WO2022105225A1

WO2022105225A1 - Azelaic acid gel, preparation method therefor and application thereof

Info

Publication number: WO2022105225A1
Application number: PCT/CN2021/101503
Authority: WO
Inventors: 王广基
Original assignee: 成都卓阳生物科技有限公司
Priority date: 2020-11-18
Filing date: 2021-06-22
Publication date: 2022-05-27
Also published as: CN112220741A

Abstract

An azelaic acid gel and a preparation method therefor, which are characterized in that: components of the gel comprise azelaic acid and a pharmaceutically acceptable gel excipient and inevitable impurities, the pharmaceutically acceptable gel excipient comprising carbitol. The gel can be used for anti-inflammation and the treatment of acne or pigmentation disorders.

Description

Azelaic acid gel and its preparation method and application

technical field

The invention relates to azelaic acid gel, a preparation method and application thereof, and belongs to the technical field of skin external medicines.

Background technique

Azelaic acid, also known as azelaic acid, appears as white to yellowish monoclinic prisms, needle-like crystals or powder. With antibacterial effect, it can directly inhibit and kill bacteria on the skin surface and in hair follicles; competitively inhibit the enzymatic process of producing dihydrotestosterone, reduce excessive skin oil caused by dihydrotestosterone factors; inhibit the production of active oxygen free radicals and role, is conducive to anti-inflammatory. Commonly used in the treatment of acne, rosacea, pigmentation disorders, etc. It has good permeability to the skin and can increase the absorption function of the skin. However, it is easily decomposed by high temperature, so it should not be added at high temperature during use. Soluble in hot water, alcohol and some polyols, slightly soluble in cold water, ether and benzene.

Currently, azelaic acid products are often made into ointments in order to increase their solubility and permeability. For example, the invention patent with the application number 201610786026.2 discloses an acne cream and a preparation method thereof, which consists of a morning cream and a night cream, wherein the night cream includes a second raw material and a cream base, and the second raw material is composed of the following substances Composition: 10% azelaic acid, 0.1% adapalene, 1% clindamycin, 1% salicylic acid, 1.5% oleaginous azone and 0.2% nepalin. Another example, the invention patent with the application number 201210230433.7 discloses an ointment for treating acne, which consists of oxymatrine 3%, vitamin E 1%, azelaic acid 2%, menthol 0.5%, 2901 5% by mass percentage, 3% of boric acid, 2% of azone and 83.5% by mass of cream base were mixed to prepare an ointment.

However, these ointments use oily raw materials to dissolve azelaic acid, and at the same time add a penetrant (usually oily raw materials) to promote its penetration in the skin, so that the products can only be oily creams or lotions. If the dosage of azelaic acid is large, the amount of oily raw materials will be large, and the dosage of strong permeability will be larger, and the side effects will be greater. Therefore, cream-type azelaic acid is relatively oily, has poor air permeability, and has large side effects.

The Chinese invention patent with the application number of CN2018108258077 discloses an azelaic acid gel, which uses 1,3-propanediol mixed with water as a solvent, and the azelaic acid is made into a gel, which can change the greasy feeling of the cream and does not It will increase the burden on the skin and block the pores, so as to avoid the corresponding side effects caused by the excessive introduction of oily substances. However, the content of azelaic acid in the gel can only reach about 18%, and the permeability of the gel is not enough. The skin absorption effect also needs to be further improved.

SUMMARY OF THE INVENTION

In order to overcome the above defects, the technical problem solved by the present invention is to provide a gelling agent of azelaic acid with better absorption.

The azelaic acid gel of the present invention has a gel component comprising azelaic acid, a pharmaceutically acceptable gel excipient, and inevitable impurities; wherein the pharmaceutically acceptable gel excipient comprises Carbitol.

In one embodiment of the present invention, the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents.

In one embodiment of the present invention, the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase, ascorbic acid and arbutin; the preservative is ethylene glycol, pentylene glycol , at least one in phenoxyethanol, glycerin, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one in polyol and azone; the moisturizing agent is hyaluronic acid At least one of sodium and polysaccharide, the polysaccharide includes dextran; the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and ammonium acryloyldimethyltaurate; The pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is at least one of α-hydroxy acid and β-hydroxy acid; Described antibacterial agent is at least among quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, retinal and mangosteen extract. One; the anti-inflammatory agent is at least one of nicotinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salt, bisabolol and plant extracts, and the plant The extract is extracted from at least one of purslane, tea tree oil, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile, and mangosteen.

In one embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:1-10. In a specific embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:2-10.

In one embodiment of the present invention, the content of azelaic acid in the gelling agent is 10-30 wt %. In a specific embodiment, the content of azelaic acid is 15-25 wt %. In a more specific embodiment, the content of azelaic acid is 18-25 wt %.

In one embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylate Cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.

In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; polyacrylic acid Ester cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.

In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propanediol; 7 parts of water; polyacrylate cross-linked polymer- 63 servings; 60 servings of carbitol.

In one embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylic acid Ester cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.

In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Acrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.

In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; polyacrylate cross-linked polymer -6 3 servings; Carbitol 60 servings.

The invention also provides a preparation method of azelaic acid gel.

The preparation method of azelaic acid gel of the present invention comprises the following steps:

a. After the polyacrylate cross-linked polymer-6 is uniformly dispersed in the carbitol, it is mixed with water to obtain solution A;

b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;

c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.

In step b, the temperature after heating is preferably lower than 65°C.

The present invention also provides the use of the azelaic acid gel of the present invention for preparing medicines, cosmetics or skin care products for treating anti-inflammatory, acne or pigmentation disorders.

The azelaic acid gel of the present invention uses azelaic acid as an active ingredient, and can be used for treating anti-inflammatory, acne or pigmentation disorders. When used, it can be applied directly to the skin.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention finds for the first time that the use of carbitol in azelaic acid gel can promote the transdermal absorption of azelaic acid in the skin, and can increase the concentration of azelaic acid in the product, improve the skin feel of the product, and thereby improve the curative effect. The azelaic acid gel of the invention has good absorption and good curative effect, and can be used for preparing medicines for treating anti-inflammatory, acne or pigmentation disorders.

Detailed ways

Carbitol, also known as diethylene glycol monoethyl ether and diethylene glycol ethyl ether, is a colorless, water-absorptive and stable liquid. It is often used as a solvent for nitrocellulose, resins, spray paints, dyes, etc. It is a high boiling point solvent. Studies have found that carbitol can not only dissolve azelaic acid so that it can be prepared into a gel, but also promote the transdermal absorption of azelaic acid. When it is used in azelaic acid gel, it can promote skin absorption of azelaic acid. diacids, thereby enhancing the efficacy of the gel.

In addition, in the existing gel system of CN2018108258077, water and 1,3 propylene glycol are used as solvents, and due to the influence of the solubility of azelaic acid in 1,3 propylene glycol, the content of azelaic acid in the gel can reach up to 18 %, if it increases, it will face defects such as crystallization and product instability. The inventor found that adding carbitol to the gel system and using carbitol as a solvent improves the solubility of azelaic acid. When it is prepared into a gel, the content of azelaic acid in the product can be increased. Thereby increasing the active ingredient concentration of the product.

In one embodiment of the present invention, the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents. The addition amount of these gelling adjuvants can be the conventional amount in the field.

In one embodiment of the present invention, the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase (SOD), ascorbic acid and arbutin; the preservative is ethyl acetate at least one of glycol, pentylene glycol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one of polyol and azone; the The moisturizing agent is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide includes dextran; the stabilizer is carbomer, poloxamer, hydroxyethyl cellulose and acryloyldimethyltaurine At least one of ammonium; the pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is α-hydroxy acid and β-hydroxy At least one in acid; Described antibacterial agent is quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, retinal aldehyde and at least one of mangosteen extracts; the anti-inflammatory agent is at least one of niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salts, bisabolol and plant extracts One, the plant extract is extracted from at least one of purslane, tea tree oil, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile and mangosteen.

The medium-chain fatty acid of the present invention is a kind of compound composed of carbon, hydrogen and oxygen, and is a fatty acid with 8-10 carbon atoms in the carbon chain.

In one embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:1-10. It was found that the solubility of azelaic acid in carbitol increased with increasing temperature. In the production of gelling agents, in order to increase the content of azelaic acid, the temperature is generally increased. However, when the temperature exceeds 65 °C, the color of the product will deepen. Therefore, in order to ensure the better properties of the product, the general production The system temperature was maintained at 60°C. At this temperature, the solubility of azelaic acid in carbitol is 52.71 g. Therefore, the weight ratio of azelaic acid to carbitol is preferably 1:2 or less. If the weight ratio of azelaic acid to carbitol is too small, that is, the amount of carbitol is too much, the content of azelaic acid in the gel will be too low, or even fail to reach an effective concentration. Therefore, preferably, azelaic acid is The weight ratio of acid to carbitol is 1:2-10.

The azelaic acid content in the azelaic acid gel can be adjusted as required. In one embodiment of the present invention, the content of azelaic acid in the gelling agent is 10-30 wt %. In a specific embodiment, the content of azelaic acid is 15-25 wt %. In a more specific embodiment, the content of azelaic acid is 18-25 wt %. In a specific embodiment, the content of azelaic acid may be 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25%, and the like.

Polyacrylate cross-linked polymer-6, abbreviated as ZEN, is produced by French company SepiMAX under the trade name SepiMAX ZEN. ZEN is an associative polymer with excellent resistance to electrolysis. It can resist the damage caused by electrolytes to the formula to the greatest extent, and at the same time, it also has good suspension stability, and can produce transparent hydrogel products with a moist and elegant touch and a velvety texture.

Wherein, there is no time sequence between step a and step b, step a may be performed first and then step b, or step b may be performed first and then step a, or step a and step b may be performed simultaneously. Just mix solution A and solution B at the end and stir well.

In step b, the heating temperature is based on the dissolution of azelaic acid until transparent. Experimental studies have shown that azelaic acid is insoluble in water, oil and polyol at room temperature, and the temperature needs to be raised to 55°C during product preparation, and when it exceeds 65°C, the product will appear darker in color. Therefore, in step b, The temperature after heating is preferably lower than 65°C.

In one embodiment of the present invention, the temperature of step b is 60°C. At this temperature, the solubility of azelaic acid in carbitol is 52.71g, which is higher than that of 1,3 propylene glycol (40.33g), which can effectively increase the content of azelaic acid in the product.

The specific embodiments of the present invention will be further described below with reference to the examples, but the present invention is not limited to the scope of the described examples.

The raw materials used in the examples are:

ZEN: purchased from France Saibiq;

Azelaic acid: purchased from Shanghai Linen Technology Development Co., Ltd.;

Carbitol: purchased from Shanghai McLean Biochemical Technology Co., Ltd.;

1,3-Propanediol: corn source, purchased from DuPont, USA;

Water: Homemade deionized water.

Example 1

Azelaic acid gel, formulated as:

Liquid A: ZEN 3%; Carbitol 10%; Water 7%.

Liquid B: azelaic acid 20%; 1,3 propylene glycol 10%; carbitol 50%.

Prepare as follows:

a. Disperse ZEN evenly in carbitol and then mix with water to obtain solution A;

Example 2

Azelaic acid gel, formulated as:

Liquid A: ZEN 2%; Carbitol 10%; Water 13%.

Liquid B: azelaic acid 15%; 1,3 propylene glycol 10%; carbitol 50%.

Prepare as follows:

Test Example 1 Transdermal absorption test

1. Experimental drug:

Product No. 1: the product of Example 2, its formula is: azelaic acid 15%, ZEN 2%, carbitol 60%, 1,3-propanediol 10%, water 13%.

Product No. 2: the product in the patent CN2018108258077, its formula is: azelaic acid 15%, ZEN 2%, 1,3-propanediol 70%, water 13%.

Product No. 3: Azelaic acid cream Reference substance: AZECLEAR Cream, HK-59866, batch number R595, Australia Frunkang Pharmaceutical Co., Ltd., the content of azelaic acid is 20%;

Base fluid: colorless, transparent gel, free of azelaic acid, consisting only of carbitol, ZEN, 1,3-propanediol and water.

2. Experimental animals

Kunming (KM) mice, SPF grade, weighing 20-24g; provided by the Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine, animal certificate number: SCXK (Chuan) 2018-19.

3. Main instruments

Electronic balance: JA1003A, d=1mg, e=10d, Shanghai Jingtian Electronic Instrument Co., Ltd. Electronic balance: LD3100-1, d=0.1g, e=1g, Shenyang Longteng Electronics Co., Ltd. MagNA LYSer homogenizer 41440103, Made in Germany; full-wavelength multi-function microplate reader: VARIOSKAN FLASH, Thermo Scientific, USA.

4. Experimental environment

SPF barrier system, Institute of Pharmacology and Toxicology, Sichuan Academy of Traditional Chinese Medicine. The indoor temperature is 20~22℃, the relative humidity is 40%~70%, and the light and dark are alternately illuminated for 12 hours. The license number is SYXK (Chuan) 2018-19. Free access to water. Standard feed was provided by the Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine.

5. Experimental method

48 KM mice, half male and half male, were divided into 4 groups with 12 mice in each group, namely No. 1 product group, No. 2 product group, No. 3 product group and matrix liquid group. Depilatory cream was used to remove the abdominal hair of mice, and the test sample solution was applied to the depilation site, with 0.5g/kg applied to each part, and the smeared area was about 3.0×3.0cm ² . The animals were euthanized by cervical dislocation 1 hour after application, and the skin of the application site was taken and removed. Deep muscle tissue, weigh 0.1 g of skin, cut into pieces, homogenize with 1 ml of 70% methanol, shake and soak for 2 h, centrifuge at 3000 r/min for 10 min, take the supernatant, and measure the absorbance at 450 nm according to the instructions of the ELISA kit. The azelaic acid concentration was calculated according to the standard curve, see Table 1.

6. Experimental results

The experimental results are shown in Table 1.

Table 1 Content of azelaic acid in mouse skin

Note: a: Significant P<0.01 compared with No. 3 product, b: Significant P<0.05 compared with No. 2 product.

As can be seen from Table 1, after smearing several azelaic acid products on the mouse skin, the content of azelaic acid in the gel products (namely product No. 1 and product No. 2) was significantly higher than that in the azelaic acid cream control group (namely, product No. 3). , with a statistical difference; at the same time, the content of azelaic acid in the skin of product No. 1 was significantly higher than that in the skin of product No. 2. It can be seen that when the same dose is applied to the skin of mice, the gel product has a higher azelaic acid content in the skin, and the azelaic acid content in the product of the present invention is significantly increased.

Example 3

The azelaic acid gel was prepared according to the method described in Example 1, wherein the total consumption of each raw material is shown in Table 2, and the properties of the prepared gel are also shown in Table 2.

Table 2

Example 4

Change the formula of azelaic acid gel, wherein, the consumption of each raw material is shown in Table 3, and the properties of the prepared gel are also shown in Table 3.

table 3

Comparative Example 1

The gel is prepared according to the product formula in the patent CN2018108258077, and its specific formula is: azelaic acid 20%, ZEN 3%, 1,3-propanediol 70%, water 7%.

Prepare as follows:

a. Disperse ZEN evenly in 1,3-propanediol and then mix with water to obtain solution A;

b. Uniformly disperse azelaic acid in 1,3-propanediol, heat to 75°C, and stir until transparent to obtain solution B;

c. Stir and mix solution A and solution B at 60°C, and then cool to room temperature.

It was found that with this formula, after cooling, crystals of azelaic acid would gradually separate out, with obvious graininess, and the fluidity of the gel would gradually deteriorate, and it would become solid after 2 weeks.

Claims

Azelaic acid gel, characterized in that: the gel component comprises azelaic acid and pharmaceutically acceptable gel excipients, and inevitable impurities; wherein, the pharmaceutically acceptable gel excipients Contains carbitol.
The azelaic acid gel according to claim 1, characterized in that: the pharmaceutically acceptable adjuvants for the gel also include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants , at least one of a pH adjusting agent, an antibacterial agent and an anti-inflammatory agent.
The azelaic acid gel according to claim 2, wherein the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase, ascorbic acid and arbutin; The agent is at least one in ethylene glycol, pentylene glycol, phenoxyethanol, glycerin, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one in polyol and azone ; Described moisturizing agent is at least one in sodium hyaluronate and polysaccharide, and described polysaccharide includes dextran; Described stabilizer is carbomer, poloxamer, hydroxyethyl cellulose and acryloyl dimethyl At least one of ammonium taurine; the pH adjuster is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is a-hydroxy acid and At least one in β-hydroxy acid; Described antibacterial agent is quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, At least one of retinal and mangosteen extract; the anti-inflammatory agent is niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salt, bisabolol, tea tree At least one of an oil and a plant extract extracted from at least one of purslane, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile, and mangosteen.
The azelaic acid gel according to claim 1 is characterized in that: the weight ratio of azelaic acid to carbitol is 1:1-10.
The azelaic acid gel according to claim 4 is characterized in that: the weight ratio of azelaic acid to carbitol is 1:2-10.
The azelaic acid gel according to any one of claims 1 to 5, wherein the content of azelaic acid is 10 to 30 wt %.
The azelaic acid gel according to claim 6, wherein the content of azelaic acid is 15-25 wt%.
The azelaic acid gel according to claim 7, wherein the content of azelaic acid is 18-25 wt%.
The azelaic acid gel according to claim 1 is characterized in that: it comprises the following components by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; Polyacrylate cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
The azelaic acid gel according to claim 9, characterized in that: it comprises the following components by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Polyacrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
The azelaic acid gel according to claim 10 is characterized in that: it comprises the following components by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; Matter-6 3 copies; Carbitol 60 copies.
The azelaic acid gel according to claim 1 is characterized in that: it is composed of the following components by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-10 parts of water ; Polyacrylate cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
The azelaic acid gel according to claim 12 is characterized in that: it is composed of the following components by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water ; Polyacrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
The azelaic acid gel according to claim 13 is characterized in that: it is composed of the following components by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; Polymer - 6 3 parts; Carbitol 60 parts.
A kind of preparation method of azelaic acid gel, is characterized in that, comprises the following steps:

a. After the polyacrylate cross-linked polymer-6 is uniformly dispersed in the carbitol, it is mixed with water to obtain solution A;

b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;

c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
The method for preparing azelaic acid gel according to claim 15, wherein in step b, the temperature after heating is lower than 65°C.
Use of the azelaic acid gel according to any one of claims 1 to 14 for preparing a drug, cosmetic or skin care product for treating anti-inflammatory, acne or pigmentation disorders.