Azelaic acid microemulsions, methods of making and using same

Abstract

This invention relates to the field of skincare product technology, and in particular to an azelaic acid microemulsion, its preparation method, and its application. The azelaic acid microemulsion is mainly prepared from the following components by mass percentage: 1%–10% azelaic acid, 10%–50% surfactant, 5%–20% co-surfactant, 10%–20% oil phase, and water; the surfactant includes at least one selected from polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and polyethylene glycol 400; the co-surfactant includes at least one selected from ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether. This invention prepares azelaic acid as a microemulsion, reducing its irritation and improving transdermal absorption while ensuring its effectiveness. It also offers advantages such as high safety, small particle size, easy storage, convenient use, good solubility, good compatibility, simple preparation, low cost, and ease of large-scale production.

Description

Technical Field

[0001] This invention relates to the field of skincare product technology, and in particular to an azelaic acid microemulsion, its preparation method, and its application. Background Technology

[0002] Currently, the term "acid peeling" has rapidly become a hot topic in skincare products, with glycolic acid, salicylic acid, and retinoic acid becoming popular choices. Azelaic acid, as one of the preferred topical treatments for rosacea, continues to gain attention. Azelaic acid is a saturated, straight-chain C9 dicarboxylic acid, with the structure shown below:

[0003]

[0004] Azelaic acid was first discovered by Nazzaro-Porro and Passi in the 1970s, and its effectiveness was first observed in pigmentation. It has been shown to work primarily through three pathways: inhibition of inflammation; inhibition of bacterial activity; and inhibition of overactive keratinocytes. Currently, 15% gels are mainly available on the market. and 20% cream It is mainly used to treat acne, pimples, and blackheads, and also has the effects of whitening and fading spots, anti-aging and hair growth, and treating pigmentation diseases. Compared with other acids, azelaic acid has the following advantages: (1) It does not exfoliate the skin and can be used by sensitive skin; (2) It can be used in the morning and evening without avoiding light; (3) It does not cause drug resistance and can be used for a long time. 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 fading spots, treating pigmentation diseases, anti-aging and hair growth.

[0005] Currently, the use of azelaic acid faces two main limitations: Firstly, azelaic acid has low solubility in water and oils, making it difficult to find an ideal solvent. Furthermore, it requires high concentrations to be effective, and its acidic nature and strong irritant properties make it difficult to increase the concentration, resulting in less than ideal practical effects. Secondly, azelaic acid has a high melting point and poor compatibility, making it difficult to prepare using conventional procedures. Therefore, azelaic acid skincare products suffer from problems such as low concentrations affecting efficacy, and high concentrations resulting in a heavy, oily feel, poor breathability, and strong irritation, negatively impacting the user experience.

[0006] The existing technologies mainly address the above problems through the following aspects, each with its own problems: (1) By compounding alkaline substances with azelaic acid, azelaic acid can exist in the form of salt in aqueous solution, thereby increasing the solubility of azelaic acid in water. However, relevant studies have shown that alkalization of azelaic acid can affect its structure and reduce its effectiveness. (2) Various surfactants and a large amount of co-surfactants are used to increase the solubility of azelaic acid, but the impact on the irritation and effectiveness of the product is unclear. (3) Plant extracts are used to reduce the irritation of azelaic acid, but the preparation method is relatively complicated and not conducive to further scale-up production.

[0007] In view of this, the present invention is hereby proposed. Summary of the Invention

[0008] One object of the present invention is to provide azelaic acid microemulsions with higher bioavailability, safety and lower skin irritation.

[0009] Another object of the present invention is to provide a method for preparing azelaic acid microemulsion.

[0010] Another object of the present invention is to provide the application of azelaic acid microemulsion in the preparation of skin care products.

[0011] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0012] Azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

[0013] Azelaic acid 1%–10%, surfactant 10%–50%, co-surfactant 5%–20%, oil phase 10%–20%, and water;

[0014] The surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and polyethylene glycol 400;

[0015] The co-surfactant includes at least one of ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether.

[0016] In a specific embodiment of the present invention, the oil phase comprises isopropyl myristate.

[0017] In a specific embodiment of the present invention, the mass ratio of the surfactant to the co-surfactant is (2-4):1.

[0018] In a specific embodiment of the present invention, the mass ratio of the sum of the mass of the surfactant and the co-surfactant to the mass of the oil phase is 9:1 to 3:7.

[0019] In a specific embodiment of the present invention, the azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

[0020] Azelaic acid 1%–10%, polyoxyethylene castor oil 2%–5%, PEG-40 hydrogenated castor oil 1%–5%, polyethylene glycol 400 10%–40%, ethanol 2%–5%, butoxydiethylene glycol 5%–10%, diethylene glycol monoethyl ether 1%–3%, isopropyl myristate 10%–20%, and water.

[0021] In a specific embodiment of the present invention, the mass ratio of the polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 in the surfactant is 1:(1-2):(5-15).

[0022] In a specific embodiment of the present invention, the mass ratio of diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol in the co-surfactant is 1:(2-4):(2-4).

[0023] The present invention also provides a method for preparing any one of the above-described azelaic acid microemulsions, comprising the following steps:

[0024] The components are mixed in proportion to obtain the azelaic acid microemulsion.

[0025] In a specific embodiment of the present invention, the preparation method includes the following steps:

[0026] (a) The surfactant, co-surfactant and oil phase are mixed evenly to obtain a transparent liquid;

[0027] (b) Add azelaic acid to the transparent liquid, stir until dissolved, then add water and stir to obtain a transparent solution with an opalescent appearance.

[0028] This invention also provides the application of any of the above-described azelaic acid microemulsions in the preparation of skin care products.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] (1) By using a certain ratio of surfactants and co-surfactants, the bioavailability of the present invention can be improved; the azelaic acid is completely dissolved by microemulsion technology, which is highly safe and significantly reduces skin irritation; the product quality is stable, it is a transparent liquid, does not easily change color, is easy to store, and the product does not contain any suspending thickeners, so it is more stable; the azelaic acid microemulsion of the present invention has a small particle size and significantly improves transdermal efficiency.

[0031] (2) The present invention prepares azelaic acid into a microemulsion, which reduces the irritation of azelaic acid and improves the transdermal absorption rate while ensuring its effectiveness. It also has the advantages of high safety, small particle size, easy storage, convenient use, good solubility, good compatibility, simple preparation, low cost, and easy to expand production.

[0032] (3) The present invention makes azelaic acid into a microemulsion, which can achieve higher transdermal absorption rate at a relatively low concentration, improve stability and safety, and bring good news to patients with skin diseases such as acne, and realize higher commercial value. Attached Figure Description

[0033] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0034] Figure 1 In this embodiment of the invention, pseudo-ternary phase diagrams are shown for Km under different conditions; wherein, (A) Km = 2:1, (B) Km = 3:1, (C) Km = 4:1;

[0035] Figure 2 This is a schematic diagram showing the change in conductivity of the azelaic acid microemulsions in Examples 8-14 of the present invention as a function of water content.

[0036] Figure 3 A photograph of the azelaic acid microemulsion sample of Example 22 of this invention;

[0037] Figure 4 The steady-state permeation amount of the azelaic acid microemulsion of Example 22 of the present invention, and the products of Comparative Example 1 and Comparative Example 2. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0039] Azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

[0040] Azelaic acid 1%–10%, surfactant 10%–50%, co-surfactant 5%–20%, oil phase 10%–20%, and water;

[0041] The surfactant includes at least one of polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and polyethylene glycol 400;

[0042] The co-surfactant includes at least one of ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether.

[0043] In different embodiments, the amounts of each component in the azelaic acid microemulsion, by mass percentage, can be exemplarily as follows:

[0044] The dosage of azelaic acid can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.

[0045] The amount of surfactant used can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.

[0046] The dosage of co-surfactant can be 5%, 8%, 10%, 12%, 15%, 18%, 20%, etc.;

[0047] The amount of oil phase can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

[0048] In practice, the water can be purified water.

[0049] The characteristics of microemulsions include: (1) isotropic transparent liquid, thermodynamically stable, filterable and sterilizable, and easy to store; (2) mostly spontaneously formed, requiring no external work, simple process, easy to prepare, and stable quality; (3) solubility is increased and surface tension is reduced through the solubilization of the oil phase in the core and the hydrocarbon chain of the surfactant; (4) microemulsions have small and uniform particle size, good dispersibility, which can increase membrane permeability, promote absorption, and improve bioavailability. This invention uses certain surfactants and co-surfactants to prepare azelaic acid into microemulsions, ensuring its effectiveness while reducing the irritation of azelaic acid and improving transdermal absorption rate. It also has the advantages of high safety, small particle size, easy storage, convenient use, good solubility, good compatibility, simple preparation, low cost, and easy to scale up production.

[0050] In a specific embodiment of the present invention, the oil phase comprises isopropyl myristate.

[0051] This invention uses isopropyl myristate (IPM) as the oil phase, which has good solubility for azelaic acid and can be compounded with surfactants and co-surfactants. This ensures both the solubility of azelaic acid in the microemulsion system and the particle size and stability.

[0052] This invention investigates the solubility of azelaic acid in different oil phases and surfactants, and the test results are shown in Table 1.

[0053] Table 1. Solubility of azelaic acid in different substances

[0054]

[0055] As shown above, the solubility of azelaic acid in different substances is as follows:

[0056] Oil phase: IPM > Caprylic / Capric Triglyceride > Isooctyl Palmitate;

[0057] Surfactants: PEG-400 > PEG-40 hydrogenated castor oil > polyoxyethylene castor oil;

[0058] Co-surfactants: Ethanol > Diethylene glycol monoethyl ether > Butoxydiethylene glycol > Propylene glycol.

[0059] PEG-400 and PEG-40 hydrogenated castor oils have relatively good solubility in azelaic acid and have a high historical usage. However, if only PEG-400 and PEG-40 hydrogenated castor oils are used without the addition of polyoxyethylene castor oil, the resulting azelaic acid microemulsion will be unstable and prone to separation during the experimental verification.

[0060] In a specific embodiment of the present invention, the mass ratio of the surfactant to the co-surfactant is (2-4):1.

[0061] In different embodiments, the mass ratio of the surfactant to the co-surfactant can be, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, etc.

[0062] In a specific embodiment of the present invention, the mass ratio of the sum of the mass of the surfactant and the co-surfactant to the mass of the oil phase is 9:1 to 3:7.

[0063] In different embodiments, the mass ratio of the sum of the surfactant and the co-surfactant to the mass of the oil phase can be, for example, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, etc.

[0064] In a specific embodiment of the present invention, the azelaic acid microemulsion is mainly prepared from the following components by mass percentage:

[0065] Azelaic acid 1%–10%, polyoxyethylene castor oil 2%–5%, PEG-40 hydrogenated castor oil 1%–5%, polyethylene glycol 400 10%–40%, ethanol 2%–5%, butoxydiethylene glycol 5%–10%, diethylene glycol monoethyl ether 1%–3%, isopropyl myristate 10%–20%, and the balance being water.

[0066] In different embodiments, the amounts of each component in the azelaic acid microemulsion, by mass percentage, can be exemplarily as follows:

[0067] The dosage of azelaic acid can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.

[0068] The dosage of polyoxyethylene castor oil can be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.

[0069] The dosage of PEG-40 hydrogenated castor oil can be 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.

[0070] The dosage of polyethylene glycol 400 can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, etc.

[0071] The amount of ethanol used can be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.

[0072] The dosage of butoxydiethylene glycol can be 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, etc.

[0073] The dosage of diethylene glycol monoethyl ether can be 1%, 1.5%, 2%, 2.5%, 3%, etc.

[0074] The dosage of isopropyl myristate can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

[0075] The azelaic acid microemulsion of the present invention simultaneously employs polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, polyethylene glycol 400, as well as ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether. This enables the formation of a stable azelaic acid microemulsion system without the addition of any suspending thickener, and ensures that the resulting azelaic acid microemulsion has a fine particle size, thereby improving transdermal absorption efficiency.

[0076] In a specific embodiment of the present invention, the mass ratio of the polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 in the surfactant is 1:(1-2):(5-15), such as 1:(1.2-1.8):(8-12), and further, it can be 1:1.5:10.

[0077] With fixed oil phase content and azelaic acid raw material content, a series of microemulsions with the same azelaic acid content were prepared using three different surfactants. Their appearance, water miscibility, and stability under cold storage (2–8℃) and hot storage (30℃) were investigated. The results are shown in Table 2. The specific preparation of the microemulsions included: weighing the oil phase and surfactants, dissolving the azelaic acid to obtain a mixture, and then adding the mixture to water.

[0078] Table 2. Results of the effect of different surfactant ratios on the stability of azelaic acid microemulsions

[0079]

[0080] In different embodiments, the mass ratio of the polyoxyethylene castor oil to the PEG-40 hydrogenated castor oil in the surfactant can be, for example, 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, etc.; and the mass ratio of the polyoxyethylene castor oil to the polyethylene glycol 400 can be, for example, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc.

[0081] In a specific embodiment of the present invention, the mass ratio of diethylene glycol monoethyl ether, ethanol and butoxydiethylene glycol in the co-surfactant is 1:(2-4):(2-4), such as 1:(2.5-3.5):(2.5-3.5), and further, it can be 1:3:3.

[0082] With fixed oil phase content and azelaic acid raw material content, a series of microemulsions with the same azelaic acid content were prepared using three different co-surfactants. Their appearance, water miscibility, and stability under cold storage (2–8℃) and hot storage (30℃) were investigated. The results are shown in Table 3. The specific preparation of the microemulsions included: weighing the oil phase and co-surfactant to dissolve the azelaic acid to obtain a mixture, and then adding the mixture to water.

[0083] Table 3. Results of the effect of different proportions of co-surfactants on the stability of azelaic acid microemulsions

[0084]

[0085] In different embodiments, the mass ratio of the diethylene glycol monoethyl ether to the ethanol in the co-surfactant 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.

[0086] The present invention also provides a method for preparing any one of the above-described azelaic acid microemulsions, comprising the following steps:

[0087] The components are mixed in proportion to obtain the azelaic acid microemulsion.

[0088] In a specific embodiment of the present invention, the preparation method includes the following steps:

[0089] (a) The surfactant, co-surfactant and oil phase are mixed evenly to obtain a transparent liquid;

[0090] (b) Add azelaic acid to the transparent liquid, stir until dissolved, then add water and stir to obtain a transparent solution with an opalescent appearance.

[0091] In a specific embodiment of the present invention, in step (a), the surfactant and the co-surfactant can be mixed in advance in proportion, heated to 60-65°C, stirred evenly, and stirred continuously for more than 0.5 hours until clear and transparent, and placed at room temperature for later use, which is a mixed surfactant (Smix); 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.

[0092] In a specific embodiment of the present invention, in step (b), after adding azelaic acid, the mixture is stirred at 60-65°C and 400-600 rpm until the azelaic acid dissolves.

[0093] In actual operation, in step (b), the water is added dropwise; then the mixture is stirred at 400-600 rpm to form a clear and transparent solution with a light blue opalescence, which is the azelaic acid microemulsion.

[0094] This invention also provides the application of any of the above-described azelaic acid microemulsions in the preparation of skin care products.

[0095] In a specific embodiment of the present invention, the skin care product includes at least one of the following: acne treatment product (azelaic acid microemulsion gel), whitening and spot-fading product (azelaic acid whitening and spot-fading essence), and anti-aging and hair growth product (15% azelaic acid combined with 5% minoxidil).

[0096] Examples 1-7

[0097] Examples 1-7 provide azelaic acid microemulsions and their preparation methods. The raw material components of the azelaic acid microemulsions in each example are shown in Table 4. The preparation methods include the following steps:

[0098] (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℃, stir magnetically until well mixed, continue for 0.5h until clear and transparent, and place at room temperature for later use. This is called mixed surfactant (Smix).

[0099] (2) Weigh out the oil phase IPM (oil) and the mixed surfactant Smix according to the proportion and mix them. Stir magnetically at 500 rpm for 10 min.

[0100] (3) Add azelaic acid to the mixture obtained in step (2) and stir magnetically at 60-65°C and 500 rpm until completely dissolved;

[0101] (4) Add purified water dropwise to the material obtained in step (3) and stir magnetically to form a clear and transparent solution with light blue opalescence, thus obtaining azelaic acid microemulsion.

[0102] In Examples 1-7, the mass ratio Km of the surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400) to the co-surfactant (ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether) was 2:1; the mass ratio of the surfactant, polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400 was 1:1.5:10; and the mass ratio of the co-surfactant, diethylene glycol monoethyl ether, ethanol, and butoxydiethylene glycol was 1:3:3.

[0103] Table 4. Raw material composition information for different azelaic acid microemulsions

[0104]

[0105] Note: When oil:Smix = 8:2 and 9:1, some azelaic acid will remain undissolved.

[0106] Examples 8-14

[0107] Examples 8-14 provide azelaic acid microemulsions and their preparation methods. The raw material components of the azelaic acid microemulsions in each example are shown in Table 5. The preparation methods include the following steps:

[0108] (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℃, stir magnetically until well mixed, continue for 0.5h until clear and transparent, and place at room temperature for later use. This is called mixed surfactant (Smix).

[0109] (2) Weigh out the oil phase IPM (oil) and the mixed surfactant Smix according to the proportion and mix them. Stir magnetically at 500 rpm for 10 min.

[0110] (3) Add azelaic acid to the mixture obtained in step (2) and stir magnetically at 60-65°C and 500 rpm until completely dissolved;

[0111] (4) Add purified water dropwise to the material obtained in step (3) and stir magnetically to form a clear and transparent solution with light blue opalescence, thus obtaining azelaic acid microemulsion.

[0112] In Examples 8-14, the mass ratio Km of the surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400) to the co-surfactant (ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether) was 3:1; the mass ratio of the surfactant, polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400 was 1:1.5:10; and the mass ratio of the co-surfactant, diethylene glycol monoethyl ether, ethanol, and butoxydiethylene glycol was 1:3:3.

[0113] Table 5. Raw material composition information for different azelaic acid microemulsions

[0114]

[0115] Examples 15-21

[0116] Examples 15-21 provide azelaic acid microemulsions and their preparation methods. The raw material components of the azelaic acid microemulsions in each example are shown in Table 6. The preparation methods include the following steps:

[0117] (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℃, stir magnetically until well mixed, continue for 0.5h until clear and transparent, and place at room temperature for later use. This is called mixed surfactant (Smix).

[0118] (2) Weigh out the oil phase IPM (oil) and the mixed surfactant Smix according to the proportion and mix them. Stir magnetically at 500 rpm for 10 min.

[0119] (3) Add azelaic acid to the mixture obtained in step (2) and stir magnetically at 60-65°C and 500 rpm until completely dissolved;

[0120] (4) Add purified water dropwise to the material obtained in step (3) and stir magnetically to form a clear and transparent solution with light blue opalescence, thus obtaining azelaic acid microemulsion.

[0121] In Examples 15-21, the mass ratio Km of the surfactant (polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400) to the co-surfactant (ethanol, butoxydiethylene glycol, and diethylene glycol monoethyl ether) was 4:1; the mass ratio of the surfactant, polyoxyethylene castor oil, PEG-40 hydrogenated castor oil, and PEG-400 was 1:1.5:10; and the mass ratio of the co-surfactant, diethylene glycol monoethyl ether, ethanol, and butoxydiethylene glycol was 1:3:3.

[0122] Table 6. Raw material composition information for different azelaic acid microemulsions

[0123]

[0124]

[0125] An experimental study was conducted based on the design of the optimal mixture using Smix, aqueous phase, and oil phase. In Examples 1-21, the total concentration of the three components was 100%. Figure 1 The pseudo-ternary phase diagrams of azelaic acid microemulsions prepared by water titration in Examples 1-21 of this invention are shown for comparison. Figure 1 The microemulsion regions obtained from the (A) to (C) phase diagrams are as follows: Figure 1 The ranges for each component selected in (B) are as follows: Smix (20%–88%), aqueous phase (0%–18%), and oil (10%–74%). The microemulsion region formed when Km = 3:1 is the largest.

[0126] Electrical conductivity is an important property of microemulsions that is highly sensitive to their structure. The conductivity of the azelaic acid microemulsions obtained in Examples 8-14 was tested, and the results are shown in [the table below]. Figure 2 .from Figure 2 As can be seen from the data, the conductivity of the azelaic acid microemulsions in Examples 8-14 deviates from the original linear increase with increasing water content, and the trend slows down until it reaches its maximum value.

[0127] Examples 22-24

[0128] Examples 22-24 provide azelaic acid microemulsions and their preparation methods. The raw material components of the azelaic acid microemulsions in each example are shown in Table 7. The preparation methods include the following steps:

[0129] (1) Mix polyoxyethylene castor oil, PEG-400, PEG-40 hydrogenated castor oil, diethylene glycol monoethyl ether, ethanol, butoxydiethylene glycol and IPM in proportion, heat to 60-65℃, and magnetically stir at 500rpm for 30min to obtain a transparent liquid.

[0130] (2) Add azelaic acid to the transparent liquid obtained in step (1) and stir magnetically at 60-65°C and 500 rpm until completely dissolved;

[0131] (3) Add purified water dropwise to the material obtained in step (2) and stir magnetically to form a clear and transparent solution with light blue opalescence, thus obtaining azelaic acid microemulsion.

[0132] Table 7. Raw material composition information for different azelaic acid microemulsions

[0133]

[0134]

[0135] Comparative Example 1

[0136] Comparative Example 1 is a moisturizing 15% azelaic acid facial cleansing gel.

[0137] Comparative Example 2

[0138] Comparative Example 2 prepared the corresponding composition according to the method of Example 10 in Publication No. CN111544381A.

[0139] Experimental Example 1

[0140] The pH, conductivity, and particle size of the products obtained in Examples 22-24 and Comparative Examples 1-2 were tested at 25°C. The products were then stored for 30 days at temperatures of 2-8°C and 65% relative humidity, and at 30°C and 65% relative humidity, respectively, to evaluate the physical stability of the azelaic acid microemulsion formulations. The test results are shown in Table 8.

[0141] Table 8. Evaluation results of the properties of different products

[0142]

[0143] As shown in Table 8, the azelaic acid microemulsions of Examples 22-24 of the present invention have stable pH and particle size, and no obvious stratification or precipitation was observed after 30 days of storage, indicating that the azelaic acid microemulsions of the present invention have good stability and smaller particle size compared with the comparative examples. Figure 3 The image shows a photograph of the azelaic acid microemulsion sample of Example 22 of the present invention. As can be seen from the image, the azelaic acid microemulsion of the present invention is a colorless, clear, and transparent liquid with a pale blue opalescence, and it does not separate or precipitate.

[0144] Experiment Example 2

[0145] Security test

[0146] The skin irritation of the azelaic acid microemulsion of Example 22 and the products of Comparative Examples 1 and 2 was investigated using the following methods:

[0147] Twelve healthy mice that had adapted to the environment were divided into three groups of four for a 14-day stimulation experiment. Before the experiment, the hair on both sides of the spine on the back, close to the skin, was clipped, with each area measuring approximately 3cm x 3cm. For each group, 0.5mL of the sample from Example 22, or Comparative Example 1 and Comparative Example 2, was placed on gauze and then on a 2.5cm x 2.5cm area of ​​skin. The average score per animal per day was calculated using the following formula. Table 9 was used to determine the skin stimulation intensity, and Table 10 was used to determine the irritation level. Table 11 shows the skin irritation test results for the products of Example 22 and Comparative Examples 1-2.

[0148]

[0149] Table 9 Skin Irritation Response Scoring

[0150] erythema: No erythema 0 Barely visible 1 moderate erythema 2 Severe erythema 3 purplish-red erythema with eschar formation 4 Edema: No edema 0 Barely visible 1 Mild edema (skin is raised but the outline is clear) 2 Moderate edema (skin bulge approximately 1 mm) 3 Severe edema (skin bulges exceeding 1 mm, and the affected area is expanding). 4

[0151] Table 10 Skin Irritation Intensity Grading

[0152] Non-irritating 0～＜0.5 Mild irritation 0.5～＜2.0 moderate irritation 2.0～＜6.0 Intensive irritation 6.0～8.0

[0153] Table 11 Results of Skin Irritation Test

[0154] Comparative Example 1 0.61 0.14 0.75 Mild irritation Comparative Example 2 0.38 0 0.38 Non-irritating Example 22 0.34 0 0.34 Non-irritating

[0155] As shown in Table 11, Comparative Example 1 was determined to be mildly irritating; Example 22 and Comparative Example 2 were non-irritating. Therefore, the azelaic acid microemulsion of the present invention has excellent safety.

[0156] In vitro permeation test

[0157] In vitro transdermal experiments were conducted using a modified Franz diffusion cell with phosphate buffer (pH = 7.4) as the receiving medium. The products of Example 22 were compared with those of Comparative Examples 1 and 2.

[0158] The prepared isolated rat abdominal skin was fixed between the supply and receiving chambers. 1 mL of different samples were slowly added to the skin surface in the supply chamber. 0.5 mL of the receiving solution was collected at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h (an equal volume of phosphate buffer was added after each sampling). The obtained samples were diluted with the mobile phase, and the azelaic acid content was determined by HPLC (triple replicates). The test results are shown below. Figure 4 .from Figure 4As can be seen from the above, the azelaic acid microemulsion of Example 22 of the present invention exhibits a higher transdermal absorption effect, indicating that the present invention can achieve higher transdermal absorption by using certain surfactants and co-surfactants to compound azelaic acid and prepare a microemulsion.

[0159] All embodiments of the present invention have been tested and found to have acne-removing effects, with a warming sensation but virtually no redness, swelling, itching, pain, or other irritation.

[0160] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An azelaic acid microemulsion, characterized in that, It is prepared from the following components by mass percentage: 1%~10% azelaic acid, 10%~50% surfactant, 5%~20% co-surfactant, 10%~20% oil phase and water; The surfactant is polyoxyethylene castor oil, PEG-40 hydrogenated castor oil and polyethylene glycol 400 in a mass ratio of 1:1.5:

10. The co-surfactant is ethanol, butoxydiethylene glycol and diethylene glycol monoethyl ether in a mass ratio of 3:3:

1. The oil phase is isopropyl myristate; the mass ratio of the surfactant to the co-surfactant is (2~4):

1.

2. The azelaic acid microemulsion according to claim 1, characterized in that, The mass ratio of the surfactant to the co-surfactant is (2.5~3.5):

1.

3. The method for preparing azelaic acid microemulsion according to claim 1 or 2, characterized in that, The process includes the following steps: mixing the components in proportion to obtain the azelaic acid microemulsion.

4. The method for preparing azelaic acid microemulsion according to claim 3, characterized in that, The process includes the following steps: (a) mixing the surfactant, co-surfactant and oil phase evenly to obtain a transparent liquid; (b) adding azelaic acid to the transparent liquid, stirring until dissolved, then adding water and stirring to obtain a transparent solution with an opalescent appearance.

5. The use of the azelaic acid microemulsion according to claim 1 or 2 in the preparation of skin care products.

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