CN112220741A

CN112220741A - Azelaic acid gel and preparation method and application thereof

Info

Publication number: CN112220741A
Application number: CN202011295511.2A
Authority: CN
Inventors: 王广基
Original assignee: Chengdu Joy Young Biotechnology Co ltd
Current assignee: Chengdu Joy Young Biotechnology Co ltd
Priority date: 2020-11-18
Filing date: 2020-11-18
Publication date: 2021-01-15
Also published as: WO2022105225A1

Abstract

The invention relates to azelaic acid gel and a preparation method and application thereof, belonging to the technical field of skin external drugs. The technical problem to be solved by the invention is to provide the azelaic acid gel with better absorption. The components of the azelaic acid gel comprise azelaic acid, pharmaceutically acceptable gel auxiliary materials and inevitable impurities; wherein the pharmaceutically acceptable gel adjuvant comprises carbitol. The invention discovers for the first time that the carbitol is used in the azelaic acid gel, can promote the transdermal absorption of azelaic acid in skin, can improve the concentration of azelaic acid in the product, and improves the skin feel of the product, thereby improving the curative effect. The azelaic acid gel provided by the invention has the advantages of good absorption and good curative effect, and can be used for treating or preventing acne and improving the cure rate of acne patients.

Description

Azelaic acid gel and preparation method and application thereof

Technical Field

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

Background

Azelaic acid, also known as azelaic acid, is a white to yellowish monoclinic prism, acicular crystals or powder in appearance. Has antibacterial effect, and can directly inhibit and kill bacteria on skin surface and in hair follicle; competitively inhibiting the enzyme process producing dihydrotestosterone and reducing excessive skin oil induced by dihydrotestosterone; inhibiting the generation and action of active oxygen free radicals, and resisting inflammation. It is used for treating acne, rosacea, and pigmentation disorder. Has good permeability to skin, and can increase absorption function of skin. However, since it is easily decomposed at high temperature, it is not preferable to add it at high temperature when it is used. It is easily soluble in hot water, alcohol and part of polyhydric alcohol, and slightly soluble in cold water, ether and benzene.

Currently, azelaic acid products are often formulated as ointments in order to increase their solubility and permeability. For example, the invention patent with application number 201610786026.2 discloses an acne cream and a preparation method thereof, wherein the acne cream comprises an early-use cream and a late-use cream, the late-use cream comprises a second raw material and a cream matrix, and the second raw material comprises the following substances: 10% azelaic acid, 0.1% adapalene, 1% clindamycin, 1% salicylic acid, 1.5% oleandone and 0.2% methylparaben. For another example, the invention patent with application number 201210230433.7 discloses an ointment for treating acne, which is prepared by mixing 3% by mass of oxymatrine, 1% by mass of vitamin E, 2% by mass of azelaic acid, 0.5% by mass of menthol, 29015% by mass of boric acid, 3% by mass of azone, and 83.5% by mass of an ointment base.

However, these ointments dissolve azelaic acid by means of oily materials, and at the same time, penetration aids (generally oily materials) are added to promote penetration into the skin, so that the product is only an oily cream or lotion. The use amount of azelaic acid is large, the use amount of oily raw materials is large, the permeability enhancing permeation-assisting dosage is large, and the side effect is large. Therefore, cream-type azelaic acid is relatively thick and oily, and has poor air permeability and large side effects.

The Chinese patent with the application number of CN2018108258077 discloses an azelaic acid gel, which is prepared by mixing 1, 3-propylene glycol and water as a solvent, and preparing azelaic acid into the gel, so that the greasy feeling of cream can be changed, the burden on skin can not be increased, pores can not be blocked, and corresponding side effects caused by excessive introduction of oily substances can be avoided, however, the content of azelaic acid in the gel can only reach about 18%, and the transdermal absorption effect of the gel is required to be further improved.

Disclosure of Invention

In order to overcome the defects, the technical problem solved by the invention is to provide an azelaic acid gel with better absorption.

The gel component of the azelaic acid gel comprises azelaic acid, pharmaceutically acceptable gel auxiliary materials and inevitable impurities; wherein the pharmaceutically acceptable gel adjuvant comprises carbitol.

In one embodiment of the invention, the pharmaceutically acceptable gel vehicle further comprises at least one of an antioxidant, a preservative, a penetration enhancer, a humectant, a stabilizer, an exfoliating agent, a pH adjuster, an antibacterial agent, and an anti-inflammatory agent.

In one embodiment of the present invention, the antioxidant is at least one of licoflavone, asiaticoside, superoxide dismutase, ascorbic acid and arbutin; the preservative is at least one of ethylene glycol, pentanediol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-alcohol; the penetration enhancer is at least one of polyalcohol and azone; the humectant is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide comprises glucan; the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and acryloyl dimethyl ammonium taurate; the pH regulator is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is at least one of an alpha-hydroxy acid and a beta-hydroxy acid; the antibacterial agent is at least one of quaternary ammonium salt-73, salicylic acid, isoprene glycol, Yunnan rhizoma paridis extract, zinc salt, lauric acid, ethyl laurate, medium-chain fatty acid, retinal and mangosteen extract; the anti-inflammatory agent is at least one of niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salts, a non-rubine alcohol and a plant extract, wherein the plant extract is at least one of purslane, tea tree oil, oat, aloe, calendula, centella asiatica, licorice, rose damascena, chamomile and mangosteen.

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

In one embodiment of the invention, the content of azelaic acid in the gelling agent is 10-30 wt%. In a particular embodiment, the azelaic acid is present in an amount of 15 to 25 wt%. In a more specific embodiment, the azelaic acid is present in an amount of from 18 to 25 weight percent.

In one embodiment of the invention, the azelaic acid gel 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; 62-5 parts of polyacrylate crosslinked polymer; 30-80 parts of carbitol.

In one embodiment of the invention, the azelaic acid gel 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; 63-3.5 parts of polyacrylate crosslinked polymer; 40-70 parts of carbitol.

In one embodiment of the invention, the azelaic acid gel comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1, 3-propylene glycol; 7 parts of water; 63 parts of polyacrylate crosslinked polymer; 60 parts of carbitol.

In one embodiment of the invention, the azelaic acid gel consists 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; 62-5 parts of polyacrylate crosslinked polymer; 30-80 parts of carbitol.

In one embodiment of the invention, the azelaic acid gel consists 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; 63-3.5 parts of polyacrylate crosslinked polymer; 40-70 parts of carbitol.

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

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

a. uniformly dispersing polyacrylate cross-linked polymer-6 in carbitol, and then uniformly mixing with water to obtain a solution A;

b. uniformly dispersing azelaic acid in carbitol and 1, 3-propylene glycol, and heating until the mixture is transparent to obtain a solution B;

c. and mixing the solution A and the solution B, uniformly stirring, and cooling to room temperature to obtain the azelaic acid gel.

In step b, the temperature after heating is preferably less than 65 ℃.

The invention also provides the application of the azelaic acid gel in the preparation of medicines, cosmetics or skin care products for treating anti-inflammatory, acne or pigmentation disorder.

The azelaic acid gel of the invention takes azelaic acid as an effective component and can be used for treating anti-inflammatory, acne or pigmentation disorder. It can be directly applied on skin.

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

the invention discovers for the first time that the carbitol is used in the azelaic acid gel, can promote the transdermal absorption of azelaic acid in skin, can improve the concentration of azelaic acid in the product, and improves the skin feel of the product, thereby improving the curative effect. The azelaic acid gel of the invention has good absorption and good curative effect, and can be used for preparing medicaments for treating anti-inflammatory, acne or pigmentation disorder.

Detailed Description

Carbitol, also known as diethylene glycol monoethyl ether and diethylene glycol diethyl ether, is a colorless, stable water-absorbing liquid, is commonly used as a solvent for cellulose nitrate, resins, lacquers, dyes, etc., and is a high-boiling-point solvent. The research finds that the carbitol can not only dissolve the azelaic acid to enable the azelaic acid to be prepared into the gel, but also promote the transdermal absorption of the azelaic acid, and the carbitol can promote the skin to absorb the azelaic acid when being used in the azelaic acid gel, thereby improving the curative effect of the gel.

In addition, in the existing gel system of CN2018108258077, water and 1,3 propanediol are used as solvents, and the content of azelaic acid in the gel can reach up to 18% under the influence of the solubility of azelaic acid in 1,3 propanediol, and if the content is increased, the gel will suffer from the defects of crystallization, unstable product and the like. The inventor finds that the solubility of azelaic acid is improved by adding carbitol into a gel system and taking the carbitol as a solvent, and the content of the azelaic acid in a product can be improved when the gel system is prepared into a gel, so that the concentration of the effective components of the product is improved.

In one embodiment of the invention, the pharmaceutically acceptable gel vehicle further comprises at least one of an antioxidant, a preservative, a penetration enhancer, a humectant, a stabilizer, an exfoliating agent, a pH adjuster, an antibacterial agent, and an anti-inflammatory agent. These gelling agent adjuvants may be added in amounts conventional in the art.

In one embodiment of the present invention, the antioxidant is at least one of licoflavone, asiaticoside, Superoxide dismutase (SOD), ascorbic acid and arbutin; the preservative is at least one of ethylene glycol, pentanediol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-alcohol; the penetration enhancer is at least one of polyalcohol and azone; the humectant is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide comprises glucan; the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and acryloyl dimethyl ammonium taurate; the pH regulator is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is at least one of an alpha-hydroxy acid and a beta-hydroxy acid; the antibacterial agent is at least one of quaternary ammonium salt-73, salicylic acid, isoprene glycol, Yunnan rhizoma paridis extract, zinc salt, lauric acid, ethyl laurate, medium-chain fatty acid, retinal and mangosteen extract; the anti-inflammatory agent is at least one of niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salts, a non-rubine alcohol and a plant extract, wherein the plant extract is at least one of purslane, tea tree oil, oat, aloe, calendula, centella asiatica, licorice, rose damascena, chamomile and mangosteen.

The medium-chain fatty acid is a compound composed of three elements of carbon, hydrogen and oxygen, and is a fatty acid with 8-10 carbon atoms in a carbon chain.

In one embodiment of the invention, the weight ratio of azelaic acid to carbitol is 1:1 to 10. It was found that the solubility of azelaic acid in carbitol increases with increasing temperature. In the production of the gel, the temperature is generally raised in order to increase the content of azelaic acid, but when the temperature exceeds 65 ℃, the color of the product is deepened, so that the system temperature is generally maintained at 60 ℃ in order to ensure the good properties of the product. At this temperature, the solubility of azelaic acid in carbitol was 52.71 g. Therefore, the weight ratio of azelaic acid to carbitol is preferably below 1: 2. If the weight ratio of azelaic acid to carbitol is too small, i.e. too much carbitol is used, the content of azelaic acid in the gel will be too low, even an effective concentration will not be reached, and therefore, the weight ratio of azelaic acid to carbitol is preferably 1: 2-10.

The content of azelaic acid in the azelaic acid gel can be adjusted according to the requirement. In one embodiment of the invention, the content of azelaic acid in the gelling agent is 10-30 wt%. In a particular embodiment, the azelaic acid is present in an amount of 15 to 25 wt%. In a more specific embodiment, the azelaic acid is present in an amount of from 18 to 25 weight percent. In particular embodiments, the azelaic acid may be present in an amount of 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25%, etc.

Polyacrylate crosspolymer-6, abbreviated as ZEN, was manufactured by Spirax corporation of France under the trade name SepimaX ZEN. ZEN is an associative polymer with excellent electrolytic resistance. Can resist the damage of electrolyte to the formula to the maximum extent, simultaneously has good suspension stability, and can produce transparent hydrogel products with moist and elegant touch feeling and velvet texture.

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

Wherein, there is no time sequence between step a and step b, step a may be performed first and then step b, step b may be performed first and then step a, or step a and step b may be performed simultaneously. Only the solution A and the solution B are mixed and stirred evenly at last.

In the step b, the heating temperature is based on that azelaic acid is dissolved to be transparent. Experimental studies show that azelaic acid is insoluble in water, oils and polyols at room temperature, and the product must be heated to 55 ℃ during its preparation, whereas the product will darken when it exceeds 65 ℃, so that the temperature after heating in step b is preferably lower than 65 ℃.

In one embodiment of the present invention, the temperature in step b is 60 ℃. At this temperature, the solubility of azelaic acid in carbitol is 52.71g, which is higher than that of 1,3 propanediol (40.33g), and the content of azelaic acid in the product can be effectively increased.

The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.

The raw materials used in the examples were:

ZEN: purchased from french seebeck;

azelaic acid: purchased from inspiring science and technology development ltd in Shanghai;

carbitol: from Shanghai Michelin Biochemical technology, Inc.;

1, 3-propanediol: corn sources, available from dupont, usa;

water: and (4) self-preparing deionized water.

Example 1

The azelaic acid gel comprises the following components:

solution A: ZEN3 percent; 10% of carbitol; and 7% of water.

And B, liquid B: 20% of azelaic acid; 10% of 1, 3-propanediol; 50% of carbitol.

The preparation method comprises the following steps:

a. uniformly dispersing ZEN in carbitol and then uniformly mixing the ZEN with water to obtain a solution A;

Example 2

The azelaic acid gel comprises the following components:

solution A: 2% of ZEN; 10% of carbitol; 13% of water.

And B, liquid B: 15% of azelaic acid; 10% of 1, 3-propanediol; 50% of carbitol.

The preparation method comprises the following steps:

Test example 1 percutaneous absorption test

1. Experimental drugs:

product No. 1: the product of example 2 has the following formula: 15% of azelaic acid, 2% of ZEN, 60% of carbitol, 10% of 1, 3-propylene glycol and 13% of water.

Product No. 2: the product in patent CN2018108258077 has the formula as follows: 15% of azelaic acid, 2% of ZEN, 70% of 1, 3-propylene glycol and 13% of water.

Product No. 3: azelaic acid cream control: AZECLEAR Cream, HK-59866, lot No. R595, Australian Furunkang pharmaceuticals Ltd, wherein the azelaic acid content is 20%;

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

2. Laboratory animal

Kunming (KM) mice, SPF grade, body weight 20-24 g; provided by the Experimental animal center of the Chinese medicinal academy of sciences of Sichuan province, the animal qualification certificate is numbered as follows: SCXK 2018-19.

3. Main instrument

An electronic balance: JA1003A, d 1mg, e 10d, shanghai essence electronics instruments ltd. An electronic balance: LD3100-1, d 0.1g, e 1g, shenyang lungteng electronics ltd. MagNA LYSer homogenizer 41440103, Made in Germany; full-wavelength multifunctional microplate reader: VARIOSKAN FLASH, Thermo Scientific, USA.

4. Experimental Environment

SPF barrier system of Pharmacology and toxicology institute of traditional Chinese medicine, Sichuan province. Indoor temperature is 20-22 ℃, relative humidity is 40% -70%, and 12-hour illumination and illumination are performed alternately in bright and dark. The license number used is SYXK 2018-19. The water is freely drunk. The standard feed is provided by laboratory animal center of Chinese medicine academy of sciences of Sichuan province.

5. Experimental methods

Taking 48 KM mice, half male and female, and dividing into 4 groups, each group comprising 12 mice, namely product 1, product 2, product 3 and matrix solution, removing abdominal hair of mice with electric hair cutter and depilatory cream one day before test, applying the sample solution to the depilated part, each part is coated with 0.5g/kg, and the application range is about 3.0 × 3.0cm²Killing animal by cervical dislocation and euthanasia 1h after smearing, taking smeared part skin, removing deep muscle tissue, weighing 0.1g skin, shearing, homogenizing with 1ml 70% methanol, shaking and soaking for 2h, centrifuging at 3000r/min, taking supernatant, measuring absorbance value at 450nm according to ELISA kit specification, calculating azelaic acid concentration according to standard curveTable 1.

6. Results of the experiment

The results are shown in Table 1.

TABLE 1 content of azelaic acid in mouse skin

Note: a: significance P <0.01, b: compared with product No. 2, the significance P is less than 0.05.

As can be seen from Table 1, after the skin of the mice is smeared with several azelaic acid products, the content of azelaic acid in the gel products (i.e. product No. 1 and product No. 2) is obviously higher than that of the azelaic acid cream control group (i.e. product No. 3), and the results are statistically different; meanwhile, the content of azelaic acid in the skin of the product No. 1 is obviously higher than that of the product No. 2. Therefore, when the gel product is applied to the skin of a mouse at the same dosage, the azelaic acid content in the skin of the gel product is higher, and the azelaic acid content in the product is more obviously increased.

Example 3

Azelaic acid gel was prepared according to the procedure described in example 1, wherein the total amount of the raw materials is shown in Table 2, and the properties of the prepared gel are also shown in Table 2.

TABLE 2

Example 4

The formula of the azelaic acid gel is changed, wherein the dosage 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 a product formula in a patent CN2018108258077, and the specific formula is as follows: azelaic acid 20%, ZEN 3%, 1, 3-propylene glycol 70%, and water 7%.

The preparation method comprises the following steps:

a. uniformly dispersing ZEN in 1, 3-propylene glycol, and then uniformly mixing with water to obtain a solution A;

b. uniformly dispersing azelaic acid in 1, 3-propylene glycol, heating to 75 ℃, and stirring until the mixture is transparent to obtain a solution B;

c. the solution A and the solution B are stirred and mixed evenly at the temperature of 60 ℃, and then cooled to the room temperature.

It was found that with this formulation, after cooling, azelaic acid crystals gradually precipitated with a distinct granular sensation, the gel flow gradually worsened and became solid after 2 weeks.

Claims

1. Azelaic acid gel, its characteristic lies in: the gel component comprises azelaic acid, pharmaceutically acceptable gel auxiliary materials and inevitable impurities; wherein the pharmaceutically acceptable gel adjuvant comprises carbitol.

2. The azelaic acid gel of claim 1 wherein: the pharmaceutically acceptable gel auxiliary material also comprises at least one of an antioxidant, a preservative, a penetration enhancer, a humectant, a stabilizer, an exfoliating agent, a pH regulator, an antibacterial agent and an anti-inflammatory agent.

3. The azelaic acid gel of claim 2 wherein: the antioxidant is at least one of licoflavone, asiaticoside, superoxide dismutase, ascorbic acid and arbutin; the preservative is at least one of ethylene glycol, pentanediol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-alcohol; the penetration enhancer is at least one of polyalcohol and azone; the humectant is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide comprises glucan; the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and acryloyl dimethyl ammonium taurate; the pH regulator is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is at least one of an alpha-hydroxy acid and a beta-hydroxy acid; the antibacterial agent is at least one of quaternary ammonium salt-73, salicylic acid, isoprene glycol, Yunnan rhizoma paridis extract, zinc salt, lauric acid, ethyl laurate, medium-chain fatty acid, retinal and mangosteen extract; the anti-inflammatory agent is at least one of niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salts, phytol, tea tree oil and plant extracts, wherein the plant extracts are extracted from at least one of purslane, oat, aloe, calendula, centella asiatica, licorice, rose damascena, chamomile and mangosteen.

4. The azelaic acid gel of claim 1 wherein: the weight ratio of azelaic acid to carbitol is 1: 1-10; preferably, the weight ratio of the azelaic acid to the carbitol is 1: 2-10.

5. Azelaic acid gel according to any of claims 1 to 4, characterized in that: the content of azelaic acid is 10-30 wt%; preferably, the content of the azelaic acid is 15-25 wt%; more preferably, the content of azelaic acid is 18 to 25 wt%.

6. The azelaic acid gel of claim 1 wherein: 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; 62-5 parts of polyacrylate crosslinked polymer; 30-80 parts of carbitol; preferably 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; 63-3.5 parts of polyacrylate crosslinked polymer; 40-70 parts of carbitol; more preferably comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1, 3-propylene glycol; 7 parts of water; 63 parts of polyacrylate crosslinked polymer; 60 parts of carbitol.

7. The azelaic acid gel of claim 1 wherein: the composition comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1, 3-propylene glycol; 1-10 parts of water; 62-5 parts of polyacrylate crosslinked polymer; 30-80 parts of carbitol; preferably consists 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; 63-3.5 parts of polyacrylate crosslinked polymer; 40-70 parts of carbitol; more preferably consists of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1, 3-propylene glycol; 7 parts of water; 63 parts of polyacrylate crosslinked polymer; 60 parts of carbitol.

8. A preparation method of azelaic acid gel is characterized by comprising the following steps:

9. The method for preparing azelaic acid gel according to claim 8, wherein: in step b, the temperature after heating is lower than 65 ℃.

10. Use of the azelaic acid gel of any one of claims 1 to 7 for the preparation of a medicament, cosmetic or dermatological product for the treatment of anti-inflammatory, acne or pigmentation disorders.