Compound miconazole nitrate lotion and preparation process thereof

Abstract

The invention relates to the technical field of medicine formulas, in particular to a compound miconazole nitrate lotion and a preparation process thereof. The invention discloses a miconazole nitrate water dispersible granule, which is prepared from the following raw materials in percentage by weight: 1.5 to 2.5 percent of miconazole nitrate, 5 to 6 percent of amphiphilic polymer, 1.5 to 2.5 percent of chlorhexidine gluconate, 0.05 to 0.1 percent of kathon, 0.1 to 0.2 percent of benzoic acid, 25 to 32 percent of surfactant, 1 to 2 percent of PEG-120 methyl glucose dioleate, 0.3 to 0.4 percent of citric acid monohydrate, 0.7 to 0.9 percent of sodium chloride and the balance of water. The compound miconazole nitrate lotion prepared by the invention has dual effects of resisting fungi and bacteria, widens the range of indications, enhances the overall antibacterial effect of the lotion, and is suitable for treating and preventing various skin infections.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical formulations, and particularly to a compound miconazole nitrate lotion and its preparation process. Background Art

[0002] Fungal skin diseases are a type of skin diseases caused by fungal infections. The main pathogenic bacteria include dermatophytes, Candida, Malassezia, etc. They are characterized by a high incidence rate and easy recurrence. Clinically common fungal skin diseases include tinea manus et pedis, tinea corporis et cruris, pityriasis versicolor, etc. They mostly show a vesicular and scaly type of manifestation. The lesions are mostly limited to one side and are contagious. Miconazole nitrate is a broad-spectrum antifungal drug. Its mechanism of action mainly inhibits the ergosterol synthase on the fungal cell membrane, prevents the synthesis of ergosterol, thereby destroying the structure and function of the fungal cell membrane and causing the death of fungi.

[0003] Although miconazole nitrate performs well in the treatment of fungal skin diseases, its efficacy for skin diseases with mixed infections or accompanied by inflammatory reactions is limited. Mixed infections usually involve multiple pathogens, including bacteria and fungi. Miconazole nitrate is only effective against fungi and ineffective against bacteria. In addition, skin diseases accompanied by inflammatory reactions may require simultaneous inhibition of inflammatory reactions and killing of pathogens, while miconazole nitrate does not have an anti-inflammatory effect. Therefore, in the treatment of skin diseases with mixed infections or accompanied by inflammatory reactions, the single use of miconazole nitrate may not achieve the ideal treatment effect.

[0004] The invention patent with the publication number of CN105079159A discloses a compound lotion of metronidazole and miconazole nitrate and its preparation method. The components of the lotion include 5 - 10 parts of metronidazole, 8 - 12 parts of miconazole nitrate, 25 - 30 parts of Corydalis yanhusuo, 45 - 50 parts of Acacia catechu, 35 - 40 parts of Clinacanthus nutans, 35 - 40 parts of Sedum aizoon, 50 - 55 parts of Polygonum multiflorum, 25 - 30 parts of Portulaca oleracea, 50 - 55 parts of Setaria viridis, 35 - 40 parts of Radix Glycyrrhizae Preparata, 15 - 20 parts of Angelica dahurica, and 8 - 12 parts of Cryptotympana pustulata. This lotion is a traditional Chinese and Western medicine mixture, which not only broadens the spectrum of bactericidal / bacteriostatic action, but also overcomes the main problem that Western medicine mainly inhibits the growth of most fungi. However, for inflammatory symptoms such as skin erythema, itching, and exudation accompanied by fungal infections (such as seborrheic dermatitis or eczema complicated with infection), it cannot quickly relieve the discomfort of patients, resulting in an extended treatment cycle and a decrease in patient compliance due to the continuous symptoms. At the same time, this lotion is a compound of traditional Chinese medicines and requires a long time to indirectly reduce inflammation through bacteriostatic action. While patients have a strong demand for immediate relief of symptoms such as itching and pain, this may lead to discontinuation of treatment midway and affect the curative effect. Summary of the Invention

[0005] In order to solve the problems mentioned in the above background art, the present invention provides a compound miconazole nitrate lotion and its preparation process.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A compound miconazole nitrate lotion, comprising the following raw materials by weight percentage: 1.5 - 2.5% of miconazole nitrate, 5 - 6% of amphiphilic polymer, 1.5 - 2.5% of chlorhexidine gluconate, 0.05 - 0.1% of Kathon, 0.1 - 0.2% of benzoic acid, 25 - 32% of surfactant, 1 - 2% of PEG - 120 methyl glucose dioleate, 0.3 - 0.4% of citric acid monohydrate, and 0.7 - 0.9% of sodium chloride, with the balance being water.

[0008] Further, the surfactant includes one or more of lauryl alcohol polyoxyethylene ether, cocamidopropyl betaine, sodium cocoamphodiacetate, cetyltrimethylammonium chloride, sodium dodecyl sulfate, polysorbate - 80, cocamidopropyl hydroxysultaine, decyl glucoside, and sodium lauroyl sarcosinate.

[0009] Further, the amphiphilic polymer is prepared through the following steps:

[0010] S1. Under nitrogen protection, mix glycerol and sodium hydroxide, heat for condensation reaction for 2 - 3 h to obtain pale yellow viscous liquid polyglycerol. Mix polyglycerol, ricinoleic acid, and n - hexane evenly, place them in a microwave reactor for treatment for 10 - 20 min, add immobilized lipase and zeolite molecular sieve, continue constant - temperature oscillation reaction for 12 - 14 h. After the reaction, filter and recover the lipase with a 200 - mesh sieve, carry out distillation under the conditions of 80°C / 10 Pa to remove unreacted substances, collect the main fraction under the conditions of 155°C / 0.1 Pa, use silica gel column chromatography (silica gel 60), with ethyl acetate / petroleum ether = 1:5 as the eluent to remove pigments and trace free acids, and collect the colorless transparent oily substance as polyglycerol ricinoleate;

[0011] S2. Add polyglycerol ricinoleate and gallic acid into a reactor, add N - methylpyrrolidone, control the temperature and stir for reflux for 1 - 2 h to remove the moisture of the raw materials. Add p - toluenesulfonic acid to the reaction system, raise the temperature and continue the reaction for 5 - 6 h. After the reaction, cool the reaction solution to 60°C, add pre - cooled absolute ethanol, filter with a suction filtration device, wash successively with a mixed solution of ether / ethanol (1:3) three times, place it in a vacuum drying oven, and dry at 40°C for 24 h to obtain a white waxy solid.

[0012] Further, in step S1, the mass ratio of glycerol to sodium hydroxide is (190 - 210):(0.95 - 1.05), and the mass ratio of polyglycerol, ricinoleic acid, n - hexane, lipase, and zeolite molecular sieve is (20 - 22):(44 - 50):(40 - 41):1:(6 - 7).

[0013] Further, in step S1, the heating temperature is 230 - 240 °C, the temperature of the microwave reaction is 50 - 60 °C, the power is 200 - 300 W, and the frequency is 2.45 - 2.55 GHz.

[0014] Further, in step S1, the temperature of the constant-temperature oscillation is 60 - 65 °C, and the speed is 200 - 300 rpm.

[0015] Further, in step S2, the mass ratio of polyglyceryl ricinoleate, gallic acid, N-methylpyrrolidone, and p-toluenesulfonic acid is (33 - 35):(6 - 7):(82 - 84):(1 - 1.65).

[0016] Further, in step S2, the temperature is controlled at 80 - 85 °C, the stirring speed is 100 - 200 rpm, and the temperature for heating up is 110 - 115 °C.

[0017] According to another aspect of the present invention, the preparation process of the above compound miconazole nitrate lotion comprises the following steps:

[0018] Add water into a mixer, heat it, add PEG-120 methyl glucoside dioleate and a surfactant, stir for 30 - 40 min until completely dissolved, sequentially add miconazole nitrate, chlorhexidine gluconate, amphiphilic polymer, Kathon, and benzoic acid, continue to stir for 15 - 25 min, add citric acid monohydrate to adjust the pH value, then add sodium chloride, perform homogenization treatment for 10 - 20 min, filter to remove impurities, and fill into containers to obtain the finished product.

[0019] Further, the heating temperature is 40 - 45 °C, the stirring speed is 500 - 600 rpm, and the homogenization treatment speed is 2000 - 3000 rpm.

[0020] Advantages of the present invention:

[0021] 1. In the technical solution of the present invention, under alkaline conditions and nitrogen protection, the hydroxyl groups of glycerol undergo dehydration condensation reactions and ring-opening polymerization through nucleophilic substitution. The primary hydroxyl group of glycerol attacks the oxygen atom of the secondary hydroxyl group of an adjacent glycerol molecule, removing a water molecule to form an ether bond and generating linear or branched polyglycerol. The polyglycerol then undergoes regioselective transesterification with ricinoleic acid under the catalysis of immobilized lipase. The serine residue of the lipase attacks the carboxyl carbon of ricinoleic acid to form an acyl-enzyme intermediate, and subsequently, the hydroxyl oxygen of the polyglycerol nucleophilically attacks the acyl carbon to complete the construction of the ester bond. The polyglycerol ricinoleate is further esterified and grafted with gallic acid. p-Toluenesulfonic acid protonates the hydroxyl group of the polyglycerol ricinoleate or the carboxyl group of gallic acid to form a more easily leaving group, and the carboxyl carbon of gallic acid is nucleophilically attacked by the hydroxyl oxygen of the polyglycerol ricinoleate to generate a phenolic ester bond and graft it onto the polyglycerol ricinoleate backbone. The benzene ring structure of gallic acid enhances the hydrophobic interaction through π-π stacking, and its three phenolic hydroxyl groups further strengthen the hydrophilicity. The rigid planar structure of gallic acid restricts the conformational freedom of the polymer chain and promotes the formation of stable micelles or lamellar structures. The resulting polymer exhibits amphiphilicity. The polyglycerol segment and the phenolic hydroxyl groups of gallic acid form a hydrogen bond network hydrophilic region, and the ricinoleic acid chain and the benzene ring of gallic acid form a hydrophobic region through hydrophobic association. Since both hydrophilic and hydrophobic segments coexist in the polymer molecule, these two segments will undergo microphase separation in a selective solvent and spontaneously form self-assembled structures such as spheres, rods, and lamellae. In the compound miconazole nitrate lotion, the self-assembly behavior helps to form a stable suspension or solution system, which can encapsulate and stabilize various components in the lotion, preventing them from separating or precipitating due to incompatibility, thereby improving the stability and uniformity of the lotion.

[0022] 2. In the technical solution of the present invention, the amphiphilic polymer has a significant solubilizing effect. Its hydrophobic segment can interact with miconazole nitrate in the lotion, and by forming stable micelles or solutions, it increases the solubility of these components in water, which is beneficial to improving the activity and effect of the lotion, ensuring that the active ingredients in the lotion can be fully dissolved and evenly distributed in the lotion, and thus acting more effectively on the skin or mucosal surface.

[0023] 3. In the technical solution of the present invention, the amphiphilic polymer also exhibits good emulsifying properties. Its hydrophilic and hydrophobic segments can interact with the aqueous phase and the oil phase respectively, mixing incompatible liquids or solids evenly to form a stable suspension or solution. In the compound miconazole nitrate lotion, it helps to evenly disperse various components (including aqueous and oily components) in water, forming a stable lotion system and improving the convenience of using the lotion.

[0024] 4. In the technical solution of the present invention, miconazole nitrate is used for fungal infections, while chlorhexidine gluconate, as a broad-spectrum antibacterial agent, effectively inhibits bacteria. The combination of the two achieves dual antifungal and antibacterial effects, expands the scope of indications, enhances the overall antibacterial effect of the lotion, and is suitable for the treatment and prevention of various skin infections.

[0025] 5. In the technical solution of the present invention, the compounding of the composite surfactant system balances detergency and mildness, reduces the damage to the skin barrier, and is suitable for sensitive skin and long-term use. The combination of Kathon and benzoic acid achieves high-efficiency anti-corrosion at low concentrations, reducing the allergy risk of traditional preservatives. Detailed implementation manners

[0026] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the scope of protection of the present invention.

[0027] Unless otherwise specified, the raw materials used in the present invention are all conventional products purchased from the market, and the immobilized lipase is prepared by the method of CN106929502A.

[0028] Preparation Example 1

[0029] The amphiphilic polymer is prepared through the following steps:

[0030] S1. Under nitrogen protection, 190 g of glycerol and 0.95 g of sodium hydroxide are mixed and heated to 230 °C for a condensation reaction for 2 h to obtain a pale yellow viscous liquid polyglycerol. 20 g of polyglycerol, 44 g of ricinoleic acid, and 40 g of n-hexane are mixed evenly, placed in a microwave reactor, treated at 50 °C for 10 min, the power of the microwave treatment is 200 W, the frequency is 2.45 GHz, 1 g of immobilized lipase and 6 g of zeolite molecular sieve are added, and the reaction continues to be carried out at a constant temperature of 60 °C with a speed of 200 rpm for 12 h. After the reaction, the lipase is recovered by filtration through a 200-mesh sieve, distilled under the conditions of 80 °C / 10 Pa to remove the unreacted substances, and the main fraction is collected under the conditions of 155 °C / 0.1 Pa. Silica gel column chromatography (silica gel 60) is used, and ethyl acetate / petroleum ether = 1:5 is used as the eluent to remove pigments and trace free acids, and a colorless transparent oily substance, polyglycerol ricinoleate, is collected.

[0031] S2. Add 33 g of polyglyceryl ricinoleate and 6 g of gallic acid to a reactor, add 82 g of N-methylpyrrolidone, control the temperature at 80 °C, stir and reflux at a speed of 100 rpm for 1 h to remove the moisture of the raw materials. Add 1 g of p-toluenesulfonic acid to the reaction system, raise the temperature to 110 °C and continue to react for 5 h. After the reaction is completed, cool the reaction solution to 60 °C, add pre-cooled absolute ethanol, filter using a suction filtration device, wash 3 times successively with an ether / ethanol (1:3) mixture, place it in a vacuum drying oven, and dry at 40 °C for 24 h to obtain a white waxy solid.

[0032] Preparation Example 2

[0033] The amphiphilic polymer is prepared through the following steps:

[0034] S1. Under nitrogen protection, mix 200 g of glycerol with 1 g of sodium hydroxide, heat to 235 °C for a condensation reaction for 2.5 h to obtain a pale yellow viscous liquid polyglycerol. Mix 21 g of polyglycerol, 46 g of ricinoleic acid, and 40.5 g of n-hexane evenly, place it in a microwave reactor, treat it at 55 °C for 15 min, the power of the microwave treatment is 250 W, and the frequency is 2.5 GHz. Add 1 g of immobilized lipase and 6.5 g of zeolite molecular sieve, continue to carry out a constant temperature oscillation reaction at 62 °C at a speed of 250 rpm for 13 h. After the reaction is completed, filter through a 200-mesh sieve to recover the lipase, carry out distillation under the conditions of 80 °C / 10 Pa to remove the unreacted substances, collect the main fraction under the conditions of 155 °C / 0.1 Pa, and use silica gel column chromatography (silica gel 60) with ethyl acetate / petroleum ether = 1:5 as the eluent to remove pigments and trace free acids, and collect a colorless transparent oily substance as polyglyceryl ricinoleate;

[0035] S2. Add 34 g of polyglyceryl ricinoleate and 6.5 g of gallic acid to a reactor, add 83 g of N-methylpyrrolidone, control the temperature at 82 °C, stir and reflux at a speed of 150 rpm for 1.5 h to remove the moisture of the raw materials. Add 1.3 g of p-toluenesulfonic acid to the reaction system, raise the temperature to 112 °C and continue to react for 5.5 h. After the reaction is completed, cool the reaction solution to 60 °C, add pre-cooled absolute ethanol, filter using a suction filtration device, wash 3 times successively with an ether / ethanol (1:3) mixture, place it in a vacuum drying oven, and dry at 40 °C for 24 h to obtain a white waxy solid.

[0036] Preparation Example 3

[0037] The amphiphilic polymer is prepared through the following steps:

[0038] S1. Under nitrogen protection, 210 g of glycerol and 1.05 g of sodium hydroxide were mixed and heated to 240 °C for a condensation reaction for 3 h to obtain a pale yellow viscous liquid, polyglycerol. Then, 22 g of polyglycerol, 50 g of ricinoleic acid, and 41 g of n-hexane were mixed evenly, placed in a microwave reactor, and treated at 60 °C for 20 min. The power of the microwave treatment was 300 W, and the frequency was 2.55 GHz. 1 g of immobilized lipase and 7 g of zeolite molecular sieve were added, and the reaction was continued at 65 °C with constant temperature oscillation at a speed of 300 rpm for 14 h. After the reaction, the lipase was recovered by filtration through a 200-mesh sieve, and distillation was carried out under the conditions of 80 °C / 10 Pa to remove the unreacted substances. The main fraction was collected under the conditions of 155 °C / 0.1 Pa. Silica gel column chromatography (silica gel 60) was used, and ethyl acetate / petroleum ether = 1:5 was used as the eluent to remove pigments and trace free acids, and a colorless transparent oily substance, polyglycerol ricinoleate, was collected;

[0039] S2. 35 g of polyglycerol ricinoleate and 7 g of gallic acid were added to a reactor, 84 g of N-methylpyrrolidone was added, the temperature was controlled at 85 °C, and the mixture was stirred and refluxed at a speed of 200 rpm for 2 h to remove the moisture of the raw materials. 1.65 g of p-toluenesulfonic acid was added to the reaction system, and the temperature was raised to 115 °C and the reaction continued for 6 h. After the reaction, the reaction solution was cooled to 60 °C, pre-cooled anhydrous ethanol was added, and filtration was carried out using a suction filtration device. It was washed 3 times with a mixture of ether / ethanol (1:3) and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain a white waxy solid.

[0040] Example 1

[0041] The preparation process of compound miconazole nitrate lotion comprises the following steps:

[0042] 59.57 g of water was added to a mixer and heated to 40 °C. 1.5 g of PEG-120 methyl glucose dioleate and 28 g of surfactants were added. Among them, the surfactants included 6 g of lauryl alcohol polyoxyethylene ether, 13 g of cocamidopropyl betaine, 8.8 g of cocoamphodiacetate disodium, and 0.2 g of cetyltrimethylammonium chloride. It was stirred at a speed of 500 rpm for 30 min until completely dissolved. 2 g of miconazole nitrate, 2 g of chlorhexidine gluconate, 5.5 g of the amphiphilic polymer prepared in Preparation Example 1, 0.08 g of Kathon, and 0.15 g of benzoic acid were added in sequence. It was continuously stirred at a speed of 500 rpm for 15 min. 0.35 g of citric acid monohydrate was added to adjust the pH value, and then 0.8 g of sodium chloride was added. It was homogenized at a speed of 2000 rpm for 10 min, filtered to remove impurities, and filled to obtain the finished product.

[0043] Example 2

[0044] The preparation process of compound miconazole nitrate lotion comprises the following steps:

[0045] Add 60.07 g of water to a mixer, heat it to 40 - 45 °C, add 1.2 g of PEG - 120 methyl glucoside dioleate and 30 g of surfactant. Among them, the surfactant includes 8 g of lauryl alcohol polyoxyethylene ether, 14 g of cocamidopropyl betaine, 7.1 g of sodium cocoyl amphodiacetate, and 0.9 g of cetyl trimethyl ammonium chloride. Stir at a speed of 550 rpm for 35 min until completely dissolved. Then add 1.8 g of miconazole nitrate, 1.7 g of chlorhexidine gluconate, 5 g of the amphiphilic polymer prepared in Preparation Example 2, 0.06 g of Kathon, and 0.12 g of benzoic acid in sequence. Continue to stir at a speed of 550 rpm for 20 min. Add 0.32 g of citric acid monohydrate to adjust the pH value, then add 0.75 g of sodium chloride, and homogenize at a speed of 2500 rpm for 15 min. Filter to remove impurities, and fill into containers to obtain the finished product.

[0046] Example 3

[0047] The preparation process of the compound miconazole nitrate lotion includes the following steps:

[0048] Add 59.13 g of water to a mixer, heat it to 45 °C, add 1.8 g of PEG - 120 methyl glucoside dioleate and 26 g of surfactant. Among them, the surfactant includes 10 g of lauryl alcohol polyoxyethylene ether, 16 g of cocamidopropyl betaine, 9.8 g of sodium dodecyl sulfate, and 0.2 g of sodium lauroyl sarcosinate. Stir at a speed of 600 rpm for 40 min until completely dissolved. Then add 2.3 g of miconazole nitrate, 2.2 g of chlorhexidine gluconate, 6 g of the amphiphilic polymer prepared in Preparation Example 3, 0.09 g of Kathon, and 0.18 g of benzoic acid in sequence. Continue to stir at a speed of 600 rpm for 25 min. Add 0.38 g of citric acid monohydrate to adjust the pH value, then add 0.85 g of sodium chloride, and homogenize at a speed of 3000 rpm for 20 min. Filter to remove impurities, and fill into containers to obtain the finished product.

[0049] Example 4

[0050] The preparation process of the compound miconazole nitrate lotion includes the following steps:

[0051] Add 61.16 g of water to a mixer, heat it to 40 °C, add 1.6 g of PEG-120 methyl glucose dioleate and 27 g of surfactants. Among them, the surfactants include 3 g of lauryl polyoxyethylene ether, 16 g of cocamidopropyl betaine, 6.6 g of polysorbate-80, and 1.4 g of cetyltrimethylammonium chloride. Stir at a speed of 500 rpm for 30 min until completely dissolved. Then add 1.7 g of miconazole nitrate, 1.9 g of chlorhexidine gluconate, 5.2 g of the amphiphilic polymer prepared in Preparation Example 1, 0.07 g of Kathon, and 0.13 g of benzoic acid. Continue to stir at a speed of 500 rpm for 15 min, add 0.33 g of citric acid monohydrate to adjust the pH value, then add 0.82 g of sodium chloride, homogenize at a speed of 2000 rpm for 10 min, filter to remove impurities, and fill into containers to obtain the finished product.

[0052] Example 5

[0053] The preparation process of the compound miconazole nitrate lotion includes the following steps:

[0054] Add 58.21 g of water to a mixer, heat it to 40 - 45 °C, add 1.3 g of PEG-120 methyl glucose dioleate and 29 g of surfactants. Among them, the surfactants include 7 g of lauryl polyoxyethylene ether, 11.5 g of cocoamphodiacetate disodium, 8 g of cocamidopropyl hydroxysulfobetaine, and 2.5 g of cetyltrimethylammonium chloride. Stir at a speed of 550 rpm for 35 min until completely dissolved. Then add 2.2 g of miconazole nitrate, 2.1 g of chlorhexidine gluconate, 5.8 g of the amphiphilic polymer prepared in Preparation Example 2, 0.06 g of Kathon, and 0.15 g of benzoic acid. Continue to stir at a speed of 550 rpm for 20 min, add 0.37 g of citric acid monohydrate to adjust the pH value, then add 0.78 g of sodium chloride, homogenize at a speed of 2500 rpm for 15 min, filter to remove impurities, and fill into containers to obtain the finished product.

[0055] Example 6

[0056] The preparation process of the compound miconazole nitrate lotion includes the following steps:

[0057] Add 57 g of water to a mixer, heat to 45 °C, add 2 g of PEG-120 methyl glucoside dioleate and 30 g of surfactant. The surfactant includes 10 g of cocamidopropyl betaine, 16 g of laureth, 9.8 g of sodium cocoyl amphodiacetate and 0.2 g of cetyltrimethylammonium chloride. Stir at a speed of 600 rpm for 40 min until completely dissolved. Sequentially add 2 g of miconazole nitrate, 2.5 g of chlorhexidine gluconate, 5 g of the amphiphilic polymer prepared in Preparation Example 3, 0.1 g of Kathon and 0.1 g of benzoic acid. Continue to stir at a speed of 600 rpm for 25 min. Add 0.4 g of citric acid monohydrate to adjust the pH value, then add 0.9 g of sodium chloride, and homogenize at a speed of 3000 rpm for 20 min. Filter to remove impurities, and fill into containers to obtain the finished product.

[0058] Comparative Example 1

[0059] The difference between this comparative example and Example 1 is that polyglycerol is used instead of the amphiphilic polymer prepared in Preparation Example 1, and the remaining steps are the same as those in Example 1.

[0060] Comparative Example 2

[0061] The difference between this comparative example and Example 2 is that ricinoleic acid is used instead of the amphiphilic polymer prepared in Preparation Example 2, and the remaining steps are the same as those in Example 2.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 3 is that gallic acid is used instead of the amphiphilic polymer prepared in Preparation Example 3, and the remaining steps are the same as those in Example 3.

[0064] (Ⅰ) Antibacterial activity test

[0065] Fungal group: Inoculate Candida albicans and Trichophyton rubrum on Sabouraud dextrose agar plates and culture at 35 °C for 48 h. Pick single colonies into 5 mL of RPMI 1640 medium and culture with shaking at 35 °C for 24 h. Take the bacterial solution and centrifuge at a speed of 3000 rpm for 10 min. Discard the supernatant, adjust the turbidity to 1×10 6 CFU / mL with sterile physiological saline, and then dilute to 1×10 3 CFU / mL.

[0066] Bacterial group: Inoculate Staphylococcus aureus in MHB and culture with shaking at 35 °C for 18 h. After centrifugation, adjust the turbidity to 1×10 6 CFU / mL and dilute to 1×10 3 CFU / mL.

[0067] Take 1 g of the compound lotion prepared in Example 1 and Comparative Example 1, dissolve it in 9 mL of sterile PBS, vortex and mix well to prepare 10% (w / v) mother liquor of Example and mother liquor of Comparative Example.

[0068] Perform 2-fold serial dilution of the lotion mother liquor with RPMI 1640 or MHB, and the concentration gradients are 64, 32, 16, 8, 4, 2, 1, 0.5 μg / mL (equivalent of miconazole nitrate) to obtain gradient-diluted lotion of Example and gradient-diluted lotion of Comparative Example.

[0069] Use a microdilution plate to add samples, add samples to the fungal group and bacterial group respectively, with a total volume of 200 μL per well, and set up experimental group, control group, positive control, negative control and growth control. The sample addition scheme is as follows:

[0070] Experimental group: Set one concentration gradient per column, repeat 3 wells for each concentration, add 100 μL of gradient-diluted lotion of Example and 100 μL of bacterial suspension.

[0071] Control group: Set one concentration gradient per column, repeat 3 wells for each concentration, add 100 μL of gradient-diluted lotion of Comparative Example and 100 μL of bacterial suspension.

[0072] Positive control: Add 100 μL of pure miconazole nitrate solution (same concentration gradient) and 100 μL of bacterial suspension.

[0073] Negative control: Add 200 μL of sterile medium.

[0074] Growth control: Add 100 μL of bacterial suspension and 100 μL of medium.

[0075] Use a multi-channel pipette to add diluted samples and bacterial suspension in sequence, avoid air bubbles, seal the plate surface with a sealing film, incubate statically at 35°C (48 h for fungi, 24 h for bacteria), and measure OD after incubation.

[0076] Fungi: Observe whether the bottom of the well is clear without precipitation, and take the lowest concentration that completely inhibits the germination of hyphae or spores as the MIC.

[0077] Bacteria: Observe whether the well is not turbid (consistent with the negative control), and take the lowest concentration without turbidity as the MIC.

[0078] Calculate the inhibition rate, inhibition rate = 1 - OD experimental group / OD growth control, and take the lowest concentration with inhibition rate ≥ 90% as the MIC. The results are shown in Table 1:

[0079] Table 1. Results of antibacterial activity test (minimum inhibitory concentration MIC, μg / mL)

[0080]

[0081]

[0082] (Ⅱ) Stability Test

[0083] The compound lotions (20 mL) prepared in Examples 1-6 and Comparative Examples 1-3 were randomly grouped after being sealed, numbered in each group and the initial state was recorded. Using a thermostatic and humidistatic chamber (Binder KBF-240), they were stored in the dark at 40 ± 2 °C and 75 ± 5% RH to avoid photodegradation. After 1 month, the samples were taken out for testing, and the changes in appearance, miconazole nitrate content and pH value were recorded. The results are shown in Table 2:

[0084] Table 2. Stability test results of Examples 1-6 and Comparative Examples 1-3

[0085] Sample Appearance (Color / Transparency) Miconazole Nitrate Content (%) pH Value Example 1 Colorless and Transparent 99.3 5.1 Example 2 Colorless and Transparent 99.5 5.2 Example 3 Colorless and Transparent 99.8 5.1 Example 4 Slightly Turbid 98.1 5.3 Example 5 Colorless and Transparent 99.0 5.1 Example 6 Colorless and Transparent 99.9 5.0 Control Example 1 Light Yellow and Turbid 94.2 5.2 Control Example 2 Light Yellow and Turbid 96.8 5.0 Control Example 3 Light Yellow and Turbid 91.5 4.8

[0086] (Ⅲ) Skin Compatibility Evaluation

[0087] Take 10 mL of fresh rabbit whole blood, mix it with 2 mL of Alsever's solution, and store it at 4 °C for no more than 72 h. Centrifuge the red blood cells at a speed of 2000 rpm for 10 min to wash them, discard the supernatant and the white blood cell layer, and wash the precipitated red blood cells 3 times with PBS, each time centrifuging at a speed of 2000 rpm for 10 min. Take 1 mL of the washed red blood cells, add 49 mL of PBS, mix well and count the blood cells, and adjust to 2×10 8 cells / mL (≈2% suspension).

[0088] Take 1 mL of each lotion sample of Example 1 and Comparative Example 1, add 9 mL of PBS, and vortex to mix until a concentration of 10% is obtained to get a 10% lotion.

[0089] Add each incubation system to a 5 mL centrifuge tube respectively, and the construction scheme of the incubation system is as follows:

[0090] Experimental group: 1 mL of 10% lotion of Example 1 + 1 mL of 2% red blood cell suspension.

[0091] Control group: 1 mL of 10% lotion of Comparative Example 1 + 1 mL of 2% red blood cell suspension.

[0092] Positive control: 1 mL of 1% Triton X-100 + 1 mL of 2% red blood cell suspension.

[0093] Negative control: 1 mL of normal saline + 1 mL of 2% red blood cell suspension.

[0094] Blank group: 1 mL of PBS + 1 mL of 2% red blood cell suspension.

[0095] Mix each group of vortices evenly, incubate in a water bath at 37 °C for 1 h, immediately place in an ice bath for 5 min after incubation, centrifuge at 2000 rpm for 10 min at 4 °C, and collect the supernatant. Transfer 200 μL of the supernatant to a 96-well plate, avoiding aspiration of the precipitate, and measure the absorbance at 540 nm using an enzyme-linked immunosorbent assay (ELISA) reader (zeroed with the blank group). Calculate the hemolysis rate (%), and the hemolysis rate (%) = (OD 测试组 - OD 阴性对照 ) / (OD 阳性对照 - OD 阴性对照 ) × 100. The results are shown in Table 3:

[0096] Table 3. Results of the erythrocyte hemolysis experiment

[0097] Sample <![CDATA[Absorbance (OD 540 )]]> Hemolysis Rate (%) Mean ± SD Example 1 0.12,0.11,0.13 4.8％ 4.7±0.5％ Control Example 1 0.45,0.47,0.46 58.3％ 58.0±1.2％ Positive Control 0.78,0.79,0.77 100％ - Positive Control 0.08,0.07,0.08 0％ -

[0098] As can be seen from Table 1, the antibacterial activity of Example 1 is significantly better than that of Comparative Example 1 and the positive control, indicating that the micelle structure formed by the amphiphilic polymer encapsulates the hydrophobic drug miconazole nitrate, improves its water solubility, and thus increases the contact area with the microbial cell membrane. The hydrophobic chain of ricinoleate is similar to the lipid layer of the fungal cell membrane (rich in ergosterol), which may promote drug transmembrane penetration. The phenolic hydroxyl group of gallic acid disrupts the integrity of the microbial membrane through hydrogen bonding and synergistically enhances the ergosterol synthesis inhibition mechanism of miconazole nitrate. In Comparative Example 1, due to the lack of an esterified hydrophobic group, effective micelles cannot be formed, and the drug dispersibility is poor, resulting in an increase in MIC.

[0099] As can be seen from Table 2, the micelle structure of the polymer isolates miconazole nitrate, reduces its direct contact with water and oxygen, and inhibits hydrolysis and oxidative degradation (the content of Comparative Example 1 decreased to 94.2%). The color of Example 1 remained colorless, while Comparative Example 3 became turbid due to the oxidation of gallic acid to form quinone substances, indicating that the phenolic hydroxyl group of gallic acid may scavenge free radicals and delay drug oxidation. The pH of Example 1 only decreased by 0.1, while the pH of Comparative Example 3 decreased by 0.4, indicating that the hydroxyl and carboxylic acid groups in the amphiphilic polymer may stabilize the system pH through hydrogen bonding.

[0100] As can be seen from Table 3, the hemolysis rate of Example 1 was only 4.7%, indicating that the polymer micelles encapsulate the ionic surfactant, reduce its direct contact with the erythrocyte membrane, and lower the risk of membrane damage. The hemolysis rate of Comparative Group 1 was as high as 58% due to the lack of a shielding structure, indicating that the hydrophobic core of polyglyceryl ricinoleate adsorbs free drugs and surfactants, while the hydrophilic outer shell (polyglycerol chain) forms a hydration layer to shield the stimulation to erythrocytes. The zwitterionic property of the amphiphilic polymer may neutralize the charge of the surfactant and reduce the electrostatic damage to the cell membrane.

[0101] In summary, in Examples 1-6, the castor oil acid ester hydrophobic core of the amphiphilic polymer may have the effect of solubilizing drugs and promoting membrane penetration, and the polyglycerol hydrophilic shell may improve water solubility and shield irritating components. Through the synergistic action of multiple mechanisms, the amphiphilic polymer achieves high-efficiency antibacterial, stable storage, and low irritation.

[0102] In the description of the specification, the description with reference to terms such as "preparation example", "example", "each example", etc. means that the specific features, structures, materials or characteristics described in connection with that example or preparation example are included in at least one example or preparation example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same example or preparation example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more examples or preparation examples.

[0103] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A compound miconazole nitrate lotion, characterized in that, It comprises the following raw materials by weight percentage: miconazole nitrate 1.5 - 2.5%, amphiphilic polymer 5 - 6%, chlorhexidine gluconate 1.5 - 2.5%, Kathon 0.05 - 0.1%, benzoic acid 0.1 - 0.2%, surfactant 25 - 32%, PEG - 120 methyl glucoside dioleate 1 - 2%, citric acid monohydrate 0.3 - 0.4% and sodium chloride 0.7 - 0.9%, and the balance is water.

2. The compound miconazole nitrate lotion according to claim 1, wherein The surfactant comprises one or more of lauryl alcohol polyoxyethylene ether, cocamidopropyl betaine, disodium cocoamphodiacetate, cetyltrimethylammonium chloride, sodium dodecyl sulfate, polysorbate - 80, cocamidopropyl hydroxysultaine, decyl glucoside and sodium lauroyl sarcosinate.

3. The compound miconazole nitrate lotion according to claim 1, characterized in that The amphiphilic polymer is prepared through the following steps: S1. Under nitrogen protection, mix glycerol and sodium hydroxide, heat and react for 2 - 3 h to obtain pale yellow viscous liquid polyglycerol. Mix polyglycerol, ricinoleic acid and n - hexane evenly, place them in a microwave reactor for treatment for 10 - 20 min, add immobilized lipase and zeolite molecular sieve, continue to react with constant temperature oscillation for 12 - 14 h. After the reaction, filter, perform secondary distillation, and purify by column chromatography to obtain a colorless and transparent oily substance, polyglycerol ricinoleate; S2. Add polyglycerol ricinoleate and gallic acid into a reactor, add N - methylpyrrolidone, control the temperature and stir and reflux for 1 - 2 h to remove the moisture of the raw materials. Add p - toluenesulfonic acid to the reaction system, raise the temperature and continue to react for 5 - 6 h. After the reaction, cool to 60 °C, filter, wash, and dry to obtain a white waxy solid, the amphiphilic polymer.

4. The compound miconazole nitrate lotion according to claim 3, characterized in that, In step S1, the mass ratio of glycerol to sodium hydroxide is (190 - 210):(0.95 - 1.05), and the mass ratio of polyglycerol, ricinoleic acid, n - hexane, lipase and zeolite molecular sieve is (20 - 22):(44 - 50):(40 - 41):1:(6 - 7).

5. The compound miconazole nitrate lotion according to claim 3, characterized in that In step S1, the heating temperature is 230 - 240 °C, the temperature of the microwave reaction is 50 - 60 °C, the power is 200 - 300 W, and the frequency is 2.45 - 2.55 GHz.

6. The compound miconazole nitrate lotion according to claim 3, wherein, In step S1, the temperature of constant temperature oscillation is 60 - 65 °C, and the speed is 200 - 300 rpm.

7. The compound miconazole nitrate lotion according to claim 3, characterized in that In step S2, the mass ratio of polyglycerol ricinoleate, gallic acid, N - methylpyrrolidone and p - toluenesulfonic acid is (33 - 35):(6 - 7):(82 - 84):(1 - 1.65).

8. The compound miconazole nitrate lotion according to claim 3, wherein In step S2, the controlled temperature is 80 - 85 °C, the stirring speed is 100 - 200 rpm, and the temperature for raising the temperature is 110 - 115 °C.

9. The preparation process of the compound miconazole nitrate lotion according to any one of claims 1-8, characterized in that, It comprises the following steps: Add water into a mixer, heat, add PEG - 120 methyl glucoside dioleate and surfactant, stir for 30 - 40 min, add miconazole nitrate, chlorhexidine gluconate, amphiphilic polymer, Kathon and benzoic acid in sequence, continue to stir for 15 - 25 min, add citric acid monohydrate, then add sodium chloride, perform homogenization treatment for 10 - 20 min, filter to remove impurities, and fill into containers to obtain the finished product.

10. The preparation process of a compound miconazole nitrate lotion according to claim 9, characterized in that, The heating temperature is 40 - 45 °C, the stirring speed is 500 - 600 rpm, and the homogenization speed is 2000 - 3000 rpm.

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