A luliconazole film-forming composition having high retention and use thereof

Abstract

The application discloses a long-acting and high-drug-loading luliconazole film-coating composition which is clinically applicable to the treatment of onychomycosis. The composition can increase the residence time and the permeation amount of the drug on the nail, resist the loss of the dose caused by water contact in daily life, reduce the frequency of the drug application of the patient, significantly improve the compliance of the patient, meet the basic theory of pharmacoeconomics, and has significant clinical application value.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202511463546.5, filed with the Chinese Patent Office on October 14, 2025, entitled "A Luriconazole Film-Forming Composition with High Retention and Its Application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a luriconezine film-forming composition with high retention and its application. Background Technology

[0003] Luliconazole, chemically named (R,E)-2-(4-(2,4-dichlorophenyl)-1,3-dithiopentane-2-ylidene)-2-(1D-imidazol-1-yl)acetonitrile, has the following structural formula: Luriconazole is an imidazole-based topical broad-spectrum antifungal agent with effective fungicidal and antifungal activities. Literature reports that luriconazole has a very low in vitro minimal inhibitory concentration (MIC). At low concentrations (MIC ≤ 4-5 ng / ml), it inhibits the growth of all filamentous fungi except for zygomycetes. It is effective against Candida, Aspergillus, Malassezia, Fusarium, and various dermatophytes, with dermatophytes being the most susceptible (MIC ≤ 4-8 ng / ml). At extremely low concentrations (Trichophyton rubrum, MIC90 = 1 ng / ml), luriconazole inhibits the activity of fungal CYP51 enzyme (sterol 14α-demethylase), thereby inhibiting ergosterol biosynthesis and interfering with fungal cell wall formation, exhibiting fungicidal activity. Simultaneously, at concentrations below MIC90, it exhibits antifungal activity by inhibiting extracellular protease secretion.

[0004] This product was initially developed by Nippon Nohyaku Co., Ltd. and approved in 2005. It was marketed in Japan under the brand name Lulicon, available in both cream and lotion formulations, each at a 1% concentration. It is indicated for the following fungal infections: tinea – athlete's foot, tinea corporis, tinea cruris; and candidiasis – interdigital erosion, chafing. The 1% Luliconazole cream was subsequently launched in India, China, and the United States in 2010, 2012, and 2013, respectively. Later, Sato Pharmaceutical developed a 1% Luliconazole topical solution, which was launched in Japan in 2016 under the brand name Laconac, for the treatment of nail fungus.

[0005] Onychomycosis accounts for 50% of all nail diseases, with an estimated prevalence of 10% in the general population and as high as 50% in people over 60 years of age. Approximately 90% of onychomycosis cases are caused by dermatophytes, with Trichophyton rubrum and Trichophyton mentagrophytes being the most common. Onychomycosis is generally difficult to treat. Oral therapy is often considered the most effective, but there are safety concerns regarding systemic exposure. Topical treatment has a greater advantage if the medication can be effectively applied to the desired site.

[0006] Creams and lotions are easy to apply to the surface of the skin, but they are difficult to remain on the nails for long periods. Furthermore, due to the difference in permeability between skin and nails, the 1% concentration of luriconazole is insufficient to achieve ideal therapeutic effects and is therefore unsuitable for treating onychomycosis. Based on 1% creams and lotions, Sato Pharmaceutical in Japan developed a 5% luriconazole topical solution for clinical use in treating onychomycosis. However, Sato Pharmaceutical's 5% luriconazole topical solution still has certain clinical drawbacks. Patent CN108883190B discloses the formulation of Sato Pharmaceutical's 5% luriconazole topical solution, which uses povidone as a hydrophilic film-forming agent to promote luriconazole absorption. However, this also makes the drug easily metabolized by sweat from daily hand washing, resulting in the drug not remaining on the nail surface for a long time. This necessitates daily application, causing inconvenience to patients' daily lives. Moreover, the treatment of onychomycosis is a very lengthy process, requiring patients to take medication continuously for more than 48 weeks to effectively control the condition, necessitating 336 applications throughout the entire treatment cycle. However, patients often fail to use medication on time and in the correct dosage during treatment. A survey showed that 40% of patients stopped using topical onychomycosis medication after only one month, and the average duration of adherence was only three months, far short of the recommended 48-week treatment course. This compliance issue leads to treatment failure and fungal resistance in clinical practice. There is an urgent clinical need for a long-acting, highly compliant topical onychomycosis treatment.

[0007] Luriconazole possesses excellent keratin-binding ability and highly effective bactericidal properties, making it a promising active ingredient for treating onychomycosis. However, it suffers from some physicochemical defects. Luriconazole exhibits poor solubility in anhydrous ethanol, at only about 2.8% (w / w). For topical formulations, dissolution is a prerequisite for penetration. To achieve ideal clinical therapeutic effects, the ideal drug composition should contain a sufficiently high concentration of the active ingredient to maintain a high concentration gradient of luriconazole during nail penetration, increasing the content of the active ingredient in the affected nail. To address the poor solubility of luriconazole, Sato Pharmaceutical in Japan used N-methylpyrrolidone and benzyl alcohol in anhydrous ethanol to increase the solubility of luriconazole in the system. However, even then, the final solubility of luriconazole in the system only reached about 5%, which limits the drug's clinical efficacy. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention utilizes deep eutectic technology to solubilize luriconazole, thereby increasing its solubility in the system and enhancing drug loading. A deep eutectic is a mixture of hydrogen bond donors and acceptors in a specific stoichiometric ratio, characterized by high stability, high solubility, and high permeability. This invention uses luriconazole as a hydrogen bond acceptor and a weak organic acid as a hydrogen bond donor to form a deep eutectic, thus increasing both the solubility and permeability of the drug.

[0009] This invention also applies polymer film-forming technology to luriconazole compositions, developing a high-concentration luriconazole coating. Through polymer film-forming technology, the luriconazole coating can form a luriconazole drug reservoir on the nail surface. This drug reservoir simultaneously possesses hydrophobic and waterproof properties as well as hydrophilic adhesive properties, resisting the destructive effects of sweat and daily handwashing. It slowly releases the drug onto the nail, maintaining a high concentration of luriconazole in the nail to achieve long-lasting bactericidal effects, thereby reducing the frequency of patient medication and improving drug compliance.

[0010] The main objective of this invention is to overcome the shortcomings of existing technologies and provide a high-drug-loading luriconazole film-forming composition with high retention and its application. The composition of this invention overcomes the poor solubility of luriconazole, improving its solubility in anhydrous ethanol. The luriconazole film-forming composition of this invention can significantly reduce the frequency of administration, prolong the retention time of luriconazole in ethanol, and improve formulation compliance. This technology is in line with pharmacoeconomic principles and is more patient-friendly.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A luriconazole composition is provided, the composition comprising luriconazole, a film-forming agent, a solubilizer, and the balance being a solvent.

[0012] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the film-forming agent is selected from one or more of the following: acrylate / octylacrylamide copolymer, ethyl cellulose, copolymer of methyl vinyl ether and monobutyl maleate, povidone, hydroxypropyl cellulose, and acrylic resin.

[0013] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the solubilizer is selected from solubilizers containing hydrogen bond donors, preferably selected from weak organic acids, more preferably selected from one or more of citric acid, lactic acid, malic acid, and maleic acid, and most preferably selected from lactic acid.

[0014] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the solvent comprises one or more of ethanol, ethyl acetate, butyl acetate, isopropanol, acetone, benzyl alcohol, N-methylpyrrolidone, diethylene glycol monoethyl ether, and propylene carbonate; preferably, the solvent is selected from a combination of anhydrous ethanol, ethyl acetate, benzyl alcohol, and N-methylpyrrolidone.

[0015] Furthermore, the present invention provides the above-mentioned louriconazole composition, wherein the film-forming agent is selected from a combination of a hydrophilic film-forming agent and a hydrophobic film-forming agent; preferably, the hydrophobic film-forming agent is selected from a mixture of acrylate / octylacrylamide copolymer (DL79) and acrylic resin RL100, and the hydrophilic film-forming agent is selected from povidone.

[0016] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the luriconazole is 1 to 15% (by mass) of the luriconazole composition, preferably 2 to 13% (by mass), or 5 to 12% (by mass), or 8 to 11% (by mass), or 9% (by mass).

[0017] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the hydrophobic film-forming agent is 2-8% (by mass) of the luriconazole composition, preferably 3-7% (by mass), 4-6% (by mass), or 5% (by mass).

[0018] Furthermore, the acrylate / octylacrylamide copolymer (DL79) in the hydrophobic film-forming agent of the present invention is 0.4-1.6% (by mass) of the luriconazole composition, preferably 0.6-1.4% (by mass), 0.8-1.2% (by mass), or 1% (by mass).

[0019] Furthermore, in the hydrophobic film-forming agent of the present invention, the acrylic resin RL100 is 1-8% (by mass) of the luriconazole composition, preferably 2-7% (by mass), 3-6% (by mass), or 4% (by mass). Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the hydrophilic film-forming agent is 0.4-1.6% (by mass) of the luriconazole composition, preferably 0.6-1.4% (by mass), 0.8-1.2% (by mass), or 1% (by mass).

[0020] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the solubilizer is citric acid or lactic acid, and the citric acid or lactic acid is 4-12% (by mass) of the luriconazole composition, preferably 5-11% (by mass), or 6-10% (by mass), or 8% (by mass). Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the benzyl alcohol is 1-7% (by mass) of the luriconazole composition, preferably 2-6% (by mass), or 3-5% (by mass), or 4% (by mass), or 5% (by mass).

[0021] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the N-methylpyrrolidone is 2 to 14% (by mass) of the luriconazole composition, preferably 4 to 12% (by mass), or 6 to 10% (by mass), or 8% (by mass).

[0022] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the ethyl acetate is 2-20% (by mass) of the luriconazole composition, preferably 4-16% (by mass), or 6-14% (by mass), or 11-14%, or 11% (by mass), or 12% (by mass).

[0023] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein the relative amount of anhydrous ethanol is the balance, preferably 40-64% (mass ratio), preferably 50-60% (mass ratio), or 51-58% (mass ratio), or 53% (mass ratio).

[0024] Furthermore, the present invention provides the above-mentioned luriconazole composition, wherein, prior to the preparation of the composition, the luriconazole together with the solvent is a deep eutectic.

[0025] Furthermore, the present invention provides a method for preparing the above-mentioned ruliconazole composition, the method comprising the following steps: (1) Add luliconazole and solubilizer to the solvent, stir until clear, and then add the solution to a round bottom flask, heat in a water bath, and evaporate by rotary evaporation to obtain a deep eutectic. (2) Add the eutectic mixture to the solvent and stir until dissolved and clear; set aside. (3) Add the film-forming agent to the above solution and stir until it is clear to obtain the ruliconazole composition; Furthermore, the present invention provides the use of the above-described ruliconazole composition in the preparation of a pharmaceutical formulation for treating onychomycosis.

[0026] Furthermore, the present invention provides a pharmaceutical preparation for treating onychomycosis, the pharmaceutical preparation comprising the above-described ruliconazole composition.

[0027] Compared with the prior art, the present invention has the following beneficial effects: 1. The luriconazole composition of the present invention overcomes the problem of poor solubility of luriconazole and develops a high-concentration luriconazole composition; the composition can significantly increase the nail penetration ability of luriconazole, promote the penetration of luriconazole, and increase the concentration of active ingredients in the diseased nail; 2. After use, the ruliconazole composition of the present invention can form a hydrophobic drug film on the nail. The drug film can resist the damage caused by hand washing and friction in daily life, and can remain on the nail for a long time to slowly release the drug, reducing the frequency of administration. 3. Compared with commercially available luriconazole topical solutions, the luriconazole composition of the present invention significantly increases the amount of drug retained in the nail after a single use, while the amount of drug permeation is not significantly increased, resulting in low safety risk. 4. Animal experiments showed that the effect of using the luriconazole composition once a week was similar to that of using the commercially available luriconazole topical solution once a day. Moreover, after the treatment, the concentration of luriconazole in the nails of guinea pigs was still ≥100 μg / g, which is more than 1000 times the MIC of luriconazole. Attached Figure Description

[0028] Figure 1 Changes in animal body weight; Figure 2 This refers to changes in the infection rate of animals during the experimental process; Figure 3 The changes in the animal's periodic score during the experiment; Figure 4 The number of fungi in each drug group after treatment; Figures 5-10 The images show the anti-crystallization effect of the film-forming agent in Examples 6 to 8, with the background of the film-forming agent as shown in Figure A. Figures 11-15 The figures show the water-repellent test results of film-forming agents at different proportions in Examples 9-38. Figures 16-20 The images show the appearance of the films formed in Examples 4 to 8, with the white film indicated by the arrow. Detailed Implementation

[0029] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0030] Screening Example 1: Selection of solubilizer for ruliconazole in anhydrous ethanol 1.1 The preparation process of the deep eutectic formed by luteconazole and solubilizer is as follows: Luriconazole and different proportions of organic weak acids were added to 200 mL of anhydrous ethanol and stirred until dissolved and clear to obtain a mixed solution. The mixed solution was added to a round-bottom flask and rotary evaporated at 40 °C and -0.06 MPa for 30-60 min until a transparent viscous liquid precipitated. The precipitated solid was placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain the luteconazole-organic weak acid deep eutectic. Luriconazole-citric acid eutectic, luriconazole-lactic acid eutectic, luriconazole-maleic acid eutectic, and luriconazole-malic acid eutectic were prepared using citric acid, lactic acid, malic acid, and maleic acid, respectively. The properties of the different eutectics are shown in Table 1. Table 1 Properties of different eutectics

[0031] 1.2 A series of luriconazole-organic acid complexes with different proportions were prepared, and the solubilizing effects of citric acid, lactic acid, malic acid, and maleic acid on luriconazole in anhydrous ethanol were determined as follows. The experimental results are shown in Table 2. Lactic acid can increase the solubility of luriconazole in anhydrous ethanol to the greatest extent. Therefore, preferably, the most preferred solubilizer in the luriconazole composition is lactic acid (further preferably, the mass percentage of lactic acid is 8%).

[0032] Table 2. Solubilizing effect of different proportions of deep eutectic compounds

[0033] Experimental results showed that after forming a deep eutectic with lactic acid or citric acid, luriconazole significantly increased its solubility in anhydrous ethanol. Therefore, the effect of the complex on transdermal permeation was investigated by in vitro transdermal permeation.

[0034] Screening Example 2: Screening of solvents in ruliconazole compositions During the composition screening process, the solubility of luriconazole monomer and luriconazole-lactic acid deep eutectic in different solvents was determined, as well as in a mixed solvent (N-methylpyrrolidone: benzyl alcohol: ethyl acetate: anhydrous ethanol = 8:4:12:53 (mass ratio)). The results are as follows. The experimental results show that, compared to the luriconazole monomer, the luriconazole-lactic acid deep eutectic significantly improves the solubility of luriconazole in various solvents. This improvement varies depending on the type of solvent. In the mixed solvent of the proposed composition, the solubility of the luriconazole-lactic acid deep eutectic was significantly improved compared to the luriconazole monomer, with a saturated solubility of approximately 11% (mass ratio).

[0035] Table 3. Solubility of luriconazole monomer and eutectic in different solvents

[0036] Screening Example 3: Prescription ratios refer to Table 4

[0037] Examples 1-3: Effects of different deep eutectic materials on penetrating armor In vitro transdermal nail transdermal studies were conducted on the above compositions. Bovine hooves were first cut into appropriately sized shapes and then sliced ​​using a semi-automatic microtome (set to a thickness of approximately 300 μm). Hooves of uniform thickness were selected and soaked in physiological saline for 24 hours for later use. Adjacent hooves were evenly distributed among the formulations to ensure relative consistency between formulations. Before application, the surface moisture of the hooves was blotted dry with absorbent paper, and the thickness was checked; the thickness difference between hooves in the same experiment was <200 μm. The hooves were removed from the physiological saline, laid flat on filter paper, blotted dry, and a portion was cut as the test hooves. These were then stored in the medium, blotted dry, and the thickness was measured using a micrometer in triplicate. The hooves were placed in a receiving pool and fixed with a drug delivery pool. The receiving pool was manually filled with the detreated receiving solution. Approximately 30 μl of sample was transferred using a pipette and transferred onto the hooves. The receiving cell was placed in a 32℃ heating block, and a magnetic stirrer was turned on for continuous stirring at 300 rpm. A solution of 0.9% NaCl-0.20% polyoxyethylene 20 oil ether-0.01% gentamicin sulfate was used as the medium, and samples were taken after 24 hours (n=6). The volume of the receiving medium was 5 ml.

[0038] Table 5. Mask penetration results for different eutectic compounds

[0039] Experimental results showed that the luriconazole-lactic acid deep eutectic compound significantly improved the permeability of luriconazole and increased the amount of luriconazole retained in the nail; the luriconazole-citric acid deep eutectic compound had the opposite effect, the formation of the complex significantly reduced the drug's permeability, and its retention in the nail was significantly lower than that in Example 3 (non-eutectic compound).

[0040] Example 4: Screening of film-forming agents Film-forming agents in pharmaceutical compositions generally possess both anti-crystallization and anti-crystallization capabilities. Anti-crystallization capability refers to the water-resistance of the film formed on a fingernail after the composition has formed, ensuring the medication is not washed away by water in daily life. Anti-crystallization capability refers to the ability of the composition to prevent the active ingredient from precipitating out as the solvent evaporates, which is crucial for promoting penetration. During the screening of film-forming agents, the anti-crystallization and anti-crystallization capabilities of different agents are examined to select a suitable one.

[0041] Currently used hydrophobic film-forming agents in the pharmaceutical field include: acrylic resin RL100, acrylic (ester) / octylacrylamide copolymer (DL79), ethyl cellulose, and poly(vinyl chloride-methyl vinyl ether / maleic anhydride) copolymer. Dissolution and crystallization inhibition experiments were conducted to investigate the crystallization inhibition effect of different film-forming agents on luriconazole.

[0042] a) Crystal suppression research: 0.1g of the drugs from Examples 4 to 8 were applied to bovine hooves and allowed to dry naturally for 24 hours. The crystallization of the active ingredients was then observed under a microscope. The results show that acrylate / octylacrylamide copolymer (DL79) and acrylic resin RL100 exhibited the best crystal-inhibiting ability, with no drug crystals observed in the field of view. Poly(vinyl chloride-methyl vinyl ether / maleic anhydride) copolymer and ethyl cellulose showed no crystal-inhibiting ability, and a large number of crystals were observed under the microscope. The mixed film-forming agent of acrylate / octylacrylamide copolymer (DL79) and acrylic resin RL100 also effectively inhibited drug crystal precipitation.

[0043] Table 6 Compositions of different film-forming agents

[0044] Table 4. Crystallization inhibition effect of film-forming agents

[0045] The above experimental results clearly demonstrate the anti-crystallization ability of acrylic (ester) / octylacrylamide copolymer (DL79) and acrylic resin RL100. Therefore, we will continue to investigate the anti-crystallization effect of different film-forming agent dosages and different film-forming agent combinations on the active ingredients.

[0046] Note: The remaining components are the same as in Example 8. 0.1g of the drug was applied to bovine hooves and allowed to dry naturally for 24 hours. The crystallization of the active ingredient was then observed under a microscope. The results are as follows. The results show that when the amount of film-forming agent is high (5%), both RL100 and DL79 have good crystal-inhibiting ability. However, as the amount of film-forming agent decreases, RL100 exhibits better crystal-inhibiting ability than DL79.

[0047] b) Waterproofing study: In addition to the anti-crystallization ability of the film-forming agent, the waterproofing ability of the film also needs to be considered during the composition development process.

[0048] Experimental Method: 0.1g of sample was evenly coated onto a glass plate (n=3). After standing for 30 minutes, the glass plate was immersed in 500ml of 1% polysorbate 80 aqueous solution. The stirring speed was set to 50rpm. 1ml samples were taken at 15min, 30min, and 60min, and the solution was replenished after each sampling. The dissolution rate of luteconazole was measured. The change in membrane mass before and after the experiment was also measured. The experimental results showed that the acrylic (ester) / octylacrylamide copolymer (DL79) had very good water resistance, but the other three film-forming agents had poor water resistance. The mixed film-forming agent (acrylic (ester) / octylacrylamide copolymer (DL79): acrylic resin RL100) also showed good water resistance.

[0049] Table 8 Hydrophobic dissolution test

[0050] The waterproofing results of the compositions in Examples 9 to 38 are as follows. The experimental results show that RL100 has poor waterproofing ability. In the film-forming agent, the waterproofing ability of the composition film is improved as the proportion of DL79 increases.

[0051] The above experimental results show that the composition of acrylate / octylacrylamide copolymer (DL79) and acrylic resin RL100, when adjusted in dosage and composition ratio, can achieve both waterproofing and anti-crystallization effects. However, during clinical use, the drug composition caused nail whitening. This whitening is due to the film formed by the composition separating upon contact with water. Although it does not affect the efficacy, it does affect the appearance of the nails. Therefore, it is necessary to adjust the dosage and composition ratio of the film-forming agent in the composition to reduce the white film phenomenon and improve patient compliance.

[0052] Film-forming agent compositions meeting the requirements of less than 10% dissolution release and no crystallization of the composition are as follows. Experimental results show that the whitening of the nails is improved as the amount of DL79 decreases. The appearance of nail whitening in some embodiments is shown in the figure below.

[0053] Table 5. Appearance of the membrane formed in different embodiments

[0054] Example 5: In vitro transdermal nail transdermal comparison of the composition—the effect of different active ingredient specifications on transdermal nail transdermal transmission. Table 9. Formulation of Luriconazole Compositions

[0055] In vitro transdermal nail transdermal studies were conducted on the above compositions. Bovine hooves were first cut into appropriately sized shapes and then sliced ​​using a semi-automatic microtome (set to a thickness of approximately 300 μm). Hooves of uniform thickness were selected and soaked in physiological saline for 24 hours for later use. Adjacent hooves were evenly distributed among the formulations to ensure relative consistency between formulations. Before application, the surface moisture of the hooves was blotted dry with absorbent paper, and the thickness was checked; the thickness difference between hooves in the same experiment was <200 μm. The hooves were removed from the physiological saline, laid flat on filter paper, blotted dry, and a portion was cut as the test hooves. These were then stored in the medium, blotted dry, and the thickness was measured using a micrometer in triplicate. The hooves were placed in a receiving pool and fixed with a drug delivery pool. The receiving pool was manually filled with the detreated receiving solution. Approximately 30 μl of sample was transferred using a pipette and transferred onto the hooves. The receiving cell was placed in a 32℃ heating block, and a magnetic stirrer was turned on for continuous stirring at 300 rpm. A solution of 0.9% NaCl-0.20% polyoxyethylene 20 oil ether-0.01% gentamicin sulfate was used as the medium, and samples were taken after 24 hours (n=6). The volume of the receiving medium was 5 ml.

[0056] Experimental results showed that the concentration of ruliconazole was specification-dependent on the retention rate of the transdermal filler, but the concentrations were consistent for both the 9% and 11% concentrations. Therefore, in subsequent compositions, a concentration of 9% ruliconazole is preferred.

[0057] Table 10: The Influence of Specifications on Transparent Armor

[0058] Example 6: In vitro transdermal comparison of the composition—single-dose comparison The luriconexazole topical solution formulation disclosed in patent CN108883190B, and the luriconexazole composition formulation of the present invention, were prepared as follows: Table 11. Formulation of Luriconazole Compositions

[0059] A single-dose comparative study was conducted between a commercially available formulation (Comparative Example 1) and the composition of the present invention (Example 8). Considering the patient's daily handwashing process, 200 μl of ultrapure water was administered daily to rinse the nails starting from day 1 of administration, and the ultrapure water was then aspirated after rinsing. The results are shown in the table below. The results show that after a single-dose administration of the composition of the present invention, the bioavailability of the active ingredient in the nails was approximately 20 times that of the commercially available product (Comparative Example 1) after a 14-day cycle.

[0060] Table 12 Comparison of single-dose administration of different compositions

[0061] Example 4: Animal experiments with different examples This study aims to compare the therapeutic effects of different onychomycosis control methods and comparative studies using in vitro onychomycosis experiments on guinea pigs. The experimental drug groups are shown in the table below.

[0062] Table 14 Grouping and Dosing Regimens

[0063] After one week of acclimatization feeding, six guinea pigs were randomly selected as a blank control group without modeling. The remaining animals were treated with 0.2 ml of fungal spore suspension (1 x 10⁻⁶) on the left hind paw and the first to third toes of the right hind paw. 8 A solution of 0.5 ml of sterile water (cfu / ml) was injected into the nail bed and between the toes (6 nails per guinea pig for modeling). The first to third toes were then wrapped with gauze, and 0.5 ml of sterile water was injected into the gauze. A leather cap was then placed over the cap for two weeks to promote infection. After two weeks, the cap was removed, and the animals were fed normally for another two weeks. During this 28-day modeling period, all animals except the control group received intramuscular injections of triamcinolone acetonide solution for 28 consecutive days. Nail discoloration indicated successful modeling.

[0064] After successfully establishing the guinea pig model of onychomycosis, the successfully modeled guinea pigs were screened and randomly divided into G2, G3, G4, and G5 groups (n=6 per group) according to their weight and infection severity. After grouping, medication was administered according to the grouping and dosing regimen designed in Table 1, for a continuous period of 4 weeks.

[0065] Evaluation indicators: Animal weight monitoring (weekly); nail photographs taken on days 0, 3, 7, 10, 14, 17, 21, 24, and 28 after drug administration to assess the degree and rate of nail infection. Infection rate = (number of infected toes / total number of models); After drug administration, the guinea pigs were euthanized, excess hair around the six model nails was shaved to expose the nail tissue, and the nails were removed using surgical instruments for fungal and drug concentration testing.

[0066] Experimental results show that the 9% ruliconazole composition of the present invention, when used once a week, can achieve the same therapeutic effect as the positive drug (comparative example 1) when used once daily.

[0067] Table 15 Drug concentration in fingernails after administration.

[0068] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A ruliconazole composition, characterized in that, The composition comprises ruliconazole, a film-forming agent, a solubilizer, and the balance being a solvent; The louriconazole and the solubilizer form a deep eutectic; The film-forming agent is selected from a combination of hydrophilic film-forming agents and hydrophobic film-forming agents, wherein the hydrophobic film-forming agent is selected from a mixture of acrylate / octylacrylamide copolymer and acrylic resin; The amount of luriconazole, calculated by mass ratio, is 1-15% of the luriconazole composition; The acrylate / octylacrylamide copolymer comprises 0.4-1.6% of the luriconazole composition, and the acrylic resin comprises 3-6% of the luriconazole composition; or the acrylate / octylacrylamide copolymer comprises 0.6-1.4% of the luriconazole composition, and the acrylic resin comprises 2-7% of the luriconazole composition.

2. The ruliconazole composition according to claim 1, characterized in that, The acrylic resin is acrylic resin RL100; And / or the acrylate / octylacrylamide copolymer is acrylate / octylacrylamide copolymer DL79; And / or the solubilizer is citric acid or lactic acid; And / or, by mass ratio, the acrylate / octylacrylamide copolymer is 0.8-1.2% of the luriconazole composition; And / or, by mass ratio, the acrylic resin is 3-5% of the luriconazole composition.

3. A ruliconazole composition, characterized in that, The composition comprises ruliconazole, a film-forming agent, a solubilizer, and the balance being a solvent; The solubilizer is lactic acid, and the ruliconazole and the solubilizer form a deep eutectic. The amount of luriconazole is 1-15% of the luriconazole composition by mass ratio, and the amount of lactic acid is 4-12% of the luriconazole composition. The film-forming agent comprises a hydrophobic film-forming agent.

4. The ruliconazole composition according to claim 3, characterized in that, The film-forming agent is selected from a combination of hydrophilic film-forming agents and hydrophobic film-forming agents; And / or the hydrophobic film-forming agent is a mixture of acrylate / octylacrylamide copolymer and acrylic resin; And / or, by mass ratio, the hydrophobic film-forming agent is 2-8% of the luriconazole composition; And / or, by mass ratio, the acrylate / octylacrylamide copolymer in the hydrophobic film-forming agent is 0.4-1.6% of the luriconazole composition; And / or, by mass ratio, the acrylic resin in the hydrophobic film-forming agent is 1-8% of the luriconazole composition.

5. The ruliconazole composition according to claim 4, characterized in that, The acrylic resin is acrylic resin RL100; And / or the acrylate / octylacrylamide copolymer is acrylate / octylacrylamide copolymer DL79; And / or, by mass ratio, the hydrophobic film-forming agent is 3-7% of the luriconazole composition; And / or, by mass ratio, the acrylate / octylacrylamide copolymer in the hydrophobic film-forming agent is 0.6-1.4% of the luriconazole composition; And / or, by mass ratio, the acrylic resin in the hydrophobic film-forming agent is 2-7% of the luriconazole composition.

6. The ruliconazole composition according to claim 5, characterized in that, The hydrophobic film-forming agent is 4-6% of the ruliconazole composition by mass ratio; And / or, by mass ratio, the acrylate / octylacrylamide copolymer in the hydrophobic film-forming agent is 0.8-1.2% of the luriconazole composition; And / or, by mass ratio, the acrylic resin in the hydrophobic film-forming agent is 3-6% of the luriconazole composition.

7. The ruliconazole composition according to claim 6, characterized in that, The hydrophobic film-forming agent is 5% of the ruliconazole composition by mass ratio; And / or, by mass ratio, the acrylate / octylacrylamide copolymer in the hydrophobic film-forming agent is 1% of the luriconazole composition; And / or, by mass ratio, the acrylic resin in the hydrophobic film-forming agent is 4% or 5% of the luriconazole composition.

8. A ruliconazole composition, characterized in that, The composition includes ruliconazole, a film-forming agent, a solubilizer, and a solvent; The film-forming agent includes at least acrylate / octylacrylamide copolymer and acrylic resin; The type and amount of the acrylate / octylacrylamide copolymer and acrylic resin are such that the luriconazole composition satisfies the following conditions: (1) After applying 0.1 g of the luriconazole composition to bovine hooves and allowing it to air dry for 24 h, no luriconazole crystals were observed under a microscope; and (2) Apply 0.1 g of the luriconazole composition evenly to a glass plate, let it stand for 30 min, then place the glass plate in 500 mL of 1% polysorbate 80 aqueous solution and stir at 50 rpm for 60 min. The release of luriconazole shall not exceed 10%.

9. The ruliconazole composition according to claim 8, characterized in that, The acrylic resin is acrylic resin RL100; And / or the acrylate / octylacrylamide copolymer is acrylate / octylacrylamide copolymer DL79; And / or, by mass ratio, the total amount of the acrylate / octylacrylamide copolymer and the acrylic resin is 2-8% of the luriconazole composition; And / or the mass ratio of the acrylate / octylacrylamide copolymer to the acrylic resin is selected from 4:1, 3:2, 2:3 and 1:4; And / or the film-forming agent further includes a hydrophilic film-forming agent; And / or the solubilizer is a solubilizer containing hydrogen bond donors.

10. The ruliconazole composition according to claim 9, characterized in that, The total amount of the acrylate / octylacrylamide copolymer and the acrylic resin, calculated by mass ratio, is 3-5% of the luriconazole composition; And / or, by mass ratio, the hydrophilic film-forming agent is 0.4-1.6% of the luriconazole composition; And / or the hydrophilic film-forming agent is polyvinylpyrrolidone; And / or the hydrogen bond donor is an organic weak acid, preferably selected from one or more of citric acid, lactic acid, malic acid and maleic acid.

11. The ruliconazole composition according to claim 9, characterized in that, The acrylic resin is acrylic resin RL100, and the acrylic (ester) / octylacrylamide copolymer is acrylic (ester) / octylacrylamide copolymer DL79; and the mass ratio of DL79 to RL100 is 4:1 to 1:4, and the total content of DL79 and RL100 is 3% to 5% of the total mass of the composition; Preferably, the mass ratio of DL79 to RL100 and their total content satisfy any of the following combinations: (1) The ratio of DL79 to RL100 is 4:1, and the total content of the two is 5% of the total mass of the composition; (2) The ratio of DL79 to RL100 is 3:2, and the total content of the two is 5% of the total mass of the composition; (3) The ratio of DL79 to RL100 is 2:3, and the total content of the two is 4% or 5% of the total mass of the composition; or (4) The ratio of DL79 to RL100 is 1:4, and the total content of the two is 3%, 4%, or 5% of the total mass of the composition; And / or the organic weak acid is lactic acid.

12. The luriconezine composition according to any one of claims 1-11, characterized in that, The solvent is selected from one or more of ethanol, ethyl acetate, isopropanol, acetone, benzyl alcohol, and N-methylpyrrolidone; And / or the hydrophilic film-forming agent is polyvinylpyrrolidone; And / or, by mass ratio, the luriconazole is 2-13% of the luriconazole composition; And / or, by mass ratio, the solubilizer is 5-11% of the ruliconazole composition; And / or, by mass ratio, the hydrophilic film-forming agent is 0.4-1.6% of the luriconazole composition; And / or the method for preparing the said ruliconazole composition includes the following steps: (1) Add luliconazole and solubilizer to the solvent, stir until clear, and then add the solution to a round bottom flask, heat in a water bath, and evaporate by rotary evaporation to obtain a deep eutectic. (2) Add the eutectic mixture to the solvent and stir until dissolved and clear; set aside. (3) Add the film-forming agent to the above solution and stir until it is clear to obtain the Luriconazole composition.

13. The ruliconazole composition according to claim 12, characterized in that, The solvent is a combination of anhydrous ethanol, ethyl acetate, benzyl alcohol, and N-methylpyrrolidone; And / or, by mass ratio, the luriconazole is 5-12% of the luriconazole composition; And / or, by mass ratio, the solubilizer is 6-10% of the ruliconazole composition; And / or, by mass ratio, the hydrophilic film-forming agent is 0.6-1.4% of the luriconazole composition; And / or, by mass ratio, the benzyl alcohol is 1-7% of the luriconazole composition; And / or, by mass ratio, the N-methylpyrrolidone is 2-14% of the luriconazole composition; And / or, by mass ratio, the ethyl acetate is 2-20% of the luriconazole composition; And / or, by mass ratio, the anhydrous ethanol is 40-64% of the luriconazole composition.

14. The ruliconazole composition according to claim 13, characterized in that, The amount of luriconazole, calculated by mass ratio, is 8-11% of the luriconazole composition; And / or, by mass ratio, the solubilizer is 8% of the ruliconazole composition; And / or, by mass ratio, the hydrophilic film-forming agent is 0.8-1.2% of the luriconazole composition; And / or, by mass ratio, the benzyl alcohol is 2-6% of the luriconazole composition; And / or, by mass ratio, the N-methylpyrrolidone is 4-12% of the luriconazole composition; And / or, by mass ratio, the ethyl acetate is 4-16% of the luriconazole composition; And / or, by mass ratio, the anhydrous ethanol is 50-60% of the luriconazole composition.

15. The ruliconazole composition according to claim 12, characterized in that, The luriconazole is 9% of the luriconazole composition by mass ratio; And / or, by mass ratio, the benzyl alcohol is 3-5% of the luriconazole composition; And / or, by mass ratio, the N-methylpyrrolidone is 6-10% of the luriconazole composition; And / or, by mass ratio, the ethyl acetate is 6-14% of the luriconazole composition; And / or, by mass ratio, the anhydrous ethanol is 51-58% of the luriconazole composition.

16. A ruliconazole composition, characterized in that, The composition comprises ruliconazole, a film-forming agent, a solubilizer, and the balance being a solvent; The solubilizer is lactic acid, and the ruliconazole and the solubilizer form a deep eutectic. The film-forming agent is selected from a combination of hydrophilic film-forming agents and hydrophobic film-forming agents, wherein the hydrophobic film-forming agent is selected from a mixture of acrylate / octylacrylamide copolymer and acrylic resin; The luriconazole is 9% of the luriconazole composition by mass ratio; The acrylate / octylacrylamide copolymer is 1% of the luriconexazole composition; The acrylic resin is 4% of the luriconazole composition; The hydrophilic film-forming agent is 1% of the luriconazole composition; The lactic acid is 8% of the ruliconazole composition; The benzyl alcohol is 4% of the luriconazole composition; The N-methylpyrrolidone is 8% of the luricone-containing composition; The ethyl acetate is 12% of the luriconexazole composition; The anhydrous ethanol is 53% of the luriconazole composition.

17. A method for preparing the ruliconazole composition according to any one of claims 1-16, characterized in that: Includes the following steps: (1) Add luliconazole and solubilizer to the solvent, stir until clear, and then add the solution to a round bottom flask, heat in a water bath, and evaporate by rotary evaporation to obtain a deep eutectic. (2) Add the eutectic mixture to the solvent and stir until dissolved and clear; set aside. (3) Add the film-forming agent to the above solution and stir until it is clear to obtain the Luriconazole composition.

18. Use of the ruliconazole composition according to any one of claims 1-16 in the preparation of a pharmaceutical formulation for treating onychomycosis.

19. A pharmaceutical preparation for treating onychomycosis, characterized in that: Includes the ruliconazole composition according to any one of claims 1-16.

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