A bifonazole solution and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a bifonazole solution, a preparation method thereof and an application thereof. The raw materials of the bifonazole solution include: bifonazole, propylene glycol, dimethyl sulfoxide, 95% ethanol, polyethylene glycol 400, panthenol, caprylic acid and water. The present invention adds polyethylene glycol 400, panthenol and caprylic acid, and there is a synergistic effect between the three, which further improves the stability of the solution to ensure better therapeutic effect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a bifonazole solution and a preparation method and application thereof. Background Art

[0002] Dermatophytosis is a superficial fungal disease of the skin caused by dermatophyte infection. Common ones include tinea manuum, pedis, tinea corporis, and tinea cruris. Among them, tinea manuum and pedis are the most common dermatophyte infection. The clinical manifestations may be of the following types: hyperkeratosis (mainly manifested as hyperkeratosis), papulosquamous type (papules and flaky scales), vesicular type (clustered and scattered small blisters), maceration type (maceration and erosion between fingers). Maceration and erosion of the skin of tinea manuum and pedis or skin damage caused by itching and scratching can lead to secondary bacterial infection of local skin tissue and extend to the dorsum of the foot, lower limbs, back of the hand, and upper limbs, complicated by acute lymphangitis, acute lymphadenitis, erysipelas, cellulitis, local skin suppurative bacterial infection, necrotizing erysipelas, paronychia, etc. Onychomycosis is more likely to cause secondary bacterial inflammation of the skin around the nails, such as paronychia.

[0003] Bifonazole is an organic compound with CAS number: 60628-96-8 and molecular formula: C 22 H 18 N2, chemical name 1-([1,1'-biphenyl]-4-yl(phenyl)methyl)-1H-imidazole, has the following structure:

[0004]

[0005] The raw material of bifonazole is an off-white to slightly yellow crystalline powder, which is odorless and tasteless. It is easily soluble in chloroform, slightly soluble in methanol or anhydrous ethanol, and almost insoluble in water. Bifonazole is a new type of imidazole topical antifungal drug with a broad-spectrum antifungal effect. It is effective against Candida albicans, various tinea, yeasts, filamentous fungi and dimorphic fungi, and has strong antibacterial activity. The main dosage forms of bifonazole on the market include bifonazole cream and bifonazole solution.

[0006] Chinese invention patent application CN1579393A discloses an external drug preparation for preventing superficial fungal infections - a coating, in particular a gel coating containing bifonazole, characterized in that it contains bifonazole, a film-forming material, a bioadhesive and a plasticizer. The coating is in a gel state, and after being applied to the skin for 2-3 minutes, it will dry by itself to form a uniform colorless and transparent invisible film and begin to release drugs. However, when the coating of the invention is used, it is easy to cause a tight feeling on the skin, causing certain discomfort to the patient, and the efficacy of the coating needs to be further improved.

[0007] Chinese invention patent application CN115463086A discloses a bifonazole solution, comprising the following raw materials in parts by weight: 0.5-1.5 parts of bifonazole, 10-30 parts of propylene glycol, 3-7 parts of dimethyl sulfoxide, 2-8 parts of glycerol, 20-60 parts of 95% ethanol and 10-18 parts of purified water, and also comprising 15-30 parts of polyethylene glycol 400.

[0008] Chinese invention patent application CN104825388A discloses a bifonazole solution, wherein each 100 g of the bifonazole solution contains the following components by weight: 1.0-1.2 g of bifonazole; 5.0-30 g of 95% by volume ethanol; 0-20 g of N,N-dimethylacetamide; 30-80 g of polyethylene glycol 200 or 8.9-38.9 g of polyethylene glycol 400; and 0-20 g of a moisturizer.

[0009] The solubility of bifonazole raw material in water is very low, so a large amount of ethanol has to be added as a co-solvent. Most of the above-mentioned bifonazole solutions contain a large amount of organic solvent ethanol. However, as an external preparation, when the patient's skin has ulcers and nerve exposure, the use of ethanol often causes severe pain in the affected area, which directly affects the clinical use of the solution.

[0010] Therefore, it is urgent to develop a bifonazole solution with less irritation and good stability. Summary of the invention

[0011] In view of the shortcomings of the prior art, the present invention provides a bifonazole solution and a preparation method and application thereof. The bifonazole solution prepared by the present invention is not only less irritating, but also has stable active ingredients after being stored for a long time.

[0012] To achieve the above-mentioned object of the invention, the technical solution of the present invention is as follows:

[0013] A bifonazole solution, the raw materials of which include bifonazole, propylene glycol, dimethyl sulfoxide, 95% ethanol, polyethylene glycol 400, panthenol, caprylic acid and water.

[0014] Preferably, the raw materials of the bifonazole solution include, by weight: 0.5-1.5 parts of bifonazole, 10-30 parts of propylene glycol, 3-7 parts of dimethyl sulfoxide, 20-50 parts of 95% ethanol, 10-20 parts of polyethylene glycol-400, 2-8 parts of panthenol, 2-8 parts of caprylic acid and 10-20 parts of water.

[0015] Further preferably, the raw materials of the bifonazole solution include: 0.8-1.2 parts of bifonazole, 15-25 parts of propylene glycol, 4-6 parts of dimethyl sulfoxide, 30-40 parts of 95% ethanol, 15-17 parts of polyethylene glycol-400, 3-5 parts of panthenol, 3-5 parts of caprylic acid and 12-18 parts of water.

[0016] Preferably, the raw materials of the bifonazole solution include: 1.0 part of bifonazole, 20 parts of propylene glycol, 5 parts of dimethyl sulfoxide, 35 parts of 95% ethanol, 16 parts of polyethylene glycol 400, 4 parts of panthenol, 4 parts of caprylic acid and 15 parts of water.

[0017] The present invention also relates to a method for preparing the bifonazole solution, comprising the following steps:

[0018] (1) mixing bifonazole with 95% ethanol and stirring to obtain a mixture A;

[0019] (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring to obtain mixture B;

[0020] (3) Mix polyethylene glycol 400, caprylic acid and mixture B, and stir to obtain a bifonazole solution.

[0021] Preferably, the stirring time in steps (1) to (3) is 10-20 min.

[0022] Preferably, the stirring temperature in step (1) is 40-60° C., and the stirring temperatures in steps (2)-(3) are all room temperature.

[0023] The present invention also relates to the use of the bifonazole solution or the bifonazole solution prepared by the preparation method in the preparation of antifungal products.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The bifonazole solution prepared by the present invention has better stability and less irritation through a specific raw material ratio;

[0026] (2) The present invention adds polyethylene glycol 400, panthenol and caprylic acid, which have a synergistic effect among the three, further improving the stability of the solution to ensure better therapeutic effects. DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0028] Polyethylene glycol 400, product number: 400, was purchased from Guangzhou Changhong Chemical Co., Ltd.

[0029] Example 1

[0030] A bifonazole solution comprises the following raw materials, measured by weight: 1.0 part of bifonazole, 20 parts of propylene glycol, 5 parts of dimethyl sulfoxide, 35 parts of 95% ethanol, 16 parts of polyethylene glycol 400, 4 parts of panthenol, 4 parts of caprylic acid and 15 parts of ethanol.

[0031] The preparation method of the above-mentioned bifonazole solution is:

[0032] (1) Mix bifonazole and 95% ethanol, and stir at 50° C. for 15 min to obtain a mixture A;

[0033] (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring at room temperature for 15 minutes to obtain mixture B;

[0034] (3) Mix polyethylene glycol 400 and caprylic acid with mixture B, and stir at room temperature for 15 minutes to obtain a colorless and clear bifonazole solution.

[0035] Example 2

[0036] A bifonazole solution comprises the following raw materials by weight: 0.8 parts of bifonazole, 15 parts of propylene glycol, 4 parts of dimethyl sulfoxide, 30 parts of 95% ethanol, 15 parts of polyethylene glycol 400, 3 parts of panthenol, 3 parts of caprylic acid and 12 parts of water.

[0037] The preparation method of the above-mentioned bifonazole solution is:

[0038] (1) mixing bifonazole with 95% ethanol and stirring at 40° C. for 10 min to obtain a mixture A;

[0039] (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring at room temperature for 10 min to obtain mixture B;

[0040] (3) Mix polyethylene glycol 400 and caprylic acid with mixture B, and stir at room temperature for 20 minutes to obtain a colorless and clear bifonazole solution.

[0041] Example 3

[0042] A bifonazole solution comprises the following raw materials by weight: 1.2 parts of bifonazole, 25 parts of propylene glycol, 6 parts of dimethyl sulfoxide, 40 parts of 95% ethanol, 17 parts of polyethylene glycol 400, 5 parts of panthenol, 5 parts of octanoic acid and 18 parts of water.

[0043] The preparation method of the above-mentioned bifonazole solution is:

[0044] (1) mixing bifonazole with 95% ethanol and stirring at 60° C. for 20 min to obtain a mixture A;

[0045] (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring at room temperature for 20 minutes to obtain mixture B;

[0046] (3) Mix polyethylene glycol 400 and caprylic acid with mixture B, and stir at room temperature for 10 minutes to obtain a colorless and clear bifonazole solution.

[0047] Comparative Examples 1-4

[0048] The difference between Comparative Examples 1-4 and Example 1 is that the added amounts of polyethylene glycol 400, panthenol and caprylic acid are different. The specific added amounts are shown in Table 1.

[0049] Table 1 Addition amount of polyethylene glycol-400, panthenol and caprylic acid in comparative examples 1-4

[0050] Polyethylene glycol-400 Panthenol bitter Comparative Example 1 24 0 0 Comparative Example 2 0 12 12 Comparative Example 3 16 8 0 Comparative Example 4 16 0 8

[0051] Comparative Example 5

[0052] A bifonazole solution, which differs from Example 1 only in that the raw material ratio is different. In this comparative example, the raw materials are, by weight, 1.0 part of bifonazole, 20 parts of propylene glycol, 8 parts of dimethyl sulfoxide, 35 parts of 95% ethanol, 10 parts of polyethylene glycol-400, 10 parts of panthenol, 1 part of caprylic acid and 15 parts of water.

[0053] Comparative Example 6

[0054] A bifonazole solution, which differs from Example 1 only in that the preparation method is different. The preparation method of this comparative example is:

[0055] (1) Mix bifonazole and 95% ethanol, and stir at 50° C. for 15 min to obtain a mixture A;

[0056] (2) The remaining raw materials are directly mixed with the mixture A and stirred evenly to obtain a bifonazole solution.

[0057] Effect test

[0058] Test Example 1

[0059] The bifonazole solutions prepared in Examples 1-3 and Comparative Examples 1-6 were placed in a constant temperature and humidity chamber at 40°C and RH20% for 6 months. Samples were taken at 0, 1, 2, 3 and 6 months, and the bifonazole content was tested by HPLC (external standard method). The relative ratio of the bifonazole content in the solution after 1, 2, 3 and 6 months to that in the initial state was calculated, and the results are shown in Table 2.

[0060] Table 2 Relative content of bifonazole in bifonazole solution

[0061] 1 month 2 months 3 months 6 months Example 1 99.9％ 99.9％ 100.2％ 100％ Example 2 99.9％ 100.1％ 100％ 99.9％ Example 3 99.9％ 100.2％ 100％ 99.9％ Comparative Example 1 99.7％ 99.7％ 99.2％ 99％ Comparative Example 2 99.5％ 99.3％ 99％ 89.7％ Comparative Example 3 99.8％ 99.2％ 99％ 89.5％ Comparative Example 4 99.7％ 99.5％ 99.1％ 89.4％ Comparative Example 5 99.6％ 99.1％ 89.7％ 89.1％ Comparative Example 6 99.9％ 99.8％ 100.0％ 99.4％

[0062] Test Example 2

[0063] The bifonazole solutions prepared in Examples 1-3 and Comparative Examples 1-6 were sprayed at 30° C., and the volatilization rates were recorded under the same environment. The specific results are shown in Table 3.

[0064] Table 3 Evaporation rate of bifonazole solution

[0065] Group Volatilization rate Example 1 15s Example 2 18s Example 3 20s Comparative Example 1 25s Comparative Example 2 30s Comparative Example 3 32s Comparative Example 4 30s Comparative Example 5 35s Comparative Example 6 22s

[0066] Test Example 3

[0067] Skin irritation test: 35 male rats (180-220g) were randomly divided into 7 groups, 5 rats in each group. 3cm×3cm skin on the back of the rats was removed with an electric shaver as the administration site. Each group was treated with 0.5mL of Example 1, Comparative Examples 1-5 and commercially available bifonazole solution every day, and the skin condition was observed after 3 days of use.

[0068] The skin irritation scores and evaluation criteria are shown in Tables 4 and 5.

[0069] Table 4 Skin irritation response scoring criteria

[0070]

[0071] Table 5 Evaluation criteria for skin irritation intensity

[0072] Points evaluate 0-0.49 Non-irritating 0.5-2.99 Mild irritant 3.0-5.99 Moderate irritation 6.0-12.00 Severe irritation

[0073] The evaluation results are shown in Table 6.

[0074] Table 6 Stimulus response scoring results

[0075] preparation erythema Edema Roughness Total score Example 1 0.2 0.15 0 0.35 Comparative Example 1 1.2 1.1 0.5 2.8 Comparative Example 2 0.6 1.8 0.2 2.6 Comparative Example 3 0.9 0.8 1.0 2.7 Comparative Example 4 1.3 1.0 0.7 3.0 Comparative Example 5 1.6 1.8 1.4 4.8 Commercially available bifonazole solution 0.3 0.2 0.1 0.6

[0076] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A bifonazole solution, wherein the raw materials of the bifonazole solution include, by weight: 0.5-1.5 parts of bifonazole, 10-30 parts of propylene glycol, 3-7 parts of dimethyl sulfoxide, 20-50 parts of 95% ethanol, 10-20 parts of polyethylene glycol-400, 2-8 parts of panthenol, 2-8 parts of caprylic acid and 10-20 parts of water; The preparation method of the bifonazole solution comprises the following steps: (1) mixing bifonazole with 95% ethanol and stirring to obtain a mixture A; (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring to obtain mixture B; (3) Mix polyethylene glycol 400, caprylic acid and mixture B, and stir to obtain a bifonazole solution.

2. The bifonazole solution according to claim 1, characterized in that: The raw materials of the bifonazole solution include: 0.8-1.2 parts of bifonazole, 15-25 parts of propylene glycol, 4-6 parts of dimethyl sulfoxide, 30-40 parts of 95% ethanol, 15-17 parts of polyethylene glycol-400, 3-5 parts of panthenol, 3-5 parts of octanoic acid and 12-18 parts of water.

3. The bifonazole solution according to claim 2, characterized in that: The raw materials of the bifonazole solution include: 1.0 part of bifonazole, 20 parts of propylene glycol, 5 parts of dimethyl sulfoxide, 35 parts of 95% ethanol, 16 parts of polyethylene glycol 400, 4 parts of panthenol, 4 parts of caprylic acid and 15 parts of water.

4. A method for preparing the bifonazole solution according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) mixing bifonazole with 95% ethanol and stirring to obtain a mixture A; (2) adding propylene glycol, dimethyl sulfoxide, panthenol and water to mixture A and stirring to obtain mixture B; (3) Mix polyethylene glycol 400, caprylic acid and mixture B, and stir to obtain a bifonazole solution.

5. The preparation method according to claim 4, characterized in that: The stirring time in steps (1) to (3) is 10-20 minutes.

6. The preparation method according to claim 4, characterized in that: The stirring temperature in step (1) is 40-60°C, and the stirring temperatures in steps (2)-(3) are all room temperature.

7. Use of the bifonazole solution according to any one of claims 1 to 3 or the bifonazole solution prepared by the preparation method according to any one of claims 4 to 6 in the preparation of antifungal products.

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