Composition for treating fungal infection of skin or nails and preparation method thereof

Abstract

The invention discloses a composition for treating fungal infection of skin or nails and a preparation method thereof. The ionic liquid containing efinaconazole and salicylic acid and the ionic liquid urea polylipoic acid gel prepared by the invention are suitable for externally applied skin or nail administration, have good nail permeability and retention property, can persistently reside in the administrated skin or nail area and are not easily influenced by water and the like in the environment; the medicine is continuously released to treat diseases, and the outer surface of the gel is not adhered to clothes. The ionic liquid urea gel irradiated by ultraviolet light is good in compliance, strong in antifungal effect and strong in infiltration promotion effect when being used for treating fungal infection of skin or nails, can be used as a clinical drug treatment method for fungal infection of skin or nails, and has important significance for treatment of fungal infection of skin or nails.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a composition for treating fungal infections of the skin or nails and a preparation method thereof. Background Art

[0002] Skin fungal infection, also known as dermatophytosis or superficial fungal disease, is an infectious disease caused by fungi invading superficial tissues such as the skin, hair, and nail plate. When fungi invade human skin and multiply in large numbers, they destroy the normal structure and function of the skin and cause a series of clinical symptoms. Common pathogenic fungi include dermatophytes (such as Trichophyton rubrum, Trichophyton mentagrophytes, etc.), yeasts (Candida) and molds. Common types and clinical manifestations include tinea capitis, tinea corporis, tinea cruris, tinea manuum, tinea pedis, tinea versicolor and onychomycosis. Because it is difficult for drugs to penetrate deep into the body, resulting in insufficient local drug concentration, onychomycosis and tinea capitis are the most difficult to treat among skin fungal infections.

[0003] Onychomycosis is a disease caused by skin fungi or non-dermatophytes infecting the nail plate or subungual tissue. Taking onychomycosis as an example, the unique therapeutic prospects of the present invention for superficial fungal diseases are verified. Onychomycosis is the most common nail disease in clinical practice. It affects approximately 10% of the general population, 20% of people over 60 years old, and 50% of people over 70 years old. Onychomycosis can cause local pain, difficulty in daily activities, and social disorders. If onychomycosis is not treated, the risk of secondary fungal or bacterial infection increases. Onychomycosis is mainly caused by skin fungi, sometimes by yeasts or molds, which can affect part or all of the components of the nail structure. Skin fungi account for 90% of the causes of the disease, of which the most common is Trichophyton rubrum (71%). About 10% of onychomycosis is caused by non-dermatophytes, such as Aspergillus, Fusarium, or Candida.

[0004] Human nails are composed of multiple layers of keratinocytes, which fuse into a dense and somewhat elastic mass, ultimately composed primarily of α-keratin. Nails are firmly attached to the musculoskeletal system and serve as the body's strongest barrier. Topical medications often have difficulty penetrating the nail plate. Local injections into nail tissue are associated with severe pain. The nail is at the end of the blood circulation system, limiting the effectiveness of systemic treatments. These factors make the treatment of onychomycosis challenging.

[0005] Due to the unique structure of the nail, the complete cure rate of efinaconazole for onychomycosis is 15.2–17.8%, which does not meet the treatment needs of most patients. More appropriate dosing regimens are needed to achieve long-term treatment and good compliance to eradicate the fungus and achieve acceptable clinical outcomes.

[0006] The present invention combines the antifungal drug efinaconazole with the nail penetration enhancer salicylic acid to produce an ionic liquid containing efinaconazole and salicylic acid. The ionic liquid and urea are then co-loaded into a system consisting of polylipoic acid (PTA) and arginine (Arg) to produce an ionic liquid-urea gel. After irradiation with ultraviolet light, the ionic liquid-urea gel continuously releases the ionic liquid and urea, softening the nails and promoting drug penetration, thereby treating fungal infections of the skin or nails. Summary of the Invention

[0007] The present invention aims to solve at least one of the above-mentioned technical problems in the prior art. To this end, the present invention aims to provide a composition for treating fungal infections of the skin or nails and a preparation method thereof.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention provides a composition comprising an ionic liquid prepared from a triazole derivative antifungal drug and an organic acid.

[0010] In some embodiments of the present invention, the glass transition temperature of the ionic liquid is -50°C to -40°C.

[0011] In some embodiments of the present invention, the glass transition temperature of the ionic liquid is -50°C to -45°C.

[0012] In some embodiments of the present invention, the triazole derivative antifungal drug includes at least one of efinaconazole, itraconazole, posaconazole or voriconazole.

[0013] In some embodiments of the present invention, the organic acid comprises at least one of salicylic acid, malic acid, tartaric acid, or citric acid.

[0014] In some embodiments of the present invention, the composition further comprises one or more pharmaceutically acceptable additives.

[0015] In some embodiments of the present invention, the additive is selected from at least one of a penetration enhancer, a moisturizer, a stabilizer, or an antioxidant.

[0016] In some embodiments of the present invention, the penetration enhancer comprises at least one of urea, N-acetyl-L-cysteine, N-methyl-2-pyrrolidone, or octadecanol.

[0017] In some embodiments of the present invention, the humectant includes at least one of ethylene glycol, betaine, maltitol, or glycerin, but is not limited thereto.

[0018] In some embodiments of the present invention, the antioxidant includes at least one of sodium bisulfite, sodium sulfite, sodium thiosulfate or sodium metabisulfite, but is not limited thereto.

[0019] In some embodiments of the present invention, the dosage form of the composition includes a cream, a gel, an ointment, a solution, a spray or a patch.

[0020] The second aspect of the present invention provides a gel containing the above composition, wherein the gel comprises polylipoic acid gel, poly (N-isopropylacrylamide) gel or tannic acid-lipoic acid hydrogel.

[0021] In some embodiments of the present invention, the gel comprises 10 to 30% by weight of the above-mentioned ionic liquid and 10 to 30% by weight of an additive.

[0022] In some embodiments of the present invention, the raw material composition of the gel is shown in the following table:

[0023]

[0024]

[0025] The third aspect of the present invention provides a method for preparing the above-mentioned gel, the preparation method comprising the following steps:

[0026] (1) dissolving a triazole derivative antifungal drug and an organic acid in an organic solvent, and evaporating the organic solvent to obtain an ionic liquid;

[0027] (2) Adding additives to the ionic liquid and loading the additives on the gel to obtain the gel.

[0028] In some embodiments of the present invention, the organic solvent includes at least one of anhydrous ethanol, methanol, acetone or acetonitrile, but is not limited thereto.

[0029] In some embodiments of the present invention, the gel is polylipoic acid gel.

[0030] In some embodiments of the present invention, the loading comprises the following steps:

[0031] (1) Add arginine to ethanol solution and dissolve;

[0032] (2) adding the ionic liquid and additives to the solution prepared in (1) and dissolving them;

[0033] (3) Add lipoic acid to the solution obtained in (2), and heat and stir to obtain the gel.

[0034] In some embodiments of the present invention, the heating temperature is 60-80°C.

[0035] In some embodiments of the present invention, the stirring time is 20-40 minutes.

[0036] In some embodiments of the present invention, the temperature at which the organic solution is evaporated is 20°C-40°C.

[0037] The fourth aspect of the present invention provides use of the above composition in the preparation of a product for preventing and / or treating fungal infections of the skin or nails.

[0038] A fifth aspect of the present invention provides use of the gel in preparing a product for preventing and / or treating fungal infections of the skin or nails, wherein the gel is treated with ultraviolet light.

[0039] In some embodiments of the present invention, the ultraviolet light irradiation treatment time is 1-15 minutes.

[0040] In some embodiments of the present invention, the ultraviolet light irradiation treatment lasts for 1-10 minutes.

[0041] In some embodiments of the present invention, the intensity of the ultraviolet light is 1 to 5 W / cm 2 .

[0042] In some embodiments of the present invention, the intensity of the ultraviolet light is 3W / cm 2 .

[0043] In some embodiments of the invention, the fungus comprises at least one of Trichophyton rubrum, Trichophyton mentagrophytes, Fusarium spp., Aspergillus fumigatus, or Candida albicans.

[0044] The beneficial effects of the present invention are:

[0045] The present invention provides a composition for treating fungal infections of the skin or nails. The prepared ionic liquid and ionic liquid urea-polylipoic acid gel are suitable for topical administration to the skin or nails, and exhibit excellent nail permeability and retention. By preparing efinaconazole as an ionic liquid, the present invention improves the solubility and permeability of efinaconazole, particularly enhancing nail permeability. Furthermore, the nail permeation-enhancing effect of the ionic liquid synergizes with that of urea, further enhancing drug penetration.

[0046] The ionic liquid urea polylipoic acid gel prepared by the present invention has a double-sided characteristic: it adheres to the administration site and has a non-adhesive outer surface. This allows the preparation to remain permanently in the skin or nail area where it is administered, making it less susceptible to environmental influences such as water, thereby achieving sustained drug release for treatment. Furthermore, the outer surface of the gel does not adhere to clothing. Furthermore, the ionic liquid urea gel irradiated with ultraviolet light exhibits good compliance for the treatment of fungal skin or nail infections, strong antifungal activity, and enhanced penetration. It can be used as a clinical drug treatment for fungal skin or nail infections, and has significant therapeutic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The figures show the appearance of efinaconazole, salicylic acid, and the ionic liquid prepared from efinaconazole and salicylic acid.

[0048] Figure 2 Differential scanning calorimetry diagrams of efinaconazole, salicylic acid, and the ionic liquid prepared from efinaconazole and salicylic acid.

[0049] Figure 3 Differential scanning calorimetry (DSC) of the physical mixture and ionic liquid prepared from efinaconazole and salicylic acid.

[0050] Figure 4 This is a storage stability diagram of the efinaconazole content in ionic liquid.

[0051] Figure 5 This is a storage stability diagram of salicylic acid content in ionic liquids.

[0052] Figure 6 This figure shows the nail penetration characteristics of efinaconazole in an ionic liquid prepared from efinaconazole and salicylic acid.

[0053] Figure 7 The figure shows the nail retention of efinaconazole in the ionic liquid prepared from efinaconazole and salicylic acid.

[0054] Figure 8 This figure shows the effect of ionic liquid prepared from efinaconazole and salicylic acid on the morphology of Fusarium.

[0055] Figure 9 Schematic diagram of self-healing of ionic liquid urea gel.

[0056] Figure 10 This is a diagram evaluating the self-healing ability of ionic liquid urea gel.

[0057] Figure 11 This is a graph showing the change in complex viscosity of ionic liquid urea gel after UV irradiation.

[0058] Figure 12 This is a diagram showing the change in surface viscosity of ionic liquid urea gel after ultraviolet light irradiation.

[0059] Figure 13 The formulation appearance and viscoelasticity graphs of polylipoic acid gel, ionic liquid gel prepared from efinaconazole and salicylic acid, urea gel and ionic liquid urea gel prepared from efinaconazole and salicylic acid.

[0060] Figure 14 This is a diagram showing the water washout resistance evaluation of ionic liquid urea gel under UV illumination.

[0061] Figure 15 Schematic diagram of the experiment to evaluate the nail softening effect of ionic liquid urea gel under ultraviolet light.

[0062] Figure 16 This is a diagram evaluating the nail softening effect of ionic liquid urea gel under ultraviolet light.

[0063] Figure 17 This is a bar chart analyzing the maximum anti-deformation force of the nail softening effect of the ionic liquid urea gel irradiated with ultraviolet light; #, ##, and ### represent significant differences compared with the control group with p<0.05, 0.01, and 0.001, respectively.

[0064] Figure 18 This is the release graph of efinaconazole from ionic liquid urea gel under UV light.

[0065] Figure 19 The release diagram of salicylic acid from ionic liquid urea gel under UV light.

[0066] Figure 20 This is a graph showing the nail penetration characteristics of efinaconazole in ionic liquid urea gel under UV light.

[0067] Figure 21 This is the retention result of efinaconazole in ionic liquid urea gel in bovine hoof under UV light.

[0068] Figure 22 This is a diagram showing the nail penetration characteristics of salicylic acid in ionic liquid urea gel under UV light.

[0069] Figure 23 This is the retention result of salicylic acid in bovine hoof in ionic liquid urea gel irradiated with UV light.

[0070] Figure 24 This figure shows the experimental results of in vitro antifungal activity of ionic liquid urea gel irradiated with ultraviolet light.

[0071] Figure 25 Figure 5 is a statistical diagram of the diameter of the inhibition zone of the in vitro antifungal activity of the ionic liquid urea gel irradiated with ultraviolet light; Figure A is a diagram of the inhibition diameter of the ionic liquid urea gel irradiated with ultraviolet light against Trichophyton rubrum; Figure B is a diagram of the inhibition diameter of the ionic liquid urea gel irradiated with ultraviolet light against Trichophyton mentagrophytes.

[0072] Figure 26 Figure 5 is a statistical graph of the diameter of the inhibition zone of the in vitro antifungal activity of the ionic liquid urea gel irradiated with ultraviolet light; A is a graph of the inhibition diameter of the ionic liquid urea gel irradiated with ultraviolet light against Fusarium spp.; B is a graph of the inhibition diameter of the ionic liquid urea gel irradiated with ultraviolet light against Aspergillus fumigatus; C is a graph of the inhibition diameter of the ionic liquid urea gel irradiated with ultraviolet light against Candida albicans. DETAILED DESCRIPTION

[0073] The present invention is further described in detail below using specific examples. Unless otherwise specified, the raw materials, reagents, and apparatus used in the examples and comparative examples are available from conventional commercial sources or by conventional methods. Unless otherwise specified, all experimental or testing methods are conventional in the art.

[0074] Example 1 Preparation of an ionic liquid containing efinaconazole and salicylic acid

[0075] This example provides the preparation of an ionic liquid containing efinaconazole and salicylic acid, and tests the properties, stability, penetration-enhancing ability, and antibacterial ability of the prepared ionic liquid. The specific experimental steps are as follows.

[0076] Efinaconazole and salicylic acid were added to anhydrous ethanol according to the amount of raw materials shown in Table 1 below, dispersed evenly, stirred at room temperature for 4 hours, and most of the ethanol was evaporated by rotary evaporation at 30°C. The resulting liquid was then vacuum dried at 30°C for 72 hours to obtain an ionic liquid containing efinaconazole and salicylic acid. Figure 1 As shown, the prepared ionic liquid is a light yellow viscous liquid.

[0077] Table 1 Raw materials for the preparation of ionic liquids containing efinaconazole and salicylic acid

[0078] raw material Usage Efinaconazole 3.00g Salicylic acid 2.97g Anhydrous ethanol 3mL

[0079] The properties, stability, penetration-enhancing ability and antibacterial ability of the prepared ionic liquid were then tested.

[0080] 1. Evaluation of the properties of ionic liquids

[0081] The ionic liquid was heated at a rate of 10°C / min over the range of 40-200°C using a differential scanning calorimeter, and the heating curves were compared with those of the same mass of efinaconazole and salicylic acid. Simultaneously, the ionic liquid was heated at a rate of 10°C / min over the range of -90-10°C, and the heating curves were compared with those of a physical mixture of efinaconazole and salicylic acid with the same composition.

[0082] The experimental results are as follows Figure 2-3As shown, the ionic liquid has no endothermic peak at the melting temperature of both efinaconazole and salicylic acid components ( Figure 2 Compared with physical mixtures, ionic liquids exhibit a glass transition temperature at -48.0℃ ( Figure 3 ), indicating that there were no efinaconazole or salicylic acid crystals in the ionic liquid, and it presented a viscous flow state.

[0083] 2. Stability evaluation of ionic liquids

[0084] The stability of efinaconazole and salicylic acid in ionic liquids is fundamental to their practical application. Therefore, the stability of the prepared ionic liquids must be evaluated. The stability of both components in ionic liquids was determined over a six-month period. The specific experimental steps are as follows.

[0085] The ionic liquid was stored at room temperature in the dark (n=3). 20 mg samples were taken after 0, 1, 2, 3, and 6 months, respectively, and dissolved in anhydrous ethanol. The contents of efinaconazole and salicylic acid in the samples were determined by HPLC, respectively. The drug contents of efinaconazole and salicylic acid ethanol solutions stored simultaneously under the same conditions were used as reference values.

[0086] The experimental results are as follows Figure 4-5 As shown, after being stored at room temperature and away from light for 6 months, the relative content of efinaconazole in the ionic liquid was 99.98% ( Figure 4 ), the relative content of salicylic acid is 97.69% ( Figure 5 ), proving that ionic liquids are completely stable.

[0087] 3. Evaluation of the penetration-enhancing ability of ionic liquids

[0088] This example provides an evaluation of the penetration-enhancing ability of the ionic liquid prepared in Example 1. The specific experimental steps are as follows.

[0089] Bovine hoof nails were sliced ​​into 200 μm-thick sections using a cryostat and mounted on diffusion cells. 25.12 mg of the following solutions were added to the diffusion cells: S1: 10% (w / w) efinaconazole in anhydrous ethanol, S2: a commercially available efinaconazole solution, S3: 20% (w / w) ionic liquid in anhydrous ethanol, S4: 20% (w / w) urea and 10% (w / w) efinaconazole in anhydrous ethanol, and S5: 20% (w / w) urea and 20% (w / w) ionic liquid in anhydrous ethanol. 4% (w / w) oleth-20 was added to the receiving cell as a receiving solution.

[0090] At 32°C and 250 rpm, 1 mL of the receiving solution was taken out at 1, 2, 4, 6, 8, 12, and 24 hours, and the same volume of blank receiving solution was added. The drug was determined by HPLC, and the cumulative permeation amount was calculated according to the following formula:

[0091]

[0092] V is the volume of the receiving solution, Vi is the sampling volume, Cn is the drug concentration of the nth sampling, Ci is the drug concentration of the ith sampling, and Q is the cumulative permeation amount of efinaconazole in the nth sampling.

[0093] After 24 hours, the ox hoof slices were washed and chopped, and the drug was extracted with anhydrous ethanol by ultrasonic wave for 60 minutes. The extract was centrifuged at 14,000 rpm for 15 minutes, and the supernatant was used to determine the content of efinaconazole by HPLC. The retention rate of the drug in the ox hoof slices was calculated.

[0094] The experimental results are as follows Figure 6-7 As shown in the results, the permeability of efinaconazole in ionic liquids in cattle hoof slices was significantly improved compared with other solutions. At the same time, ionic liquids showed higher permeability than 10% efinaconazole solution containing 20% ​​urea, while no drug permeation was detected in 10% efinaconazole solution and commercial solution after 24 hours ( Figure 6 ).at the same time, Figure 7 It can be seen that the nail retention amount of efinaconazole in the ionic liquid is much higher than that of the commercially available efinaconazole solution or the anhydrous ethanol solution of efinaconazole, and the anhydrous ethanol solution containing 20% ​​urea and 20% ionic liquid further increases the nail retention amount of efinaconazole.

[0095] At the same time, the combination index (CI) of ionic liquid and urea penetration enhancement was calculated by King's method, and the formula is as follows:

[0096]

[0097] King's method explains the significance of CI values ​​as follows: CI values ​​between 0.85 and 1.15 indicate simple addition; between 1.15 and 20 indicate enhancement, and >20 indicates significant enhancement; CI values ​​between 0.85 and 0.55 indicate antagonism, and <0.55 indicates obvious antagonism.

[0098] At 24 h, the enhanced permeation effect of ionic liquid resulted in 3.12 ± 0.40% permeation of efinaconazole through the nail, as shown in the permeation rate P A The penetration enhancement effect of urea resulted in 1.57±0.30% transungual penetration of efinaconazole, which was expressed as the permeability P B The enhanced permeation of efinaconazole by ionic liquid and urea resulted in a permeation of 5.75±0.76% through the nail, as shown in the permeation rate P AB .

[0099] The calculated combined index of ionic liquid and urea in promoting nail penetration is 1.24, and there is an enhanced penetration-promoting effect in the combined application, so the two have a synergistic nail penetration-promoting effect.

[0100] 4. Evaluation of the antifungal ability of ionic liquids

[0101] The antifungal activity of the prepared ionic liquid was evaluated. Fusarium was a standard strain purchased from the China Industrial Microbiological Culture Collection. The specific experimental steps are as follows.

[0102] (1) Inoculate Fusarium spp. on Sabouraud dextrose agar (SDA) and invert the plate for culture (28 ± 2°C).

[0103] (2) Pick up the activated single colony of Fusarium spp. in (1) and add it to 2 mL of Sabouraud dextrose broth (SDB). Use a McFarland turbidimeter tube to adjust the turbidity of the bacterial solution to 0.5 McFarland units (1-5×10 6 CFU / mL).

[0104] (3) The following solutions were added to the bacterial solution prepared in (2): S1: anhydrous ethanol; S2: 10% (w / w) efinaconazole solution in anhydrous ethanol; S3: 10% (w / w) salicylic acid solution in anhydrous ethanol; S4: 20% (w / w) ionic liquid solution in anhydrous ethanol; the volume ratio of bacterial solution to drug solution in each group was 9:1, that is, 0.2 mL of the above solution was mixed with 1.8 mL of bacterial solution, and the mixed bacterial solution was cultured at 28±2°C for 24 hours.

[0105] (4) The bacterial solution after culture in (3) was fixed with 2.5% glutaraldehyde solution and dehydrated in 30%, 50%, 70%, 90% and anhydrous ethanol, respectively. The treated bacterial solution was dropped onto a glass slide, air-dried, and the fungal morphology was observed using an optical microscope and a scanning electron microscope.

[0106] The experimental results are as follows Figure 8 As shown, when 20% ionic liquid anhydrous ethanol solution was used to treat Fusarium, the effect was similar to that produced by the efinaconazole solution. The hyphae structure of Fusarium collapsed and shrank and could not maintain a complete structure, which proved that the efinaconazole in the ionic liquid played a good antibacterial effect. Compared with salicylic acid, efinaconazole is the main component of the antibacterial effect.

[0107] In summary, the above experimental results successfully prepared an ionic liquid with a mass ratio of efinaconazole to salicylic acid close to 1:1, which is stable for a long time at room temperature and protected from light, and has excellent penetration-promoting, combined penetration-promoting and antibacterial effects.

[0108] Example 2 Preparation of ionic liquid urea gel

[0109] This example provides a method for preparing an ionic liquid urea gel prepared from the ionic liquid obtained in Example 1, as well as an evaluation of the self-healing ability of the prepared ionic liquid urea gel and an examination of the effects of ultraviolet light on the complex viscosity and surface adhesion of the ionic liquid urea gel. The specific experimental steps are as follows.

[0110] (1) Add 0.19 g of arginine to 0.87 g of 70% ethanol and stir to dissolve in a 70°C water bath.

[0111] (2) 0.54 g of ionic liquid and 0.54 g of urea were added to the solution prepared in (1) and dissolved.

[0112] (3) 0.58 g of lipoic acid was added to the solution prepared in (2) and rapidly stirred at 70° C. for 30 min. During the heating process, lipoic acid polymerized into polylipoic acid to obtain an ionic liquid urea gel. The raw material contents of the prepared gel are shown in Table 2 below.

[0113] Table 2 Ionic liquid urea gel raw material content

[0114] raw material Content (w / w) Lipoic acid 21％ Arginine 7％ urea 20％ Ionic liquids 20％ Anhydrous ethanol 9％ water 23％

[0115] The self-healing ability of the prepared ionic liquid urea gel was then evaluated, and the effect of ultraviolet light on the complex viscosity and surface adhesion of the ionic liquid urea gel was tested, as follows.

[0116] 1 Evaluation of the self-healing ability of ionic liquid urea gel

[0117] In daily activities, the skin or nails inevitably come into contact with foreign matter, which can cause the preparations applied to the nails to be scratched or deformed. Therefore, it is necessary to evaluate the self-healing ability of the prepared ionic liquid urea gel. The specific experimental steps are as follows.

[0118] Rhodamine B and trypan blue were added to the ionic liquid urea gel to obtain gel blocks of different colors. The self-healing ability of the gel was observed by placing the gel blocks in contact with each other. At the same time, the ionic liquid urea gel (IL-URE-PTG) was loaded onto a rheometer. At 32°C and a frequency of 1 Hz, low shear strain (1%) and high shear strain (100%, 200%, 300%) were alternately applied to the sample. Each stage lasted for 100 seconds, and the changes in the sample's mechanical modulus were recorded.

[0119] The results are as follows Figure 9-10 As shown, the separated ionic liquid urea gel can quickly fuse and recover into a single gel ( Figure 9 ). Under the switching conditions of high shear strain and low shear strain, ionic liquid urea can still recover its original mechanical modulus ( Figure 10). This indicates that ionic liquid urea exhibits good self-healing ability and is suitable for application on skin or nails.

[0120] 2 Effect of UV light on the complex viscosity of ionic liquid urea gel

[0121] The effect of ultraviolet light on the complex viscosity of the ionic liquid urea gel prepared in Example 2 was detected. The specific experimental steps are as follows.

[0122] The ionic liquid urea gel was placed on the sample stage of the rheometer and the rheometer was used at 32°C for 3 W / cm 2 After UV irradiation for 1, 2, 3, 4, and 5 minutes, the viscoelastic changes in the shear strain range of 0.1 to 100% were measured, and the complex viscosity of the samples was calculated according to the following formula, and the average values ​​were compared.

[0123]

[0124] where |η * | is the complex viscosity, G' is the storage modulus, G" is the loss modulus, and ω is the angular frequency.

[0125] The experimental results are as follows Figure 11 As shown in the Figure 3, the complex viscosity of the ionic liquid urea gel increases with the extension of UV irradiation time, indicating that UV treatment can enhance the cross-linking of the ionic liquid urea gel.

[0126] 3 Effect of UV light on the surface adhesion of ionic liquid urea gel

[0127] The effect of ultraviolet light on the surface adhesion of the ionic liquid urea gel prepared in Example 2 was detected. The specific experimental steps are as follows.

[0128] 0.1 g of ionic liquid urea gel was applied to a glass slide and irradiated with ultraviolet light for 5 minutes. Another glass slide with rat skin attached was placed on the upper surface of the gel. The two glass slides were separated by pulling them in the normal direction using an electronic universal testing machine. The pulling force was recorded. The ionic liquid urea gel that had not been irradiated with ultraviolet light was used as a control.

[0129] The experimental results are as follows Figure 12As shown, UV-treated ionic liquid urea gels exhibit significantly reduced adhesion to the top surface compared to untreated gels. This is because disulfide bonds within polylipoic acid molecules break under UV light, forming sulfhydryl radicals. These sulfhydryl radicals between different polylipoic acid molecules rearrange and reorganize, causing secondary crosslinking of the ionic liquid urea gel, altering the gel's viscoelasticity and surface viscosity. Ionic liquid urea gels are designed for application to the skin or nails. Due to frequent contact with the environment during daily activities, they require a certain degree of adhesion to ensure they adhere to the application area after administration. However, the adhesion of the top surface should be limited to prevent loss of the gel from contact with foreign matter. Secondary crosslinking of the ionic liquid urea gels by UV light irradiation reduces the adhesion of the top surface, minimizing loss due to daily activities. This facilitates the gel's prolonged retention in the application area, releasing efinaconazole and salicylic acid to treat fungal skin or nail infections.

[0130] Comparative Example 1 Preparation of Blank Polylipoic Acid Gel

[0131] This example provides the preparation of a blank polylipoic acid gel, which differs from the ionic liquid urea gel prepared in Example 2 in that the gel prepared in this example does not contain urea or ionic liquid. The specific experimental steps are as follows.

[0132] (1) Add 0.19 g of arginine to 1.94 g of 70% ethanol and stir to dissolve in a 70°C water bath.

[0133] (2) 0.58 g of lipoic acid was added to the solution prepared in (1) and rapidly stirred at 70° C. for 30 min. During the heating process, lipoic acid polymerized into polylipoic acid to obtain a blank polylipoic acid gel. The raw material content of the gel is shown in Table 3 below.

[0134] Table 3 Blank polylipoic acid gel raw material content

[0135] raw material Content (w / w) Lipoic acid 21％ Arginine 7％ Anhydrous ethanol 21％ water 51％

[0136] Comparative Example 2 Preparation of ionic liquid gel

[0137] This example provides the preparation of an ionic liquid gel, which differs from the ionic liquid urea gel prepared in Example 2 in that the gel prepared in this example does not contain urea. The specific experimental steps are as follows.

[0138] (1) Add 0.19 g of arginine to 1.41 g of 70% ethanol and stir to dissolve in a 70°C water bath.

[0139] (2) 0.54 g of ionic liquid was added to the solution prepared in (1) and dissolved.

[0140] (3) 0.58 g of lipoic acid was added to the solution prepared in (2) and rapidly stirred at 70° C. for 30 min. During the heating process, lipoic acid polymerized into polylipoic acid to obtain an ionic liquid gel. The raw material content of the gel is shown in Table 4 below.

[0141] Table 4 Raw materials for preparation of ionic liquid gel

[0142] raw material Content (w / w) Lipoic acid 21％ Arginine 7％ Ionic liquids 20％ Anhydrous ethanol 15％ water 37％

[0143] Comparative Example 3 Preparation of urea gel

[0144] This example provides a method for preparing a urea gel. The difference between this example and the ionic liquid urea gel prepared in Example 2 is that the gel prepared in this example does not contain an ionic liquid. The specific experimental steps are as follows.

[0145] (1) Add 0.19 g of arginine to 1.41 g of 70% ethanol and stir to dissolve in a 70°C water bath.

[0146] (2) 0.54 g of urea was added to the solution prepared in (1) and dissolved.

[0147] (3) 0.58 g of lipoic acid was added to the solution prepared in (2) and rapidly stirred at 70° C. for 30 min. During the heating process, lipoic acid polymerized into polylipoic acid to obtain an ionic liquid gel. The raw material content of the gel is shown in Table 5 below.

[0148] Table 5 Raw materials for preparation of urea gel

[0149]

[0150]

[0151] Effect Example 1 Viscoelasticity Evaluation of Ionic Liquid Urea Gel

[0152] This example provides viscoelastic evaluations of the blank polylipoic acid gel (F1) prepared in Comparative Example 1, the ionic liquid gel (F2) prepared in Comparative Example 2, the urea gel (F3) prepared in Comparative Example 3, and the ionic liquid urea gel (F4) prepared in Example 2. The appearance and content (w / w) of the ionic liquid gels prepared in each group are shown in FIG. Figure 13 shown.

[0153] In this example, the storage modulus (G') and loss modulus (G") of each gel composite were measured by a rheometer at 32°C and an amplitude of 1% within an angular frequency range of 0.1 to 100 rad / s.

[0154] The experimental results are as follows Figure 13As shown, the storage modulus (G') of each group of gel composites within the scanning range is always higher than the loss modulus (G"), reflecting that each group of gel composites is in a semi-solid form. By adding ionic liquid and urea to the polylipoic acid gel, a semi-solid ionic liquid urea gel can be prepared.

[0155] Effect Example 2 Effect of UV Light on Wet Adhesion of Ionic Liquid Urea Gel Surface

[0156] Skin and nails are easily exposed to water or humid environments during daily activities and may be washed away by water. Therefore, formulations applied to body surfaces must exhibit the necessary wet adhesion. Therefore, this example investigates the effect of UV light on the wet adhesion of the ionic liquid urea gel prepared in Example 2. The specific experimental steps are as follows.

[0157] 0.2 g of ionic liquid urea gel was coated on a glass slide and the UV light intensity was 3 W / cm 2 The sample was immersed in water and shaken at 50 rpm. The state of the hydrogel and the change of residual mass over time were recorded to investigate the effect of the humid environment on the gel retention.

[0158] The experimental results are as follows Figure 14 As shown in the figure, the residual mass of the ionic liquid urea gel after 12 hours of experiment was 42.31%, showing good wet adhesion and water washability. After the ionic liquid urea gel was treated with ultraviolet light, its wet adhesion was further enhanced, with the residual mass of 58.21% after 12 hours.

[0159] Effect Example 3 Evaluation of the nail softening ability of ionic liquid urea gel

[0160] This example provides an evaluation of the nail softening ability of the ionic liquid urea gel prepared in Example 2 after UV irradiation. The specific experimental steps are as follows.

[0161] 0.3 g of the following formula was applied to bovine hoof sections and incubated for 12 hours. Control group: 70% ethanol; ionic liquid group: 70% ethanol solution containing 20% ​​(w / w) ionic liquid; urea group: 70% ethanol solution containing 20% ​​(w / w) urea; ionic liquid + urea group: 70% ethanol solution containing 20% ​​(w / w) ionic liquid and 20% (w / w) urea; blank gel group: blank polylipoic acid gel; ionic liquid urea gel; UV + blank gel group: UV light (light intensity of 3 W / cm 2 Blank polylipoic acid gel irradiated with UV light (5 min continuous light treatment); UV + ionic liquid gel group: UV light (light intensity of 3 W / cm 2 Ionic liquid gel irradiated with UV light (5 min continuous light treatment); UV + urea gel group: UV light (light intensity of 3 W / cm2 urea gel irradiated with UV light (light intensity of 3 W / cm 2 The ionic liquid urea gel was then treated with continuous light for 5 minutes. Hoof nail sections from each group were then removed, cleaned, and placed on an electronic universal testing machine to measure their maximum deformation resistance.

[0162] The maximum deformation resistance test diagram is as follows Figure 15 The experimental results are shown in Figure 16-17 As shown in Figure 2, the ionic liquid urea gel irradiated by UV light significantly reduced the maximum deformation resistance of cattle hoof slices ( Figure 16 ). The blank polylipoic acid gel treated with UV light can also soften the cattle hoof slices. It is speculated that this may be because the ultraviolet light causes some of the disulfide bonds in the polylipoic acid molecules to break, and the resulting sulfur free radicals have an impact on the disulfide bonds in the nail structure, breaking the disulfide bonds in the nails and changing the dense structure of the nails. The combination of ionic liquid or urea and ultraviolet light (continuous 5 minutes of light treatment) gel can further soften the nails. Among them, the ionic liquid urea gel irradiated with UV light has the most obvious reduction in the maximum deformation resistance ( Figure 17 ).

[0163] Effect Example 4 Evaluation of the Release of Efinaconazole and Salicylic Acid by Ionic Liquid Urea Gel

[0164] This example provides tests on the release rates of efinaconazole and salicylic acid in the ionic liquid urea gel prepared in Example 2, the ionic liquid gel prepared in Comparative Example 2, and the ionic liquid urea gel irradiated with ultraviolet light.

[0165] Ionic liquid gel, ionic liquid urea gel, and ionic liquid urea gel irradiated with UV light (5 minutes of continuous illumination) were placed in the donor cell of a Franz diffusion cell. The receiving cell was filled with 4% Oleth-20 as the receiving medium and a mixed cellulose ester membrane with a pore size of 0.45 μm was used as the separator. At 32°C and 250 rpm, 1 mL samples were taken at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h, and the same volume of blank receiving solution was added. The release of efinaconazole and salicylic acid was measured by HPLC.

[0166] The experimental results are as follows Figure 18-19 As shown in Figure 2, the release rate of efinaconazole from the ionic liquid urea gel irradiated by UV light was 89.21±1.66% at 72h ( Figure 18 ), the release rate of salicylic acid was 97.43±3.04% ( Figure 19). The fitting release curve prepared by the scatter plot shows that the release of efinaconazole by UV light + ionic liquid urea gel is characterized by stages. The release curve at 0 to 4 hours and its fitting equation Q = 12.87t 1 / 2 -0.32, which is consistent with the Higuchi equation, indicating that efinaconazole leaves the gel by pore diffusion. At 4 to 24 hours, the most suitable fitting equation for the release curve is Q = 13.80t 0.48 , which is consistent with the Ritger-Peppas equation, and n = 0.48, indicating that the release of efinaconazole from UV light + ionic liquid urea gel in the range of 4 to 24 h is a combination of pore diffusion and skeleton corrosion ( Figure 18 ). In the stage where diffusion is the main release mode, there is no difference in the release of efinaconazole by ionic liquid urea gel with or without light. After 4 hours, UV pretreatment makes the release rate of drug by ionic liquid urea gel slightly slower than that of untreated ionic liquid urea gel. The reason is that UV light slows down the skeleton corrosion rate of ionic liquid urea gel. In addition, the fitting results show that the release mode of salicylic acid by ionic liquid urea gel irradiated with UV light is the same as that of efinaconazole (the fitting equation for 0-4 hours is Q=30.87t 1 / 2 +3.48, pore diffusion; 4~24h fitting equation is Q=41.85t 0.31 , which is pore diffusion + skeleton corrosion).

[0167] Compared to the ionic liquid gel, the urea-added formulation released both efinaconazole and salicylic acid at a faster rate. Combined with the diffusion-release mechanism present during gelation, it is speculated that urea also acts as a pore-forming agent in the gel, increasing the porosity of the gel and enhancing the release of other small molecules.

[0168] Effect Example 5 Evaluation of the Penetration-Promoting Ability of Ionic Liquid Urea Gel

[0169] This example provides a test of the enhanced penetration of efinaconazole and salicylic acid into bovine hoof nail sections using the ionic liquid urea gel prepared in Example 2, a 10% efinaconazole solution, a commercially available efinaconazole solution, the ionic liquid gel prepared in Comparative Example 2, and the ionic liquid urea gel of Example 2 exposed to UV light (continuous 5 minutes of illumination). The specific experimental steps are as follows.

[0170] The ox hoof piece was fixed on the diffusion cell, and 25.12 mg of the following prescriptions were added to the cell: efinaconazole solution group: 10% (w / w) efinaconazole solution in anhydrous ethanol; commercial solution group: efinaconazole commercial solution (JUL); ionic liquid gel; ionic liquid urea gel; UV + ionic liquid urea gel group: UV light (light intensity of 3W / cm 2The cumulative nail penetration and retention of efinaconazole or salicylic acid in each formulation were measured using the same method as described in Example 1 for evaluating penetration enhancement.

[0171] The experimental results are as follows Figure 20-23 As shown in Figure 2, the UV-irradiated ionic liquid urea gel significantly increased the penetration of efinaconazole into nails compared with the other groups ( Figure 20 ) and retention ( Figure 21 ); at the same time, UV light treatment also increased the penetration rate of salicylic acid on the nails ( Figure 22 ) and retention ( Figure 23 ).

[0172] Effect Example 6 In vitro antifungal evaluation of ionic liquid urea gel

[0173] This example provides an in vitro antifungal evaluation of the ionic liquid urea gel prepared in Example 2, following UV irradiation. The in vitro antifungal activity was verified using the disc diffusion method. Trichophyton rubrum, Trichophyton mentagrophytes, Fusarium spp., Aspergillus fumigatus, and Candida albicans were all standard strains purchased from the China Industrial Microbial Culture Collection. The specific experimental procedures are as follows.

[0174] (1) Trichophyton rubrum, Trichophyton mentagrophytes, Fusarium spp., Aspergillus fumigatus, and Candida albicans were inoculated on Sabouraud dextrose agar (SDA) and cultured in an inverted manner (28 ± 2°C). All fungi were identified by ITS1F / ITS4 sequencing.

[0175] (2) After activation, single colonies were picked and added to 2 mL of normal saline (0.85%), and the turbidity of the bacterial solution was adjusted to 0.5 McFarland units (1-5×10 6 CFU / mL), and the bacterial solution was spread on MH agar plates. A paper slip was placed in the center of the plate, and 10 mg of each of the following formulations was added: control group: anhydrous ethanol; efinaconazole solution group: 10% (w / w) efinaconazole solution in anhydrous ethanol; ionic liquid group: 20% (w / w) ionic liquid solution in anhydrous ethanol; blank gel: polylipoic acid gel; ionic liquid urea gel; UV + ionic liquid urea gel group: UV light (light intensity of 3W / cm 2 The fungi in each group were cultured in an incubator (28 ± 2°C). The growth of Fusarium spp., Aspergillus fumigatus, and Candida albicans was observed after 48 hours, and the growth of Trichophyton rubrum and Trichophyton mentagrophytes was observed after 120 hours. The diameter of the inhibition zone was measured with a vernier caliper.

[0176] The experimental results are as follows Figures 24-26As shown in Figure 2, the ionic liquid urea gel irradiated by UV light has a significant inhibitory effect on Trichophyton rubrum, Trichophyton mentagrophytes, Fusarium spp., Aspergillus fumigatus and Candida albicans ( Figure 24 ). Figure 25 and Figure 26 As can be seen, the inhibitory effect of the UV-irradiated ionic liquid urea gel against several fungi is in the following order: Trichophyton rubrum = Trichophyton mentagrophytes > Aspergillus fumigatus > Candida albicans > Fusarium spp. Comparison with the efinaconazole solution reveals that the antifungal activity of the UV-irradiated ionic liquid urea gel is derived from efinaconazole, while the urea gel exhibits no antifungal activity. There was no difference in the antifungal activity of the efinaconazole-containing formulations among the groups.

[0177] Based on the above experimental results, the UV-irradiated gel prepared in this example for enhancing nail penetration and nail drug delivery compliance can still exert the full antibacterial activity of efinaconazole.

[0178] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A composition, characterized in that The composition comprises an ionic liquid containing a triazole derivative antifungal drug and an organic acid.

2. The composition according to claim 1, characterized in that The triazole derivative antifungal drug includes at least one of efinaconazole, itraconazole, posaconazole or voriconazole; preferably, the organic acid includes at least one of salicylic acid, malic acid, tartaric acid or citric acid.

3. The composition according to claim 1, characterized in that The composition further comprises one or more pharmaceutically acceptable additives; the additives are selected from at least one of a penetration enhancer, a moisturizer, a stabilizer or an antioxidant.

4. The composition according to claim 3, characterized in that The penetration enhancer includes at least one of urea, N-acetyl-L-cysteine, N-methyl-2-pyrrolidone or octadecanol.

5. The composition according to any one of claims 1 to 4, characterized in that The dosage form of the composition includes cream, gel, ointment, solution, spray or patch.

6. A gel comprising the composition according to any one of claims 1 to 5, characterized in that The gel includes polylipoic acid gel, poly N-isopropylacrylamide gel or tannic acid-lipoic acid hydrogel.

7. The gel according to claim 6, characterized in that The gel comprises the ionic liquid according to claim 1 in a mass ratio of 10 to 30% and an additive in a mass ratio of 10 to 30%.

8. The method for preparing the gel according to any one of claims 6 to 7, characterized in that: The preparation method comprises the following steps: (1) dissolving a triazole derivative antifungal drug and an organic acid in an organic solvent, and evaporating the organic solvent to obtain an ionic liquid; (2) Adding additives to the ionic liquid and loading the additives on the gel to obtain the gel.

9. Use of the composition according to any one of claims 1 to 5 in the preparation of a product for preventing and / or treating fungal infections of the skin or nails.

10. Use of the gel according to any one of claims 6 to 7 in preparing a product for preventing and / or treating fungal infections of the skin or nails, characterized in that: The gel is treated with ultraviolet light; preferably, the ultraviolet light treatment time is 1-15 minutes; preferably, the ultraviolet light intensity is 1-5W / cm 2 .

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