CN116211724A - Azelaic acid microemulsion and its preparation method and application - Google Patents

Abstract

The invention relates to the technical field of skin care products, in particular to an azelaic acid microemulsion and its preparation method and application. Azelaic acid microemulsion is mainly prepared from the following components in terms of mass percentage: 1% to 10% of azelaic acid, 10% to 50% of surfactant, 5% to 20% of cosurfactant, and 10% of oil phase %～20% and water; the surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400; the co-surfactant includes ethanol, butoxybis At least one of glycol and diethylene glycol monoethyl ether. In the present invention, azelaic acid is made into a microemulsion. On the premise of ensuring its use effect, the irritation of azelaic acid is reduced, and the transdermal absorption rate is improved. At the same time, it also has high safety, small particle size, easy preservation, convenient use, It has the advantages of good solubility, good compatibility, simple preparation, low cost, and favorable expansion of production.

Description

Azelaic acid microemulsion and its preparation method and application

technical field

The invention relates to the technical field of skin care products, in particular to an azelaic acid microemulsion and its preparation method and application.

Background technique

At present, in skin care products, the term "acid treatment" has quickly become a hot topic, and fruit acid, salicylic acid, vitamin A acid, etc. The heat continued to rise. Azelaic Acid is a saturated straight-chain C9 dicarboxylic acid with the following structure:

和20％乳膏/>

主要用于治疗痤疮、粉刺、青春痘，还具有美白淡斑、抗老育发、治疗色素类疾病等作用。与其它酸相比，壬二酸主要有以下优点：(1)对皮肤没有剥脱性，敏感肌也可使用；(2)早晚皆可使用，无需避光；(3)无耐药性，可以长期使用。更多的研究发现壬二酸不仅有祛痘控油效果，还有美白淡斑、治疗色素性皮肤疾病、抗老育发等作用。Azelaic acid was first discovered by Nazzaro-Porro and Passi in the 1970s, and its effectiveness was first observed in hyperpigmentation. Azelaic acid has been shown to act mainly through the following 3 pathways: inhibition of inflammation; inhibition of bacterial activity; inhibition of hyperactive keratinocytes. At present, there are mainly 15% gels on the market

and 20% cream />

It is mainly used to treat acne, pimples, and pimples. It also has the effects of whitening and lightening spots, anti-aging and hair growth, and treating pigmentary diseases. Compared with other acids, azelaic acid has the following advantages: (1) It has no exfoliation on the skin, and can be used on sensitive skin; (2) It can be used in the morning and evening, and there is no need to avoid light; (3) It has no drug resistance and can be used long-term use. More studies have found that azelaic acid not only has the effect of removing acne and controlling oil, but also has the effects of whitening and lightening spots, treating pigmented skin diseases, and anti-aging and hair growth.

At present, the use of azelaic acid mainly has the following two limitations: on the one hand, the solubility of azelaic acid in water and oil esters is low, it is difficult to find an ideal solvent, and azelaic acid needs a high concentration to play its role. It is acidic and irritating, and the concentration is difficult to increase, so the actual use effect is not ideal; on the other hand, azelaic acid has a high melting point and poor compatibility, so it is difficult to prepare according to ordinary procedures. Therefore, when the concentration of azelaic acid skin care products is low, the use effect is affected; when the concentration is high, the oily feeling is heavy, the air permeability is poor, and the irritation is strong, which affects the user experience and other problems.

In the prior art, the above-mentioned problems are mainly solved through the following aspects, and there are corresponding problems respectively: (1) Azelaic acid exists in the form of salt in aqueous solution by compounding alkaline substances and azelaic acid, thereby adding Increase the solubility of azelaic acid in water, but relevant studies have shown that the alkalinization of azelaic acid will affect its structure and reduce the use effect; (2) Use a variety of surfactants and a large number of co-surfactants to increase the solubility of azelaic acid , but the impact on the irritation and effectiveness of the product is not clear; (3) plant extracts are used to reduce the irritation of azelaic acid, but the preparation method is relatively complicated, which is not conducive to further scale-up production.

In view of this, the present invention is proposed.

Contents of the invention

An object of the present invention is to provide azelaic acid microemulsion, which has higher bioavailability, safety and lower skin irritation.

Another object of the present invention is to provide a preparation method of azelaic acid microemulsion.

Another object of the present invention is to provide the application of azelaic acid microemulsion in the preparation of skin care products.

In order to realize the above-mentioned purpose of the present invention, special adopt following technical scheme:

Azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

Azelaic acid 1%-10%, surfactant 10%-50%, co-surfactant 5%-20%, oil phase 10%-20% and water;

The surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400;

The co-surfactant includes at least one of ethanol, butoxydiethylene glycol and diethylene glycol monoethyl ether.

In a particular embodiment of the invention, the oil phase comprises isopropyl myristate.

In a specific embodiment of the present invention, the mass ratio of the surfactant to the co-surfactant is (2-4):1.

In a specific embodiment of the present invention, the mass ratio of the mass sum of the surfactant and the co-surfactant to the oil phase is 9:1˜3:7.

In a specific embodiment of the present invention, the azelaic acid microemulsion is mainly made of the following components by mass percentage:

Azelaic acid 1%-10%, polyoxyethylene castor oil 2%-5%, PEG-40 hydrogenated castor oil 1%-5%, polyethylene glycol 400 10%-40%, ethanol 2%-5%, 5% to 10% of butoxydiethylene glycol, 1% to 3% of diethylene glycol monoethyl ether, 10% to 20% of isopropyl myristate and water.

In a specific embodiment of the present invention, in the surfactant, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 is 1:(1～2):(5 ~15).

In a specific embodiment of the present invention, in the co-surfactant, the mass ratio of diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol is 1:(2～4):(2 ~4).

The present invention also provides a preparation method of any one of the above-mentioned azelaic acid microemulsions, comprising the steps of:

The components are mixed in proportion to obtain the azelaic acid microemulsion.

In a specific embodiment of the present invention, the preparation method includes the following steps:

(a) uniformly mixing the surfactant, the co-surfactant and the oil phase to obtain a transparent liquid;

(b) Adding azelaic acid into the transparent liquid, stirring until dissolved, then adding water, stirring to obtain a transparent solution with opalescence.

The present invention also provides the application of any one of the above azelaic acid microemulsions in the preparation of skin care products.

Compared with prior art, the beneficial effect of the present invention is:

(1) The present invention can improve the bioavailability by adopting a certain ratio of surfactant and co-surfactant; adopt microemulsification technology to completely dissolve azelaic acid, which has high safety and significantly reduces skin irritation; the product The quality is stable, it is a transparent liquid, it is not easy to change color, and it is easy to store, and the product does not contain any suspension thickener, so the stability is higher; the particle size of the azelaic acid microemulsion of the present invention is small, and the transdermal efficiency is significantly improved.

(2) In the present invention, azelaic acid is made into a microemulsion. Under the premise of ensuring its use effect, the irritation of azelaic acid is reduced, the transdermal absorption rate is improved, and it also has high safety, small particle size, easy storage, The invention has the advantages of convenient use, good solubility, good compatibility, simple preparation, low cost, and favorable expansion of production.

(3) In the present invention, azelaic acid is made into a microemulsion, which can achieve a higher transdermal absorption rate at a relatively low concentration, improve stability and safety, and bring good news to patients with acne and other skin diseases. Realize higher business value.

Description of drawings

In order to more clearly illustrate the specific implementation of the present invention or the technical solutions in the prior art, the following will briefly introduce the accompanying drawings that need to be used in the specific implementation or description of the prior art. Obviously, the accompanying drawings in the following description The drawings show some implementations of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

Fig. 1 is the pseudo ternary phase diagram when Km is in different situations in the embodiment of the present invention; wherein, (A) Km=2:1, (B) Km=3:1, (C) Km=4:1 ;

Fig. 2 is the schematic diagram of the variation of the electrical conductivity of the azelaic acid microemulsions of Examples 8 to 14 of the present invention with water content;

Fig. 3 is the photo of the azelaic acid microemulsion sample of the embodiment of the present invention 22;

Fig. 4 shows the steady-state penetration of the azelaic acid microemulsion of Example 22 of the present invention, the products of Comparative Example 1 and Comparative Example 2.

Detailed ways

The technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific embodiments, but those skilled in the art will understand that the embodiments described below are some of the embodiments of the present invention, rather than all of them. It is only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

Azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

Azelaic acid 1%-10%, surfactant 10%-50%, co-surfactant 5%-20%, oil phase 10%-20% and water;

The surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400;

The co-surfactant includes at least one of ethanol, butoxydiethylene glycol and diethylene glycol monoethyl ether.

As in different embodiments, in terms of mass percentage, the amounts of each component in the azelaic acid microemulsion can be exemplified as follows:

The amount of azelaic acid can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.;

The amount of surfactant can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% etc.;

The consumption of cosurfactant can be 5%, 8%, 10%, 12%, 15%, 18%, 20% etc.;

The amount of oil phase can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

In actual operation, the water may be purified water.

The characteristics of microemulsions include: (1) isotropic transparent liquid, thermodynamically stable, filterable and sterilizable, and easy to preserve; (2) mostly formed spontaneously without external force, simple process, easy to prepare, and stable quality; ( 3) Through the solubilization of the oil phase of the inner core and the hydrocarbon chain of the surfactant, the solubility is increased and the surface tension is reduced; (4) The particle size of the microemulsion is small and uniform, and the dispersion is good, which can increase the permeability of the membrane , to promote absorption and increase its bioavailability. The present invention uses certain surfactants and co-surfactants to make azelaic acid into a microemulsion, and on the premise of ensuring its use effect, reduces the irritation of azelaic acid, improves the transdermal absorption rate, and has high safety , small particle size, easy to store, convenient to use; good solubility, good compatibility, simple preparation, low cost, beneficial to expand production and the like.

In a particular embodiment of the invention, the oil phase comprises isopropyl myristate.

The present invention adopts isopropyl myristate (IPM) as the oil phase, on the one hand, it has good solubility to azelaic acid, on the other hand, it can be compounded with surfactant and co-surfactant, while taking into account the guarantee of microemulsion While ensuring the solubility of azelaic acid in the system, the particle size and stability are guaranteed.

The present invention investigates the solubility of azelaic acid in different oil phases and surfactants, and the test results are shown in Table 1.

Table 1 Solubility of azelaic acid in different substances

It can be seen from the above that the solubility of azelaic acid in different substances is as follows:

Oil phase: IPM > caprylic capric triglyceride > isooctyl palmitate;

Surfactant: PEG-400>PEG-40 hydrogenated castor oil>polyoxyethylene castor oil;

Co-surfactants: ethanol > diethylene glycol monoethyl ether > butoxydiethylene glycol > propylene glycol.

PEG-400 and PEG-40 hydrogenated castor oil have relatively good solubility for azelaic acid, and the highest historical usage is also high, but if only PEG-400 and PEG-40 hydrogenated castor oil is used without adding polyoxyethylene castor oil When using sesame oil, the obtained azelaic acid microemulsion will be unstable and easy to separate during the experimental verification.

In a specific embodiment of the present invention, the mass ratio of the surfactant to the co-surfactant is (2-4):1.

As in different implementations, the mass ratio of the surfactant to the co-surfactant can be exemplarily 2:1, 2.5:1, 3:1, 3.5:1, 4:1 and so on.

In a specific embodiment of the present invention, the mass ratio of the mass sum of the surfactant and the co-surfactant to the oil phase is 9:1˜3:7.

As in different embodiments, the mass ratio of the mass sum of the surfactant and the co-surfactant to the oil phase can be exemplarily 9:1, 8:2, 7:3, 6: 4, 5:5, 4:6, 3:7, etc.

In a specific embodiment of the present invention, the azelaic acid microemulsion is mainly made of the following components by mass percentage:

Azelaic acid 1%-10%, polyoxyethylene castor oil 2%-5%, PEG-40 hydrogenated castor oil 1%-5%, polyethylene glycol 400 10%-40%, ethanol 2%-5%, 5% to 10% of butoxydiethylene glycol, 1% to 3% of diethylene glycol monoethyl ether, 10% to 20% of isopropyl myristate and the balance of water.

As in different embodiments, in terms of mass percentage, the amounts of each component in the azelaic acid microemulsion can be exemplified as follows:

The amount of azelaic acid can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.;

The consumption of polyoxyethylene castor oil can be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% etc.;

The consumption of PEG-40 hydrogenated castor oil can be 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% etc.;

The consumption of polyethylene glycol 400 can be 10%, 15%, 20%, 25%, 30%, 35%, 40% etc.;

The amount of ethanol can be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.;

The amount of butoxydiethylene glycol can be 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% etc.;

The consumption of diethylene glycol monoethyl ether can be 1%, 1.5%, 2%, 2.5%, 3% etc.;

The amount of isopropyl myristate can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

In the azelaic acid microemulsion of the present invention, polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, polyethylene glycol 400 and ethanol, butoxydiethylene glycol, diethylene glycol monoethyl ether are used simultaneously, which can Without adding any suspension thickener, a stable azelaic acid microemulsion system is formed, and the particle size of the azelaic acid microemulsion obtained is ensured to be small, thereby improving transdermal absorption efficiency.

In a specific embodiment of the present invention, in the surfactant, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 is 1:(1～2):(5 ~15), such as 1: (1.2 ~ 1.8): (8 ~ 12), further can be 1: 1.5: 10.

With fixed oil phase content and azelaic acid raw material content, three different surfactants were used to prepare a series of microemulsions with the same azelaic acid content. Storage (30°C) stability was investigated, and the results are shown in Table 2. The preparation of the specific microemulsion includes: weighing the oil phase and the surfactant to dissolve the azelaic acid to obtain a mixed solution, and then adding the mixed solution to water.

Table 2 The results of different surfactant ratios on the stability index of azelaic acid microemulsion

As in different embodiments, in the surfactant, the mass ratio of the polyoxyethylene castor oil to the PEG-40 hydrogenated castor oil can be exemplarily 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, etc.; the mass ratio of the polyoxyethylene castor oil to the polyethylene glycol 400 can be exemplarily 1:5, 1:6, 1: 7. 1:8, 1:9, 1:10, etc.

In a specific embodiment of the present invention, in the co-surfactant, the mass ratio of diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol is 1:(2～4):(2 ~4), such as 1:(2.5~3.5):(2.5~3.5), further can be 1:3:3.

With fixed oil phase content and azelaic acid raw material content, three different co-surfactants were used to prepare a series of microemulsions with the same azelaic acid content. Thermal storage (30°C) stability was investigated, and the results are shown in Table 3. The preparation of the specific microemulsion includes: weighing the oil phase and co-surfactant to dissolve azelaic acid to obtain a mixed solution, and then adding the mixed solution to water.

Table 3 The results of different co-surfactant ratios on the stability index of azelaic acid microemulsion

As in different embodiments, in the co-surfactant, the mass ratio of the diethylene glycol monoethyl ether to the ethanol can be 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, etc.; the mass ratio of the diethylene glycol monoethyl ether to the butoxydiethylene glycol can be 1:2, 1 : 2.2, 1: 2.5, 1: 2.8, 1: 3, 1: 3.2, 1: 3.5, 1: 3.8, 1: 4, etc.

The present invention also provides a preparation method of any one of the above-mentioned azelaic acid microemulsions, comprising the steps of:

The components are mixed in proportion to obtain the azelaic acid microemulsion.

In a specific embodiment of the present invention, the preparation method includes the following steps:

(a) uniformly mixing the surfactant, the co-surfactant and the oil phase to obtain a transparent liquid;

(b) Adding azelaic acid into the transparent liquid, stirring until dissolved, then adding water, stirring to obtain a transparent solution with opalescence.

In a specific embodiment of the present invention, in step (a), the surfactant and the co-surfactant can be mixed in proportion in advance, heated to 60-65°C, stirred evenly, and kept stirring for more than 0.5h until It is clear and translucent, and it is a mixed surfactant (Smix) that is stored at room temperature for later use; then the oil phase is mixed with the mixed surfactant in proportion, and stirred at 400-600 rpm for more than 10 minutes to obtain a transparent liquid.

In a specific embodiment of the present invention, in step (b), after adding azelaic acid, stir at 60-65° C. at 400-600 rpm until the azelaic acid dissolves.

In actual operation, in step (b), the water is added dropwise; then stirred at 400-600 rpm to form a clear and transparent solution with light blue opalescence, which is the azelaic acid microemulsion .

The present invention also provides the application of any one of the above azelaic acid microemulsions in the preparation of skin care products.

In a specific embodiment of the present invention, the skin care products include acne-removing products (azelaic acid microemulsion gel), whitening and blemish-relieving products (azelaic acid whitening and blemish-reducing essence), anti-aging and hair-growing products (15% azelaic acid At least one of diacid compound 5% minoxidil) and the like.

Examples 1-7

Embodiments 1 to 7 provide azelaic acid microemulsions and preparation methods thereof. The raw material components of azelaic acid microemulsions in each embodiment are shown in Table 4. The preparation method includes the following steps:

(1) Mix polyoxyethylene castor oil, PEG-400, PEG-40 hydrogenated castor oil, diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol in proportion, heat to 60-65°C, and magnetically Stir and mix, last for 0.5h until clear and translucent, store at room temperature for later use, called mixed surfactant (Smix);

(2) Weigh the oil phase IPM (oil) in proportion and mix it with the mixed surfactant Smix, and stir magnetically at 500rpm for 10min;

(3) Adding azelaic acid to the mixed material obtained in step (2), 60～65°C, 500rpm magnetic stirring is in a completely dissolved state;

(4) Add purified water dropwise to the material obtained in step (3), and magnetically stir to form a clear and transparent solution with light blue opalescence to obtain azelaic acid microemulsion.

In embodiment 1～7, surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400) and co-surfactant (ethanol, butoxydiethylene glycol and diethylene glycol monoethyl ether ) mass ratio Km=2:1; in the surfactant, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400 is 1:1.5:10; diethylene glycol in the co-surfactant The mass ratio of monoethyl ether, ethanol and butoxydiethylene glycol is 1:3:3.

Table 4 Raw material composition information of different azelaic acid microemulsions

Note: when oil:Smix=8:2 and 9:1, azelaic acid is partially insoluble

Embodiment 8-14

Embodiments 8 to 14 provide azelaic acid microemulsions and preparation methods thereof. The raw material components of azelaic acid microemulsions in each embodiment are shown in Table 5. The preparation methods include the following steps:

(1) Mix polyoxyethylene castor oil, PEG-400, PEG-40 hydrogenated castor oil, diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol in proportion, heat to 60-65°C, and magnetically Stir and mix, last for 0.5h until clear and translucent, store at room temperature for later use, called mixed surfactant (Smix);

(2) Weigh the oil phase IPM (oil) in proportion and mix it with the mixed surfactant Smix, and stir magnetically at 500rpm for 10min;

(3) Adding azelaic acid to the mixed material obtained in step (2), 60～65°C, 500rpm magnetic stirring is in a completely dissolved state;

(4) Add purified water dropwise to the material obtained in step (3), and magnetically stir to form a clear and transparent solution with light blue opalescence to obtain azelaic acid microemulsion.

In embodiment 8～14, surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400) and co-surfactant (ethanol, butoxy diglycol and diethylene glycol monoethyl ether ) mass ratio Km=3:1; in the surfactant, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400 is 1:1.5:10; diethylene glycol in the co-surfactant The mass ratio of monoethyl ether, ethanol and butoxydiethylene glycol is 1:3:3.

Table 5 Raw material composition information of different azelaic acid microemulsions

Examples 15-21

Examples 15-21 provide azelaic acid microemulsions and preparation methods thereof. The raw material components of azelaic acid microemulsions in each example are shown in Table 6. The preparation methods include the following steps:

(1) Mix polyoxyethylene castor oil, PEG-400, PEG-40 hydrogenated castor oil, diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol in proportion, heat to 60-65°C, and magnetically Stir and mix, last for 0.5h until clear and translucent, store at room temperature for later use, called mixed surfactant (Smix);

(2) Weigh the oil phase IPM (oil) in proportion and mix it with the mixed surfactant Smix, and stir magnetically at 500rpm for 10min;

(3) Adding azelaic acid to the mixed material obtained in step (2), 60～65°C, 500rpm magnetic stirring is in a completely dissolved state;

(4) Add purified water dropwise to the material obtained in step (3), and magnetically stir to form a clear and transparent solution with light blue opalescence to obtain azelaic acid microemulsion.

In embodiment 15～21, surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400) and co-surfactant (ethanol, butoxy diglycol and diethylene glycol monoethyl ether ) mass ratio Km=4:1; in the surfactant, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and PEG-400 is 1:1.5:10; diethylene glycol in the co-surfactant The mass ratio of monoethyl ether, ethanol and butoxydiethylene glycol is 1:3:3.

Table 6 Raw material composition information of different azelaic acid microemulsions

Based on Smix, water phase and oil phase (oil), the optimal mixture experiment was designed. In Examples 1-21, the total concentration of the three components is 100%. Fig. 1 is the pseudo ternary phase diagram of the azelaic acid microemulsion prepared by the water titration method in Examples 1 to 21 of the present invention, compared with the microemulsion regions obtained in (A) to (C) phase diagrams in Fig. 1, The scope of selecting each component in (B) of Fig. 1 is as follows: Smix (20%～88%), water phase (0%～18%), oil (10%～74%), formed by Km=3:1 The microemulsion area is the largest.

Conductivity is an important property of microemulsions that are sensitive to structure. The conductivity of the azelaic acid microemulsions obtained in Examples 8-14 was tested, and the test results are shown in FIG. 2 . It can be seen from Fig. 2 that the electrical conductivity of the azelaic acid microemulsions of Examples 8-14 deviated from the original straight line with the increase of water content, and the trend slowed down until reaching the maximum value.

Examples 22-24

Examples 22 to 24 provide azelaic acid microemulsions and preparation methods thereof. The raw material components of azelaic acid microemulsions in each example are shown in Table 7. The preparation methods include the following steps:

(1) Mix polyoxyethylene castor oil, PEG-400, PEG-40 hydrogenated castor oil, diethylene glycol monoethyl ether, ethanol, butoxydiethylene glycol and IPM in proportion, and heat to 60-65°C , 500rpm magnetic stirring for 30min, until a transparent liquid is obtained;

(2) Add azelaic acid to the transparent liquid obtained in step (1), and magnetically stir at 60-65° C. and 500 rpm to be in a completely dissolved state;

(3) Add purified water dropwise to the material obtained in step (2), and magnetically stir to form a clear and transparent solution with light blue opalescence to obtain azelaic acid microemulsion.

Table 7 Raw material composition information of different azelaic acid microemulsions

Comparative example 1

Comparative example 1 is quality moisturizing 15% azelaic acid cleansing gel.

Comparative example 2

Comparative example 2 refers to the method of Example 10 in CN111544381A to prepare the corresponding composition.

Experimental example 1

At 25°C, the pH, electrical conductivity and particle size of the products obtained in Examples 22 to 24 and Comparative Examples 1 to 2 were tested, and tested respectively at a temperature of 2 to 8°C, a relative humidity of 65%, a temperature of 30°C, The relative humidity was 65%, and the physical stability of the azelaic acid microemulsion formulation was evaluated for 30 days. The test results are shown in Table 8.

Table 8 The property evaluation results of different products

It can be seen from Table 8 that the azelaic acid microemulsions of Examples 22 to 24 of the present invention have stable pH and particle size, and there is no obvious layering or precipitation after being placed for 30 days, which shows that the azelaic acid microemulsions of the present invention have good stability, which is comparable to that of the azelaic acid microemulsion of the present invention. The ratio is smaller than the particle size. Figure 3 is a photo of the azelaic acid microemulsion sample of Example 22 of the present invention. It can be seen from the figure that the azelaic acid microemulsion of the present invention is a colorless, clear and transparent liquid with light blue opalescence, no layering and no precipitation .

Experimental example 2

security test

Explore the azelaic acid microemulsion of embodiment 22 and the product of comparative example 1 and 2 to skin irritation, concrete method is as follows:

12 healthy mice that had adapted to the environment were divided into 3 groups, 4 mice in each group, and the stimulation experiment was carried out for 14 days. Before the start of the test, the hair on both sides of the back and spine close to the skin was cut off, and the range of hair removal was about 3cm×3cm for each piece. Every group gets respectively the sample 0.5mL of embodiment 22, or comparative example 1, comparative example 2 and places it on the gauze, and then places it on the skin of the size of 2.5cm * 2.5cm, and calculates the average score of every animal every day according to the following formula, with Table 9 judges the intensity of skin irritation, judges the irritation according to the scoring grades in Table 10, and Table 11 shows the skin irritation test results of the products of Example 22 and Comparative Examples 1-2.

Table 9 Skin Irritation Score

stimulus response score/point erythema: no erythema 0 barely visible 1 moderate erythema 2 severe erythema 3 Purple erythema with eschar formation 4 Edema: no edema 0 barely visible 1 Mild edema (clearly outlined skin bulges) 2 Moderate edema (skin swelling about 1mm) 3 Severe edema (skin bulge exceeding 1mm, expanding in scope) 4

Table 10 Skin Irritation Intensity Grading

strength average score/point non-irritating 0～＜0.5 mild irritant 0.5～＜2.0 Moderate irritation 2.0～＜6.0 intensity irritant 6.0～8.0

Table 11 Skin irritation test results

sample erythema edema total score irritant Comparative example 1 0.61 0.14 0.75 mild irritant Comparative example 2 0.38 0 0.38 non-irritating Example 22 0.34 0 0.34 non-irritating

From the experimental data in Table 11, it can be seen that Comparative Example 1 is judged as mild irritation; Example 22 and Comparative Example 2 are non-irritating. It can be known that the azelaic acid microemulsion of the present invention has good safety.

In Vitro Penetration Test

The modified Franz diffusion cell was used for in vitro transdermal experiment, and the receiving medium was phosphate buffer (pH=7.4), and the products of Example 22 were compared with the products of Comparative Examples 1-2.

Fix the treated isolated rat abdominal skin between the supply pool and the receiving pool, slowly add 1mL of different samples to the skin surface in the supply chamber, and take it out and receive it at 0.5h, 1h, 2h, 4h, 6h, and 8h. 0.5mL of solution (an equal amount of phosphate buffer was added after each sampling). The obtained samples were diluted with mobile phase, and the content of azelaic acid was determined by HPLC (parallel 3 times). The test results are shown in Figure 4. It can be seen from Figure 4 that the azelaic acid microemulsion of Example 22 of the present invention exhibits a higher transdermal absorption effect, indicating that the present invention combines certain surfactants and co-surfactants with azelaic acid and Made into microemulsion to achieve higher transdermal absorption.

The embodiments of the present invention all have acne-removing effect after testing, and there is a sense of heat but basically no irritation such as redness, swelling, itching and pain.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, rather than limiting them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: It is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the technical solutions of the various embodiments of the present invention. scope.

Claims (10)

1. Azelaic acid microemulsion is characterized in that, mainly by the following components by mass percentage, make: Azelaic acid 1%-10%, surfactant 10%-50%, co-surfactant 5%-20%, oil phase 10%-20% and water; The surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400; The co-surfactant includes at least one of ethanol, butoxydiethylene glycol and diethylene glycol monoethyl ether. 2. Azelaic acid microemulsion according to claim 1, characterized in that, the oil phase comprises isopropyl myristate. 3. azelaic acid microemulsion according to claim 1, is characterized in that, the mass ratio of described tensio-active agent and described co-surfactant is (2～4): 1; Preferably, the mass ratio of the surfactant to the co-surfactant is (2.5-3.5):1. 4. azelaic acid microemulsion according to claim 1, is characterized in that, the mass ratio of the mass sum of described tensio-active agent and described co-surfactant to described oily phase is 9:1～3: 7. 5. azelaic acid microemulsion according to claim 1, is characterized in that, mainly is made by following component by mass percent: Azelaic acid 1%-10%, polyoxyethylene castor oil 2%-5%, PEG-40 hydrogenated castor oil 1%-5%, polyethylene glycol 400 10%-40%, ethanol 2%-5%, 5% to 10% of butoxydiethylene glycol, 1% to 3% of diethylene glycol monoethyl ether, 10% to 20% of isopropyl myristate and the balance of water. 6. azelaic acid microemulsion according to claim 1, is characterized in that, in described tensio-active agent, the mass ratio of described polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 is 1: (1~2): (5~15); Preferably, the mass ratio of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 is 1:(1.2-1.8):(8-12). 7. azelaic acid microemulsion according to claim 1, is characterized in that, in described tensio-active agent, in described cosurfactant, described diethylene glycol monoethyl ether, ethanol and butoxyl The mass ratio of diethylene glycol is 1:(2~4):(2~4); Preferably, the mass ratio of diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol is 1:(2.5-3.5):(2.5-3.5). 8. The preparation method of the azelaic acid microemulsion described in any one of claims 1 to 7, is characterized in that, comprises the steps: The components are mixed in proportion to obtain the azelaic acid microemulsion. 9. the preparation method of azelaic acid microemulsion according to claim 8, is characterized in that, comprises the steps: (a) uniformly mixing the surfactant, the co-surfactant and the oil phase to obtain a transparent liquid; (b) Adding azelaic acid into the transparent liquid, stirring until dissolved, then adding water, stirring to obtain a transparent solution with opalescence. 10. Application of the azelaic acid microemulsion described in any one of claims 1 to 7 in the preparation of skin care products.

Images