Ketoconazole cream and preparation method thereof

Abstract

The invention discloses ketoconazole emulsifiable paste and a preparation method thereof, and the ketoconazole emulsifiable paste is prepared from the following components in parts by weight: 1 to 25 parts of ketoconazole, 1 to 80 parts of stearic acid, 1 to 55 parts of glyceryl monostearate and glyceryl distearate, 1 to 130 parts of light liquid paraffin, 0.1 to 1 part of ethylparaben, 100 to 350 parts of glycerol, 0.1 to 2 parts of edetate disodium, 1 to 6 parts of triethanolamine and 1 to 5 parts of anhydrous sodium sulfite. 0.1 to 2 parts of butylated hydroxytoluene, and 100 to 450 parts of purified water. The stability, the drug effect and the safety are comprehensively improved, the bacteriostasis effect on candida albicans is obvious, the treatment efficiency is improved, and the better fungal infection resisting effect is achieved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical manufacturing, and in particular to a ketoconazole cream and a preparation method thereof. Background Art

[0002] Ketoconazole is a broad-spectrum antifungal drug widely used in the treatment of dermatophyte, Candida and other infections.

[0003] Currently, commercially available ketoconazole creams mostly use low-concentration formulas below 2%. At concentrations greater than 5%, ketoconazole is susceptible to oxidative degradation, leading to decreased efficacy. Existing technologies have attempted to add single antioxidants (such as vitamin E), but crystallization still occurs in high-humidity environments. Furthermore, traditional creams rely on propylene glycol to enhance penetration, but its use in dosages greater than 30% can cause skin irritation, making it difficult to treat deep fungal infections. Furthermore, emulsification systems often utilize a single nonionic surfactant (such as perchlorate), which can easily stratify during high-temperature storage. Summary of the Invention

[0004] In view of the problems of existing ketoconazole cream, the present invention provides a ketoconazole cream and a preparation method thereof. The ketoconazole cream comprises the following components in parts by weight: 1-25 parts of ketoconazole, 1-80 parts of stearic acid, 1-55 parts of glyceryl mono- and distearate, 1-130 parts of light liquid paraffin, 0.1-1 part of ethylparaben, 100-350 parts of glycerol, 0.1-2 parts of disodium edetate, 1-6 parts of triethanolamine, 1-5 parts of anhydrous sodium sulfite, 0.1-2 parts of butylated hydroxytoluene, and 100-450 parts of purified water.

[0005] The present invention also provides a method for preparing the ketoconazole cream, comprising the following steps: (1) Preparation of oil phase: Mix mono- and distearic acid glyceryl, light liquid paraffin, stearic acid, and ethyl hydroxybenzoate, heat until melted, pass through a 150-mesh sieve, and keep warm at the first temperature; add butylated hydroxytoluene before emulsification, stir and dissolve for later use; (2) Preparation of aqueous phase: Mix purified water, glycerol, disodium edetate, and triethanolamine, heat and dissolve, and keep warm at the first temperature; add anhydrous sodium sulfite before emulsification, stir and dissolve, and then pass through a 150 mesh sieve for later use; (3) Ketoconazole pretreatment: Mix ketoconazole with a small amount of purified water, stir evenly, and pass through a 150-mesh sieve for later use to obtain a ketoconazole mixture; (4) Emulsification: When the temperatures of the oil phase and the water phase both reach the second temperature, slowly pour the water phase into the oil phase and stir; when the temperature drops to the third temperature, add the ketoconazole mixture, continue stirring and cool to room temperature, and the ketoconazole cream can be obtained.

[0006] Furthermore, the first temperature is 70-85°C, the second temperature is 60-75°C, and the third temperature is 50-70°C.

[0007] Compared with the existing technology, the ketoconazole cream and its preparation method in the present invention construct a dual antioxidant system by using anhydrous sodium sulfite and butylated hydroxytoluene, and use glycerin and light liquid paraffin to form a co-permeation enhancer, which comprehensively improves stability, efficacy and safety, has a significant antibacterial effect on Candida albicans, improves treatment efficiency, and has better antifungal infection efficacy.

[0008] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0009] To make the objects, features, and advantages of the present invention more readily apparent, the following detailed description of the specific embodiments of the present invention is provided in conjunction with the following examples. Several embodiments of the present invention are provided in the examples. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these examples are provided to provide a more thorough and comprehensive understanding of the present invention.

[0010] Example 1 This embodiment provides a ketoconazole cream, comprising the following components in parts by weight: 1 part of ketoconazole, 20 parts of stearic acid, 15 parts of glyceryl mono- and distearate, 30 parts of light liquid paraffin, 0.3 parts of ethyl hydroxybenzoate, 150 parts of glycerol, 0.5 parts of disodium edetate, 2 parts of triethanolamine, 1 part of anhydrous sodium sulfite, 0.3 parts of butylated hydroxytoluene, and 280 parts of purified water.

[0011] Example 2 This embodiment provides a ketoconazole cream, comprising the following components in parts by weight: 10 parts of ketoconazole, 40 parts of stearic acid, 30 parts of mono- and distearic glyceryl, 70 parts of light liquid paraffin, 0.6 parts of ethyl hydroxybenzoate, 250 parts of glycerol, 1.0 parts of disodium edetate, 4 parts of triethanolamine, 1.0 parts of anhydrous sodium sulfite, 0.8 parts of butylated hydroxytoluene, and 350 parts of purified water.

[0012] Example 3 This embodiment provides a ketoconazole cream, comprising the following components in parts by weight: 25 parts of ketoconazole, 80 parts of stearic acid, 55 parts of glyceryl mono- and distearate, 130 parts of light liquid paraffin, 1.0 part of ethyl hydroxybenzoate, 350 parts of glycerol, 2.0 parts of disodium edetate, 6 parts of triethanolamine, 2.0 parts of anhydrous sodium sulfite, 2.0 parts of butylated hydroxytoluene, and 450 parts of purified water.

[0013] Example 4 This embodiment provides a ketoconazole cream, comprising the following components in parts by weight: 10 parts of ketoconazole, 40 parts of stearic acid, 30 parts of mono- and distearic glyceryl, 70 parts of light liquid paraffin, 0.6 parts of ethyl hydroxybenzoate, 250 parts of glycerol, 1.0 parts of disodium edetate, 4 parts of triethanolamine, 0.8 parts of butylated hydroxytoluene, and 350 parts of purified water. The difference between this embodiment and embodiment 2 is that anhydrous sodium sulfite is not added in this embodiment.

[0014] Example 5 This embodiment provides a ketoconazole cream, comprising the following components in parts by weight: 10 parts of ketoconazole, 40 parts of stearic acid, 30 parts of mono- and distearic glyceryl, 70 parts of light liquid paraffin, 0.6 parts of ethylparaben, 250 parts of glycerol, 1.0 parts of disodium edetate, 4 parts of triethanolamine, 1.0 parts of anhydrous sodium sulfite, and 350 parts of purified water. The difference between this embodiment and embodiment 2 is that butylated hydroxytoluene is not added in this embodiment.

[0015] Comparative Example 1 This comparative example 1 provides a commercially available ketoconazole cream, comprising ketoconazole, propylene glycol, sorbitan monostearate, polysorbate 60, cetostearyl alcohol, anhydrous sodium sulfite, isopropyl myristate, and purified water; Comparative Example 2 This comparative example 2 provides a commercially available ketoconazole cream, comprising ketoconazole, light liquid paraffin, propylene glycol, cetostearyl alcohol, peregal O, white vaseline, anhydrous sodium sulfite, ethyl hydroxybenzoate, isopropyl myristate, and purified water; The appearance, pH value, centrifugation test, accelerated test (storage at 40°C and 75% RH for 1 month), and light test (measuring the change in ketoconazole content and color of the cream after 10 days of 4500 lux light) of the ketoconazole cream in the above examples and control examples were evaluated below. Please refer to Table 1 for specific results: Table 1

[0016] Furthermore, the in vitro antibacterial effect of the ketoconazole cream in the above examples and control examples was verified by agar diffusion method, wherein: 1. The strains used were ATCC standard strains (Candida albicans ATCC 90028, Trichophyton rubrum ATCC 28188); 2. Prepare Sabouraud agar plates and spread fungal spore suspension (1×10 6 CFU / mL); 3. Punch a hole (6 mm in diameter) and add 50 mg of the ketoconazole cream described in the above examples and control examples; 4. Culture: 35℃ / 48h (Candida albicans), 28℃ / 72h (Trichophyton rubrum); 5. Measure the diameter of the inhibition zone (mm).

[0017] Please refer to Table 2 for the specific verification results: Table 2

[0018] Furthermore, the ketoconazole creams in the above examples and control examples were subjected to a guinea pig tinea model treatment test, wherein the animal model was a guinea pig back infected with Candida albicans (n=6 / group, with an infection focus of 20 mm in diameter). Groups A to E were treated with the ketoconazole creams in the above examples, groups F to G were treated with the ketoconazole creams in the above control examples, group H was a blank matrix, and group I was an untreated infection group. Evaluation indicators included healing time (i.e., the number of days for complete resolution of skin lesions) and fungal load (scraping of dandruff after 7 days of treatment, plate count log 10 CFU / g), please refer to Table 3 for specific results: Table 3

[0019] Among them, the histopathological scoring standard is: 0 indicates no inflammation, and 4 indicates severe abscess.

[0020] Furthermore, the skin retention effect of the ketoconazole cream in the above examples and control examples was verified. The specific method was to use an in vitro skin transdermal experiment for 24 hours, peel off the stratum corneum and dermis, extract ketoconazole by ultrasound, and detect the specific retention amount. For specific results, please refer to Table 4: Table 4

[0021] Furthermore, the ketoconazole creams in Examples 1-3 and Comparative Examples 1 and 2 were distributed to 10 groups of subjects for use testing and evaluation.

[0022] in: 1. Ten groups of subjects, each with 30 participants, completed the test, and 30 participants had valid test data. Groups 1-2 used the ketoconazole cream described in Example 1, Groups 3-4 used the ketoconazole cream described in Example 2, Groups 5-6 used the ketoconazole cream described in Example 3, Groups 7-8 used the ketoconazole cream described in Control Example 1, and Groups 9-10 used the ketoconazole cream described in Control Example 2. Subject Description: Subjects aged 18-50 years with epidermal fungal infections, peeling, and redness in the infected area. The treatment period was 7 days. Validity criteria for the test items: Three options were set: "1. Cured," "2. Substantially Cured," and "3. Not Cured."

[0023] 1. The subjects experienced symptom relief after using the product; 2. It can alleviate redness and peeling after use; 3. It can relieve itching after use; 4. After use, the infected area will shrink; Second, collect data from each subject to evaluate the results according to the above rules, fill out the questionnaire, and determine whether the product has better antifungal infection efficacy based on the results of each option.

[0024] 3. Results and Conclusions In group 1.1-2, 42 subjects reported that their symptoms were cured, and 18 subjects reported that their symptoms were almost cured; In group 2.3-4, 49 subjects reported that their symptoms were cured, and 11 subjects reported that their symptoms were almost cured; In the 3.5-6 group, 56 subjects reported that their symptoms were cured, and 4 subjects reported that their symptoms were almost cured; In group 4.7-8, 36 subjects indicated that their symptoms were cured, 22 subjects indicated that their symptoms were almost cured, and 2 subjects indicated that their symptoms were not cured; 5. In Group 9-10, 33 subjects indicated that their symptoms were cured, 24 subjects indicated that their symptoms were almost cured, and 3 subjects indicated that their symptoms were not cured.

[0025] The test results show that the ketoconazole creams in Examples 1-3 have better effects in resisting fungal infections and slowing down epidermal peeling and redness than those in Control Examples 1-2.

[0026] The present invention also provides a method for preparing the ketoconazole cream, comprising the following steps: (1) Preparation of oil phase: Mix mono- and distearic acid glyceryl, light liquid paraffin, stearic acid, and ethyl hydroxybenzoate, heat until melted, pass through a 150-mesh sieve, and keep warm at 70-85°C; add butylated hydroxytoluene before emulsification, stir and dissolve for later use; (2) Preparation of aqueous phase: Mix purified water, glycerol, disodium edetate, and triethanolamine, heat and dissolve, and keep warm at 70-85°C; add anhydrous sodium sulfite before emulsification, stir and dissolve, then pass through a 150-mesh sieve for later use; (3) Ketoconazole pretreatment: Mix ketoconazole with a small amount of purified water, stir evenly, and pass through a 150-mesh sieve for later use to obtain a ketoconazole mixture; (4) Emulsification: When the temperature of the oil phase and the water phase both reach 60-75°C, slowly pour the water phase into the oil phase and stir; when the temperature drops to 50-70°C, add the ketoconazole mixture, continue stirring and cool to room temperature to obtain the ketoconazole cream.

[0027] In summary, the ketoconazole cream and preparation method thereof in the above embodiments of the present invention construct a dual antioxidant system by using anhydrous sodium sulfite and butylated hydroxytoluene, and use glycerol and light liquid paraffin to form a co-permeation enhancer, which comprehensively improves stability, efficacy and safety, has a significant antibacterial effect on Candida albicans, improves treatment efficiency, and has better antifungal infection efficacy.

[0028] Throughout this specification, reference to terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0029] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A ketoconazole cream, characterized in that, The following components are included in parts by weight: 1-25 parts of ketoconazole, 1-80 parts of stearic acid, 1-55 parts of glyceryl mono- and distearate, 1-130 parts of light liquid paraffin, 0.1-1 part of ethylparaben, 100-350 parts of glycerol, 0.1-2 parts of disodium edetate, 1-6 parts of triethanolamine, 1-5 parts of anhydrous sodium sulfite, 0.1-2 parts of butylated hydroxytoluene, and 100-450 parts of purified water.

2. A method for preparing ketoconazole cream, characterized in that, The following steps are involved: (1) Preparation of oil phase: Mix mono- and distearic acid glyceryl, light liquid paraffin, stearic acid, and ethyl hydroxybenzoate, heat until melted, pass through a 150-mesh sieve, and keep warm at the first temperature; add butylated hydroxytoluene before emulsification, stir and dissolve for later use; (2) Preparation of aqueous phase: Mix purified water, glycerol, disodium edetate, and triethanolamine, heat and dissolve, and keep warm at the first temperature; add anhydrous sodium sulfite before emulsification, stir and dissolve, and then pass through a 150 mesh sieve for later use; (3) Ketoconazole pretreatment: Mix ketoconazole with a small amount of purified water, stir evenly, and pass through a 150-mesh sieve for later use to obtain a ketoconazole mixture; (4) Emulsification: When the temperatures of the oil phase and the water phase both reach the second temperature, slowly pour the water phase into the oil phase and stir; when the temperature drops to the third temperature, add the ketoconazole mixture, continue stirring and cool to room temperature, and the ketoconazole cream can be obtained.

3. The preparation method according to claim 2, characterized in that The first temperature is 70-85°C, the second temperature is 60-75°C, and the third temperature is 50-70°C.

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