Fluconazole ear drops and a method for preparing the same

Abstract

The application discloses fluconazole ear drops and a preparation method thereof, and belongs to the technical field of ear drop preparations. The fluconazole ear drops contain the following components in percentage by mass: 0.6%-2.0% of fluconazole, 8%-20% of propylene glycol and / or diethylene glycol monoethyl ether, 20%-32% of glycerol or capryl capric acid polyethylene glycol glycerol ester, 0.1%-1% of hydroxypropyl methyl cellulose, 0.05%-0.2% of anhydrous disodium hydrogen phosphate, and water in a residual amount. The solubility of fluconazole is increased through improvement of the prescription of the fluconazole ear drops, the content of fluconazole in the prepared fluconazole ear drops reaches 2%, and the fluconazole ear drops have good stability. Compared with the prior art, the fluconazole ear drops have a better treatment effect on ear fungal infections.

Description

Technical Field

[0001] This invention belongs to the field of ear drop preparation technology, specifically, it relates to a fluconazole ear drop and its preparation method. Background Technology

[0002] Otomycosis is a superficial infection of the external auditory canal caused by fungi. It is a common infectious disease in otolaryngology clinics. Clinical symptoms generally include itching and a feeling of fullness, sometimes with intense itching, which is worse at night. It often recurs and is difficult to cure completely.

[0003] Currently, the main treatment for otofungal infections is topical therapy, which involves applying antifungal medication topically after cleaning and drying the ear canal. Fluconazole is a triazole broad-spectrum antifungal drug. Its mechanism of action primarily involves interfering with the fungal cell membrane by inhibiting the activity of cholesterol 14-α demethylase, thereby hindering ergosterol synthesis in the fungal cell membrane, increasing fungal cell permeability, and inhibiting fungal growth and reproduction. Fluconazole (trade name DIFLUCAN®) was originally developed by Pfizer. Tablets were approved by the FDA in the United States in 1990. Suspension and injectable formulations were subsequently developed. In China, it is marketed under the brand name "Dualcon®" (capsules and injections), primarily used for deep fungal infections, urinary tract infections, and skin fungal infections.

[0004] For the treatment of otofungal diseases, systemic medications such as oral or injectable drugs reach the superficial lesions of the skin in much less quantity and time than topical treatments. Moreover, long-term systemic use of some antifungal drugs can place a significant burden on the liver and kidneys, and even lead to the risk of liver and kidney damage. Therefore, for these patients with special treatment needs, topical treatment is a better option.

[0005] In the past, clinicians commonly used antifungal creams, but due to the anatomical structure of the ear and the low fluidity of the cream, it was difficult for the drug to reach the hidden corners of the ear. Moreover, the cream could cause discomfort and hearing loss after being applied to the tympanic membrane. At the same time, the operation was more complicated for doctors. In contrast, water-based formulations have better fluidity, and the drug can reach the lesions in the ear more effectively, showing better treatment effect and ease of operation.

[0006] Patent document CN111012741A discloses a fluconazole ear drop solution and its preparation method. The fluconazole ear drop solution comprises the following components by mass percentage: 0.2-0.6% fluconazole, 0.1-1.0% hydroxypropyl methylcellulose, 2-10% propylene glycol, 0.003-0.01% benzalkonium bromide, 0.1-1% amino acids, and the remainder is water. The ear drop solution prepared by this invention has good bactericidal and anti-inflammatory effects; however, the preparation process is complex, and the low solubility of fluconazole affects further improvement of its efficacy. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a fluconazole ear drop solution and its preparation method. By improving the formulation of the fluconazole ear drop solution, this invention increases the solubility of fluconazole and enhances the therapeutic effect on fungal infections of the ear.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a fluconazole ear drop solution comprising, by mass percentage, the following components: fluconazole 0.6%-2.0%, propylene glycol and / or diethylene glycol monoethyl ether 8%-20%, glycerol or caprylic / capric acid polyethylene glycol glyceride 20%-32%, hydroxypropyl methylcellulose 0.1%-1%, anhydrous disodium hydrogen phosphate 0.05%-0.2%, anhydrous citric acid, and water as the balance.

[0010] The amount of anhydrous citric acid added in this invention is sufficient to adjust the pH of the fluconazole ear drops to 3-6.

[0011] In some embodiments, the fluconazole ear drops comprise, by weight percentage, the following components: fluconazole 1.0%-2.0%, propylene glycol and / or diethylene glycol monoethyl ether 8%-20%, glycerol or caprylic / capric glyceride polyethylene glycol glyceride 20%-32%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid, and water to balance.

[0012] In some embodiments, the mass ratio of propylene glycol to glycerol or polyethylene glycol glycerol octanoate / capric acid is 2-5:5-8.

[0013] In some embodiments, the fluconazole ear drops comprise, by weight percentage, the following components: fluconazole 1.0%-2.0%, propylene glycol 8%-20%, glycerol or caprylic / capric glyceride polyethylene glycol glyceride 20%-32%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid 0.05%-0.2%, and water as the balance.

[0014] In some embodiments, the fluconazole ear drops comprise, by weight percentage, the following components: fluconazole 1.5%-2.0%, propylene glycol 0-15%, diethylene glycol monoethyl ether 10%-15%, glycerin 20%-22%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid, and water to balance.

[0015] In some embodiments, the mass ratio of the diethylene glycol monoethyl ether to glycerol is 3:4.

[0016] In some embodiments, the mass ratio of the diethylene glycol monoethyl ether, propylene glycol, and glycerin is 10:15:22.

[0017] Secondly, the present invention provides a method for preparing the above-mentioned fluconazole ear drops, comprising the following steps:

[0018] (1) Dissolve the prescribed amount of hydroxypropyl methylcellulose in water, cool to room temperature, stir until the solution is clear, add the prescribed amount of anhydrous disodium hydrogen phosphate, stir to dissolve, and obtain solution A;

[0019] (2) Add the prescribed amount of fluconazole to propylene glycol and / or diethylene glycol monoethyl ether and stir to dissolve. Cool to room temperature to obtain solution B;

[0020] (3) Add solution B to solution A, stir evenly, add the prescribed amount of glycerol or caprylic / capric acid glycerol ester and stir evenly, adjust the pH to 3.0-6.0 with anhydrous citric acid solution, add water to the total volume, stir evenly, filter sterilize, and fill.

[0021] In some implementations, the temperature of the water in step (1) is 60-90°C; preferably 65-85°C.

[0022] In some embodiments, the temperature of the propylene glycol and / or diethylene glycol monoethyl ether in step (2) is 40-60°C, preferably 45-55°C.

[0023] The beneficial effects of this invention are as follows:

[0024] (1) This invention improves the formulation of fluconazole ear drops, thereby increasing the solubility of fluconazole and providing technical support for further improving the therapeutic effect of fluconazole ear drops on fungal infections of the ear.

[0025] (2) The fluconazole ear drops of the present invention contain 2% fluconazole and have good stability. Compared with the prior art, the local administration concentration of the invention is higher and the onset of action is faster. It can inhibit the reproduction of ear fungi more quickly and has a better therapeutic effect on ear fungal infections.

[0026] (3) Experiments have shown that, compared with fluconazole ear drops with a fluconazole content of less than 0.6%, fluconazole ear drops with a fluconazole content of 1%-2% have a therapeutic effect on ear fungal infections caused by Aspergillus, thus expanding the indications for fluconazole ear drops and achieving unexpected technical results.

[0027] (4) Compared with the prior art, the fluconazole ear drops preparation method of the present invention is simple, low in cost, and more suitable for industrial production.

[0028] (5) This invention improves the fluconazole ear drops, increasing the solubility of fluconazole and making the topical ear drops more effective in treating fungal infections of the external auditory canal. The fluconazole ear drops of this invention do not rely on systemic blood circulation for transport, resulting in better therapeutic effects and higher efficiency compared to systemic administration. Moreover, as a liquid formulation, it has better fluidity than other antifungal creams, allowing for more complete coverage within the ear canal, easier access to lesions and pathogens in corners, more complete treatment, less ear canal blockage, better patient compliance, and the ability to reach the middle ear to exert its effects, perfectly meeting the actual treatment needs of otofungal infections. Detailed Implementation

[0029] The following description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0030] Therefore, the present invention is not to be limited to the embodiments shown herein, but can be applied to a wider scope consistent with the principles and novel features disclosed herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0031] As used in this invention, the singular forms “a,” “an,” and “the (said)” include the plural forms unless the context clearly indicates otherwise.

[0032] All numerical values ​​or expressions relating to component amounts, process conditions, etc., used in this invention shall be understood to be modified by the word "about" in all cases. When referring to a quantity or range of values, the quantity or range is an approximation within experimental variability (or within statistical experimental error). In this invention, the term "about" shall have the meaning of being within 10%, preferably within 5%, of the specified value or range.

[0033] All ranges relating to the same component or property include endpoints that can be combined independently. Because these ranges are continuous, they encompass every numerical value between the minimum and maximum value. It should also be understood that any numerical range referenced in this invention is intended to include all subranges within that range.

[0034] The term "treatment" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of the disease described herein. In some implementations, treatment may be administered after the disease has appeared or one or more signs or symptoms have been observed. Treatment may also continue after symptoms have subsided, for example, to delay and / or prevent recurrence.

[0035] This invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in this invention are all commercially available products in this technical field, the water involved is water for injection, the percentages involved are all mass percentages, and the room temperature is 20-25℃.

[0036] Examples 1-7: Fluconazole Ear Drops

[0037] Fluconazole ear drops of the corresponding embodiments were prepared according to the prescription in Table 1 and the following preparation method.

[0038] The preparation method is as follows:

[0039] (1) Dissolve the prescribed amount of hydroxypropyl methylcellulose in water at 70°C, cool to room temperature, stir until the solution is clear, add the prescribed amount of anhydrous disodium hydrogen phosphate, stir to dissolve, and obtain solution A;

[0040] (2) Add the prescribed amount of fluconazole to propylene glycol and / or diethylene glycol monoethyl ether at 50°C and stir to dissolve. Cool to room temperature to obtain solution B.

[0041] (3) Add solution B to solution A, stir evenly, add the prescribed amount of glycerol or caprylic / capric acid PEG-glycerol ester and stir evenly, adjust the pH to 3.0-6.0 with anhydrous citric acid solution, add water to the total volume, stir evenly, filter through a 0.22μm microporous filter to remove bacteria, and fill through a plastic bottle blow-fill-seal machine.

[0042] Table 1. Prescription table for fluconazole ear drops in Examples 1-7

[0043]

[0044] Note: The appropriate amount is for adjusting the pH of the fluconazole ear drops to 3-6.

[0045] Comparative Examples 1-7: Fluconazole Ear Drops

[0046] Fluconazole ear drops of the corresponding proportions were prepared according to the prescription in Table 2 using the following preparation method.

[0047] The preparation method is the same as in Example 1.

[0048] Table 2. Prescription table for fluconazole ear drops (Comparative Examples 1-7)

[0049]

[0050] Note: The appropriate amount is for adjusting the pH of the fluconazole ear drops to 3-6.

[0051] Efficacy evaluation of fluconazole ear drops for fungal ear infections.

[0052] 1. Fluconazole ear drops (FCZR)

[0053] Fluconazole ear drops of different concentrations were prepared according to the prescription in Table 3 using the following preparation method.

[0054] Table 3. Prescriptions for Fluconazole Ear Drops at Different Concentrations

[0055]

[0056] Note: The appropriate amount is for adjusting the pH of the fluconazole ear drops to 3-6.

[0057] The preparation method is as follows:

[0058] (1) Dissolve the prescribed amount of hydroxypropyl methylcellulose in water at 70°C, cool to room temperature, stir until the solution is clear, add the prescribed amount of anhydrous disodium hydrogen phosphate, stir to dissolve, and obtain solution A;

[0059] (2) Add the prescribed amount of fluconazole to propylene glycol and / or diethylene glycol monoethyl ether at 50°C and stir to dissolve. Cool to room temperature to obtain solution B.

[0060] (3) Add solution B to solution A, stir evenly, add the prescribed amount of glycerol or caprylic / capric acid PEG-glycerol ester and stir evenly, adjust the pH to 3.0-6.0 with anhydrous citric acid solution, add water to the total volume, stir evenly, filter through a 0.22μm microporous filter to remove bacteria, and fill through a plastic bottle blow-fill-seal machine.

[0061] 2. Therapeutic effect on fungal ear infection in SD rats

[0062] In the model animals, a suspension of Candida albicans [CMCC(F)98001, batch number 980012a21-1, source: China National Institutes for Food and Drug Control] was injected into the ear canals of both ears to induce an ear canal fungal infection model. The normal control group and the cyclophosphamide control group (simulating immunocompromised individuals) were injected with blank culture medium accordingly. Drugs were administered according to Table 4. On days 5, 10, and 15 of drug administration, secretions from the right external auditory canal of each group were swabbed to detect fungal colonization.

[0063] Table 4 Animal Grouping and Dosing Table

[0064]

[0065] Note: 1. For groups 1-4, administer the corresponding concentration of fluconazole ear drops via ear drops; for the remaining groups, administer physiological saline via ear drops. 2. The interval between two doses of BID administration should be at least 6 hours. 3. M refers to male rats and F refers to female rats.

[0066] The results of fungal counts in ear canal secretions from rats with ear canal infections treated with fluconazole ear drops are shown in Table 5.

[0067] Table 5. Effects of fungal counts in ear canal secretions of rats with ear canal infection ( (n=10)

[0068]

[0069] Note: Compared with the normal control group ++ P ≤0.01; compared with the cyclophosphamide control group ## P ≤0.01; compared with the model control group * P ≤0.05, ** P ≤0.01.

[0070] The results showed that on days 5, 10, and 15 after administration, the fungal load in the ear canal secretions of rats in the model control group was significantly increased compared with the normal control group and the cyclophosphamide control group. P ≤0.01). On days 5, 10, and 15 of administration, compared with the model control group, the fungal load in ear canal secretions was significantly reduced in each dosage group (≤0.01). P ≤0.05 or P The concentration of fluconazole ear drops (≤0.01%) indicates that the fluconazole ear drops of the present invention have a good therapeutic effect on ear fungal infections caused by Candida. Furthermore, starting from day 10, it was observed that the higher the dosage, the lower the fungal load in the ear canal secretions, indicating that the higher the active ingredient in the fluconazole ear drops, the higher its local concentration, and the better its therapeutic effect on ear fungal infections.

[0071] 3. Therapeutic effect on fungal ear infections in Hartley guinea pigs

[0072] In the model animals, a suspension of Aspergillus niger [CMCC(F)98003, batch number 0A1004, source: China National Institutes for Food and Drug Control] was injected into the external auditory canals of both ears to induce a fungal infection model of the external auditory canal. The normal control group and the cyclophosphamide control group (simulating immunocompromised individuals) were injected with blank culture medium accordingly. Drugs were administered according to Table 6. On days 5, 10, and 15 of drug administration, secretions from the right external auditory canal of each group were swabbed to detect fungal colonization.

[0073] Table 6 Animal Grouping and Dosing Table

[0074]

[0075] Note: 1. For groups 1-4, administer the corresponding concentration of fluconazole ear drops via ear drops; for the remaining groups, administer physiological saline via ear drops. 2. The interval between two doses of BID administration should be at least 6 hours. 3. M refers to male rats and F refers to female rats.

[0076] Table 7 shows the results of fungal counts in the external auditory canal secretions of guinea pigs infected with fluconazole ear drops.

[0077] Table 7. Effects of external ear canal infection on fungal counts in guinea pig external ear canal secretions ( (n=10)

[0078]

[0079] Note: Compared with the normal control group ++ P ≤0.01; compared with the cyclophosphamide control group ## P ≤0.01; compared with the model control group ** P ≤0.01.

[0080] On days 5, 10, and 15 after administration, compared with the normal control group and the cyclophosphamide control group, the fungal load in the external auditory canal secretions of guinea pigs in the model control group was significantly increased. P ≤0.01). On days 5, 10, and 15 of administration, compared with the model control group, the fungal load in the external auditory canal secretions of dose groups 3 and 4 was significantly reduced ( ). P ≤ 0.01), the fungal load in the external auditory canal secretions of group 1 did not decrease significantly ( P >0.05). This indicates that high-dose fluconazole ear drops have a therapeutic effect on ear fungal infections caused by Aspergillus, while low-dose fluconazole ear drops have no therapeutic effect on ear fungal infections caused by Aspergillus.

[0081] The above description, in conjunction with specific embodiments, further illustrates the present invention. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of the present invention can be made without departing from the spirit and scope of the invention, and all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. A fluconazole ear drop, characterized by, The product comprises the following components by weight percentage: fluconazole 1.5%-2.0%, propylene glycol and / or diethylene glycol monoethyl ether 8%-20%, glycerol or caprylic / capric acid 20%-32%, hydroxypropyl methylcellulose 0.1%-1%, anhydrous disodium hydrogen phosphate 0.05%-0.2%, anhydrous citric acid and water balance; The mass ratio of propylene glycol to glycerol or caprylic / capric acid glycerol ester is 2-5:5-8.

2. The fluconazole ear drop according to claim 1, characterized by, The product comprises the following components by weight percentage: fluconazole 1.5%-2.0%, propylene glycol and / or diethylene glycol monoethyl ether 8%-20%, glycerol or caprylic / capric glyceride polyethylene glycol glyceride 20%-32%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid and water balance.

3. The fluconazole eardrop according to claim 1, wherein The product comprises the following components by mass percentage: fluconazole 1.5%-2.0%, propylene glycol 8%-20%, glycerol or caprylic / capric acid 20%-32%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid 0.05%-0.2%, and water as the balance.

4. The fluconazole eardrop according to claim 1, wherein The product comprises the following components by mass percentage: fluconazole 1.5%-2.0%, propylene glycol 0-15%, diethylene glycol monoethyl ether 10%-15%, glycerin 20%-22%, hydroxypropyl methylcellulose 0.5%-1%, anhydrous disodium hydrogen phosphate 0.1%-0.2%, anhydrous citric acid, and water to balance.

5. The fluconazole eardrop according to claim 1, wherein The mass ratio of diethylene glycol monoethyl ether to glycerol is 3:

4.

6. The fluconazole eardrop according to claim 1, wherein The mass ratio of diethylene glycol monoethyl ether, propylene glycol and glycerin is 10:15:

22.

7. A process for the preparation of fluconazole ear drops according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Dissolve the prescribed amount of hydroxypropyl methylcellulose in water, cool to room temperature, stir until the solution is clear, add the prescribed amount of anhydrous disodium hydrogen phosphate, stir to dissolve, and obtain solution A; (2) Add the prescribed amount of fluconazole to propylene glycol and / or diethylene glycol monoethyl ether and stir to dissolve. Cool to room temperature to obtain solution B; (3) Add solution B to solution A, stir evenly, add the prescribed amount of glycerol or caprylic / capric acid glycerol ester and stir evenly, adjust the pH to 3.0-6.0 with anhydrous citric acid solution, add water to the total volume, stir evenly, filter sterilize, and fill.

8. The preparation method according to claim 7, characterized in that, The temperature of the water in step (1) is 60-90℃.

9. The preparation method according to claim 7, characterized in that, The temperature of the propylene glycol and / or diethylene glycol monoethyl ether in step (2) is 40-60°C.

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