A solution of biphenylbenzazole and a preparation method thereof

Abstract

This invention provides a bifonazole solution and its preparation method. Adjusting the pH of this bifonazole solution to 5.5-7.5 significantly reduced the increase in both the maximum unknown single impurity and total impurities, resulting in a significant improvement in product stability. Adding polyethylene glycol 400 to the solution effectively reduced the product's irritant properties.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a bifonazole solution and its preparation method. Background Technology

[0002] Bifonazole is an antifungal agent developed by Bayer AG in Germany. Its main component is the imidazole derivative bifonazole. Bifonazole is a broad-spectrum antifungal drug that exerts its antifungal effect against dermatophytes and Candida by inhibiting cell membrane synthesis. It is mainly used to treat fungal skin diseases such as tinea pedis, tinea manuum, tinea corporis, tinea cruris, and tinea versicolor. Like other imidazole antifungals, bifonazole has potent, broad-spectrum antifungal activity and good skin penetration. Common dosage forms of bifonazole include solutions, suppositories, creams, gels, and vaginal tablets. Solutions are the most widely used dosage form, offering advantages such as a broad antibacterial spectrum, strong antibacterial activity, high safety, convenient administration, strong penetration, and effective and long-lasting treatment. Furthermore, studies on experimental guinea pig ringworm have shown that bifonazole has a relatively long skin retention time. Therefore, some have suggested that even with reduced frequency of administration in clinical practice, bifonazole may still be as effective as traditional antifungal drugs. In 1978, Germany and in 1980, Japan respectively launched clinical trials of once-daily administration.

[0003] Bifonazole solution was included in the 89th and 93rd batches of the "Reference Preparations Catalog for Generic Drugs" published by the NMPA. Referring to the instructions for the reference preparation (trade name: Canespie®), the Spanish marketed specification for bifonazole solution is 10 mg / ml, and the dosage form is a topical solution. According to the 2025 edition of the Chinese Pharmacopoeia, Part II (1509), the dosage form for this product is a topical application. Therefore, it is determined that the developed specification for this product is consistent with the reference preparation, at 10 mg / ml. Summary of the Invention

[0004] The technical problem solved by this invention is to provide a bifonazole solution and its preparation process, which improves the stability of the bifonazole solution.

[0005] To achieve the above objectives, in a first aspect, the present invention provides a bifonazole solution having a pH value of 5.5 to 7.5.

[0006] Specifically, the bifonazole solution comprises bifonazole, isopropyl myristate, sodium hydroxide and hydrochloric acid, and 96% (v / v) ethanol.

[0007] Specifically, the pH adjuster of the bifonazole solution is sodium hydroxide and hydrochloric acid.

[0008] Secondly, the present invention provides a bifonazole solution, characterized in that it includes the steps of weighing, preparing, filtering, filling and packaging.

[0009] Specifically, polyethylene glycol 400 is added to the solution.

[0010] Compared with the prior art, the advantages of the present invention are as follows:

[0011] 1. By controlling the pH value of the drug solution between 5.5 and 7.5, this invention helps to reduce the growth rate of impurities G, E, the maximum unknown single impurity, and total impurities during the stability period.

[0012] 2. The bifonazole solution preparation method provided by the present invention, by adding polyethylene glycol 400 to the solution preparation, significantly reduces the irritation to ulcerated wounds and mucous membranes, and is suitable for sensitive sites.

[0013] The bifonazole solution prepared using the above technique showed a significant decrease in the growth trends of impurity G, impurity E, maximum unknown single impurity, and total impurities during the stabilization process, and a significant reduction in irritation. Detailed Implementation

[0014] In the following embodiments, unless otherwise specified, the testing equipment and instruments used are commonly used reagents and instruments in the art, and the methods used are conventional methods in the art. Those skilled in the art can understand how to specifically implement the methods and achieve the corresponding results based on the content of the embodiments.

[0015] Example 1

[0016] A bifonazole solution, with the following prescription:

[0017]

[0018] The preparation method of this bifonazole solution is as follows:

[0019] ① Weighing: Weigh out the prescribed amount of bifonazole and ethanol, and set aside.

[0020] ② Solution preparation: Add the prescribed amount of ethanol, set the water bath temperature to 40℃, start stirring, and add the prescribed amount of bifonazole until completely dissolved. Weigh isopropyl myristate and determine the final weight, then stir for 30 minutes until a homogeneous solution is obtained. Add a pH adjuster to control the pH value at 5.0~5.5.

[0021] ③ Filtration: The medicine solution is filtered through a 0.45μm primary filter and two 0.22μm sterile filters.

[0022] ④ Filling and sealing: Use a filling and sealing machine for filling, with a volume ≥30ml, and adjust the filling and sealing speed to 100~400 bottles / min.

[0023] ⑤ Packaging.

[0024] Example 2

[0025] A bifonazole solution, with the following prescription:

[0026]

[0027] The preparation method of this bifonazole solution is as follows:

[0028] ① Weighing: Weigh out the prescribed amount of bifonazole and ethanol, and set aside.

[0029] ② Solution preparation: Add the prescribed amount of ethanol, set the water bath temperature to 40℃, start stirring, and add the prescribed amount of bifonazole until completely dissolved. Weigh isopropyl myristate and determine the final weight, then stir for 30 minutes until a homogeneous solution is obtained. Add a pH adjuster to control the pH value at 5.5~6.5.

[0030] ③ Filtration: The medicine solution is filtered through a 0.45μm primary filter and two 0.22μm sterile filters.

[0031] ④ Filling and sealing: Use a filling and sealing machine for filling, with a volume ≥30ml, and adjust the filling and sealing speed to 100~400 bottles / min.

[0032] ⑤ Packaging.

[0033] Example 3

[0034] A bifonazole solution, with the following prescription:

[0035]

[0036] The preparation method of this bifonazole solution is as follows:

[0037] ① Weighing: Weigh out the prescribed amount of bifonazole and ethanol, and set aside.

[0038] ② Solution preparation: Add the prescribed amount of ethanol, set the water bath temperature to 40℃, start stirring, and add the prescribed amount of bifonazole until completely dissolved. Weigh isopropyl myristate and determine the final weight, then stir for 30 minutes until a homogeneous solution is obtained. Add a pH adjuster to control the pH value at 6.5~7.5.

[0039] ③ Filtration: The medicine solution is filtered through a 0.45μm primary filter and two 0.22μm sterile filters.

[0040] ④ Filling and sealing: Use a filling and sealing machine for filling, with a volume ≥30ml, and adjust the filling and sealing speed to 100~400 bottles / min.

[0041] ⑤ Packaging.

[0042] Example 4

[0043] A bifonazole solution, which differs from Example 2 in that polyethylene glycol 400 is added during the solution preparation process.

[0044] Stability test

[0045] 1. Test Methods

[0046] The bifonazole solutions prepared in Examples 1-4 of this application and the original reagents were placed at 60°C for 30 days and at 25°C for 3 months. The properties, pH value and related substances were used as test indicators (the limit requirements of the test items are shown in the table below) for comparison.

[0047]

[0048] 2. Test Results

[0049]

[0050] Preliminary stability study results indicate that:

[0051] The self-made formulation and the reference formulation showed relatively stable properties at 60℃ and 25℃, with no changes. The pH of both the self-made formulation and the reference formulation increased slightly after being placed at 60℃ for 30 days, with a consistent trend. The formulations of Examples 2, 3, and 4 showed a slower growth trend in the maximum unknown single impurity and total impurities of related substances compared to the reference formulation, indicating that the impurity levels were better than those of the reference formulation. The total impurity growth rate of Example 1 was faster than that of Examples 2, 3, and 4, but slightly worse than that of the reference formulation.

[0052] The results above show that adjusting the pH of the bifonazole solution to 5.5-7.5 provides a greater advantage in stability compared to the original formulation.

[0053] Stimulation test

[0054] 1. Test Methods

[0055] Twenty patients with erosive athlete's foot were selected, with 10 randomly selected as experimental cases and 10 as control cases. In a randomized, double-blind manner, the drugs of Example 4 and Example 2 of the present invention were sprayed onto the affected areas of the experimental and control patients, respectively, and the patients were interviewed about their pain after the drug was applied.

[0056] 2. Test Results

[0057]

[0058] The above data indicate that adding polyethylene glycol 400 to the solution significantly reduces irritation to ulcerated wounds and mucous membranes, making it suitable for sensitive areas. Based on the stability results, the formulation of Example 4 is preferred, and the pH value is controlled within the range of 5.5 to 7.5, effectively reducing the irritation of this product while maintaining high stability.

[0059] Although the present invention has described the above embodiments, this does not limit the scope of patent protection of the present invention. Therefore, any changes and modifications to the embodiments described herein, or equivalent structural or procedural transformations made using the content of this specification, that directly or indirectly apply the above technical solutions to other related technical fields, are all included within the scope of patent protection of the present invention.

Claims

1. A solution of a biphenylbenzazole, characterized in that, Its raw materials include bifonazole, isopropyl myristate, pH adjuster, and ethanol.

2. According to claim 1, the characteristic is that, The pH adjuster is sodium hydroxide or hydrochloric acid.

3. According to claim 2, the characteristic is that Use the pH adjuster to adjust the pH of the solution to 5.5-7.

5.

4. The bifonazole solution according to claim 1, characterized in that, It includes steps such as weighing, preparation, filtering, filling, and packaging.

5. The bifonazole solution according to claim 4, characterized in that, In the process of preparing the solution, polyethylene glycol 400 is added.

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