular weight sodium hyaluronate, the high molecular weight sodium hyaluronate, glycerin and hydroxypropyl cellulose are as follows: 7-10% of low-molecular-weight sodium hyaluronate, 75-80% of high-molecular-weight sodium hyaluronate, 6-8% of glycerol and 6-8% of hydroxypropyl cellulose; and/or the presence of a gas in the gas,

the first solvent is an ethanol water solution with the mass fraction of 15-25%; and/or the presence of a gas in the gas,

the solid content of the viscous liquid is 6.9-8.1%.

8. The whitening and freckle-removing soluble microneedle patch according to any one of claims 4 to 7, wherein the preparation method of the inclusion liquid of the oxidized resveratrol and the resveratrol comprises the following steps: under the condition of stirring, adding a mixed solution of oxyresveratrol and resveratrol into a water solution of hydroxypropyl-beta cyclodextrin, and continuously stirring until complete inclusion is achieved; preferably, the mixed solution of oxyresveratrol and resveratrol has a mass fraction of 1-5%, and the solvent is an ethanol aqueous solution with a mass fraction of 50-70%; the mass fraction of the water solution of the hydroxypropyl-beta cyclodextrin is 3-6%.

9. The preparation method of the whitening and freckle-removing soluble microneedle patch as claimed in any one of claims 4 to 8, is characterized by comprising the following steps:

10. The preparation method of the soluble microneedle patch for whitening and removing freckles according to claim 9, wherein the centrifugal rotation speed is 3000-4000 r/min, and the centrifugal time is 3-5 min; and/or the presence of a gas in the gas,

the pressure of the vacuum environment is-0.07 MPa to-0.09 MPa; and/or the presence of a gas in the gas,

the thickness of the liquid which is coated on the microneedle mould by the viscous liquid is 1 +/-0.5 mm; and/or the presence of a gas in the gas,

the drying temperature is room temperature, the humidity is 15-25%, and the drying time is 12-20 h; and/or the presence of a gas in the gas,

the preparation method of the whitening and freckle-removing soluble microneedle patch further comprises the step of packaging the obtained whitening and freckle-removing soluble microneedle patch in a clean environment with the temperature of 18-25 ℃ and the humidity of 30-50% RH.