Ketoconazole cream and preparation method thereof

Abstract

The ketoconazole emulsifiable paste comprises ketoconazole, an emulsifier, a buffer pair, a stabilizer, an antibacterial agent and an oily matrix which are used as active ingredients, the invention provides a preparation method of the ketoconazole emulsifiable paste, overcomes the problem of poor stability of a ketoconazole emulsifiable paste preparation, and obtains the ketoconazole emulsifiable paste which can be stored for a long time, can keep the paste uniform and stable, has low ketoconazole D impurity content, and can be used for preparing the ketoconazole emulsifiable paste. And the characteristics of the paste and the stability of the active ingredients can still be kept in different environments (including temperature, humidity and illumination).

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a ketoconazole cream and a preparation method thereof. Background Art

[0002] Ketoconazole, chemical name is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine, molecular formula is C26H28Cl2N4O4, it is an imidazole broad-spectrum antifungal drug. Ketoconazole is an imidazole antifungal drug, its mechanism of action is to inhibit the biosynthesis of ergosterol in fungal cell membrane, affect the permeability of cell membrane, and inhibit its growth. Ketoconazole can be used to treat superficial and deep fungal diseases, such as skin and nail ringworm, vaginal candidiasis, gastrointestinal fungal infections, etc., as well as systemic infections caused by Candida albicans, Coccidioides, Histoplasma, etc. Because of the unstable groups such as amide and ether groups in its structure, it is very easy to oxidize and discolor, thus affecting the stability and efficacy of its preparations.

[0003] CN113440477B discloses a low-viscosity ketoconazole cream, comprising the following components: ketoconazole: 2 parts by weight, white vaseline: 0.6-1 parts by weight, octadecyl alcohol: 2-5 parts by weight, mono- and distearic acid glyceryl: 3-6 parts by weight, propylene glycol: 12-25 parts by weight, light liquid paraffin: 1.5-9 parts by weight, sodium lauryl sulfate: 0.4-0.6 parts by weight, triethanolamine: 0.1-0.4 parts by weight, carbomer 940: 0.15-0.2 parts by weight, purified water: added to 100 parts by weight. Ketoconazole cream of the present invention, on the basis of known prescriptions, by changing the type and amount of auxiliary materials, a low-viscosity ketoconazole cream is prepared, which is conducive to the smooth progress of the filling process. The determination of related substances is not involved.

[0004] CN115212214B discloses a composition and preparation method of a naftifine ketoconazole cream. The cream is composed of naftifine hydrochloride and ketoconazole active ingredients, an oily base, a humectant, an emulsifier, water, and optional adjuvants such as preservatives, antioxidants and chelating agents. The naftifine ketoconazole cream obtained by the present invention is easy to apply, non-greasy, can enhance skin emollient, significantly improves skin desquamation and cracking phenomena such as tinea manuum, tinea corporis, tinea capitis, and skin candidiasis, is easier for patients to accept, and has better stability than commercially available naftifine ketoconazole cream. The determination of related substances is not related to. Summary of the invention

[0005] In view of the defects of the prior art, the present invention provides a ketoconazole cream and a preparation method thereof, which overcomes the problem of poor stability of ketoconazole cream preparations and obtains a ketoconazole cream which can keep the cream uniform and stable during long-term storage, and can still keep the cream properties and active ingredients stable under different environments (including temperature, humidity, and light), and is convenient for transportation and storage.

[0006] To achieve the above purpose, the present invention adopts the following scheme: a ketoconazole cream, comprising ketoconazole as an active ingredient, an emulsifier, a buffer pair, a stabilizer, an antibacterial agent and an oily base; the emulsifier is selected from one or more of glycerol monostearate polyoxyethylene ether and hydroxyalkylphenol polyoxyethylene ether; the buffer pair is selected from one or more of acetic acid-sodium acetate buffer and mercaptopropionic acid / sodium mercaptopropionate buffer; the pH range formed by the buffer pair being dissolved in water is 4.5-5.5; and the stabilizer is polyethylene glycol stearate.

[0007] The ketoconazole cream, the oily base comprises liquid paraffin, white vaseline, lanolin and triethanolamine.

[0008] In the ketoconazole cream, the antibacterial agent is one or more of methylparaben and ethylparaben.

[0009] The ketoconazole cream comprises the following components in parts by weight per 100 parts by weight: 2 parts of ketoconazole, 2-4 parts of emulsifier, 20-40 parts of buffer, 2-5 parts of stabilizer, 2-4 parts of antibacterial agent and 17-42 parts of oily matrix, and the balance is purified water.

[0010] The ketoconazole cream, the oily base comprises the following components in parts by weight: 5-12 parts of liquid paraffin, 5-10 parts of white vaseline, 5-15 parts of lanolin and 2-5 parts of triethanolamine.

[0011] The preparation method of the ketoconazole cream comprises the following steps:

[0012] 1) Preparation of aqueous phase: Heat purified water to 70°C to 75°C, add buffer, emulsifier and antibacterial agent, stir and mix, and keep warm for later use;

[0013] 2) Preparation of oil phase: Heat the oily matrix until it is melted to obtain the oil phase material, and keep it at 70°C to 75°C for later use;

[0014] 3) Preparation of main drug dispersion: dispersing ketoconazole in polyethylene glycol stearate to obtain main drug dispersion suspension;

[0015] 4) Total mixing: Mix the oil phase material and the water phase material, add the main drug dispersion suspension, and add purified water to make up the amount, the pH range is 4.5-5.5;

[0016] 5) Cooling: Mix evenly and cool to room temperature to obtain ketoconazole cream.

[0017] Through repeated experiments, the inventor unexpectedly found that when ketoconazole cream contains ketoconazole, emulsifiers such as glycerol monostearate polyoxyethylene ether, hydroxyalkylphenol polyoxyethylene ether and buffer pairs, the stability of ketoconazole cream can be improved, and ketoconazole can be inhibited from being decomposed into ketoconazole D. After testing, the ketoconazole cream has no obvious change in properties under high temperature, high humidity and light test conditions, and can adapt to various environmental conditions encountered in storage and transportation. At the same time, the ketoconazole cream preparation process disclosed by the present invention is simple and easy to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the structural formula of ketoconazole D impurity. DETAILED DESCRIPTION

[0019] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0020] Embodiment 1:

[0021] Ketoconazole 20g, glyceryl monostearate polyoxyethylene ether 30g, buffered acetic acid-sodium acetate buffer 300g, polyethylene glycol stearate 40g, methylparaben 30g, liquid paraffin 100g, white vaseline 80g, lanolin 100g and triethanolamine 40g, the preparation method is as follows:

[0022] 1) Preparation of aqueous phase: Heat purified water to 72° C., add acetic acid-sodium acetate buffer (pH=5), glyceryl monostearate polyoxyethylene ether and methylparaben, stir and mix, and keep warm for later use;

[0023] 2) Preparation of oil phase: heating the oily matrix, including light liquid paraffin, white vaseline, lanolin, and triethanolamine until melted to obtain the oil phase material, and keeping the temperature at 72° C. for later use;

[0024] 3) Preparation of main drug dispersion: dispersing ketoconazole in polyethylene glycol stearate to obtain main drug dispersion suspension;

[0025] 4) Total mixing: Mix the oil phase material and the water phase material, add the main drug, add purified water to make up to 1000g, stir and disperse the suspension, the pH is 5.0;

[0026] 5) Cooling: Mix evenly and cool to room temperature to obtain ketoconazole cream.

[0027] Embodiment 2:

[0028] Ketoconazole 20g, glyceryl monostearate polyoxyethylene ether 20g, buffered acetic acid-sodium acetate buffer 400g, polyethylene glycol stearate 20g, methylparaben 40g, liquid paraffin 50g, white vaseline 100g, lanolin 50g and triethanolamine 50g, the preparation method is as follows:

[0029] 1) Preparation of aqueous phase: Heat purified water to 72° C., add acetic acid-sodium acetate buffer (pH=5), glyceryl monostearate polyoxyethylene ether and methylparaben, stir and mix, and keep warm for later use;

[0030] 2) Preparation of oil phase: heating the oily matrix, including light liquid paraffin, white vaseline, lanolin, and triethanolamine until melted to obtain the oil phase material, and keeping the temperature at 72° C. for later use;

[0031] 3) Preparation of main drug dispersion: dispersing ketoconazole in polyethylene glycol stearate to obtain main drug dispersion suspension;

[0032] 4) Total mixing: Mix the oil phase material and the water phase material, add the main drug, add purified water to make up to 1000g, stir and disperse the suspension, the pH is 4.9;

[0033] 5) Cooling: Mix evenly and cool to room temperature to obtain ketoconazole cream.

[0034] Embodiment 3:

[0035] Ketoconazole 20g, glyceryl monostearate polyoxyethylene ether 40g, buffered acetic acid-sodium acetate buffer 200g, polyethylene glycol stearate 50g, methylparaben 20g, liquid paraffin 120g, white vaseline 50g, lanolin 150g and triethanolamine 20g, the preparation method is as follows:

[0036] 1) Preparation of aqueous phase: Heat purified water to 72° C., add acetic acid-sodium acetate buffer (pH=5), glyceryl monostearate polyoxyethylene ether and methylparaben, stir and mix, and keep warm for later use;

[0037] 2) Preparation of oil phase: heating the oily matrix, including light liquid paraffin, white vaseline, lanolin, and triethanolamine until melted to obtain the oil phase material, and keeping the temperature at 72° C. for later use;

[0038] 3) Preparation of main drug dispersion: dispersing ketoconazole in polyethylene glycol stearate to obtain main drug dispersion suspension;

[0039] 4) Total mixing: Mix the oil phase material and the water phase material, add the main drug, add purified water to make up to 1000g, stir and disperse the suspension, the pH is 5.2;

[0040] 5) Cooling: Mix evenly and cool to room temperature to obtain ketoconazole cream.

[0041] Example 4: Physical property comparison experiment of influencing factors (high temperature, high humidity, light) of samples from Example 1-3 and commercially available ketoconazole cream (Hainan Kaijian Pharmaceutical Co., Ltd., National Medicine Standard H20074170)

[0042] The properties are required to be a white cream, the pH is required to be 4.5-5.5, the particle size is required to not detect particles larger than 180μm, and the centrifugal stability test requires that 10g of the cream be placed in a graduated centrifuge tube and centrifuged at a speed of 2500r / min for 30min. The results show no stratification phenomenon. The results are shown in Table 1.

[0043] Table 1

[0044]

[0045] The results show that under the test conditions of influencing factors (high temperature, high humidity, and light), the samples of Examples 1-3 of the present invention have good physical stability and are superior to the commercially available ketoconazole cream.

[0046] Example 5: Example 1-3 group samples and commercially available ketoconazole cream (Hainan Kaijian Pharmaceutical Co., Ltd., national medicine standard H20074170) were tested for influencing factors (high temperature, high humidity, light) and ketoconazole D impurity and content comparison experiment

[0047] Ketoconazole D impurity and ketoconazole main drug content in the sample are determined: Ketoconazole reference substance and ketoconazole impurity D are purchased from China Food and Drug Inspection Institute, diluted with anhydrous ethanol-mobile phase A (70:30), and ketoconazole standard and ketoconazole impurity D standard solutions are accurately configured to make a solution containing about 8 mg per 1 mL as a self-control solution. Accurately weigh about 4 g of the samples of Example 1-3 and commercially available ketoconazole cream (Hainan Kaijian Pharmaceutical Co., Ltd., National Medicine Standard H20074170), place in a 50 mL volumetric flask, add about 35 mL of anhydrous ethanol, place in a 60 ° C water bath, heat and shake, dissolve ketoconazole, cool to room temperature, dilute to scale with mobile phase A, shake well, cool in an ice bath for 2 hours, filter, and take the subsequent filtrate as the test solution of the ointment, and the ketoconazole concentration is about 0.8 mg / mL. Agilent HPLC was used, a ZORBAX Eclipse Plus C18 column (250 mm × 4.6 mm, 5 mm) was selected, 10 mmol / L tetrabutylammonium hydrogen sulfate solution-acetonitrile (85:15) was used as mobile phase A, 10 mmol / L tetrabutylammonium hydrogen sulfate solution-acetonitrile (20:80) was used as mobile phase B, the flow rate was 1 mL / min, the detection wavelength was 220 nm, the injection volume was 5 mL, and the results are shown in Table 2.

[0048] Table 2

[0049]

[0050] The experimental results show that under the experimental conditions of influencing factors (high temperature, high humidity, and light), the impurity content of ketoconazole D in the samples of Examples 1-3 increases slightly, while the impurity content of ketoconazole D in the commercially available ketoconazole cream increases rapidly. In the observation of the content of the main drug of ketoconazole, the samples of Examples 1-3 are more stable than the commercially available ketoconazole cream, indicating that the emulsifier, buffer, stabilizer, antibacterial agent and oily matrix in the present invention are appropriately selected, which can effectively avoid the decomposition of ketoconazole and improve the efficacy of ketoconazole.

[0051] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A ketoconazole cream, characterized in that, The invention comprises ketoconazole as an active ingredient, an emulsifier, a buffer pair, a stabilizer, an antibacterial agent and an oily matrix; the emulsifier is selected from one or more of glycerol monostearate polyoxyethylene ether and hydroxyalkylphenol polyoxyethylene ether; the buffer pair is selected from one or more of acetic acid-sodium acetate buffer and mercaptopropionic acid / sodium mercaptopropionate buffer; the pH range formed by the buffer pair being dissolved in water is 4.5-5.5; and the stabilizer is polyethylene glycol stearate.

2. Ketoconazole cream according to claim 1, characterized in that, The oily base includes liquid paraffin, white petrolatum, lanolin and triethanolamine.

3. Ketoconazole cream according to claim 1, characterized in that, The antibacterial agent is one or more of methylparaben and ethylparaben.

4. The ketoconazole cream according to claim 1, characterized in that Every 100 parts by weight of the ketoconazole cream comprises the following components in parts by weight: 2 parts of ketoconazole, 2-4 parts of emulsifier, 20-40 parts of buffer, 2-5 parts of stabilizer, 2-4 parts of antibacterial agent and 17-42 parts of oily base, and the balance is purified water.

5. The ketoconazole cream according to claim 4, characterized in that The oily base comprises the following components in parts by weight: 5-12 parts of liquid paraffin, 5-10 parts of white vaseline, 5-15 parts of lanolin and 2-5 parts of triethanolamine.

6. A ketoconazole cream according to any one of claims 1 to 5, characterized in that The preparation method comprises the following steps: 1) Preparation of aqueous phase: Heat purified water to 70°C to 75°C, add buffer, emulsifier and antibacterial agent, stir and mix, and keep warm for later use; 2) Preparation of oil phase: Heat the oily matrix until it is melted to obtain the oil phase material, and keep it at 70°C to 75°C for later use; 3) Preparation of main drug dispersion: dispersing ketoconazole in polyethylene glycol stearate to obtain main drug dispersion suspension; 4) Total mixing: Mix the oil phase material and the water phase material, add the main drug dispersion suspension, and add purified water to make up the amount, the pH range is 4.5-5.5; 5) Cooling: Mix evenly and cool to room temperature to obtain ketoconazole cream.

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