Bifonazole solution and preparation method thereof

Abstract

The invention provides a bifonazole solution as well as a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The bifonazole solution is prepared from the following raw materials: bifonazole, sulfobutyl-beta-cyclodextrin, poloxamer 407, epsilon-polylysine, ceramide NP, cholesterol and water. The bifonazole solution prepared by the invention does not use an organic solvent, so that the irritation of the bifonazole solution to a user is remarkably reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a bifonazole solution and a preparation method thereof. BACKGROUND

[0002] Dermatomycosis is a superficial mycosis of the skin caused by dermatophytes, and common dermatophytes include hand-foot tinea, onychomycosis, body tinea, and groin tinea. Among them, hand-foot tinea is the most common dermatophyte infection, and the clinical manifestations can be of the following types: hyperkeratosis (mainly manifested as hyperkeratosis), papular and scaly (papules and scaly), blister (clustered and scattered small blisters), and immersion (interdigital immersion erosion). Skin tissue secondary bacterial infection can occur in local skin tissue secondary bacterial infection and spread to the dorsum pedis, lower extremities, back of the hand, and upper extremities due to skin erosion caused by itching and scratching or hand-foot tinea skin immersion erosion. Onychomycosis is more likely to cause bacterial inflammation around the nail of the fingers and toes, such as paronychia.

[0003] Bifonazole is a new type of imidazole topical antifungal drug, which is suitable for the treatment of tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor, tinea inguinalis, and fungal infection in skin folds. Bifonazole, CAS No. 60628-96-8, has a molecular formula of C 22 H 18 N2, and a chemical name of 1-([1,1 '-biphenyl]-4-yl(phenyl)methyl)-1H-imidazole, and a structure as shown below: .

[0004] Bifonazole is a white to slightly yellow crystalline powder, odorless, tasteless, easily soluble in chloroform, slightly soluble in methanol or anhydrous ethanol, and almost insoluble in water. The main dosage forms of commercially available bifonazole include bifonazole cream and bifonazole solution.

[0005] Chinese Patent Application CN115463086A discloses a bifonazole solution, which comprises the following raw materials 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 further comprises 15-30 parts of polyethylene glycol 400.

[0006] Chinese patent application CN104825388A discloses a bifonazole solution, wherein each 100g of the bifonazole solution contains the following components by weight: 1.0-1.2g of bifonazole; 5.0-30g of 95% ethanol by volume; 0-20g of N,N-dimethylacetamide; 30-80g of polyethylene glycol 200 or 8.9-38.9g of polyethylene glycol 400; and 0-20g of humectant.

[0007] Most of the bifonazole solutions disclosed above contain a large amount of the organic solvent ethanol. This is because the solubility of bifonazole raw material in water is very low, necessitating the addition of a large amount of ethanol as a co-solvent. While the use of ethanol and other co-solvents solves the problem of poor solubility, as a topical preparation, its use often causes severe pain at the affected area when the patient has skin ulcers or exposed nerves. This directly affects the clinical use of the solution. Therefore, there is an urgent need to develop a solution with new components that meets the requirements of low irritation and high stability to satisfy clinical needs. Summary of the Invention

[0008] To address the aforementioned problems, this invention provides a bifonazole solution and its preparation method. This bifonazole solution does not use organic solvents, significantly reducing its irritation to users.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a bifonazole solution comprising the following raw materials: bifonazole, sulfobutyl-β-cyclodextrin, poloxamer 407, ε-polylysine, ceramide NP, cholesterol, and water.

[0010] Preferably, the mass ratio of bifonazole to sulfobutyl-β-cyclodextrin is 1:5-10.

[0011] Preferably, the mass of poloxamer 407 is 18%-24% of the total mass of the raw materials.

[0012] Preferably, the mass ratio of ceramide NP to cholesterol is 4-6:1-2.

[0013] More preferably, the mass ratio of ceramide NP to cholesterol is 5:2.

[0014] Preferably, the ingredients, by weight, include the following: 0.8-1.2 parts bifonazole, 6-8 parts sulfobutyl-β-cyclodextrin, 18-24 parts poloxamer 407, 0.05-0.15 parts ε-polylysine, 0.2-0.8 parts ceramide NP, and 0.1-0.3 parts cholesterol, with water made up to 100 parts.

[0015] More preferably, the ingredients, by weight, include the following: 0.8-1.0 parts bifonazole, 6-6.5 parts sulfobutyl-β-cyclodextrin, 18-20 parts poloxamer 407, 0.05-0.10 parts ε-polylysine, 0.2-0.5 parts ceramide NP, and 0.1-0.2 parts cholesterol, with water made up to 100 parts.

[0016] More preferably, the ingredients, by weight parts, include: 1 part bifonazole, 6.5 parts sulfobutyl-β-cyclodextrin, 20 parts poloxamer 407, 0.1 part ε-polylysine, 0.5 parts ceramide NP and 0.2 parts cholesterol, with water to make up to 100 parts.

[0017] Preferably, the water is purified water.

[0018] Secondly, the present invention provides a method for preparing the above-mentioned bifonazole solution, comprising the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with some water, bifonazole is added and stirred to form an inclusion complex solution; S2: The inclusion complex solution was mixed with poloxamer 407 to obtain mixture 1; S3: Ceramide NP, cholesterol, and the remaining water are mixed to obtain mixture 2; S4: Mix mixture 1, mixture 2 and ε-polylysine, filter, sterilize, and obtain the final product.

[0019] Preferably, in step S1, the mass of the water portion is 35%-45% of the total mass of water in the raw material.

[0020] More preferably, in step S1, the mass of the water portion is 40% of the total mass of water in the raw material.

[0021] Preferably, in step S1, the mixing is performed by stirring, and the temperature is 1-5℃.

[0022] More preferably, in step S1, the mixing is stirring, and the temperature is 4°C.

[0023] Preferably, in step S1, the stirring temperature is 1-5℃, the stirring time is 40-50h, and the stirring is carried out in the dark.

[0024] More preferably, in step S1, the stirring temperature is 4°C, the stirring time is 48 hours, and the stirring is carried out in the dark.

[0025] Preferably, in step S2, the mixing is performed by stirring, at a temperature of 20-25°C, for a time of 3-5 hours; More preferably, the mixing is performed by stirring at a temperature of 25°C for 4 hours.

[0026] Preferably, in step S3, the mixing temperature is 20-25°C and the time is 0.5-1h.

[0027] Preferably, in step S4, the mixing temperature is 20-25°C and the time is 20-30 min.

[0028] Preferably, in step S4, the filtration is filtration using a 0.20-0.24 μm filter membrane.

[0029] Preferably, the bifonazole solution should be stored in the dark at 4-25°C.

[0030] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention improves the solubility of bifonazole in water by using sulfobutyl-β-cyclodextrin to encapsulate bifonazole at low temperature, avoiding the use of organic solvents and significantly reducing irritation to users.

[0031] 2. This invention achieves temperature-sensitive gel controlled release by using poloxamer 407 in combination with an inclusion system. After liquid administration, body temperature triggers gelation, reducing volatilization and prolonging the local retention time to 8-10 hours, thus reducing the likelihood of needing to repeat the administration.

[0032] 3. This invention utilizes ceramide NP and cholesterol in combination with other raw materials to repair the skin barrier, achieving efficient delivery while reducing irritation and enhancing skin protection; furthermore, the use of ε-polylysine significantly improves the stability of the solution.

[0033] 4. By using specific raw materials and proportions, this invention further achieves the effect of significantly reducing irritation and improving stability. Detailed Implementation

[0034] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further illustrated below with specific embodiments. However, these embodiments are merely preferred embodiments and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. It is worth noting that the raw materials used in this invention are all common commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0035] Example 1 A bifonazole solution, by weight, comprises the following ingredients: 1 part bifonazole, 6.5 parts sulfobutyl-β-cyclodextrin, 20 parts poloxamer 407, 0.1 part ε-polylysine, 0.5 parts ceramide NP and 0.2 parts cholesterol, with purified water to make up to 100 parts.

[0036] The preparation method includes the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with purified water (the mass of purified water is 40% of the total mass of purified water in the raw material), stirred at 4°C, and bifonazole is added and stirred at 4°C in the dark for 48 hours to form an inclusion complex solution. S2: The inclusion complex solution was stirred with poloxamer 407 at 25°C for 4 hours to obtain mixture 1; S3: Ceramide NP, cholesterol, and the remaining purified water were mixed at 20°C for 0.5 h to obtain mixture 2; S4: Mixture 1, mixture 2 and ε-polylysine are mixed at 25°C for 25 min, filtered through a 0.22 μm filter membrane, and sterilized to obtain the product. It should be stored in the dark at 4-25°C.

[0037] Example 2 A bifonazole solution, comprising, by weight parts: 1.2 parts bifonazole, 6.0 parts sulfobutyl-β-cyclodextrin, 24 parts poloxamer 407, 0.05 parts ε-polylysine, 0.8 parts ceramide NP and 0.3 parts cholesterol, with purified water to a total of 100 parts.

[0038] The preparation method includes the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with purified water (the mass of purified water is 35% of the total mass of purified water in the raw material), stirred at 1°C, and bifonazole is added and stirred at 5°C in the dark for 40 hours to form an inclusion complex solution. S2: The inclusion complex solution was stirred with poloxamer 407 at 20°C for 5 hours to obtain mixture 1; S3: Ceramide NP, cholesterol, and the remaining purified water were mixed at 22°C for 0.5 h to obtain mixture 2; S4: Mixture 1, mixture 2 and ε-polylysine are mixed at 20°C for 30 min, filtered through a 0.20 μm filter membrane, sterilized, and then stored in the dark at 4-25°C.

[0039] Example 3 A bifonazole solution, by weight parts, comprises the following raw materials: 0.8 parts bifonazole, 8 parts sulfobutyl-β-cyclodextrin, 18 parts poloxamer 407, 0.15 parts ε-polylysine, 0.2 parts ceramide NP and 0.1 parts cholesterol, with purified water to make up to 100 parts.

[0040] The preparation method includes the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with purified water (the mass of purified water is 45% of the total mass of purified water in the raw material), stirred at 5°C, and bifonazole is added and stirred at 1°C in the dark for 50 h to form an inclusion complex solution. S2: The inclusion complex solution was stirred with poloxamer 407 at 22°C for 3 hours to obtain mixture 1; S3: Ceramide NP, cholesterol, and the remaining purified water were mixed at 25°C for 1 hour to obtain mixture 2; S4: Mixture 1, mixture 2 and ε-polylysine are mixed at 22°C for 20 min, filtered through a 0.24 μm filter membrane, sterilized, and then stored in the dark at 4-25°C.

[0041] Comparative Example 1 A bifonazole solution, compared to Example 1, differs only in the mass fractions of the raw materials: The ingredients, by weight, include the following: 1.5 parts bifonazole, 10 parts sulfobutyl-β-cyclodextrin, 16 parts poloxamer 407, 0.4 parts ε-polylysine, 0.1 parts ceramide NP, and 0.3 parts cholesterol, with purified water to make up to 100 parts.

[0042] The rest remains the same as in Example 1.

[0043] Comparative Example 2 Prepared according to the preparation method of Example 1 in Chinese patent application CN 118615240 A.

[0044] Comparative Example 3 A bifonazole solution, compared to Example 1, with only the raw materials changed: The ingredients, by weight, include the following: 1 part bifonazole, 6.5 parts sulfobutyl-β-cyclodextrin, 20 parts poloxamer 188, 0.1 parts nisin, 0.7 parts ceramide NP, and purified water to make up to 100 parts.

[0045] The preparation method includes the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with purified water (the mass of purified water is 40% of the total mass of purified water in the raw material), stirred at 4°C, and bifonazole is added and stirred at 4°C in the dark for 48 hours to form an inclusion complex solution. S2: The inclusion complex solution was stirred with poloxamer 188 at 25°C for 4 hours to obtain mixture 1; S3: Ceramide NP and the remaining purified water were mixed at 20°C for 0.5 h to obtain mixture 2; S4: Mixture 1, mixture 2 and nisin are mixed at 25°C for 25 min, filtered through a 0.22 μm filter membrane, and sterilized to obtain the product. It should be stored in the dark at 4-25°C.

[0046] Test Example 1 The bifonazole solutions prepared in Examples 1-3 and Comparative Examples 1-3 were placed in a constant temperature and humidity chamber at 40°C and RH 20% for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months, and the content of bifonazole was determined by HPLC (external standard method). The relative content of bifonazole in the solutions after 1, 2, 3, and 6 months compared with the initial state was calculated. The results are shown in Table 1. Table 1. Relative content (%) of bifonazole

[0047] As shown in Table 1, the bifonazole solution prepared in this invention has significantly better stability than the comparative example.

[0048] Test Example 2 The bifonazole solutions prepared in Examples 1-3 and Comparative Examples 1-3 were sprayed at 30°C, and the evaporation rates were recorded under the same conditions. The specific results are shown in Table 2. Table 2. Evaporation rate of bifonazole solvent (s)

[0049] As shown in Table 2, the bifonazole solution prepared in this invention evaporates significantly faster than the comparative example.

[0050] Test Example 3 Skin irritation test: Thirty-five male rats (180-220g) were randomly divided into seven groups of five each. A 3cm × 3cm area of ​​skin was shaved off the back of each rat using an electric shaver and used as the administration site. Each group received 0.5mL of each of the following solutions daily: Examples 1-3, Comparative Examples 1-3, and commercially available bifonazole solution. Skin condition was observed after three days of treatment.

[0051] Skin irritation scores and evaluation criteria are shown in Tables 3 and 4.

[0052] Table 3. Skin Irritation Response Scoring Criteria

[0053] Table 4. Evaluation Criteria for Skin Irritation Intensity

[0054] The evaluation results are shown in Table 5: Table 5. Stimulus Response Scores

[0055] As shown in Table 5, the bifonazole solution prepared in this invention is significantly less irritating than the comparative example.

[0056] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A bifonazole solution, characterized in that, It includes the following ingredients: bifonazole, sulfobutyl-β-cyclodextrin, poloxamer 407, ε-polylysine, ceramide NP, cholesterol, and water.

2. The bifonazole solution according to claim 1, characterized in that, The mass ratio of bifonazole to sulfobutyl-β-cyclodextrin is 1:5-10.

3. The bifonazole solution according to claim 1, characterized in that, The mass of poloxamer 407 is 18%-24% of the total mass of the raw materials.

4. The bifonazole solution according to claim 1, characterized in that, The mass ratio of ceramide NP to cholesterol is 4-6:1-2.

5. The bifonazole solution according to claim 1, characterized in that, The ingredients, by weight, include the following: 0.8-1.2 parts bifonazole, 6-8 parts sulfobutyl-β-cyclodextrin, 18-24 parts poloxamer 407, 0.05-0.15 parts ε-polylysine, 0.2-0.8 parts ceramide NP, and 0.1-0.3 parts cholesterol, with water to make up to 100 parts.

6. The method for preparing the bifonazole solution according to any one of claims 1-5, characterized in that, Includes the following steps: S1: Sulfobutyl-β-cyclodextrin is mixed with some water, bifonazole is added and stirred to form an inclusion complex solution; S2: The inclusion complex solution was mixed with poloxamer 407 to obtain mixture 1; S3: Ceramide NP, cholesterol, and the remaining water are mixed to obtain mixture 2; S4: Mix mixture 1, mixture 2 and ε-polylysine, filter, sterilize, and obtain the final product.

7. The preparation method according to claim 6, characterized in that, In step S1, the mass of the water is 35%-45% of the total mass of water in the raw material; the stirring temperature is 1-5℃, the stirring time is 40-50h, and the stirring is carried out in the dark.

8. The preparation method according to claim 6, characterized in that, In step S2, the mixing is performed by stirring at a temperature of 20-25°C for 3-5 hours.

9. The preparation method according to claim 6, characterized in that, In step S3, the mixing temperature is 20-25℃ and the time is 0.5-1h.

10. The preparation method according to claim 6, characterized in that, In step S4, the mixing temperature is 20-25℃ and the time is 20-30 min; the filtration is performed using a 0.20-0.24 μm filter membrane.

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