Azelaic acid liquid salt, its preparation method and application

Abstract

This invention relates to a liquid azelaic acid salt, which is a room-temperature liquid salt produced by mixing azelaic acid with an amino-containing compound. The amino-containing compound is a primary, secondary, or tertiary amine; it does not contain a cyclic structure, has no more than 10 carbon atoms, and does not contain any amino-containing compounds that are prohibited or restricted from use in cosmetics or topical skin medications. The present invention forms a liquid salt by combining azelaic acid with several specific amino-containing compounds. Its typical characteristics are that it is a liquid salt at room temperature, possessing liquid properties, and can be directly applied to the skin. It can also be diluted and miscible with water or other solvents to prepare formulations, increasing the azelaic acid content in the formulation to an effective concentration. This effectively improves the solubility and compatibility of azelaic acid and solves the skin irritation problems caused by existing solubilizers.

Description

Technical Field

[0001] This invention belongs to the field of topical skin medicines or cosmetics, specifically relating to azelaic acid liquid salt, its preparation method, and its application. Background Technology

[0002] Azelaic acid is a 9-carbon straight-chain dicarboxylic acid, also known as azelaic acid. It is a colorless or pale yellow crystal or powder with a melting point of 98-103℃. It is slightly soluble in cold water, soluble in hot water and ether, and readily soluble in ethanol. Azelaic acid can directly inhibit melanocytes, inhibit and kill bacteria, and has anti-inflammatory and cell proliferation-inhibiting pharmacological effects. Therefore, azelaic acid is widely used in the treatment of acne, melasma, rosacea, and hyperpigmentation. However, when used in topical products, the required dosage of azelaic acid is relatively high, and its low solubility greatly limits its application.

[0003] Currently, azelaic acid is used clinically in dosage forms such as creams, ointments, and gels, for example... Cream Cream gel, Azelaic acid is typically found in gels and similar formulations. While the concentration of azelaic acid in these formulations is generally 10-20%, its solubility in water is only about 0.24 g / 100 g. Even with cream or gel bases containing large amounts of surfactants, complete dissolution of azelaic acid in the formulation is not achievable. This not only results in a gritty texture or demulsification but also reduces the bioavailability of azelaic acid. Furthermore, excessive use of oily excipients leads to a heavy, oily feel in the product, and the use of large amounts of surfactants causes significant side effects. Therefore, increasing the solubility of azelaic acid is crucial for improving the efficacy, compatibility, and product stability of related formulations / cosmetics.

[0004] For example, Chinese Patent Publication No. CN108553411B discloses an azelaic acid gel and its preparation method, which increases the solubility of azelaic acid by using 1,3-propanediol. Although this allows azelaic acid to be completely dissolved in the formulation, the amount of 1,3-propanediol used is as high as 60-74%. 1,3-propanediol is a hygroscopic viscous liquid, and contact with it by people with allergies may irritate the local skin, causing skin allergies, erythema, itching, and other discomforts, and may also cause side effects such as local burning pain. As another example, Chinese Patent Publication No. CN112220741A discloses a transparent gel with an azelaic acid concentration of 20%. This method uses carbitol as a solvent to increase the solubility of azelaic acid in the formulation, but its amount is as high as 40-70%, and it needs to be combined with 10%-30% 1,3-propanediol, which is also prone to causing adverse reactions such as skin irritation and allergies. Chinese Patent Publication No. CN111956637A discloses an azelaic acid acne ointment and its preparation method, which uses 15%-25% fatty alcohol, 50%-70% polyol, and 2%-10% emulsifier to solubilize azelaic acid. Clearly, the extensive use of these alcohol solvents also poses a risk of skin irritation and other side effects. Chinese Patent Publication No. CN111249224B discloses an oil-free azelaic acid gel, which uses 1%-3% shellac resin and 10%-22% 1,3-propanediol in combination to increase the solubility of azelaic acid. The irritation and side effects of high concentrations of 1,3-propanediol on the skin cannot be ignored. Shellac resin is an amphiphilic block copolymer and can exert a solubilizing effect similar to a surfactant. However, shellac resin is a high molecular weight polymer with high viscosity, which may hinder the transdermal absorption of azelaic acid and cause discomfort such as a heavy feeling and stuffiness / lack of breathability on the skin. Chinese Patent Publication No. CN111544381B discloses a topical skin administration composition for azelaic acid, which increases the solubility of azelaic acid through microemulsion. Microemulsions consist of an oil phase, surfactants, and co-surfactants, requiring large amounts of surfactants and co-surfactants to form, which can easily cause skin irritation. Furthermore, the microemulsion itself cannot penetrate the stratum corneum; azelaic acid needs to be released from the microemulsion droplets to be absorbed. The stronger the solubilizing effect of the microemulsion droplets, the more likely it is to hinder the release and transdermal absorption of azelaic acid, making it difficult to improve its absorption and utilization rate. Chinese Patent Publication No. CN114767559A discloses a method for preparing an azelaic acid liposome cream, but its solubilizing effect on azelaic acid is limited; the concentration of azelaic acid in each embodiment does not exceed 5%, and low concentrations of azelaic acid are insufficient to exert its bactericidal and anti-inflammatory activities. Chinese Patent Publication No. CN108143639A discloses an azelaic acid acne cream, which uses hydroxypropyl-β-cyclodextrin to increase the solubility of azelaic acid. However, the maximum content of azelaic acid in the formulation is 2%, which cannot reach the release level equivalent to that of FDA-approved drugs.Chinese patent publication CN112587446A discloses an azelaic acid composition that uses β-cyclodextrin to increase the solubility of azelaic acid. However, the maximum content of azelaic acid in the formulation is 4%, which still cannot achieve the release level equivalent to that of FDA-approved drugs.

[0005] Clearly, traditional methods such as adding organic solvents, encapsulating with nanocarriers, and encapsulating with cyclodextrins have limited solubilizing ability for azelaic acid and cannot simultaneously address the issues of azelaic acid solubilization and excipient irritation, thus failing to fully realize the physiological activity and therapeutic effects of azelaic acid.

[0006] Chinese Patent Publication No. CN112624918B discloses a method for preparing azelaic acid with an organic base to form a eutectic, which improves the apparent solubility of azelaic acid to some extent, but the solubilizing effect is still limited. The preferred eutectic can only increase the solubility of azelaic acid to 63.22 g / L, which is still lower than the concentration requirements of azelaic acid in commercially available formulations. It should be noted that there is a fundamental difference between a eutectic and a salt. The former is formed by non-ionic and non-covalent bonds, while the latter is a crystalline compound formed by the substitution of some or all of the acidic hydrogen by metal or metalloid groups, resulting in ionic or electrovalent bonds (bonds formed by two atoms sharing electrons). Therefore, although this patent uses a combination of azelaic acid and an organic base, no proton transfer occurs in the eutectic, and azelaic acid still exists in a free form. Even after the eutectic dissolves, azelaic acid remains in a free form, thus having a limited solubilizing effect. However, if azelaic acid is salted with an organic base, it exists in an ionic state, which can further improve its solubility. For example, Chinese Patent Publication No. CN110623949A discloses a whitening composition of azelaic acid monometallic salt and monobenzone, and its preparation method, which uses a salt-forming method to increase the solubility of azelaic acid. However, the solubilizing ability of monometallic salts is limited, and the content of azelaic acid in the formulation is still difficult to exceed 10%. Another example is Chinese Patent Publication No. CN113248364A, which discloses a method for solubilizing azelaic acid by compounding it with alkaline substances (such as theophylline, echinocoline, carnitine, etc.) to increase its solubility in water. Similar to the aforementioned monometallic salts, this also increases the solubility of azelaic acid through salt formation, but the specific solubilizing ability is not disclosed in its specification. Most importantly, these salts are solid at room temperature and still require water to dissolve in the formulation, failing to improve the compatibility of azelaic acid and severely limiting the formulation form of the product. The solubility of these salts also limits the content of azelaic acid in the formulation and its activity. Summary of the Invention

[0007] (a) Technical problems to be solved

[0008] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a liquid salt of azelaic acid and its preparation method. The liquid salt is formed by azelaic acid and several specific amino-containing compounds. Its typical characteristics are that it is a liquid salt at room temperature, has liquid properties, can be directly applied to the skin, or can be diluted and miscible with water or other solvents to prepare preparations. It can increase the content of azelaic acid in the preparation to an effective concentration, effectively improve the solubility and compatibility of azelaic acid, and solve the skin irritation problems caused by various existing solubilizers.

[0009] (II) Technical Solution

[0010] In a first aspect, the present invention provides a liquid azelaic acid salt, which is a salt that is liquid at room temperature, produced by mixing azelaic acid and an amino-containing compound, wherein the amino-containing compound is a compound containing a primary amine, a secondary amine, or a tertiary amine; the amino-containing compound does not contain a cyclic structure, has no more than 10 carbon atoms, and does not contain amino-containing compounds that are prohibited or restricted from use in cosmetics or topical skin medications, such as choline, diethanolamine, etc.

[0011] According to a preferred embodiment of the present invention, the amine-containing compound contains hydroxyl groups, and the number of hydroxyl groups is one or more. Preferably, the number of hydroxyl groups in the amine-containing compound is ≥3.

[0012] According to a preferred embodiment of the present invention, the number of carbon atoms in the amine-containing compound does not exceed 7.

[0013] According to a preferred embodiment of the present invention, wherein,

[0014] The amino-containing compound is meglumine or tromethamine; or

[0015] The amine-containing compound is a combination of triethanolamine and meglumine or tromethamine; or

[0016] The amino-containing compound is a combination of tromethamine and meglumine; or

[0017] The combination of the amino compounds triethanolamine, meglumine, and tromethamine.

[0018] Preferably, the amine-containing compound is a combination of triethanolamine and meglumine in a molar ratio of 0.5-1:0.5-1, or a combination of triethanolamine and tromethamine in a molar ratio of 0.5-1:0.5-1, or a combination of triethanolamine, meglumine, and tromethamine in a molar ratio of 0.5-1:0.5-1:0.5-1.

[0019] According to a preferred embodiment of the present invention, the total molar ratio of azelaic acid to the amine-containing compound in the azelaic acid liquid salt is 2:1-1:2; more preferably 1:1.5-1:2.

[0020] Secondly, the present invention provides a method for preparing azelaic acid liquid salt, comprising: dissolving azelaic acid and an amine-containing compound in an organic solvent or a mixture of organic solvent and water, stirring evenly at room temperature or by heating, and removing the solvent to obtain the azelaic acid liquid salt; wherein the method for removing the solvent is: first evaporating (e.g., rotary evaporation) to remove most of the organic solvent, and further removing the residual solvent (a small amount of organic solvent and water) by freeze drying or vacuum drying.

[0021] Thirdly, the present invention also relates to a method for preparing a topical skin medicine or skin care product containing azelaic acid, comprising: first preparing the azelaic acid liquid salt, diluting it with sterile water or without dilution, and then adding a moisturizer (such as glycerin), a therapeutic / cosmetic active substance, a matrix material, or a functional additive to prepare a topical skin medicine or skin care product; the product form of the topical skin medicine or skin care product is semi-solid or liquid; the formulation is a dispersion, emulsion, ointment, gel, mask, spray, sheet with non-woven fabric as the adsorption substrate, etc., as medical products or skin care products.

[0022] The functional additives include one or more of the following: preservatives, mildew inhibitors, emulsifiers, foaming agents (for skin cleansing products), antioxidants, fragrances, pH adjusters, etc. The product may also be without the aforementioned functional additives.

[0023] According to a preferred embodiment of the present invention, the content of azelaic acid liquid salt in the topical skin medicine or skin care product is 0.1-80 wt%; preferably 2-40 wt%.

[0024] Fourthly, the present invention also relates to the use of the azelaic acid liquid salt in the preparation of topical skin medicines or skin care products.

[0025] Preferably, the topical skin medication or skin care product is a skin medication or skin care product for whitening and removing blemishes (including melasma and hyperpigmentation), treating acne, or combating acne or rosacea.

[0026] (III) Beneficial Effects

[0027] This invention provides an azelaate that is liquid at room temperature and miscible with water. It not only significantly improves the solubility of azelaic acid in water but also enhances its compatibility. The azelaate can be directly diluted or mixed evenly with ointments, gels, or other bases to complete the formulation. This effectively increases the absolute content / concentration of azelaic acid in the formulation, thereby better exerting its therapeutic activity and reducing the formulation's dependence on solubilizers, emulsifiers, surfactants, alcohol solvents, amphiphilic copolymers such as shellac resin, and oily excipients. It solves the technical problems of current azelaic acid formulations, such as the difficulty in increasing the concentration of azelaic acid to an effective level, side effects such as skin discomfort or allergies caused by the use of large amounts of excipients, and the fact that it is a solid at room temperature, making it difficult to be compatible with other components. Attached Figure Description

[0028] Figure 1 This invention relates to a type of azelaic acid liquid saline dispersion and a commercially available formulation. Transdermal transport volume during ex vivo transdermal delivery.

[0029] Figure 2 This invention relates to a type of azelaic acid liquid saline dispersion and a commercially available formulation. The amount of skin residue during ex vivo transdermal treatment.

[0030] Figure 3 This invention relates to a type of azelaic acid liquid salt gel and its marketed formulation. Transdermal transport volume during ex vivo transdermal delivery.

[0031] Figure 4 This invention relates to a type of azelaic acid liquid salt gel and its marketed formulation. The amount of skin residue during ex vivo transdermal treatment.

[0032] Figure 5 This invention provides a preferred azelaic acid liquid salt gel and a commercially available formulation. The effect of saline solution on the inhibition of ear swelling rate in acne model mice.

[0033] Figure 6 This invention provides a preferred azelaic acid liquid salt gel (1) and a commercially available formulation. (2) Pathological sections of the ears of acne model mice and healthy mice after administration of saline (3) and physiological saline (4).

[0034] Figure 7 This invention provides a preferred azelaic acid liquid salt gel (1) and a commercially available formulation. (2) The condition of the back skin of positive control (3) and healthy rats (4) after administration.

[0035] Figure 8 This invention provides a preferred azelaic acid liquid salt gel (1) and a commercially available formulation. (2) Positive control (3) and healthy rat (4) back pathological sections after administration. Detailed Implementation

[0036] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0037] This invention primarily involves screening amine compounds that form salts with azelaic acid to identify specific amine compounds that can form liquid salts with azelaic acid. A key characteristic of these compounds is that the azelaic acid salt is liquid at room temperature, exhibiting solvent properties, allowing for direct application to the skin, and is miscible with water. Therefore, this not only improves the solubility of azelaic acid but also enhances its compatibility, allowing for direct dilution or uniform mixing with ointments, gels, and other bases to complete formulation. These amine compounds share common properties, primarily being compounds containing primary, secondary, or tertiary amines; and typically lacking cyclic structures and containing no more than 10 carbon atoms. Amine compounds without cyclic structures and with no more than 10 carbon atoms react more readily with azelaic acid to form liquid salts at room temperature. Furthermore, the amine compounds possess one or more hydroxyl groups, and these multiple hydroxyl molecules readily form hydrogen bonds, ultimately resulting in a nearly viscous, watery substance that is easily dispersed in water or aqueous dispersions.

[0038] It should be noted that the applicant had screened other types of amine-containing compounds (see comparative examples), all of which could form salts with azelaic acid, but were solid at room temperature and could not form liquid salts that were liquid at room temperature, thus completely lacking the characteristics and application advantages of the azelaic acid liquid salt described in this invention. The same applies to metal salts formed with inorganic bases such as sodium hydroxide; they are solid at room temperature and cannot be directly applied to the skin, and their application is limited by the solubility of these salts in formulations. Furthermore, in this invention, the compounds that form salts with azelaic acid do not include amine-containing compounds that are prohibited or restricted from use in cosmetics or topical skin medications, such as choline and diethanolamine (a Group 2B carcinogen), which should be excluded. The azelaic acid liquid salt involved in this invention is fundamentally different from other azelaic acid salts and is the embodiment of the innovation of this application.

[0039] Examples 1-17

[0040] Examples 1-17 are liquid salts of azelaic acid, which are liquid at room temperature. 1.88 g of azelaic acid and the amounts of the amine-containing compounds listed in Table 1 were mixed, dissolved in 20 mL of ethanol and an appropriate amount of water, and rotary evaporated under reduced pressure at 60 °C for 2 h. The product was then freeze-dried to obtain the reaction product. Examples 1-4 used single-component amine-containing compounds; Examples 5-13 used combinations of two of the three amine-containing compounds: tromethamine, meglumine, and triethanolamine; and Examples 14-17 used combinations of tromethamine, meglumine, and triethanolamine.

[0041] Table 1: Liquid salts of azelaic acid that are liquid at room temperature

[0042]

[0043]

[0044]

[0045] Examples 18-38

[0046] Examples 18-38 are azelaic acid liquid saline dispersions: Azelaic acid liquid salts with the compositions shown in Table 2 are mixed evenly with water to obtain the desired solution. Since these azelaic acid liquid salts are liquid at room temperature and possess solvent properties, they are miscible with water, allowing for azelaic acid concentrations in the formulations up to 40% (w / w). Rheological studies show that the obtained azelaic acid liquid saline dispersions are all Newtonian fluids with a certain viscosity, facilitating coating. The azelaic acid liquid saline dispersions in the table below can be used as anti-acne or whitening cosmetics, all composed of azelaic acid liquid salts and water, without any other solubilizers or dispersants.

[0047] Table 2: Formulation of Azelaic Acid Liquid Saline Dispersion

[0048]

[0049]

[0050] Examples 39-54

[0051] Examples 39-54 are azelaic acid liquid salt gels with different matrices: According to the formulations in Table 3, the azelaic acid liquid salts of the shown composition are mixed evenly with a small amount of water. A separate small amount of water is added to the gel matrix and allowed to swell completely. The two are then mixed, and the glycerol content shown in the prescription is added. Water is then added to the final volume and mixed evenly to obtain the gel. Rheological studies show that the obtained azelaic acid liquid salt gels are all non-Newtonian fluids with shear properties, suitable for skin application. All the gels described below consist of azelaic acid liquid salt, glycerol, a gel matrix (ZEN or carbomer), and water, and do not contain any other solubilizers or dispersants.

[0052] Table 3: Formulations of various azelaic acid ionic liquid gels

[0053]

[0054]

[0055] Note: In the table above, * indicates Carbomer 940; ** indicates Carbomer U20.

[0056] Comparative Examples 1-24

[0057] Comparative Examples 1-24 show the different azelaic acid salts obtained by changing the compounds that form salts with azelaic acid. The specific methods are as follows: 1.88 g of azelaic acid and the amount of the compound used in Table 4 (molar ratio 1:1) are mixed, 20 mL of ethanol and an appropriate amount of water are added to dissolve the mixture, and the mixture is rotary evaporated under reduced pressure at 60 °C for 2 h. The product is then freeze-dried to obtain the reaction product.

[0058] Table 4: Different types of azelaate

[0059]

[0060]

[0061] The experimental results above show that although azelaic acid can form salts with all the compounds in Table 4, except for the triethanolamine salt which is semi-solid, the other salts are solid at room temperature and do not exhibit the properties of liquid salts. Solids are more difficult to homogenize than liquids, and cannot effectively improve the solubility of azelaic acid or the compatibility of azelaic acid products. However, if triethanolamine is combined with tromethamine or meglumine before forming salts with azelaic acid, a stable and relatively homogeneous viscous liquid can be obtained (see Table 1). Therefore, changing the base or amine-containing compound that forms salts with azelaic acid does not necessarily yield a salt that is liquid at room temperature.

[0062] Test Example 1: In vitro transdermal properties of azelaic acid liquid saline dispersion

[0063] Experimental Methods: Hair was removed from the abdominal skin of SD rats using depilatory cream, and the rats were fed for one day to allow the stratum corneum to recover. The rats were then sacrificed, and the abdominal skin was harvested, with connective tissue and fat layers scraped off for use in the skin transport experiment. The diffusion cell had a receiving area of ​​1.77 cm². 2 The Franz diffusion cell was used, with a receiving solution of phosphate buffer solution in a volume of 7.7 mL. The skin surface temperature was controlled at 32 ± 1 °C using a constant temperature water bath. The drug delivery volume was 0.3 mL, and the drug delivery sample was the azelaic acid liquid saline dispersion prepared in Examples 23 and 27, and... At each time point, 0.2 mL of the receiving solution was collected and subjected to HPLC analysis to calculate the transdermal transport capacity of azelaic acid. The same procedure was followed, but skin samples were collected at each time point, minced, and extracted from the skin using an organic solvent. The extracted azelaic acid was then determined by HPLC to calculate the skin retention capacity of azelaic acid.

[0064] Experimental results: Figure 1 The image shows an azelaic acid liquid saline dispersion and a marketed formulation. The amount of transdermal transported outside the body. Results were observed after 4 hours. The skin permeability of the formulation was higher than that of the azelaic acid liquid saline dispersions in Examples 23 and 27; the azelaic acid liquid salts with different compositions in each example had basically similar in vitro transdermal effects. Since acne, pigmentation, and other conditions occur on the skin, treatment of these diseases requires higher local drug concentrations on the skin, rather than greater skin permeability, as this could lead to toxic side effects. Therefore, the skin retention of each formulation was further investigated. Figure 2 ). Figure 2 In the text, each group of bar charts, from left to right, represents Examples 23, 27, and... During the first 8 hours after administration, each formulation exhibited considerable skin retention. However, from 12 hours post-administration, the azelaic acid liquid saline dispersion of Example 23 showed a higher retention rate compared to... Higher skin retention capacity of azelaic acid; the skin retention capacity of azelaic acid in Example 27 was slightly lower than... However, there was no significant difference; furthermore, the skin retention capacity of the azelaic acid liquid saline dispersion in the other embodiments of the present invention was also similar to that of the other embodiments. There are no significant differences, and in terms of formulation, the composition of each embodiment of the present invention is more advanced than that of the others. Much simpler.

[0065] Test Example 2: In vitro transdermal properties of azelaic acid liquid salt gel

[0066] Experimental methods: The methods for investigating in vitro transdermal and skin retention were the same as in Test Example 1. The test formulations were azelaic acid liquid salt gels from Examples 39-44 and

[0067] Experimental results: Figure 3 The images show the various azelaic acid liquid salt gels and their marketed formulations. The in vitro transdermal transport capacity was similar to that of the azelaic acid liquid saline dispersion in Test Example 1, starting 4 hours after administration. The transdermal transport capacity of the azelaic acid liquid saline gels in Examples 39-44 was lower than that of the gels in Examples 39-44. from Figure 4 As observed, except for the slightly lower skin retention of azelaic acid liquid salt gel in Examples 41 and 44 measured at 12 hours, the results showed that... In addition, the skin retention of azelaic acid liquid salt gel in other embodiments measured at other times was actually higher than that of other embodiments. In particular, the 24-hour measurement indicates that azelaic acid liquid salt gel is suitable for the treatment of local skin diseases such as acne and pigmentation.

[0068] Test Example 3: Anti-acne ability of azelaic acid liquid salt gel

[0069] Experimental method: Apply 50 μL of 4% croton oil acetone solution to the left ear of Balb / c mice. After 15 min, apply 50 μL of azelaic acid liquid salt gel to the same area (Example 42). Or use physiological saline (negative control). Measure the thickness of both ears using calipers at 4 and 24 hours after medication application, and calculate the ear swelling rate using the following formula:

[0070] Swelling rate = (Left ear thickness - Right ear thickness) / Right ear thickness × 100%

[0071] The mice were sacrificed 24 hours later, their ears were cut off, stained with hematoxylin and eosin, and then subjected to pathological analysis. The normal right ear was used as a control.

[0072] Experimental results: Azelaic acid liquid salt gel (Example 42) Changes in ear swelling rate in acne model mice after administration of physiological saline (negative control) are as follows: Figure 5 As shown. It can be seen that the azelaic acid liquid salt gel (Example 42) exhibits better performance in the first 4 hours than... They exhibited stronger therapeutic effects, while showing similar efficacy over 24 hours. However, it should be noted that the concentration of azelaic acid in the azelaic acid liquid salt gel (Example 42) was only 10%, lower than... 15% of the total. The results of ear pathological section analysis in mice after administration of each formulation are as follows: Figure 6 As shown (1 is azelaic acid liquid salt gel (Example 42); 2 is...) Group 3 was physiological saline; Group 4 was a healthy group. As shown in the figure, after induction with croton oil, the untreated negative control group exhibited pathological phenomena such as epidermal thickening, while the azelaic acid liquid saline gel (Example 42) and... Both methods effectively inhibit epidermal thickening in the ear and have similar therapeutic effects. The above experiments demonstrate that when the desired therapeutic effect is similar, the azelaic acid liquid salt used in this invention can achieve comparable therapeutic effects at a lower concentration.

[0073] Test Example 4: Skin Irritation of Azelaic Acid Liquid Salt Gel

[0074] Experimental Methods: Hair was removed from the backs of SD rats using depilatory cream, and the rats were fed for one day to allow the stratum corneum to recover. 1 mL of azelaic acid liquid salt gel (Example 42) or [other gel] was applied to the backs of the rats daily. The positive control group was treated with 4% paraformaldehyde solution daily for five days. The condition of the rats' back skin was photographed every other day, and on the fifth day, the rats' back skin was taken, stained with hematoxylin and eosin, and then subjected to pathological analysis. Healthy rats were used as controls.

[0075] Experimental results: Azelaic acid liquid salt gel (Example 42) The condition of the back skin in the positive control and healthy group on each day is as follows: Figure 7 (1 is azelaic acid liquid salt gel (Example 42); 2 is...) Group 3 was a paraformaldehyde solution (positive control group); Group 4 was a healthy group. As shown in the figure, the back skin of the positive control group showed obvious inflammatory reaction. A mild inflammatory response was observed, while the azelaic acid liquid salt gel (Example 42) remained normal, similar to the skin of the healthy group. Figure 8 (1 is azelaic acid liquid salt gel (Example 42); 2 is...) Group 4 (3 is the positive control group; 4 is the healthy group) shows azelaic acid liquid salt gel (Example 42). The results of pathological sections of skin treated in the positive control group and healthy skin were also shown. The positive control group exhibited more severe pathological phenomena such as epidermal-dermal separation (indicated by black arrows). A few minor pathological phenomena were observed, such as slight dilation of hair follicles and flattening of the epithelium (indicated by black arrows). The skin tissue of the azelaic acid liquid salt gel (Example 42) remained normal compared to the healthy group. Therefore, the azelaic acid liquid salt gel (Example 42) has advantages over commercially available formulations. Better safety; it will not induce inflammatory reactions or damage to the epidermis.

[0076] In summary, this invention provides a liquid azelaic acid salt that is liquid at room temperature, overcoming the shortcomings of poor solubility and compatibility of azelaic acid. It overcomes the concentration limitations of azelaic acid in formulations or cosmetics without the need for additional solubilizing excipients, avoiding the skin irritation and toxicity caused by large amounts of solubilizing excipients. This provides a safe and effective product for the treatment or improvement of acne, melasma, rosacea, hyperpigmentation, etc. The liquid azelaic acid salt of this invention has the following advantages:

[0077] (1) The azelaic acid liquid salt of the present invention uses raw materials that do not contain any toxic or harmful substances, avoiding the use of large amounts of alcohol solvents, which can easily lead to skin allergies, itching, redness and swelling, and has good safety. (2) The azelaic acid liquid salt of the present invention has the ability to be miscible with water, solving the problems of azelaic acid solubility and compatibility. (3) It can increase the effective content of azelaic acid in the preparation. (4) It simplifies the number of components in the preparation product, saves the cost of auxiliary agents, and simplifies the production process. (5) Since it is a liquid salt at room temperature, it is easy to mix it evenly with other materials, such as water, solvents, ointments / gels, etc., to prepare the preparation. Compared with solids, it effectively ensures the uniform distribution of the effective ingredients and the stability of the product properties. (6) The azelaic acid liquid salt gel of the present invention has a higher than Stronger skin retention capacity, exhibiting better performance at lower doses. Similar acne treatment capabilities, but with better safety.

[0078] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a topical skin medicine or skin care product containing azelaic acid, characterized in that, include: Azelaic acid liquid salt is first prepared, and after being diluted with sterile water or undiluted, moisturizers, therapeutic / cosmetic active substances, matrix materials, or functional additives are added to prepare a topical skin medicine or skin care product; the product form of the topical skin medicine or skin care product is semi-solid or liquid; the formulation is a dispersion, emulsion, ointment, gel, mask, spray, or sheet-like medical product or skin care product with non-woven fabric as the absorbent substrate; the topical skin medicine or skin care product does not contain any solubilizers or dispersants; The preparation method of the azelaic acid liquid salt is as follows: azelaic acid and an amine-containing compound are dissolved in an organic solvent or a mixture of organic solvent and water, stirred evenly at room temperature or by heating, and the solvent is removed to obtain the azelaic acid liquid salt; wherein, the solvent removal method is as follows: first evaporate to remove most of the organic solvent, and the residual solvent is further removed by freeze drying or vacuum drying; The amino-containing compound is meglumine or tromethamine; or the amino-containing compound is a combination of triethanolamine and meglumine or tromethamine; or the amino-containing compound is a combination of tromethamine and meglumine; or the amino-containing compound is a combination of triethanolamine, meglumine and tromethamine.

2. The method for preparing a topical skin medication or skincare product according to claim 1, characterized in that, In the azelaic acid liquid salt, the total molar ratio of azelaic acid to the amine-containing compound is 2:1-1:

2.

3. The method for preparing a topical skin medication or skincare product according to claim 1, characterized in that, The content of azelaic acid liquid salt in the aforementioned topical medication or skin care product is 0.1-80 wt%.

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