Preparation method of high-stability adapalene gel

Abstract

This invention discloses a method for preparing highly stable adapalene gel, belonging to the field of pharmaceutical preparation technology. This invention uses a eutectic solvent (DES) as the drug carrier (menthol, thymol, and octanol), which is milder than traditional organic solvents and can reduce the photocatalytic degradation of adapalene, thereby maintaining the chemical stability of the drug. The adapalene gel obtained by this invention, especially the gel prepared by using menthol, thymol, and octanol in a molar ratio of 1:1:0.1, exhibits stable performance and has broad application prospects.

Description

Technical Field

[0001] This invention discloses a method for preparing highly stable adapalene gel, belonging to the field of pharmaceutical preparation technology. Background Technology

[0002] Adapalene (chemical name 6) [3 (1 adamantyl) 4 [Methoxyphenyl] 2 Naphthoic acid), C 28 H 28 O3, with a molecular weight of 412.52 g / mol and CAS number 106 685 40 9. It belongs to the third generation of retinoid drugs and has a good anti-inflammatory effect, which is effective in treating acne.

[0003] Adapalene is almost insoluble in water and has very low solubility in common oil phases (such as mineral oil and vegetable oil), leading to the following problems in the gel production process: (1) Adapalene cannot be easily dissolved in aqueous or oily gel matrices. (2) During preparation and storage, especially when exposed to temperature changes, vibration, or dilution, trace amounts of dissolved adapalene are prone to recrystallization. These microcrystals not only affect the product's appearance (such as producing a grainy feel and reduced transparency) but also severely weaken its efficacy. (3) Due to its insolubility, adapalene can only be dispersed in the entire gel system as solid microparticles. If the dispersion process is poor, it can lead to uneven content in different batches or even different parts of the same gel, affecting the accuracy of the dosage.

[0004] Currently, many researchers have tried to improve the solubility of adapalene by adding different solvents to achieve the stability of the gel system. For example, a mixture of ethanol and propylene glycol can improve the solubility of adapalene. However, both ethanol and propylene glycol can interact with the stratum corneum, causing adverse reactions such as burning sensation, erythema, dryness, and desquamation. In clinical use, "irritation" is a common cause of decreased patient compliance. Furthermore, ethanol evaporates quickly, which can easily lead to changes in the solvent ratio during use, thereby affecting the drug concentration and the stability of the formulation.

[0005] Oxidation is typically a chain reaction triggered by factors such as light, oxygen, metal ion impurities, or high temperatures. Adapalene, a molecule with a naphthalene ring and phenolic hydroxyl group structure, is particularly sensitive to oxidation. Once adapalene is oxidized, the gel gradually turns dark yellow, yellowish-brown, or even brown. Degradation can accompany the oxidation process, potentially altering the gel's viscosity and texture. Current technologies typically employ the addition of antioxidants to prevent adapalene oxidation. However, adding additional antioxidants increases costs and necessitates assessing their impact on drug efficacy.

[0006] Meanwhile, preservatives are often required in the preparation of adapalene gel. Therefore, there is an urgent need for a method to prepare adapalene gel with high solubility, no need for additional preservatives, and high antioxidant capacity to meet market demand. Summary of the Invention

[0007] This invention provides a method for preparing adapalene gel, the method comprising the following steps: S1, Gel phase: Carbomer was added to an aqueous propylene glycol solution and stirred to obtain a gel phase; S2, Drug Phase: Menthol, thymol, and octanol are mixed and stirred in a molar ratio of 1:(1~1.5):0.1 to form a transparent and homogeneous DES solution; Adapalene is added to the DES solution and stirred until homogeneous to obtain the drug phase; S3, Gel Preparation: The drug phase obtained in S2 and the gel phase obtained in S1 are stirred and mixed, and a pH adjuster is added to prepare adapalene gel.

[0008] In one embodiment of the present invention, the formulation of the adapalene gel specifically includes, by weight percentage, 2-4% propylene glycol, 1.0-1.2% carbomer, at least 0.1% adapalene, 3-4% DES solution, 0.15-0.2% pH adjuster, and the remainder being water. In one embodiment of the present invention, the amount of propylene glycol added is 2% (w / w), 3% (w / w), or 4% (w / w). In one embodiment of the present invention, the amount of carbomer added is 1.1% (w / w) or 1.2% (w / w). In one embodiment of the present invention, in step S1, after adding carbomer, the stirring conditions are: 500~550 rpm, 70~100 min.

[0009] In one embodiment of the present invention, in step S1, after adding carbomer, the stirring speed is 500 rpm, 510 rpm, 520 rpm, 530 rpm, 540 rpm or 550 rpm, and the stirring time is 30 min, 31 min, 32 min, 33 min, 34 min or 35 min.

[0010] In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are stirred at a molar ratio of 1:(1~1.5):0.1 for 30~35 min at 55~60°C and 1000~1200 rpm to form a transparent and uniform DES solution. In one embodiment of the present invention, in step S2, the added adapalene mass fraction is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%. In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1:0.1. In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.1:0.1; In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.2:0.1; In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.3:0.1; In one embodiment of the present invention, in step S2, adapalene is added to the DES solution. After stirring at 1000-1200 rpm for the first 1-2 minutes, it is dispersed until uniform under stirring conditions of 25-28°C, 500-550 rpm, and 10-15 minutes.

[0011] In one embodiment of the present invention, the carbomer is a carbomer homopolymer type C.

[0012] In one embodiment of the present invention, in step S3, the drug phase is added to the gel phase, and the stirring conditions are: 25~28℃, 500~550 rpm, 10~15min.

[0013] In one embodiment of the present invention, in step S3, sodium hydroxide solution is used as a pH adjuster to adjust the pH to the range of 4.8-5.2.

[0014] The present invention also provides adapalene gel prepared by the above preparation method.

[0015] The present invention also provides the application of a eutectic solvent in the preparation of highly stable adapalene gel, wherein the eutectic solvent is menthol, thymol, or octanol; In one embodiment of the present invention, the molar ratio of menthol, thymol, and octanol is 1:(1~1.5):0.1; In one embodiment of the present invention, the application is to use the above-mentioned eutectic solvent when preparing adapalene gel; In one embodiment of the present invention, the application specifically includes the following steps: S1, Gel phase: Carbomer was added to an aqueous propylene glycol solution and stirred to obtain a gel phase; S2, Drug Phase: Menthol, thymol, and octanol are mixed and stirred in a molar ratio of 1:(1~1.5):0.1 to form a transparent and homogeneous DES solution; Adapalene is added to the DES solution and stirred until homogeneous to obtain the drug phase; S3, Gel Preparation: The drug phase obtained in S2 and the gel phase obtained in S1 are stirred and mixed, and a pH adjuster is added to prepare adapalene gel.

[0016] In one embodiment of the present invention, the formulation of the adapalene gel, by weight percentage, specifically includes 2-4% propylene glycol, 1.0-1.2% carbomer, at least 0.1% adapalene, 3-4% DES solution, 0.15-0.2% pH adjuster, and the remainder being water. In one embodiment of the present invention, the formulation of the adapalene gel specifically includes, by weight percentage, 4% propylene glycol, 1.1% carbomer, at least 0.1% adapalene, 4% DES solution, 0.18% pH adjuster, and the remainder being water. In one embodiment of the present invention, in step S1, after adding carbomer, the stirring conditions are: 500~550 rpm, 70~100 min. In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are stirred at a molar ratio of 1:(1~1.5):0.1 for 30~35 min at 55~60°C and 1000~1200 rpm to form a transparent and uniform DES solution. In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1:0.1. In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.1:0.1; In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.2:0.1; In one embodiment of the present invention, in step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.3:0.1; In one embodiment of the present invention, in step S2, adapalene is added to the DES solution. After stirring at 1000-1200 rpm for the first 1-2 minutes, it is dispersed until uniform under stirring conditions of 25-28°C, 500-550 rpm, and 10-15 minutes.

[0017] In one embodiment of the present invention, the carbomer is a carbomer homopolymer type C.

[0018] In one embodiment of the present invention, in step S3, the drug phase is added to the gel phase, and the stirring conditions are: 25~28℃, 500~550 rpm, 10~15min.

[0019] In one embodiment of the present invention, in step S3, sodium hydroxide solution is used as a pH adjuster to adjust the pH to the range of 4.8-5.2.

[0020] Beneficial effects (1) The present invention uses a eutectic solvent (DES) as a drug carrier (menthol, thymol, octanol). Compared with traditional organic solvents, it is milder and can reduce the photocatalytic degradation of adapalene, thereby maintaining the chemical stability of the drug. At the same time, the method of the present invention can achieve a gel with high solubility and stability of adapalene without adding metal chelating agents and preservatives. Furthermore, since the eutectic solvent (DES) formed by the present invention firmly "encapsulates" adapalene, it reduces the skin irritation of adapalene without affecting drug release. At the same time, the DES solution also isolates oxygen, ensuring that adapalene is not oxidized or interfered with by metal ions. On this basis, menthol, thymol, and octanol, as antioxidants, can also preferentially react with oxygen, further increasing the stability of the adapalene gel.

[0021] (2) Menthol and thymol in the eutectic solvent DES of this invention are classic natural penetration enhancers. They can reversibly interfere with the lipid structure of the stratum corneum and reduce the skin barrier function, thereby helping adapalene dissolved in the eutectic solvent DES to penetrate the skin more effectively. Common side effects of adapalene are dry skin, erythema, and irritation. By solubilizing and enhancing penetration with the eutectic solvent DES, the need for traditional irritating solvents may be reduced. At the same time, the components such as thymol in the eutectic solvent DES have certain anti-inflammatory and soothing properties, which may, to some extent, offset the initial irritation caused by adapalene.

[0022] (3) The adapalene gel obtained by the present invention, especially the gel prepared by menthol, thymol and octanol in a molar ratio of 1:1:0.1, has stable performance and broad application prospects. Detailed Implementation

[0023] The detection method for adapalene content involved in the following examples is as follows: Test solution: Weigh an appropriate amount of this product (approximately equivalent to 2 mg of adapalene) accurately, place it in a 100 ml volumetric flask, add the mobile phase to dissolve the adapalene and dilute to the mark, shake well, and filter.

[0024] Reference solution: Weigh approximately 20 mg of adapalene reference standard accurately, place it in a 100 ml volumetric flask, dissolve it in 5 ml of tetrahydrofuran, dilute to the mark with the mobile phase, and shake well. Accurately measure 5 ml of the solution and place it in a 50 ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0025] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-tetrahydrofuran-trifluoroacetic acid-water (42:32:0.02:26) was used as the mobile phase; the detection wavelength was 270 nm; and the injection volume was 20 μl.

[0026] System suitability test: The theoretical plate number, calculated based on the adapalene peak, shall not be less than 3000.

[0027] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method.

[0028] The viscosity detection method involved in the following embodiments: Take this product and determine its properties according to the method described in the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0633, Method III. Use an NDJ-1 type rotary viscometer with rotor No. 4 at a speed of 6 revolutions per minute, while keeping the rotor 2 cm below the liquid surface.

[0029] The particle size detection method involved in the following embodiments: Take an appropriate amount of this product and spread it into a uniform thin layer with an area equivalent to that of a coverslip. Examine the drug particles in two fields of view under a 400x microscope according to the method for determination of particle size and particle size distribution (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982, Method I).

[0030] The specific steps of the DES solution selection experiment involved in the following examples are as follows: 1. Experimental Design Hydrogen bond acceptors (HBAs) were selected as choline chloride (ChCl), citric acid, and menthol. Select hydrogen bond donors (HBD): urea, ethylene glycol, glycerol, propylene glycol, lactic acid, thymol, octanol; A DES solution was formed by mixing hydrogen bond acceptors and hydrogen bond donors in a 1:1 molar ratio, heating in a 60°C water bath, and stirring at 1000 rpm for 30 minutes.

[0031] Add 2 mL of each of the above DES solutions to excess adapalene, place in a 25°C constant temperature water bath shaker and shake for 48 hours. Use HPLC to determine the concentration of adapalene in the solution and calculate its saturated solubility in each DES solution.

[0032] 2. Experimental Results (1) When the hydrogen bond acceptor (HBA) is chosen to be choline chloride (ChCl): When the hydrogen bond donor is urea (urea decomposes to produce cyanate when heated, usually above 80°C or stored for a long time, and is hygroscopic and easily crystallizes), the prepared system is unstable and easily decomposes. When the hydrogen bond donor is ethylene glycol or glycerol, the resulting DES solution has high viscosity and poor fluidity when cooled to room temperature, and may undergo partial degradation under high temperature or strong oxidizing conditions. When the hydrogen bond donor is lactic acid, which is an organic acid, the DES system is acidic. Since the addition of lactic acid will greatly affect the viscosity and gel structure of the carbomer (gel matrix), it usually leads to a decrease in the viscosity of the system or even complete destruction of the gel. When the hydrogen bond donors are thymol and octanol, a homogeneous and stable DES solution cannot be formed under the above experimental conditions.

[0033] (2) When citric acid is chosen as the hydrogen bond acceptor (HBA): Since citric acid is a strong hydrogen bond donor, the DES formed is highly polar and can effectively destroy the molecular lattice of adapalene, which may significantly improve its solubility; however, the addition of citric acid will greatly affect the viscosity and gel structure of carbomer (gel matrix), usually leading to a decrease in the viscosity of the system or even complete destruction of the gel. Therefore, the DES system with citric acid as the hydrogen bond acceptor (HBA) was abandoned.

[0034] (3) When menthol is chosen as the hydrogen bond acceptor (HBA): Experimental results showed that adapalene had the highest solubility when thymol was selected as the hydrogen bond acceptor (HBA), which was significantly higher than when urea, ethylene glycol, glycerol, propylene glycol, octanol, or lactic acid were selected as the HBA.

[0035] 3. Based on the above experiments, in order to further increase the solubility of adapalene, the binary DES system was changed to a ternary system. The effect of the DES solution prepared by mixing menthol, thymol, and octanol in a molar ratio of 1:1:(0.1~1) on the solubility of adapalene was investigated. The results showed that the solubility of adapalene did not change significantly with the increase of octanol. Therefore, considering both cost and effectiveness, the DES solution prepared by menthol, thymol, and octanol in a molar ratio of 1:1:0.1 was selected.

[0036] Example 1: The preparation method of adapalene gel-1 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0037] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0038] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were heated in a 60°C water bath at a molar ratio of 1:1:0.1 (1.956 g menthol, 1.881 g thymol, and 0.163 g octanol) and stirred at 1000 rpm for 30 minutes to form a clear and homogeneous DES solution (4%). Adapalene 0.3 g (0.3%) was added to the DES solution after it had cooled to room temperature. The solution was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C with stirring at 500 rpm until homogeneous (no visible particles, approximately 10 minutes).

[0039] (4) Adding the drug phase: The drug phase dispersion obtained in step (3) is slowly and in a thin stream transferred to the gel phase obtained in step (2) and mixed under stirring (28°C, 500 rpm, 10 min); (5) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0040] (6) If the pH value is within the specified range, add the remaining amount of purified water (5.12 g) to make the formula 100%.

[0041] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%).

[0042] Example 2: The preparation method of adapalene gel-2 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0043] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0044] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were heated in a 60°C water bath at a molar ratio of 1:1.1:0.1 (1.868 g menthol, 1.976 g thymol, and 0.156 g octanol) and stirred at 1000 rpm for 30 minutes to form a transparent and homogeneous DES solution (4%). Adapalene 0.3 g (0.3%) was added to the DES solution after it had cooled to room temperature. The solution was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C and 500 rpm until homogeneous (no visible particles, approximately 10 minutes).

[0045] (4) Adding the drug phase: The drug phase dispersion obtained in step (3) is slowly and in a thin stream transferred to the gel phase obtained in step (2) and mixed under stirring (28°C, 500 rpm, 10 min); (5) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0046] (6) If the pH value is within the specified range, add the remaining amount of purified water (5.12 g) to make the formula 100%.

[0047] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%).

[0048] Example 3: The preparation method of adapalene gel-3 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0049] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0050] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were heated in a 60°C water bath at a molar ratio of 1:1.2:0.1 (1.788 g menthol, 2.063 g thymol, and 0.149 g octanol) and stirred at 1000 rpm for 30 minutes to form a transparent and homogeneous DES solution (4%). Adapalene 0.3 g (0.3%) was added to the DES solution after it had cooled to room temperature. The solution was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C and 500 rpm until homogeneous (no visible particles, approximately 10 minutes).

[0051] (4) Adding the drug phase: The drug phase dispersion obtained in step (3) is slowly and in a thin stream transferred to the gel phase obtained in step (2) and mixed under stirring (28°C, 500 rpm, 10 min); (5) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0052] (6) If the pH value is within the specified range, add the remaining amount of purified water (5.12 g) to make the formula 100%.

[0053] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%).

[0054] Example 4: The preparation method of adapalene gel-4 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0055] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0056] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were heated in a 60°C water bath at a molar ratio of 1:1.3:0.1 (1.714 g menthol, 2.143 g thymol, and 0.143 g octanol) and stirred at 1000 rpm for 30 minutes to form a transparent and homogeneous DES solution (4%). Adapalene 0.3 g (0.3%) was added to the DES solution after it had cooled to room temperature. The solution was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C and 500 rpm until homogeneous (no visible particles, approximately 10 minutes). (4) Adding the drug phase: The drug phase dispersion obtained in step (3) is slowly and in a thin stream transferred to the gel phase obtained in step (2) and mixed under stirring (28°C, 500 rpm, 10 min); (5) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0057] (6) If the pH value is within the specified range, add the remaining amount of purified water (5.12 g) to make the formula 100%.

[0058] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%).

[0059] Comparative Example 1: Specifically, the process is the same as in Example 1, except that the rotation speed (500 rpm) in step (4) is adjusted to 300 rpm, 400 rpm, 600 rpm, and 900 rpm respectively; adapalene gel-5, adapalene gel-6, adapalene gel-7, and adapalene gel-8 are prepared respectively.

[0060] Comparative Example 2: Specifically, the process is the same as in Example 1, except that the rotation speed in step (3) is adjusted (the rotation speed during dispersion until uniformity is achieved at 28°C and 500 rpm) to be 300 rpm, 400 rpm, 600 rpm, and 900 rpm respectively; adapalene gel-9, adapalene gel-10, adapalene gel-11, and adapalene gel-12 are prepared respectively.

[0061] Comparative Example 3: Specifically, the same as in Example 1, except that the ratio of menthol, thymol, and octanol in the drug phase in step (4) is adjusted to 1:1:0.1: Adapalene gel-13 (2:1:0.1) and adapalene gel-14 (1:1:0.2) are prepared according to the molar ratios of 2:1:0.1 and 1:2:0.1, respectively.

[0062] Comparative Example 4: The specific details are the same as in Example 1, except that... Adjusting step (4) the ratio of menthol, thymol, and octanol in the drug phase to 1:1:0.1 is adjusted to: menthol, carvacrol, and octanol in a molar ratio of 1:1:0.1, thus preparing adapalene gel-15.

[0063] Adjusting step (4): The ratio of menthol, thymol, and octanol in the drug phase is adjusted to 1:1:0.1: Menthol, thymol, and dodecanol are adjusted to 1:1:0.1 to prepare adapalene gel-16.

[0064] Example 5: The obtained adapalene gel was subjected to performance testing: (1) Detection of traits Table 1: Properties of different gels

[0065] (2) The adapalene gel prepared above was stored at a high temperature of 40°C (without controlling humidity and protecting from light). The content of adapalene in the adapalene gel was measured after 10 days and then measured again after 20 days. In order to better reflect the product status, the drug content after 0 days, 10 days and 20 days of storage was compared with the initial amount of drug added (the initial amount of drug added was defined as 100%). The results are shown in Table 2.

[0066] (3) The adapalene gel prepared above was stored at a relative humidity of 75% ± 5% (room temperature 25℃, protected from light). The content of adapalene in the adapalene gel was measured after 10 days and after 20 days. In order to reflect the product status, the drug content after 0 days, 10 days and 20 days of storage was compared with the initial amount of drug added (the initial amount of drug added was defined as 100%). The results are shown in Table 2.

[0067] Table 2: Results of High Temperature and High Humidity Stability Tests

[0068] (4) The particle size and viscosity of the obtained gel were tested, and the results are shown in Table 3.

[0069] Table 3: Performance Testing

[0070] As shown in the table, the rotation speed has a significant impact on the preparation and addition of the drug phase, with the optimal rotation speed range being 500~550 rpm. The ratio of menthol, thymol, and octanol also has a significant impact on the results, with the molar ratio ranging from 1:(1~1.5):0.1.

[0071] (5) Total impurities The adapalene gel prepared above was stored (at room temperature 25°C, protected from light), and the total impurity content in the gel was measured at different times. Since no metal chelating agents or preservatives were added during the preparation of the gel, this experiment was conducted to detect the total amount of impurities other than those in the adapalene formulation during storage. The results are shown in Table 4.

[0072] Table 4: Results of Total Impurities in Adapalene Gel

[0073] Example 6: The preparation method of adapalene gel-17 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0074] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0075] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were mixed in a molar ratio of 1:1:0.1 (1.956 g menthol, 1.881 g thymol, and 0.163 g octanol) and heated in a 60°C water bath. The mixture was stirred at 1000 rpm for 30 minutes to form a clear and homogeneous DES solution (4%). Adapalene 0.7 g (0.7%) was added to the DES solution after it had cooled to room temperature. The mixture was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C with stirring at 500 rpm until homogeneous (no visible particles, approximately 10 minutes).

[0076] (5) Adding the drug phase: The drug phase dispersion obtained in step (4) is slowly and in a thin stream transferred to the gel phase obtained in step (3) and mixed under stirring (28°C, 500 rpm, 10 min); (6) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0077] (7) If the pH value is within the specified range, add the remaining amount of purified water (4.72g) to make the formula 100%.

[0078] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%). Example 7: The preparation method of adapalene gel-18 includes the following steps: (1) Aqueous phase: Add 84.3g (84.3%) of purified water and 4g (4%) of humectant propylene glycol to the main mixing container, and stir at 200rpm to obtain the aqueous phase.

[0079] (2) Gel phase: Under stirring (500 rpm), add 1.1 g (1.10%) of pre-weighed carbomer homopolymer C to the aqueous phase obtained in step (1), and continue stirring (500 rpm, 70~80 min) until the carbomer is fully hydrated to a uniform and transparent state.

[0080] (3) Drug phase: In a stainless steel container, menthol, thymol, and octanol were mixed in a molar ratio of 1:1:0.1 (1.956 g menthol, 1.881 g thymol, and 0.163 g octanol) and heated in a 60°C water bath. The mixture was stirred at 1000 rpm for 30 minutes to form a clear and homogeneous DES solution (4%). Adapalene 1.0 g (1.0%) was added to the DES solution after it had cooled to room temperature. The mixture was dispersed at 1000 rpm for the first 1-2 minutes, and then at 28°C with stirring at 500 rpm until homogeneous (no visible particles, approximately 10 minutes).

[0081] (5) Adding the drug phase: The drug phase dispersion obtained in step (4) is slowly and in a thin stream transferred to the gel phase obtained in step (3) and mixed under stirring (28°C, 500 rpm, 10 min); (6) Adjust the pH value: Dissolve 0.18g of sodium hydroxide (0.18%) in 1g (1%) of pure water in another container to prepare a sodium hydroxide solution. Slowly add this sodium hydroxide solution to the mixture, stirring continuously during the addition process. Measure the pH value while adding the solution and adjust the pH value to the range of 4.8-5.2.

[0082] (7) If the pH value is within the specified range, add the remaining amount of purified water (4.42 g) to make the formula 100%.

[0083] If the pH value is below or above the specified range, adjust the pH value to 5.0 ± 0.2 using hydrochloric acid or sodium hydroxide solution. Then add enough purified water to bring the total mass to 100g (to make the formula 100%). The properties of the prepared adapalene gel-17 and adapalene gel-18 were tested, and the results are shown in Table 5 below. Table 5: Experimental Results

[0084] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A method for preparing adapalene gel, characterized in that, The method includes the following steps: S1, Gel phase: Carbomer was added to an aqueous propylene glycol solution and stirred to obtain a gel phase; S2, Drug Phase: Menthol, thymol, and octanol are mixed and stirred in a molar ratio of 1:(1~1.5):0.1 to form a transparent and homogeneous DES solution; Adapalene is added to the DES solution, and after stirring at 1000~1200 rpm for the first 1~2 min, it is dispersed at 25~28℃, 500~550 rpm, for 10~15 min until homogeneous to obtain the drug phase; S3, Gel preparation: After mixing the drug phase obtained in S2 with the gel phase obtained in S1, a pH adjuster is added to prepare adapalene gel. The stirring conditions are: 25~28℃, 500~550 rpm, 10~15min.

2. The preparation method according to claim 1, characterized in that, The adapalene gel comprises, by weight percentage, 2-4% propylene glycol, 1.0-1.2% carbomer, at least 0.1% adapalene, 3-4% DES solution, 0.15-0.2% pH adjuster, and the remainder being water.

3. The preparation method according to claim 1, characterized in that, The adapalene gel, by weight percentage, specifically comprises 4% propylene glycol, 1.1% carbomer, at least 0.1% adapalene, 4% DES solution, 0.18% pH adjuster, and the remainder being water.

4. The preparation method according to claim 1 or 2, characterized in that, In step S1, after adding carbomer, the stirring conditions are: 500~550 rpm, 70~100 min.

5. The preparation method according to claim 1, characterized in that, In step S2, menthol, thymol and octanol are stirred at a molar ratio of 1:(1~1.5):0.1 for 30~35 min at 55~60℃ and 1000~1200 rpm to form a transparent and uniform DES solution.

6. The preparation method according to claim 1, characterized in that, In step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1:0.

1.

7. The preparation method according to claim 1, characterized in that, In step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.1:0.

1.

8. The preparation method according to claim 1, characterized in that, In step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.2:0.

1.

9. The preparation method according to claim 1, characterized in that, In step S2, menthol, thymol, and octanol are added in a molar ratio of 1:1.3:0.

1.

10. The preparation method according to claim 1, characterized in that, The carbomer is a carbomer homopolymer of type C.

11. The preparation method according to claim 1, characterized in that, In step S3, sodium hydroxide solution is used as a pH adjuster to adjust the pH to the range of 4.8-5.

2.

12. Adapalene gel prepared by any of the preparation methods according to claims 1 to 11.

13. The application of eutectic solvents in the preparation of highly stable adapalene gels, characterized in that, The eutectic solvent is menthol, thymol, and octanol; the molar ratio of menthol, thymol, and octanol is 1:(1~1.5):0.1; the application is to use the above-mentioned eutectic solvent in the preparation of adapalene gel; the application specifically includes the following steps: S1, Gel phase: Carbomer was added to an aqueous propylene glycol solution and stirred to obtain a gel phase; S2, Drug Phase: Menthol, thymol, and octanol are mixed and stirred in a molar ratio of 1:(1~1.5):0.1 to form a transparent and homogeneous DES solution; Adapalene is added to the DES solution, and after stirring at 1000~1200 rpm for the first 1~2 min, it is dispersed at 25~28℃, 500~550 rpm, for 10~15 min until homogeneous to obtain the drug phase; S3, Gel preparation: After mixing the drug phase obtained in S2 with the gel phase obtained in S1, a pH adjuster is added to prepare adapalene gel. The stirring conditions are: 25~28℃, 500~550 rpm, 10~15min.

14. The application according to claim 13, characterized in that, The adapalene gel, by weight percentage, specifically comprises 2-4% propylene glycol, 1.0-1.2% carbomer, at least 0.1% adapalene, 3-4% DES solution, 0.15-0.2% pH adjuster, and the remainder being water.

15. The application according to claim 13, characterized in that, The adapalene gel, by weight percentage, specifically comprises 4% propylene glycol, 1.1% carbomer, at least 0.1% adapalene, 4% DES solution, 0.18% pH adjuster, and the remainder being water.

16. The application according to claim 13, characterized in that, In step S1, after adding carbomer, the stirring conditions are: 500~550 rpm, 70~100 min.

17. The application according to claim 13, characterized in that, In step S2, menthol, thymol and octanol are stirred at a molar ratio of 1:(1~1.5):0.1 for 30~35 min at 55~60℃ and 1000~1200 rpm to form a transparent and uniform DES solution.

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