Adapalene benzoyl peroxide gel and preparation method thereof

Abstract

The invention discloses adapalene benzoyl peroxide gel. The adapalene benzoyl peroxide gel is prepared from adapalene, benzoyl peroxide, 3%-7% of diethylene glycol monoethyl ether, 0.1%-0.3% of caprylic / capric polyethylene glycol glyceride and other pharmaceutically acceptable auxiliary materials. Through synergistic combination of the specific solvent and the surfactant, the problem that benzoyl peroxide is difficult to uniformly disperse only by conventional stirring in the prior art is successfully solved. According to the preparation method, the gel which is uniform in medicine dispersion, fine and smooth in texture and free of gravel feeling can be obtained only through conventional stirring, and complex processes such as high shearing, ultrasonic or spray drying and the like with safety risks do not need to be relied on. The process is simple, the cost is low, the production safety is high, and the obtained product has excellent stability and transdermal absorption performance.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a kind of adapalene peroxide benzoyl gel and preparation method thereof. BACKGROUND

[0002] Acne is a high-incidence and universal skin disease, with a global prevalence rate of 9.4%, ranking eighth among chronic diseases worldwide. Studies have shown that the overall prevalence of acne in the Chinese population is about 8.1% (115 million people), and about 85.1% of adolescents will develop acne, with 3% to 7% of acne patients leaving scars. The "China Acne Treatment Guidelines" recommends adapalene and peroxide benzoyl for acne treatment and recommends combination therapy, pointing out that combination therapy can target acne induced by different pathophysiological factors, and has a faster and better effect on inflammatory lesions and comedones. Adapalene peroxide benzoyl gel (trade name: Epiduo®) has been marketed since 2007 and has been sold in many countries and regions, bringing treatment to acne patients.

[0003] Xu Hao published "Preparation and Quality Research of Adapalene Peroxide Benzoyl Gel" discloses a prescription and process for preparing adapalene peroxide benzoyl gel. The stirring process is selected to prepare the gel. Patent application CN101780028A discloses a compound gel composition mainly composed of adapalene and peroxide benzoyl, which is prepared by stirring process. Patent application CN117731603A discloses a process for mass production of adapalene peroxide benzoyl gel, which is prepared by high-speed shearing dispersion of active phase 1 containing peroxide benzoyl, high-speed shearing dispersion of active phase 2 containing adapalene, and stirring of the remaining excipients to form a compound gel. Patent application CN117731604A discloses a preparation method of adapalene peroxide benzoyl gel, which is prepared by high-speed shearing dispersion of active phase 1 containing peroxide benzoyl, followed by alternating ultrasonic and high-speed shearing dispersion in an ice water bath, high-speed shearing dispersion of active phase 2 containing adapalene in an ice water bath, and stirring of the remaining excipients to form a compound gel. Patent application CN119157825A discloses a kind of adapalene peroxide benzoyl gel and preparation method thereof, adapalene and peroxide benzoyl are prepared into a solid dispersion by spray drying, and then mixed with an aqueous phase to form a compound gel.

[0004] It is known that the existing technology cannot completely disperse peroxide benzoyl by stirring process, and the prepared gel has a rough appearance and a sand-like feel when applied; homogeneous and high-speed shearing dispersion process can disperse peroxide benzoyl well, but the production process is complex; preparing adapalene and peroxide benzoyl into a solid dispersion introduces organic solvents, and the high temperature of spray drying may cause peroxide benzoyl to explode, posing a safety risk in the production process.

[0005] Therefore, it is still a problem to be solved for the adapalene and benzoyl peroxide gel to make two raw materials uniformly distributed in the adapalene and benzoyl peroxide gel by a safe, simple and effective process. SUMMARY

[0006] In view of the above problems in the prior art, the present application provides an adapalene and benzoyl peroxide gel which, under the premise of ensuring production safety, reduces the process complexity and production cost by changing the formulation of the drug and at a lower cost.

[0007] In order to achieve the purpose of the present application, the present application adopts the following technical solutions:

[0008] An adapalene and benzoyl peroxide gel, comprising: adapalene, benzoyl peroxide, SEPINEO P600 (acrylamide / sodium acryloyldimethyl taurate copolymer & isohexadecane & polysorbate 80 & sorbitan oleate), sodium docusate, disodium edetate, glycerin, poloxamer 124, propylene glycol, diethylene glycol monoethyl ether, caprylocaproyl macrogol glycerides, purified water.

[0009] Further, the content of the diethylene glycol monoethyl ether is 3.0% to 7.0% by weight percentage, and the content of the caprylocaproyl macrogol glycerides is 0.1% to 0.3% by weight percentage.

[0010] Further, the content of the diethylene glycol monoethyl ether is 4.0%, and the content of the caprylocaproyl macrogol glycerides is 0.2%.

[0011] Further, the content of the diethylene glycol monoethyl ether is 3.0%, and the content of the caprylocaproyl macrogol glycerides is 0.3%.

[0012] Further, the content of the diethylene glycol monoethyl ether is 7.0%, and the content of the caprylocaproyl macrogol glycerides is 0.1%.

[0013] Further, the adapalene and benzoyl peroxide gel comprises 0.1% of adapalene, 2.5% of benzoyl peroxide, 0.05% of sodium docusate, 4.0% of SEPINEO P600, 0.1% of disodium edetate, 4.0% of glycerin, 0.2% of poloxamer 124, and 4.0% of propylene glycol, and the balance is purified water.

[0014] The preparation method of the adapalene and benzoyl peroxide gel comprises the following steps:

[0015] (1) preparing an aqueous phase: dissolving disodium edetate in a proper amount of purified water to obtain an aqueous phase;

[0016] (2) Preparation of the active phase: dissolve sodium docusate in a proper amount of purified water; mix glycerol, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and caprylocaproyl macrogol glycerides under stirring, and then add adapalene and benzoyl peroxide under continuous stirring to form a preliminary dispersion; add the aqueous solution containing sodium docusate to the preliminary dispersion, and mix uniformly to obtain the active phase;

[0017] (3) Preparation of the gel phase: add the water phase to the active phase, and then add SEPINEO P600 under stirring, and continue to stir until a uniform gel is formed.

[0018] Further, in the step (2), the stirring time of the mixture of glycerol, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and caprylocaproyl macrogol glycerides is about 5 minutes, and the stirring time after adding adapalene and benzoyl peroxide is about 20 minutes.

[0019] Further, in the step (3), the stirring time after adding SEPINEO P600 is at least 30 minutes.

[0020] The application of the adapalene benzoyl peroxide gel in the preparation of a medicament for treating acne.

[0021] Compared with the prior art, the application has the following beneficial technical effects:

[0022] (1) Process simplification: the process is simplified by formula innovation, and the combination of 3.0%~7.0% diethylene glycol monoethyl ether and 0.1%~0.3% caprylocaproyl macrogol glycerides designed carefully can achieve a dispersion effect comparable to a complex process by using only a conventional stirring process, so that the raw drug is uniformly distributed in the gel matrix, and there is no need to pay special attention to the particle size control problem.

[0023] (2) Reduction of equipment requirements and production cost: expensive high-shear equipment is no longer needed, and ordinary stirring devices can meet the production needs, thereby reducing the technical threshold of the operator and the production cost.

[0024] (3) The product prepared by the technical scheme of the application has no visible stratification, precipitation or thinning phenomenon in the observation period, and has no sand feeling when being applied. In addition, in-vitro transdermal experiments show that it can effectively promote the distribution of the active ingredient in the target layer of the skin, thereby providing a guarantee for the curative effect, and good stability and drug delivery efficiency are also taken into account. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 It is a microscopic observation diagram of Example 1 of the application;

[0026] Figure 2These are microscopic images of Embodiment 2 of the present invention;

[0027] Figure 3 These are microscopic images of Embodiment 3 of the present invention;

[0028] Figure 4 These are microscopic images of Embodiment 4 of the present invention;

[0029] Figure 5 These are microscopic images of Embodiment 5 of the present invention;

[0030] Figure 6 These are microscopic images of Embodiment 6 of the present invention;

[0031] Figure 7 These are microscopic images of Embodiment 7 of the present invention;

[0032] Figure 8 This is a microscopic observation image of Embodiment 8 of the present invention. Detailed Implementation

[0033] The present invention will be further illustrated below with specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Any technical solutions obtained by simple improvements to the present invention or by equivalent substitutions of conventional means or components based on the technical solutions of the present invention are within the scope of protection of the present invention.

[0034] Unless otherwise specified, all conditions in this invention shall be carried out under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, all raw materials, reagents or instruments used shall be commercially available conventional products.

[0035] Example 1

[0036] prescription:

[0037] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0038] Preparation method:

[0039] (1) Aqueous phase: Weigh 40% of the prescribed amount of purified water, dissolve disodium edetate in the water to obtain the aqueous phase.

[0040] (2) Active phase: Weigh 60% of the prescribed amount of purified water, add sodium docusate to the water, and stir until dissolved. Place glycerol, propylene glycol, and poloxamer 124 in another container and stir for 5 minutes. While stirring continuously, add adapalene and benzoyl peroxide, and continue stirring for 20 minutes to obtain a preliminary dispersion. Add the pre-dissolved sodium docusate aqueous solution to the preliminary dispersion to obtain the active phase;

[0041] (3) Gel phase: Add the water phase to the active phase, and add SEPINEO P600 under stirring, stir for at least 30 minutes, and obtain.

[0042] Example 2

[0043] The prescription is the same as Example 1, and the difference is that the preparation method is replaced by high-speed shearing instead of direct stirring.

[0044] Preparation method:

[0045] (1) Water phase: Take 40% of the prescription amount of purified water, and dissolve edetate disodium in water to obtain the water phase.

[0046] (2) Active phase: Take 60% of the prescription amount of purified water, and add sodium docusate to the water and stir until dissolved. Mix and wet glycerol, propylene glycol, poloxamer 124, adapalene and benzoyl peroxide, add the previously dissolved sodium docusate solution, and high-speed shear at 7500 rpm under ice water bath conditions for 60 min to obtain the active phase.

[0047] (3) Gel phase: Add the water phase to the active phase, and add SEPINEO P600 under stirring, stir for at least 30 minutes, and obtain.

[0048] Example 3

[0049] According to the prescription and preparation process screened in Xu Hao's "Preparation and Quality Research of Adapalene and Benzoyl Peroxide Gel" to prepare the sample.

[0050] Prescription:

[0051] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Sodium hydroxide pH adjuster 0.2 Purified water solvent Add to 100

[0052] The prescription is more than the pH regulator sodium hydroxide in Example 1, and the difference in process is that the thickening agent SEPINEO P600 is added first, and then the active component suspension is added, and only dispersed by stirring.

[0053] Preparation method:

[0054] (1) Take 95% of the prescription amount of purified water, add edetate disodium, sodium docusate and glycerol, and stir. Add SEPINEO P600 to the above container.

[0055] (2) Take 2% of the prescription amount of purified water, add poloxamer 124, and add adapalene while stirring. Take the prescription amount of propylene glycol, and add benzoyl peroxide. Add the above adapalene suspension and benzoyl peroxide suspension to the (1) container, and stir for 30 min.

[0056] (3) Take 3% of the prescription amount of purified water, dissolve the prescription amount of sodium hydroxide, and add it to the above (2) container and continue stirring.

[0057] Example 4

[0058] Formulation:

[0059] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 Diethylene glycol monoethyl ether Solubilizers and penetration enhancers 4.0 Caprylic / Capric ... Wetting agents and penetration enhancers 0.2 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0060] The difference between the formulation and Example 1 is that the auxiliary material 4.0% diethylene glycol monoethyl ether and 0.2% capryol 90 are added. The preparation method is the same as Example 1.

[0061] Preparation method:

[0062] (1) Water phase: Take 40% of the prescription amount of purified water, dissolve disodium edetate in water to obtain the water phase.

[0063] (2) Active phase: Take 60% of the prescription amount of purified water, add sodium docusate to the water and stir until dissolved. Place glycerin, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and capryol 90 in another container and stir for 5 minutes. Add adapalene and benzoyl peroxide under continuous stirring and continue stirring for 20 minutes to obtain a preliminary dispersion. Add the previously dissolved sodium docusate aqueous solution to the preliminary dispersion to obtain the active phase.

[0064] (3) Gel phase: Add the water phase to the active phase, and add SEPINEO P600 under stirring for at least 30 minutes.

[0065] Example 5

[0066] Formulation:

[0067] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 Diethylene glycol monoethyl ether Solubilizers and penetration enhancers 3.0 Caprylic / Capric ... Wetting agents and penetration enhancers 0.3 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0068] The difference between the formulation and Example 1 is that the auxiliary material 3.0% diethylene glycol monoethyl ether and 0.3% capryol 90 are added. The preparation method is the same as Example 1.

[0069] Preparation method:

[0070] (1) Water phase: Take 40% of the prescription amount of purified water, dissolve disodium edetate in water to obtain the water phase.

[0071] (2) Active phase: Take 60% of the prescription amount of purified water, add sodium docusate to the water and stir until dissolved. Place glycerin, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and capryol 90 in another container and stir for 5 minutes. Add adapalene and benzoyl peroxide under continuous stirring and continue stirring for 20 minutes to obtain a preliminary dispersion. Add the previously dissolved sodium docusate aqueous solution to the preliminary dispersion to obtain the active phase.

[0072] (3) Gel phase: Add the water phase to the active phase, and add SEPINEO P600 under stirring, and stir for at least 30 minutes, and then the gel phase is obtained.

[0073] Example 6

[0074] Prescription:

[0075] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 Diethylene glycol monoethyl ether Solubilizers and penetration enhancers 7.0 Caprylic / Capric ... Wetting agents and penetration enhancers 0.1 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0076] The difference between the prescription and Example 1 is that the auxiliary materials 7.0% diethylene glycol monoethyl ether and 0.1% capryol 90 are added. The preparation method is the same as that of Example 1.

[0077] Preparation method:

[0078] (1) Water phase: Take 40% of the prescription amount of purified water, and dissolve edetate disodium in the water to obtain the water phase.

[0079] (2) Active phase: Take 60% of the prescription amount of purified water, and add sodium docusate to the water and stir until dissolved. Put glycerol, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and capryol 90 in another container and stir for 5 minutes. Add adapalene and benzoyl peroxide under continuous stirring, and continue to stir for 20 minutes to obtain a preliminary dispersion. Add the previously dissolved sodium docusate aqueous solution to the preliminary dispersion to obtain the active phase.

[0080] (3) Gel phase: Add the water phase to the active phase, and add SEPINEO P600 under stirring, and stir for at least 30 minutes, and then the gel phase is obtained.

[0081] Example 7

[0082] Prescription:

[0083] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 Diethylene glycol monoethyl ether Solubilizers and penetration enhancers 8.0 Caprylic / Capric ... Wetting agents and penetration enhancers 0.1 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0084] The difference between the prescription and Example 1 is that the auxiliary materials 7.0% diethylene glycol monoethyl ether and 0.1% capryol 90 are added. The preparation method is the same as that of Example 1.

[0085] Preparation method:

[0086] (1) Water phase: Take 40% of the prescription amount of purified water, and dissolve edetate disodium in the water to obtain the water phase.

[0087] (2) Active phase: Take 60% of the amount of purified water, and add sodium docusate into the water, and stir until dissolved. Take glycerin, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and caprylocaproyl polyoxylglycerides into another container, and stir for 5 minutes. Add adapalene and benzoyl peroxide into the container under continuous stirring, and continue to stir for 20 minutes to obtain a preliminary dispersion. Add the previously dissolved sodium docusate solution into the preliminary dispersion to obtain the active phase;

[0088] (3) Gel phase: Add the water phase into the active phase, and add SEPINEO P600 under stirring for at least 30 minutes to obtain the gel.

[0089] Example 8

[0090] Formulation:

[0091] composition effect Percentage (%w / w) Adapalin Active ingredients 0.1 Benzoyl peroxide Active ingredients 2.5 Sodium edetate Chelating agents 0.1 Diethylene glycol monoethyl ether Solubilizers and penetration enhancers 8.0 glycerin Moisturizer 4.0 Sodium docusate surfactants 0.05 Polosham 124 wetting agent 0.2 Propylene glycol Wetting agents and penetration enhancers 4.0 SEPINEO P600 Thickener 4.0 Purified water solvent Add to 100

[0092] The difference between the formulation and Example 1 is that the auxiliary material 8.0% diethylene glycol monoethyl ether is added. The preparation method is the same as that of Example 1.

[0093] Preparation method:

[0094] (1) Water phase: Take 40% of the amount of purified water, and dissolve edetate disodium in the water to obtain the water phase.

[0095] (2) Active phase: Take 60% of the amount of purified water, and add sodium docusate into the water, and stir until dissolved. Take glycerin, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and caprylocaproyl polyoxylglycerides into another container, and stir for 5 minutes. Add adapalene and benzoyl peroxide into the container under continuous stirring, and continue to stir for 20 minutes to obtain a preliminary dispersion. Add the previously dissolved sodium docusate solution into the preliminary dispersion to obtain the active phase;

[0096] (3) Gel phase: Add the water phase into the active phase, and add SEPINEO P600 under stirring for at least 30 minutes to obtain the gel.

[0097] Performance test

[0098] 1. Appearance and use feeling results

[0099] Visually observe the appearance of the gel; observe the texture of the gel under a microscope: take an appropriate amount of gel and place it on a glass slide, lightly press the cover glass to disperse, and observe under a microscope (magnification 40x) to observe the texture of the gel. Figures 1-8 Use feeling: take an appropriate amount of gel and apply it on the back of the hand, repeat 5 times, and record the use feeling, and the results are recorded in the following table:

[0100]

[0101] Example 1: No diethylene glycol monoethyl ether or capryol 981 was added, only stirring process, raw materials were obvious agglomeration, smearing obvious grit.

[0102] Example 2: No diethylene glycol monoethyl ether or capryol 981 was added, high-speed shearing process instead of stirring process, raw materials were well dispersed, smearing touch delicate, indicating that high-speed shearing process helps to disperse the raw materials.

[0103] Example 3: Added sodium hydroxide, adjusted the feeding sequence, first added thickening agent SEPINEO P600, then added active ingredient suspension, dispersion process only included stirring, active ingredient suspension: peroxide benzoyl was difficult to disperse in the amount of propylene glycol, adapalene remained suspended in the amount of purified water and poloxamer 124, could not be wetted, the production process was not smooth, the finished product had small particles, smearing grit obvious.

[0104] Example 4: Added 4.0% diethylene glycol monoethyl ether and 0.2% capryol 981, only through stirring process can make raw materials disperse well, indicating that the addition of the above-mentioned auxiliary materials helps to reduce the complexity of the process.

[0105] Example 5: Added 3.0% diethylene glycol monoethyl ether and 0.3% capryol 981, Example 6: added 7.0% diethylene glycol monoethyl ether and 0.1% capryol 981, only through stirring process can make raw materials disperse well. It is shown that reducing the concentration of diethylene glycol monoethyl ether while increasing the concentration of capryol 981, or increasing the concentration of diethylene glycol monoethyl ether while reducing the concentration of capryol 981 can also obtain good properties of the gel, which helps to reduce the complexity of the process.

[0106] Example 7: Added 8.0% diethylene glycol monoethyl ether and 0.1% capryol 981, Example 8: only added 8.0% diethylene glycol monoethyl ether, obtained gel is not delicate, raw materials agglomeration. It is shown that when the concentration of diethylene glycol monoethyl ether is too high, it may compete with the gel matrix for water, or directly destroy the hydration layer of the high molecular chain, resulting in incomplete hydration of the gel matrix, unstable overall gel structure, and precipitation of raw materials. When the concentration of capryol 981 is too low or does not exist, it leads to insufficient surfactant molecules to completely cover the surface of the drug particles, the "exposed" area will make the particles collide with each other in Brownian motion, and re-agglomerate into larger particles, thereby destroying the delicacy of the gel.

[0107] From the results: compared with Example 4, Example 5, Example 6, the use of 3%~7% diethylene glycol monoethyl ether and 0.1%~0.3% capryol 981 can make the raw materials reach a good dispersion state under stirring.

[0108] 2. In vitro permeation study

[0109] According to the FDA's "In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry" and CDE's "Technical Guidelines for In Vitro Release (IVRT) and In Vitro Permeation (IVPT) Studies of Topical Chemical Generic Drugs (Trial)", the in vitro permeation of the above examples was determined by diffusion cell. Since Example 1, Example 3, Example 7 and Example 8 have obvious material drug agglomeration and uneven distribution, only Example 2, 4, 5, 6 were subjected to in vitro permeation study. The results are as follows:

[0110]

[0111] Note: A represents adapalene; B represents benzoyl peroxide; P value of T test is compared: Example 4~6 compared with Example 2 respectively.

[0112] Comparing Example 4, Example 5, Example 6 with Example 2 respectively, the distribution of stratum corneum and dermis of Example 4, Example 5, Example 6 is significantly better than Example 2, which shows that the use of diethylene glycol monoethyl ether and caprylocaproyl macrogol glycerides can improve the permeation rate in a certain range of concentration formula.

[0113] 3. Stability study

[0114] According to the "Guidelines for Stability Testing of Raw Materials and Preparations" in the Chinese Pharmacopoeia 2025 Edition Volume IV 9001, Example 4, Example 5 and Example 6 were placed under accelerated conditions (30°C ± 2°C, relative humidity 65% ± 5% RH) to investigate the stability of the preparation. The specific results are as follows:

[0115]

[0116] The results show that: up to the accelerated-12 months, the properties of Example 4, 5 and 6 have not changed since 0 months, and the use is good.

[0117] The in vitro permeation experiment of Example 4, Example 5 and Example 6 after being placed under the above accelerated-12 months condition was compared with the results of 0 months to further confirm the stability of the preparation, and the results are as follows:

[0118]

[0119] Note: A represents adapalene; B represents peroxide benzoyl; P value of T test: comparison of accelerated 12 months of Examples 4~6 with 0 months of Examples 4~6.

[0120] The results show that there is no significant difference in the distribution of stratum corneum and dermis between Examples 4, 5 and 6 after being placed under the accelerated-12-month condition and 0 months (p>0.05). In summary, the stability of Examples 4, 5 and 6 is good.

[0121] The above description is merely preferred embodiments of the present application, but not to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. An adapalene-peroxybenzoyl gel, characterized in that, Including adapalene, benzoyl peroxide, SEPINEOP600, sodium docusate, disodium edetate, glycerol, poloxamer 124, propylene glycol, diethylene glycol monoethyl ether, PEG-glycerol octanoate, and purified water.

2. The adapalene peroxybenzoyl gel according to claim 1, characterized in that, The content of diethylene glycol monoethyl ether is 3.0% to 7.0% by weight, and the content of polyethylene glycol glycerol octanoate and decanoate is 0.1% to 0.3%.

3. The adapalene peroxybenzoyl gel according to claim 2, characterized in that, The content of diethylene glycol monoethyl ether is 4.0%, and the content of octanoic acid decanoic acid polyethylene glycol glyceride is 0.2%.

4. The adapalene peroxybenzoyl gel according to claim 2, characterized in that, The content of diethylene glycol monoethyl ether is 3.0%, and the content of octanoic acid decanoic acid polyethylene glycol glyceride is 0.3%.

5. The adapalene peroxybenzoyl gel according to claim 2, characterized in that, The content of diethylene glycol monoethyl ether is 7.0%, and the content of octanoic acid decanoic acid polyethylene glycol glyceride is 0.1%.

6. The adapalene peroxybenzoyl gel according to any one of claims 1-5, characterized in that, By weight percentage, it includes 0.1% adapalene, 2.5% benzoyl peroxide, 0.05% sodium docusate, 4.0% SEPINEO P600, 0.1% disodium edetate, 4.0% glycerol, 0.2% poloxamer 124, 4.0% propylene glycol, with the balance being purified water.

7. The method for preparing adapalene peroxybenzoyl gel according to any one of claims 1-6, characterized in that, Includes the following steps: (1) Preparation of aqueous phase: Dissolve disodium edetate in an appropriate amount of purified water to obtain an aqueous phase; (2) Preparation of active phase: Sodium docusate is dissolved in an appropriate amount of purified water; glycerol, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and octanoic acid decanoic acid polyethylene glycol glycerol are mixed and stirred, and adapalene and benzoyl peroxide are added under continuous stirring to form a preliminary dispersion; the aqueous solution of sodium docusate is added to the preliminary dispersion and mixed evenly to obtain the active phase; (3) Preparation of gel phase: Add the aqueous phase to the active phase, add SEPINEO P600 while stirring, and continue stirring until a uniform gel is formed.

8. The preparation method according to claim 7, characterized in that, In step (2), the mixing time for glycerol, propylene glycol, poloxamer 124, diethylene glycol monoethyl ether and caprylic / capric glycerol ester is about 5 minutes. After adding adapalene and benzoyl peroxide, the mixing time is continued for about 20 minutes.

9. The preparation method according to claim 7, characterized in that, In step (3), after adding SEPINEO P600, the stirring time is at least 30 minutes.

10. The use of the adapalene peroxybenzoyl gel according to any one of claims 1-6 in the preparation of a medicament for the treatment of acne.

Images