An azelaic acid dispersion system, formulations containing azelaic acid, methods of preparation and use

Abstract

This application discloses an azelaic acid dispersion system, an azelaic acid-containing formulation, a preparation method, and applications. The azelaic acid dispersion system of this application solves the solubility problem of azelaic acid, stabilizing the dispersion of azelaic acid at concentrations of 20% or higher in a cream, while simultaneously reducing the irritation of azelaic acid during use and synergistically reducing skin pigmentation. The azelaic acid-containing formulation of this application, through the compounding of components, can improve the stability and efficacy of the formulation, forming a uniform, stable, and delicately lightweight cream. It also reduces the irritation of azelaic acid during use, enhances its effect in lightening skin melanin, helps improve acne and restore post-acne pigmentation, and is convenient to use and highly safe.

Description

Technical Field

[0001] This application relates to the field of acne prevention and treatment technology, specifically to an azelaic acid dispersion system, a preparation containing azelaic acid, a preparation method, and its application. Background Technology

[0002] Acne is a chronic inflammatory skin disease of the pilosebaceous unit that commonly occurs during adolescence and primarily affects the face. Most acne patients experience pigmentation and scarring, which can negatively impact their mental health and quality of life. According to the "Chinese Acne Treatment Guidelines (2019 Revised Edition)," azelaic acid is a second-line recommended medication and is a pregnancy category B drug. 20% azelaic acid cream is a topical medication for treating acne vulgaris with good safety profile and is recommended for treating post-inflammatory hyperpigmentation; it can be used in combination with other medications. High concentrations of azelaic acid can improve the treatment efficiency of acne, but its extremely low solubility in water and oil, coupled with its high melting point, presents challenges for high-concentration formulations. Furthermore, high concentrations of azelaic acid can be irritating during use, and its concentration is difficult to maintain stably in formulations, often resulting in discoloration. Current common solutions include encapsulating azelaic acid and preparing it into azelaic acid derivatives. However, problems remain, such as low dosage of azelaic acid in formulations and alterations to its essential structure, making it difficult to achieve true therapeutic efficacy. Solving the technical challenges of applying azelaic acid in formulations remains an unresolved issue. Summary of the Invention

[0003] The purpose of this application is to provide an azelaic acid dispersion system, an azelaic acid-containing formulation, a preparation method, and applications. The azelaic acid dispersion system of this application addresses the problem of low azelaic acid content in existing azelaic acid systems. Furthermore, the azelaic acid-containing formulation of this application exhibits high stability, high efficacy, and low irritation.

[0004] This application provides an azelaic acid dispersion system comprising azelaic acid and a polyol system, wherein the polyol system includes propylene glycol, glycerol, and 1,2-pentanediol; the mass ratio of azelaic acid, propylene glycol, glycerol, and 1,2-pentanediol is (5~10):(5~10):(0.8~1.2):(0.8~1.2). This azelaic acid dispersion system solves the problem of dissolving and dispersing azelaic acid with a mass percentage of 15% or more, especially 20% or more, in a system. The polyol system of this application allows azelaic acid to form a relatively stable dispersion, which is beneficial for its use in subsequent cream formulations.

[0005] In some implementations, the mass ratio of azelaic acid, propylene glycol, glycerol, and 1,2-pentanediol is 20:20:3:3.

[0006] In some embodiments, the azelaic acid dispersion system is prepared by the following method: high-speed homogenization at a speed of 2900 rpm to 3000 rpm, a dispersion temperature of 60°C to 65°C, and a dispersion time of 5 min to 10 min.

[0007] This application also provides a formulation containing azelaic acid, including the azelaic acid dispersion system described above.

[0008] In some embodiments, the azelaic acid-containing preparation described in this application is a cream.

[0009] In some embodiments, the azelaic acid content is 15% to 45% by mass, or 15% to 35% by mass, or 15% to 25% by mass, based on the total mass of the formulation. For example, the azelaic acid content in the formulation may be any value or a range of any two of the following: 15%, 20%, 25%, 30%, 35%, 40%, and 45%.

[0010] In some embodiments, the formulation further includes functional oils, which include one or more of sesame seed oil, egg yolk oil, and sea buckthorn seed oil.

[0011] In some embodiments, the mass ratio of sesame seed oil, egg yolk oil and sea buckthorn seed oil is (0.8~1.2):(0.8~1.2):(0.8~1.2).

[0012] In some specific embodiments, the mass ratio of sesame seed oil, egg yolk oil and sea buckthorn seed oil is 1:1:1.

[0013] The combination of sesame seed oil, egg yolk oil, and sea buckthorn seed oil in this application can better inhibit inflammatory factors.

[0014] In some embodiments, the total mass percentage of the sesame seed oil, egg yolk oil, and sea buckthorn seed oil is 5% to 8% based on the total mass of the preparation, such as any value or a range of any two of the following: 5%, 6%, 7%, and 8%.

[0015] In some embodiments, the functional oils of this application also include sunflower seed wax.

[0016] In some embodiments, the mass percentage of sunflower seed wax, based on the total mass of the preparation, is 2% to 8%, such as any value or a range of any two values ​​among 2%, 3%, 4%, 5%, 6%, 7%, and 8%.

[0017] The sunflower seed wax of this application exhibits a linear crystal morphology, forming a favorable crystalline matrix that creates a tight and robust oil-phase network, fixing the oil phase between its numerous thin-plate crystals. Due to its high oil-binding capacity, it can form a high-hardness three-dimensional wax network structure even at low dosages, providing a stable framework for the cream and aiding in the dispersion and retention of active ingredients. It can also stabilize the dispersion and content of high-alkalinity azelaic acid, such as 20% azelaic acid, in the cream. Simultaneously, the functional oil combination in this application can synergistically reduce pigmentation and alleviate skin irritation during use.

[0018] In this application, egg yolk oil is rich in unsaturated fatty acids such as palmitoleic acid, oleic acid, and linoleic acid, as well as cholesterol and various vitamins, which are beneficial for the recovery of the skin's lipid barrier and have protective and anti-inflammatory effects. Sesame seed oil is a common edible vegetable oil containing various antioxidants and bioactive substances, including sesamin and sesamolin, representing sesamol compounds. Sesamol reduces lipoxygenase levels through its free radical scavenging activity and potential redox inhibitor properties, exhibiting its potential anti-inflammatory activity, which can soothe skin irritation and relieve inflammation. Sea buckthorn oil is rich in unsaturated fatty acids, vitamins, triterpenes, steroidal compounds, and trace elements, and has strong antioxidant capacity and wound-healing effects. The combination of these three oils can reduce skin irritation and relieve inflammation of acne-prone skin, accelerate the repair and healing of acne-damaged skin, and synergistically reduce post-acne pigmentation.

[0019] In some embodiments, the formulation further includes a thickener system comprising one or more of ammonium acryloyldimethyl taurate / VP copolymer, Viscolam AT 100 P, SEPIPLUS 265, and xanthan gum.

[0020] In some embodiments, the thickener system includes one or more of ammonium acryloyldimethyl taurate / VP copolymer, Viscolam AT 100 P, and xanthan gum.

[0021] In some embodiments, the mass percentage of the ammonium acryloyl dimethyl taurate / VP copolymer is 0.5% to 1.5% based on the total mass of the formulation, such as any value or a range of any two of the following: 0.5%, 0.9%, 1.0%, and 1.5%.

[0022] In some embodiments, the Viscolam AT 100 P content by weight is 0.15% to 0.4% based on the total mass of the formulation, such as any value or a range of any two values ​​from 0.15%, 0.25%, 0.30%, 0.35%, 0.40%.

[0023] In some embodiments, the xanthan gum content is 0.01% to 0.1% by weight of the total mass of the preparation, such as any value or a range of any two of 0.01%, 0.05%, and 0.1%.

[0024] In some embodiments, the mass ratio of the ammonium acryloyl dimethyl taurate / VP copolymer, Viscolam AT 100 P and xanthan gum is (0.5~1.5):(0.15~0.4):(0.01~0.1).

[0025] In some embodiments, the mass ratio of the ammonium acryloyl dimethyl taurate / VP copolymer, Viscolam AT 100 P, and xanthan gum is 0.9:0.25:0.05.

[0026] In some embodiments, the formulation further includes an emulsifier system, the emulsifier system comprising one or both of PolyAquoltM-2W and MONTANOV 68.

[0027] In some embodiments, the emulsifier includes PolyAquoltM-2W, and the mass percentage of PolyAquoltM-2W is 2.5% to 3.5% based on the total mass of the formulation, such as any value or a range of any two of 2.5%, 3.0%, and 3.5%.

[0028] In some embodiments, the mass ratio of emulsifier PolyAquoltM-2W, thickener ammonium acryloyl dimethyl taurate / VP copolymer, Viscolam AT 100 P, and xanthan gum is 3:0.9:0.25:0.05.

[0029] In some embodiments, the formulation further includes an active composition comprising one or both of hydrolyzed flax extract and L-arginine.

[0030] This application further incorporates an aqueous moisturizing and soothing substance into the formulation. This substance is hydrolyzed flax extract, which contains flaxseed polysaccharides. By improving cell hydrophilicity, it enhances the skin tissue's own water-locking function. The resulting polysaccharide hydrocolloid can synergistically alleviate skin damage and reduce irritation. Simultaneously, L-arginine can also act as a pH stabilizing agent.

[0031] In some embodiments, the hydrolyzed flax extract has a mass percentage content of 0.5% to 1.5% based on the total mass of the preparation, such as any value or a range of any two of 0.5%, 1.0%, and 1.5%.

[0032] In some embodiments, the mass percentage of L-arginine is 1% to 2% based on the total mass of the preparation, such as any value or a range of any two of 1.0%, 1.5%, and 2.0% of L-arginine.

[0033] In some embodiments, the formulation further includes an emollient system comprising one or both of polydimethylsiloxane and myristyl myristate.

[0034] In some embodiments, the mass percentage of polydimethylsiloxane is 0.5% to 1.5% based on the total mass of the formulation, such as any value or a range of any two of 0.5%, 1.0%, and 1.5%.

[0035] In some embodiments, the mass percentage of myristyl myristate is 1.5% to 2.5% based on the total mass of the preparation, such as any value or a range of any two of 1.5%, 2.0%, and 2.5%.

[0036] In some embodiments, the formulation further includes tocopherol acetate, wherein the mass percentage of tocopherol acetate is 0.5% to 1.5% based on the total mass of the formulation, such as any value or a range of any two of 0.5%, 1.0%, and 1.5%.

[0037] The azelaic acid-containing formulations, such as creams, described in this application can solve the problem of dissolving and dispersing high concentrations of azelaic acid in the system. While stabilizing the high concentration of azelaic acid, they reduce the irritation of azelaic acid during use and have a synergistic effect of reducing skin melanin. This can improve acne while enhancing the improvement and recovery of post-acne pigmentation.

[0038] In some embodiments, this application also provides a formulation containing azelaic acid, comprising, by weight: 15-25 parts azelaic acid, 15-25 parts propylene glycol, 2.5-3.5 parts glycerin, 2.5-3.5 parts 1,2-pentanediol, 1.5-2.5 parts sesame seed oil, 1.5-2.5 parts egg yolk oil, 1.5-2.5 parts sea buckthorn seed oil, 0.5-1.5 parts tocopheryl acetate, 0.5-1.5 parts polydimethylsiloxane, 1.5-2.5 parts myristyl myristate, 2.5-3.5 parts sunflower seed wax, 0.5-1.5 parts ammonium acryloyl dimethyl taurate / VP copolymer, and 0.15-0.4 parts ViscolamAT 100. P, 0.01 to 0.1 parts xanthan gum, 2.5 to 3.5 parts PolyAquolt M-2W, 0.5 to 1.5 parts hydrolyzed flax extract, 1 to 2 parts L-arginine, 0.2 to 1 part preservative.

[0039] In some embodiments, a formulation containing azelaic acid further includes water, which is added to 100 parts by weight.

[0040] In some embodiments, this application also provides a cream containing azelaic acid, wherein, based on the total mass of the cream, the cream comprises: 15%~25% azelaic acid, 15%~25% propylene glycol, 2.5%~3.5% glycerin, 2.5%~3.5% 1,2-pentanediol, 1.5%~2.5% sesame seed oil, 1.5%~2.5% egg yolk oil, 1.5%~2.5% sea buckthorn seed oil, 0.5%~1.5% tocopheryl acetate, 0.5%~1.5% polydimethylsiloxane, 1.5%~2.5% myristyl myristate, 2.5%~3.5% sunflower seed wax, 0.5%~1.5% ammonium acryloyl dimethyl taurate / VP copolymer, and 0.15%~0.4% Viscolam AT 100. P, 0.01%~0.1% xanthan gum, 2.5%~3.5% PolyAquolt M-2W, 0.5%~1.5% hydrolyzed flax extract, 1%~2% L-arginine, 0.2%~1% preservatives.

[0041] Accordingly, this application also provides a method for preparing an azelaic acid-containing preparation, comprising the following steps: Preparation of azelaic acid dispersion system: Azelaic acid is mixed with a polyol system, heated, and homogenized to form a premixed dispersion phase; Preparation of the oil phase: Weigh the functional oils and emulsifier system in the oil phase and heat to 80℃~85℃ to dissolve; Preparation of the thickening phase: The thickener system is heated and stirred at 80℃~85℃ to swell and form a thickening phase; Preparation of active ingredient solution: Arginine was dissolved in water and then mixed with hydrolyzed flax extract to form an active ingredient solution; Preparation of cream: After heating and dissolving the oil phase and the thickening phase, the mixture is homogenized at a high speed of 2900-3000 rpm. Then, the azelaic acid dispersion system is added and homogenized at a high speed. After homogenization and cooling, the active ingredient solution and preservative are added and stirred evenly.

[0042] Accordingly, the embodiments of this application also provide the application of the above-mentioned azelaic acid dispersion system, or the above-mentioned azelaic acid-containing preparation, or the preparation method of the above-mentioned azelaic acid-containing preparation, in the preparation of acne treatment preparations.

[0043] The beneficial effects of this application are as follows: This application provides an azelaic acid dispersion system, an azelaic acid-containing formulation, a preparation method, and an application. The azelaic acid dispersion system of this application solves the solubility problem of azelaic acid, stabilizing the dispersion and content of azelaic acid (e.g., 20%) in a paste, while reducing the irritation of azelaic acid during use and synergistically reducing skin pigmentation. The azelaic acid-containing formulation of this application, through the compounding of components, can improve the stability and efficacy of the formulation, forming a uniform, stable, and delicately light paste. It also reduces the irritation of azelaic acid during use, enhances its effect of lightening skin melanin, helps improve acne and restore post-acne pigmentation, and is convenient to use and highly safe. Attached Figure Description

[0044] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 The inhibition rate of the inflammatory factor TNF-α in each test case of this application; Figure 2 The inhibition rate of the inflammatory factor IL-6 in each test case of this application; Figure 3 This is a fingerprint spectrum showing the stability characteristics of the sample from Example 1 of this application under heat-resistant conditions (40°C). Figure 4 This is a fingerprint spectrum of the stability characteristics of the sample in Example 1 of this application under freeze-thaw conditions (-20°C); Figure 5 The thermodynamic stability parameter TSI level of the sample in Example 1 of this application under heat resistance conditions (40°C); Figure 6The thermodynamic stability parameter TSI level of the sample in Example 1 of this application under freeze-thaw conditions (-20°C); Figure 7 The variations in azelaic acid content are shown in the various embodiments of this application. Figure 8 These are the results of melanin inhibition experiments in Example 1, Comparative Example 1, and Example 17 of this application; Figure 9 This application demonstrates the effect of Example 1 in improving acne treatment; Figure 10 Example 1 of this application demonstrates the effect of improving acne scars; Figure 11 Example 1 of this application demonstrates the effect of improving acne inflammation; Figure 12 This application demonstrates the effect of Example 1 in improving acne inflammation. Detailed Implementation

[0046] The technical solutions in the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application. In addition, in the description of this application, the term "comprising" means "including but not limited to". The terms first, second, third, etc. are used only as illustrative purposes and do not impose numerical requirements or establish an order. Various embodiments of this application may exist in the form of a range; it should be understood that the description in the form of a range is only for convenience and conciseness and should not be construed as a hard limitation on the scope of this application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single values ​​within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which applies regardless of the range. Additionally, whenever a numerical range is specified in this document, it means that any referenced number (fraction or integer) within the range is included.

[0047] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples are all commercially available. Azelaic acid in this application is from Beijing Belles Biotechnology Co., Ltd.; propylene glycol is from Dow Chemical (Shanghai) Co., Ltd.; glycerol is from PROCTER & GAMBLE INTERNATIONAL OPERATIONS SA SINGAPORE BRANCH; 1,2-pentanediol is from Symrise Fragrance & Flavor (Nantong) Co., Ltd.; ammonium acryloyl dimethyl taurate / VP copolymer is from Clariant Chemical Technology (Shanghai) Co., Ltd.; Viscolam AT 100 P is from Lamberti SpA; xanthan gum is from CP Kelco Singapore Pte., Ltd.; egg yolk oil is from Junmu Biotechnology Co., Ltd.; sesame seed oil is from Cui Zi brand; sea buckthorn seed oil is from Yaqi Industrial (Shanghai) Co., Ltd.; tocopheryl acetate is from DSM Naturitional Products Ltd.; Poly Aquolt M-2W is from Innovacos Corp.; polydimethylsiloxane is from Dow Chemical (Shanghai) Co., Ltd.; myristyl myristate is from Croda Singapore. Pte Ltd; sunflower seed wax is from Henan Fumei Biotechnology Co., Ltd.; hydrolyzed flax extract is from Shanghai Ruixi Trading Co., Ltd.; arginine is from Sinopharm Chemical Reagent Co., Ltd.; succinyl glycol 68 is from Symrise Fragrance & Flavor (Nantong) Co., Ltd.; SEPIPLUS 265 is from SEPPIC SA.

[0048] I. Preparation of Azelaic Acid Premixed Dispersion A high-content (43.5%) dispersion system of azelaic acid was prepared by compounding azelaic acid with different polyols in equal proportions, and heating and homogenization were carried out under different process parameters. The ratios of azelaic acid to polyols in different dispersions are as follows: Dispersion 1, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:0:20:3:3, and its dispersion parameters are high-speed homogenization, with a homogenization speed of 2900 rpm to 3000 rpm, a dispersion temperature of 60℃ to 65℃, and a dispersion time of 6 min; Dispersion 1A, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:0:20:3:3, is different in that it is homogenized at a medium-low speed, with a homogenization speed of 2000 rpm to 2500 rpm, a dispersion temperature of 45℃ to 50℃, and a time of 6 min. Dispersion 2, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:20:3:0:3, and its dispersion parameters are high-speed homogenization, with a homogenization speed of 2900 rpm to 3000 rpm, a dispersion temperature of 60℃ to 65℃, and a dispersion time of 6 min; Dispersion 2A, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:20:3:0:3, is different in that the dispersion parameters are medium-low speed homogenization, with a homogenization speed of 2000 rpm to 2500 rpm, a dispersion temperature of 45℃ to 50℃, and a dispersion time of 6 min; Dispersion 3, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:3:0:20:3, and its dispersion parameters are high-speed homogenization, with a homogenization speed of 2900 rpm to 3000 rpm, a dispersion temperature of 60℃ to 65℃, and a dispersion time of 6 min; Dispersion 3A, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:3:0:20:3, is different in that it is homogenized at a medium-low speed, with a homogenization speed of 2000 rpm to 2500 rpm, a dispersion temperature of 45℃ to 50℃, and a time of 6 min. Dispersion 4, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:3:3:0:20, and its dispersion parameters are high-speed homogenization, with a homogenization speed of 2900 rpm to 3000 rpm, a dispersion temperature of 60℃ to 65℃, and a dispersion time of 6 min; Dispersion 4A, wherein the mass ratio of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol is 20:3:3:0:20, is different in that the dispersion parameters are medium-low speed homogenization, with a homogenization speed of 2000 rpm to 2500 rpm, a dispersion temperature of 45℃ to 50℃, and a dispersion time of 6 min. The obtained dispersions were subjected to centrifugal stability, thermal cycling stability, and high-temperature accelerated stability tests. Centrifugal stability test conditions: 2000 rpm / min, 30 min; Thermal cycling test conditions: Samples were placed in a pre-adjusted constant temperature incubator (40±2℃) for 24 h, then removed and placed in a pre-adjusted refrigerator (-5±2℃) for 24 h, then removed again and placed back into the (40±2℃) constant temperature incubator, repeated 5 times; High-temperature accelerated stability test conditions: Samples were placed at 50±2℃ and 75±5% relative humidity for 30 days; The various dispersions and test results are shown in Tables 1 and 2.

[0049] Table 1. Azelaic acid premixed dispersion and preparation conditions

[0050]

[0051] Table 2. Stability test results of azelaic acid premixed dispersion

[0052] In the table, "-" indicates that a stable dispersed system has not yet been formed.

[0053] The experimental results show that the optimal method for preparing 20g of azelaic acid powder into a dispersion is dispersion 2, which consists of azelaic acid powder, propylene glycol, glycerol, ethanol, and 1,2-pentanediol in a mass ratio of 20:20:3:0:3. The dispersion process parameters are high-speed homogenization at 2900-3000 rpm, a dispersion temperature of 60-65℃, and a dispersion time of 6 minutes. The optimal solvent for dispersing azelaic acid powder is an equal proportion of propylene glycol. Small amounts of glycerol and pentanediol can also aid in dissolution and uniform dispersion. As seen in dispersions 1, 1A, 3, and 3A, ethanol did not play a significant dispersing role and was easily affected by temperature changes.

[0054] II. Screening of functional oils in the oil phase Azelaic acid can easily cause skin irritation during use, and skin pigmentation and inflammation in the later stages of acne are also important factors affecting acne health. Therefore, after pre-screening with oil phases, sesame seed oil, egg yolk oil, and sea buckthorn seed oil were selected. Skin inflammatory factor inhibition experiments were conducted to determine whether these oil phases could be used as functional oils in the technical solution of this application. The proportions of the components in each test example are shown in Table 3.

[0055] Table 3. Proportion of functional oils (parts by mass) in different experimental cases

[0056] An LPS-macrophage inflammation model was established, and inflammatory factors were measured to screen oil-phase anti-inflammatory compositions. Cells were cultured at 5 × 10⁶ cells / mL. 3 Cells were seeded per well into 96-well culture plates. After 24 h of seeding, cells were stimulated for 24 h with different concentrations of LPS (100 μg / mL, 75 μg / mL, 50 μg / mL, 25 μg / mL, 10 μg / mL, 5 μg / mL, 2.5 μg / mL, 1 μg / mL). The optimal stimulation conditions for LPS were determined by combining cell viability and cytokine (NO) levels, and an inflammation model was established for subsequent experiments (LPS concentration 5 μg / mL). The levels of TNF-α and IL-6 in the cell supernatant were measured using an ELISA kit according to the product instructions. The NO level in the cell culture supernatant was measured according to the product instructions.

[0057] Cytokine inhibition rate % = (Model group - Experimental group) / Model group × 100% Cells were loaded at 5 × 10 3 Cells were seeded per well into 96-well plates. After 24 hours, cells containing LPS (final concentration 5 μl / mL) and different concentrations of experimental samples (reconstituted with DMSO to final concentrations of 10 μL / mL, 5 μL / mL, and 1 μL / mL) were cultured at 37±1℃ for 24 hours. Cell viability was then determined by the MTT assay. Appropriate concentrations were selected based on cell viability for subsequent assays of inflammatory factors. The components of each experimental sample and their inhibitory effects on different inflammatory factors are shown below. Figure 1 and Figure 2 As shown.

[0058] The experimental results show that, at different concentrations, the overall inhibitory effect of experimental cases 1-6 on inflammatory factors was higher than that of experimental cases 7-10. Figure 1 The results show that Example 1 exhibited superior inhibitory effects on TNF-α at different concentrations compared to other examples. Figure 2 The results show that, at sample concentrations of 5–10 μL / mL, the inhibitory effects of experiments 7–10 on IL-6 were significantly lower than those of experiments 1–6, with experiment 1 showing the best inhibitory effect on inflammatory factors. Figure 1 and Figure 2 The results showed that the combination of the three oils in Experiment 1 had a synergistic effect in inhibiting inflammatory factors. The oil phases selected in this application were sesame seed oil, egg yolk oil and sea buckthorn seed oil in a mass ratio of 1:1:1 for subsequent experiments.

[0059] III. Preparation of Azelaic Acid Cream Based on the preparation experiments of the azelaic acid premixed dispersion and the screening results of functional oils in the oil phase, dispersion 2 and Experimental Example 1 were further prepared into a cream. The component contents of each embodiment are shown in Tables 4 and 5. The specific preparation methods are as follows: 1. Preparation of the oil phase Weigh the oils and emulsifiers from the oil phase, heat them in a water bath to 80℃~85℃, stir with auxiliary stirring, keep warm for 30 minutes, and observe the state of the oil phase. A clear, transparent state without particles indicates complete dissolution. The functional oil combination in the oil phase is added before homogenization. In the oil phase, in addition to the functional oil combination and commonly used moisturizing oils, sunflower seed wax plays an important role in the subsequent state and structure of the cream. Therefore, it is necessary to pay attention to the dissolution state of this substance in the oil phase and whether it can be evenly distributed in the cream afterward.

[0060] 2. Preparation of the thickening phase Different thickeners, including ammonium acryloyl dimethyl taurate / VP copolymer, Viscolam AT 100 P, SEPIPLUS265, and xanthan gum, were weighed in proportion and heated and stirred at 80℃~85℃ to swell, forming a thickening phase. The thickening phase was a semi-transparent, homogeneous, non-flowing gel.

[0061] 3. Preparation of active ingredient solution Arginine was dissolved in water and then mixed with hydrolyzed flax extract to form an active ingredient solution.

[0062] 4. Preparation of Cream After the heated and dissolved oil phase is mixed with the thickening phase, the high-speed homogenizer is run at 2900 rpm to 3000 rpm for 6 min. Then, the azelaic acid dispersed phase is added, and the high-speed homogenizer is continued for 5 min. After homogenization and cooling, the system is cooled to below 45°C, and the active ingredient solution and preservative are added. The mixture is stirred at medium to low speed for 5 min.

[0063] Table 4 Component parameters of Examples 1-8

[0064]

[0065] The amount of each component added in the table is in parts by mass, and the balance refers to adding up to 100 parts by mass.

[0066] Table 5 Component parameters of Examples 9-17

[0067]

[0068] The amount of each component added in the table is in parts by mass, and the balance refers to adding up to 100 parts by mass.

[0069] IV. Physicochemical properties and stability of the cream Sample stability was tested using a Turbiscan Lab stability analyzer (Formulaction, Turbiscan Lab, France) with multiple light scattering. The instrument's measuring probe consists of a pulsed near-infrared light source (wavelength 880 nm) and two synchronized detectors. The probe moves vertically within the sample cell, ranging from 0 to 55 mm, to scan the entire sample. Transmitted and backscattered light data are collected every 40 μm. The resulting graphs characterize the uniformity of sample concentration and particle size. The test results were obtained by measuring the ΔBS value and thermodynamic stability parameter (TSI) value under heat resistance conditions (40℃) and freeze-thaw conditions (-20℃) within 24 hours. Generally, 0 < ΔBS < 5% is considered absolutely stable, 5% < ΔBS < 8% is considered relatively stable, and ΔBS > 8% is considered unstable. A TSI value between 0 and 0.5 is considered A+ level, indicating good stability; a TSI value between 0.5 and 1 is considered A level, indicating fair stability; a TSI value between 1.0 and 3.0 is considered B level, indicating moderate stability, and so on. Simultaneously, the measured characteristic fingerprint spectrum was also used. More stable samples yielded more stable and unchanged fingerprint spectrum signals, with a neat, flat, and fluctuation-free spectrum. The test results of various embodiments and comparative examples are shown in Table 6.

[0070] Table 6. Stability test results of each cream sample

[0071]

[0072] In the table, "-" indicates that a stable system has not yet been formed.

[0073] The results of Examples 1 and 9 show that sunflower seed wax has a certain promoting effect on the stability of the cream. However, the results of Examples 1 and 2 show that excessive sunflower seed wax content can affect the stability of the system. Furthermore, the results of Examples 3 and 4 show that in the SEPIPLUS 265 thickening system, excessive sunflower seed wax content results in poor solubility and particle precipitation in the product appearance.

[0074] The experimental results comparing Examples 1 and 5, and Examples 2 and 6, show that replacing PolyAquoltM-2W with MONTANOV 68 significantly reduced the stability of the product.

[0075] The experimental results comparing Examples 1 and 7, Examples 2 and 8, and Examples 13 and 15 show that replacing the ammonium acryloyl dimethyl taurate / VP copolymer with SEPIPLUS 265 in the thickener system significantly reduces the stability of the product.

[0076] The experimental results of Examples 1 and 10, or Examples 9 and 10, show that when sunflower seed wax is not added to the system and the emulsifier is replaced by MONTANOV 68 instead of PolyAquolt M-2W, the stability of the product decreases. However, the experimental results of both examples show that sunflower seed wax and PolyAquolt M-2W contribute significantly to the stability of the product. Similarly, the comparison between Examples 15 and 16 also shows that PolyAquolt M-2W has a better stabilizing effect on the system than MONTANOV 68 emulsifier.

[0077] Comparing Example 1 and Example 11, in Example 11, no sunflower seed wax was added and the thickener ammonium acryloyl dimethyl taurate / VP copolymer was replaced with SEPIPLUS 265. Similarly, comparing Example 9 and Example 11, without adding sunflower seed wax, the ammonium acryloyl dimethyl taurate / VP copolymer was replaced with SEPIPLUS 265. The stability of the products decreased in both cases, indicating that sunflower seed wax and ammonium acryloyl dimethyl taurate / VP copolymer have a synergistic effect on the stability of the products.

[0078] As can be seen from the comparison between Examples 11 and 12, or from the comparison between Examples 13 and 14, the emulsifier PolyAquoltM-2W has a better stabilizing effect on the system than MONTANOV 68.

[0079] According to the experimental results in Table 6, the ΔBS of Examples 1, 9, 13, and 17 under high-temperature freeze-thaw conditions was all within 5%, and their thermodynamic stability was all above Grade A. This indicates that the combination of emulsifier PolyAquoltM-2W, thickener ammonium acryloyldimethyl taurate / VP copolymer, Viscolam AT 100 P, and xanthan gum is the optimal stable combination.

[0080] The results of Examples 1 and 13 show that the stability of the product also decreases when the active substances hydrolyzed flax extract and L-arginine are not added to the system, indicating that the active substances of this application also contribute to the stability of the system.

[0081] The results from Examples 1 and 17 show that the natural oil system in this application can not only inhibit inflammatory factors, but also contribute to the improvement of product stability.

[0082] In summary, the product prepared in Example 1 of this application exhibits the best stability, and its relevant test parameters are shown in [link to relevant test parameters]. Figures 3-6 As shown.

[0083] IV. Determination of Azelaic Acid Content in Cream The azelaic acid content in the above embodiments was analyzed using gas chromatography, with quantification using the external standard method. An appropriate amount of sample (accurate to 0.001 g) was weighed, 2 mL of ethanol was added, and the mixture was vortexed for 1 min. Then, 0.8 mL of concentrated sulfuric acid was added, and the mixture was vortexed for 1 min. Derivatization was performed at room temperature for 10 min; this was the derivatization solution. 5 mL of n-hexane was added to the derivatization solution, and the mixture was vortexed for 2 min. After centrifugation for 5 min, the upper n-hexane layer was collected in a 50 mL graduated tube. The lower derivatization layer was extracted twice more by adding 5 mL of n-hexane, and the three n-hexane layer extracts were combined in a 50 mL graduated tube. Add saturated sodium bicarbonate solution dropwise to the hexane extract, cap, shake while continuously releasing gas, centrifuge for 5 min, transfer the hexane layer to a 15 mL graduated tube, blow with nitrogen at room temperature to 3 mL, transfer to a 5 mL volumetric flask, wash the 15 mL graduated tube with a small amount of hexane, combine the washes with the washes in the 5 mL volumetric flask, and accurately dilute to the mark. This is the sample solution, ready for instrumental testing. The changes in azelaic acid content in each example are as follows: Figure 7 As shown.

[0084] The experimental results show that the azelaic acid content in Examples 1, 13, and 17 remained stable within 6 months of storage at room temperature, while the azelaic acid content in Example 9 decreased after 3 months. These results indicate that, in this application, sunflower seed wax can form a high-hardness three-dimensional wax network with other oils at a relatively low dosage, which not only stabilizes the appearance and structure of the azelaic acid cream but also promotes the stability of its content.

[0085] V. Experiment on the effect of azelaic acid cream in inhibiting melanin In the later stages of acne, acne scars and pigmentation are important issues that need to be addressed. Therefore, the melanin inhibition effect of each embodiment in this application was examined. Examples 1, 13, and 17 were subjected to an intracellular pigmentation inhibition experiment to determine the melanin content.

[0086] Logarithmic growth phase B16-F10 cells were seeded in T25 cell culture flasks and cultured overnight at 37°C in a 5% CO2 incubator. After stimulating the cells with 5 mL of different concentrations of sample (1%, 0.1%, 0.01%) for 48 h, the supernatant was discarded, and the cells were washed twice with 1 mL PBS. 500 μL of trypsin was added to each flask. After all cells detached, 500 μL of DMEM complete medium was added to stop digestion, and the cells were centrifuged at 1000 rpm for 5 min. The supernatant was discarded, and 700 μL of 1 mol·L⁻¹ sodium bicarbonate was added to each flask. -1 NaOH (containing 10% DMSO) was added, and the sample was incubated in a water bath at 80℃ for 30 min. 200 μL of the solution was absorbed into each well, and three replicates were set up for each concentration sample. The absorbance was measured at 490 nm.

[0087] Cmelanin = (OD sample - OD blank control) / (OD cell control - OD blank control) × 100% In the formula: Cmelanin is the relative content of melanin, %; ODsample is the absorbance of the reaction system containing the test sample; ODblank is the absorbance of the empty plate without any substance; ODcell is the absorbance of the reaction system without the test sample.

[0088] The melanin inhibition experimental results of Examples 1, 13, and 17 are shown below. Figure 8 As shown.

[0089] The experimental results show that Examples 1 and 13 have a high inhibitory effect on pigment in melanocytes. In this application, the combination of natural functional oils in the functional oil phase also has the effect of assisting in the inhibition of melanin. Among them, sea buckthorn seed oil contains unsaturated fatty acids, flavonoids and vitamin C, which can synergistically enhance the whitening and melanin-lightening effects with azelaic acid.

[0090] VI. Mildness Test of Azelaic Acid Cream High-content azelaic acid is prone to cause irritation and burning sensation during application. Therefore, based on the results of the melanin inhibition experiment, pH measurement and chicken embryo irritation test were performed on the samples of Example 1 and Example 13. The test method was carried out in accordance with the experimental standard "SN / T 2329 - 2009". Experimental materials: chicken embryos, SPF grade (White Leghorn chicken), provided by Xingxing Dahuanong Poultry & Egg Co., Ltd. (Production License: SCXK(Guangdong)2018-0019); other materials: incubator with automatic rotating tray, stereomicroscope, electronic timer, egg candler, pipette and disposable matching tips, pointed forceps, electronic timer, etc. Test conditions: incubator temperature 37.5±0.2°C, relative humidity 55%~65%. Control: 1% SDS was used as positive control, and normal saline was used as negative control. HET-CAM procedure: 9-day-old chicken embryos were taken for egg candling examination, and the position of the air chamber was marked on the surface of the eggshell; the marked eggshell part was peeled off with a dental serrated curved forceps to expose the white egg membrane, an appropriate amount of normal saline was added to moisten the egg membrane, and then the egg membrane was carefully peeled off with a curved dental forceps to expose the chorioallantoic membrane. Visually observe the integrity of the chorioallantoic membrane and whether there are bleeding points and other changes. If there are bleeding points or damage to the chorioallantoic membrane (CAM), the chicken embryo shall be eliminated and cannot be used for further testing. Careful operation shall be taken not to damage the integrity of the egg membrane. 0.3 g of the test sample was directly dropped onto the surface of the CAM, the reaction of the CAM was observed, and the occurrence time of each toxic effect within 5 minutes of application was recorded. 6 valid chicken embryos were tested for each sample.

[0091] Result calculation and evaluation:

[0092] In the formula: sec H is the average time (in seconds, s) when hemorrhage is first observed on the CAM; sec L is the average time (in seconds, s) when lysis of blood vessels is first observed on the CAM; sec C is the average time (in seconds, s) when coagulation is first observed on the CAM.

[0093] The eye irritation of the test substance is classified according to the calculated IS value in accordance with Table 7, and the test results of Example 1 and Example 13 are shown in Table 8 and Table 9.

[0094] Table 7 Irritation Classification and Evaluation Table

[0095] Table 8 Irritation Score Table of Example 13

[0096] Table 9 Irritation Score Table of Example 1

[0097] According to the experimental results, the irritation of Example 1 is lower than that of Example 13. The pH value of the product shows that Example 1 is less acidic, which is one reason for its lower irritation. Arginine in Example 1, as a basic amino acid, can regulate the pH of the system, stabilizing it above 4 and reducing irritation. Simultaneously, the hydrolyzed flax extract can improve the skin's own water-locking function by enhancing cell hydrophilicity, keeping the skin moisturized and synergistically reducing irritation.

[0098] VII. Human Efficacy Test of Azelaic Acid Cream Based on the irritation evaluation test, human efficacy testing was conducted on Example 1. Ten subjects were selected. Volunteer inclusion criteria: age 18-35 years, self-assessment of oily or combination skin with obvious acne symptoms. According to the "Clinical Grading of Acne" standard, they met the requirements for grade 2-3 mild to moderate acne symptoms. During the testing phase, the subjects had no skin allergies and had not taken any medications that could affect the experiment; they had not participated in any similar tests within one month prior to the test. They were able to strictly adhere to the requirements of the test method and signed informed consent forms. Exclusion criteria: those who experienced adverse reactions or failed to comply with the test requirements during the test. Product usage method: Depending on the size and area of ​​facial acne, the product was applied either to the affected areas or to the entire acne area. Photos were taken and follow-up was conducted at weeks 0, 1, and 2 of product use to compare the before-and-after results. The improvement in acute acne and acne scars was observed within 2 weeks. Improvement in some subjects is shown in [link to relevant documentation]. Figures 9-12 Experimental results show that this application can enhance the solubility, stability, and efficacy of high-concentration azelaic acid in the system. It soothes the irritation of azelaic acid and has a good effect on improving acne, pimples, and acne scars.

[0099] As can be seen from the technical solution of this application, this application pre-mixes and disperses azelaic acid with a specific proportion of polyol solvent to prepare a stable premixed dispersion through premixing and stepwise homogenization. This premixed dispersion is then combined with a specific proportion of functional oil phase to prepare a cream. The sunflower seed wax in the functional oil phase forms a high-hardness three-dimensional wax network structure at a low dosage, providing a stable framework for the cream and stabilizing the dispersion and content of 20% azelaic acid in the cream. Simultaneously, the oil combination in the functional oil phase synergistically reduces pigmentation and improves skin irritation during use. This results in a uniform, stable, and lightweight cream with a 20% azelaic acid content, which helps improve acne and subsequent acne scar pigmentation, and is convenient and safe to use.

[0100] In the above embodiments, the descriptions of each embodiment have different focuses. For parts not described in detail in a certain embodiment, please refer to the relevant descriptions in other embodiments.

[0101] The foregoing has provided a detailed description of an azelaic acid dispersion system, an azelaic acid-containing preparation, a preparation method, and an application provided in the embodiments of this application. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the methods and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.

Claims

1. An azelaic acid dispersion system, characterized in that, The system includes azelaic acid and a polyol system, wherein the polyol system includes propylene glycol, glycerol and 1,2-pentanediol; the mass ratio of azelaic acid, propylene glycol, glycerol and 1,2-pentanediol is (5~10):(5~10):(0.8~1.2):(0.8~1.2).

2. A preparation containing azelaic acid, characterized in that, Including the azelaic acid dispersion system as described in claim 1; and / or, The azelaic acid content is 15% to 45% by weight based on the total mass of the preparation.

3. The preparation containing azelaic acid according to claim 2, characterized in that, The preparation also includes functional oils, which include one or more of sesame seed oil, egg yolk oil, and sea buckthorn seed oil.

4. The preparation containing azelaic acid according to claim 3, characterized in that, The mass ratio of sesame seed oil, egg yolk oil, and sea buckthorn seed oil is (0.8~1.2):(0.8~1.2):(0.8~1.2); and / or, The functional oils also include sunflower seed wax.

5. The preparation containing azelaic acid according to claim 2, characterized in that, The formulation also includes a thickener system comprising one or more of ammonium acryloyldimethyl taurate / VP copolymer, Viscolam AT 100 P, SEPIPLUS 265, and xanthan gum.

6. The preparation containing azelaic acid according to claim 2, characterized in that, The formulation further includes an emulsifier system, said emulsifier system comprising one or both of PolyAquoltM-2W and MONTANOV 68; and / or, The formulation also includes an active composition comprising one or both of hydrolyzed flax extract and L-arginine.

7. The preparation containing azelaic acid according to claim 2, characterized in that, The formulation further includes a skin-moisturizing system, which comprises one or both of polydimethylsiloxane and myristyl myristate; and / or, The formulation also includes tocopherol acetate.

8. A preparation containing azelaic acid, characterized in that, The formulation, by weight, comprises: 15-25 parts azelaic acid, 15-25 parts propylene glycol, 2.5-3.5 parts glycerin, 2.5-3.5 parts 1,2-pentanediol, 1.5-2.5 parts sesame seed oil, 1.5-2.5 parts egg yolk oil, 1.5-2.5 parts sea buckthorn seed oil, 0.5-1.5 parts tocopheryl acetate, 0.5-1.5 parts polydimethylsiloxane, 1.5-2.5 parts myristyl myristate, 2.5-3.5 parts sunflower seed wax, 0.5-1.5 parts ammonium acryloyl dimethyl taurate / VP copolymer, and 0.15-0.4 parts Viscolam AT 100. P, 0.01 to 0.1 parts xanthan gum, 2.5 to 3.5 parts PolyAquolt M-2W, 0.5 to 1.5 parts hydrolyzed flax extract, 1 to 2 parts L-arginine, 0.2 to 1 part preservative.

9. A method for preparing an azelaic acid-containing preparation, characterized in that, Includes the following steps: Preparation of azelaic acid dispersion system: Azelaic acid is mixed with a polyol system, heated, and homogenized to form a premixed dispersion phase; Preparation of the oil phase: Weigh the functional oils and emulsifier system in the oil phase and heat to 80℃~85℃ to dissolve; Preparation of the thickening phase: The thickener system is heated and stirred at 80℃~85℃ to swell and form a thickening phase; Preparation of active ingredient solution: Arginine was dissolved in water and then mixed with hydrolyzed flax extract to form an active ingredient solution; Preparation of cream: After heating and dissolving the oil phase and the thickening phase, the mixture is homogenized at a high speed of 2900-3000 rpm; then the azelaic acid dispersion system is added and homogenization at a high speed is continued. After homogenization and cooling, add the active ingredient solution and preservative, and stir until homogeneous.

10. The use of an azelaic acid dispersion system as described in claim 1, or an azelaic acid-containing preparation as described in any one of claims 2 to 8, or an azelaic acid-containing preparation prepared by the method described in claim 9, in the preparation of an acne treatment preparation.

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