Azelaic acid gel and its preparation method and use

Abstract

The present invention belongs to the field of medicine, health care products and skin care products, and specifically relates to a kind of azelaic acid gel and its preparation method and use. The purpose of the present invention is to provide a kind of azelaic acid gel product with good product transparency, no drawing, no stickiness and refreshing. The azelaic acid gel of the present invention comprises the following components: azelaic acid, ammonium acryloyldimethyl taurate / VP copolymer, and solvent; the weight percentage of the components is as follows: 10-30% azelaic acid, 0.5-5% ammonium acryloyldimethyl taurate / VP copolymer, 60-90% solvent, and the sum of the weight percentages of the three is 100%. The azelaic acid gel of the present invention can achieve the purpose of treating or preventing acne and whitening skin care, and azelaic acid itself is antibacterial, and no additional preservatives need to be added. In particular, 1,3-propylene glycol can be stored at ultra-low temperature as a solvent, and no azelaic acid crystals are precipitated after being stored in a 10°C environment for more than half a year. The system is stable and can be used by people in cold areas in the north, providing a new choice for the public to treat and prevent acne or whiten.

Description

Technical Field

[0001] The invention belongs to the field of medicines, health products and skin care products, and specifically relates to azelaic acid gel and a preparation method and application thereof. Background Art

[0002] Azelaic acid, also known as azelaic acid, is a natural straight-chain saturated dicarboxylic acid containing 9 carbon atoms isolated from the culture medium of Pityrosporum ovale. Its molecular formula is HOOC-(CH2)7-COOH, its molecular weight is 188.22, and its structural formula is shown in Formula I. It has the appearance of white to slightly yellow monoclinic prisms, needle-shaped crystals or powder, and is easily soluble in hot water, alcohol and some polyols, and slightly soluble in cold water.

[0003]

[0004] Azelaic acid has the following pharmacological effects, but is not limited to them: a) Antibacterial effect: Azelaic acid can inhibit bacterial protein synthesis, directly inhibit and kill aerobic and anaerobic bacteria on the skin surface and in the hair follicles. At higher concentrations, it has a killing effect on Staphylococcus epidermidis, Pseudomonas aeruginosa, Proteus, Candida albicans, Propionibacterium acnes, etc. Its effect depends on pH. When the pH is low, it can quickly enter the cell to exert its antibacterial effect, and the amount of azelaic acid that penetrates into abnormal cells is greater than that of normal cells. It is often used as an external antibacterial agent. b) Regulating sebaceous gland function: Azelaic acid can competitively inhibit the action of 5-α reductase, inhibit the conversion of excessive androgens into dihydrotestosterone, and ultimately inhibit the excessive secretion of free fatty acids in the sebaceous glands. c) Prevent skin keratinization: It has an anti-keratinization effect on normal skin and acne-infected skin, reduces the synthesis of filamentous keratin, and prevents excessive keratinization of hair follicles. d) Treatment of pigmentation: Azelaic acid has a competitive inhibitory effect on tyrosinase in hyperfunctional melanocytes, reducing pigment synthesis, but does not inhibit pigment synthesis in normal pigment cells. On the other hand, it can destroy the respiratory chain of melanocyte mitochondria, inhibit the synthesis of cell DNA, and hinder the proliferation of abnormal melanocytes.

[0005] Based on the above pharmacological effects of azelaic acid, the inventors use it to remove acne, control oil, exfoliate, soften keratin, and treat pigmentation, so as to achieve the purpose of treating acne and / or whitening.

[0006] The existing azelaic acid gel mainly uses polyacrylate cross-linked polymer-6 as a thickener. The polyacrylate cross-linked polymer-6 powder is made to absorb water and thicken to form a gel, and then azelaic acid or azelaic acid complex is dissolved in 1,3-propylene glycol, and then added to the gel formed by polyacrylate cross-linked polymer-6. The azelaic acid gel structure formed by polyacrylate cross-linked polymer-6 as a thickener is unstable. At low temperatures, azelaic acid will precipitate from the gel structure to form crystals. Once azelaic acid precipitates and crystallizes, it will not penetrate into the skin, affecting the transdermal absorption of azelaic acid in the skin, and thus cannot play a role in treating and preventing acne. Therefore, it is not suitable for people in cold northern regions. Moreover, the product prepared using polyacrylate cross-linked polymer-6 as a thickener is not crystal clear, slightly foggy, has high viscosity, has a drawing phenomenon, and is sticky and not refreshing when used.

[0007] In this application context, the inventors of the present application provide a new azelaic acid gel product and a preparation method thereof. Summary of the invention

[0008] The first technical problem solved by the present invention is to provide a nonanedioic acid gel product which has good transparency, is not stringy, is not sticky, and is refreshing.

[0009] In order to achieve the above-mentioned purpose, the azelaic acid gel of the present invention comprises the following components: azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, and solvent; the weight percentages of the components are as follows: 10-30% azelaic acid, 0.5-5% ammonium acryloyldimethyltaurate / VP copolymer, and 60-90% solvent, and the sum of the weight percentages of the three is 100%.

[0010] Preferably, the azelaic acid gel comprises the following components in weight percentage: 10-25% azelaic acid, 0.5-5% ammonium acryloyldimethyltaurate / VP copolymer, and 60-90% solvent, and the sum of the weight percentages of the three is 100%.

[0011] Further preferably, the azelaic acid gel comprises the following components in weight percentage: 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25% azelaic acid, 0.5-5% ammonium acryloyldimethyltaurate / VP copolymer, and 60-90% solvent, and the sum of the three weight percentages is 100%.

[0012] Still further preferably, the azelaic acid gel comprises the following components in weight percentage: 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25% azelaic acid, 1-2% ammonium acryloyldimethyltaurate / VP copolymer, and 60-90% solvent, and the sum of the three weight percentages is 100%.

[0013] More preferably, the azelaic acid gel comprises the following components in weight percentage: 10-20% azelaic acid, 0.5-5% ammonium acryloyldimethyltaurate / VP copolymer, and 60-90% solvent, and the sum of the weight percentages of the three is 100%.

[0014] Still more preferably, the azelaic acid gel comprises the following components in weight percentage: 10-15% azelaic acid, 1-2% ammonium acryloyldimethyltaurate / VP copolymer, and 83-84% solvent, and the sum of the weight percentages of the three is 100%.

[0015] More preferably, the azelaic acid gel comprises the following components in weight percentage: 15% azelaic acid, 1.5% ammonium acryloyldimethyltaurate / VP copolymer, and 83.5% solvent, and the sum of the weight percentages of the three is 100%.

[0016] In the above technical scheme, the solvent is any one of 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol and other polyols, ethoxydiglycol, water, ethanol or any mixture thereof; preferably, the solvent is any one of 1,2-propylene glycol and 1,3-propylene glycol or any mixture thereof; most preferably, the solvent is 1,3-propylene glycol.

[0017] When 1,3-propylene glycol and 1,2-propylene glycol are mixed as the solvent, the weight ratio is 1,3-propylene glycol:1,2-propylene glycol=1-9:1-9.

[0018] Preferably, when 1,3-propylene glycol and 1,2-propylene glycol are mixed, the weight ratio includes but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, and 2:1.

[0019] When azelaic acid is dissolved in 1,3-propylene glycol or / and 1,2-propylene glycol as a solvent, the weight ratio of azelaic acid to the solvent is 1:2-10.

[0020] The azelaic acid gel prepared by using the above components uses ammonium acryloyldimethyltaurate / VP copolymer as a thickener, and any one of 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol and other polyols, ethoxydiglycol, water, ethanol or any mixture thereof is used as a solvent to dissolve the azelaic acid, so that the ammonium acryloyldimethyltaurate / VP copolymer is thickened to form a transparent gel, and the azelaic acid is fully dissolved in the gel system, so that the azelaic acid gel has the characteristics of good product transparency, no stringiness, no stickiness, and refreshing.

[0021] The azelaic acid gel of the present invention is a gel system obtained by mixing water with other solvents. When the amount of water added accounts for ≤8% of the total amount of the gel components, the gel system is stable at room temperature and no crystals are precipitated; when the amount of water added accounts for ≤4% of the total amount of the gel components, the gel system is stable at 0°C and no crystals are precipitated.

[0022] In particular, the use of 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerin, diglycerin and other polyols, ethoxydiglycol is a water-free gel product. The above solvents are used to dissolve azelaic acid to thicken the ammonium acryloyldimethyltaurate / VP copolymer to form a transparent gel, and the azelaic acid is fully dissolved in the gel system to obtain azelaic acid gel with good product transparency, no drawing, no stickiness, and refreshing characteristics.

[0023] The most special thing is that using 1,3-propylene glycol as the solvent can make the gel not easy to freeze at low temperatures, the gel structure is stable, and the temperature has little effect on it. It can be stored at ultra-low temperatures. Even if it is stored in a -10°C environment for more than half a year, there is still no precipitation of azelaic acid crystals. The system is stable. When people in cold northern regions use it, it will not affect the transdermal absorption of azelaic acid in the skin, and it can penetrate the skin very well.

[0024] On the basis of the above-mentioned gel, it also includes acceptable gel excipients and inevitable impurities, wherein the acceptable gel excipients are at least one of antioxidants, preservatives, penetration enhancers, moisturizers, thickeners, exfoliants, pH regulators, antibacterial agents and anti-inflammatory agents.

[0025] Furthermore, the antioxidant includes but is not limited to at least one of superoxide dismutase, ascorbic acid, tocopherol acetate, and butylated hydroxytoluene.

[0026] Furthermore, the preservative includes but is not limited to at least one of 1,2-hexanediol, 1,2-pentanediol, phenoxyethanol, caprylhydroxamic acid, parabens, o-cymene-5-ol, p-hydroxyacetophenone, and sorbic acid.

[0027] Furthermore, the penetration enhancer includes but is not limited to at least one of dipropylene glycol and azone.

[0028] Furthermore, the moisturizing agent includes but is not limited to at least one of urea, sodium hyaluronate and polysaccharide.

[0029] More preferably, the polysaccharide includes but is not limited to dextran.

[0030] Furthermore, the thickener includes but is not limited to at least one of polyquaternium-37, ammonium acryloyldimethyltaurate, and hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer.

[0031] Furthermore, the exfoliating agent includes but is not limited to at least one of α-hydroxy acid and its salts and esters, β-hydroxy acid and its salts and esters, and salicylic acid.

[0032] Furthermore, the pH adjuster includes but is not limited to at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, triethanolamine and arginine.

[0033] Furthermore, the antibacterial agent includes but is not limited to at least one of quaternary ammonium salt-73, isopentyl glycol, chlorhexidine diacetate, chlorhexidine digluconate, and hexamidine di(hydroxyethylsulfonate) salt.

[0034] Furthermore, the anti-inflammatory agent includes but is not limited to at least one of bisabolol, tea tree oil, dipotassium glycyrrhizinate and plant extracts, and the plant extracts include at least one extracted from purslane, oats, aloe vera, calendula, Centella asiatica, licorice, chamomile and mangosteen.

[0035] The second technical problem solved by the present invention is to provide a method for preparing the azelaic acid gel of the present invention, comprising the following steps:

[0036] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, and solvent by weight percentage;

[0037] B. The solvent is heated to 50-80° C., and the ammonium acryloyldimethyltaurate / VP copolymer is dispersed in the solvent to obtain gel A;

[0038] C. Heat the solvent to 50-80°C, add azelaic acid to the solvent, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0039] D. Add solution B to gel A, maintain the temperature at 50-80°C and stir to mix evenly, then cool to room temperature to obtain.

[0040] Further preferred:

[0041] Step B: heating the solvent to 60-65° C., dispersing the ammonium acryloyldimethyltaurate / VP copolymer in the solvent, and obtaining gel A.

[0042] Step C, heating the solvent to 60-65° C., adding azelaic acid to the solvent, stirring to completely dissolve the azelaic acid, and obtaining a transparent solution B.

[0043] Step D: Add solution B to gel A, stir and mix evenly while maintaining the temperature at 60-65° C., and then cool to room temperature to obtain the product.

[0044] In the above technical scheme, the solvent is at least one of 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol and other polyols, ethoxydiglycol, water, ethanol or any mixture thereof.

[0045] Preferably, the solvent is any one or any combination of 1,3-propylene glycol and / or 1,2-propylene glycol.

[0046] Preferably, the solvent is at least one of 1,3-propylene glycol and 1,2-propylene glycol;

[0047] Most preferably, the solvent is 1,3-propylene glycol.

[0048] Furthermore, when the solvent is a mixture of 1,3-propylene glycol and 1,2-propylene glycol, the weight ratio is 1,3-propylene glycol:1,2-propylene glycol=1-9:1-9.

[0049] Preferably, when the solvent is a mixture of 1,3-propylene glycol and 1,2-propylene glycol, the weight ratio includes but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, and 2:1.

[0050] In step B, the ratio of ammonium acryloyldimethyl taurate / VP copolymer to 1,3-propylene glycol is in the range of 0.5-10% of ammonium acryloyldimethyl taurate / VP copolymer and 15-25% of 1,3-propylene glycol; in step C, the ratio of azelaic acid to 1,3-propylene glycol is in the range of 10-30% of azelaic acid and 45-75% of 1,3-propylene glycol; and in steps B and C, the weight percentage of ammonium acryloyldimethyl taurate / VP copolymer, azelaic acid and 1,3-propylene glycol is 100%.

[0051] Most preferably, in step B, the weight ratio of ammonium acryloyldimethyl taurate / VP copolymer to 1,3-propylene glycol is 1.5% of ammonium acryloyldimethyl taurate / VP copolymer and 20% of 1,3-propylene glycol, and in step C, the weight ratio of azelaic acid to 1,3-propylene glycol is 15% of azelaic acid and 63.5% of 1,3-propylene glycol, and in steps B and C, the total weight percentage of ammonium acryloyldimethyl taurate / VP copolymer, azelaic acid and 1,3-propylene glycol is 100%.

[0052] When the azelaic acid gel of the present invention is prepared by using acceptable gelling agent excipients on the basis of the above technical solution, the preparation method comprises the following steps:

[0053] (1) Weighing azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, solvent, and acceptable gelling agent excipients according to weight percentage;

[0054] (2) heating the solvent to 50-80° C., dispersing the ammonium acryloyldimethyltaurate / VP copolymer and an acceptable thickener in the gelling agent auxiliary material in the solvent to obtain gel A;

[0055] (3) heating the solvent to 50-80° C., adding azelaic acid to the solvent, and stirring to completely dissolve the azelaic acid to obtain a transparent solution B;

[0056] (4) Add other acceptable gelling excipients to the solvent, stir and dissolve until solution C is obtained;

[0057] (5) adding solution B to gel A, stirring and mixing at a temperature of 50-80° C., and then cooling to room temperature to obtain gel D;

[0058] (6) Add solution C to gel D and stir to mix evenly.

[0059] Further preferred:

[0060] Step (2), heating the solvent to 60-65° C., dispersing the ammonium acryloyldimethyltaurate / VP copolymer in the solvent, and obtaining gel A.

[0061] Step (3), heating the solvent to 60-65°C, adding azelaic acid to the solvent, stirring to completely dissolve the azelaic acid, and obtaining a transparent solution B.

[0062] Step (5), adding solution B to gel A, stirring and mixing evenly while maintaining the temperature at 60-65, and then cooling to room temperature to obtain the product.

[0063] In the above technical solution, the solvent is at least one of 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol and other polyols, ethoxydiglycol, water, ethanol or any mixture thereof.

[0064] Preferably, the solvent is any one or any combination of 1,3-propylene glycol and / or 1,2-propylene glycol.

[0065] Preferably, the solvent is at least one of 1,3-propylene glycol and 1,2-propylene glycol.

[0066] Most preferably, the solvent is 1,3-propylene glycol.

[0067] Furthermore, when the solvent is a mixture of 1,3-propylene glycol and 1,2-propylene glycol, the weight ratio is 1,3-propylene glycol:1,2-propylene glycol=1-9:1-9.

[0068] Preferably, when the solvent is a mixture of 1,3-propylene glycol and 1,2-propylene glycol, the weight ratio includes but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, and 2:1. In step (2), the ratio of ammonium acryloyldimethyl taurate / VP copolymer to 1,3-propylene glycol is in the range of 0.5-10% of ammonium acryloyldimethyl taurate / VP copolymer and 15-25% of 1,3-propylene glycol; in step (3), the ratio of azelaic acid to 1,3-propylene glycol is in the range of 10-30% of azelaic acid and 45-75% of 1,3-propylene glycol; and in steps (2) and (3) (4), the weight percentage of ammonium acryloyldimethyl taurate / VP copolymer, azelaic acid, 1,3-propylene glycol and acceptable excipients is 100%.

[0069] Most preferably, in step (2), the weight ratio of ammonium acryloyldimethyl taurate / VP copolymer to 1,3-propylene glycol is 1.5% of ammonium acryloyldimethyl taurate / VP copolymer and 20% of 1,3-propylene glycol, and in step (3), the weight ratio of azelaic acid to 1,3-propylene glycol is 15% of azelaic acid and 63.5% of 1,3-propylene glycol, and in steps (2) and (3) (4), the weight percentage of ammonium acryloyldimethyl taurate / VP copolymer, azelaic acid, 1,3-propylene glycol and acceptable excipients is 100%.

[0070] The third technical problem solved by the present invention is to provide the use of the azelaic acid gel of the present invention in the preparation of medicines and skin care products for treating or preventing acne. In particular, the azelaic acid gel of the present invention is used in the preparation of medicines and skin care products with acne removal effects, oil control effects, exfoliation effects, and keratin softening effects. Since the azelaic acid gel of the present invention is easy for azelaic acid to be transdermally absorbed in the skin, it can penetrate the skin well and can greatly improve the cure rate of acne patients.

[0071] The fourth technical problem solved by the present invention is to provide the use of the azelaic acid gel of the present invention in the preparation of medicines and skin care products with whitening effects. In particular, the use of the azelaic acid gel of the present invention in the preparation of medicines and skin care products with the effect of improving pigmentation. Since the azelaic acid gel of the present invention is easy for azelaic acid to be transdermally absorbed in the skin, it can penetrate the skin well and can greatly improve the skin whitening effect of the user.

[0072] The inventors of the present invention have utilized polyols to prepare azelaic acid gel in a low-water system or even a water-free system. In particular, conventional thickeners achieve the purpose of thickening by dissolving in water and opening their molecular chains. However, the pH of the azelaic acid gel system is relatively low, and a thickener that is resistant to low pH and electrolytes is required. However, most thickeners are intolerant to low pH and electrolytes. Therefore, the inventors hope to create a low-water system or even a water-free system to dissolve azelaic acid. Ultimately, through multiple screening of low-water systems or even water-free systems and thickeners, the raw material composition and preparation process of the azelaic acid gel of the present invention were determined. The azelaic acid in the azelaic acid gel of the present invention is easily absorbed through the skin and can penetrate the skin well, thereby achieving the purpose of treating or preventing acne and whitening the skin. In addition, based on the antibacterial characteristics of azelaic acid itself, there is no need to add additional preservatives. Moreover, polyols such as 1,2-propylene glycol and 1,3-propylene glycol selected from numerous solvents can achieve the purpose of dissolving azelaic acid in an anhydrous system. In particular, 1,3-propylene glycol is not easy to freeze at low temperatures, has a stable gel structure, is minimally affected by temperature, and can be stored at ultra-low temperatures. Even if stored in a -10°C environment for more than half a year, no azelaic acid crystals are precipitated. The system is stable and can be used by people in cold northern regions, providing a new choice for the public to treat and prevent acne or whiten their skin. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 Skin red zone a value test result chart.

[0074] Figure 2 Skin oil content.

[0075] Figure 3 Skin stratum corneum cell exfoliation index.

[0076] Figure 4 Clinical Assessment - Comedonal count.

[0077] in, Figure 1-4 Significance marking method: “ns” indicates no significant difference, P ≥ 0.05; “*” indicates significant difference, 0.01 ≤ P < 0.05; “**”, 0.001 ≤ P < 0.01; “***”, P < 0.001.

[0078] Figure 5 Example of improvement from D0 to D28 in the red zone of subject 7 (Crosspolarized light source mode photo).

[0079] Figure 6 Improvement example of red zone D0 to D28 for subject 12 (Crosspolarized light source mode photo).

[0080] Figure 7Improvement example of red zone D0 to D28 for subject 19 (Crosspolarized light source mode photo).

[0081] Figure 8 Example of improvement of acne of subject 2 from D0 to D28 (Standard2 light source mode photo).

[0082] Fig. 9 14 subjects showed improvement in acne from D0 to D28 (Standard2 light source mode photos).

[0083] Fig.10 Improvement of acne on subject 27 from D0 to D28 (Standard2 light source mode photo). DETAILED DESCRIPTION

[0084] The following describes specific embodiments of the present invention but does not limit the present invention.

[0085] When the inventors of the present invention investigated the azelaic acid gel system, they found that most conventional thickeners are dissolved in water and their molecular chains are opened to thicken the gel system. However, the pH of the azelaic acid gel system is low, and a thickener that is resistant to low pH and electrolytes is required. However, most thickeners are intolerant to low pH and electrolytes. Currently, polyacrylate cross-linked polymer-6 is often used as a thickener. The polyacrylate cross-linked polymer-6 powder is made to absorb water and thicken to form a gel. Then, azelaic acid or azelaic acid complex is dissolved in 1,3-propylene glycol and then added to the gel formed by the polyacrylate cross-linked polymer-6. However, the azelaic acid gel structure formed by using the polyacrylate cross-linked polymer-6 as a thickener is unstable. At low temperatures, azelaic acid will precipitate from the gel structure to form crystals. Once azelaic acid precipitates and crystallizes, it will not penetrate into the skin, affecting the transdermal absorption of azelaic acid in the skin, and thus cannot play a role in treating and preventing acne. Therefore, it is not suitable for use by people in cold northern regions. At the same time, the product prepared by using polyacrylate cross-linked polymer-6 as a thickener is not crystal clear, slightly foggy, has high viscosity, has a drawing phenomenon, and is sticky and not refreshing when used.

[0086] Therefore, the inventors considered an anhydrous system and used polyols instead of water to dissolve azelaic acid and achieve the expected thickening effect of the thickener. The following screening experiments were conducted on the components, ratios and preparation process of azelaic acid gel.

[0087] 1. Matrix component thickener and polyol screening test

[0088] 1. Screening of the matrix formula components of azelaic acid gel. The preliminary designed reagents are shown in Table 1:

[0089] Table 1

[0090]

[0091] Glossary:

[0092] 1. Azelaic acid, also known as azelaic acid, is a natural straight-chain saturated dicarboxylic acid containing 9 carbon atoms separated from the culture medium of Pityrosporum ovale, with a molecular formula of HOOC-(CH2)7-COOH and a molecular weight of 188.22. It has the appearance of white to slightly yellow monoclinic prisms, needle-shaped crystals or powder, and is easily soluble in hot water, alcohol and some polyols, and slightly soluble in cold water.

[0093] 2. Polyacrylate cross-linked polymer-6 is a polymer with strong electrolyte tolerance and can be stable in a wide pH range (2 to 10).

[0094] 3. Polyquaternium-37 is a cationic polymer that can be used as a thickener, suspending agent and conditioner. Its dispersibility is characterized by good viscosity in a wide range of pH values.

[0095] 4. Sodium polyacryloyldimethyl taurate is a polymer that does not require neutralization, is resistant to high-speed shearing, and has a certain tolerance to some electrolytes.

[0096] 5. Ammonium acryloyldimethyltaurate / VP copolymer is a rheology modifier and polymer emulsifier, which is sensitive to electrolytes. Therefore, ammonium acryloyldimethyltaurate / VP copolymer is not suitable for the production of thick shampoo, shower gel and other products with a large amount of electrolytes in water content. It can be used in the pH range of 4.0-9.0. A pH lower than 4.0 will cause the decomposition of the acid in the polymer, thereby reducing the viscosity, and a pH greater than 9.0 will cause the release of ammonium salts. The addition amount is generally recommended to be 0.5-2.0%.

[0097] 6. Ammonium acryloyldimethyltaurate / behenylether-25 methacrylate crosspolymer is a new type of carbomer. It is easier to disperse than traditional carbomers, has certain emulsification ability, and has a wider pH range of use.

[0098] 7. Carbitol is also known as ethoxydiglycol, diethylene glycol ethyl ether, diethylene glycol ethyl ether, CAS111-90-0, molecular formula C6H 14 O3, structural formula: HOCH2CH2OCH2CH2OCH2CH3, molecular weight 134.17. Diethylene glycol ethyl ether is often used as a solvent for nitrocellulose, resin, spray paint, dye, etc. It is a high boiling point solvent.

[0099] 8. Both 1,3-propylene glycol and 1,2-propylene glycol are colorless, transparent, slightly viscous liquids. They are odorless, hygroscopic, slightly sweet, and miscible with water and alcohol. They are good solvents and can also be used as moisturizers and antifreeze agents. The most common one on the market is 1,2-propylene glycol, which is mostly used in veterinary injections, pharmaceutical intermediates, food additives, etc., while 1,3-propylene glycol is less used.

[0100] 9. 1,3-Butanediol has the characteristics of good hygroscopicity, odorlessness, low toxicity, good water solubility, etc. It also has the reactivity of diols and is used as a solvent and moisturizer in cosmetics.

[0101] The polyacrylate cross-linked polymer-6, polyquaternium-37, sodium polyacryloyldimethyl taurate, ammonium acryloyldimethyl taurate / VP copolymer, and ammonium acryloyldimethyl taurate / behenyl alcohol polyether-25 methacrylate cross-linked polymer involved in the design concept of the present invention are all high molecular polymers, and their aqueous solutions are almost neutral, slowly swell in water, and their curled molecules will open due to electrical repulsion, thereby achieving the effect of thickening. However, the hydroxyl groups in polyols are relatively less active than the hydroxyl groups in water, and it is relatively difficult to open the thickener molecular chain, so it is necessary to find a thickener that can also open the molecular chain of the less active hydroxyl groups to thicken it. According to the team's experience in gel preparation, the inventors of the present application tentatively set the amount of polyacrylate cross-linked polymer-6 to 3.0%, the amount of polyquaternium-37 to 1.0%, the amount of sodium polyacryloyldimethyl taurate to 0.5%, the amount of ammonium acryloyldimethyl taurate / VP copolymer to 1.0%, and the amount of ammonium acryloyldimethyl taurate / behenyl alcohol polyether-25 methacrylate cross-linked polymer to 1.0%. Based on the above-mentioned addition amounts, different polyols were added to thicken them, thereby selecting suitable thickeners and polyols. The preparation process uses different polyols as solvents, and the addition amount is 100% of the sum of the weight ratio of the thickener to prepare basic gels. The results are shown in Tables 2-5.

[0102] Table 2 Effect of 1,3-propylene glycol as solvent on thickener

[0103]

[0104] Result analysis: From Table 2, it can be seen that 1,3-propylene glycol can thicken polyacrylate cross-linked polymer-6 and ammonium acryloyldimethyltaurate / VP copolymer to form gel, but polyacrylate cross-linked polymer-6 has a bad skin feel.

[0105] Table 3 Effect of 1,2-propylene glycol as solvent on thickener

[0106]

[0107] Result analysis: From Table 3, it can be seen that 1,2-propylene glycol can thicken polyacrylate cross-linked polymer-6 and ammonium acryloyldimethyltaurate / VP copolymer to form gel, but polyacrylate cross-linked polymer-6 has a bad skin feel.

[0108] Table 4 Effect of 1,3-butanediol as solvent on thickener

[0109]

[0110] Result analysis: From Table 4, it can be seen that the addition of 1,3-butylene glycol, polyacrylate crosspolymer-6, polyquaternium-37, sodium polyacryloyldimethyl taurate, ammonium acryloyldimethyl taurate / VP copolymer, and ammonium acryloyldimethyl taurate / behenyl alcohol polyether-25 methacrylate crosspolymer cannot thicken the product.

[0111] Table 5 Effect of carbitol as solvent on thickener

[0112]

[0113] Result analysis: From Table 5, it can be seen that the addition of carbitol, polyacrylate crosspolymer-6, polyquaternium-37, sodium polyacryloyldimethyl taurate, ammonium acryloyldimethyl taurate / VP copolymer, and ammonium acryloyldimethyl taurate / behenyl alcohol polyether-25 methacrylate crosspolymer cannot thicken the product.

[0114] From the results of Tables 2 to 5, it can be seen that: theoretically, the activity of the hydroxyl groups on 1,2-propylene glycol and 1,3-propylene glycol is stronger than that on 1,3-butylene glycol and carbitol. By adding 1,2-propylene glycol and 1,3-propylene glycol, both polyacrylate cross-polymer-6 and ammonium acryloyldimethyl taurate / VP copolymer can be thickened, but the skin feel of polyacrylate cross-polymer-6 is not ideal. Summarizing the analysis of the above four experimental results, it is further verified that the activity of the hydroxyl groups on 1,2-propylene glycol and 1,3-propylene glycol is stronger than that on 1,3-butylene glycol and carbitol, while sodium polyacryloyldimethyl taurate and ammonium acryloyldimethyl taurate / behenyl alcohol polyether-25 methacrylate cross-polymer cannot thicken, indicating that these two thickeners have higher requirements for the activity of hydroxyl groups. After the ammonium acryloyldimethyltaurate / VP copolymer is thickened by 1,2-propylene glycol and 1,3-propylene glycol, the skin feels very refreshing, non-sticky, and easy to apply. Therefore, the inventors chose ammonium acryloyldimethyltaurate / VP copolymer as a thickener and 1,2-propylene glycol and 1,3-propylene glycol as solvents to further study the azelaic acid gel.

[0115] 2. Screening test of compatibility of azelaic acid and thickener

[0116] Thickener: Ammonium acryloyldimethyltaurate / VP copolymer

[0117] Solvent: 1,2-propylene glycol, 1,3-propylene glycol

[0118] Additive: Azelaic acid

[0119] The design formula is shown in Table 6:

[0120] Table 6

[0121]

[0122] Process steps:

[0123] 1. Accurately weigh the thickener into a beaker and set aside, record it as A;

[0124] 2. Accurately weigh azelaic acid into a beaker, then add polyol, and heat to 60-65°C while stirring to completely dissolve the azelaic acid to obtain solution B;

[0125] 3. Slowly add solution B into solution A while stirring, mix well to obtain a gel.

[0126] The results are shown in Table 7:

[0127] Table 7

[0128]

[0129] From the results in Table 7, in the anhydrous system, azelaic acid has no effect on the structure of ammonium acryloyldimethyltaurate / VP copolymer. Both 1# and 2# formulations can stabilize azelaic acid without crystal precipitation. However, since the consistency is too small, it does not meet the inventor's requirements for the gel system, so the amount of ammonium acryloyldimethyltaurate / VP copolymer is increased to improve the consistency. The optimization results are shown in Table 8:

[0130] Table 8

[0131]

[0132] It can be seen from Table 8 that the consistency of ammonium acryloyldimethyltaurate / VP copolymer is more suitable when the addition amount is 1.4% and 1.6%. The inventors tentatively set the amount of ammonium acryloyldimethyltaurate / VP copolymer at 1.4% to 1.6%.

[0133] 3. Stability inspection

[0134] In order to more accurately determine the amount of ammonium acryloyldimethyltaurate / VP copolymer, the inventors added an intermediate number to conduct a preliminary investigation on the stability of the product, that is, the ratio of ammonium acryloyldimethyltaurate / VP copolymer was 1.4%, 1.5%, and 1.6%. The stability investigation conditions were room temperature environment (the ambient temperature will change with seasonal temperature changes), 0°C refrigerator environment, and -10°C refrigerator environment. The stability investigation results are shown in Table 9:

[0135] Table 9

[0136]

[0137] As can be seen from Table 9, the anhydrous system azelaic acid gel made with 1,2-propylene glycol as solvent is relatively ideal at room temperature, but at 0℃ and -10℃, azelaic acid will precipitate from the system. After returning to room temperature, azelaic acid is not completely dissolved. It may scratch the skin when used in winter and cold areas in the north, and is not conducive to the absorption of azelaic acid, thus greatly reducing the effect of azelaic acid. The anhydrous system azelaic acid gel made with 1,3-propylene glycol as solvent can withstand the environment of 0℃ and -10℃. Therefore, 1,2-propylene glycol and 1,3-propylene glycol can both be used as solvents for azelaic acid gel at room temperature, but 1,3-propylene glycol is the most preferred solvent to resist the defect of azelaic acid precipitation when 1,2-propylene glycol is used as solvent in low temperature environment.

[0138] According to the previous experience of the team, when a product is cold-resistant and stable in a short period of time, the cold-resistant time will be appropriately increased, and the product system may be damaged to a certain extent. In order to more accurately reflect that the anhydrous system azelaic acid gel made with 1,3-propylene glycol as solvent can withstand cold environments, the inventors increased the cold-resistant time at room temperature, 0°C and -10°C for samples 4#, 5#, and 6# in Table 9 to examine the stability of the product. The results are shown in Table 10:

[0139] Table 10

[0140]

[0141] From the results in Table 10, it can be seen that samples 4#, 5#, and 6# did not precipitate crystals in the 180-day cold resistance test at room temperature and 0°C and -10°C. Therefore, the formula system is very stable in a cold environment. Considering the product form and cost, the formula corresponding to sample 5# in Table 9 is selected as the preferred formula of azelaic acid gel.

[0142] 4. Antibacterial efficacy test

[0143] Since azelaic acid itself has antibacterial effects, a gel sample was prepared using formula 5# in Table 9, a certain number of different strains were artificially introduced, and then the number of several strains in the sample at different times was measured to verify the antibacterial effect of the formula. The results are shown in Table 11:

[0144] Table 11 Antibacterial efficacy test

[0145]

[0146] It can be seen from Table 11 that although no preservatives are added to the formula system, the product still has a strong antibacterial effect, so no preservatives need to be added to the formula.

[0147] 5. Determination of the formula of azelaic acid gel

[0148] Based on the above research results and trials in different regions and populations, the formula of azelaic acid gel was determined. In order to facilitate production, the inventors decided to use part of the polyol to dissolve the azelaic acid and the other part to disperse the thickener, so that the thickener molecular chain can be unfolded and thickened in advance. By adding different proportions of polyols to the thickener, the thickening effect, the dissolution of azelaic acid and the difficulty of preparation were observed. The results are shown in Table 12;

[0149] Table 12 Polyol group addition test

[0150]

[0151] From the results in Table 12, it can be seen that the appropriate reduction of polyols does not affect the dissolution of azelaic acid, while the amount of polyols added has a certain effect on the thickening of the thickener. When the amount of polyols is small, the thickener molecular chain is difficult to unfold. When the amount of polyols added is 15% and 20%, the thickener molecular chain is well unfolded. In order to facilitate mass production in the future, the inventors choose to set the amount of polyols added in phase B to 20%.

[0152] The formula is shown in Table 13:

[0153] Table 13 Azelaic acid gel formula

[0154]

[0155] VI. Determination of technical indicators of azelaic acid gel

[0156] According to the publicly announced enterprise standard Q / HY 01 technical standard requirements for skin care gel and the "Technical Specifications for Safety of Cosmetics" (2015 edition), the azelaic acid gel prepared according to Table 13 of "V. Determination of the formula of azelaic acid gel" was tested for various technical requirements. The results are shown in Table 14.

[0157] Table 14 Determination of technical indicators of azelaic acid gel of the present invention

[0158]

[0159] Note: Microbiological indicators and harmful substance limits are tested by a third party

[0160] 7. Formula expansion

[0161] In actual production, the same basic formula can be added with other auxiliary materials according to different purposes of use, and the order of adding auxiliary materials can be determined according to the characteristics of different auxiliary materials. In order to verify whether this formula also has this characteristic, the inventor conducted further research on this.

[0162] 7.1 In order to reduce the redness and swelling caused by acne, the inventor added the anti-inflammatory agent tea tree oil to the formula. The designed formula and results are shown in Table 15.

[0163] Table 15 Expanded formula 1

[0164]

[0165] Process steps:

[0166] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, 1,3-propylene glycol, and tea tree oil by weight percentage;

[0167] B. 1,3-propylene glycol is heated to 60-65° C., and ammonium acryloyldimethyltaurate / VP copolymer is dispersed in 1,3-propylene glycol to obtain gel A;

[0168] C. Heat 1,3-propylene glycol to 60-65°C, add azelaic acid to 1,3-propylene glycol, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0169] D. Add solution B to gel A, stir and mix evenly while keeping the temperature at 60-65°C, and then cool to room temperature to obtain gel C;

[0170] E. Add tea tree oil to gel C and stir to mix evenly.

[0171] Conclusion: The experiment shows that when the maximum amount of tea tree oil added is 6%, the product is still a gel. Therefore, we believe that gel can be produced when the amount of tea tree oil added is ≤6%.

[0172] 7.2 Since o-cymene-5-ol can kill bacteria, it is generally used as a preservative, but it can also be used as a bactericide. In order to increase the killing effect on Propionibacterium acnes, the inventors added the preservative o-cymene-5-ol to the formula to enhance the effect of treating acne. The designed formula and results are shown in Table 16.

[0173] Table 16 Expanded formula 2

[0174]

[0175] Process steps:

[0176] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, 1,3-propylene glycol, and o-cymene-5-ol according to weight percentage;

[0177] B. 1,3-propylene glycol is heated to 60-65° C., and ammonium acryloyldimethyltaurate / VP copolymer is dispersed in 1,3-propylene glycol to obtain gel A;

[0178] C. Heat 1,3-propylene glycol to 60-65°C, add azelaic acid and o-cymene-5-ol to 1,3-propylene glycol, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0179] D. Add solution B to gel A, maintain the temperature at 50-80°C and stir to mix evenly, then cool to room temperature to obtain.

[0180] Conclusion: It can be seen from the experimental results and the records in Table 16 that when the maximum addition amount of o-cymene-5-ol is 4%, the product is still a transparent gel. Therefore, the inventors believe that gel can be prepared when the addition amount of o-cymene-5-ol is ≤4%.

[0181] 7.3 Since salicylic acid is fat-soluble, it can penetrate into the deep layers of the pores along the sebaceous glands that secrete oil, which helps dissolve the old accumulated stratum corneum in the pores and improve the blocked pores. It can thus block the formation of acne and shrink the enlarged pores. Therefore, the inventors added the exfoliating agent salicylic acid to the formula in the hope of increasing the exfoliating and acne-removing effects. The designed formula and results are shown in Table 17.

[0182] Table 17 Expanded formula 3

[0183]

[0184] Process steps:

[0185] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, 1,3-propylene glycol, and salicylic acid by weight percentage;

[0186] B. 1,3-propylene glycol is heated to 60-65° C., and ammonium acryloyldimethyltaurate / VP copolymer is dispersed in 1,3-propylene glycol to obtain gel A;

[0187] C. Heat 1,3-propylene glycol to 60-65°C, add azelaic acid and salicylic acid to 1,3-propylene glycol, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0188] D. Add solution B to gel A, maintain the temperature at 50-80°C and stir to mix evenly, then cool to room temperature to obtain.

[0189] Conclusion: It can be seen from the experimental results and the records in Table 17 that when the maximum amount of salicylic acid added is 4%, the product is still a transparent gel. Therefore, we believe that gel can be produced when the amount of salicylic acid added is ≤4%.

[0190] 7.4 According to the extended formula of salicylic acid and o-cymene-5-ol, it can be seen that when the amount of salicylic acid and o-cymene-5-ol added is 4%, gel can be prepared. In order to further increase the exfoliation and acne removal effects, the inventor pre-compounded the exfoliating agent salicylic acid and the preservative o-cymene-5-ol. First, the inventor halved the total amount of the two on the basis of the extended formula, making the total amount of the two 4% for investigation, and added group 4#. According to the maximum addition limit of salicylic acid ≤2% and o-cymene-5-ol ≤0.1% in cosmetics, the designed formula and results are shown in Table 18:

[0191] Table 18 Expanded formula 4

[0192]

[0193] Process steps:

[0194] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, 1,3-propylene glycol, salicylic acid, and o-cymene-5-ol according to weight percentage;

[0195] B. 1,3-propylene glycol is heated to 60-65° C., and ammonium acryloyldimethyltaurate / VP copolymer is dispersed in 1,3-propylene glycol to obtain gel A;

[0196] C. Heat 1,3-propylene glycol to 60-65°C, add azelaic acid, salicylic acid, and o-cymene-5-ol to 1,3-propylene glycol, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0197] D. Add solution B to gel A, maintain the temperature at 50-80°C and stir to mix evenly, then cool to room temperature to obtain.

[0198] Conclusion: It can be seen from the experimental results and the records in Table 18 that when the amount of salicylic acid added in the formula is 2% and the amount of cymene-5-ol added is 0.1%, a transparent gel can be made. When the maximum total amount of salicylic acid and cymene-5-ol added is 4%, the product can also be made into a transparent gel. Therefore, when the total amount of salicylic acid and cymene-5-ol added is ≤4%, a gel can be made.

[0199] 7.5 In order to reduce costs, the inventor decided to try adding a small amount of water. The designed formula and results are shown in Table 19.

[0200] Table 19 Expanded formula 5

[0201]

[0202] Process steps:

[0203] A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, 1,3-propylene glycol, salicylic acid, and o-cymene-5-ol according to weight percentage;

[0204] B. 1,3-propylene glycol is heated to 60-65° C., and ammonium acryloyldimethyltaurate / VP copolymer is dispersed in 1,3-propylene glycol to obtain gel A;

[0205] C. Heat 1,3-propylene glycol to 60-65°C, add azelaic acid, salicylic acid, and o-cymene-5-ol to 1,3-propylene glycol, and stir to completely dissolve the azelaic acid to obtain a transparent solution B;

[0206] D. Heat water to 85-90°C, maintain the temperature at 85-90°C for 30 minutes for sterilization, and then cool to room temperature to obtain solution C;

[0207] E. Add solution B to gel A, stir and mix evenly while maintaining the temperature at 50-80°C, then cool to room temperature, add solution C, stir and mix evenly, and you have the product.

[0208] It can be seen from the above experimental results and the records in Table 19 that, through observations in three temperature environments, namely, room temperature, 0°C, and -10°C, the inventors found that when 8% of water was added, no crystals were precipitated at room temperature for 72 hours, and when 10% of water was added, crystals were precipitated at room temperature for 72 hours; when 4% of water was added, no crystals were precipitated at 0°C for 72 hours, and when 6% of water was added, crystals were precipitated at 0°C for 72 hours; when 1% of water was added, crystals were precipitated at 0°C and -10°C for 24 hours. Therefore, when stored in different temperature environments, different amounts of water may not be added or may be added in small amounts, and the maximum amount of water added may not exceed 8%.

[0209] According to the above-mentioned extended formula applicant's inventor team, based on previous formula design experience, in addition to the above-mentioned extended formulas, it is believed that excipients such as antioxidants, preservatives, penetration enhancers, moisturizers, thickeners, exfoliants, pH adjusters, antibacterial agents, solvents and anti-inflammatory agents can be added according to the different efficacy requirements of the products and without considering the cold resistance and stability requirements, for example:

[0210] 1. In order to increase the anti-inflammatory effect, anti-inflammatory agents can be added to the formula, such as: one or more of bisabolol, tea tree oil, dipotassium glycyrrhizate and plant extracts. When oily ingredients such as bisabolol or tea tree oil are used, appropriate antioxidants such as superoxide dismutase, ascorbic acid, tocopherol acetate, butylated hydroxytoluene, etc. will also be considered.

[0211] 2. In order to make the product take effect faster, you can add appropriate penetration enhancers such as dipropylene glycol and azone.

[0212] 3. In order to increase the moisturizing effect, you can add appropriate amounts of moisturizers such as urea, sodium hyaluronate, and polysaccharides.

[0213] 4. Due to the subjective individual differences in skin feel, one or more thickeners selected from polyquaternium-37, ammonium acryloyldimethyl taurate, and hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer can be appropriately compounded.

[0214] 5. In order to enhance the effect of softening skin keratin, you can also add appropriate amounts of exfoliants such as α-hydroxy acids and their salts and esters, β-hydroxy acids and their salts and esters, such as salicylic acid.

[0215] 6. In the cosmetics industry, since regulations stipulate that products with a pH value of less than 3.5 need to undergo human trial safety evaluation, in order to reduce this cost, the product pH value can be adjusted to no less than 3.5 by appropriately adding pH adjusters such as potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, triethanolamine and arginine.

[0216] 7. In order to increase the acne removal effect, antibacterial agents such as quaternary ammonium salt-73, isopentyl glycol, chlorhexidine diacetate, chlorhexidine digluconate, and hexamidine di(hydroxyethyl sulfonate) salt can also be added to the formula.

[0217] 8. Since there are few manufacturers of 1,3-propylene glycol and its price is relatively high, in order to reduce costs, the content of 1,3-propylene glycol can be appropriately reduced, and polyols such as 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol, and solvents such as ethoxydiglycol and ethanol can be increased.

[0218] 8. Efficacy verification test of azelaic acid gel of the present invention

[0219] 1. Test samples

[0220] Sample name: Azelaic acid gel prepared according to Table 13 of "V. Determination of Azelaic Acid Gel Formula"

[0221] Sample properties: gel

[0222] How to use: After cleansing, apply an appropriate amount of this product to problematic areas.

[0223] Frequency of use: 1-2 times a day

[0224] 2. Testing cycle

[0225] June 10, 2022 - July 8, 2022

[0226] 3. Test Purpose

[0227] Evaluate the effectiveness of the test samples in removing acne, controlling oil, and removing dead skin cells

[0228] 4. Test environment

[0229] Temperature: 21±1℃; Humidity: 50±10%RH.

[0230] 5. Test Methods

[0231] 5.1 Method Reference

[0232] 1) T / TDCA004-2021 Test method for anti-acne efficacy of cosmetics.

[0233] 2) T / ZHCA002-2018 Test method for oil control efficacy of cosmetics.

[0234] 3) Skin keratin pasting technology and its clinical application Wang Xi, Li Li.

[0235] 5.2 Testing Process

[0236] D0:

[0237] 1) Subject information registration, laboratory technicians screened out subjects with more than 5 acne on their faces and oily skin, and signed informed consent after completing the inclusion and exclusion criteria;

[0238] 2) The subjects cleaned their faces with the designated cleansing samples and sat in a laboratory at 21±1°C and 50±10% RH for 30 minutes;

[0239] 3) Test the basic value of the subject's skin: Visia-CR takes photos and analyzes the red zone a value, Sebumeter tests the skin oil content, Corneofix tape peels off the keratin, VC20 takes photos of the keratin, and experts evaluate the acne count;

[0240] 4) Laboratory technicians instruct subjects on how to use samples according to sample usage requirements and usage sites, and provide written test precautions and instructions for use;

[0241] 5) The subject receives the sample and leaves the laboratory.

[0242] D28:

[0243] 1) The subjects cleaned their faces with the designated cleansing samples and sat in a laboratory at 21±1℃ and 50±10%RH for 30 minutes;

[0244] 2) Test the subjects’ skin data for 28 days: Visia-CR takes photos and analyzes the red zone a value, Sebumeter tests the skin oil content, Corneofix tape peels off the keratin, VC20 takes photos of the keratin, and experts evaluate the acne count;

[0245] 3) The subjects filled out the questionnaire and collected the usage log.

[0246] 5.3 Test items

[0247] Table 20 Test Items

[0248]

[0249] D0 refers to the first day of the subject's visit, and D28 refers to the subject's visit 28 days after using the sample.

[0250] 6. Subject criteria

[0251] The inclusion and exclusion criteria for the subjects are as follows:

[0252] Inclusion criteria:

[0253] 1) Healthy men and women, aged 20-40, with oily and acne-prone skin, and at least 5 acne spots;

[0254] 2) Be able to cooperate well with the experimenters and maintain a regular life during the study;

[0255] 3) Be able to read and understand all the contents of the informed consent form and voluntarily sign the informed consent form;

[0256] 4) Agree not to use any cosmetics, drugs or health products that may affect the results during the trial;

[0257] 5) Other corresponding inclusion criteria.

[0258] Exclusion criteria:

[0259] 1) Those who have used antihistamines in the past week or tried immunosuppressants in the past month;

[0260] 2) Those who have used any anti-inflammatory drugs in the tested area within the past two months;

[0261] 3) Those who have suffered from skin diseases (such as psoriasis, eczema, psoriasis, skin cancer, etc.);

[0262] 4) Patients with insulin-dependent diabetes;

[0263] 5) Patients who are receiving treatment for asthma or other chronic respiratory diseases;

[0264] 6) Those who have received anti-cancer chemotherapy in the past 6 months;

[0265] 7) Patients with immunodeficiency or autoimmune diseases;

[0266] 8) Lactating or pregnant women;

[0267] 9) Bilateral mastectomy and bilateral axillary lymph node removal;

[0268] 10) Those who are concerned about the test results due to scars, pigmentation, atrophy, port wine stains, uneven skin color, folliculitis or other blemishes on the skin to be tested;

[0269] 11) Have any other health problems or chronic diseases;

[0270] 12) Use of retinoids, alpha hydroxy acids, salicylic acid, hydroquinone in the past 3 months, or prescription drugs (antibiotics, retinoids, alpha hydroxy acids and steroids) in the past 6 months, oral contraceptives (if you have been taking the same contraceptive for the past 6 months, you can continue to take it);

[0271] 13) Experts or professionals believe that there are other iatrogenic reasons that will affect the evaluation results.

[0272] 7. Data Statistical Methods

[0273] 7.1 Descriptive Statistics

[0274] Instrument measurements: mean, standard error, maximum, minimum.

[0275] Self-assessment of subjects: percentage of recognition / satisfaction.

[0276] 7.2 Difference Analysis

[0277] If the instrument test data conforms to the normal distribution, the paired T test is used to analyze the difference between the two groups of data; if the data does not conform to the normal distribution, the non-parametric (Wilcoxon) test is used to analyze the difference between the two groups of data, and the test confidence level is 0.05.

[0278] 8. Test Results

[0279] 8.1 Completion Status of Subjects

[0280] A total of 33 subjects were included in this study, and 32 subjects were finally completed, with an age range of 20-40 years old, including 11 males and 21 females, with an average age of 33.81 years old. Details are shown in Table 21.

[0281] Table 21 Details of 33 subjects

[0282] Subject number Code age gender Subject number Code age gender 1 CJ 40 female 18 FT 37 male 2 GYM 40 male 19 QUR 35 female 3 TX 35 female 20 GSS 30 female 4 TN 32 male 21 HMX 34 female 5 Wlq 36 female 22 ZH 26 male 6 JQ 36 female 23 LY 26 female 7 LQ 37 female 24 WXJ 39 female 8 QUR 39 male 25 DQL 22 female 9 CYM 40 female 26 LqCy 35 female 010-Exit ZZX 28 female 27 SJ 40 female 11 CW 37 male 28 WY 40 female 12 LTJ 25 female 29 ZY 20 female 13 TQ 35 female 30 CGR 40 female 14 YYW 35 female 31 CSC 40 female 15 DWD 38 male 32 LSJ 29 male 16 YRX 20 male 33 CJ 40 male 17 SQ 24 male / / / / / / / /

[0283] 8.2 Feedback on adverse reactions during use

[0284] Table 22 Human trial test results

[0285]

[0286] Table 23 Grading standards for adverse skin reactions

[0287] Grading Skin reactions 0 No response 1 Faint erythema 2 Erythema, infiltration, papules 3 Erythema, edema, papules, blisters 4 Erythema, edema, bullae

[0288] Note: Refer to the 2015 edition of the "Technical Specifications for Safety of Cosmetics" for the grading standards for adverse skin reactions in human trials.

[0289] Result description: After using the sample for 28 days, the skin reactions in the observed areas were all level 0, and no adverse reactions occurred on the skin.

[0290] 8.3 Skin red zone a value test results

[0291] See Table 24 and Figure 1 .

[0292] Table 24 Skin red zone a value test results (the smaller the measured value, the lighter the skin redness)

[0293]

[0294] Note: Improvement rate (%) = (basic value - test value after using the sample for N days) / basic value * 100%.

[0295] According to Table 24 and Figure 1 Result description: After using the sample for 28 days, the improvement rate of the a value of the skin red area was 35.45%, which was significantly better than the baseline value.

[0296] 8.4 Skin oil content test results

[0297] See Table 25 and Figure 2 .

[0298] Table 25 Skin oil content test results (the smaller the measured value, the lower the skin oil content

[0299]

[0300] Note: Improvement rate (%) = (basic value - test value of sample used for N days) / basic value * 100%

[0301] According to Table 25 and Figure 2 Result description: After using the sample for 28 days, the improvement rate of skin oil content was 13.60%, which was significantly better than the baseline value.

[0302] 8.5 Skin stratum corneum cell exfoliation index test results

[0303] See Table 26 and Figure 3 .

[0304] Table 26 Skin stratum corneum cell exfoliation index test results (the smaller the measured value, the less skin stratum corneum cell exfoliation)

[0305]

[0306] Note: Improvement rate (%) = (basic value - test value of sample used for N days) / basic value * 100%

[0307] According to Table 26 and Figure 3 Result description: After using the sample for 28 days, the improvement rate of skin stratum corneum cell exfoliation index was 23.45%, which was significantly better than the baseline value.

[0308] 8.6 Clinical Evaluation - Comedonal Count Test Results

[0309] See Table 27 and Figure 4 .

[0310] Table 27 Clinical evaluation - comedonal count test results (the smaller the comedonal count, the fewer comedones)

[0311]

[0312] Note: Improvement rate (%) = (basic value - test value of sample used for N days) / basic value * 100%

[0313] According to Table 27 and Figure 4 Result description: After using the sample for 28 days, the improvement rate of clinical evaluation-acne count was 73.67%, which was significantly better than the baseline value.

[0314] 8.7 Subject Self-Assessment

[0315] Table 28 Self-evaluation of subjects

[0316] Feelings after using the sample-1 D28 Recognition 1. Acne was reduced after using the sample 93.75％ 2. The sample can quickly soothe redness and swelling and accelerate the drying of acne 96.88％ 3. The sample can relieve discomfort in acne areas (pain, itching, etc.) 96.88％ 4. Skin oiliness has improved after using the sample 90.63％ 5. The sample has an exfoliating effect after use 90.63％ 6. Overall recognition of the samples used 100.00％ Feelings after using the sample-2 D28 Recognition 7. The trial sample is mild and non-irritating 100.00％

[0317] 1-6: 1 means strongly disagree, 2 means somewhat disagree, 3 means neither agree nor disagree, 4 means somewhat agree, 5 means strongly agree;

[0318] 1-6: D28 recognition is the sum of the percentages of “4 points relatively recognized” and “5 points very recognized” after using the sample for 28 days;

[0319] 7: 1 point means "yes", 2 points means "no";

[0320] 7: D28 recognition is the percentage of “1 point yes” after using the sample for 28 days.

[0321] 9. Test conclusion

[0322] 32 subjects used the test sample for 28 consecutive days, and the results showed the following effects:

[0323] ●The instrument test results show:

[0324] 1) Compared with the baseline value, the skin oil content was significantly reduced after 28 days of use (P<0.05);

[0325] 2) Compared with the baseline value, the a value of the skin red area was significantly reduced after 28 days of use (P<0.05);

[0326] 3) Compared with the baseline value, the skin stratum corneum cell exfoliation index was significantly reduced after 28 days of use of the sample (P<0.05).

[0327] The visual assessment results showed:

[0328] 1) Compared with the baseline value, after 28 days of use of the sample, the clinical evaluation-acne count was significantly reduced (P<0.05).

[0329] The subjective evaluation results showed that:

[0330] 1) After 28 days of using the sample, 100% of the subjects overall agreed with the sample;

[0331] 2) After using the sample for 28 days, 100% of the subjects considered the sample to be mild and non-irritating.

[0332] The safety assessment results show that:

[0333] 1) 32 subjects used the samples for 28 days and no adverse reactions were observed on the skin.

[0334] 10. Improve the display of effective examples

[0335] 10.1 Red Zone Improvement Effective Example Demonstration: See Figure 5-7 Examples of red zone improvement (Crosspolarized light source mode photos), including D0 to D28 improvement examples for subjects 7, 12, and 19.

[0336] 10.2 Effective examples of acne improvement: see Figure 8-10 Examples of acne improvement (Standard2 light source mode photos), showing improvement from D0 to D28 for subjects 2, 14, and 27.

[0337] In summary, the azelaic acid gel of the present invention has the following characteristics:

[0338] 1. The present invention adopts 1,2-propylene glycol, 1,3-propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, polyethylene glycol-400, glycerol, diglycerol and other polyols, ethoxydiglycol, water and ethanol as solvents to solve the problems of poor transparency, stringiness, stickiness and unclearness of existing azelaic acid gel products on the market at room temperature; in particular, the use of 1,3-propylene glycol can also solve the problem of easy precipitation of azelaic acid in the existing azelaic acid gel on the market at low temperature, such as being able to cope with the transportation, use and storage scenarios of extremely low ambient temperatures in winter in Northeast, Northwest and East China.

[0339] 2. The present invention uses ammonium acryloyldimethyltaurate / VP copolymer as a thickener, and uses 1,3-propylene glycol or 1,2-propylene glycol as a solvent to dissolve azelaic acid and replace water to thicken the ammonium acryloyldimethyltaurate / VP copolymer to form a transparent gel, so that azelaic acid is fully dissolved in the gel system, which is a novel anhydrous formula. The prepared gel has no drawing phenomenon, the skin feels more refreshing, the skin is refreshing and not greasy after use, the product is crystal clear, the gel does not contain water, and the gel structure is stable. In particular, using 1,3-propylene glycol as a solvent, the prepared gel is not easy to freeze, the temperature has little effect on it, and it can be stored at ultra-low temperatures. Even if it is stored in a -10°C environment for half a year, there is still no precipitation of azelaic acid crystals. The system is stable, and the use of people in cold northern regions does not affect the transdermal absorption of azelaic acid in the skin, and can penetrate the skin well. The azelaic acid gel of the present invention can be used in the treatment or prevention of acne or dull skin, greatly improving the cure rate of acne patients.

[0340] 3. The azelaic acid gel of the present invention can not only refresh and nourish the skin, but also balance and regulate the skin's oil secretion, unclog the pores, and inhibit and kill bacteria on the skin surface and in the hair follicles, thereby achieving the effect of stopping and removing acne.

[0341] 4. Since azelaic acid itself has antibacterial effects, it can effectively play an antibacterial role in product formulas without the need to add preservatives, thereby improving the safety and mildness of the product.

[0342] 5. The azelaic acid gel of the present invention has a reasonable product formula design, a simple and easy-to-operate production process, and all product indicators meet the technical requirements specified in the enterprise standard "Skin Care Gel" Q / HY 01 and "Cosmetic Safety Technical Specifications" (2015 edition), with stable quality.

Claims

1. Azelaic acid gel, characterized in that: The composition is composed of the following components: azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, and solvent; the weight percentages of the components are as follows: Azelaic acid 10-30%, ammonium acryloyldimethyltaurate / VP copolymer 0.5-5%, the solvent is added until the sum of the weight percentages of the three is 100%; The solvent is any one of 1,2-propylene glycol and 1,3-propylene glycol or any mixture thereof.

2. The azelaic acid gel according to claim 1, characterized in that: It is composed of the following components in weight percentage: Azelaic acid 10-25%, ammonium acryloyldimethyltaurate / VP copolymer 0.5-5%, the solvent is added until the sum of the weight percentages of the three is 100%.

3. The azelaic acid gel according to claim 1, characterized in that: It is composed of the following components in weight percentage: Azelaic acid 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23% or 25%, ammonium acryloyldimethyltaurate / VP copolymer 1-2%, the solvent is added until the sum of the weight percentages of the three is 100%.

4. The azelaic acid gel according to claim 1, characterized in that: It is composed of the following components in weight percentage: Azelaic acid 10-20%, ammonium acryloyldimethyltaurate / VP copolymer 0.5-5%, the solvent is added until the sum of the weight percentages of the three is 100%.

5. The azelaic acid gel according to claim 1, characterized in that: It is composed of the following components in weight percentage: Azelaic acid 10-15%, ammonium acryloyldimethyltaurate / VP copolymer 1-2%, solvent 83-84%, the sum of the weight percentages of the three is 100%.

6. The azelaic acid gel according to claim 1, characterized in that: It is composed of the following components in weight percentage: Azelaic acid 15%, ammonium acryloyldimethyltaurate / VP copolymer 1.5%, solvent 83.5%, the sum of the three weight percentages is 100%.

7. The azelaic acid gel according to any one of claims 1 to 6, characterized in that: The solvent is 1,3-propylene glycol.

8. The azelaic acid gel according to claim 1, characterized in that: When the solvent is a mixture of 1,3-propylene glycol and 1,2-propylene glycol, the weight ratio is 1,3-propylene glycol: 1,2-propylene glycol = 1-9: 1-9.

9. The azelaic acid gel according to claim 8, characterized in that: When 1,3-propylene glycol and 1,2-propylene glycol are mixed, the weight ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:

1.

10. The azelaic acid gel according to claim 1, characterized in that: When azelaic acid is dissolved in 1,3-propylene glycol or / and 1,2-propylene glycol as a solvent, the weight ratio of azelaic acid to the solvent is 1:2-10.

11. Azelaic acid gel, characterized in that: The invention is composed of the following components: azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, solvent, and acceptable gel excipients, wherein the acceptable gel excipients are at least one of antioxidants, preservatives, penetration enhancers, moisturizers, thickeners, exfoliants, pH regulators, antibacterial agents, and anti-inflammatory agents; the weight percentages of the components are as follows: Azelaic acid 10-30%, ammonium acryloyldimethyltaurate / VP copolymer 0.5-10%, acceptable gelling agent excipients and solvents are added until the sum of the four weight percentages is 100%; The solvent is any one of 1,2-propylene glycol and 1,3-propylene glycol or any mixture thereof; The azelaic acid gel is an anhydrous system.

12. The azelaic acid gel according to claim 11, characterized in that: The antioxidant is at least one of superoxide dismutase, ascorbic acid, tocopherol acetate and butylated hydroxytoluene.

13. The azelaic acid gel according to claim 11, characterized in that: The preservative is at least one of 1,2-hexanediol, 1,2-pentanediol, phenoxyethanol, caprylhydroxamic acid, parabens, o-cymene-5-ol, p-hydroxyacetophenone and sorbic acid.

14. The azelaic acid gel according to claim 11, characterized in that: The penetration enhancer is at least one of dipropylene glycol and azone.

15. The azelaic acid gel according to claim 11, characterized in that: The moisturizing agent is at least one of urea, sodium hyaluronate and polysaccharide.

16. The azelaic acid gel according to claim 15, characterized in that: The polysaccharide is dextran.

17. The azelaic acid gel according to claim 11, characterized in that: The thickener is at least one of polyquaternium-37, ammonium acryloyldimethyltaurate, and hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer.

18. The azelaic acid gel according to claim 11, characterized in that: The exfoliating agent is at least one of α-hydroxy acid and its salts and esters, β-hydroxy acid and its salts and esters, and salicylic acid.

19. The azelaic acid gel according to claim 11, characterized in that: The pH regulator is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, triethanolamine and arginine.

20. The azelaic acid gel according to claim 11, characterized in that The antibacterial agent is at least one of quaternary ammonium salt-73, isopentyl glycol, chlorhexidine diacetate, chlorhexidine digluconate, and hexamidine di(hydroxyethylsulfonic acid) salt.

21. The azelaic acid gel according to claim 11, characterized in that: The anti-inflammatory agent is at least one of bisabolol, dipotassium glycyrrhizinate and plant extracts, and the plant extracts include at least one extracted from purslane, oats, aloe, calendula, centella asiatica, licorice, chamomile and mangosteen.

22. The azelaic acid gel according to claim 21, characterized in that: The anti-inflammatory agent is tea tree oil.

23. The method for preparing azelaic acid gel according to any one of claims 1 to 10, characterized in that: The gelling agent component is composed of azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, and solvent, and comprises the following steps: A. Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, and solvent by weight percentage; B. The solvent is heated to 50-80° C., and the ammonium acryloyldimethyltaurate / VP copolymer is dispersed in the solvent to obtain gel A; C. Heat the solvent to 50-80°C, add azelaic acid to the solvent, and stir to completely dissolve the azelaic acid to obtain a transparent solution B; D. Add solution B to gel A, maintain the temperature at 50-80°C and stir to mix evenly, then cool to room temperature to obtain.

24. The method for preparing azelaic acid gel according to claim 23, characterized in that: Step B: heating the solvent to 60-65° C., dispersing the ammonium acryloyldimethyltaurate / VP copolymer in the solvent to obtain gel A; Step C: Heat the solvent to 60-65° C., add azelaic acid to the solvent, and stir to completely dissolve the azelaic acid to obtain a transparent solution B; Step D: Add solution B to gel A, maintain the temperature at 60-65 degrees, stir and mix evenly, and then cool to room temperature to obtain the product.

25. The method for preparing azelaic acid gel according to claim 24, characterized in that: In step B, the weight ratio of ammonium acryloyldimethyl taurate / VP copolymer and 1,3-propylene glycol is: 1.5% of ammonium acryloyldimethyl taurate / VP copolymer and 20% of 1,3-propylene glycol. In step C, the weight ratio of azelaic acid and 1,3-propylene glycol is: 15% of azelaic acid and 63.5% of 1,3-propylene glycol. In steps B and C, the total weight percentage of ammonium acryloyldimethyl taurate / VP copolymer, azelaic acid and 1,3-propylene glycol is 100%.

26. The method for preparing azelaic acid gel according to any one of claims 11 to 22, characterized in that: The method is composed of azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, solvent, and acceptable gelling agent excipients, and includes the following steps: (1) Weigh azelaic acid, ammonium acryloyldimethyltaurate / VP copolymer, solvent, and acceptable gelling agent excipients according to weight percentage; (2) heating the solvent to 50-80° C., dispersing the ammonium acryloyldimethyltaurate / VP copolymer and a thickener in an acceptable gelling agent auxiliary material in the solvent to obtain gel A; (3) heating the solvent to 50-80°C, adding azelaic acid to the solvent, stirring to completely dissolve the azelaic acid, and obtaining a transparent solution B; (4) adding other acceptable gelling excipients into the solvent, stirring and dissolving to obtain solution C; (5) Add solution B to gel A, stir and mix evenly while maintaining the temperature at 50-80°C, and then cool to room temperature to obtain gel D; (6) Add solution C to gel D and stir to mix evenly.

27. The method for preparing azelaic acid gel according to claim 26, characterized in that: At least one of the following is met: In the step (2), the solvent is heated to 60-65° C., and the ammonium acryloyldimethyltaurate / VP copolymer is dispersed in the solvent to obtain gel A; In step (3), the solvent is heated to 60-65° C., azelaic acid is added to the solvent, and stirred to completely dissolve the azelaic acid to obtain a transparent solution B; In the step (5), solution B is added to gel A, the temperature is maintained at 60-65°C and stirred to mix evenly, and then cooled to room temperature to obtain the product.

28. Use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines and skin care products for treating acne; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines, health products, and skin care products with acne-removing effects; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines, health products, and skin care products with oil control effects; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines and skin care products with exfoliating effects; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines and skin care products having the effect of softening keratin; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines and skin care products with whitening effects; Or, use of the azelaic acid gel according to any one of claims 1 to 22 in the preparation of medicines and skin care products with the effect of improving pigmentation.

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