An external use long-acting efinaconazole composition, a preparation method and application thereof

Abstract

The application provides a long-acting external use efinaconazole composition, a preparation method and application, and belongs to the technical field of pharmaceutical compositions.The long-acting external use efinaconazole composition comprises the following components in percentage by weight: efinaconazole 0.5-3%, a film forming agent 3-7%, a gel agent 2-3%, a plasticizer 3-7%, a cosolvent 0.78-1.56% and a solvent in a residual amount.The application forms a eutectic mixture of efinaconazole and lactic acid, improves the solubility and permeability of the active ingredient, dissolves in the solvent of an ethanol system, and adds the film forming agent and the plasticizer, so that a drug depot is formed on the surface of the skin through the film forming principle, the drug is released slowly, the clinical compliance is improved, the frequency of drug administration is reduced, the bioavailability of the drug in the stratum corneum is increased, the effectiveness and safety of the drug can be improved, the basic theory of pharmacoeconomics is met, and the clinical value of the product is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical composition technology, specifically relating to a topical long-acting effluconazole composition, its preparation method, and its application. Background Technology

[0002] Ifluconazole, its chemical name is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidinyl-1-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol, and its structural formula is:

[0003]

[0004] Superficial fungal infections are caused by pathogenic fungi invading the stratum corneum, hair follicles, and nail plates of the skin, leading to a decline in the patient's quality of life. Superficial fungal infections can be caused by dermatophytes, Candida species, Malassezia species, etc., with dermatophytes being the most common. Clinically, tinea pedis (athlete's foot) is the most common, followed by tinea corporis (jock itch), tinea cruris (jock itch), and onychomycosis (nail fungus). Most patients choose topical medications for treatment, a small number choose a combination of oral and topical medications, and a very small number choose oral medications alone.

[0005] Clinically, medications for treating tinea pedis and manuum (hand fungus) have significant shortcomings. Treating tinea pedis and manuum is a long-term process, and the current mainstream treatment involves long-term, repeated application of various antifungal creams, typically for 2-4 weeks, requiring 1-3 applications daily, which is inconvenient for patients. Research shows that the vast majority of patients cannot adhere to regular medication use, leading to a high recurrence rate. Furthermore, the need to repeatedly apply medication with the fingers during treatment increases the risk of transmission and spread of the fungal infection.

[0006] Efluconazole is the first topical triazole antifungal drug, developed by Japanese company Kenshin Pharmaceutical and Canadian company Vania International Pharmaceutical. It is marketed as a topical application for the treatment of onychomycosis and other nail fungal infections. The drug was first approved by Health Canada on October 2, 2013, followed by approval from the US Food and Drug Administration on June 6, 2014, and approval from the Japanese Pharmaceuticals and Medical Devices Agency on July 4, 2014. Literature reports that iefluconazole has strong bactericidal activity. For example, Tatsumi Y et al. determined the minimum inhibitory concentration (MIC) of iefluconazole in vitro. In vitro experiments showed that the MIC of iefluconazole against dermatophytes was approximately 0.00098 μg / ml. This result indicates that iefluconazole has a very strong antifungal effect against dermatophytes, and this active ingredient has the potential to treat tinea pedis and manuum.

[0007] For example, Chinese patent CN111295202A discloses a topical onychomycosis treatment agent. This invention provides a topical onychomycosis treatment agent containing antifungal active substances such as icofol, volatile components, additives such as medium-chain triglycerides, and penetration enhancers such as ethyl lactate. This formulation can significantly improve nail permeability and, from the point of view of efficacy and formulation performance, possesses excellent characteristics as a pharmaceutical product.

[0008] However, existing topical formulations containing icoconazole require repeated and prolonged administration, resulting in long treatment courses and unsatisfactory therapeutic effects. Therefore, there is a need to develop a topical long-acting icoconazole composition and preparation method that can significantly reduce the frequency of use, shorten the treatment course, and improve efficacy. Summary of the Invention

[0009] Addressing the shortcomings of existing technologies, this invention aims to provide a topical long-acting icoconazole composition, its preparation method, and its application. This composition is clinically suitable for the treatment of tinea pedis and manuum in adults, achieving long-term treatment, reducing the frequency of drug administration, decreasing fungal infection and spread during drug use, expanding formulation compliance, improving formulation delivery results, and enhancing drug efficacy. This technology aligns with pharmacoeconomic principles, improving both drug efficacy and safety.

[0010] This invention employs a polymer film-forming system, a long-acting local drug delivery system for the skin using high-molecular polymers as film-forming materials. This system establishes a sustained-release drug reservoir on and within the skin, preventing the drug from being washed away by sweat or consumed by friction during daily life, thus achieving a long-lasting local therapeutic effect. For the treatment of skin diseases requiring long-term continuous medication (such as tinea pedis), the polymer film-forming system can significantly shorten the frequency of administration and improve drug compliance.

[0011] Furthermore, during the development of eutectic coating agents, deep eutectic technology was introduced into the polymer film-forming system. Eutectic mixtures are eutectic blends composed of hydrogen bond donors and acceptors in a specific stoichiometric ratio, exhibiting high stability, high solubility, and high permeability.

[0012] To overcome the low solubility and low permeability of iefluconazole, this invention uses iefluconazole as a hydrogen bond acceptor and adds lactic acid as a hydrogen bond donor to form an iefluconazole-lactic acid eutectic. The formation of hydrogen bonds in the eutectic causes lattice delocalization of the constituent molecules, reducing the lattice energy and resulting in a significantly lower melting point of the mixture than that of each component. This significantly increases the solubility in ethanol, allowing iefluconazole to exhibit supersaturation during film formation, promoting drug burst release, increasing the amount of drug released, and overcoming the limitations of iefluconazole's solubility and permeability.

[0013] The efconazole / lactic acid eutectic of the present invention has excellent solubility in ethanol. This easy solubility can overcome the characteristic of compound precipitation during drug use, thereby increasing the supersaturation characteristics of the drug and increasing the bioavailability of the drug in the stratum corneum.

[0014] An unexpected discovery was made that when eutectic technology is used to prepare effluent / lactic acid eutectic compounds, and effluent is loaded onto a polymer film-forming system, the protective effect of the film allows the drug solution to remain on the skin surface for an extended period, providing sufficient time for drug penetration and absorption into the stratum corneum. Eeffluent compositions prepared using this principle can quickly and significantly treat tinea pedis. Compared to traditional treatments that require repeated, long-term administration (treatment courses typically last 2-4 weeks, requiring 1-3 doses daily), effluent film-forming agents significantly reduce the frequency of administration and increase patient compliance.

[0015] To achieve the above objectives, the present invention adopts the following technical solution:

[0016] This invention employs a specific composition to dissolve ieconazole in an ethanol system solvent, with the addition of a film-forming agent and a plasticizer. Through film formation, a drug reservoir is created on the skin surface, allowing for sustained drug release. Lactic acid is added to the composition to form a deep eutectic with ieconazole, increasing the solubility and supersaturation capacity of ieconazole in the system, thereby increasing the burst release and penetration of the drug. This invention can be understood as an improvement to a dermal formulation, where the selected composition allows the formulation to possess both immediate and sustained-release capabilities, resulting in a long-acting ieconazole dermal formulation that enhances drug efficacy without increasing safety risks. Clinically, this improved ieconazole composition makes the drug suitable for the treatment of tinea pedis and tinea manuum in adults.

[0017] Specifically, the present invention provides a topical long-acting effluconazole composition, comprising the following components by weight percentage:

[0018] Ifluconazole 0.5-3%, film-forming agent 3-7%, gelling agent 2-3%, plasticizer 3-7%, co-solvent 0.78-1.56%, and balance solvent.

[0019] Preferably, the topical long-acting effluconazole composition comprises the following components by weight percentage:

[0020] The ingredients are: 0.5-3% ciproconazole, 5% film-forming agent, 2.5% gelling agent, 5% plasticizer, 0.78-1.56% co-solvent, and the balance solvent.

[0021] in,

[0022] The film-forming agent is selected from acrylate / octylacrylamide copolymers.

[0023] The gelling agent is selected from one or more of hydroxypropyl cellulose, hydroxypropyl chitosan, and povidone;

[0024] Preferably, the gelling agent is hydroxypropyl cellulose.

[0025] The plasticizer is selected from one or more of medium-chain triglycerides, triethyl citrate, and polyethylene glycol 400;

[0026] Preferably, the plasticizer is a medium-chain triglyceride.

[0027] The co-solvent is selected from one or more of lactic acid, citric acid, maleic acid, and malic acid;

[0028] Preferably, the co-solvent is lactic acid.

[0029] The solvent is selected from one or more of anhydrous ethanol, isopropanol, and acetone;

[0030] Preferably, the solvent is anhydrous ethanol.

[0031] As some preferred embodiments, the mass ratio of icoconazole to lactic acid is 1:0.78-1.56; preferably, the mass ratio of icoconazole to lactic acid is 1:1.56.

[0032] In some other preferred embodiments, the mass ratio of the film-forming agent to the plasticizer is 1:1.

[0033] In some other preferred embodiments, the mass ratio of the film-forming agent to efconazole is 3-7:1;

[0034] Preferably, the mass ratio of the film-forming agent to effluconazole is 5:1.

[0035] More preferably, the mass ratio of the acrylate / octylacrylamide copolymer to ivorconazole is 5:1.

[0036] In some other preferred embodiments, the mass ratio of the gelling agent to cifluconazole is 2-3:1;

[0037] Preferably, the mass ratio of the gelling agent to ciproconazole is 2.5:1.

[0038] More preferably, the mass ratio of hydroxypropyl cellulose to ciprofloxacin is 2.5:1.

[0039] In a preferred embodiment, the topical long-acting effluconazole composition comprises the following components by weight percentage:

[0040] The ingredients are: 1% iriconazole, 5% acrylate / octylacrylamide copolymer, 2.5% hydroxypropyl cellulose, 5% medium-chain triglycerides, 1.56% lactic acid, and the balance being solvent.

[0041] The present invention also provides a method for preparing the above-mentioned topical long-acting effluconazole composition, comprising the following steps:

[0042] (1) Add icofol and solubilizer to the solvent, stir until dissolved and clear to obtain a solution; add the solution to a round bottom flask, heat in a water bath, and evaporate by rotary evaporation to obtain a eutectic.

[0043] (2) Add the eutectic to a mixed solvent of solvent and plasticizer and stir until clear to prepare an active phase for later use;

[0044] (3) Add the film-forming agent to the active phase, stir until dissolved and clear, and obtain a mixture for later use;

[0045] (4) Add the gel to the mixture and stir until it is clear to obtain the topical long-acting efconazole composition.

[0046] Preferably, the present invention also provides a method for preparing the above-mentioned topical long-acting effluconazole composition, comprising the following steps:

[0047] (1) Add aniconazole and lactic acid to anhydrous ethanol, stir at 300-800 rpm until clear, and obtain anhydrous ethanol solution; add the anhydrous ethanol solution to a round bottom flask, heat in a water bath to 40℃, negative pressure -0.06Mpa, rotary evaporate for 30-60min, evaporate the anhydrous ethanol, and obtain aniconazole-lactic acid eutectic.

[0048] (2) Add the efconazole-lactic acid eutectic to a mixed solvent of anhydrous ethanol and medium-chain triglycerides and stir at 300-800 rpm until clear to prepare the active phase for later use;

[0049] (3) Add the acrylic (ester) / octylacrylamide copolymer to the active phase, stir until dissolved and clear, and obtain a mixture for later use;

[0050] (4) Add hydroxypropyl cellulose to the mixture and stir until it is clear to obtain the topical long-acting fluoroconazole composition.

[0051] The present invention also provides the application of the above-mentioned topical long-acting effluconazole composition in the preparation of a pharmaceutical formulation for treating tinea pedis and manuum.

[0052] The present invention also provides a pharmaceutical preparation for treating tinea pedis and manuum, the pharmaceutical preparation for treating tinea pedis and manuum comprising the above-mentioned topical long-acting icoconazole composition.

[0053] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0054] (1) The composition provided by the present invention is reasonably designed. It uses erucic acid as the active ingredient and uses a polymer film-forming system for drug loading, so that the formulation has a sustained-release effect. Based on the eutectic technology, erucic acid is paired with lactic acid as a hydrogen bond acceptor and lactic acid as a hydrogen bond donor to increase the solubility and supersaturation capacity of erucic acid in the system, so that the formulation has a high osmotic pressure and high permeability. The resulting composition improves the delivery result of erucic acid. Efluconazole can remain in the stratum corneum for a long time and effectively inhibit the growth and reproduction of fungi, which can improve the efficacy and safety of the drug, conform to the basic theory of pharmacoeconomics, and enhance the clinical value of the product.

[0055] (2) In vitro transdermal results showed that the AUC of the stratum corneum of the skin after one application of the efconazole composition prepared in this invention was [data missing]. 0-24h The AUC of the stratum corneum retention after 24 hours is more than 5 times that of ciprofloxacin cream after a single application. 0-24h ≥200μg·h / cm 2 AUC of 24-hour retention in other dermal layers besides the stratum corneum. 0-24h ≥80 μg·h / g, system exposure AUC 0-24h ≤15μg·h / cm 2 After the animal experiments, the keratin layer of guinea pigs was extracted using the tape peeling method for testing, and the concentration of iefluconazole was ≥30 ng / cm³. 2 It is more than 1,000 times the MIC of ciprofloxacin.

[0056] In addition, the erucic acid composition has the following advantages: ① It significantly increases the amount of dermal stratum corneum retained, improves clinical efficacy, and enriches the active ingredient in the stratum corneum, with no significant increase in exposure to other dermal layers and systemic systems; ② Animal experiments show that the erucic acid composition used once a week has similar effects to commercially available ruliconazole cream used once a day, and after treatment, the concentration of erucic acid in the stratum corneum of guinea pigs is still ≥30 ng / cm³. 2 It is more than 1,000 times the MIC of ciprofloxacin. Attached Figure Description

[0057] Figure 1 Image of guinea pig skin appearance on day 0 of drug administration;

[0058] Figure 2 Image of guinea pig skin appearance 7 days after drug administration;

[0059] Figure 3 Image of guinea pig skin appearance 14 days after drug administration;

[0060] Figure 4 A comparison chart of positive rates in guinea pig hair samples;

[0061] Figure 5 This is a graph showing the concentration of icofol in the cuticle of guinea pigs. Detailed Implementation

[0062] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0064] Example 1: A topical long-acting effluconazole composition and its preparation method

[0065] The components are as follows, expressed as a percentage by weight:

[0066] 30g of ciproconazole, 150g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0067] The preparation method is as follows:

[0068] (1) Add erucic acid and lactic acid to 200 mL of anhydrous ethanol and stir until clear to obtain a mixed solution; add the mixed solution to a round bottom flask, and evaporate at 40 °C and negative pressure -0.06 MPa for 30-60 min until a transparent viscous liquid precipitates out. Place the precipitated solid in a vacuum drying oven and dry at 40 °C for 24 h to obtain the erucic acid-lactic acid eutectic.

[0069] (2) Dissolve the efconazole-lactic acid eutectic in a mixed solvent of anhydrous ethanol and medium-chain triglycerides until clear, and prepare the active phase for later use;

[0070] (3) Add the acrylic (ester) / octylacrylamide copolymer to the active phase and dissolve until clear to obtain a mixture for later use;

[0071] (4) Add hydroxypropyl cellulose to the mixture and dissolve until clear to obtain the topical long-acting fluoroconazole composition.

[0072] Example 2: A topical long-acting effluconazole composition and its preparation method

[0073] The difference from Example 1 is that the molar ratio of icoconazole to lactate is 1:3, and the weight ratio is 1:0.78. That is, the components, by weight percentage, are as follows:

[0074] 30g of ciproconazole, 150g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 23.4g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0075] The preparation method is the same as in Example 1.

[0076] Example 3: A topical long-acting effluconazole composition and its preparation method

[0077] The difference from Example 1 is that hydroxypropyl cellulose is replaced with hydroxypropyl chitosan, while the other components, their contents, and preparation methods are the same as in Example 1.

[0078] Example 4: A topical long-acting effluconazole composition and its preparation method

[0079] The difference from Example 1 is that hydroxypropyl cellulose is replaced with povidone, while the other components, their contents, and preparation methods are the same as in Example 1.

[0080] Example 5: A topical long-acting effluconazole composition and its preparation method

[0081] The difference from Example 1 is that lactic acid is replaced with maleic acid, while the other components, their contents, and preparation methods are the same as in Example 1.

[0082] Example 6: A topical long-acting effluconazole composition and its preparation method

[0083] The difference from Example 1 is that lactic acid is replaced with malic acid, while the other components, their contents, and preparation methods are the same as in Example 1.

[0084] Example 7: A topical long-acting effluconazole composition and its preparation method

[0085] The difference from Example 1 is that lactic acid is replaced with citric acid, while the other components, their contents, and preparation methods are the same as in Example 1.

[0086] Example 8: A topical long-acting effluconazole composition and its preparation method

[0087] The difference from Example 1 is that the weight percentage of icoconazole is 0.5%, which is the following components by weight percentage: 15g of icoconazole, 150g of acrylate / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0088] The preparation method is the same as in Example 1.

[0089] Example 9:

[0090] The difference from Example 1 is that the weight percentage of icoconazole is 3%, which is the following components by weight percentage: 90g of icoconazole, 150g of acrylate / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0091] The preparation method is the same as in Example 1.

[0092] Example 10:

[0093] The difference from Example 1 is that the amounts of acrylate / octylacrylamide copolymer and medium-chain triglyceride are both adjusted to 3%, i.e., the components are as follows by weight percentage:

[0094] 30g of ciproconazole, 90g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 90g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0095] The preparation method is the same as in Example 1.

[0096] Example 11:

[0097] The difference from Example 1 is that the amounts of acrylate / octylacrylamide copolymer and medium-chain triglyceride are both adjusted to 7%, i.e., the components are as follows by weight percentage:

[0098] 30g of ciproconazole, 210g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 210g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0099] The preparation method is the same as in Example 1.

[0100] Example 12:

[0101] The difference from Example 1 is that the amount of hydroxypropyl cellulose used is adjusted to 2%, that is, the components by weight percentage are as follows:

[0102] 30g of ciproconazole, 150g of acrylic acid (ester) / octylacrylamide copolymer, 60g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0103] The preparation method is the same as in Example 1.

[0104] Example 13:

[0105] The difference from Example 1 is that the amount of hydroxypropyl cellulose was adjusted to 3%, 30g of icoconazole, 150g of acrylate / octylacrylamide copolymer, 90g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 46.8g of lactic acid, and anhydrous ethanol was added to make up to 3000g.

[0106] The preparation method is the same as in Example 1.

[0107] Comparative Example 1: An icofol cream and its preparation method

[0108] Efluconazole 30g, propylene glycol 1200g, benzyl alcohol 60g, oleic acid 150g, Labrafilm 1944 150g, glyceryl monooleate 90g, cetearyl alcohol 202.5g, Labrosol 30g, polysorbate 80 30g, stearic acid 22.5g, purified water to bring the total to 3000g.

[0109] The preparation method is as follows:

[0110] (1) Add iriconazole, propylene glycol, benzyl alcohol, oleic acid, Labrafilm 1944, glyceryl monooleate, cetearyl alcohol, labrosol, polysorbate 80, and stearic acid to an oil pan, heat to 70±5℃, stir until dissolved and clear, and set aside.

[0111] (2) Add purified water to a water pot and heat it to 70±5℃ for later use;

[0112] (3) Transfer the purified water to the oil pan, evacuate to a pressure of not less than -0.06 MPa, and start the homogenizer / stirrer at 2000±500 rpm / 35±15 rpm / 15 min;

[0113] (4) Stop homogenization, turn on the cooling water, maintain the vacuum degree not lower than -0.06Mpa, maintain stirring at 35±15rpm, and cool down to 35±5℃ to obtain the product.

[0114] Comparative Example 2:

[0115] The difference from Example 1 is that the acrylic (ester) / octylacrylamide copolymer is replaced with poly(vinyl chloride-methyl vinyl ether / maleic anhydride) copolymer, while the other components, their contents, and the preparation method are the same as in Example 1.

[0116] Comparative Example 3:

[0117] The difference from Example 1 is that the acrylic (ester) / octylacrylamide copolymer is replaced with ethyl cellulose, while the other components, their contents, and the preparation method are the same as in Example 1.

[0118] Comparative Example 4:

[0119] The difference from Example 1 is that the acrylic (ester) / octylacrylamide copolymer is replaced with acrylic resin RL100, while the other components, their contents, and the preparation method are the same as in Example 1.

[0120] Comparative Example 5:

[0121] The difference from Example 1 is that the molar ratio of icoconazole to lactate is 1:2, and the weight ratio is 1:0.52. That is, the components, by weight percentage, are as follows:

[0122] 30g of ciproconazole, 150g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, 15.6g of lactic acid, and anhydrous ethanol to make up to 3000g.

[0123] The preparation method is the same as in Example 1.

[0124] Comparative Example 6:

[0125] The difference from Example 1 is that the molar ratio of icoconazole to lactate is 1:0, and the weight ratio is 1:0, meaning no lactate is added. The components, by weight percentage, are as follows:

[0126] 30g of ciproconazole, 150g of acrylic acid (ester) / octylacrylamide copolymer, 75g of hydroxypropyl cellulose, 150g of medium-chain triglycerides, and anhydrous ethanol to bring the total to 3000g.

[0127] The preparation method is as follows:

[0128] (1) Dissolve evaconazole in a mixture of anhydrous ethanol and medium-chain triglycerides until clear, and prepare an active phase for later use;

[0129] (2) Add the acrylic (ester) / octylacrylamide copolymer to the active phase and dissolve until clear to obtain a mixture for later use;

[0130] (3) Add hydroxypropyl cellulose to the mixture and dissolve until clear to obtain the topical long-acting fluoroconazole composition.

[0131] Effect test:

[0132] 1. Solubility test:

[0133] The properties of the eufluconazole-lactic acid eutectic prepared in step (1) of Examples 1 and 5-7 and their solubility in anhydrous ethanol were tested. The test results are shown in Table 1 below.

[0134] Table 1

[0135]

[0136] As shown in Table 1, different organic acids, when forming DES eutectics with iefluconazole, can all improve the solubility of iefluconazole in ethanol to some extent. Among various organic acids, the eutectic formed by lactic acid and iefluconazole has the characteristic of being infinitely miscible with ethanol. Therefore, using lactic acid as a co-solvent can better improve the solubility of iefluconazole.

[0137] 2. Hydrophobicity test

[0138] The type of pharmaceutical adjuvant has a direct impact on the retention ability of a pharmaceutical composition on the skin. Based on this, the hydrophobicity of the pharmaceutical composition was studied.

[0139] Experimental Methods: 0.1 g of samples prepared in Examples 1, 10-11, and Comparative Examples 1-4 were uniformly spread on glass plates (n=3). After standing for 30 min, the ethanol was evaporated, and the drug film was formed. The glass plates were then immersed in 500 ml of 0.1% SDS aqueous solution. The stirring speed was set to 50 rpm. 1 ml samples were taken at 15 min, 30 min, and 60 min each time. The solution was replenished after each sampling. The dissolution rate of icofol was measured, and the change in drug mass before and after the experiment was also measured. The test results are shown in Tables 2-5.

[0140] Table 2 Results of dissolution test

[0141]

[0142] Table 3. Results of Drug Quality Testing

[0143]

[0144] According to the test results in Tables 2 and 3 above, the composition obtained by combining acrylic (ester) / octylacrylamide copolymer with other excipients described in this invention has the best protective effect on the active pharmaceutical ingredient, iefluconazole. The hydrophobic film formed can protect the active ingredient from the effects of water washing. However, the compositions obtained by combining other types of film-forming agents, such as acrylic resin RL100, ethyl cellulose, and poly(vinyl chloride-methyl vinyl ether / maleic anhydride) copolymer with other excipients described in this invention, cannot effectively protect iefluconazole and will affect the stability of the composition.

[0145] Table 4. Results of dissolution test

[0146]

[0147] Table 5. Results of Drug Quality Testing

[0148]

[0149] According to the test results in Tables 4 and 5 above, the hydrophobic film formed by using acrylic (ester) / octylacrylamide copolymer with medium-chain triglycerides has good water resistance; and when the dosage of film-forming agent and plasticizer is in the range of 3-7%, the resulting composition can effectively protect ciproconazole and improve the stability of the composition.

[0150] 3. Rheological and viscosity testing

[0151] The design of topical drug formulations needs to consider the rheological characteristics of the product to improve patient compliance and daily storage; it also needs to have a certain viscosity to maintain the stability of the drug in its daily state; and the drug usually needs to have the characteristics of a power-law fluid, with the ability to thin at shear, so as to facilitate patient application.

[0152] The rheological profiles and viscosities of the topical long-acting icoconazole compositions prepared in Examples 1, 3-4 and 12-13 were determined using a rotational rheometer and a viscometer.

[0153] Detection method:

[0154] Viscosity was measured using a Bollerfeld DV2T viscometer with an SC4-18 rotor. The test temperature was 25℃, the constant temperature time was 10 min, the measuring speed was 80 rpm, the running time was 120 seconds, and the data acquisition time was 10 seconds.

[0155] Rheological curves were determined using a TA Instruments HA-10 rheometer (USA). The test mode was rotational CR mode, ramp scan, logarithmic coordinates, with a 40mm stainless steel plate as the fixture. The test temperature was 25℃, the holding time was 60 seconds, the shearing time was 240 seconds, the shearing range was 1000-0.01, and the gap was 0.5mm. The test results are shown in Table 6 below.

[0156] Table 6

[0157]

[0158] According to the test results in Table 6, the rheological curves of the topical long-acting effluconazole compositions prepared in Examples 1, 3-4 and 12-13 all show power-law fluid characteristics, indicating that the obtained compositions are easy to apply; and during the standing process, the compositions have high viscosity and can maintain their own shape.

[0159] 4. Transdermal permeability testing

[0160] The transdermal absorption of the compositions prepared in Examples 1-2 and Comparative Examples 1 and 5-6 was compared, with a drug application area of ​​1.77 cm². 2 A Franz diffusion cell with a receiving volume of 8 mL was used, with the skin of a one-month-old Bama miniature pig as the osmotic barrier, at a concentration of 10 mg / cm³. 2 The drug was applied at a dose of approximately 17.7 mg. The receiving solution was physiological saline for in vitro transdermal testing. The temperature was set at 32℃, the rotation speed at 600 rpm, n=6, and the sampling time points were 1, 2, 4, 8, 12, and 24 hours.

[0161] After the transdermal test, the stratum corneum of the pigskin was separated from other dermal layers using an adhesive tape peeling method. The tape was applied 11 times in total. The stratum corneum covered by the first application contained the remaining drug, and the remaining stratum corneum was covered by the next 10 applications. The content of icorconazole in the stratum corneum was then determined. The results are shown in Table 7.

[0162] Table 7. Content of ciproconazole in the stratum corneum

[0163]

[0164] According to the test results in Table 7 above, compared with iefluconazole cream (Comparative Example 1), the iefluconazole film-forming agent, regardless of whether it contains lactic acid as a co-solvent, has a lower AUC in the stratum corneum. 0-24h All of them are much larger than those of ciproconazole cream (Comparative Example 1).

[0165] A comparison of Examples 1-2 and Comparative Examples 5-6 shows that when the weight ratio of iefluconazole to lactic acid is 1:0.78%-1.56% (i.e., a molar ratio of 1:3-6), the AUC of iefluconazole in the stratum corneum is [data missing]. 0-24h≥200μg·h / cm 2 AUC in the dermis outside the stratum corneum 0-24h ≥80 μg·h / g; systemic exposure ≤15 μg·h / cm 2 .

[0166] 5. Antibacterial activity test

[0167] Keratin in the skin can bind to active pharmaceutical ingredients (APIs). Once bound, the API does not possess bactericidal activity; only the free API has bactericidal properties. Therefore, when evaluating the bactericidal activity of APIs, it is insufficient to consider only in vitro bacteriostatic or bactericidal concentrations; the reduction in bactericidal or bacteriostatic activity due to the binding of the API to keratin must also be taken into account.

[0168] During the preparation of antibacterial compositions, it is necessary to reasonably control the concentration of active pharmaceutical ingredients in order to ensure the free amount of active pharmaceutical ingredients in the skin and to ensure the bactericidal or bacteriostatic effect.

[0169] Examples 1 and 8-9 prepared icoconazole-lactic acid eutectics with different concentrations of active pharmaceutical ingredient. 18 mg of each icoconazole-lactic acid eutectic was incubated with keratin powder for 24 hours to obtain keratin-bound icoconazole-lactic acid eutectics. The keratin-bound icoconazole-lactic acid eutectics were added to a fungal culture medium and incubated for 24 hours. The antibacterial effect of the keratin-bound icoconazole-lactic acid eutectics was evaluated based on the size of the inhibition zone formed in the fungal culture medium. The results are shown in Table 8 below.

[0170] Table 8 Results of Antibacterial Effect Test

[0171]

[0172] According to the test results in Table 8 above, when the concentration of the active ingredient evaconazole is 0.5%-3%, the area of ​​the inhibition zone formed is similar, and they have similar antibacterial effects.

[0173] 6. Animal pharmacodynamics studies

[0174] Animal pharmacodynamic studies were conducted on Example 1, Comparative Example 1, Comparative Example 6, Luliconazole Cream (positive group), blank coating group (negative group), and blank cream group (negative group).

[0175] Five-week-old male guinea pigs were purchased. After one week of acclimatization, six guinea pigs were randomly selected as a blank control group. The remaining animals were injected intraperitoneally with dexamethasone (10 mg / kg) for three consecutive days before fungal inoculation. One day before Trichophyton rubrum inoculation, the hair on the back of the guinea pigs was shaved with a shaver, and the hair roots were removed with depilatory cream to expose smooth, bare back skin. On the day of inoculation, the shaved area was disinfected with alcohol. After the alcohol dried, the skin was abraded with sterile coarse sandpaper until pinpoint bleeding occurred. The fungal suspension was evenly applied to a 3cm × 3cm area of ​​broken skin. Except for the blank control group, all animals were inoculated with fungal suspension (1 × 10⁻⁶ mg / kg) on ​​their skin surface. 8 After the bacterial culture (cfu / ml) was completely absorbed, the mice were returned to their cages. Following inoculation, dexamethasone was injected intraperitoneally for four consecutive days, and the signs, skin erythema, scaling, and hair appearance of each group were observed daily. Four days after fungal inoculation, the appearance of erythema, scaling, and irregular hair growth at the model site confirmed successful model establishment.

[0176] After successfully establishing the guinea pig fungal infection model, 42 successfully modeled guinea pigs were screened and randomly divided into four groups according to weight and infection severity: a model control group, a control group (Example 1), a control group (Comparative Example 1), a control group (Comparative Example 6), a ruconazole cream (positive group), a blank coating group (negative group), a blank cream group (negative group), and a blank group, with 6 guinea pigs in each group. Grouping and administration were carried out according to Table 9 below.

[0177] Table 9 Grouping and Dosing Regimens

[0178]

[0179] Evaluation indicators:

[0180] Skin photos are taken after modeling to assess the degree of skin inflammation and infection (once a week).

[0181] Fungal detection: Day 0 was designated as the first day of drug administration. All animals underwent testing on Day 0, Day 3, Day 7, Day 10, and Day 14 (guinea pig skin appearance is shown in the table below). Figure 1-3 Ten hairs were randomly selected from the guinea pig modeling area and inoculated into PDA medium for culture. The positive rate of hair fungus was calculated based on the fungal growth.

[0182] Sample collection and testing: After administration, the guinea pigs were euthanized, and the stratum corneum of the guinea pigs was sampled using the tape peeling method to determine the concentration of icofol in the stratum corneum.

[0183] Test results:

[0184] according to Figure 4The results showed that the once-weekly administration of the erucic acid composition prepared in Example 1 was similar to the once-daily administration of the erucic acid cream prepared in Comparative Example 1 and the commercially available ruliconazole cream, indicating that the erucic acid composition prepared in Example 1 could achieve the intended therapeutic effect. The once-weekly administration of the erucic acid composition prepared in Comparative Example 6 was less effective and could not effectively control fungal growth. This may be due to the lower AUC of the erucic acid composition prepared in Comparative Example 6. 0-24h This is due to the lower level.

[0185] according to Figure 5 The results showed that after the experiment, the stratum corneum of guinea pig skin was sampled using the tape peeling method. The 2nd to 11th layers of tape were used as the stratum corneum of guinea pigs, and the concentration of icoconazole in the stratum corneum was measured. On the 15th day of treatment (7 days after administration), the concentration of icoconazole in the stratum corneum was more than 1000 times its MIC.

[0186] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A topical long-acting effluconazole composition, characterized in that: It includes the following components by weight percentage: Ifluconazole 0.5-3%, film-forming agent 3-7%, gelling agent 2-3%, plasticizer 3-7%, co-solvent 0.78-1.56% and balance solvent; The film-forming agent is selected from acrylate / octylacrylamide copolymers; The co-solvent is lactic acid; Among them, icoconazole and lactic acid are prepared into icoconazole / lactic acid eutectic by deep eutectic technology.

2. The topical long-acting effluconazole composition according to claim 1, characterized in that: It includes the following components by weight percentage: The ingredients are: 0.5-3% ciproconazole, 5% film-forming agent, 2.5% gelling agent, 5% plasticizer, 0.78-1.56% co-solvent, and the balance solvent.

3. The topical long-acting effluconazole composition according to claim 1, characterized in that: The gelling agent is selected from one or more of hydroxypropyl cellulose, hydroxypropyl chitosan, and povidone.

4. The topical long-acting effluconazole composition according to claim 3, characterized in that: The gelling agent is hydroxypropyl cellulose.

5. The topical long-acting effluconazole composition according to claim 1, characterized in that: The plasticizer is selected from one or more of medium-chain triglycerides, triethyl citrate, and polyethylene glycol 400.

6. The topical long-acting effluconazole composition according to claim 5, characterized in that: The plasticizer is a medium-chain triglyceride.

7. The topical long-acting effluconazole composition according to claim 1, characterized in that: The solvent is selected from one or more of anhydrous ethanol, isopropanol and acetone.

8. The topical long-acting effluconazole composition according to claim 7, characterized in that: The solvent is anhydrous ethanol.

9. The topical long-acting effluconazole composition according to claim 1, characterized in that: The mass ratio of icoconazole to cosolvent is 1:0.78-1.

56.

10. The topical long-acting effluconazole composition according to claim 9, characterized in that: The mass ratio of efconazole to lactic acid is 1:1.

56.

11. The topical long-acting effluconazole composition according to claim 1, characterized in that: The mass ratio of the film-forming agent to the plasticizer is 1:

1.

12. The topical long-acting effluconazole composition according to claim 1, characterized in that: The mass ratio of the acrylate / octylacrylamide copolymer to icoconazole is 3-7:

1.

13. The topical long-acting effluconazole composition according to claim 4, characterized in that: The mass ratio of hydroxypropyl cellulose to ciprofloxacin is 2-3:

1.

14. The topical long-acting effluconazole composition according to any one of claims 1-13, characterized in that: It includes the following components by weight percentage: The ingredients are: 1% ciproconazole, 5% acrylate / octylacrylamide copolymer, 2.5% hydroxypropyl cellulose, 5% medium-chain triglycerides, 1.56% lactic acid, and the balance being solvent.

15. A method for preparing the topical long-acting effluconazole composition according to any one of claims 1-14, characterized in that: Includes the following steps: (1) Add icofonazole and solubilizer to the solvent, stir until clear, and obtain a solution; add the solution to a round bottom flask, heat in a water bath, and evaporate by rotary evaporation to remove the solvent and obtain a eutectic. (2) Add the eutectic to a mixed solvent of solvent and plasticizer and stir until clear to prepare an active phase for later use; (3) Add the film-forming agent to the active phase, stir until dissolved and clear, and obtain a mixture for later use; (4) Add the gel to the mixture and dissolve until clear to obtain the topical long-acting effluconazole composition.

16. The use of the topical long-acting effluconazole composition according to any one of claims 1-14 in the preparation of a pharmaceutical formulation for treating tinea pedis and manuum.

17. A pharmaceutical preparation for treating tinea pedis and tinea manuum, characterized in that: Includes the topical long-acting effluconazole composition according to any one of claims 1-14.

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