Miconazole nitrate cream and process for its preparation

Abstract

The application provides a miconazole nitrate cream and a preparation process, and belongs to the technical field of external medicines, and is characterized in that the miconazole nitrate cream comprises the following components in terms of mass fraction: 1.8wt-2.0wt% miconazole nitrate, 0.3wt-2.0wt% allantoin eugenol amide ester penetration enhancer, 3wt%-5wt% medium-chain triglyceride, 5wt%-10wt% glycerol monostearate, 8wt%-15wt% white petrolatum, 6wt-12wt% glycerol, 0.01wt%-0.10wt% bis(hydroxymethyl)imidazole alkyl urea, 6wt%-12wt% octadecanol, 1wt%-3wt% triethanolamine, and the balance is purified water. The preparation process comprises cream preparation, miconazole nitrate emulsion homogenization and miconazole nitrate cream preparation. The application prepares a nano miconazole nitrate cream product with uniform and delicate texture from the aspects of drug particle size optimization and homogenization. The added allantoin eugenol amide ester penetration enhancer is safe and non-irritating, and the use of the miconazole nitrate cream not only promotes the penetration of the cream and accelerates the recovery of the skin, but also has certain antioxidant function and can effectively prevent the cream from yellowing and deteriorating.

Description

Technical Field

[0001] The invention belongs to the technical field of external-use medicines, and particularly relates to miconazole nitrate cream and a preparation process thereof. Background Art

[0002] Tinea is a common dermatological disease, including tinea corporis, tinea cruris, and tinea manuum and pedis. It is caused by localized fungal infection, which penetrates deep into the skin and reproduces. Fungi can survive for long periods at -20°C and remain active for over a year on hair, nails, and dandruff, even at temperatures of 120°C, for up to 10 minutes. When the body's immune system is weakened or external factors are unfavorable, systemic or localized fungal infections may develop.

[0003] Miconazole nitrate is a synthetic 1-phenylethylimidazole derivative, a broad-spectrum imidazole antifungal drug, and a commonly used drug for the treatment of skin ringworm. It is safe, highly effective, multi-functional, and has unique multi-directional fungal inhibition characteristics. It is suitable for the treatment of systemic and disseminated infections caused by fungi such as Cryptococcus neoformans and Candida albicans. Miconazole nitrate (miconazole nitrate), molecular formula C 19 H 14 Cl4N2O·HNO3, the nitrate form of miconazole, works by inhibiting the activity of the fungal cytochrome P450 enzyme system and interfering with fungal cell membrane synthesis, thereby preventing fungal growth and reproduction. Studies have reported that miconazole nitrate can inhibit most clinically isolated fungi at concentrations below 4 μg / mL, with an overall efficacy rate approaching 80%. It achieves particularly high inhibition rates against Cryptococcus neoformans, Candida species, C. immitis, Blastomyces dermatitidis, and Histoplasma capsulatum.

[0004] Because fungal infections are prone to recurrence, miconazole nitrate cream currently has a long treatment cycle (2 to 5 weeks) for fungal infections such as ringworm, and the drug must be continued for 10 days to prevent recurrence. Furthermore, miconazole nitrate cream has a short release and sustained action time and a relatively thin matrix, resulting in insufficient skin permeability. This is especially true for areas with thicker stratum corneum, such as the soles of the feet and palms, making it difficult for the drug to penetrate the skin and reach deep infection sites, thus affecting its effectiveness in treating deep fungal infections. Furthermore, when fungal biofilms form at the lesion site, the antibacterial effect of miconazole nitrate is greatly weakened, necessitating the search for new methods to break through the fungal biofilm barrier.

[0005] Therefore, improving the miconazole nitrate process to obtain a miconazole nitrate product with more uniform particle size and smaller particle size can not only improve its efficacy, but also deeply treat fungal infections, and has a broad market prospect. Summary of the Invention

[0006] In order to solve the above problems, this section aims to provide miconazole nitrate cream and its preparation process to increase the absorption rate of the drug and thus enhance its efficacy.

[0007] The present invention provides a miconazole nitrate cream, which comprises the following components in parts by mass:

[0008] 1.8wt% to 2.0wt% miconazole nitrate, 0.3wt% to 2.0wt% allantoin eugenol amide ester penetration enhancer, 3wt% to 5wt% medium chain triglycerides, 5wt% to 10wt% glyceryl monostearate, 8wt% to 15wt% white vaseline, 6wt% to 12wt% glycerol, 0.01wt% to 0.10wt% bis(hydroxymethyl)imidazolidinyl urea, 6wt% to 12wt% octadecyl alcohol, 1wt% to 3wt% triethanolamine, and the balance is purified water; the structural formula of the allantoin eugenol amide ester penetration enhancer is as follows:

[0009]

[0010] As a preferred technical solution of the present invention, the miconazole nitrate is prepared by the following steps:

[0011] a. 2-amino-2',4'-dichloroacetophenone reacts with glyoxal, formaldehyde and ammonium acetate in 1,4-dioxane to obtain intermediate 1;

[0012] b. Reductive etherification reaction of intermediate 1 with 2,4-dichlorobenzyl alcohol and chlorodimethylsilane in acetic acid-acetonitrile medium to obtain miconazole microparticles;

[0013] c. After the miconazole microparticles are sand-milled, nitric acid is added to the mixture until the pH value is 1 to 1.5 to obtain miconazole nitrate.

[0014] As a preferred technical solution of the present invention, the molar ratio of 2-amino-2',4'-dichloroacetophenone to glyoxal, formaldehyde and ammonium acetate in process a is (1-1.2):1:1:1; in process b, the molar ratio of the intermediate 1 to 2,4-dichlorobenzyl alcohol and chlorodimethylsilane is 1:(1.1-1.2):(1.2-1.4), and the volume ratio of acetic acid to 1,4-dioxane is (0.5-1):10.

[0015] As a preferred technical solution of the present invention, the sand milling process conditions are as follows: a miconazole-propylene glycol slurry with a solid content of 30% to 50% is sand milled with a grinding medium in a sand mill for 3 to 6 hours; the grinding medium is a mixed zirconia bead of Φ1.8 to 2.0 mm, Φ1.0 to 1.2 mm and Φ0.4 to 0.6 mm in a mass ratio of (1 to 4): (3 to 5): (2 to 5); the mass ratio of the grinding medium to the slurry is (4 to 6): 1.

[0016] As a preferred technical solution of the present invention, the synthesis process of the allantoin eugenol amide ester penetration enhancer is as follows: allantoin and eugenol are reacted in a water bath at 60-80°C under an acidic catalyst for 3-6 hours, wherein the molar ratio of allantoin, eugenol and acidic catalyst is 1:(1.1-1.3):(0.2-0.5); the acidic catalyst is one of phosphoric acid, sulfuric acid and p-toluenesulfonic acid.

[0017] The allantoin eugenol amide ester permeation enhancer of the present invention is a novel, highly effective, safe, and non-toxic transdermal absorption enhancer. It significantly enhances the transdermal penetration of drugs, thereby improving their utilization and efficacy within the body. It also forms hydrogen bonds or van der Waals interactions with drug molecules, making them more stable and less susceptible to oxidation or degradation, thereby extending the drug's shelf life. It exhibits safety and good compatibility.

[0018] The present invention also provides a preparation process of the miconazole nitrate cream, comprising the following steps: separately preparing an oil phase matrix and an aqueous phase matrix, and then mixing them to obtain a cream; high-pressure homogenizing nano-miconazole nitrate, an allantoin eugenol amide ester permeation enhancer, and a solvent to obtain a homogenized miconazole nitrate emulsion; subjecting the miconazole nitrate and the allantoin amide ester permeation enhancer to a high-pressure homogenization process in medium-chain triglycerides, and then mixing them with the cream to obtain a uniformly dispersed paste; and degassing, cooling, and perfusion packaging to obtain the miconazole nitrate cream.

[0019] The oil phase matrix includes white vaseline, glyceryl monostearate, and stearyl alcohol, and the water phase matrix includes purified water, bis(hydroxymethyl)imidazolidinyl urea, glycerol, and triethanolamine.

[0020] As a preferred technical solution of the present invention, the preparation process of the cream is specifically as follows:

[0021] S1. Add white petrolatum, glyceryl monostearate, and stearyl alcohol to container A, heat and stir at 75-80°C and 400-600 rpm until completely melted to obtain an oil phase matrix; add purified water, bis(hydroxymethyl)imidazolidinyl urea, glycerol, and triethanolamine to container B, heat the system to 60-65°C, and stir to obtain an aqueous phase matrix;

[0022] S2. Slowly add the oil phase matrix into the water phase matrix while it is still hot, and heat and stir at 70-75° C. and 1000-1500 rpm until a milky white cream is formed.

[0023] As a preferred technical scheme of the present application, the high-pressure homogenization process is specifically as follows: the nitromideconazole and the allantoin eugenol amide ester penetration agent and the medium-chain triglyceride are mixed in pure water, and a coarse dispersion system with a solid content of 10% to 25% is obtained by ultrasonic dispersion at a power of 150 to 200 W; the coarse dispersion system is subjected to homogenization circulation for 3 to 8 times in a high-pressure homogenizer at a homogenization pressure of 800 to 1000 bar, and nitromideconazole emulsion is obtained.

[0024] The high-pressure homogenization method is to force the coarse dispersion system containing the drug to pass through a narrow gap under high pressure, so as to generate high shear force and cavitation effect, and make the drug particles broken into nanoscale size. If the pressure is too high, the chemical structure or crystal form of the miconazole may be damaged, thereby affecting the drug efficacy. By virtue of the action of the high-pressure homogenizer, the lipid-like material is dissolved and then added into the water phase containing the surfactant, and the primary emulsion is formed, and then the high-pressure homogenizer is used for treatment, so that the liposome solution with small particle size and uniform distribution is formed.

[0025] The present application has the following beneficial effects:

[0026] The added allantoin eugenol amide ester penetration agent is safe and non-irritating, and when used together with the nitromideconazole, not only promotes the penetration of the ointment and accelerates the recovery of the skin, but also has certain antioxidant function and can effectively prevent the cream from yellowing and deteriorating.

[0027] The present application is optimized from the perspective of drug particle size optimization and homogenization, and a nanoscale nitromideconazole cream product with uniform and delicate texture is prepared. The allantoin eugenol amide ester penetration agent of the present application is safe and non-irritating, and when used together with the nitromideconazole, not only promotes the penetration of the ointment and accelerates the recovery of the skin, but also has certain antioxidant function and can effectively prevent the cream from yellowing and deteriorating. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The reaction equation for preparing the nitromideconazole in the present application.

[0029] Figure 2 The nuclear magnetic resonance spectrum of the allantoin eugenol amide ester penetration agent of the present application.

[0030] Figure 3 The cumulative penetration curve of the nitromideconazole cream of each example and the comparative example. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more clearly understood, the specific embodiments of the present invention are described in detail below with reference to specific embodiments. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0032] Unless otherwise specified, all percentages in the present invention are by weight.

[0033] Unless otherwise specified, all drugs used in the present invention are commercially available.

[0034] CLBN-60 high-efficiency pin-type horizontal nano-sand mill, 45kW power, Chile (Shanghai) Machinery Technology Co., Ltd.; 0.2-2mm. AH-PILOT 16 high-pressure homogenizer, with a maximum homogenization pressure of 1000 bar, no residue, a processing flow rate of 50-60 L / h, and a minimum sample processing volume of 50 mL, 5.5kW power, Antos Nanotechnology (Suzhou) Co., Ltd.

[0035] Toughened yttria zirconia beads (94.6% ZrO2 + 2.2% Y2O3, Φ0.4-0.6 mm, Φ1.0-1.2 mm, Φ1.8-2.0 mm), Chile (Shanghai) Machinery Technology Co., Ltd., specific parameters are shown in Table 1.

[0036] Table 1

[0037] Zirconium bead specifications <![CDATA[真密度g / cm 3 ]]> Bulk density / g / cm 3 ]] Mohs hardness / grade Bending strength / MPa Φ0.4~0.6mm 6.00 3.85 9 900 Φ1.0~1.2mm 6.00 3.82 9 900 Φ1.8~2.0mm 6.00 3.79 9 900

[0038] In the following specific embodiment, the preparation steps of miconazole nitrate used are as follows:

[0039] a. Place 0.12 mol of 2-amino-2',4'-dichloroacetophenone, 10 mmol of glyoxal, 10 mmol of ammonium acetate, and acetic acid (2 mL, 35 mmol) into a 20 mL glass tube with an 18 cm body length and a 9 cm neck. Add 20 mL of 1,4-dioxane and mix thoroughly. Degas the mixture by freezing with liquid nitrogen, seal the tube under vacuum, return to room temperature, and incubate in a 60°C oven for 3 days. After the reaction is complete, filter the precipitate, wash it with ethanol (10 mL x 5), dichloromethane (10 mL x 5), and tetrahydrofuran (10 mL x 5), collect it by filtration, and dry it in vacuo at 110°C to obtain Intermediate 1 with a yield of 82.4%.

[0040] 1H NMR (400HZ, CDCl3): δ7.86~7.84(d,1H,J=7.15Hz), 7.67(t,1H,J=1.26Hz), 7.54(d,1H,J=1.76Hz), 7.3 9(dd,1H,J=6.97,1.68Hz), 7.33(dd,1H,J=3.19,1.31Hz), 7.01(dd,1H.J=3.25,1.28Hz), 5.86(s,2H).

[0041] b: Under argon protection, 0.25 mmol of intermediate 1 and 2.75 mmol of 2,4-dichlorobenzyl alcohol were dissolved in 5 mL of acetonitrile, and 2.75 mmol of dimethylsilyl chloride was added and mixed. The reaction mixture was stirred at room temperature for 15 hours, and then quenched by adding 1 mL of NaHCO3 aqueous solution; the mixture was washed with saturated brine, separated and extracted, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (pentane / ethyl acetate = 8:1) to obtain miconazole microparticles with a yield of 74% and a purity of 99.7%. The synthesis diagram of miconazole nitrate is shown in Figure 1 .

[0042] 1 H NMR: δ7.70(t,1H,J=1.48Hz),7.52(d,1H,J=1.61Hz),7.44(d,2H,J=1.16,0.60Hz),7.4 4~7.42(dd,2H,J=6.99,0.50Hz),7.39(dd,1H,J=6.79,1.69Hz),7.34~7.31(ddd,2H,J= 7.81,7.43,6.62Hz),7.21(dd,1H,J=3.37,1.48Hz),7.07(dd,1H,J=3.39,1.37Hz),5.1 6(td,1H,J=4.01,0.75Hz), 4.72(s,2H), 4.43~4.36(ddd,2H,J=14.30,10.59,3.98Hz).

[0043] c. Disperse miconazole microparticles in a 50% propylene glycol-water solution to premix a slurry with a solids content of 35%, and add it to the raw material barrel of a sand mill. Load the sand mill chamber with a mixture of 1.8-2.0 mm, 1.0-1.2 mm, and 0.4-0.6 mm zirconium oxide beads in a mass ratio of 2:5:3, for a filling rate of 80%. Turn on the reflux condenser to control the temperature in the sand mill chamber to no more than 20°C. Set the sand mill speed to 500 rpm and the linear speed to 10 m / s. Sand mill the mixture with the grinding media in the sand mill for 4.5 hours. After sand milling, a fine slurry is obtained. Add nitric acid to the fine slurry until the solution pH reaches ~1, causing a large amount of white solid to precipitate. Filter and dry the mixture to obtain miconazole nitrate.

[0044] A Bettersize 2000 intelligent laser particle size analyzer was used to analyze the particle size distribution width (SPAN) of miconazole microparticles, sand-milled miconazole fine slurry, and miconazole nitrate. SPAN = (D90 - D10) / D50. The results are shown in Table 2.

[0045] Table 2

[0046] Particle size parameters Miconazole microparticles Miconazole fine slurry after sand grinding Miconazole nitrate D50 / μm 158.4±19.2 8.9±1.4 10.4±3.5 SPAN 1.67 0.92 1.03

[0047] From Table 2, the particle size of the miconazole slurry after sand grinding is reduced by an order of magnitude and the distribution is more uniform; the particle size of miconazole nitrate is slightly larger than that of miconazole fine slurry, which is due to the agglomeration or combination of some particles in the process of forming solids after the addition of nitric acid.

[0048] In the following specific embodiment, the synthesis steps of the allantoin eugenol amide ester penetration enhancer are as follows: 11 mmol of eugenol and 1 mmol of p-toluenesulfonic acid are dissolved in tetrahydrofuran, and then 10 mmol of allantoin is added and mixed; the reaction mixture is stirred in a 65°C water bath for 5 hours. After the reaction is completed, the precipitate is cooled to room temperature, and the precipitate is recrystallized from ethyl acetate. After evaporation of the solvent, the product is obtained with a yield of 81.4%. Its NMR results are shown in FIG. Figure 2 .

[0049] Examples 1 to 4

[0050] Miconazole nitrate cream was obtained according to the following preparation process:

[0051] Preparation of the cream: white petrolatum, glyceryl monostearate, and stearyl alcohol were added to container A, heated to 75°C with stirring at a stirring speed of 500 rpm, and passed through a 150-mesh sieve to obtain an oil phase matrix; purified water, bis(hydroxymethyl)imidazolidinyl urea, glycerol, and triethanolamine were added to container B, the system was heated to 60°C, and stirred at 500 rpm to obtain an aqueous phase matrix; while hot, the oil phase matrix was slowly added to the aqueous phase matrix and mixed, and heated and stirred at 70°C and 1500 rpm until a milky white cream was formed.

[0052] Preparation of miconazole nitrate cream: Miconazole nitrate is mixed with an allantoin urea permeation enhancer and medium-chain triglycerides in purified water, and ultrasonically emulsified at 150W for 10 minutes to obtain a coarse dispersion with a solid content of 18.8%. A high-pressure homogenization process is repeated five times at a pressure of 1000 bar to obtain a homogeneous miconazole nitrate emulsion. The homogeneous miconazole nitrate emulsion is heated to 40-50°C and added to the cream while hot. The mixed system is stirred at 60°C and a high speed of 2500 rpm for 30 minutes to obtain a uniformly dispersed paste, which is then degassed, cooled, and poured for packaging.

[0053] The formula of miconazole nitrate cream in Examples 1 to 4 is shown in Table 3.

[0054] Table 3

[0055]

[0056] Example 5

[0057] The difference between this embodiment and embodiment 1 is that the mass ratio of the three types of zirconia beads with diameters of 1.8-2.0 mm, 1.0-1.2 mm, and 0.4-0.6 mm is changed to 1:4:5.

[0058] Examples 6-7

[0059] The difference between this embodiment and embodiment 1 is that the number of cycles of high-pressure homogenization is 3 times and 8 times.

[0060] Comparative Example 1

[0061] The difference from Example 1 is that the sanding process is omitted in step (1).

[0062] Comparative Example 2

[0063] The difference from Example 1 is that the high-pressure homogenization process is omitted in step (3).

[0064] Comparative Example 3

[0065] The difference from Example 1 is that step (2) is omitted, that is, no synthetic penetration enhancer is added in step (3).

[0066] Comparative Example 4

[0067] The difference from Example 1 is that the penetration enhancer is allantoin and eugenol mixed in a mass ratio of 1:1.

[0068] 1. The miconazole nitrate creams in the above examples and comparative examples were subjected to skin safety tests.

[0069] The test method is a human skin patch test: each application example product is diluted and placed in a patch tester at a dose of 20-30 mg. The patch tester containing the test substance is then applied to the subject's flexed forearm using non-irritating tape. Gently press the patch with the palm of your hand to evenly adhere to the skin for 48 hours. After removing the patch tester, observe the skin reaction 30 minutes after the indentation disappears. After 24 hours, the patch tester containing the test substance is again applied to the subject's back or flexed forearm using non-irritating tape. Gently press the patch with the palm of your hand to evenly adhere to the skin for 48 hours. After removing the patch tester, observe the skin reaction 30 minutes after the indentation disappears. The skin reaction grading criteria for the occlusive patch test are shown in Table 4, and the patch test results are shown in Table 5.

[0070] Table 4

[0071]

[0072] Table 5

[0073]

[0074] As shown in Table 5, no adverse skin reactions occurred in all miconazole nitrate cream products. It is preliminarily concluded that the use safety of the miconazole nitrate cream with allantoin eugenol amide ester permeation enhancer involved in the present invention is highly guaranteed and is not expected to cause adverse skin reactions.

[0075] 2. Basic technical indicators inspection:

[0076] Physical properties: This product should be a white, delicate and shiny cream with appropriate pH.

[0077] Drug Identification: Dissolve this product in a 9:1 volume ratio of methanol-hydrochloric acid solution (0.1 mol / L) and dilute to a solution containing 0.4 mg of miconazole nitrate per 1 mL. Determine the solution by UV-Vis spectrophotometry (General Chapter 0401 of the Pharmacopoeia of the People's Republic of China: 2020 Edition) over a wavelength range of 240-300 nm. Maximum absorption occurs at wavelengths of 264 nm, 272 nm, and 280 nm, with absorbances of approximately 0.40, 0.50, and 0.44, respectively.

[0078] Content Determination: Determined by high-performance liquid chromatography (General Chapter 0512 of the Pharmacopoeia of the People's Republic of China: 2020 Edition). Chromatographic conditions: Inersil C18 column (4.6 mm × 250 mm, 5 μm); mobile phase: 0.5% ammonium acetate solution-acetonitrile and methanol (1:1) mixture (v:v = 15:85); detection wavelength: 238 nm, flow rate: 1.0 mL / min, column temperature: 30°C, injection volume: 20 μL.

[0079] Accurately weigh miconazole nitrate reference substance (purity 99%, Wuhan Nengmaike Industrial Co., Ltd.) and dissolve it in chloroform-methanol (1:1) to 8.0 mg / mL; then dilute it with chloroform-methanol (1:1) to a concentration (C) gradient of 0.5, 1.0, 2.0, 4.0, and 8.0 mg / mL. Determine the peak area (S) under the following chromatographic conditions:

[0080] Use octadecylsilane bonded silica gel as filler; methanol-acetonitrile 11.5% ammonium acetate solution (40:40:20) as mobile phase; detection wavelength is 230nm. Take 10μL of system suitability test solution and inject it into liquid chromatograph; take 10μL of reference solution and inject it into liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 25% of the full scale; then accurately measure 10μL of test solution and reference solution respectively, inject them into liquid chromatograph, and record the chromatogram to 2 times the retention time of the main component peak. Use S as the vertical axis and C as the horizontal axis for regression calculation. The regression equation is: S=102.1+0.5718, R 2 =99.98%.

[0081] Accurately weigh 2.5 g of miconazole nitrate ointment into a 50 mL volumetric flask and dissolve it to volume with chloroform-methanol (1:1); calculate the miconazole nitrate content based on the peak area and the above regression equation.

[0082] Particle size: The particle size and SPAN value of the cream were measured using a Bettersize 2000 intelligent laser particle size analyzer.

[0083] Cream stability: After packaging, the miconazole nitrate cream was subjected to an accelerated stability test. Three parallel samples of the packaged product were placed in a 55°C constant temperature box for 3 months. After being taken out, the miconazole nitrate content was determined and the properties of the cream were observed.

[0084] The above test results are summarized in Table 6.

[0085] Table 6

[0086]

[0087] 3. In vitro percutaneous permeability test:

[0088] The transdermal diffusion test method was used. The test apparatus was a vertical Franz diffusion cell, YB-P6 intelligent transdermal tester (Shanghai Jingsheng Scientific Instrument Co., Ltd.), and its effective transdermal diffusion area was 3.4 cm*3.2 cm=10.88 cm 2 The volume of the receiving chamber is 17mL (vertical). The back skin of Bama Xiang pigs, which has a structure similar to human skin, is used to more realistically simulate the transdermal properties of human skin.

[0089] Remove the hair from the pig skin with electric scissors, peel off the skin of the required area, remove the subcutaneous fat and fascia tissue, and rinse it with saline. Soak the treated skin in saline for about 30 minutes, take it out and dry it with filter paper for later use.

[0090] A 60% polyethylene glycol 400-40% saline solution was used as the receptor solution for the in vitro percutaneous permeation test. Porcine skin was fixed between the two halves of a diffusion cell, and 17 mL of the receptor solution was added to the cell. After pre-equilibration in a (32±1)°C water bath for 1 hour, 0.5 g of miconazole nitrate ointment was evenly applied to the porcine skin surface. At 0.5, 1, 2, 4, 6, 8, and 24 hours, 2 mL of the absorption solution was aspirated from the receptor chamber, filtered through a 0.22 μm microfiltration membrane, and analyzed on a high-performance liquid chromatograph (EClassical 3200, Dalian Yilite Analytical Instrument Co., Ltd.). Simultaneously, an equal amount of blank receptor solution was added to the receptor cell.

[0091] Cumulative permeation (μg / cm 2 ) is calculated as:

[0092]

[0093] Where C n is the drug concentration measured at the nth sampling point; V is the volume of the receiving chamber; C i is the drug concentration measured at the i-th sampling point; V is the sampling volume; A is the permeation area (cm 2 ).

[0094] The cumulative permeation curve of the above miconazole nitrate cream sample is shown in Figure 3 .

[0095] Combined with Table 2, Table 6 and Figure 3 In Comparative Example 1 or Comparative Example 2, since the particle size of the miconazole raw material was not optimized or the miconazole nitrate emulsion was not subjected to high-pressure homogenization operation, the particle size of the final cream product differed by several times, which was not conducive to the absorption of the product on the skin surface; among them, the high-pressure homogenization process had a greater impact on the particle size and uniformity of the cream product.

[0096] Comparison of Comparative Examples 3, 4, and 5 with Example 1 demonstrates that the allantoin eugenolamide permeation enhancer provided by the present invention has higher transdermal efficiency than a physical mixture of allantoin and eugenol. Allantoin eugenolamide forms a stable structure through chemical bonding, making it more suitable for use in complex environments, while mixed permeation enhancers rely on physical mixing. As shown in Table 5, the allantoin eugenolamide permeation enhancer is a permeation enhancer without causing damage or irritation to the skin.

[0097] In summary, the preparation process of the miconazole nitrate cream provided by the present invention is optimized from three perspectives: improving the purity of the raw materials, sand-milling to refine the particle size of the raw materials, and homogenizing the cream, thereby preparing a nano-scale miconazole nitrate cream product with a uniform and fine texture; and by adding an allantoin eugenol amide ester penetration enhancer, the solubility of the drug in the skin is further improved, thereby increasing the skin penetration rate of the miconazole nitrate drug.

[0098] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A miconazole nitrate cream, characterized in that, The invention comprises the following components in parts by mass: 1.8wt%~2.0wt% miconazole nitrate, 0.3wt%~2.0wt% allantoin eugenol amide ester penetration enhancer, 3wt%~5wt% medium chain triglycerides, 5wt%~10wt% glyceryl monostearate, 8wt%~15wt% white petrolatum, 6wt%~12wt% glycerol, 0.01wt%-0.10wt% bis(hydroxymethyl)imidazolidinyl urea, 6wt%~12wt% octadecyl alcohol, 1wt%~3wt% triethanolamine, and the balance is purified water; the structural formula of the allantoin eugenol amide ester penetration enhancer is as follows: ； Described miconazole nitrate is prepared by the following steps: a. 2-amino-2',4'-dichloroacetophenone reacts with glyoxal, formaldehyde and ammonium acetate in 1,4-dioxane to obtain intermediate 1; b. Reductive etherification reaction of intermediate 1 with 2,4-dichlorobenzyl alcohol and chlorodimethylsilane in acetic acid-acetonitrile medium to obtain miconazole microparticles; c. After sand milling the miconazole microparticles, nitric acid was added until the pH was 1-1.5 to obtain miconazole nitrate; the sand milling process conditions were as follows: a miconazole-propylene glycol slurry with a solid content of 30%-50% was sand milled for 3-6 hours with a grinding medium; the grinding medium was a mixed zirconia bead with diameters of 1.8-2.0 mm, 1.0-1.2 mm, and 0.4-0.6 mm in a mass ratio of (1-4):(3-5):(2-5); the mass ratio of the grinding medium to the slurry was (4-6):1; The preparation process of the miconazole nitrate cream is as follows: An oily phase matrix and an aqueous phase matrix are separately prepared and mixed to obtain a cream; the oily phase matrix comprises white petrolatum, glyceryl monostearate, and stearyl alcohol, and the aqueous phase matrix comprises purified water, bis(hydroxymethyl)imidazolidinyl urea, glycerol, and triethanolamine; Nano-miconazole nitrate and allantoin amide ester permeation enhancer are subjected to high-pressure homogenization in medium-chain triglycerides to obtain a homogenized miconazole nitrate emulsion; The homogenized miconazole nitrate emulsion is mixed with the cream to obtain a uniformly dispersed paste, which is then degassed, cooled, poured and packaged to obtain the miconazole nitrate cream.

2. miconazole nitrate cream as claimed in claim 1, is characterized in that, In process a, the molar ratio of the 2-amino-2',4'-dichloroacetophenone to glyoxal, formaldehyde and ammonium acetate is (1-1.2):1:1:1; in process b, the molar ratio of the intermediate 1 to 2,4-dichlorobenzyl alcohol and chlorodimethylsilane is 1:(1.1-1.2):(1.2-1.4), and the volume ratio of acetic acid to acetonitrile is (0.5-1):

10.

3. miconazole nitrate cream as claimed in claim 1, is characterized in that, The synthesis process of the allantoin eugenol amide ester penetration enhancer is as follows: allantoin and eugenol are reacted in a water bath at 60-80°C under an acidic catalyst for 3-6 hours, wherein the molar ratio of allantoin, eugenol and the acidic catalyst is 1:(1.1-1.3):(0.2-0.5); the acidic catalyst is one of phosphoric acid, sulfuric acid and p-toluenesulfonic acid.

4. miconazole nitrate cream as claimed in claim 1, is characterized in that, In its preparation process, the preparation process of the cream is specifically as follows: S1. Add white petrolatum, glyceryl monostearate, and stearyl alcohol to container A, heat and stir at 75-80°C and 400-600 rpm until completely melted to obtain an oil phase matrix. Add purified water, bis(hydroxymethyl)imidazolidinyl urea, glycerol, and triethanolamine to container B, heat the system to 60-65°C, and stir at 400-600 rpm to obtain an aqueous phase matrix. S2. Slowly add the oil phase matrix into the water phase matrix while it is still hot, and heat and stir at 70-75°C and 1000-1500 rpm until a milky white cream is formed.

5. miconazole nitrate cream according to claim 1, characterized in that, In its preparation process, the high-pressure homogenization process is specifically as follows: miconazole nitrate, allantoin eugenol amide ester permeation enhancer, and medium-chain triglycerides are mixed in pure water, and ultrasonically dispersed at a power of 150-200W to obtain a coarse dispersion system with a solid content of 10%-25%; the coarse dispersion system is homogenized in a high-pressure homogenizer at a homogenization pressure of 800-1000 bar for 3-8 cycles to obtain a miconazole nitrate emulsion.

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