Enconazole self-emulsifying drug delivery system composition and preparation method thereof

Abstract

The invention discloses an enconazole self-emulsifying drug delivery system composition and a preparation method thereof, and belongs to the technical field of medicines. The enconazole self-emulsifying composition is prepared from enconazole, an oil phase and an emulsifying agent, the oil phase is sorbitan fatty acid esters; the emulsifying agent is polysorbate; the sum of the sorbitan fatty acid esters and the polysorbates is greater than or equal to 10% and less than 100%. After the self-emulsifying composition is dispersed in water, the particle size is not higher than 10 microns, and after the self-emulsifying composition is stored for 6 weeks at room temperature, the enconazole is not degraded and is uniformly dispersed in an emulsified solution, and the stability is good.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an enilconazole self-emulsifying drug delivery system composition and a preparation method thereof. Background Art

[0002] Enilconazole is an imidazole broad-spectrum antifungal drug with the following structural formula:

[0003]

[0004] Enilconazole can inhibit the activity of sterol 14α-demethylase and block the synthesis of ergosterol, an important component of fungal cell membrane, to inhibit fungal proliferation and promote fungal death. It has a broad spectrum of activity against dermatophytes and is particularly sensitive to pathogens such as Microsporum canis, Trichophyton mentagrophytes and Microsporum gypseum that cause superficial skin infections in animals. The drugs commonly used in veterinary clinics to prevent and treat canine fungal skin diseases mainly include acrylamide drugs (terbinafine hydrochloride, etc.) and imidazole antifungal drugs (ketoconazole, fluconazole, itraconazole, etc.). The dosage forms include sprays, oral solutions and topical ointments, such as terbinafine hydrochloride spray / tablets / liniment, compound ketoconazole ointment, compound fluconazole cream, itraconazole oral solution, etc. Canine fungal skin diseases are mostly systemic fungal infections. Some topical sprays and ointments have a good therapeutic effect on local skin lesions, but it is difficult to achieve a systemic therapeutic effect. Antifungal oral solutions and tablets can be taken orally to achieve systemic therapeutic effects, but long-term use will have obvious side effects such as liver and kidney toxicity. Enilconazole solution is used to prevent and treat canine fungal skin diseases by topical administration. It has high antibacterial activity against most common skin fungi as well as Aspergillus, Malassezia, and yeast. Enilconazole solution is hardly absorbed by the skin through topical administration, and has the advantages of low toxicity and low residue. It has broad prospects for use in the clinical treatment of pet fungal skin diseases.

[0005] However, pure enilconazole has problems in the medication process, such as uneven dispersion leading to slow efficacy and poor stability, which makes it difficult to store for a long time. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides an enilconazole self-emulsifying drug delivery system composition and a preparation method thereof, which greatly improves the dispersibility and stability of enilconazole by dissolving enilconazole in a mixed solvent consisting of an oil phase and an emulsifier in a specific ratio, so that the composition exerts a better drug effect.

[0007] According to a first aspect of the present invention, the present invention first provides an enilconazole self-emulsifying composition, comprising: enilconazole, an oil phase and an emulsifier;

[0008] The oil phase is sorbitan fatty acid esters; the emulsifier is polysorbate;

[0009] The sum of the sorbitan fatty acid esters and the polysorbates is greater than or equal to 10% and less than 100%.

[0010] Preferably, the sorbitan fatty acid ester is selected from one or a combination of sorbitan fatty acid ester 20, sorbitan fatty acid ester 40, sorbitan fatty acid ester 60, sorbitan fatty acid ester 80, and sorbitan fatty acid ester 85, preferably sorbitan fatty acid ester 20 and sorbitan fatty acid ester 80; the polysorbate is selected from one or a combination of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0011] Preferably, the sum of the sorbitan fatty acid esters and the polysorbates is greater than or equal to 80% and less than 95%.

[0012] Preferably, in the composition, by mass fraction, the enilconazole content is 5% to 20%, the oil phase content is 40% to 60%, and the emulsifier content is 40% to 60%; more preferably, the enilconazole content is 5% to 15%.

[0013] Preferably, in the composition, by mass fraction, one of the sorbitan fatty acid esters or a combination thereof is 5% to 80%; in the composition, by mass fraction, one of the polysorbates or a combination thereof is 5% to 80%.

[0014] According to another aspect of the present invention, the present invention also provides a method for preparing the self-emulsifying composition, comprising:

[0015] The emulsifier and the oil phase in the above proportion are weighed into a stainless steel stirring tank, the temperature is controlled at 30-70° C. and stirred for 1-3 hours to mix evenly, and then the enilconazole in the above proportion is added, the temperature is controlled at 30-70° C. and stirred for 1-3 hours until the drug solution is clear and transparent, and the enilconazole is completely dissolved, filtered and filled to obtain the enilconazole composition of the emulsified drug delivery system.

[0016] The present invention also provides a use of the self-emulsifying composition for preparing an external preparation.

[0017] The present invention also provides a use of the self-emulsifying composition for preparing a drug for preventing and treating canine dermatophyte diseases by topical administration.

[0018] The present invention has the following beneficial effects:

[0019] 1. The particle size of the self-emulsifying composition of the present invention after being dispersed in pure water is not higher than 10 μm. After being stored at room temperature for 6 weeks, enilconazole is not degraded and remains uniformly dispersed in the emulsified solution, and the emulsification stability is good;

[0020] 2. The self-emulsifying composition of the present invention is hardly penetrated by the skin after being diluted and emulsified through topical administration, and the particle size and content in the emulsion can be kept stable for a long time, which is conducive to better exerting the efficacy of the drug.

[0021] 3. The self-emulsifying composition of the present invention has good stability at relatively high temperatures and good storage stability.

[0022] 4. Compared with other nano-preparations (particle size less than 10 μm), the self-emulsifying composition of the present invention has a simple preparation process, low equipment requirements, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a particle size detection diagram of the enilconazole solution product after dilution provided in Example 4 of the present invention.

[0024] Figure 2 This is a particle size detection diagram of the enilconazole solution product after dilution provided in Example 5 of the present invention.

[0025] Figure 3 This is a particle size detection diagram of the enilconazole solution product after dilution provided in Example 6 of the present invention.

[0026] Figure 4 It is the chromatogram of related substances of the enilconazole solution product of Example 4 of the present invention on Day 0.

[0027] Figure 5 It is a chromatogram of related substances of the product of enilconazole solution in Example 4 of the present invention after accelerated testing for 180 days. DETAILED DESCRIPTION

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, the materials and reagents used in the following examples are all common commercial products and can be purchased on the market.

[0030] The present invention will be further described below by way of examples, which are not intended to further limit the present invention. It should be understood by those skilled in the art that equivalent replacements or corresponding improvements made to the present invention still fall within the scope of protection of the present invention.

[0031] Example 1

[0032] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 20 and polysorbate 20 into a glass three-necked bottle, heat to 30°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 30°C for 3 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0033] Example 2

[0034] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio of the formula in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 40 and polysorbate 40 into a glass three-necked bottle, heat to 40°C and stir for 2 hours. Mix evenly. Add enilconazole and continue stirring at 40°C for 2 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0035] Example 3

[0036] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 60 and polysorbate 60 into a glass three-necked bottle, heat to 50°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 50°C for 2 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0037] Example 4

[0038] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 80 and polysorbate 80 into a glass three-necked bottle, heat to 60°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 60°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0039] Example 5

[0040] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 85 and polysorbate 60 into a glass three-necked bottle, heat to 60°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 60°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0041] Example 6

[0042] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 80 and polysorbate 40 into a glass three-necked bottle, heat to 70°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 70°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0043] Example 7

[0044] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 60 and polysorbate 20 into a glass three-necked bottle, heat to 60°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 60°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0045] Example 8

[0046] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 40 and polysorbate 40 into a glass three-necked bottle, heat to 50°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 50°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0047] Example 9

[0048] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 20 and polysorbate 60 into a glass three-necked bottle, heat to 40°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 40°C for 2 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0049] Example 10

[0050] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 40 and polysorbate 80 into a glass three-necked bottle, heat to 30°C and stir for 2 hours. Mix evenly. Add enilconazole and continue stirring at 30°C for 3 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0051] Embodiment 11

[0052] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 60 and polysorbate 60 into a glass three-necked bottle, heat to 40°C and stir for 2 hours. Mix evenly. Add enilconazole and continue stirring at 40°C for 2 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0053] Example 12

[0054] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 80 and polysorbate 40 into a glass three-necked bottle, heat to 50°C and stir for 2 hours. Mix well. Add enilconazole and continue stirring at 50°C for 1.5 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0055] Embodiment 13

[0056] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 85 and polysorbate 20 into a glass three-necked bottle, heat to 60°C and stir for 2 hours. Mix well. Add enilconazole and continue stirring at 60°C for 2 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0057] Embodiment 14

[0058] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 20 and polysorbate 60 into a glass three-necked bottle, heat to 70°C and stir for 1 hour. Mix well. Add enilconazole and continue stirring at 70°C for 1 hour to dissolve all the enilconazole. Filter and fill to obtain the product.

[0059] Embodiment 15

[0060] Measure the raw and auxiliary materials by mass fraction according to the dosage ratio in Table 1 below. The batch size is 5 kg. Add sorbitan fatty acid ester 40 and polysorbate 40 into a glass three-necked bottle, heat to 60°C and stir for 1.5 hours. Mix well. Add enilconazole and continue stirring at 60°C for 1.5 hours to dissolve all the enilconazole. Filter and fill to obtain the product.

[0061] Table 1: Ratio of raw material usage in Examples 1 to 15

[0062]

[0063] Test Example 1: Particle Size Determination

[0064] Using the weighing method, the composition prepared in the above embodiment was weighed, diluted to 50 times with purified water, and placed at room temperature for 0 days, 2 weeks, 4 weeks and 6 weeks, respectively. The particle size was detected and the data was analyzed using a Malvern particle size distribution analyzer. The results are shown in Table 2.

[0065] Table 2: Particle size stability of samples of Examples 1 to 15 after dilution

[0066]

[0067] In Examples 1 to 15, the emulsions formed by dilution with water contain sorbitan fatty acid esters as the oil phase, and the particle size D90 of the emulsions is not higher than 10 μm. In Examples 1, 2, 3, 4, 5, 6, 7, 11, 12, 13, 14 and 15, D90 is in the range of 2 μm-4 μm. After being placed for 6 weeks, there is no obvious change in the particle size, and the quality is stable.

[0068] Test Example 2: Stability test of the formula under high temperature (40°C) conditions

[0069] The stability of formulations 4, 5 and 6 was investigated for 6 months. The formulations were divided into vials and sealed. They were placed under accelerated test conditions of 40°C ± 2°C. Samples were taken at 0, 30, 60, 90 and 180 days. The properties were visually inspected, and the enilconazole content and related substances were detected by high performance liquid chromatography. The particle size of the emulsion after sample dilution was detected using a Malvern particle size distribution analyzer. The results are shown in Table 3.

[0070] Table 3: Stability study of samples under accelerated test conditions at 40℃±2℃

[0071]

[0072] The self-emulsifying composition prepared using sorbitan fatty acid esters and nonionic surfactant polysorbates was stored at high temperature (40°C) for 6 months. The properties, enilconazole content and related substances, and the particle size test results after emulsification showed no downward trend, indicating good stability. Test Example 3: In vitro release of enilconazole in the solution after self-emulsification of the formula sample

[0073] In the in vitro release experiment, the Franz diffusion test apparatus and HPLC method were used to determine the concentration of enilconazole in the receiving medium, calculate the cumulative release amount, and draw the release curve. The instrument used was TK-24BL transdermal diffusion tester (instrument manufacturer: Kaikai Technology).

[0074] Table 4: Test results of average cumulative release amount (%) of receiving medium

[0075]

[0076] The experimental results showed that when 2 mL of a 2 mg / mL self-prepared enilconazole solution was loaded, the concentration of enilconazole detected in the receiving medium (pH 6.8 phosphate buffer) showed a significant increasing trend during the 0-1 h period. After 2 h, the concentration of enilconazole in the receiving medium remained basically balanced and no longer increased significantly, entering a plateau period. The concentration of the drug solution was stable, which can provide effective and safe data for clinical use.

[0077] Test Case 4: Clinical Trial

[0078] This experiment was a multi-site, drug-controlled, randomized, blinded field experiment on the efficacy of enilconazole solution on canine dermatophytosis. According to the "Technical Guidelines for Field Experiments on the Efficacy Evaluation of Topical Antimicrobial Drugs for Pets", 120 test dogs were randomly divided into two groups, with 60 dogs in each group.

[0079] Table 5: Experimental animal grouping and dosing schedule

[0080]

[0081] Investigation indicators: On SD0 (before administration), SD8 (during administration) and SD16 (after administration), the selected animals were clinically examined, including general health examination and clinical symptom scores of the affected part, and body temperature, respiration, heart rate, visible mucosal color, drinking water, feeding, feces, urine and skin infection were observed. SD22 was the return visit day. Peripheral blood samples of the experimental dogs were collected before feeding in the morning of SD0 and SD16 for routine blood tests and blood biochemistry tests; samples of the affected part were collected on SD0 and SD16 for pathogen count and calculation of the negative conversion rate of Microsporum canis.

[0082] The indicator bacteria used in this experiment was Microsporum canis

[0083] Confirmation of Microsporum canis: Hold the dog in the cage, collect the dandruff or hair roots at the edge of the affected part with a sterile surgical blade or hemostatic forceps, and inoculate it on Sabouraud dextrose agar (SDA) aseptically. Culture it for 5 days under aerobic conditions, 95% humidity, and a constant temperature of 28°C. Then, preliminarily exclude the foreign bacteria based on the colony morphology (Microsporum canis grows as white fluff on SDA, and the back is stained yellow). The colony suspected of Microsporum canis is transferred to rice culture medium (RGM), cultured under the same conditions for 3 days, and the morphology of the macrosporum is observed by staining. If spindle-shaped, thick-walled, thorny macrosporum with more than 6 septa appears, it is identified as Microsporum canis.

[0084] Counting of Microsporum canis: The amount of fungal sampling at the lesion by cotton swab brushing and hemostatic forceps hair plucking is difficult to control, so this experiment uses lesion scraping. The dogs were kept in Baoding, the affected part was exposed, and a blunt sterile surgical blade or the back edge of the blade was used to scrape continuously along the hair flow direction at the junction of the skin disease and health until slight bleeding occurred. The scrapings were evenly spread on the slide, with the diameter of the coating surface being about 1.0 cm; after drying, they were stained with Wright-Giemsa stain. The sum of the number of microspores of Microsporum canis in the field of view of 5 different directions (upper left, upper right, middle, lower left, and lower right) was counted under a microscope at 10x100 times (oil objective) to determine the change in the number of Microsporum canis in the lesion before and after medication, and the negative conversion rate of Microsporum canis was calculated. The specific calculation method is as follows.

[0085]

[0086] Effectiveness Evaluation Criteria

[0087] 1. Single efficacy

[0088] (1) Cure: After medication, the isolation rate of pathogenic bacteria on the skin turns negative ≥ 80%, inflammatory secretions disappear significantly, the affected area has no odor, rashes, dandruff, pustules, etc. disappear significantly, and cancer itching symptoms disappear significantly;

[0089] (2) Effective: After medication, the isolation rate of pathogenic bacteria on the skin turns negative by ≥60%, inflammatory secretions decrease, the affected area has almost no odor, rashes, dandruff, pustules, etc. decrease, and severe itching symptoms are alleviated;

[0090] (3) Ineffectiveness: After medication, the isolation rate of pathogenic bacteria on the skin is less than 60%, inflammatory secretions still exist, the affected area still has an odor, the rash, dandruff, pustules, etc. have not decreased, and the affected area still has obvious cancer itching symptoms.

[0091] Table 6: Criteria for judging the validity of a single case specific clinical symptom score (SCS)

[0092] Note: “-” means no meaning.

[0093] Note: SCS clinical symptom scoring criteria:

[0094] 1. A small amount of dandruff and hair loss

[0095] 2. Excessive dandruff, sparse hair and broken hair

[0096] 3. Excessive dandruff, sparse and broken hair, local redness and swelling, etc.

[0097] 4. Excessive dandruff, sparse and broken hair, multiple redness, swelling, and exudation

[0098] 5. Excessive dandruff, sparse and broken hair, multiple or large areas of redness, swelling, exudation, ulceration, and scabs. 2. Judgment of the therapeutic effect of the whole group of cases

[0099] Significant effect: significant efficiency ≧80%;

[0100] Effective: 80%> apparent efficiency ≧ 60%;

[0101] Ineffective: significant efficiency <60%.

[0102] Safety evaluation standards

[0103] The test drug and control drug in this experiment are both enilconazole solution. No obvious adverse reactions and side effects have been found. Various indicators of experimental animals will be monitored during the experiment. Whether transient, controllable or uncontrollable adverse reactions, they should be included in the clinical examination.

[0104] Return visit plan

[0105] A clinical examination or communication (telephone, WeChat, etc.) follow-up was conducted one week after administration. The clinical examination of the follow-up mainly observed the state of the lesions, changes in the color of the visible mucosa, mental state and allergic reactions, and asked about diet and bowel movements. The communication follow-up mainly included the recovery of the affected area, diet, bowel movements, and whether there was any tingling, rash, itching, etc.

[0106] Processing of follow-up results: ① Cases with recurrence of lesions and severe itching were recorded as “ineffective”; ② Cases with no recurrence of lesions and no worsening of symptoms compared with after medication, and occasional itching were recorded as “effective”; ③ No abnormalities were recorded as “markedly effective”; ④ Mental state, visible mucosa, defecation, vomiting and other symptoms were used as “sick animal safety” indicators and included in adverse reactions.

[0107] Statistical analysis plan

[0108] SPSS 26.0 was used for statistical analysis in this experiment. The measurement data with normal distribution and homogeneity of variance were expressed as mean ± standard deviation. Descriptive form. Comparison between two groups of data - paired sample t-test for within-group analysis and independent sample t-test for between-group analysis; comparison between more than two groups of data - one-way ANOVA supplemented by LSD post hoc multiple comparison for pairwise analysis. Measurement data that do not conform to normal distribution or homogeneity of variance are described in proportion form, with Wilcoxon rank sum test for within-group analysis and Mann-Whitney U rank sum test for between-group analysis.

[0109] The significance of the difference is reflected by the p-value. p < 0.01 indicates extremely significant difference, 0.01 < p < 0.05 indicates significant difference, and p > 0.05 indicates no significant difference.

[0110] Test Results and Analysis

[0111] 1. It was evaluated that the test drug and the control drug had no significant effect on the heart rate, respiratory rate, body temperature, mental state, appetite, defecation and urination conditions, color of visible mucous membranes, and various index data of blood routine and blood biochemistry of the test dogs.

[0112] 2. Specific Clinical Symptoms

[0113] The distribution of the specific clinical symptom score SCS of the test drug group and the control drug group on different experimental days is shown in Table 6. On experimental day SD0, the proportions of SCS scores of 1 and 2 in both groups were relatively high (70.00% in the test drug group and 68.33% in the control drug group), and the proportions of SCS scores of 3, 4, and 5 were relatively low (30.00% in the test drug group and 31.67% in the control drug group), indicating that most of the test dogs with fungal skin diseases had mild symptoms.

[0114] Non-parametric test was performed on the specific clinical symptom scores SCS of the two groups. The results of between-group analysis showed that there was no significant difference in the SCS scores of the two groups on SD0, SD8, SD16, and SD22 (p > 0.05); while the results of within-group analysis showed that there was an extremely significant difference in the SCS scores of the two groups before and after the experiment (p < 0.01). The median SCS scores of the test drug group and the control drug group decreased from 2 (SD0) to 0 (SDn). The above results indicate that econazole solution can significantly improve the specific clinical symptoms of the affected parts of the test dogs and there is no rebound phenomenon on the follow-up visit day.

[0115] Table 7: Statistical Analysis of SCS in the Test Drug Group and the Control Drug Group

[0116]

[0117]

[0118] Note: "**" is marked when p < 0.01, indicating extremely significant difference; "*" is marked when 0.01 < p < 0.05, indicating significant difference; no mark is used when p > 0.05, indicating no significant difference; p1 is the result of comparison between the test drug group and the control drug group on the same experimental day, p2 is the result of comparison between SD0 and SD 16 comparison result, p3 is the result of comparison between SD0 and SD 22 comparison result, "-" indicates meaningless.

[0119] 3. Analysis of the negative conversion rate of Microsporum canis

[0120] Non-parametric test analysis was performed on the negative conversion rate of Microsporum canis in the test drug group and the control drug group. As shown in Table 8, the average negative conversion rates of Microsporum canis in the test drug group and the control drug group were both greater than 80%, and there was no significant difference between the two groups of data (p > 0.05).

[0121] The results showed that the test drug and the control drug had comparable and strong effects on clearing Microsporum canis at the lesions of fungal dermatosis in the test dogs.

[0122] Table 8: Statistical analysis of the negative conversion rate of Microsporum canis in the test drug group and the control drug group ( %)

[0123] project Test drug group Control drug group P Microsporum canis negative conversion rate 86.51±6.85 87.79±7.65 0.174

[0124] Note: p < 0.01 indicates extremely significant difference "**", 0.01 < p < 0.05 indicates significant difference "*", p > 0.05 indicates no significant difference without mark; p is the result of comparison between the test drug group and the control drug group.

[0125] 4. Efficacy evaluation

[0126] (1) Efficacy evaluation of individual cases

[0127] The SCS scores and the negative conversion rates of Microsporum canis of each test dog in the test drug group and the control drug group were statistically analyzed. According to the efficacy evaluation criteria for individual cases (see Table 9), the following data were obtained. In the test drug group, a total of 52 cases were evaluated as cured, accounting for 86.67%, a total of 8 cases were evaluated as effective, accounting for 13.33%, and the number of ineffective cases was 0; in the control drug group, a total of 54 cases were evaluated as cured, accounting for 90.00%, a total of 6 cases were evaluated as effective, accounting for 10.00%, and the number of ineffective cases was 0.

[0128] Table 9: Statistical analysis of efficacy evaluation of individual cases

[0129]

[0130]

[0131] (2) Efficacy evaluation of the population

[0132] According to the group effectiveness evaluation criteria, the therapeutic effects of the two groups of test dogs were judged (see Table 10). The cure rate in the test drug group was 86.67%, which was greater than 80.00%, and was evaluated as markedly effective; the cure rate in the control drug group was 90.00%, which was greater than 80.00%, and was evaluated as markedly effective.

[0133] The results showed that enilconazole solution had a significant therapeutic effect on Microsporum canis infection.

[0134] Table 10: Statistical results of group effectiveness evaluation

[0135]

[0136] 5. Safety evaluation

[0137] During the experiment, the physiological and mental states of the test dogs after medication were observed, and various indicators were monitored. No transient, controllable or uncontrollable adverse reactions occurred.

[0138] 6. Adverse events

[0139] During the experiment, no adverse events were observed in all the test dogs after medication.

Claims

1. An enilconazole self-emulsifying composition, characterized in that: include: Enilconazole, oil phase and emulsifier; The oil phase is sorbitan fatty acid esters; the emulsifier is polysorbate; The sum of the sorbitan fatty acid esters and the polysorbates is greater than or equal to 10% and less than 100%.

2. The enilconazole self-emulsifying composition according to claim 1, characterized in that: The sorbitan fatty acid esters are selected from one or a combination of sorbitan fatty acid ester 20, sorbitan fatty acid ester 40, sorbitan fatty acid ester 60, sorbitan fatty acid ester 80, and sorbitan fatty acid ester 85, preferably sorbitan fatty acid ester 20 and sorbitan fatty acid ester 80; the polysorbates are selected from one or a combination of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

3. An enilconazole self-emulsifying composition according to claim 1 or 2, characterized in that: The sum of the sorbitan fatty acid esters and the polysorbates is greater than or equal to 80% and less than 95%.

4. The enilconazole self-emulsifying composition according to claim 1, characterized in that: In the composition, by mass fraction, the content of enilconazole is 5% to 20%, the content of the oil phase is 40% to 60%, and the content of the emulsifier is 40% to 60%. More preferably, the content of enilconazole is 5% to 15%.

5. An enilconazole self-emulsifying composition according to any one of claims 1 to 3, characterized in that: In the composition, one or a combination of the sorbitan fatty acid esters accounts for 5% to 80% by mass; in the composition, one or a combination of the polysorbates accounts for 5% to 80% by mass.

6. A method for preparing the self-emulsifying composition according to any one of claims 1 to 5, characterized in that: include: The emulsifier and the oil phase in the above proportion are weighed into a stainless steel stirring tank, the temperature is controlled at 30-70° C. and stirred for 1-3 hours to mix evenly, and then the enilconazole in the above proportion is added, the temperature is controlled at 30-70° C. and stirred for 1-3 hours until the drug solution is clear and transparent, and the enilconazole is completely dissolved, filtered and filled to obtain the enilconazole composition of the emulsified drug delivery system.

7. Use of the self-emulsifying composition according to any one of claims 1 to 5 for preparing an external preparation.

8. Use of the self-emulsifying composition according to any one of claims 1 to 5 for preparing a drug for preventing and treating dermatophyte diseases in dogs by topical administration.

Images