A solution of miconazole nitrate and a method for preparing the same

Abstract

The present invention relates to a solution of miconazole nitrate. The solution of miconazole nitrate formulation comprises miconazole nitrate, glyceryl laurate, 1,3-butanediol, polyethylene glycol 400, water. The solution of miconazole nitrate prepared by the present invention avoids the use of dimethyl sulfoxide and ethanol. The addition of glyceryl laurate effectively increases the antibacterial properties of miconazole nitrate, while increasing the stability of the solution.

Description

Technical Field

[0001] This invention relates to a pharmaceutical preparation, and more specifically to a miconazole nitrate solution and its preparation method. Background Technology

[0002] Miconazole is a synthetic imidazole antifungal agent widely used for the topical treatment of fungal skin infections in farm animals and other veterinary species. First developed and introduced in the late 1960s, it is one of the earliest azole antifungal agents and, due to its broad spectrum of activity, excellent safety profile, and availability in various convenient dosage forms, has become one of the most commonly used topical antifungal drugs in veterinary medicine. It is effective against dermatophytes, yeasts, and some Gram-positive bacteria, making it widely applicable in treating various superficial skin infections affecting livestock.

[0003] Miconazole's mechanism of action involves inhibiting fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme crucial for the conversion of lanosterol to ergosterol in the fungal cell membrane. Ergosterol is a component specific to fungal cell membranes, functioning analogously to cholesterol in mammalian cell membranes. By blocking ergosterol synthesis, miconazole leads to the accumulation of toxic sterol intermediates, causing defects in the fungal cell membrane, resulting in altered permeability and ultimately cell death. At high concentrations, miconazole can also directly disrupt the fungal cell membrane through physical interactions with membrane lipids.

[0004] Miconazole is available in a variety of topical formulations, designed for different clinical uses and ease of use. Creams and ointments deliver high concentrations of the drug to local lesions and are easy to apply to scattered areas of infection. Sprays can be used to treat larger lesions without requiring extensive handling, and are particularly suitable for animals that resist direct application. Miconazole-containing shampoos are often used in combination with chlorhexidine to provide systemic treatment and are very effective against widespread fungal infections. Powder formulations combine drying and antifungal activity, making them suitable for treating moist lesions. Lotions fall between creams and sprays, offering a degree of intermediate properties.

[0005] Because miconazole nitrate is poorly soluble in water and has low solubility in ethanol (only 0.7% saturation concentration), which is insufficient for clinical needs, 30%–40% dimethyl sulfoxide (DMSO) is often added to formulations to increase its solubility, resulting in a 3% miconazole nitrate topical solution. This topical solution is relatively stable at room temperature, but significant crystallization occurs when the temperature drops below 10°C in winter. Qualitative analysis of the precipitated crystals revealed that the main component was DMSO, with a small amount of miconazole nitrate. DMSO crystallizes at 18.5°C. This formulation has a high DMSO content and readily crystallizes at low temperatures in ethanol, indicating an unstable formulation.

[0006] The literature (Lin Huizhen, Zhang Xianzhu, Cai Hongsheng. Preparation of miconazole liniment. Chinese Journal of Hospital Pharmacy, 1993, 13(8):360.) discloses the following prescription: miconazole nitrate 20g, sodium benzoate 8g, azone 10mL, and 95% ethanol added to 1000mL. Since sodium benzoate is slightly soluble in alcohol, it should be dissolved in a small amount of water first. After use, the bottle should be tightly sealed to prevent needle-like crystals from precipitating on the bottle wall after ethanol evaporation, which would affect the efficacy.

[0007] The literature (Preparation and Quality Control of 3% Miconazole Nitrate Liniment, Chinese Pharmaceutical Journal, October 1995, Vol. 30, No. 10, pp. 606-607) discloses the following formula: miconazole nitrate 3.0g, sodium benzoate 1.35g, polysorbate-80 0.5mL, laurocapram 1.0mL, distilled water 5.0mL, and ethanol to 100mL. This preparation dissolves quickly at room temperature. If the temperature is low, appropriate heating is necessary to facilitate the solubilization of polysorbate and indirect molecular complexation.

[0008] CN201810083331.4 discloses an anti-tinea miconazole nitrate topical solution, comprising the following components in the specified proportions: miconazole nitrate 6g, boric acid 10g, benzoic acid 60g, azone 30mL, and ethanol 1000mL. The product exhibits significant antibacterial and sterilization effects, and shows marked therapeutic efficacy against psoriasis, tinea manuum, and tinea pedis.

[0009] JP2015054857A discloses a miconazole nitrate formulation, which avoids miconazole nitrate powder adhering to a metal mixing tank and causing powder to fly away. This invention relates to dispersing miconazole nitrate in a solution containing at least one component selected from propylene glycol and butylene glycol, including mixing the dispersion with a component containing a surfactant and water in a metal mixing tank to manufacture a miconazole nitrate formulation.

[0010] Existing formulations containing large amounts of ethanol and propylene glycol suffer from drawbacks such as high skin irritation and easy ethanol evaporation during storage. There is a need in this field for a miconazole nitrate solution and its preparation method. Summary of the Invention

[0011] To address the above problems, this invention provides a miconazole nitrate solution formulation. Its preparation method is simple, the raw materials are readily available, and it is suitable for industrial production.

[0012] The specific technical solution of the present invention is as follows: A miconazole nitrate solution, comprising miconazole nitrate, glyceryl monolaurate, 1,3-butanediol, polyethylene glycol 400, and water.

[0013] Preferably, 100 mL of miconazole nitrate solution contains 1.15–2.30 g of miconazole nitrate, 2–10 g of glyceryl monolaurate, 2–8 g of 1,3-butanediol, and 10–20 g of polyethylene glycol 400.

[0014] More preferably, 100 mL of miconazole nitrate solution contains 1.15 g of miconazole nitrate, 8 g of glyceryl monolaurate, 5 g of 1,3-butanediol, and 15 g of polyethylene glycol 400.

[0015] The present invention also provides a method for preparing the above-mentioned miconazole nitrate solution, which includes the following steps: Dissolve 80%–90% of the total volume of water for injection, 1,3-butanediol, and polyethylene glycol 400 by stirring at 40–50°C. Then add glyceryl monolaurate and stir to dissolve at 40–50°C. Next, add miconazole nitrate and continue stirring to dissolve at 40–50°C. Cool to room temperature, add water to bring the volume to the prepared volume, stir until homogeneous, filter through a 0.22 μm microporous membrane, and package to obtain the miconazole nitrate solution.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The miconazole nitrate solution prepared by this invention avoids the use of dimethyl sulfoxide and ethanol. The addition of glyceryl monolaurate effectively increases the antibacterial properties of miconazole nitrate while also increasing the stability of the solution. Detailed Implementation

[0017] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments and other contents of the present invention are only used to illustrate the present invention and are not intended to limit the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0018] Example 1 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Dissolve 80%–90% of the total volume of water for injection, 1,3-butanediol, and polyethylene glycol 400 by stirring at 40–50°C. Then add glyceryl monolaurate and stir to dissolve at 40–50°C. Next, add miconazole nitrate and continue stirring to dissolve at 40–50°C. Cool to room temperature, add water to bring the volume to the prepared volume, stir until homogeneous, filter through a 0.22 μm microporous membrane, and package to obtain the miconazole nitrate solution.

[0019] Example 2 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0020] Example 3 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0021] Example 4 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0022] Example 5 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0023] Comparative Example 1 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Add miconazole nitrate to dimethyl sulfoxide and stir to dissolve. Add fragrance while stirring. Add ethanol until the volume is full and stir well to obtain the final product.

[0024] Comparative Example 2 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0025] Comparative Example 3 Preparation of miconazole nitrate solution: 1. Prescription 2. Preparation process: Same as in Example 1.

[0026] Verification Implementation Examples 1. Stability Testing Following the guidelines for stability testing of pharmacopoeia preparations, the miconazole nitrate solutions prepared in Examples 1-5 and Comparative Examples 1-3 of this invention were aliquoted into high-density polyethylene plastic bottles and packaged in commercially available cardboard boxes. These were then placed at a temperature of 40±2℃ and a relative humidity of RH 75±5% for 6 months, and samples were taken for testing. Freshly prepared samples were also stored at -5℃ for one week to observe their condition. The results are shown in Table 1.

[0027] Table 1. Results of stability studies for samples in each embodiment. The experimental results show that the samples prepared in Examples 1-5 of this invention have good stability. The addition of glyceryl monolaurate significantly enhanced the stability of the formulation. In Example 4, the amount of glyceryl monolaurate added was relatively small, and after 6 months of accelerated testing, the total impurities were significantly increased compared to the samples in other examples. In contrast, Examples 1-3 did not contain glyceryl monolaurate, and after 6 months of accelerated testing, the total impurities were significantly increased. Furthermore, low-temperature testing revealed that glyceryl monolaurate increased the solubility of miconazole nitrate.

[0028] 2. Antibacterial performance test Experimental methods: Common pathogenic fungi in canine dermatomycosis cases were selected, including Microsporum canis (…). Microsporum dog SDA medium was prepared using conventional methods. The pathogenic fungus was inoculated into the center of the SDA medium and activated at 28°C for 7-10 days. The bacterial concentration was then adjusted to 7.8 × 10⁻⁶. 6 The cfu / mL concentration of the samples from Examples 1-5 of this invention and Comparative Examples 1-3 was diluted 5 times with water before use. The samples were sprayed onto the surface of SDA culture medium using a nozzle at a rate of 0.5 mL per plate. The inhibition rate was statistically analyzed at 1 h and 12 h, as shown in Table 2. Table 2 Antibacterial effects of samples from each example The miconazole nitrate solution prepared by the method of this invention has a high inhibitory effect on the pathogenic fungi of canine dermatophytes, and the effect is long-lasting.

Claims

1. A miconazole nitrate solution, characterized in that, The formulation contains miconazole nitrate, glyceryl monolaurate, 1,3-butanediol, polyethylene glycol 400, and water.

2. The miconazole nitrate solution as described in claim 1, characterized in that, 100 mL of miconazole nitrate solution contains 1.15–2.30 g of miconazole nitrate, 2–10 g of glyceryl monolaurate, 2–8 g of 1,3-butanediol, and 10–20 g of polyethylene glycol 400.

3. The miconazole nitrate solution as described in claim 1, characterized in that, 100 mL of miconazole nitrate solution contains 1.15 g miconazole nitrate, 8 g glyceryl monolaurate, 5 g 1,3-butanediol, and 15 g polyethylene glycol 400.

4. The method for preparing miconazole nitrate solution according to any one of claims 1-3, characterized in that, Includes the following steps: Dissolve 80%–90% of the total volume of water for injection, 1,3-butanediol, and polyethylene glycol 400 by stirring at 40–50°C. Then add glyceryl monolaurate and stir to dissolve at 40–50°C. Next, add miconazole nitrate and continue stirring to dissolve at 40–50°C. Cool to room temperature, add water to bring the volume to the prepared volume, stir to mix thoroughly, filter through a 0.22 μm microporous membrane, and package to obtain the miconazole nitrate solution.

Images