A luliconazole cream and a method for preparing the same

Abstract

The application provides a luliconazole cream and a preparation method thereof. In the preparation process of the cream, phenoxyethanol and hydroxybenzyl ester are used as a composite bacteriostatic agent, polysorbate 60 and Span 60 are used as a composite emulsifier, cetylstearyl alcohol and isopropyl myristate are used as an oil phase matrix, model numbers of medium-chain triglycerides, important auxiliary material ratios, and process parameters such as control of high-shear emulsification and cooling rate are optimized, so that the prepared cream has the advantages of uniform particle size, good stability, high transdermal absorption rate, simple preparation method, low cost, and the like, and is suitable for large-scale industrial production.

Description

Technical Field

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

[0002] Luliconazole, chemically named (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-1,3-dithiopentane-2-ide]-2-imidazol-1-ylacetonitrile, has the molecular formula C2. 14 H9Cl2N3S2, with a molecular weight of 354.28, is a novel imidazole broad-spectrum antifungal drug. It exerts its bactericidal and bacteriostatic effects by inhibiting the synthesis of ergosterol in fungal cell membranes. Clinically, it is mainly used to treat fungal skin infections such as tinea pedis, tinea corporis, tinea cruris, and tinea versicolor.

[0003] Luriconazole is a lipid-soluble drug, practically insoluble in water, but exhibiting some solubility in ethanol, propylene glycol, and oil-based matrices. Due to the presence of the stratum corneum barrier in the skin, luriconazole in conventional cream formulations has difficulty effectively penetrating deep into the skin, resulting in low bioavailability and poor efficacy. Furthermore, the sulfide bond and unsaturated double bond in the luriconazole molecule make it sensitive to light, heat, and oxidation, and it is prone to degradation during formulation preparation and storage, generating oxidative impurities and the cis isomer (Z-isomer), thus affecting product safety.

[0004] Chinese patent CN108143711A discloses a topical cream composition containing luriconazole, employing liposome technology to enhance transdermal absorption. However, the formulation contains large amounts of ethanol and lecithin, making the preparation method complex and costly. Furthermore, the liposomes exhibit poor stability, easily leading to aggregation and stratification during long-term storage. WO2019070221A1 discloses a luriconazole topical cream using benzyl alcohol as a solvent to dissolve the active ingredient. However, this patent does not specify emulsification process parameters, cooling rate, or cream particle size control, resulting in a cream with a wide particle size distribution. The stability and transdermal absorption effect still require improvement.

[0005] Chinese patent CN120131747 A discloses a luriconazole composition containing essential oil, a cream, and its preparation method and application. This patent argues that using a chemical penetration enhancer (isopropyl myristate) to promote drug absorption may cause skin irritation. Therefore, tea tree oil is used to replace the chemical enhancer to achieve synergistic antifungal effects and reduce irritation. However, this patent still has room for further exploration: for example, completely removing isopropyl myristate may affect the spreadability and transdermal absorption performance of the cream; although tea tree oil has certain efficacy, it is a common contact sensitizer and its safety needs to be considered; high shear speed and lack of programmed cooling control may adversely affect the structure and particle size distribution of the cream, thereby affecting the physical stability of the formulation; at the same time, the penetration-enhancing mechanism of tea tree oil is similar to that of existing chemical penetration enhancers, and its rationality and long-term safety still require more systematic research and verification.

[0006] Therefore, it is of great significance to develop a luliconazole cream with a simple formulation, low cost, uniform particle size, good stability and high transdermal absorption efficiency, and to establish a preparation method suitable for large-scale commercial production. Summary of the Invention

[0007] The purpose of this invention is to provide a ruliconazole cream based on existing technology, which can solve the problems of uneven particle size, poor stability, low transdermal absorption rate, and difficulty in scaling up the production process of existing creams. In the preparation process of the cream, phenoxyethanol and methylparaben are used as a composite antibacterial agent, polysorbate 60 and Span 60 are used as a composite emulsifier, and cetearyl alcohol and isopropyl myristate are used as the oil phase matrix. The type of medium-chain triglycerides, the ratio of important excipients, and the process parameters such as controlling high-shear emulsification and cooling rate are optimized, so that the prepared cream has the advantages of uniform particle size (particle size D90 of 2-5μm), good stability (total impurities ≤0.5% after 6 months of accelerated processing), high transdermal absorption rate, simple preparation method, and low cost, making it suitable for large-scale industrial production.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned ruliconazole cream.

[0009] The technical solution of the present invention is as follows: A luriconazole cream is made from the following components in weight percentages: luriconazole 0.5-2%, medium-chain triglycerides 5-15%, cetearyl alcohol 1-9%, isopropyl myristate 1-10%, polysorbate 60 1-5%, Span 60 0.1-3.5%, phenoxyethanol 0.1-1%, butylated hydroxytoluene 0.001-0.03%, methylparaben 0.05-0.2%, propylene glycol 2-10%, and purified water to 100%.

[0010] The cream of this invention comprises the active ingredient ruliconazole and excipients. The excipients include an oil phase matrix, a complex emulsifier, a complex antibacterial agent, an antioxidant, and a solvent. The oil phase matrix comprises medium-chain triglycerides, cetearyl alcohol, and isopropyl myristate. The complex emulsifier comprises polysorbate 60 (Tween 60) and Span 60 (stearosorbide), which together constitute the complex emulsifier. The complex antibacterial agent comprises phenoxyethanol and methylparaben. The antioxidant is butylated hydroxytoluene (BHT). The solvent is propylene glycol.

[0011] Medium-chain triglycerides (MCTs) are mixtures of triglycerides formed by the esterification of caprylic acid (C8) and decanoic acid (C10) with glycerol. Reverse engineering studies have revealed that an MCT formulation with a caprylic acid to decanoic acid mass ratio of 7:3 best matches the solubility and skin permeability of luriconazole. This MCT formulation possesses suitable viscosity and polarity, effectively dissolving luriconazole and promoting its deep penetration into the skin. Different MCT formulations (e.g., caprylic acid to decanoic acid mass ratios of 6:4 or 8:2) affect the solubility and skin permeability of luriconazole. Therefore, in this invention, the mass ratio of caprylic acid to decanoic acid is controlled to be 6-8:2-4, for example, 6:4, 6.5:3.5, 7:3, 7.5:3.5, or 8:2; preferably, the mass ratio is controlled to be 6.5-7.5:2.5-3.5; more preferably, the mass ratio is controlled to be 7:3.

[0012] Cetearyl alcohol (Cetearyl alcohol) serves as the oil phase matrix and thickener, giving the cream suitable viscosity and spreadability; isopropyl myristate (IPM), as the oil phase solvent and transdermal penetration enhancer, can disrupt the lipid bilayer structure of the stratum corneum and increase drug transdermal throughput.

[0013] This invention addresses the characteristics of ruliconazole, including its high lipid solubility, poor water solubility, sensitivity to light and heat, and easy oxidation. Extensive and long-term formulation screening and process research were conducted. Specific experiments revealed that when polysorbate 60 and Span 60 were selected as composite emulsifiers, and the mass ratio of polysorbate 60 to Span 60 was controlled within the range of 2-5:1, while the mass ratio of cetearyl alcohol to isopropyl myristate was controlled within the range of 1-3:1, the resulting cream exhibited excellent emulsification stability and transdermal absorption performance.

[0014] Cetearyl alcohol, as a long-chain fatty alcohol, can participate in the formation of a lamellar liquid crystal phase at the oil-water interface, enhancing the viscoelasticity and stability of the cream. The fatty acid chains of both polysorbate 60 and Span 60 are mainly stearic acid (C18), which is similar in length to the alkyl chain of cetearyl alcohol (cetearearyl alcohol, mainly containing cetyl alcohol C16 and stearyl alcohol C18), resulting in good structural matching. This facilitates the formation of a dense and ordered molecular arrangement at the interface, improving the high-temperature stability of the cream. Furthermore, the saturated chain structure is less prone to oxidative degradation during high-temperature formulation compared to emulsifiers containing unsaturated bonds.

[0015] In this invention, when polysorbate 60 and Span 60 are selected as composite emulsifiers, and the mass ratio of polysorbate 60 to Span 60 is controlled within the range of 2-5:1, it can be, but is not limited to, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1. Preferably, the mass ratio of polysorbate 60 to Span 60 is controlled to be 3.5-4.5:1; more preferably, the mass ratio of polysorbate 60 to Span 60 is controlled to be 3-4:1.

[0016] In this invention, the mass ratio of hexadecanoic acid to isopropyl myristate is controlled within the range of 1-3:1, and can be, but is not limited to, 1:1, 1.2:1, 1.5:1, 1.6:1, 1.67:1, 1.7:1, 2:1, 2.2:1, 2.5:1 or 3:1. Preferably, the mass ratio of hexadecanoic acid to isopropyl myristate is controlled at 1.5-2.5:1; more preferably, the mass ratio of hexadecanoic acid to isopropyl myristate is controlled at 1.67-2:1.

[0017] In selecting the antibacterial agent, this invention uses phenoxyethanol instead of benzyl alcohol. Phenoxyethanol has better solubility and stability in the oil phase and has a certain synergistic effect on the dissolution of ruconazole, while avoiding the skin irritation and allergic reactions that benzyl alcohol may cause. Methylparaben, as an aqueous antibacterial agent, forms a broad-spectrum antibacterial system with phenoxyethanol.

[0018] In a preferred embodiment, the luliconazole cream provided by the present invention is made of the following components in weight percentage: luliconazole 0.8-1.2%, medium-chain triglycerides 8-11%, cetearyl alcohol 3-7%, isopropyl myristate 1.5-4.5%, polysorbate 60 2-4%, Span 60 0.5-1.2%, phenoxyethanol 0.3-0.7%, butylated hydroxytoluene 0.005-0.015%, methylparaben 0.08-0.15%, propylene glycol 4-6%, and purified water to 100%; wherein, the medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 6.5-7.5:2.5-3.5; the mass ratio of cetearyl alcohol to isopropyl myristate is 1.5-2.5:1, and the mass ratio of polysorbate 60 to Span 60 is 3.5-4.5:1.

[0019] In a more preferred embodiment, the luliconazole cream provided by the present invention is made of the following components in weight percentage: 1% luliconazole, 9-10% medium-chain triglycerides, 4-5% cetearyl alcohol, 2-3% isopropyl myristate, 2.5-3.5% polysorbate 60, 0.75-1% Span 60, 0.4-0.6% phenoxyethanol, 0.008-0.012% butylated hydroxytoluene, 0.11-0.13% methylparaben, 4.5-5.5% propylene glycol, and purified water to 100%; wherein the medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1.67-2:1, and the mass ratio of polysorbate 60 to Span 60 is 3-4:1.

[0020] For example, the luriconezine cream provided by this invention is made from the following components in weight percentage: 1% luriconezine, 9% medium-chain triglycerides, 5% cetearyl alcohol, 3% isopropyl myristate, 3% polysorbate 60, 0.75% Span 60, 0.5% phenoxyethanol, 0.01% butylated hydroxytoluene, 0.12% methylparaben, 5% propylene glycol, and 72.62% purified water. The medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, with a mass ratio of caprylic acid to capric acid of 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1.67:1; and the mass ratio of polysorbate 60 to Span 60 is 4:1.

[0021] For example, the luriconezine cream provided by this invention is made from the following components in weight percentage: 1% luriconezine, 10% medium-chain triglycerides, 4% cetearyl alcohol, 2% isopropyl myristate, 3% polysorbate 60, 1% Span 60, 0.5% phenoxyethanol, 0.01% butylated hydroxytoluene, 0.12% methylparaben, 5% propylene glycol, and 73.37% purified water. The medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, with a mass ratio of caprylic acid to capric acid of 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 2:1; and the mass ratio of polysorbate 60 to Span 60 is 3:1.

[0022] The present invention also provides a method for preparing the above-mentioned liconazole cream, comprising the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 75-85℃ until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase. (2) Addition of active ingredients: Under the condition of controlling the temperature at 75-85℃, add ruliconazole to the oil phase obtained in step (1), stir evenly, and obtain a uniform mixed solution; (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 75-85℃ until completely dissolved to obtain aqueous phase; (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 75-85℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), stirred evenly, purified water at 75-85℃ is added to make up to the volume, and then high shear emulsification is performed. The high shear rate is 2000-4000 rpm, and the shearing time is 10-20 minutes to form an emulsion. (5) Cooling and filling: Place the emulsion obtained in step (4) in a water bath at 15-30℃, turn on the stirring, control the cooling rate at 1-3℃ / min, stop stirring when the temperature of the emulsion drops below 35℃, fill and seal to obtain the cream.

[0023] In this invention, in step (1), the mixture is stirred at 75-85°C until completely dissolved. The stirring and dissolving temperature can be, but is not limited to, 75°C, 78°C, 80°C, 82°C or 85°C. Preferably, the stirring and dissolving temperature is 78-82°C; more preferably, the stirring and dissolving temperature is 80°C.

[0024] In this invention, in step (2), the temperature is controlled at 75-85°C, but is not limited to 75°C, 78°C, 80°C, 82°C or 85°C. Preferably, the temperature is controlled at 78-82°C; more preferably, the temperature is controlled at 80°C.

[0025] In this invention, in step (3), the mixture is stirred at 75-85°C until completely dissolved. The stirring and dissolving temperature can be, but is not limited to, 75°C, 78°C, 80°C, 82°C or 85°C. Preferably, the stirring and dissolving temperature is 78-82°C; more preferably, the stirring and dissolving temperature is 80°C.

[0026] In this invention, in step (4), the temperature is controlled at 75-85°C, but is not limited to 75°C, 78°C, 80°C, 82°C or 85°C. Preferably, the temperature is controlled at 78-82°C; more preferably, the temperature is controlled at 80°C.

[0027] In this invention, in step (4), purified water at 75-85°C is added. The temperature can be, but is not limited to, 75°C, 78°C, 80°C, 82°C or 85°C. Preferably, purified water at 78-82°C is added; more preferably, purified water at 80°C is added.

[0028] During the experiment, it was found that using high-shear emulsification in step (4), controlling the shearing speed at 2000-4000 rpm and the shearing time at 10-20 min, could control the cream particle size to 1-10 μm (preferably 2-5 μm) with a D90. When the shearing speed is too low or the time is too short, the cream particle size is large, and the transdermal absorption rate decreases; when the shearing speed is too high or the time is too long, the cream viscosity decreases, and ruliconazole is easily degraded due to mechanical shearing and local overheating, resulting in an increase in related substances. The shearing speed can be 2000 rpm, 2500 rpm, 3000 rpm, 3500 rpm, or 2000 rpm, preferably 3000-3500 rpm. The shearing time can be 10 min, 12 min, 15 min, or 20 min, preferably 12-15 min.

[0029] Programmed cooling avoids phase separation or local crystallization caused by rapid cooling, while also avoiding the problem of excessively long residence time of ruliconazole at high temperatures and increased degradation risk due to excessively slow cooling. Furthermore, in step (5), the cooling rate during the cooling stage has a significant impact on the quality of the cream. Controlling the cooling rate to 1~3℃ / min, preferably 2-3℃ / min, allows the cream to maintain a stable structure during cooling, avoiding phase separation or particle size increase caused by rapid cooling. If the cooling is too fast (>5℃ / min), the cream is prone to stratification and crystallization; if the cooling is too slow (<0.5℃ / min), production efficiency is low, and ruliconazole remains at high temperatures for too long, increasing the risk of degradation.

[0030] In step (5), the emulsion obtained in step (4) is placed in a water bath at 15-30°C, preferably at 20-25°C.

[0031] The advantages of using the technical solution of this invention are as follows: This invention provides a luriconezine cream using a specific type of medium-chain triglyceride (caprylic acid to capric acid in a mass ratio of 7:3), cetearyl alcohol, and isopropyl myristate as the oil phase matrix, polysorbate 60 and Span 60 as composite emulsifiers, and phenoxyethanol and methylparaben as composite antibacterial agents. Specific excipient ratios and process parameters were selected to solve problems such as uneven particle size, poor stability, low transdermal absorption, and easy degradation of active ingredients in existing creams. The cream provided by this invention has advantages such as uniform particle size (D90 of 2~5μm), good stability (total impurities ≤0.5% after 6 months of accelerated processing), high transdermal absorption, simple preparation method, and low cost, making it suitable for large-scale industrial production. Detailed Implementation

[0032] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0033] Example 1 A luriconezine cream, wherein the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, wherein the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1; and the mass ratio of polysorbate 60 to Span 60 is 4:1; specifically, it is made of the following components by weight:

[0034] The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 80°C until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase.

[0035] (2) Addition of active ingredients: Under the condition of controlling the temperature at 80℃, add ruconazole to the oil phase obtained in step (1), stir and dissolve for 10 min to obtain a uniform mixed solution.

[0036] (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 80°C until completely dissolved to obtain aqueous phase.

[0037] (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 80℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), and after stirring evenly, purified water at 80℃ is added to make up to the total volume, and then high shear emulsification is performed. The high shear rate is 3000 rpm and the shearing time is 15 minutes to form an emulsion.

[0038] (5) Cooling and filling: The obtained emulsion is placed in a water bath at 20-25℃, stirring is turned on, and the cooling rate is controlled at 2℃ / min. Stirring is stopped when the temperature of the emulsion drops below 35℃. The cooled emulsion is then filled into a pharmaceutical aluminum tube, 10g / tube.

[0039] Example 2 A luriconezol cream differs from Example 1 in that it contains 10% medium-chain triglycerides, 4% cetearyl alcohol, 2% isopropyl myristate, 3% polysorbate 60, and 1.0% Span 60. The medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid, capric acid, and glycerol, with a mass ratio of caprylic acid to capric acid of 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 2:1; and the mass ratio of polysorbate 60 to Span 60 is 3:1. The cream is prepared using the same method as in Example 1, based on the following weight proportions.

[0040]

[0041] Example 3 A luriconezine cream differs from Example 1 in that: the shearing speed is 3500 rpm, the shearing time is 12 min; the cooling rate during the cooling phase is 3 °C / min; wherein, the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1, and the mass ratio of polysorbate 60 to Span 60 is 4:1; it is made from the following components by weight.

[0042]

[0043] The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 80°C until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase.

[0044] (2) Addition of active ingredients: Under the condition of controlling the temperature at 80℃, add ruconazole to the oil phase obtained in step (1), stir and dissolve for 10 min to obtain a uniform mixed solution.

[0045] (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 80°C until completely dissolved to obtain aqueous phase.

[0046] (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 80℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), and after stirring evenly, purified water at 80℃ is added to make up to the total volume, and then high shear emulsification is performed. The high shear rate is 3500 rpm and the shearing time is 12 minutes to form an emulsion.

[0047] (5) Cooling and filling: The obtained emulsion is placed in a water bath at 20-25℃, stirring is turned on, and the cooling rate is controlled at 3℃ / min. Stirring is stopped when the temperature of the emulsion drops below 35℃. The cooled emulsion is then filled into a pharmaceutical aluminum tube, 10g / tube.

[0048] Comparative Example 1 A luriconezol cream differs from Example 1 in that the amount of polysorbate 60 is 3%, the amount of Span 60 is 2%, and the mass ratio of polysorbate 60 to Span 60 is 3:2; wherein, the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1; specifically, it is made from the following components by weight, and the preparation method of the cream is the same as that of Example 1.

[0049]

[0050] Comparative Example 2 A luliconazole cream differs from Example 1 in that the amount of cetearyl alcohol is 2%, the amount of isopropyl myristate is 8%, and the mass ratio of cetearyl alcohol to isopropyl myristate is 1:4; wherein, the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of polysorbate 60 to Span 60 is 4:1; specifically, it is made from the following components by weight, and the preparation method of the cream is the same as that of Example 1.

[0051]

[0052] Comparative Example 3 A luriconezine cream differs from Example 1 in that: the shearing speed is 1500 rpm and the shearing time is 30 min; wherein, the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1, and the mass ratio of polysorbate 60 to Span 60 is 4:1; it is made from the following components by weight.

[0053]

[0054] The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 80°C until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase.

[0055] (2) Addition of active ingredients: Under the condition of controlling the temperature at 80℃, add ruconazole to the oil phase obtained in step (1), stir and dissolve for 10 min to obtain a uniform mixed solution.

[0056] (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 80°C until completely dissolved to obtain aqueous phase.

[0057] (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 80℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), and after stirring evenly, purified water at 80℃ is added to make up to the total volume, and then high shear emulsification is performed. The high shear rate is 1500 rpm and the shearing time is 30 minutes to form an emulsion.

[0058] (5) Cooling and filling: The obtained emulsion is placed in a water bath at 20-25℃, stirring is turned on, and the cooling rate is controlled at 3℃ / min. Stirring is stopped when the temperature of the emulsion drops below 35℃. The cooled emulsion is then filled into a pharmaceutical aluminum tube, 10g / tube.

[0059] Comparative Example 4 A luliconazole cream, differing from Example 1 in that: during the cooling stage, it is rapidly cooled in a 5°C ice-water bath, wherein the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1; and the mass ratio of polysorbate 60 to Span 60 is 4:1; it is made from the following components by weight.

[0060]

[0061] The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 80°C until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase.

[0062] (2) Addition of active ingredients: Under the condition of controlling the temperature at 80℃, add ruconazole to the oil phase obtained in step (1), stir and dissolve for 10 min to obtain a uniform mixed solution.

[0063] (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 80°C until completely dissolved to obtain aqueous phase.

[0064] (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 80℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), and after stirring evenly, purified water at 80℃ is added to make up to the total volume, and then high shear emulsification is performed. The high shear rate is 3000 rpm and the shearing time is 15 minutes to form an emulsion.

[0065] (5) Cooling and filling: The obtained emulsion is placed in a 5°C ice water bath for rapid cooling. Stirring is stopped when the temperature of the emulsion drops below 35°C. The cooled emulsion is then filled into a pharmaceutical aluminum tube, 10g / tube.

[0066] Comparative Example 5 A luriconezine cream differs from Example 1 in that the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, wherein the mass ratio of caprylic acid to capric acid is 5:5 (instead of the 7:3 ratio in Example 1), wherein the mass ratio of polysorbate 60 to Span 60 is 4:1; specifically, it is made from the following components by weight, and the preparation method of the cream is the same as that of Example 1.

[0067]

[0068] Comparative Example 6 A luliconazole cream, differing from Example 1 in that benzyl alcohol is used instead of phenoxyethanol, wherein the medium-chain triglyceride is a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, the mass ratio of caprylic acid to capric acid being 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1:67:1, and the mass ratio of polysorbate 60 to Span 60 is 4:1; specifically, it is made of the following components by weight.

[0069]

[0070] The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 80°C until completely dissolved. Add polysorbate 60, Span 60, benzyl alcohol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase.

[0071] (2) Addition of active ingredients: Under the condition of controlling the temperature at 80℃, add ruconazole to the oil phase obtained in step (1), stir and dissolve for 10 min to obtain a uniform mixed solution.

[0072] (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 80°C until completely dissolved to obtain aqueous phase.

[0073] (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 80℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), and after stirring evenly, purified water at 80℃ is added to make up to the total volume, and then high shear emulsification is performed. The high shear rate is 3000 rpm and the shearing time is 15 minutes to form an emulsion.

[0074] (5) Cooling and filling: The obtained emulsion is placed in a water bath at 20-25℃, stirring is turned on, and the cooling rate is controlled at 2℃ / min. Stirring is stopped when the temperature of the emulsion drops below 35℃. The cooled emulsion is then filled into a pharmaceutical aluminum tube, 10g / tube.

[0075] Comparative Example 7 A ruliconazole cream is prepared according to the cream formulation and preparation method disclosed in Example 3 of Chinese Patent CN120131747A.

[0076] Quality evaluation and stability study 1. Physicochemical properties and particle size determination of cream The creams prepared in the examples and comparative examples were used to determine their appearance, pH value, viscosity and particle size distribution (measured by laser particle size analyzer, D90 value). The results are shown in Table 1 below.

[0077]

[0078] As shown in Table 1, the creams in Examples 1-3 have a delicate and glossy appearance, suitable pH value, moderate viscosity, and particle size D90 below 4 μm, indicating that the formulation and preparation method of the cream in this invention can produce a delicate cream with uniform particle size. In Comparative Example 1, the improper ratio of composite emulsifier resulted in an excessively low HLB value, leading to a rough cream with large particle size. In Comparative Example 2, the improper ratio of oil phase matrix (excessive isopropyl myristate) resulted in excessively low viscosity and poor spreadability. In Comparative Example 3, insufficient shear speed led to incomplete emulsification, resulting in larger particle size and slight stratification. In Comparative Example 4, excessively rapid cooling damaged the cream structure, resulting in stratification and increased particle size. In Comparative Example 5, the improper type of medium-chain triglyceride (MCT) (mass ratio of caprylic acid to capric acid was 5:5) affected viscosity and spreadability, resulting in slightly larger particle size. In Comparative Example 6, benzyl alcohol was used instead of phenoxyethanol. The appearance and particle size of the cream were similar to those of the examples, but the stability was poor (see Table 2). In Comparative Example 7, tea tree oil was used instead of isopropyl myristate, and benzyl alcohol was used instead of phenoxyethanol. At the same time, the preparation process used high shear speed (8000-15000 rpm) and vacuum treatment instead of programmed cooling, resulting in a lower viscosity of the cream. In addition, due to the volatility and oxidative instability of tea tree oil, a slight oil phase precipitation occurred after standing, and the appearance was pale yellow, indicating poor stability.

[0079] 2. Determination of content and related substances The content of luriconazole and related substances in each sample was determined by high performance liquid chromatography (HPLC). Chromatographic conditions: C18 column (250 mm × 4.6 mm, 5 μm); mobile phase: acetonitrile-water (60:40); detection wavelength: 296 nm; flow rate: 1.0 mL / min; column temperature: 30 ℃.

[0080] The creams prepared in the examples and comparative examples were subjected to accelerated testing for 6 months at 40℃±2℃ and 75%±5% relative humidity. The content and total impurity content at 0 days and 6 months were determined, and the results are shown in Table 2 below.

[0081]

[0082] As shown in Table 2, the samples obtained in Examples 1-3 showed a decrease in content of less than 1% after 6 months of accelerated testing, and the total impurity content was less than 0.3%, indicating that the cream of the present invention has excellent chemical stability. The total impurity content of the samples in Comparative Examples 1-4 was significantly higher than that of the Examples; in Comparative Example 5, the type of chain triglyceride (MCT) was inappropriate (the mass ratio of caprylic acid to capric acid was 5:5), and the stability was acceptable, but worse than that of the Examples. In Comparative Example 6, benzyl alcohol was used instead of phenoxyethanol, and the total impurity content of the cream reached 0.89%, significantly higher than that of Example 1 (0.18%), indicating that phenoxyethanol can better maintain the stability of luliconazole than benzyl alcohol, which may be related to the oxidation of benzyl alcohol at high temperature and its interaction with luliconazole. In Comparative Example 7, the terpenoid components in tea tree oil are easily oxidized at high temperatures, which accelerates the degradation of luriconazole. After 6 months of accelerated testing, the content decreased to 95.8%, and the total impurities were as high as 1.12%, which was significantly higher than that in Example 1 (content 99.6%, total impurities 0.18%). This indicates that there is still room for further optimization in terms of the chemical stability of the luriconazole cream in this patent.

[0083] 3. In vitro transdermal absorption test In vitro transdermal absorption assays were performed using the Franz diffusion cell method. Mouse skin was extracted and fixed onto the diffusion cell. The receiving chamber was filled with pH 7.4 phosphate buffer, and 0.5 g of each sample cream was added to the supply chamber. The mixture was stirred in a 32°C water bath. Samples were taken at 1 h, 2 h, 4 h, 6 h, and 8 h to determine the concentration of ruliconazole in the receiving chamber. The cumulative permeation (Q) and transdermal absorption rate (Jss) were calculated. The results are shown in Table 3 below.

[0084] Table 3 Results of in vitro transdermal absorption tests for examples and comparative examples

[0085] As shown in Table 3, the samples obtained in Examples 1-3 had significantly higher cumulative permeation and transdermal absorption rates at 8 hours than Comparative Examples 1-5, Comparative Example 7, and the commercially available Luzu®. Among them, Example 1 showed the highest transdermal absorption rate. Comparative Example 1 (due to an improper ratio of composite emulsifier) ​​and Comparative Example 4 (due to excessively rapid cooling) had the worst transdermal absorption due to large particle size and structural damage. Comparative Example 5 used an improper type of chain triglyceride (MCT) (the mass ratio of caprylic acid to capric acid was 5:5), resulting in slightly worse transdermal absorption than the examples, but better than some comparative examples, indicating that the MCT type affects transdermal absorption. Comparative Example 6 used benzyl alcohol instead of phenoxyethanol, resulting in transdermal absorption similar to Example 1, but slightly lower. Although Comparative Example 7 used tea tree oil as a "natural penetration enhancer", its 8-hour cumulative penetration amount (45.6 μg / cm²) and transdermal absorption rate (5.68 μg / cm² / h) were both lower than those of Example 1 (52.5 μg / cm², 7.56 μg / cm² / h), indicating that the penetration-enhancing effect of tea tree oil is not as good as that of the present invention.

[0086] 4. Antibacterial efficacy test According to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 1121, Antimicrobial Efficacy Test Method, Candida albicans, Aspergillus niger, and Staphylococcus aureus were inoculated, and the logarithmic decrease in the number of microorganisms in each sample at 14 and 28 days was determined, as shown in Table 4.

[0087]

[0088] Examples 1-3 all meet the pharmacopoeia requirements, indicating that the antibacterial cream system of the present invention is effective. Comparative Examples 1-7 all meet the pharmacopoeia requirements for antibacterial efficacy. In Comparative Example 6, benzyl alcohol was used instead of phenoxyethanol, and the antibacterial effect was similar to that of the examples, but due to its poor stability, it was not considered a preferred option. Comparative Example 7 also meets the pharmacopoeia requirements for antibacterial efficacy. However, due to the volatility and oxidative instability of tea tree oil, and the fact that benzyl alcohol accelerates drug degradation, this method has serious stability defects and was not considered a preferred option.

[0089] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A ruliconazole cream, characterized in that, The cream is made from the following components in weight percentage: 0.5-2% ruliconazole, 5-15% medium-chain triglycerides, 1-9% cetearyl alcohol, 1-10% isopropyl myristate, 1-5% polysorbate 60, 0.1-3.5% Span 60, 0.1-1% phenoxyethanol, 0.001-0.03% butylated hydroxytoluene, 0.05-0.2% methylparaben, 2-10% propylene glycol, and purified water to 100%; wherein the medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 6-8:2-4; the mass ratio of cetearyl alcohol to isopropyl myristate is 1-3:1, and the mass ratio of polysorbate 60 to Span 60 is 2-5:

1.

2. The ruliconazole cream according to claim 1, characterized in that, The preparation method of the cream includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 75-85℃ until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase. (2) Addition of active ingredients: Under the condition of controlling the temperature at 75-85℃, add ruliconazole to the oil phase obtained in step (1), stir evenly, and obtain a uniform mixed solution; (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 75-85℃ until completely dissolved to obtain aqueous phase; (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 75-85℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), stirred evenly, purified water at 75-85℃ is added to make up to the volume, and then high shear emulsification is performed. The high shear rate is 2000-4000 rpm, and the shearing time is 10-20 minutes to form an emulsion. (5) Cooling and filling: Place the emulsion obtained in step (4) in a water bath at 15-30℃, turn on the stirring, control the cooling rate at 1-3℃ / min, stop stirring when the temperature of the emulsion drops below 35℃, fill and seal to obtain the cream.

3. The ruliconazole cream according to claim 2, characterized in that, The cream is made from the following components in weight percentage: 0.8-1.2% ruliconazole, 8-11% medium-chain triglycerides, 3-7% cetearyl alcohol, 1.5-4.5% isopropyl myristate, 2-4% polysorbate 60, 0.5-1.2% Span 60, 0.3-0.7% phenoxyethanol, 0.005-0.015% butylated hydroxytoluene, 0.08-0.15% methylparaben, 4-6% propylene glycol, and purified water to 100%; wherein the medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 6.5-7.5:2.5-3.5; the mass ratio of cetearyl alcohol to isopropyl myristate is 1.5-2.5:1, and the mass ratio of polysorbate 60 to Span 60 is 3.5-4.5:

1.

4. The ruliconazole cream according to claim 3, characterized in that, The cream is made from the following components in weight percentage: 1% ruliconazole, 9-10% medium-chain triglycerides, 4-5% cetearyl alcohol, 2-3% isopropyl myristate, 2.5-3.5% polysorbate 60, 0.75-1% Span 60, 0.4-0.6% phenoxyethanol, 0.008-0.012% butylated hydroxytoluene, 0.11-0.13% methylparaben, 4.5-5.5% propylene glycol, and purified water to 100%; wherein the medium-chain triglycerides are a mixture of triglycerides formed by esterification of caprylic acid and capric acid with glycerol, and the mass ratio of caprylic acid to capric acid is 7:3; the mass ratio of cetearyl alcohol to isopropyl myristate is 1.67-2:1, and the mass ratio of polysorbate 60 to Span 60 is 3-4:

1.

5. The ruliconazole cream according to claim 4, characterized in that, The cream is made from the following components in weight percentage: 1% ruliconazole, 9% medium-chain triglycerides, 5% cetearyl alcohol, 3% isopropyl myristate, 3% polysorbate 60, 0.75% Span 60, 0.5% phenoxyethanol, 0.01% butylated hydroxytoluene, 0.12% methylparaben, 5% propylene glycol, and 72.62% purified water.

6. The ruliconazole cream according to claim 4, characterized in that, The cream is made from the following components in weight percentage: 1% ruliconazole, 10% medium-chain triglycerides, 4% cetearyl alcohol, 2% isopropyl myristate, 3% polysorbate, 1% Span 60, 0.5% phenoxyethanol, 0.01% butylated hydroxytoluene, 0.12% methylparaben, 5% propylene glycol, and 73.37% purified water.

7. The method for preparing ruliconazole cream according to claim 1, characterized in that, Includes the following steps: (1) Preparation of oil phase: Mix medium chain triglyceride, isopropyl myristate and cetearyl alcohol, and stir at 75-85℃ until completely dissolved. Add polysorbate 60, Span 60, phenoxyethanol and dibutylhydroxytoluene to the resulting mixed solution in sequence, and stir again to mix evenly to obtain the oil phase. (2) Addition of active ingredients: Under the condition of controlling the temperature at 75-85℃, add ruliconazole to the oil phase obtained in step (1), stir evenly, and obtain a uniform mixed solution; (3) Preparation of aqueous phase: Mix methylparaben and propylene glycol and stir at 75-85℃ until completely dissolved to obtain aqueous phase; (4) Phase mixing and emulsification: Under the condition of controlling the temperature at 75-85℃, the aqueous phase obtained in step (3) is added to the mixed solution obtained in step (2), stirred evenly, purified water at 75-85℃ is added to make up to the volume, and then high shear emulsification is performed. The high shear rate is 2000-4000 rpm, and the shearing time is 10-20 minutes to form an emulsion. (5) Cooling and filling: Place the emulsion obtained in step (4) in a water bath at 15-30℃, turn on the stirring, control the cooling rate at 1-3℃ / min, stop stirring when the temperature of the emulsion drops below 35℃, fill and seal to obtain the cream.

8. The preparation method according to claim 7, characterized in that, In step (1), the stirring and dissolving temperature is 78-82℃, preferably 80℃; in step (2), the temperature is controlled at 78-82℃, preferably 80℃; in step (3), the stirring and dissolving temperature is 78-82℃, preferably 80℃; in step (4), the temperature is controlled at 78-82℃, preferably 80℃; the temperature of the purified water is 78-82℃, preferably 80℃.

9. The preparation method according to claim 6, characterized in that, In step (4), the shearing rate is 3000-3500 rpm and the shearing time is 12-15 minutes.

10. The preparation method according to claim 6, characterized in that, In step (5), the water bath temperature is 20~25℃; the cooling rate is 2-3℃ / min.

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