Adapalene benzoyl peroxide gel and preparation method thereof

Abstract

The invention relates to adapalene benzoyl peroxide gel. The adapalene benzoyl peroxide gel is prepared from adapalene, benzoyl peroxide, docusate sodium, edetate disodium, glycerol, poloxamer 124, propylene glycol and an acrylamide / acryloyl sodium dimethyl taurate copolymer amp, wherein the acrylamide / acryloyl sodium dimethyl taurate copolymer amp is a mixture of sodium acetate and sodium acetate; isohexadecane amp; isohexadecane amp; 80 amp of polysorbate; adding sorbitan oleate and purified water; the preparation method of the adapalene benzoyl peroxide gel comprises the following steps: S1, preparing a solid dispersion; S2, preparing an active component phase; S3, preparing a water phase; and S4, preparing the gel. The adapalene benzoyl peroxide gel and the preparation method thereof provided by the invention are used for solving the problem of uniformity of two raw material medicines in the adapalene benzoyl peroxide gel, so that the uniformity and the particle size of the two raw material medicines in a container in the gel meet regulations, and the preparation quality and the clinical curative effect are guaranteed. The gel preparation is simple in technological process, easy to operate and suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an adapalene benzoyl peroxide gel and a preparation method thereof. Background Art

[0002] Adapalene, English name is Adapalene, chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, molecular formula is C 28 H 28 O3, molecular weight 412.52; white to slightly yellowish white powder, insoluble in water or ethanol, slightly soluble in tetrahydrofuran; structural formula is as follows:

[0003]

[0004] Benzoyl peroxide, English name is Benzoyl Peroxide, chemical name is dibenzoyl peroxide, molecular formula is C 14 H 10 O4, molecular weight is 242.23; it is a white crystalline powder; it is easily soluble in acetone, slightly soluble in methanol or ethanol, and very slightly soluble in water; its structural formula is as follows:

[0005]

[0006] Adapalene is a third-generation retinoid drug with good anti-inflammatory effects and a good therapeutic effect on acne. Benzoyl peroxide is an oxidant. After being applied to the skin, it can slowly release new ecological oxygen, which can kill Propionibacterium acnes and is suitable for the treatment of common acne. Galderma Labs LP launched Adapalene Benzoyl Peroxide Gel in the United States in 2008 under the trade name Epiduo. The specifications are 0.1% / 2.5%. It is used to treat common acne with acne, papules and pustules. It is suitable for adults, adolescents and children over 9 years old.

[0007] Children. Adapalene benzoyl peroxide gel is only included in the US draft, and is not included in the 2020 edition of the Chinese Pharmacopoeia or other national pharmacopoeias.

[0008] The solubility of adapalene and benzoyl peroxide raw materials in water is insoluble and very slightly soluble, respectively, resulting in the raw materials being basically insoluble in the gel matrix. The microscopic state of adapalene benzoyl peroxide gel (trade name: Epiduo, licensee: Galderma Laboratorium GmbH) was observed under a microscope, and the test results showed that both raw materials were in a suspended state. Therefore, the preparation process of this product needs to ensure that the above two raw materials are evenly distributed in the adapalene benzoyl peroxide gel, and the uniformity and particle size in the container of the product meet the requirements. Patent CN101780028 applied by Beijing Li Lesheng Pharmaceutical Technology Co., Ltd. discloses a compound gel composition with adapalene and dibenzoic acid peroxide as the main components. The present invention uses adapalene and dibenzoic acid peroxide as active ingredients and adopts a stirring process to prepare the gel. Patent CN202080052185 applied by Bosch Health Ireland Ltd. discloses a topical composition, which is a topical gel preparation, comprising clindamycin phosphate, benzoyl peroxide and adapalene, as well as a gelling agent, a polyol and water, and its preparation method is a mixing process. Patent CN117731603 applied by Shanghai Shangyao Xinya Pharmaceutical Co., Ltd. discloses a process for mass production of adapalene benzoyl peroxide gel, and its preparation process is that benzoyl peroxide and adapalene are dispersed by high-speed shear respectively and then stirred with auxiliary materials to form a gel. Patent CN117731604 applied by Shanghai Shangyao Xinya Pharmaceutical Co., Ltd. discloses a method for preparing adapalene benzoyl peroxide gel, and its preparation process is that benzoyl peroxide is dispersed by high-speed shear first, and then dispersed by alternating ultrasonic and high-speed shear processes; adapalene is dispersed by high-speed shear process, and then stirred with auxiliary materials to form a gel.

[0009] The existing technology cannot make the two raw materials dispersed evenly in the gel through the stirring process; the two raw materials can be dispersed evenly in the gel by homogenizing the two raw materials separately or by homogenizing and ultrasonic alternating process, but the production operation process is complicated. Therefore, it is still a problem that needs to be solved for the adapalene benzoyl peroxide gel to make the two raw materials evenly distributed in the adapalene benzoyl peroxide gel by a simpler and more effective process. Summary of the invention

[0010] In view of the shortcomings of the prior art, an adapalene benzoyl peroxide gel and a preparation method thereof are provided to solve the problem of uniformity of two raw materials in the adapalene benzoyl peroxide gel, so that the uniformity and particle size of the two raw materials in the gel meet the requirements, and the quality of the preparation and clinical efficacy are guaranteed. The gel preparation process is relatively simple, easy to operate, and suitable for industrial-scale production.

[0011] In order to obtain a gel with good uniformity and particle size in the container, the inventors conducted in-depth research and unexpectedly found that a solid dispersion of adapalene and benzoyl peroxide can be prepared by a spray drying process. The solid dispersion with uniform particle size is mixed with the remaining auxiliary materials and stirred evenly to obtain adapalene benzoyl peroxide gel. The uniformity and particle size of the prepared gel in the container meet the requirements, and the patient compliance is good.

[0012] The present invention is achieved through the following technical solutions:

[0013] The invention discloses an adapalene benzoyl peroxide gel, which comprises adapalene, benzoyl peroxide, docusate sodium, disodium edetic acid, glycerol, poloxamer 124, propylene glycol, acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate and purified water.

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

[0015] S1. Prepare a solid dispersion by adding a prescribed amount of adapalene, benzoyl peroxide and poloxamer 124 into an organic solvent, stirring at room temperature to completely disperse the materials, transferring the liquid into a spray drying device, and spray drying to obtain a solid dispersion of adapalene and benzoyl peroxide;

[0016] S2. Prepare the active ingredient phase, weigh the prescribed amount of propylene glycol, add docusate sodium, stir to dissolve, then add an appropriate amount of purified water and the solid dispersion obtained in step S1, stir evenly to obtain the active ingredient phase;

[0017] S3, preparing an aqueous phase, weighing an appropriate amount of purified water, adding the remaining excipients except acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and sorbitan oleate into the purified water, stirring to dissolve, and obtaining an aqueous phase;

[0018] S4, preparing a gel, adding the active ingredient phase prepared in step S2 to the aqueous phase prepared in step S3, adding purified water to the prescribed amount, stirring evenly, adding the prescribed amount of acrylamide / sodium acryloyldimethyl taurate copolymer & isohexadecane & polysorbate 80 & sorbitan oleate to the above liquid, stirring evenly, filling, and obtaining a gel.

[0019] In order to further realize the present invention, the following technical solutions may be preferably selected:

[0020] Preferably, the organic solvent in step S1 is one of acetone, dichloromethane or ethanol.

[0021] Preferably, the organic solvent in step S1 is acetone.

[0022] Preferably, in step S1, the solid content of adapalene and benzoyl peroxide in acetone is 0.01-1%.

[0023] Preferably, the temperature of the spray-dried material in step S1 is 20-25°C;

[0024] The process temperature in steps S2, S3 and S4 is 20-25°C.

[0025] Preferably, in the solid dispersion of step S1, the particle size of adapalene is D90<10 μm, D99<25 μm, and the particle size of benzoyl peroxide is D95<20 μm, D99<50 μm.

[0026] Through the above technical solution, the beneficial effects of the present invention are:

[0027] The present invention disperses the pemabet raw material drug with a fixed particle size range in a Tween 80 solution, then emulsifies it, and uses the preparation equipment of the present invention to granulate it. The prepared particles have good mixing uniformity, no content loss, and fast dissolution and release speed.

[0028] The quality is equivalent to that of the original research. The specific reasons are analyzed as follows:

[0029] 1. The present invention solves the problem of uniformity of two raw materials in the gel through a relatively simple preparation process. The process is easy to operate and is suitable for industrial-scale production.

[0030] 2. The spray drying process of the present invention is used to prepare a solid dispersion of adapalene and benzoyl peroxide, and a gel is prepared using the solid dispersion and the excipients in the prescription to solve the problem of content uniformity so that the uniformity in the gel container meets the requirements: the adapalene content of the curled end, the middle and the end near the cap of a gel tube should all be 95.0% to 105.0% of the labeled amount, the benzoyl peroxide content should all be 90.0% to 110.0% of the labeled amount, and the difference between the maximum value and the minimum value should not exceed 10.0%.

[0031] 3. According to the spray drying process of the present invention, solid dispersions of adapalene and benzoyl peroxide are prepared, and gels are prepared using the solid dispersions and the excipients in the prescription to solve the particle size problem and make the particle sizes of the two raw materials uniform: the particle size of adapalene is D90 <20 μm, D99 <50 μm; the particle size of benzoyl peroxide is D95 <25 μm, D99 <100 μm.

[0032] 4. The gel prepared according to the present invention is fine and uniform, and has good patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a microscope observation image (20 times × 10 times) of Adapalene (fluorescence) according to Example 1 of the present invention;

[0034] Figure 2 This is a microscope observation image (20 times × 10 times) of benzoyl peroxide (polarized light) according to Example 1 of the present invention;

[0035] Figure 3 This is a microscope observation image (20 times × 10 times) of Adapalene (fluorescence) involved in Comparative Example 1 of the present invention;

[0036] Figure 4 This is a microscope observation image (20 times × 10 times) of benzoyl peroxide (polarized light) involved in Comparative Example 1 of the present invention;

[0037] Figure 5 This is a microscope observation image (20 times × 10 times) of Adapalene (fluorescence) involved in Comparative Example 2 of the present invention;

[0038] Figure 6 This is a microscope observation image (20 times × 10 times) of benzoyl peroxide (polarized light) involved in Comparative Example 2 of the present invention;

[0039] Figure 7 This is a microscope observation image (20 times × 10 times) of Adapalene (fluorescence) involved in Comparative Example 3 of the present invention; Figure 8 This is a microscope observation picture (20 times × 10 times) of benzoyl peroxide (polarized light) according to Comparative Example 4 of the present invention. DETAILED DESCRIPTION

[0040] In the description of the present invention, it is also necessary to explain that, unless otherwise clearly specified and limited, the terms "set", "install", "connect", and "connect" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0041] The following will be combined with the drawings in the embodiments of the invention to clearly and completely describe the technical solutions in the embodiments of the invention. Obviously, the described embodiments are only part of the embodiments of the invention, not all of the embodiments. Based on the embodiments of the invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the invention.

[0042] Embodiment 1:

[0043] The invention discloses an adapalene benzoyl peroxide gel, which comprises adapalene, benzoyl peroxide, docusate sodium, disodium edetic acid, glycerol, poloxamer 124, propylene glycol, acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate and purified water.

[0044]

[0045]

[0046] A preparation method of adapalene benzoyl peroxide gel comprises the following steps:

[0047] S1. Prepare solid dispersion: add the prescribed amount of adapalene, benzoyl peroxide and poloxamer 124 into acetone with a solid content of 0.5%, stir at room temperature to disperse the materials completely, transfer the above liquid to the spray drying equipment, set the air inlet temperature to 20-25°C and the air volume to 20-30m 3 / h, atomization pressure of 1.0-2.5MPa, liquid supply speed of 3.0-6.0r / min, spray drying to obtain a solid dispersion of adapalene and benzoyl peroxide;

[0048] S2. Prepare the active ingredient phase, weigh the prescribed amount of propylene glycol, add docusate sodium, stir to dissolve, then add an appropriate amount of purified water and the solid dispersion obtained in step S1, stir evenly to obtain the active ingredient phase;

[0049] S3, preparing an aqueous phase, weighing an appropriate amount of purified water, adding the remaining excipients except acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and sorbitan oleate into the purified water, stirring to dissolve, and obtaining an aqueous phase;

[0050] S4, preparing a gel, adding the active ingredient phase prepared in step S2 to the aqueous phase prepared in step S3, adding purified water to the prescribed amount, stirring evenly, adding the prescribed amount of acrylamide / sodium acryloyldimethyl taurate copolymer & isohexadecane & polysorbate 80 & sorbitan oleate to the above liquid, stirring evenly, filling, and obtaining a gel.

[0051] The process temperature in steps S2, S3 and S4 is 20-25°C.

[0052] The particle size of adapalene in the solid dispersion of step S1 is D90<10μm, D99<25μm, and the particle size of benzoyl peroxide is D95<20μm, D99<50μm.

[0053] Comparative Example 1:

[0054] The sample was prepared according to Example 1 in patent CN101780028 of Beijing Li Lesheng Pharmaceutical Technology Co., Ltd.

[0055] Components Dosage Adapalene 0.1g Benzoyl peroxide 2.5g Edetate Disodium 0.1g Docusate Sodium 0.05g glycerin 4g Propylene glycol 4g Poloxamer 124 0.2g Carbomer 4g Purified water qs100ml

[0056] Preparation method:

[0057] 1. Take the prescribed amount of carbomer, add 40% of the prescribed amount of purified water, stir to dissolve, leave overnight, and set aside to form intermediate I.

[0058] 2. Take 50% of the prescribed amount of purified water, gradually add poloxamer 124, docusate sodium, edetate disodium, glycerol, and propylene glycol while stirring continuously, and continue stirring for 20 minutes to dissolve.

[0059] 3. Take the prescribed amount of adapalene and benzoyl peroxide, stir until uniform, and form intermediate II.

[0060] 4. Take the above intermediate I, slowly add intermediate II while stirring, add water to 100g, stir evenly, and you have it.

[0061] Comparative Example 2:

[0062] The samples were prepared according to the example in patent CN117731603 of Shanghai SPH New Asia Pharmaceutical Co., Ltd.

[0063]

[0064]

[0065] Preparation method:

[0066] 1. Preparation of aqueous phase 1: Weigh aqueous phase 1 according to the prescription, stir until docusate sodium is dissolved, and set aside.

[0067] 2. Preparation of active phase 1: Weigh benzoyl peroxide, propylene glycol, poloxamer 124 and glycerin according to the prescription, stir and mix with a glass rod until the benzoyl peroxide is completely wetted, then add aqueous phase 1, and disperse in an ice-water bath at 17,000 rpm for 60 minutes.

[0068] 3. Preparation of active phase 2: Adapalene, propylene glycol, poloxamer 124 and glycerol were weighed according to the prescription amount, stirred with a glass rod until the adapalene was completely wetted, and then the prescription amount of purified water was added, and high-speed shear dispersion was performed at 7000 rpm for 30 minutes.

[0069] 4. Preparation of aqueous phase 2: Weigh aqueous phase 2 according to the prescription, stir until disodium edetate is dissolved, mix with active phase 2, stir evenly, add SEPINEO P 600 and stir until a uniform gel is formed.

[0070] 5. Finally, add active phase 1 and stir evenly to form a drug-containing compound gel.

[0071] Comparative Example 3:

[0072] The samples were prepared according to the example in patent CN117731604 of Shanghai SPH New Asia Pharmaceutical Co., Ltd.

[0073] Prescription: 5% purified water is used for dehydrated phase 1, 15% purified water is used for active phase 1, and the rest is the same as the prescription of comparative example 2.

[0074] Preparation method:

[0075] 1. Preparation of aqueous phase 1: same as Comparative Example 2.

[0076] 2. Preparation of active phase 1: Same as comparative example 2, after the raw materials and excipients were completely wetted, aqueous phase 1 was added, and the mixture was dispersed in an ice-water bath and at a high speed of 7000 rpm for 30 min. Then, the shear head was rinsed with 120 ml of purified water, the rinse solution and the benzoyl peroxide dispersion were combined, and the mixture was ultrasonicated in an ice-water bath for 1 h. It was observed that there were still drug particles in the dispersion. Then, the mixture was dispersed in an ice-water bath and at a high speed of 7000 rpm for 30 min, and after ultrasonication for 40 min, it was observed that there were no drug particles in the dispersion, and a uniformly dispersed benzoyl peroxide dispersion was prepared.

[0077] 3. Preparation of active phase 2: Same as comparative example 2, except that the high-speed shear dispersion was carried out at 7000 rpm for 20 min.

[0078] 4. Preparation of water phase 2: same as Comparative Example 2.

[0079] 5. Same as comparative example 2.

[0080] The properties, uniformity, particle size, and uniformity in the container of the adapalene benzoyl peroxide gel prepared in Example 1 and Comparative Examples 1, 2, and 3 were tested. The acceptable standards and test results are as follows:

[0081]

[0082]

[0083]

[0084] Comparative Example 1 (prepared according to Example 1 of Beijing Tetra Pak Patent CN101780028) The gel prepared by the stirring process is visually uneven, has agglomeration, and has a noticeable frosted feel when touched; when the particle size is observed under a microscope, there is obvious coagulation; the contents of adapalene and benzoyl peroxide in the curled end, middle, and near-cap end of the gel are quite different, and the uniformity in the container does not meet the requirements, indicating that the process cannot make the adapalene and benzoyl peroxide in the gel in a suspended state uniformly dispersed.

[0085] Comparative Example 2 (samples were prepared according to the examples in Shanghai Shangyao Xinya Patent CN117731603) Benzoyl peroxide and adapalene were dispersed by high-speed shearing and then stirred with the auxiliary materials to form a gel. The gel was fine and uniform, easy to spread, and had no frosted feeling. Although the particle size of benzoyl peroxide met the requirements, there were particles close to the upper limit. Although the uniformity in the container met the requirements, there were differences in the contents of the curled end, the middle and the near-cap end. During the experiment, it was found that the raw materials splashed to the tank wall during homogenization. Because both raw materials in this product are insoluble in water, the raw materials splashed to the tank wall cannot participate in the subsequent homogenization operation, so there is a risk of exceeding the particle size limit.

[0086] Comparative Example 3 (prepared according to the sample in the embodiment of Shanghai Shangyao Xinya patent CN117731604) Benzoyl peroxide was first dispersed by high-speed shearing, and then dispersed by alternating ultrasound and high-speed shearing process; Adapalene was dispersed by high-speed shearing process, and then stirred with auxiliary materials to form a gel. This process can effectively reduce the particle size of the raw materials, so that the two raw materials are evenly dispersed in the prepared gel, and the properties, uniformity, particle size, and uniformity in the device of the gel all meet the requirements. However, this process requires multiple high-speed shearing and ultrasound, and the operation process is complicated.

[0087] According to Example 1 of the present invention, a spray drying process is used to prepare a solid dispersion of adapalene and benzoyl peroxide, and a gel is prepared by using the solid dispersion and the auxiliary materials in the prescription. The process is simple, and the properties, uniformity, particle size, and uniformity in the device of the obtained gel all meet the requirements. The present invention achieves the purpose of uniformly distributing the two raw materials in the adapalene benzoyl peroxide gel by simple and effective process means.

[0088] Finally, it should be noted that the above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An adapalene benzoyl peroxide gel, characterized in that: The adapalene benzoyl peroxide gel comprises adapalene, benzoyl peroxide, docusate sodium, disodium edetic acid, glycerol, poloxamer 124, propylene glycol, acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate, and purified water.

2. A method for preparing adapalene benzoyl peroxide gel, characterized in that: The following steps are involved: S1. Prepare a solid dispersion by adding a prescribed amount of adapalene, benzoyl peroxide and poloxamer 124 into an organic solvent, stirring at room temperature to completely disperse the materials, transferring the liquid into a spray drying device, and spray drying to obtain a solid dispersion of adapalene and benzoyl peroxide; S2. Prepare the active ingredient phase, weigh the prescribed amount of propylene glycol, add docusate sodium, stir to dissolve, then add an appropriate amount of purified water and the solid dispersion obtained in step S1, stir evenly to obtain the active ingredient phase; S3, preparing an aqueous phase, weighing an appropriate amount of purified water, adding the remaining excipients except acrylamide / sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and sorbitan oleate into the purified water, stirring to dissolve, and obtaining an aqueous phase; S4, preparing a gel, adding the active ingredient phase prepared in step S2 to the aqueous phase prepared in step S3, adding purified water to the prescribed amount, stirring evenly, adding the prescribed amount of acrylamide / sodium acryloyldimethyl taurate copolymer & isohexadecane & polysorbate 80 & sorbitan oleate to the above liquid, stirring evenly, filling, and obtaining a gel.

3. The method for preparing an adapalene benzoyl peroxide gel according to claim 2, wherein: The organic solvent in step S1 is one of acetone, dichloromethane or ethanol.

4. The method for preparing an adapalene benzoyl peroxide gel according to claim 3, wherein: In step S1, the organic solvent is acetone.

5. The method for preparing adapalene benzoyl peroxide gel according to claim 4, characterized in that: In the step S1, the solid content of adapalene and benzoyl peroxide in acetone is 0.01-1%.

6. The method for preparing adapalene benzoyl peroxide gel according to claim 2, wherein: The temperature of the spray-dried material in step S1 is 20-25°C; The process temperature in steps S2, S3 and S4 is 20-25°C.

7. The method for preparing adapalene benzoyl peroxide gel according to claim 2, characterized in that: The particle size of adapalene in the solid dispersion of step S1 is D90<10μm, D99<25μm, and the particle size of benzoyl peroxide is D95<20μm, D99<50μm.

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