Essential oil-containing luliconazole composition, cream and preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a luliconazole composition containing essential oil, cream and a preparation method and application of the luliconazole composition. The present application provides a composition containing tea tree essential oil that promotes the skin permeability of luliconazole and has an antibacterial function, the tea tree essential oil and luliconazole form a synergistic antifungal effect, the transdermal absorption is enhanced by a natural terpene component, and the irritation to the skin is significantly reduced.

Description

Technical Field

[0001] The present application belongs to the field of biomedicine technology, and specifically relates to a luliconazole composition containing essential oil, a cream, and a preparation method and application thereof. Background Art

[0002] Luliconazole is a known broad-spectrum imidazole topical antifungal drug that can be used to treat tinea pedis, tinea cruris and tinea corporis caused by fungal infections. It inhibits the biosynthesis of ergosterol on the fungal cell membrane by reducing the activity of lanosterol demethylase, thereby achieving the effect of inhibiting fungal growth and reproduction.

[0003] Luliconazole is usually prepared into a cream as an external preparation and has been widely used in clinical practice, but it has low solubility and poor skin permeability, which limits its therapeutic effect. In addition, it also has certain side effects when used topically, such as mild skin irritation, such as itching, erythema, burning sensation, etc.

[0004] Traditional technologies rely on chemical penetration enhancers (such as eucalyptol, isopropyl myristate) or nanocarrier technology (such as ethosomes, nanoemulsions) to enhance the efficacy of cream preparations. For example, traditional technologies rely on chemical penetration enhancers to promote drug absorption, which may cause skin irritation. Long-term use of a single drug can easily lead to fungal resistance and has limited efficacy on fungal infections accompanied by inflammation (such as eczema combined with ringworm).

[0005] In summary, the traditional luliconazole cream promotes drug absorption to a certain extent by adding chemical accelerators, but it still has the problem of skin irritation and drug resistance that may be caused by long-term use. Therefore, how to further reduce skin irritation while ensuring the drug absorption effect is a technical problem that needs to be solved urgently in this field. Summary of the invention

[0006] Based on this, one embodiment of the present application provides a luliconazole composition containing essential oils, and a preparation method and application thereof.

[0007] On the one hand, the present application provides a luliconazole composition containing essential oil, comprising the following raw materials:

[0008] Luliconazole, sorbitan stearate, tea tree oil, polysorbate 60, cetostearyl alcohol, medium chain triglycerides, methylparaben, benzyl alcohol, butylated hydroxytoluene, propylene glycol and purified water.

[0009] The present application provides a composition, which contains tea tree essential oil that promotes the skin permeability of luliconazole and has antibacterial function. The tea tree essential oil and luliconazole form a synergistic antifungal effect, enhance transdermal absorption through natural terpene components, and significantly reduce skin irritation.

[0010] In some of these embodiments, by weight, the raw materials include the following:

[0011] 0.5 - 1.5 parts of luliconazole, 0.5 - 1 part of sorbitan stearate, 1 - 2 parts of tea tree essential oil, 2 - 6 parts of polysorbate 60, 2 - 8 parts of cetearyl alcohol, 4 - 10 parts of medium-chain triglycerides, 0.1 - 0.5 parts of methylparaben, 0.5 - 2 parts of benzyl alcohol, 0.01 - 0.05 parts of dibutylhydroxytoluene, 5 - 10 parts of propylene glycol, and 50 - 90 parts of purified water.

[0012] In some of these embodiments, by weight, the raw materials include the following:

[0013] 0.8 - 1.2 parts of luliconazole, 0.6 - 0.8 part of sorbitan stearate, 1.8 - 2 parts of tea tree essential oil, 3 - 4 parts of polysorbate 60, 5 - 6 parts of cetearyl alcohol, 8 - 10 parts of medium-chain triglycerides, 0.1 - 0.2 parts of methylparaben, 1 - 1.5 parts of benzyl alcohol, 0.03 - 0.04 parts of dibutylhydroxytoluene, 6 - 8 parts of propylene glycol, and 60 - 80 parts of purified water.

[0014] In some of these embodiments, by weight, the raw materials include the following:

[0015] 1 part of luliconazole, 0.75 part of sorbitan stearate, 2 parts of tea tree essential oil, 3.2 parts of polysorbate 60, 5.8 parts of cetearyl alcohol, 8.85 parts of medium-chain triglycerides, 0.14 part of methylparaben, 1 part of benzyl alcohol, 0.02 part of dibutylhydroxytoluene, 6 parts of propylene glycol, and 73 parts of purified water.

[0016] On the other hand, the present application provides a luliconazole cream containing essential oil, and the cream contains the luliconazole composition containing essential oil as described above.

[0017] On the other hand, the present application provides a preparation method of the luliconazole cream containing essential oil, including:

[0018] Adding the methylparaben to the purified water, stirring and dispersing evenly, performing the first heating treatment, mixing, and preparing component A;

[0019] Mixing the sorbitan stearate, the polysorbate 60, the cetearyl alcohol, the medium-chain triglycerides, the benzyl alcohol, the dibutylhydroxytoluene, and the propylene glycol, performing the second heating treatment, and then performing the stirring treatment;

[0020] Adding the luliconazole, performing the cooling treatment, then adding the tea tree essential oil, mixing, and preparing component B; and,

[0021] Mixing component A and component B, performing the homogenization treatment and the vacuum treatment to prepare the luliconazole cream containing essential oil.

[0022] In some of these embodiments, the temperature of the first heating treatment is 40°C to 50°C.

[0023] In some of these embodiments, the temperature of the second heating treatment is 70°C to 80°C.

[0024] In some of these embodiments, the temperature of the cooling treatment is 40°C to 50°C.

[0025] In some of these embodiments, the rotation speed of the stirring treatment is 50 rpm to 100 rpm.

[0026] In some of these embodiments, the rotation speed of the homogenization treatment is 8000 rpm to 15000 rpm, and the time is 15 min to 30 min.

[0027] In some of these embodiments, the conditions of the vacuum treatment include: the degree of vacuum is -0.08 MPa to -0.06 MPa, and the temperature is 35°C to 45°C. Detailed implementation manners

[0028] The present application will be further described in detail below in conjunction with the implementation manners and embodiments. It should be understood that these implementation manners and embodiments are only used to illustrate the present application and not to limit the scope of the present application. The purpose of providing these implementation manners and embodiments is to make the understanding of the disclosed content of the present application more thorough and comprehensive. It should also be understood that the present application can be implemented in many different forms and is not limited to the implementation manners and embodiments described herein. Those skilled in the art can make various changes or modifications without departing from the connotation of the present application, and the equivalent forms obtained also fall within the protection scope of the present application. In addition, in the following description, a large number of specific details are given to provide a more thorough understanding of the present application. It should be understood that the present application can be implemented without one or more of these details.

[0029] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as commonly understood by those skilled in the technical field to which the present application belongs.

[0030] Term

[0031] Unless otherwise stated or there is a contradiction, the terms or phrases used herein have the following meanings:

[0032] As used herein, the alternative scopes of the terms "and / or", "or / and", and "and / or" include any one of two or more related listed items, as well as any and all combinations of the related listed items. The said any and all combinations include combinations of any two related listed items, any more than two related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctive combinations selected from "and / or", "or / and", and "and / or", it should be understood that in this application, this technical solution undoubtedly includes the technical solution connected by "logical AND", and undoubtedly also includes the technical solution connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A + B. Another example is the technical solution of "A, and / or, B, and / or, C, and / or, D", which includes any one of A, B, C, and D (i.e., the technical solution connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, combinations of any two or any three of A, B, C, and D, and also includes the combination of the four items A, B, C, and D (i.e., the technical solution connected by "logical AND").

[0033] In this application, when it comes to "multiple", "diverse", "multiple times", "multiple elements", etc., without special limitation, it means greater than or equal to 2 in quantity. For example, "one or more" means one or greater than or equal to two.

[0034] As used herein, "their combinations", "any combination thereof", "any combination mode thereof", etc. include all suitable combination modes of any two or more than two of the listed items.

[0035] In this article, the "suitable" in "suitable combination mode", "suitable mode", "any suitable mode", etc. is subject to being able to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0036] In this application, "further", "even further", "especially", etc. are used for descriptive purposes, indicating differences in content, but should not be construed as limiting the protection scope of this application.

[0037] In this application, "optionally", "optional", "optional" mean having or not having, that is, any one of the two parallel solutions selected from "having" or "not having". If "optional" appears multiple times in a technical solution, without special instructions and without contradictions or mutual restrictions, each "optional" is independent.

[0038] In this application, for the technical features described in an open-ended manner, it includes the closed technical solutions composed of the listed features, as well as the open technical solutions containing the listed features.

[0039] In this application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the selectable numerical values are considered continuous within the above numerical intervals, and include the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical range, as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints. In this article, it is equivalent to directly listing each integer. For example, when t is an integer selected from 1 to 10, it means that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In addition, when multiple range descriptions of features or characteristics are provided, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed in this article should be understood to include any and all sub-ranges subsumed therein.

[0040] The temperature parameter in this application, unless otherwise specified, allows both constant temperature treatment and variation within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuation within a range such as ±5°C, ±4°C, ±3°C, ±2°C, ±1°C is allowed.

[0041] In this application, %(w / w) and wt% both represent weight percentages, %(v / v) refers to volume percentages, and %(w / v) refers to mass-volume percentages.

[0042] All documents mentioned in this application are cited as references in this application as if each document was cited separately as a reference. Unless it conflicts with the invention purpose and / or technical solution of this application, the cited documents involved in this application are cited for all contents and all purposes. When this application involves cited documents, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited together. When this application involves cited documents, the examples and preferred methods of the relevant technical features cited can also be incorporated as references into this application, but only to the extent that this application can be implemented. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or be amended adaptively according to the description in this application.

[0043] Tea tree essential oil is a natural terpene compound with antibacterial, anti-inflammatory, and penetration-enhancing effects, and has been listed as a safe ingredient (GRAS) by the FDA. Research shows that its active ingredients (such as terpinene-4-ol) can enhance the antifungal effect by destroying the fungal cell membrane and reduce the inflammatory response at the same time. However, there is no report in the prior art on combining it with luliconazole to achieve synergistic effects.

[0044] On the one hand, this application provides a luliconazole composition containing essential oil, comprising the following raw materials:

[0045] Luliconazole, sorbitan stearate, tea tree essential oil, polysorbate 60, cetearyl alcohol, medium-chain triglycerides, methylparaben, benzyl alcohol, dibutylhydroxytoluene, propylene glycol, and purified water.

[0046] The present application provides a composition containing tea tree essential oil that promotes the skin permeability of luliconazole and has antibacterial function. The tea tree essential oil forms a synergistic antifungal effect with luliconazole, enhances transdermal absorption through natural terpene components, and significantly reduces skin irritation.

[0047] In some embodiments, by weight, the composition comprises the following raw materials:

[0048] 0.5 - 1.5 parts of luliconazole, 0.5 - 1 part of sorbitan stearate, 1 - 2 parts of tea tree essential oil, 2 - 6 parts of polysorbate 60, 2 - 8 parts of cetearyl alcohol, 4 - 10 parts of medium-chain triglycerides, 0.1 - 0.5 part of methylparaben, 0.5 - 2 parts of benzyl alcohol, 0.01 - 0.05 part of dibutylhydroxytoluene, 5 - 10 parts of propylene glycol, and 50 - 90 parts of purified water.

[0049] In some embodiments, by weight, the composition comprises the following raw materials:

[0050] 0.8 - 1.2 parts of luliconazole, 0.6 - 0.8 part of sorbitan stearate, 1.8 - 2 parts of tea tree essential oil, 3 - 4 parts of polysorbate 60, 5 - 6 parts of cetearyl alcohol, 8 - 10 parts of medium-chain triglycerides, 0.1 - 0.2 part of methylparaben, 1 - 1.5 parts of benzyl alcohol, 0.03 - 0.04 part of dibutylhydroxytoluene, 6 - 8 parts of propylene glycol, and 60 - 80 parts of purified water.

[0051] In some embodiments, by weight, the composition comprises the following raw materials:

[0052] 1 part of luliconazole, 0.75 part of sorbitan stearate, 2 parts of tea tree essential oil, 3.2 parts of polysorbate 60, 5.8 parts of cetearyl alcohol, 8.85 parts of medium-chain triglycerides, 0.14 part of methylparaben, 1 part of benzyl alcohol, 0.02 part of dibutylhydroxytoluene, 6 parts of propylene glycol, and 73 parts of purified water.

[0053] On the other hand, the present application provides a luliconazole cream containing essential oil, and the cream contains the luliconazole composition containing essential oil described above.

[0054] On the other hand, the present application provides a preparation method of the luliconazole cream containing essential oil, comprising:

[0055] Adding the methylparaben to purified water and stirring until evenly dispersed, performing the first heating treatment, mixing, and preparing Component A;

[0056] Mix the sorbitan stearate, the polysorbate 60, the cetearyl alcohol, the medium-chain triglyceride, the benzyl alcohol, the butylated hydroxytoluene, and the propylene glycol, perform a second heating treatment, and then perform a stirring treatment;

[0057] Add the luticonazole, perform a cooling treatment, then add the tea tree essential oil, and mix to prepare Component B; and,

[0058] Mix Component A and Component B, perform a homogenization treatment and a vacuum treatment to prepare a luticonazole cream containing essential oil.

[0059] Using the preparation method of the present application can ensure the full dissolution and mixing of the components. First, methylparaben is added to purified water and stirred until evenly dispersed to ensure its full dissolution. Methylparaben is a commonly used preservative, and pre-dissolving it helps to exert its preservative effect in the subsequent process. And sorbitan stearate, polysorbate 60, cetearyl alcohol, medium-chain triglyceride, benzyl alcohol, butylated hydroxytoluene, and propylene glycol: These components are mixed in the second heating treatment to ensure their full dissolution and mixing at a higher temperature to form a uniform matrix.

[0060] Furthermore, adding luticonazole after the cooling treatment can avoid the destruction of its active ingredients by high temperature. Finally, adding the tea tree essential oil ensures the stability of its active ingredients at a lower temperature and avoids volatilization at high temperature.

[0061] In some embodiments, the temperature of the first heating treatment is 40°C to 50°C. For example, the temperature of the first heating treatment is 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C and any value in between.

[0062] In some embodiments, the temperature of the second heating treatment is 70°C to 80°C. For example, the temperature of the second heating treatment is 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, or 80°C and any value in between.

[0063] In some embodiments, the temperature of the cooling treatment is 40°C to 50°C. For example, the temperature of the cooling treatment is 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C and any value in between.

[0064] In some of these embodiments, the rotation speed of the stirring treatment is 50 rpm to 100 rpm. For example, the rotation speed of the stirring treatment is 50 rpm, 52 rpm, 54 rpm, 56 rpm, 58 rpm, 60 rpm, 62 rpm, 64 rpm, 66 rpm, 68 rpm, 70 rpm, 72 rpm, 74 rpm, 76 rpm, 78 rpm, 80 rpm, 82 rpm, 84 rpm, 86 rpm, 88 rpm, 90 rpm, 92 rpm, 94 rpm, 96 rpm, 98 rpm or 100 rpm, as well as any value in between.

[0065] In some of these embodiments, the rotation speed of the homogenization treatment is 8000 rpm to 15000 rpm, and the time is 15 min to 30 min. For example, the rotation speed is 8000 rpm, 8500 rpm, 9000 rpm, 9500 rpm, 10000 rpm, 10500 rpm, 11000 rpm, 11500 rpm, 12000 rpm, 12500 rpm, 13000 rpm, 13500 rpm, 14000 rpm, 14500 rpm or 15000 rpm, as well as any value in between.

[0066] In some of these embodiments, the conditions of the vacuum treatment include: the vacuum degree is -0.08 MPa to -0.06 MPa, and the temperature is 35 °C to 45 °C. For example, the vacuum degree is -0.08 MPa, -0.07 MPa or -0.06 MPa, as well as any value in between. For example, the temperature is 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C or 45 °C, as well as any value in between.

[0067] The embodiments of the present application will be described in detail below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. For the experimental methods without specific conditions in the following examples, the guidance given in the present application should be preferentially referred to. It can also be carried out according to the experimental manuals or conventional conditions in the art, or according to the conditions recommended by the manufacturer, or referring to the experimental methods known in the art.

[0068] In the following specific examples, for the measurement parameters of the raw material components, if there is no special description, there may be slight deviations within the weighing accuracy range. For the temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0069] It should be understood that in various embodiments of the present application, the magnitudes of the serial numbers of the above processes do not mean the sequence of execution. The execution sequence of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.

[0070] Example 1

[0071] This example provides a method for preparing clotrimazole cream containing essential oil.

[0072] 1. Add 0.5 part of methylparaben to 70 parts of purified water, stir and disperse evenly, heat to 40 - 50 °C, and stir to obtain Component A for standby.

[0073] 2. Add 0.6 part of sorbitan stearate, 6 parts of polysorbate 60, 6 parts of cetostearyl alcohol, 7.85 parts of medium-chain triglyceride, 1 part of benzyl alcohol, 0.05 part of dibutylhydroxytoluene, and 6 parts of propylene glycol to a vacuum emulsifying tank, turn on the heating and raise the temperature to 80 °C, start stirring at a speed of 100 rpm to fully melt, dissolve, and mix the oil-phase components evenly. Add 1 part of clotrimazole, stir to dissolve, then turn on the refrigeration, and after cooling to 40 °C with stirring, add 1 part of tea tree essential oil, and stir fully to disperse it evenly to obtain Component B.

[0074] 3. Add Component A to Component B with stirring. After the transfer is completed, turn on the homogenization, and at the same time turn on the vacuum. The homogenization speed is 8000 rpm, the homogenization time is 20 min, the scraping wall stirring speed is 50 rpm, and the vacuum degree is 0.07 MPa. Keep the temperature at 40 °C during this process.

[0075] 4. After the above process is completed, turn on the cooling to 28 °C, and an external cream composition containing clotrimazole and tea tree essential oil can be prepared.

[0076] Example 2

[0077] This example provides a method for preparing clotrimazole cream containing essential oil.

[0078] 1. Add 0.3 part of methylparaben to 72 parts of purified water, stir and disperse evenly, heat to 40 °C, and stir to obtain Component A for standby.

[0079] 2. Add 0.3 part of sorbitan stearate, 3.5 parts of polysorbate 60, 6 parts of cetostearyl alcohol, 7.85 parts of medium-chain triglyceride, 1 part of benzyl alcohol, 0.05 part of dibutylhydroxytoluene, and 6 parts of propylene glycol to a vacuum emulsifying tank, turn on the heating and raise the temperature to 80 °C, start stirring at a speed of 100 rpm to fully melt, dissolve, and mix the oil-phase components evenly. Add 1 part of clotrimazole, stir to dissolve, then turn on the refrigeration, and after cooling to 40 °C with stirring, add 2 parts of tea tree essential oil, and stir fully to disperse it evenly to obtain Component B.

[0080] 3. Add component A to component B under stirring. After the transfer is completed, start homogenization and at the same time start vacuum. The homogenization speed is 8000 rpm, the homogenization time is 20 min, the scraping wall stirring speed is 50 rpm, and the vacuum degree is -0.07 MPa. Keep the temperature at 40 °C during this process.

[0081] 4. After the above process is completed, start cooling to 28 °C, and an external cream composition containing luliconazole and tea tree essential oil can be obtained.

[0082] Example 3

[0083] This example provides a preparation method of luliconazole cream containing essential oil.

[0084] 1. Add 0.14 parts of methylparaben to 73 parts of purified water and stir to disperse evenly. Heat to 40 °C and stir to obtain component A for standby.

[0085] 2. Add 0.75 parts of sorbitan stearate, 3.2 parts of polysorbate 60, 5.8 parts of cetostearyl alcohol, 8.85 parts of medium-chain triglyceride, 1 part of benzyl alcohol, 0.02 parts of dibutylhydroxytoluene, and 6 parts of propylene glycol to a vacuum emulsification tank. Start heating and raise the temperature to 80 °C. Start stirring at a speed of 100 rpm to fully melt, dissolve, and mix the oil-phase components evenly. Add 1 part of luliconazole, stir to dissolve, then start refrigeration. After cooling to 40 °C under stirring, add 2 parts of tea tree essential oil and stir well to disperse evenly to obtain component B.

[0086] 3. Add component A to component B under stirring. After the transfer is completed, start homogenization and at the same time start vacuum. The homogenization speed is 8000 rpm, the homogenization time is 20 min, the scraping wall stirring speed is 50 rpm, and the vacuum degree is -0.07 ± 0.01 MPa. Keep the temperature at 40 °C during this process.

[0087] 4. After the above process is completed, start cooling to 28 °C, and an external cream composition containing luliconazole and tea tree essential oil can be obtained.

[0088] Comparative Example 1

[0089] This comparative example provides a preparation method of luliconazole cream without essential oil

[0090] 1. Add 0.15 parts of methylparaben to 67.83 parts of purified water, heat to 45 °C, and stir to dissolve to obtain component A for standby.

[0091] 2. Add 2 parts of sorbitan stearate, 6 parts of isopropyl myristate, 4 parts of polysorbate 60, 10 parts of cetostearyl alcohol, 8 parts of medium-chain triglycerides, 1 part of benzyl alcohol, 0.02 part of butylated hydroxytoluene, and 1 part of propylene glycol into a vacuum emulsifying tank. Start heating and raise the temperature to 80 °C. Start stirring at a speed of 100 rpm to fully melt, dissolve, and mix the oil-phase components evenly. Add 1 part of luliconazole, stir until dissolved, then start refrigeration and cool down to 40 °C while stirring to obtain Component B.

[0092] 3. Add Component A to Component B under stirring. After the transfer is completed, start homogenization and at the same time start the vacuum. The homogenization speed is 8000 rpm, the homogenization time is 20 min, the scraping wall stirring speed is 50 rpm, and the vacuum degree is -0.07 MPa. Keep the temperature at 40 °C during this process.

[0093] 4. After the above process is completed, start cooling down to 28 °C to obtain the topical cream composition containing luliconazole.

[0094] Result verification:

[0095] I. Use the Franz diffusion cell method to compare the transdermal absorption rates of the topical cream compositions prepared in Examples 1 - 3 and Comparative Example 1.

[0096] Apply the cream evenly on the polypropylene film and measure the release rate at 37 °C for 6 hours. The results are shown in Table 1 below.

[0097] Table 1

[0098]

[0099]

[0100] The results show that the transdermal absorption rates of Examples 1 - 3 are all significantly higher than that of Comparative Example 1. The release rate of Example 3 is increased by 42% compared with Comparative Example 1, indicating that tea tree essential oil can significantly improve the transdermal absorption rate of luliconazole.

[0101] II. Use the microdilution method to determine the minimum inhibitory concentration (MIC) of Examples 1 - 3 and Comparative Example 1 against Trichophyton rubrum, Candida albicans, and Malassezia furfur. The results are shown in Table 2.

[0102] Table 2

[0103]

[0104] The results show that the MIC values of Examples 1 - 3 against the three common pathogenic fungi are all significantly lower than those of the comparative example, and the antibacterial activity is increased by 50% - 60%. The combination of tea tree essential oil and luliconazole has a significant synergistic antibacterial effect.

[0105] III. Use 12 guinea pigs with fungal infection models to evaluate the therapeutic effect of the cream and its irritation to the skin.

[0106] Method for establishing the model in guinea pigs: Select healthy guinea pigs (weighing 200 g - 250 g), shave the hair on their backs and scratch the skin (with a diameter of about 1 cm), and inoculate Trichophyton rubrum (1×10 CFU / mL). 48 hours after inoculation, confirm that the infection model is successfully established.

[0107] Randomly divide the guinea pigs into 2 groups, with 6 in each group, and apply the cream of Example 3 and the cream of Comparative Example 1 respectively, once a day for 14 consecutive days. Observe and compare the clinical symptoms and score according to the degree of erythema, desquamation, and pruritus (0 - 3 points, 0 means none, 3 means severe).

[0108] After the administration is completed, take the skin tissue at the infected site, homogenize it and inoculate it on Sabouraud agar medium, and count the colony - forming units (CFU / g) after culturing for 48 hours to determine the fungal load at the infected site. The results are shown in Table 3 below.

[0109] Table 3

[0110]

[0111] The results show that the clinical symptom score of the group of Example 3 on the 14th day is significantly lower than that of the comparative example group, indicating that the anti - inflammatory effect of tea tree essential oil accelerates the symptom relief; the fungal clearance rate of the group of Example 3 is 95.0%, which is significantly higher than that of the comparative example group (88.0%), proving that the combination of tea tree essential oil and clotrimazole has a stronger antifungal effect and reduces skin irritation.

[0112] It can be verified from the above results that the examples with added tea tree essential oil are superior to the comparative examples in terms of transdermal absorption, antibacterial activity, and skin irritation. The active ingredients in tea tree essential oil (such as terpinene - 4 - ol) combined with clotrimazole can significantly improve the inhibitory effect on common pathogenic fungi (such as Trichophyton rubrum, Candida albicans, Malassezia spp., etc.). Tea tree essential oil has a unique inhibitory effect on some drug - resistant strains (such as Malassezia), and the combination with clotrimazole can expand the antibacterial spectrum and is applicable to a wider range of fungal infection types. Traditional creams mostly rely on chemical penetration enhancers (such as isopropyl myristate), and the terpene components in tea tree essential oil (such as α - terpinene, γ - terpinene) can effectively promote the transdermal absorption of clotrimazole, reduce the dependence on chemical penetration enhancers, and reduce skin irritation. It can be seen that the formulations of Examples 1 - 3 all show good stability and clinical applicability, and are applicable to various skin problems with fungal infections and accompanying inflammation.

[0113] The above-described embodiments merely represent several implementation manners of the present application, facilitating a specific and detailed understanding of the technical solution of the present application, but should not be construed as a limitation on the scope of patent protection of the application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can be made, and these all fall within the protection scope of the present application. In addition, it should be understood that after reading the above teachings of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments based on the technical solution provided by the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A luliconazole composition containing essential oil, characterized in that: Including the following ingredients: Luliconazole, sorbitan stearate, tea tree oil, polysorbate 60, cetostearyl alcohol, medium chain triglycerides, methylparaben, benzyl alcohol, butylated hydroxytoluene, propylene glycol and purified water.

2. The luliconazole composition containing essential oil according to claim 1, characterized in that: By weight, it includes the following raw materials: 0.5-1.5 parts of luliconazole, 0.5-1 parts of sorbitan stearate, 1-2 parts of tea tree essential oil, 2-6 parts of polysorbate 60, 2-8 parts of cetostearyl alcohol, 4-10 parts of medium chain triglycerides, 0.1-0.5 parts of methylparaben, 0.5-2 parts of benzyl alcohol, 0.01-0.05 parts of butylated hydroxytoluene, 5-10 parts of propylene glycol and 50-90 parts of purified water.

3. The luliconazole composition containing essential oil according to claim 1, characterized in that: By weight, it includes the following raw materials: 0.8-1.2 parts of luliconazole, 0.6-0.8 parts of sorbitan stearate, 1.8-2 parts of tea tree essential oil, 3-4 parts of polysorbate 60, 5-6 parts of cetostearyl alcohol, 8-10 parts of medium chain triglycerides, 0.1-0.2 parts of methylparaben, 1-1.5 parts of benzyl alcohol, 0.03-0.04 parts of butylated hydroxytoluene, 6-8 parts of propylene glycol and 60-80 parts of purified water.

4. The luliconazole composition containing essential oil according to claim 1, characterized in that: By weight, it includes the following raw materials: 1 part of luliconazole, 0.75 parts of sorbitan stearate, 2 parts of tea tree oil, 3.2 parts of polysorbate 60, 5.8 parts of cetostearyl alcohol, 8.85 parts of medium chain triglycerides, 0.14 parts of methylparaben, 1 part of benzyl alcohol, 0.02 parts of butylated hydroxytoluene, 6 parts of propylene glycol and 73 parts of purified water.

5. A luliconazole cream containing essential oil, characterized in that: The cream contains the luliconazole composition containing essential oil according to any one of claims 1 to 4.

6. The method for preparing the luliconazole cream containing essential oil according to claim 5, characterized in that: include: The methylparaben is added to purified water and stirred to be uniformly dispersed, and a first heating treatment is performed and mixed to prepare component A; The sorbitan stearate, the polysorbate 60, the cetostearyl alcohol, the medium chain triglyceride, the benzyl alcohol, the butylated hydroxytoluene and the propylene glycol are mixed, subjected to a second heating treatment, and then subjected to a stirring treatment; Adding the luliconazole, cooling the mixture, and then adding the tea tree essential oil and mixing the mixture to prepare component B; and, The component A and the component B are mixed, homogenized and vacuum treated to prepare a luliconazole cream containing essential oil.

7. The method for preparing luliconazole cream containing essential oil according to claim 6, characterized in that: The temperature of the first heating treatment is 40°C to 50°C; and / or The temperature of the second heating treatment is 70°C to 80°C; and / or The temperature of the cooling treatment is 40°C to 50°C.

8. The method for preparing luliconazole cream containing essential oil according to claim 6, characterized in that: The rotation speed of the stirring treatment is 50 rpm to 100 rpm.

9. The method for preparing luliconazole cream containing essential oil according to claim 6, characterized in that: The homogenization conditions include: a rotation speed of 8000 rpm to 15000 rpm and a time of 15 min to 30 min.

10. The method for preparing luliconazole cream containing essential oil according to claim 6, characterized in that: The conditions of the vacuum treatment include: a vacuum degree of -0.08 MPa to -0.06 MPa and a temperature of 35°C to 45°C.

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