Itraconazole transdermal cream and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to itraconazole transdermal cream and a preparation method thereof. According to the itraconazole transdermal cream provided by the invention, the itraconazole and the clove essential oil are jointly applied by adopting an emulsification method, the limitation of single use of the itraconazole and the clove essential oil is broken through, the bioavailability of the itraconazole and the clove essential oil is improved, and the itraconazole transdermal cream acts on an infected part after being subjected to transdermal absorption through local administration, so that the itraconazole is absorbed into blood and reaches the skin of the whole body to play a role; the traditional Chinese medicine composition can achieve the same blood concentration and effect of oral administration, is convenient to use, reduces liver toxicity and gastrointestinal tract adverse reactions, and reduces the risk of adverse reactions and drug interaction at the same time.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to itraconazole transdermal cream and its preparation method. Background Technology

[0002] Fungal skin diseases are characterized by their long course, difficulty in cure, high recurrence rate, and relatively challenging treatment. They are highly contagious between humans and animals, making them a zoonotic disease. Therefore, developing novel, highly effective, and safe antifungal drugs is crucial for controlling and preventing fungal skin diseases. Itraconazole is a broad-spectrum antifungal drug that inhibits fungal growth by interfering with ergosterol synthesis in the fungal cell membrane. However, it has low water solubility, poor stability, and oral administration may cause liver damage. Essential oils, as oily mixtures, can dissolve ittraconazole and, due to their excellent antibacterial effects, show great potential in in vitro antibacterial applications. However, the stability and poor water solubility of essential oils limit their application in topical treatment. Therefore, improving the application limitations of both drugs and enhancing their bioavailability is an urgent problem to be solved. Summary of the Invention

[0003] Based on the above technical problems, the purpose of this invention is to provide itraconazole transdermal cream and its preparation method.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides an itraconazole transdermal cream, characterized in that the itraconazole transdermal cream is composed of the following components in parts by weight: 1-3 parts itraconazole, 2-4 parts essential oil, 2-13 parts oil phase, 15-73 parts polar phase, 7-8 parts emulsifier, 1-3 parts skin feel modifier, 1-2 parts antioxidant, 3-5 parts transdermal penetration enhancer, and 0.1-0.5 parts preservative. The essential oil is selected from one or more of the following: thyme essential oil, thyme essential oil, sage essential oil, celery essential oil, clove essential oil, oregano essential oil, peppermint essential oil, bay leaf essential oil, clove basil essential oil, tea tree essential oil, and green tea essential oil.

[0005] The itraconazole transdermal cream provided by this invention uses itraconazole and clove essential oil as core raw materials. It adopts an emulsification method to combine itraconazole and essential oil, which breaks through the limitations of using itraconazole and essential oil alone and improves their bioavailability. It acts directly on the infected site through local administration, which can effectively inhibit or kill pathogenic fungi, while reducing the risk of adverse reactions and drug interactions.

[0006] Furthermore, the oil phase is selected from one or more of cetyl alcohol, ozone oil, oleyl alcohol, and polydimethylsiloxane.

[0007] Furthermore, the polar phase is selected from one or more of polyethylene glycol 400, polyethylene glycol 3000, polyethylene glycol 3350, and diethylene glycol ethyl ether.

[0008] Furthermore, the emulsifier is selected from one or more of the following: triglycerides, PEG-50 caprylate-capric acid-capric acid, glyceryl caprylate, glyceryl capric acid, glyceryl succinate, glyceryl monostearate, cetearyl alcohol-50, cetearyl alcohol-70, polyvinylpyrrolidone, Tween 20, Tween 80, and Span 80.

[0009] Furthermore, the skin feel modifier is selected from one or more of tapioca starch, polymethylsilsesquioxane, and talc.

[0010] Furthermore, the antioxidant is selected from one or more of 2,6-di-tert-butyl-p-cresol, 4-hydroxy-3-tert-butyl-anisole, butylated hydroxyanisole, vitamin E, benzoic acid, and benzalkonium bromide.

[0011] Furthermore, the transdermal penetration enhancer is selected from one or more of azone, lauryl azone, anhydrous ethanol, and propylene glycol.

[0012] Furthermore, the preservative is selected from one or more of sodium benzoate, benzyl alcohol, potassium sorbate, p-hydroxybenzoate, benzalkonium bromide, chlorhexidine gluconate, and chlorhexidine acetate.

[0013] The present invention also provides a method for preparing itraconazole transdermal cream, characterized in that the preparation method includes the following steps: S1. Mix the oil phase and emulsifier to obtain a mixed oil; S2. Mix itraconazole and essential oil and heat to dissolve itraconazole, obtaining a mixed drug. S3. Mix and emulsify the mixed oil and polar phase to obtain an emulsion. Mix the emulsion with the mixed drug, skin feel modifier, antioxidant, transdermal penetration enhancer and preservative. After shearing and homogenizing the emulsion, cool and solidify to obtain the itraconazole transdermal cream.

[0014] The present invention has the following beneficial effects: This invention provides an itraconazole transdermal cream prepared by emulsification, overcoming the limitations of itraconazole's low solubility, poor stability, and liver damage caused by oral administration. By combining itraconazole with essential oils, the antifungal effect is enhanced, while reducing the dosage and side effects of single drugs. This develops a more convenient and easy-to-use topical itraconazole drug delivery system, improving drug stability and bioavailability, and providing a new option for the treatment of clinical fungal skin diseases. Attached Figure Description

[0015] Figure 1Figures show the in vitro antibacterial results of ITZ and EU solutions against Microsporum canis and Candida albicans. In Figure A, ITZ solution shows the in vitro antibacterial results of ITZ solution against Microsporum canis and Candida albicans, and EU solution shows the in vitro antibacterial results of EU solution against Microsporum canis and Candida albicans.

[0016] Figure 2 For ITZ and EU solutions M.canis and C. albicans The combined drug susceptibility test results are shown in the figure. In this figure, A represents the effects of ITZ and EU solutions on... M.canis The combined drug susceptibility test results are shown in the figure. B represents the effects of ITZ and EU solutions on each other. C. albicans The combined drug susceptibility test results are shown in the figure.

[0017] Figure 3 The appearance of ITZ-EU cream.

[0018] Figure 4 Figure showing the in vitro antibacterial results of the cream. Figure 5 To observe the effects of the cream on the skin using scanning electron microscopy M.canis and C. albicans Influence diagram of appearance Figure 6 For creams and M.canis and C. albicans The graph shows the results of quantitative protein leakage and ATP level detection during co-incubation, where A represents the cream and... M.canis The graph shows the quantitative results of protein leakage during co-incubation, with B representing the mixture of cream and... C. albicans The graph shows the quantitative results of protein leakage during co-incubation, where C represents the mixture of cream and... M.canis The graph shows the ATP level detection results of co-incubation, where D represents the cream and... C. albicans ATP level detection results during co-incubation (image) Figure 7 The results are from the skin irritation test of the ITZ-EU cream.

[0019] Figure 8 H&E pathological sections of mouse organs used in in vivo safety testing.

[0020] Figure 9 Figures show the results of quantitative fungal analysis on day 3 and day 7 of skin tissue homogenate plating in a mouse model of fungal infection treated with cream. In the figures, A shows the effect of the skin tissue homogenate plating, B shows the results of quantitative fungal analysis on day 3 of the skin homogenate treatment in the mouse model of fungal infection, and C shows the results of quantitative fungal analysis on day 7 of the skin homogenate treatment in the mouse model of fungal infection.

[0021] Figure 10 This is a H&E pathological section of skin tissue from a mouse fungal infection model.

[0022] Figure 11These are Masson pathological sections and quantitative analysis diagrams of collagen fiber content in skin tissue from a mouse fungal infection model. In the diagram, A is a Masson pathological section and B is a quantitative analysis diagram of collagen fiber content.

[0023] Figure 12 PAS pathological sections of skin tissue from a mouse fungal infection model.

[0024] Figure 13 The images show immunohistochemical staining and quantitative analysis of TNF-α and IL-6 in skin tissue from a mouse fungal infection model. In the images, A is the immunohistochemical staining image of TNF-α, B is the quantitative analysis image of TNF-α, C is the immunohistochemical staining image of IL-6, and D is the quantitative analysis image of IL-6.

[0025] Figure 14 This is a graph showing the change in the area of ​​fungal infection in mice treated with a cream.

[0026] Figure 15 This figure shows the results of quantitative analysis of the infection area in a mouse model of fungal infection treated with cream.

[0027] Figure 16 The graph shows the results of ITZ blood drug concentration detection in mice treated with ITZ-EU cream on days 0, 3, and 7. Detailed Implementation

[0028] The present invention will now be described in detail with reference to specific embodiments, but these should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments can be obtained commercially unless otherwise specified.

[0029] Example 1 I. In vitro antifungal activity detection of itraconazole (ITZ) and clove oil (EU) solutions.

[0030] 1. Experimental materials: Microsporum canis ( Microsporum canis E.Bodin ex Guég , M.canis Purchased from Beina Chuanglian Biotechnology Co., Ltd. (BNCC259680). Staphylococcus aureus (ATCC25923), Escherichia coli (ATCC25922), and Candida albicans (BNCC259680) were present. Candida albicans CPRobin Berkhout , C. albicans The following materials were purchased from the China Industrial Microbial Culture Collection Center (CICC1965): SPF-grade SD rats, 6 weeks old, 150.0±12.5g, were purchased from SPF Beijing Biotechnology Co., Ltd. This experiment has been reviewed and approved by the Ethics Committee of Beijing Agricultural College. Clove essential oil (eugenol content greater than 85%) was purchased from Ji'an Zhongxiang Natural Plant Co., Ltd.

[0031] 2. Reagent Preparation: Weigh 0.05 g of ITZ and dissolve it in 50 g of 5% (v / v) methanol solution. Weigh 0.05 g of EU and dissolve it in 50 g of 2% (v / v) Tween-20 solution to prepare 1 mg / g ITZ stock solution and 1 mg / g EU stock solution. In a clean bench, filter the ITZ and EU stock solutions through a 0.22 µm filter membrane for sterilization, and then perform serial dilutions with sterile liquid culture medium to obtain test sample solutions with concentrations of 500.00 μg / g, 250.00 μg / g, 125.00 μg / g, 62.50 μg / g, 31.25 μg / g, 15.63 μg / g, 7.81 μg / g, 3.91 μg / g, 1.96 μg / g, and 0.98 μg / g.

[0032] 3. Determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ITZ and EU solutions: 100 µL of the prepared sample solutions of different concentrations were added sequentially to the first 10 wells of a 96-well plate, followed by the addition of the same volume of the bacterial suspension (5 × 10⁻⁶). 5 The last two wells were filled with 200 µL of bacterial suspension (containing 100 µL of liquid culture medium and 100 µL of the test bacterial solution) and 200 µL of sterile liquid culture medium, respectively, as positive and negative controls. The 96-well plate was incubated at 28 °C for 72 h before observation. The last clear well was the MIC. 10 µL of liquid from each clear well was dropped onto sterile solid culture medium. The lowest drug concentration at which no fungal growth was observed was the MBC. Each experiment was repeated three times.

[0033] 4. Combined susceptibility testing of ITZ and EU solutions: The micro-checkerboard dilution method was used to determine the susceptibility of combined ITZ and EU applications. M.canis , C. albicans The antifungal effect was assessed. Five levels (4MIC, 2MIC, MIC, 1 / 2MIC, and 1 / 4MIC) determined in the ITZ and EU were selected for testing, and each test was independently repeated three times.

[0034] The primary indicator for assessing the interaction between two drugs when used in combination is the partial inhibitory concentration (FIC) index, which is used to evaluate the effectiveness of combined use and the interaction mechanism between the drugs.

[0035] FIC index = (MIC drugA combined / MIC A) + (MIC drugB combined / MIC B) Where: "MIC A" is the MIC (μg / g) under the sole use of ITZ; "MIC drugA combined" is the MIC (μg / g) after the combined use of ITZ; MIC B is the MIC (μg / g) under the sole use of EU; "MIC drugB combined" is the MIC (μg / g) after the combined use of EU.

[0036] According to the value of the FIC index, the interaction mode between drugs is determined: when the FIC index ≤ 0.5, it indicates a synergistic effect; if 0.5 < FIC index ≤ 1, it shows an additive effect; when 1 < FIC index ≤ 2, it is regarded as an indifferent effect; and when the FIC index > 2, it indicates an antagonistic effect.

[0037] 5. Experimental results: The MIC and MBC results of ITZ and EU solutions against M.canis and C. albicans show that ITZ and EU solutions have inhibitory effects on both pathogenic bacteria of two fungal skin diseases, and the inhibitory effect increases with the increase of concentration, showing a dose-dependent relationship. The antibacterial effect of ITZ solution against Figure 1 is the best, with MIC being 15.63 μg / g and MBC being 31.25 μg / g; the inhibitory effect on M.canis is relatively weaker, with MIC being 31.25 μg / g and MBC being 62.50 μg / g. The antibacterial effect of EU solution against C. albicans is the best, with MIC being 7.81 μg / g and MBC being 15.63 μg / g; the inhibitory effect on M.canis is relatively weaker, with MIC being 15.63 μg / g and MBC being 31.25 μg / g. C. albicans

[0038] Table 1 and Figure 2 are the results of the combined drug sensitivity test of ITZ and EU solutions against two pathogenic bacteria of fungal skin diseases. According to the value of the FIC index, the interaction mode between the two solutions can be determined. When 0.5 < FIC index ≤ 1, it shows an additive effect; when 1 < FIC index ≤ 2, it is regarded as an indifferent effect. Therefore, the combined use of ITZ solution and EU solution shows an additive effect on M.canis and an indifferent effect on C. albicans .

[0039] Table 1: Results of the combined drug sensitivity test of ITZ and EU solutions against M.canis and C. albicans II. Preparation and detection of cream.

[0040] 1. Preparation method of cream: Prepare the cream according to the formula in Table 2.​​

[0041] (1) Preparation of oil phase mixture: Weigh out the amounts of cetyl alcohol (HDL), ozone oil, polydimethylsiloxane (PDMS) and emulsifier triglyceride (TG) in Table 2 and add them to a beaker. Place the beaker in a 60°C water bath and heat and stir until completely dissolved.

[0042] (2) Preparation of polar phase: Weigh out the amounts of polyethylene glycol 400 (PEG400), polyethylene glycol 3000 (PEG3000) and diethylene glycol ethyl ether (DGME) in Table 2 and add them to another beaker. Place the beaker in a 60°C water bath and heat and stir until completely dissolved.

[0043] (3) Preparation of ITZ-EU mixed drug: Weigh the amount of ITZ and EU in Table 2 and add them to a beaker. Place it in a 60°C water bath and heat and stir until the ITZ powder is completely dissolved.

[0044] (4) Shearing and mixing: The oil phase is slowly poured into the polar phase, and sheared for 15 min at 10,000 r / min under constant temperature heating at 60℃. After the oil phase mixture and the polar phase are completely emulsified, an emulsion is obtained. First, the ITZ-EU mixed drug is added, and then the formulated amounts of skin feel modifier polymethylsilsesquioxane, antioxidant 2,6-di-tert-butyl-p-cresol (BH), transdermal penetration enhancer laurocapram, and preservative sodium benzoate are added and mixed. After mixing, the mixture is sheared at 10,000 r / min for 5 min, and finally cooled to room temperature to solidify. The prepared cream is as follows: Figure 3 As shown.

[0045] Table 2: ITZ-EU Cream Formulation Composition 2. Establishment of scoring criteria for creams: The main evaluation indicators are appearance, stability and pH of creams. The comprehensive score Y is obtained by adding the scores of appearance (Y1), high temperature test (Y2), low temperature test (Y3), centrifugation test (Y4) and pH test (Y5), that is, Y=Y1+Y2+Y3+Y4+Y5.

[0046] (1) Appearance evaluation criteria: The paste is uniform in color, fine in texture and easy to apply, and does not change color after being left to stand, which is 3 points; the paste has good spreadability but has a grainy feel, and the color changes after being left to stand, which is 2 points; the paste is too hard, difficult to apply or too thin, which is 1 point; the paste has oil-water separation or drug liquid separation, which is 0 points.

[0047] (2) High temperature test scoring criteria: Take an appropriate amount of paste, place it in a centrifuge tube, seal it, put it in a 55℃ constant temperature incubator for 24 hours, take it out, restore it to room temperature, and observe it. Compared with the room temperature static state, no obvious change in the paste is scored as 3 points, softening is scored as 2 points, oil droplet precipitation is scored as 1 point, and oil-water separation or drug solution separation is scored as 0 points.

[0048] (3) Low temperature test scoring criteria: Take an appropriate amount of paste and put it into a sealed centrifuge tube. Place it in a -20℃ refrigerator for 24 hours and then take it out. After restoring to room temperature, observe it. Compared with the room temperature state, no change in the paste is scored as 3 points, hardening of the texture is scored as 2 points, oil droplet precipitation is scored as 1 point, and oil-water separation or drug liquid separation is scored as 0 points.

[0049] (4) Centrifugation test scoring criteria: Weigh an equal amount of paste into a centrifuge tube, centrifuge at 3500 r / min for 15 min and observe. Compared with the room temperature standing state, no obvious change in the paste is scored as 3 points, uneven color of the paste is scored as 2 points, oil droplet precipitation is scored as 1 point, oil-water separation or drug precipitation is scored as 0 points.

[0050] (5) pH scoring standard: Weigh 1g of cream and add 10mL of pure water. After shaking evenly, use a pH meter to measure the pH value of each group. A pH value of 4.4~8.3 is counted as 1 point, and the rest are counted as 0 points.

[0051] 3. Stability determination of the cream: The prepared ITZ-EU cream was dispensed into test tubes and sealed. It was stored at 25°C in a dark place. The cream was taken out at 0, 1, 3, and 6 months for observation and scoring. 1g of ITZ-EU cream was dissolved in methanol and filtered through a 0.22μm microporous membrane. The ITZ content was determined by high-performance liquid chromatography (HPLC). The experiment was repeated three times, and the average value was taken.

[0052] 4. Texture testing of the cream: The prepared ITZ-EU cream was tested for its physical properties using a physical property testing instrument, mainly including force, time, and displacement. Analysis was performed using a two-dimensional coordinate system and mathematical analysis methods to measure the cream's hardness (F), cohesiveness (C1), consistency (C2), viscosity index (V), and spreadability (S). The test was repeated three times, and the average value was taken.

[0053] 5. Accelerated degradation test of creams: (1) Strong light irradiation test: The prepared ITZ-EU cream was sealed in a colorless transparent glass bottle and placed in a light box equipped with fluorescent lamps. The light irradiation test was carried out under strong light conditions of 4500±500 Lx. Samples were taken at 0d, 7d, and 14d, and the cream was scored. The changes in ITZ content in the cream were detected by high performance liquid chromatography, and the texture was analyzed. The test was repeated 3 times, and the average value was taken.

[0054] (2) High temperature test: The prepared ITZ-EU cream was sealed in a colorless transparent glass bottle and placed in a constant temperature oven at 40℃. Samples were taken at 0d, 7d and 14d and the cream was scored. The changes in ITZ content in the cream were detected by high performance liquid chromatography and the texture was analyzed. The test was repeated 3 times and the average value was taken.

[0055] (3) Cold resistance test: The prepared ITZ-EU cream was sealed in a colorless transparent glass bottle and placed in a -20℃ refrigerator. Samples were taken at 0d, 7d and 14d to score the cream, detect the change in ITZ content in the cream by high performance liquid chromatography and analyze the texture. The test was repeated 3 times and the average value was taken.

[0056] 6. Experimental results: Table 3 shows the stability test results of the prepared 20 mg / g ITZ-EU cream. There were no significant changes in the cream score and ITZ content in the cream at 0, 1, 3 and 6 months, and there were no significant differences between groups (P>0.05). The prepared ITZ-EU cream has good stability and can be stored at room temperature (24℃) for a short period of time.

[0057] Table 3: Results of stability tests on ITZ-EU cream Note: Different lowercase letters indicate significant differences between groups at the 0.05 level.

[0058] Table 4 shows the results of physical property testing of the prepared ITZ-EU cream using a physical property testing instrument. Its firmness value is 58.88±7.63g, indicating that the ITZ-EU cream has a certain structural stability and will not easily deform or collapse. Its cohesiveness is 208.87±24.52g•sec, reflecting the adhesive force within the cream. Higher cohesiveness means stronger binding force between the cream's components, which helps maintain the cream's integrity and prevents delamination or separation. Its consistency value is -38.23±5.64g, indicating that the cream becomes more fluid under shear force, facilitating its spread on the skin. The negative consistency value also indicates that the cream has a certain degree of plasticity and can recover its original shape after pressure is applied. The viscosity index was -15.97 ± 1.07 g•sec. This parameter describes the flow behavior of the cream at different shear rates. A negative value indicates that the cream exhibits shear thinning properties, meaning that the viscosity decreases when shear force is applied, which helps improve the cream's spreadability. The spreading property was 5.65 ± 0.77 g / sec. This parameter directly reflects the ease with which the cream spreads on the skin. Higher spreading property means that the cream can be more easily and evenly distributed on the skin surface, improving the coverage area and absorption efficiency of the drug.

[0059] Table 4: Texture Analysis Results of ITZ-EU Cream Table 5 shows the results of accelerated degradation tests on the prepared 20 mg / g ITZ-EU cream, including textural and drug content analysis. After 14 days of storage under strong light (4500±500 Lx), high temperature (40℃), and low temperature (-20℃), the ITZ content in the ITZ-EU cream showed no significant changes. After strong light exposure, the textural properties of the ITZ-EU cream remained largely unchanged within 14 days, maintaining good physical properties. The cohesiveness and viscosity index of the ITZ-EU cream decreased significantly after high and low temperature treatments (P<0.01) within 14 days, indicating that long-term high or low temperature storage may weaken the binding force between the cream components, damaging the integrity of the cream and reducing its application performance.

[0060] Table 5: Results of Accelerated Degradation Test of ITZ-EU Cream Note: ** indicates a highly significant difference, P<0.01.

[0061] III. Evaluation of the in vitro antibacterial activity of the cream.

[0062] 1. Preparation and determination of experimental cream solution EU cream is an ITZ-free cream, blank cream is an ITZ- and EU-free cream, and Control cream is the one without any added ingredients.

[0063] Accurately weigh 1g of ITZ-EU ointment, EU ointment, empty ointment, and commercially available ketoconazole ointment (KCZ@ointment), and dissolve them in 1g of physiological saline to prepare stock solutions. Inside a clean bench, each cream stock solution was filtered and sterilized using a 0.22µm filter membrane, and then serially diluted with sterile broth to obtain test sample solutions with concentrations of 500.00μg / g, 250.00μg / g, 125.00μg / g, 62.50μg / g, 31.25μg / g, 15.63μg / g, 7.81μg / g, 3.91μg / g, 1.96μg / g, and 0.98μg / g, namely ITZ-EUointment (quantified by ITZ concentration in the cream) and EUointment (quantified by EU concentration in the cream); and concentrations of 500.00μg / g, 250.00μg / g, 125.00μg / g, and 0.98μg / g. The test sample solutions were prepared with concentrations of Emptyointment (quantified as Emptyointment concentration) of 62.50 μg / g, 31.25 μg / g, 15.63 μg / g, 7.81 μg / g, 3.91 μg / g, 1.96 μg / g, and 0.98 mg / g; and the test sample solutions were prepared with concentrations of KCZ@ointment (quantified as KTZ concentration in cream) of 625.00 μg / g, 312.50 μg / g, 156.25 μg / g, 78.13 μg / g, 39.06 μg / g, 19.53 μg / g, 9.77 μg / g, 4.88 μg / g, 2.44 μg / g, and 1.22 μg / g.

[0064] 2. Determination of MIC and MBC of ITZ-EU cream against fungi The MIC and MBC of the cream were determined using the micro-checkerboard dilution method.

[0065] ITZ-EU cream, EU cream, commercially available cream, and blank cream were compared. M.canis , C. albicans The MIC and MBC results are shown in Table 6 and Figure 4 ITZ-EU cream, EU cream, and commercially available ketoconazole cream have inhibitory effects on two fungal dermatophytes, with the inhibitory effect increasing with increasing concentration, exhibiting a dose-dependent effect. ITZ-EU cream... M.canis and C. albicansBoth exhibited strong antibacterial activity, with MIC and MBC values ​​of 7.81 μg / g and 15.63 μg / g, respectively. EU cream To M.canis and C. albicans The MIC and MBC were 15.63 μg / g and 31.25 μg / g, respectively. In contrast, commercially available ketoconazole creams showed weaker antifungal effects against both fungi. M.canis and C. albicans The MIC and MBC were 39.06 μg / g and 78.13 μg / g, respectively. The blank cream showed no antifungal activity against either of these fungi.

[0066] Table 6: Antimicrobial test results of ITZ-EU cream against fungi 3. Determination of MIC and MBC of ITZ-EU cream against bacteria The MIC and MBC of the cream were determined using the micro-checkerboard dilution method.

[0067] ITZ-EU cream, EU cream, commercially available ketoconazole cream, and blank cream were compared. S.aureus , E. coli The MIC and MBC results are shown in Table 7. ITZ-EU cream, EU cream, and commercially available ketoconazole cream all showed inhibitory effects against both bacteria, with the inhibitory effect increasing with increasing concentration, exhibiting a dose-dependent effect. ITZ-EU cream... S.aureus and E. coli Both exhibited strong antibacterial activity, with MIC and MBC values ​​of 62.5 μg / g and 125 μg / g, respectively.

[0068] Table 7: Antibacterial test results of ITZ-EU cream against Staphylococcus aureus and Escherichia coli 4. Determination of the diameter of the inhibition zone of ITZ-EU cream The in vitro antibacterial effect of ITZ-EU cream was determined using the inhibition zone method.

[0069] Table 8 shows the inhibition zone results of ITZ-EU cream, EU cream, commercially available ketoconazole cream, and blank cream against two fungi. ITZ-EU cream showed... M.canis and C. albicans The antibacterial effect was the best, with inhibition zone diameters of 28.33±4.36 mm and 27.67±3.51 mm, respectively. EU cream... M.canis and C. albicansThe inhibition zone diameters of the two products were 16.67±2.52 mm and 22.33±0.58 mm, respectively, while those of the commercially available ketoconazole cream were 20.67±0.58 mm and 22.67±1.53 mm, respectively. The blank cream showed small inhibition zone diameters against both fungi, at 5.33±0.58 mm and 5.67±0.58 mm, respectively, indicating no antibacterial effect. Statistical analysis showed that there was no significant difference between the ITZ-EU cream and the commercially available ketoconazole cream. M.canis There were significant differences in antibacterial efficacy between ITZ-EU cream and EU cream (P<0.05); and extremely significant differences between ITZ-EU cream and EU cream and commercially available ketoconazole cream. C. albicans There were significant differences in antibacterial efficacy between EU cream and commercially available ketoconazole cream (P<0.05). M.canis and C. albicans There was no significant difference in the antibacterial effect among the samples (P>0.05).

[0070] Table 8: Effects of Creams on M.canis and C. albicans The diameter of the inhibition zone (X±SD, mm) Note: Different lowercase letters indicate significant differences between groups at the 0.05 level, and different uppercase letters indicate significant differences between groups at the 0.01 level.

[0071] 5. Fungal co-incubation test for creams Four cream solutions with MIC concentrations were prepared and sterilized by filtration through a 0.22 µm filter membrane to obtain the cream solutions. The experimental group used 1×10⁻⁶... 8 Five mL of CFU / mL bacterial suspension was mixed with an equal volume of cream solution, and the control group was incubated with the same volume of liquid culture medium at 28℃ and 120 rpm for 24 h in a shaker. The prepared co-incubation bacterial suspension was centrifuged at 3500 rpm, the supernatant was discarded, and the fungal cells were fixed with 2.5% glutaraldehyde solution. After dehydration with a gradient of 60%, 70%, 80%, 90%, and 100% ethanol, 1 µL of the dehydrated fungal cells was dropped onto a silicon wafer and dried at room temperature. The dried sample was then plated with gold for 2 min in a gold sputtering apparatus, and then fixed on the sample stage for observation using a scanning electron microscope. The target area was located, the resolution was adjusted, and a slow scan was performed to locate the target fungal cells, observe their microscopic morphology, and take photographs. ATPase assay reagents and BCA protein concentration assay kits were used. The ATP level and protein leakage of the fungi in the co-incubated samples were measured according to the kit instructions, and the experiment was repeated three times.

[0072] Figure 5 The results showed that the untreated M.canisThe mycelium has thick walls and smooth hyphae, exhibiting a uniform rod-like structure. In contrast, after treatment with different creams, the morphology of the cells treated with the blank cream remained relatively intact, showing no significant changes; the morphology of the cells treated with the EU cream began to show irregular changes; the surface of the cells treated with the commercially available ketoconazole cream became rougher and more wrinkled; and the cells treated with the ITZ-EU cream showed more significant damage, with severely damaged hyphal structures and fragmentation. Untreated cells... C. albicans The surface was smooth and flat, with regular, uniform spherical shapes. In contrast, after treatment with different creams, the bacterial morphology of the blank cream remained relatively intact, showing no significant changes; the bacterial surfaces treated with EU cream and commercially available ketoconazole cream were no longer smooth, and began to show depressions and irregular wrinkles; the bacterial surface damage was most severe in the ITZ-EU cream treatment, showing obvious morphological distortion and leakage of bacterial contents. These results are consistent with the inhibition zone results, indicating that the degree of bacterial damage is related to the composition of the cream.

[0073] Results of ATP level and quantitative protein leakage detection of cream co-incubated with fungi: Figure 6 For different creams and M.canis and C. albicans Results of protein leakage quantification and ATP level detection after co-incubation. For M.canis The ITZ-EU cream increased fungal protein leakage to 15.66 μg / mL, indicating severe cell membrane damage. This was significantly different from the protein leakage caused by commercially available ketoconazole cream (P<0.05), and extremely significantly different from the protein leakage caused by the EU cream and the blank cream (P<0.01). Simultaneously, the ITZ-EU cream decreased fungal ATP levels to 136.45 mM, indicating disrupted energy metabolism. This was not significantly different from the ATP levels after treatment with commercially available KCZ cream (P>0.05), but extremely significantly different from the ATP levels after treatment with the EU cream and the blank cream (P<0.01). C. albicans The ITZ-EU cream also increased fungal protein leakage to 13.95 μg / mL, demonstrating the strongest cell membrane damage, which was significantly different from the protein leakage caused by the commercially available KCZ cream, EU cream, and blank cream (P<0.01). Simultaneously, the ITZ-EU cream decreased fungal ATP levels to 105.47 mM, indicating disruptive effects on energy metabolism, and was significantly different from the ATP levels after treatment with the commercially available ketoconazole cream, EU cream, and blank cream (P<0.01).

[0074] In summary, ITZ-EU cream has the effect of M.canis and C. albicansAll of them exhibited the strongest cell membrane damage and energy metabolism disruption effects. These results suggest that ITZ-EU cream may exert its strong antibacterial effect in vitro by disrupting the integrity of fungal cell membranes and inhibiting fungal energy metabolism.

[0075] IV. In vivo safety evaluation of the cream.

[0076] 1. Experimental Animals: SPF-grade SD rats, 6 weeks old, 150.0±12.5g, purchased from Spiford Beijing Biotechnology Co., Ltd. This experiment has been reviewed and approved by the Ethics Committee of Beijing University of Agriculture. New Zealand white rabbits, 4 months old, weighing 15.3±2.1kg, purchased from Beijing Xishan Breeding Farm. SPF-grade Kunming mice (KM mice), 8 weeks old, weighing 30.0±0.8g, purchased from Spiford Beijing Biotechnology Co., Ltd. This experiment has been reviewed and approved by the Ethics Committee of Beijing University of Agriculture.

[0077] 2. Skin Irritation Test: Six healthy adult New Zealand white rabbits, weighing no less than 2.0 kg, were selected. Each rabbit was housed individually in a cage, clearly labeled and numbered, and allowed to acclimatize to the test environment for 7 days. 24 hours prior to the test, the fur on both sides of the spine on the backs of the six rabbits was removed, creating an area of ​​approximately 15cm x 15cm, which served as the test and observation site. When conducting irritation studies on broken skin, a crisscross pattern was drawn at the application site with a syringe needle until bleeding was observed.

[0078] 0.5g of ITZ-EU cream (20mg / g concentration) was applied directly to shaved or broken skin, covered with two layers of gauze (2.5cm × 2.5cm), and secured with non-irritating adhesive tape and bandage. Three rabbits were used as the experimental group, with one application site on each side of the back of each rabbit's spine. Multiple administrations were administered for 1, 4, and 7 consecutive days. 0.9% saline and 1% Triton X-100 were applied to the back of each rabbit's spine, respectively, with three rabbits serving as negative and positive control groups. The experiment lasted 7 days, with the drug applied once daily. Skin erythema and edema were observed after application, and skin reactions were scored. The average skin score for each group at each observation time point was calculated, and the irritation intensity was evaluated according to Tables 9-10.

[0079] Table 9: Skin Irritation Reaction Scoring Criteria Table 10: Evaluation Criteria for Skin Irritation Intensity 3. In vivo safety test in mice: KM mice were anesthetized using a respiratory anesthesia device (containing 4% isoflurane). After complete anesthesia, the fur on the backs of the mice was completely shaved using a small animal shaver. 0.5g of ITZ-EU cream was applied to the backs of the shaved mice in the experimental group for 7 days, with the drug applied once daily, and any abnormal reactions were recorded. After 7 days of application, heart, liver, spleen, lung, and kidney tissues were collected from the 6 treated mice in the experimental group and the 6 untreated mice in the control group. The tissues were fixed in 10% formaldehyde solution, embedded in paraffin, sectioned, and stained with H&E for histopathological examination.

[0080] 4. Experimental Results: Figure 7 Table 11 shows the skin irritation test results of ITZ-EU cream. In single and multiple applications on intact skin, ITZ-EU cream did not cause any irritation on days 1, 4, and 7, with a score of 0.00, which was significantly different from the score of 1% Triton X-100 (P<0.01). This indicates that ITZ-EU cream is well tolerated and non-irritating on intact skin. In single applications on broken skin, the irritation score was 1.33±0.58 on day 1, but dropped to 0.00 on days 4 and 7, showing a significantly different score from the score of 1% Triton X-100 (P<0.01), indicating that there may have been slight irritation at the beginning of the test, but the irritation disappeared as the skin recovered. After repeated application of ITZ-EU cream to broken skin, the irritation score was 1.67±0.58 on day 1, decreasing to 0.33±0.58 on day 4, and reaching 0.00 on day 7. This score was significantly different from that of 1% Triton X-100 (P<0.01), showing a similar trend of initial mild irritation followed by gradual recovery. Skin irritation tests indicated that ITZ-EU cream did not show significant skin irritation on either intact or broken skin. Even if there was a mild initial irritation, it recovered quickly, demonstrating good skin compatibility.

[0081] Table 11: Evaluation of skin irritation intensity of ITZ-EU cream (n=6) Note: Different lowercase letters indicate significant differences between groups at the 0.05 level, and different uppercase letters indicate significant differences between groups at the 0.01 level.

[0082] Figure 8These are H&E pathological sections of organs from mice in an in vivo safety test of ITZ-EU cream. As shown in the figures, after 7 days of continuous administration of ITZ-EU cream, no significant pathological changes were observed in any organ compared to untreated mice. Cardiac cardiomyocytes were neatly arranged, with intact fibrous structures, without breakage or inflammatory infiltration. The liver capsule was intact, and the boundaries between hepatocyte cords and cytoplasm were clear, with no inflammatory cell infiltration. The white and red pulp of the spleen were clearly defined, without any abnormal lesions. The bronchioles of the lungs were normal in morphology, and the alveolar structure was intact, without inflammatory cell infiltration. The kidney tissue structure was normal, the glomeruli were intact, without hyperplasia or thickening of the basement membrane; the renal tubules showed no dilation or edema, and the epithelial cells were intact; the boundary between the cortex and medulla was clear, with no inflammatory cell infiltration.

[0083] V. Study on the application effect of ITZ-EU cream in a mouse fungal infection model.

[0084] 1. Establishment and grouping of a mouse fungal infection model: SPF-grade Kunming mice (KM mice), 8 weeks old, 30.0±1.3g, were purchased from Spiford Beijing Biotechnology Co., Ltd. This experiment has been reviewed and approved by the Ethics Committee of Beijing Agricultural College. After 7 days of acclimatization, the KM mice were weighed, numbered, and randomly divided into 6 groups of 6 mice each. Before the experiment, the backs of the mice were shaved, and 50μL of 1×10⁻⁶ solution was subcutaneously injected at single points on both sides of the back. 8 CFU / mL M.canis Bacterial solution. Two days later, after observing obvious nodules forming at the injection site accompanied by skin redness and swelling, a 7-day continuous cream treatment was initiated.

[0085] The experimental groups are as follows: (1) Negative control group: No subcutaneous injection was given. M.canis Healthy mice were treated with 0.1g of physiological saline solution daily.

[0086] (2) Positive control group: subcutaneous injection M.canis Mice were infected with the bacterial solution without any treatment.

[0087] (3) Empty ointment group: subcutaneous injection M.canis Mice were infected with bacterial solution, and a blank cream of 5 mg / kg was applied to the infected area daily according to the mouse's body weight.

[0088] (4) EU ointment group: subcutaneous injection M.canis Mice were infected with the bacterial solution, and EU cream with a concentration of 5 mg / g (5 mg / kg) was applied to the infected area daily according to the mouse's body weight.

[0089] (5) Ketoconazole cream treatment group (KCZ@ointment Group): subcutaneous injection M.canis Mice were infected with bacterial solution, and commercially available ketoconazole cream at a dose of 5 mg / kg was applied to the infected area daily, based on the mice's body weight.

[0090] (6) ITZ-EU ointment group: subcutaneous injection M.canis Mice were infected with bacterial solution, and ITZ-EU cream at a concentration of 5 mg / g (5 mg / kg) was applied to the infected area daily according to the mice's body weight.

[0091] 2. Sample Collection and Processing: On day 3 of the experiment, half of the mice in each group were randomly anesthetized using a respiratory anesthesia device (containing 4% isoflurane). After complete anesthesia, 1.5 mL of blood was collected from the heart and stored in lithium heparin anticoagulant tubes. After standing for 40 min, the blood was centrifuged at 3500 rpm for 15 min. The separated serum was aliquoted into cryovials and stored at -80°C using liquid nitrogen for later analysis. Full-thickness skin from the fungal infection site on the right back of the mice was removed and stained with paraformaldehyde for tissue sectioning (H&E, Masson, PAS, IL-6, and TNF-α immunohistochemical staining). Full-thickness skin from the fungal infection site on the left back of the mice was removed, and 0.10 ± 0.02 g of skin tissue was weighed and placed in 1 mL of sterile saline for fungal quantification in the skin tissue homogenate. On day 7 of the experiment, the other half of the mice in each group were sampled, and the samples were processed in the same manner as on day 3.

[0092] 4. Quantitative analysis of fungi in skin tissue homogenate: 0.10±0.02g of skin tissue placed in 1mL of sterile physiological saline was thoroughly homogenized and diluted 10 times with sterile physiological saline. 100μL of the homogenate was spread on Sabouraud dextrose agar and incubated at 28℃ for 24h. The fungal count was performed immediately after colony formation and before hyphae growth.

[0093] 5. Cure rate of mouse fungal infection model: The changes in subcutaneous nodules at the infection site of each group of mice were photographed at 0d, 3d and 7d, and quantitative analysis was performed using Image Pro Plus J. The cure rate of mouse fungal infection was calculated to determine the recovery status of infected mice.

[0094] 6. Detection of blood drug concentration in mice: Plasma samples from days 3 and 7 were thawed at 4°C. 100 μL of each plasma sample was taken and 500 μL of methanol was added. The mixture was vortexed for 5 min to ensure full contact between the plasma and methanol. ITZ was extracted from the plasma. After precipitating the plasma proteins, the mixture was centrifuged at 12000 r / min for 15 min. The supernatant was collected and 400 μL of mobile phase was added. The mixture was vortexed for 3 min. The ITZ content was detected by high performance liquid chromatography.

[0095] 7. Experimental Results: Figure 9 Quantitative analysis results of fungal activity in skin tissue homogenates from infection sites on days 3 and 7 in different treatment groups. On day 3, the ketoconazole cream treatment group... M.canis The growth of fungi was minimal in the ITZ-EU cream treatment group, with no significant difference (P>0.05), indicating similar therapeutic effects. Fungal quantification results in both the commercially available ketoconazole cream and ITZ-EU cream treatment groups showed significantly lower levels than the EU cream and blank cream treatment groups (P<0.01), demonstrating optimal therapeutic efficacy. Fungal quantification results on day 7 showed that the ITZ-EU cream treatment group had the least fungal growth, with a significantly different growth rate compared to the commercially available ketoconazole cream treatment group (P<0.05), and a highly significant difference compared to the EU cream and blank cream treatment groups (P<0.01). Overall, ITZ-EU cream was the most effective in inhibiting fungal growth, followed by ketoconazole cream and EU cream, while the blank cream showed the least effect. These results indicate that ITZ-EU cream can significantly reduce subcutaneous fungal load in mice within 7 days and is effective in treating in vivo fungal infections.

[0096] Figure 10 H&E-stained sections of skin tissue at the infection site 7 days after treatment. In the dorsal skin tissue of mice in the negative control group, the connective tissue was loose, the adipose tissue was intact, the basal layer was obvious, collagen fibers were abundant and clearly visible, and blood vessels were clear without inflammatory cell infiltration. In the dorsal skin tissue of mice injected with fungal infection but not treated in the positive control group, a large number of necrotic foci were visible, with vasodilation and congestion, disordered collagen fiber arrangement, and a large number of inflammatory cell infiltrations at the subcutaneous infection site (indicated by red arrows), forming inflammatory necrotic foci. In the blank cream, EU cream, and commercially available ketoconazole cream treatment groups, compared with the negative control group, a small amount of inflammatory cell infiltration was observed (indicated by red arrows), and some connective tissue was disordered. In the skin tissue of the ITZ-EU cream treatment group, there was no inflammatory cell infiltration at the fungal infection model site, and the loose connective tissue returned to normal. The results show that ITZ-EU cream can significantly reduce skin lesions caused by subcutaneous fungal infection in mice within 7 days and has a good effect on treating fungal infections in vivo.

[0097] Figure 11 Masson staining sections of skin tissue from the infected site 7 days after treatment. Masson staining is mainly used to distinguish tissue structures such as collagen fibers, muscle fibers, and cell nuclei, with collagen fibers typically stained blue. The figures show that the collagen fibers in the negative control group were tightly and orderly arranged, while those in the positive control group and the blank cream treatment group were disordered and loose, with the quantitative results significantly lower than those in the negative control group (P<0.01). The collagen fiber arrangement in the EU cream and commercially available ketoconazole cream treatment groups returned to normal, repairing the collagen fiber disorder caused by fungal infection; their quantitative results showed no significant difference compared to the negative control group (P>0.05). The collagen fiber arrangement in the ITZ-EU treatment group was even denser, and its quantitative results were significantly higher than those in the KCZ commercially available cream treatment group (P<0.01), indicating that the ITZ-EU cream not only significantly repairs damage caused by fungal infection but also effectively stimulates collagen fiber regeneration.

[0098] Figure 12 This is a PAS-stained section of skin tissue from the infected site 7 days after treatment. PAS staining can be used to detect fungi, bacteria, and other microorganisms. With PAS staining, fungal polysaccharides are stained red, while cell nuclei are stained blue, which helps in observing the distribution of fungi in tissue sections. As shown in the figure, in the dorsal skin tissue of healthy mice in the negative control group, the connective tissue was loose, the adipose tissue was intact, the basal layer was obvious, and no fungal polysaccharides were observed in hair follicles and sebaceous glands. In the dorsal skin tissue of mice injected with fungal infection but not treated in the positive control group, a large amount of fungal polysaccharides were observed in the connective tissue hair follicles and epithelial hair follicles, and PAS positivity was indicated by a purplish-red color (indicated by the red arrow). In the treatment groups of the blank cream, EU cream, and KCZ commercially available cream, compared with the negative control group, a small amount of fungal polysaccharides were observed in the connective tissue hair follicles, and PAS positivity was indicated by a purplish-red color (indicated by the red arrow). In the skin tissue of the ITZ-EU cream treatment group, no fungal polysaccharides were observed in hair follicles and sebaceous glands. The results showed that ITZ-EU cream could reduce the number of subcutaneous fungi in mice within 7 days, and was effective in treating fungal infections in vivo.

[0099] Figure 13Immunohistochemical staining sections of skin tissue at the infection site for TNF-α and IL-6 were prepared 7 days after treatment. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are both pro-inflammatory cytokines involved in the initiation and maintenance of the inflammatory response. The figures show that the two pro-inflammatory factors were almost not expressed in the negative control group, while TNF-α and IL-6 were overexpressed in the positive control group, significantly higher than in the negative control group (P<0.01). Compared with the blank cream, EU cream, and commercially available ketoconazole cream treatment groups, the positive control group showed a highly significant reduction in the expression levels of both pro-inflammatory factors (P<0.01), reducing the local inflammatory response caused by fungal infection. There was no significant difference in TNF-α expression between the ITZ-EU treatment group and the negative control group (P>0.05), while IL-6 expression was significantly lower in the ITZ-EU treatment group than in the other treatment groups (P<0.05), demonstrating that ITZ-EU cream can reduce the local inflammatory response caused by fungal infection.

[0100] Figure 14 Images of fungal infection sites in different groups on days 0, 3, and 7. The figures show that on day 0 of the experiment... M.canis Following infection, obvious nodules were observed in the injection area, accompanied by local redness and swelling, indicating that the experiment successfully established a deep skin fungal infection model. After 7 days of treatment, the size of the abscess nodules caused by subcutaneous fungal infection in the positive control group did not change significantly, while the various creams showed different therapeutic effects.

[0101] pass Figure 15 Quantitative analysis of subcutaneous infection area in mice revealed that both commercially available ketoconazole cream and ITZ-EU cream reduced the infection area to 50% within 3 days, significantly lower than that of EU cream and the blank cream (P<0.01). After 7 days of treatment, ITZ-EU cream showed the best therapeutic effect, with the infection area remaining at only 13.06%±4.27%, significantly lower than the ketoconazole cream treatment group (P<0.05), EU cream, and the blank cream (P<0.01). These results indicate that ITZ-EU cream can significantly accelerate the elimination of abscesses caused by subcutaneous fungal infection within 7 days, confirming its effectiveness in clearing deep subcutaneous fungi.

[0102] Figure 16 The results show the ITZ concentration in mice after treatment with ITZ-EU cream on days 0, 3, and 7. As can be seen from the figure, the ITZ content in the mice gradually increased over 7 days, demonstrating an effective antifungal effect.

[0103] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the invention.

Claims

1. Itraconazole transdermal cream, characterized in that, The itraconazole transdermal cream is composed of the following components in parts by weight: 1-3 parts itraconazole, 2-4 parts essential oil, 2-13 parts oil phase, 15-73 parts polar phase, 7-8 parts emulsifier, 1-3 parts skin feel modifier, 1-2 parts antioxidant, 3-5 parts transdermal penetration enhancer, and 0.1-0.5 parts preservative. The essential oil is selected from one or more of the following: thyme essential oil, thyme essential oil, sage essential oil, celery essential oil, clove essential oil, oregano essential oil, peppermint essential oil, bay leaf essential oil, clove basil essential oil, tea tree essential oil, and green tea essential oil.

2. The itraconazole transdermal cream as described in claim 1, characterized in that, The oil phase is selected from one or more of cetyl alcohol, ozone oil, oleyl alcohol, and polydimethylsiloxane.

3. The itraconazole transdermal cream as described in claim 1, characterized in that, The polar phase is selected from one or more of polyethylene glycol 400, polyethylene glycol 3000, polyethylene glycol 3350, and diethylene glycol ethyl ether.

4. The itraconazole transdermal cream as described in claim 1, characterized in that, The emulsifier is selected from one or more of the following: triglycerides, PEG-50 caprylate-capric acid, glyceryl caprylate, glyceryl capric acid, glyceryl capric acid, glyceryl succinate, glyceryl monostearate, cetearyl alcohol-50, cetearyl alcohol-70, polyvinylpyrrolidone, Tween 20, Tween 80, and Span 80.

5. The itraconazole transdermal cream as described in claim 1, characterized in that, The skin feel modifier is selected from one or more of tapioca starch, polymethylsilsesquioxane, and talc.

6. The itraconazole transdermal cream as described in claim 1, characterized in that, The antioxidant is selected from one or more of 2,6-di-tert-butyl-p-cresol, 4-hydroxy-3-tert-butyl-anisole, butylated hydroxyanisole, and vitamin E.

7. The itraconazole transdermal cream as described in claim 1, characterized in that, The transdermal penetration enhancer is selected from one or more of azone, laurocapram, anhydrous ethanol, and propylene glycol.

8. The itraconazole transdermal cream as described in claim 1, characterized in that, The preservative is selected from one or more of sodium benzoate, benzyl alcohol, potassium sorbate, p-hydroxybenzoate, benzalkonium bromide, chlorhexidine gluconate, and chlorhexidine acetate.

9. A method for preparing the itraconazole transdermal cream according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1. Mix the oil phase and emulsifier to obtain a mixed oil; S2. Mix itraconazole and essential oil and heat to dissolve itraconazole, obtaining a mixed drug. S3. Mix and emulsify the mixed oil and polar phase to obtain an emulsion. Mix the emulsion with the mixed drug, skin feel modifier, antioxidant, transdermal penetration enhancer and preservative. After shearing and homogenizing the emulsion, cool and solidify to obtain the itraconazole transdermal cream.

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