Demelting high-content salicylic acid composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medical cosmetology, and discloses a melting-eliminating high-content salicylic acid composition as well as a preparation method and application thereof. The composition comprises salicylic acid, polyethylene glycol-8 and PPG-14-polyglycerol-2-ether, the weight fraction ratio of the salicylic acid to the polyethylene glycol-8 to the PPG-14-polyglycerol-2-ether is 3: (4-6): (1-3), and the weight percentage of the salicylic acid in the composition is 25%-30%. According to the composition disclosed by the invention, polyethylene glycol-8 and PPG-14-polyglycerol-2-ether in a specific proportion are taken as cofluxing agents, a stable homogeneous system is formed after the cofluxing agents and salicylic acid are co-melted, no salicylic acid melting peak exists in DSC scanning, and the problems that salicylic acid is poor in solubility and easy to crystallize and separate out in a formula are solved. The composition has good mildness, is not added with an organic solvent, a pH regulator and other components, and is verified by rabbit acute eye irritation tests and multiple skin irritation tests to be non-irritant. The preparation process is simple and easy to operate, and industrial production is facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical cosmetology, and particularly relates to a high-content salicylic acid composition with no crystallization, a preparation method and application thereof. BACKGROUND

[0002] Salicylic acid, also known as o-hydroxybenzoic acid, is an organic acid extracted from birch, wintergreen leaves and willow bark, and has the effects of bacteriostasis, anti-inflammation, pore dredging, keratolytic, oil control and acne removal. In recent years, with the development of science and technology and the growth of consumer demand, chemical peeling has become a fast, safe and effective clinical treatment method, and has been widely used in dermatology and cosmetology departments, mainly for the treatment of skin problems such as acne, chloasma, skin photoaging, keratotic diseases, post-inflammatory hyperpigmentation and acne scars. 10% to 30% concentration of salicylic acid is a commonly used chemical peeling agent. However, the solubility of salicylic acid in water is extremely low (2 g / L at 20℃), making it difficult to add high content in the formula, and salicylic acid is prone to crystallization, which seriously affects the stability and efficacy of the product.

[0003] At present, the preparation methods of commonly used high-content salicylic acid preparations mainly include the following: dissolving salicylic acid with organic solvents such as ethanol, but high content of organic solvents will increase skin irritation; neutralizing salicylic acid to form water-soluble salicylic acid salt, but the peeling effect will be significantly reduced; other technologies such as salicylic acid structure modification, liposome wrapping, microcapsule wrapping and supramolecular deep eutectic can solve the solubility or irritation problem of salicylic acid to some extent, but the preparation process is often complex and the cost is high. SUMMARY

[0004] In order to overcome the shortcomings of the prior art, the present application provides a high-content salicylic acid composition with no crystallization, which is formed by a eutectic agent of a specific ratio of polyethylene glycol-8 and PPG-14-polyglyceryl-2-ether, and a stable homogeneous system is formed after eutectic with salicylic acid, which can effectively solve the problems of poor solubility of salicylic acid and easy crystallization in the formula.

[0005] To achieve the above-mentioned purpose, in a first aspect, the present application provides a high-content salicylic acid composition with no crystallization, comprising salicylic acid, polyethylene glycol-8 and PPG-14-polyglyceryl-2-ether, wherein the weight fraction ratio of salicylic acid, polyethylene glycol-8 and PPG-14-polyglyceryl-2-ether is 3:(4-6):(1-3), and the weight percentage of salicylic acid in the composition is 25%-30%.

[0006] Preferably, the structural formula of PPG-14-polyglyceryl-2-ether is: wherein p+q+r+s=14.

[0007] Preferably, the appearance of the high-content salicylic acid composition without melting is colorless transparent liquid.

[0008] Preferably, the appearance of the high-content salicylic acid composition without melting is colorless transparent liquid in the range of-15℃ to 49℃.

[0009] Preferably, the DSC curve of the high-content salicylic acid composition without melting has no melting peak of salicylic acid in the range of-20℃ to 200℃.

[0010] In a second aspect, the present application provides a preparation method of the high-content salicylic acid composition without melting, comprising the following steps: accurately weighing salicylic acid, polyethylene glycol-8 and PPG-14-polyglyceryl-2-ether according to the weight ratio, mixing and heating to 75℃ to 85℃, stirring until the salicylic acid is completely dissolved, and cooling to room temperature to obtain the high-content salicylic acid composition without melting.

[0011] In a third aspect, the present application provides the use of the high-content salicylic acid composition without melting in medical and cosmetic products.

[0012] Compared with the prior art, the present application has at least the following beneficial effects: (1) The composition greatly improves the solubility and formula stability of salicylic acid. By using polyethylene glycol-8 and PPG-14-polyglyceryl-2-ether in a specific ratio to form a eutectic solvent, and then forming a composition with salicylic acid, the composition is still a colorless transparent liquid at-15℃, and the DSC curve of the composition has no melting peak of salicylic acid in the range of-20℃ to 200℃; (2) The composition has good mildness, and no organic solvents and pH adjusters are added. The results of acute eye irritation test and multiple skin irritation test on rabbits are all non-irritating; (3) The preparation process of the composition is simple and easy to operate. After mixing the components, stirring at 75 to 85℃ until the salicylic acid is dissolved, and cooling to room temperature, the composition can be obtained, which is convenient for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 Fig. 1 is a diagram of the initial state of the composition in Example 1 and the state after being placed at-15℃, 25℃ and 49℃ for 3 months; Figure 2 Fig. 2 is a DSC spectrum of the composition in Example 1; Figure 3 Fig. 3 is a DSC spectrum of pure salicylic acid solid; Figure 4 Fig. 4 is a diagram of the initial state of the composition in Example 2 and the state after being placed at-15℃, 25℃ and 49℃ for 3 months; Figure 5The DSC spectrum of the composition in Example 2; Figure 6 The images show the initial state of the composition in Example 3 and its state after being placed at -15°C, 25°C, and 49°C for 3 months. Figure 7 The DSC spectrum of the composition in Example 3; Figure 8 The images show the initial state of the composition in Example 4 and its state after being placed at -15°C, 25°C, and 49°C for 3 months. Figure 9 The DSC spectrum of the composition in Example 4; Figure 10 This is an optical microscope image of a commercially available salicylic acid gel sample from Comparative Example 1. Figure 11 The images show the initial state of a commercially available salicylic acid gel sample in Comparative Example 1 and its state after being placed at -15℃ and 49℃ for 24 hours. Figure 12 The DSC spectrum of a commercially available salicylic acid gel sample in Comparative Example 1; Figure 13 The images show the initial state of the composition in Comparative Example 2 and its state after being placed at -15°C, 25°C, and 49°C for 24 hours. Figure 14 The images show the initial state of the composition in Comparative Example 3 and its state after being placed at -15°C, 25°C, and 49°C for 24 hours. Figure 15 The images show the initial state of the composition in Comparative Example 4 and its state after being placed at -15°C, 25°C, and 49°C for 24 hours. Detailed Implementation

[0014] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the claims.

[0015] Unless otherwise specified, the raw materials and materials used in the embodiments of the present invention were purchased through general commercial channels.

[0016] The source information of the raw materials, materials, and instruments involved in the following embodiments or comparative examples is as follows: Salicylic acid, manufacturer: MERCK, CAS No.: 69-72-7; Polyethylene glycol-8, manufacturer: Clariant, CAS No.: 25322-68-3; PPG-14-polyglycerol-2-ether, Manufacturer: Jiangxi Shouxin New Materials Co., Ltd., CAS No.: 61710-63-2; A commercially available salicylic acid gel sample contains 30% salicylic acid; the gel is white and milky. Differential scanning calorimeter (DSC), manufacturer: METTLER TOLEDO, model: DSC 3.

[0017] In this invention, 1h, 24h, etc., represent 1 hour, 24 hours, etc.; 4d, 7d, etc., represent 4 days, 7 days, etc.

[0018] <Example 1> Accurately weigh 300g of salicylic acid, 600g of polyethylene glycol-8 and 100g of PPG-14-polyglycerol-2-ether in a mass fraction ratio of 3:6:1. Heat to 80℃ and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain a melted high-content salicylic acid composition, referred to as Composition 1.

[0019] The initial state of composition 1 is a colorless, transparent liquid. A portion of composition 1 was divided into three portions and placed in stability test chambers at -15℃, 25℃, and 49℃ for three months, respectively. The precipitation of salicylic acid was observed and recorded. Figure 1 As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:6:1, the initial salicylic acid completely dissolves, forming a stable, colorless, and transparent liquid, and does not precipitate within 3 months at -15°C, 25°C, and 49°C. Differential scanning calorimetry (DSC) was used to scan the composition 1 and pure salicylic acid solid of this embodiment within the range of -20°C to 200°C, with a heating rate of 10°C / min. The results are shown below. Figure 2 and Figure 3 As shown in the DSC spectrum, salicylic acid has a characteristic peak near 160℃, which is its melting point. However, the DSC curve of composition 1 in this embodiment is smooth and does not show the melting peak of salicylic acid, indicating that composition 1 forms a stable homogeneous system.

[0020] The acute eye irritation and repeated skin irritation tests of composition 1 of this embodiment were conducted on rabbits. Three rabbits weighing 2.0~3.0kg were selected and placed in the experimental animal room environment (temperature: 20℃~26℃, relative humidity: 40%~70%) for 3 days before the test.

[0021] (1) Acute eye irritation test: Examine both eyes of rabbits 24 hours before the start of the test (including examination with sodium fluorescein). Rabbits with eye irritation symptoms, corneal defects, and conjunctival damage cannot be used for the test. Gently pull open the lower eyelid of one eye of the rabbit and use composition 1 prepared in this example as the test substance. Take 0.1 mL of the test substance and instill it into the conjunctival sac. Passively close the upper and lower eyelids for 1 second to prevent loss of the test substance. The other eye is left untreated as a self-control. Do not rinse the eyes within 24 hours after instilling the test substance. Examine the rabbit eyes at 1 hour, 24 hours, 48 ​​hours, and 72 hours after instilling the test substance, as well as on the 4th and 7th days. According to the "Cosmetic Safety Technical Specifications" (2015 edition), if no irritation reaction occurs after 72 hours, the test can be terminated. If eye irritation persists within 7 days, the observation period needs to be extended to determine the reversibility or irreversibility of the damage, generally not exceeding 21 days, and observation reports should be provided at 7 days, 14 days, and 21 days. Eye irritation reactions can be examined using a magnifying glass, a handheld slit lamp, a biological microscope, or other suitable instruments. In this embodiment, a handheld slit lamp was used for reaction examination. After 24 hours of observation and recording, all rabbits' eyes were further examined with sodium fluorescein.

[0022] (2) Repeated skin irritation test: 24 hours before the test, the hair on both sides of the spine on the back of the rabbit was shaved, taking care not to damage the epidermis. The hair removal area was 3cm × 3cm on both the left and right sides. Composition 1 prepared in this example was used as the test substance. 0.5mL of the test substance was applied directly to one side of the skin, covering an area of ​​2.5cm × 2.5cm. Purified water was applied to the other side as a control. The application was repeated once a day for 7 consecutive days. The results were observed one hour after each application. Starting from the second day, the hair should be shaved before each application, and any residual test substance should be removed with water.

[0023] According to the provisions of the "Cosmetic Safety Technical Specifications" (2015 edition), the intensity of irritation to the eyes of the test substance was determined, and the result of composition 1 in this embodiment was non-irritating; the intensity of irritation to the skin of the test substance was determined, and the result of composition 1 in this embodiment was non-irritating.

[0024] <Example 2> Accurately weigh 300g of salicylic acid, 500g of polyethylene glycol-8 and 200g of PPG-14-polyglycerol-2-ether in a mass fraction ratio of 3:5:2. Heat to 80℃ and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain a melted high-content salicylic acid composition, referred to as composition 2.

[0025] The initial appearance of composition 2 is a colorless and transparent liquid. A portion of composition 2 was divided into three portions and placed in stability test chambers at -15℃, 25℃, and 49℃ for three months, respectively. The precipitation of salicylic acid was observed and recorded. Figure 4As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:5:2, the initial salicylic acid completely dissolves, forming a stable, colorless, and transparent liquid, and does not precipitate within 3 months at -15°C, 25°C, and 49°C. Using a differential scanning calorimeter, the composition 2 of this example was scanned within the range of -20°C to 200°C at a heating rate of 10°C / min. The results are as follows. Figure 5 As shown in the DSC spectrum, the curve of composition 2 in this embodiment is smooth and there is no melting peak of salicylic acid, indicating that composition 2 forms a stable homogeneous system.

[0026] The acute eye irritation and repeated skin irritation tests of composition 2 of this embodiment were conducted on rabbits, using the same test methods as described in Example 1. According to the provisions of the "Cosmetic Safety Technical Specifications" (2015 edition), the intensity of eye irritation of the test substance was determined, and the result for composition 2 of this embodiment was non-irritating; the intensity of skin irritation of the test substance was also determined, and the result for composition 2 of this embodiment was non-irritating.

[0027] <Example 3> Accurately weigh 300g of salicylic acid, 400g of polyethylene glycol-8 and 300g of PPG-14-polyglycerol-2-ether in a mass fraction ratio of 3:4:3. Heat to 80℃ and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain a melted high-content salicylic acid composition, referred to as composition 3.

[0028] The initial appearance of composition 3 is a colorless and transparent liquid. A portion of composition 3 was divided into three portions and placed in stability test chambers at -15℃, 25℃, and 49℃ for three months, respectively. The precipitation of salicylic acid was observed and recorded. Figure 6 As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:4:3, the salicylic acid completely dissolves, forming a stable, colorless, and transparent liquid, and does not precipitate within 3 months at -15°C, 25°C, and 49°C. Using a differential scanning calorimeter, the composition 3 of this embodiment was scanned within the range of -20°C to 200°C at a heating rate of 10°C / min. The results are as follows. Figure 7 As shown in the DSC spectrum, the curve of composition 3 in this embodiment is smooth and there is no melting peak of salicylic acid, indicating that composition 3 forms a stable homogeneous system.

[0029] The acute eye irritation and repeated skin irritation tests were conducted on composition 3 of this embodiment in rabbits, using the same methods as described in Example 1. According to the provisions of the "Cosmetic Safety Technical Specifications" (2015 edition), the intensity of eye irritation of the test substance was determined, and the result for composition 3 of this embodiment was non-irritating; the intensity of skin irritation of the test substance was also determined, and the result for composition 3 of this embodiment was non-irritating.

[0030] <Example 4> Accurately weigh 300g of salicylic acid, 600g of polyethylene glycol-8 and 300g of PPG-14-polyglycerol-2-ether in a mass fraction ratio of 3:6:3. Heat to 80℃ and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain a melted high-content salicylic acid composition, referred to as composition 4.

[0031] The initial state of composition 4 is a colorless, transparent liquid. A portion of composition 4 was divided into three portions and placed in stability test chambers at -15°C, 25°C, and 49°C for three months, respectively. The precipitation of salicylic acid was observed and recorded. Figure 8 As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:6:3, the salicylic acid completely dissolves, forming a stable, colorless, and transparent liquid, and does not precipitate within 3 months at -15°C, 25°C, and 49°C. Using a differential scanning calorimeter, the composition 4 of this example was scanned within the range of -20°C to 200°C at a heating rate of 10°C / min. The results are as follows. Figure 9 As shown in the DSC spectrum, the curve of composition 4 in this embodiment is smooth and there is no melting peak of salicylic acid, indicating that composition 4 forms a stable homogeneous system.

[0032] The acute eye irritation and repeated skin irritation tests of composition 4 in this embodiment were conducted on rabbits, using the same methods as described in Example 1. According to the provisions of the "Cosmetic Safety Technical Specifications" (2015 edition), the intensity of eye irritation of the test substance was determined, and the result for composition 4 in this embodiment was non-irritating; the intensity of skin irritation of the test substance was also determined, and the result for composition 4 in this embodiment was non-irritating.

[0033] <Comparative Example 1> A commercially available salicylic acid gel, formulated with poloxamer 407 and lauryl ether-4, is loaded with 30% salicylic acid. The sample appears as a white, viscous emulsion. A portion of the sample is referred to as composition 5.

[0034] The microstructure of composition 5 was observed using an optical microscope (LEICA DM2700 M) at a magnification of 200x (200×). It was observed that salicylic acid was dispersed in the formulation as crystals of varying sizes. The results are as follows: Figure 10As shown. A portion of composition 4 was divided into two portions and placed at -15℃ and 49℃ for 24 hours. It was observed that salicylic acid recrystallized and precipitated at 49℃, as shown in the figure. Figure 11 As shown. Using a differential scanning calorimeter, the temperature was increased at a rate of 10℃ / min, and the temperature was scanned within the range of -20℃ to 200℃. The results are as follows. Figure 12 As shown in the figure. The DSC spectrum shows that composition 5 has characteristic peaks in the range of 110~130℃, indicating that the high content salicylic acid-poloxam 407 system is a heterogeneous system.

[0035] <Comparative Example 2> Weigh 300g of salicylic acid and 700g of polyethylene glycol-8 accurately according to a mass fraction ratio of 3:7, heat to 80℃, stir until the salicylic acid is completely dissolved, and cool to room temperature to obtain composition 6.

[0036] A portion of the composition was divided into three parts (6 parts each) and placed in stability test chambers at -15℃, 25℃, and 49℃ for 24 hours respectively. Salicylic acid precipitation was observed. Figure 13 As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:7:0, the system is unstable and salicylic acid recrystallizes out.

[0037] <Comparative Example 3> Accurately weigh 300g of salicylic acid, 300g of polyethylene glycol-8, and 400g of PPG-14-polyglycerol-2-ether according to a mass fraction ratio of 3:3:4. Heat to 80°C and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain composition 7.

[0038] Take a portion of the composition, divide it into 3 parts (7 parts each), and place them in stability test chambers at -15℃, 25℃, and 49℃ for 24 hours respectively. Salicylic acid precipitation was observed. Figure 14 As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:3:4, the system is unstable and salicylic acid recrystallizes out.

[0039] <Comparative Example 4> Accurately weigh 300g of salicylic acid, 400g of polyethylene glycol-8, and 100g of PPG-14-polyglycerol-2-ether according to a mass fraction ratio of 3:4:1. Heat to 80°C and stir until the salicylic acid is completely dissolved. Cool to room temperature to obtain composition 8.

[0040] Eight portions of the composition were divided into three parts and placed in stability test chambers at -15℃, 25℃, and 49℃ for 24 hours respectively. Salicylic acid precipitation was observed. Figure 15As shown, when the mass fraction ratio of salicylic acid, polyethylene glycol-8 and PPG-14-polyglycerol-2-ether is 3:4:1, the salicylic acid content is 37.5%, the system is unstable, and salicylic acid recrystallizes out.

[0041] In summary, the present invention provides a high-content salicylic acid composition that, when the mass fraction ratio of salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:(4~6):(1~3), and the salicylic acid content is 25%~30%, forms a stable homogeneous system. This composition exhibits good stability and mildness, and its preparation process is simple, providing valuable insights for solving the challenges of developing high-content salicylic acid formulations.

[0042] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A high-content salicylic acid composition for melting, characterized in that, The composition includes salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether, wherein the weight fraction ratio of the salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether is 3:(4~6):(1~3), and the weight percentage of the salicylic acid in the composition is 25%~30%.

2. The high-content salicylic acid composition for melting as described in claim 1, characterized in that, The structural formula of the PPG-14-polyglycerol-2-ether is: ， Where p+q+r+s=14.

3. The high-content salicylic acid composition for melting as described in claim 1, characterized in that, The melted high-content salicylic acid composition is a colorless and transparent liquid.

4. The high-content salicylic acid composition for melting as described in claim 1, characterized in that, Within the temperature range of -15℃ to 49℃, the appearance of the high-content salicylic acid composition is a colorless and transparent liquid.

5. The high-content salicylic acid composition for melting as described in claim 1, characterized in that, Within the temperature range of -20℃ to 200℃, the DSC curve of the high-content salicylic acid composition that has been melted does not show a melting peak of salicylic acid.

6. A method for preparing the high-content salicylic acid composition according to claim 1, characterized in that, Includes the following steps: Accurately weigh salicylic acid, polyethylene glycol-8, and PPG-14-polyglycerol-2-ether according to the weight ratio, mix them, heat to 75℃~85℃, stir until the salicylic acid is completely dissolved, and cool to room temperature to obtain the melted high-content salicylic acid composition.

7. The use of the high-content salicylic acid composition that is defused according to any one of claims 1 to 6 in medical aesthetic products.

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