Preparation method of fusidic acid cream

Abstract

The invention provides a preparation method of fusidic acid emulsifiable paste, and relates to the field of pharmaceutical preparations, and the preparation method comprises the following steps: step 1, preparation of fusidic acid nanoparticles, step 2, preparation of an oil phase of the emulsifiable paste, step 3, preparation of a water phase of the emulsifiable paste, step 4, emulsification, and step 5, mixing. According to the fusidic acid nanoparticles, firstly, a composite carrier is prepared, then fusidic acid, PLGA, the composite carrier and absolute ethyl alcohol are mixed, a nanoparticle oil phase is obtained, then PVA, PVP, sodium dodecyl glucoside sulfonate and dipotassium ethylenediaminetetraacetate are mixed with deionized water, a nanoparticle water phase is obtained, and finally a nanoparticle suspension is obtained through mixing. The fusidic acid emulsifiable paste prepared by the method can effectively solve the problems that the traditional emulsifiable paste bulk drugs are easy to agglomerate, the drug molecule particle size is large and the like, and the transdermal absorption rate and bioavailability of fusidic acid are improved, so that the antibacterial effect is enhanced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of fusidic acid cream. Background Art

[0002] Fusidic Acid is an antibiotic mainly used for treating infections caused by Gram-positive bacteria (especially staphylococci). Fusidic acid cream is a topical drug containing fusidic acid, and its main curative effects include: 1. Treating skin infections: Fusidic acid cream is commonly used to treat skin infections caused by sensitive bacteria, such as impetigo, folliculitis, furunculosis, and carbuncles; 2. Treating wound and burn infections: For small-area wounds, cuts, abrasions, and burns, fusidic acid cream can prevent and treat secondary bacterial infections; 3. Treating eczema and dermatitis: In the treatment of inflammatory skin diseases such as eczema and dermatitis, fusidic acid cream can be used to control secondary bacterial infections; 4. Treating other skin inflammations: Fusidic acid cream can also be used to treat other skin diseases caused by sensitive bacteria, such as erythema, papules, and pustules.

[0003] Chinese patent document CN107224426A discloses a topical cream composition containing fusidic acid. Aiming at the defects that fusidic acid preparations are prone to oxidation degradation and hydrolysis, by adding antioxidants, hydrolysis stabilizers, etc. to the preparation system, the occurrence of oxidation and hydrolysis reactions is avoided, and by selecting the particle size and dissolution of the raw drug, the dissolution problem of fusidic acid is solved to a certain extent, so that it exists in the cream in a molecular state, which not only enhances the stability of fusidic acid cream, but also significantly inhibits the generation of oxidant hydrolysis impurities. Chinese patent document CN116115555A discloses a fusidic acid cream composition, which comprises or consists of the following raw material components: fusidic acid, liquid paraffin, cyclomethicone, polysorbate 80, ethylene glycol distearate, isopropyl palmitate, preservative, antioxidant, and water; the prepared fusidic acid cream composition has a good emulsified state and significantly improves the stability of the cream.

[0004] However, fusidic acid raw material drug is insoluble in water and hydrophobic solutions, but can be dissolved in ethanol and polar organic solutions; directly mixing fusidic acid raw material drug with the cream matrix to prepare the cream not only easily causes the agglomeration of the raw material drug and leads to poor dispersion uniformity of fusidic acid, but also easily results in poor skin barrier penetration ability due to the large particle size and strong hydrophobicity of the drug molecules, thereby affecting the antibacterial effect and curative effect of fusidic acid cream. Summary of the Invention

[0005] In view of the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a preparation method of fusidic acid cream. The fusidic acid cream prepared by this method can effectively solve the problems such as easy aggregation of the raw material drug of traditional cream and large particle size of drug molecules, improve the transdermal absorption rate and bioavailability of fusidic acid, and thus enhance its antibacterial effect.

[0006] The purpose of the present invention is achieved through the following technical solutions: A preparation method of fusidic acid cream, comprising: Step 1, preparation of fusidic acid nanoparticles: First, crosslink chitosan and sodium carboxymethyl cellulose to obtain a composite carrier; then add fusidic acid, PLGA (polylactic acid-glycolic acid copolymer), and the composite carrier into absolute ethanol, mix and stir to obtain the oil phase of nanoparticles; afterwards, dissolve PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate in deionized water respectively, mix and stir, and adjust the pH after cooling to room temperature to obtain the aqueous phase of nanoparticles; finally, slowly drop the oil phase of nanoparticles into the aqueous phase of nanoparticles, stir and emulsify at high speed, and sequentially pass through homogenization and purification to obtain a nanoparticle suspension; Step 2, preparation of the cream oil phase: Mix the oil phase and the emulsifier, and stir evenly; Step 3, preparation of the cream aqueous phase: Dissolve the humectant and the preservative in deionized water and stir evenly; Step 4, emulsification: Slowly introduce the cream oil phase into the cream aqueous phase, stir and emulsify to form a primary emulsion matrix, and cool; Step 5, mixing: Add the nanoparticle suspension to the primary emulsion matrix and stir evenly to obtain the product.

[0007] Based on the further optimization of the above scheme, in the fusidic acid cream, the weight percentages of each component are: 1-5% of the nanoparticle suspension, 10-20% of the oil phase, 3-8% of the emulsifier, 5-10% of the humectant, 0.1-0.5% of the preservative, and the rest is deionized water.

[0008] Based on the further optimization of the above scheme, the specific preparation method of the composite carrier is as follows: First, add chitosan to a 2% glacial acetic acid solution, and stir magnetically until completely dissolved to obtain solution A; then add sodium carboxymethyl cellulose to deionized water, stir and dissolve in a water bath, and cool to room temperature to obtain solution B; slowly drop solution B into solution A, stir evenly to obtain a composite carrier solution; finally, dialyze and freeze-dry the composite carrier solution to obtain a composite carrier powder.

[0009] For further optimization based on the above scheme, the mass ratio of chitosan to sodium carboxymethylcellulose is 7.5 - 8.5:4.5 - 5.5; the mass - to - volume ratio of chitosan to glacial acetic acid solution is 0.75 - 0.85 g:9.5 - 10.5 mL; the volume ratio of glacial acetic acid solution to deionized water is 9.5 - 10.5:39.5 - 40.5.

[0010] For further optimization based on the above scheme, the dialysis uses a dialysis bag with a molecular weight cut - off of 10 kDa and is dialyzed in deionized water for 24 h, and the deionized water is changed every 4 h.

[0011] For further optimization based on the above scheme, the mass - to - volume ratio of fusidic acid, PLGA (molecular weight 10 kDa), composite carrier, and absolute ethanol is 0.9 - 1.1 g:1.5 - 1.7 g:0.3 - 0.5 g:12 - 13 mL; the mass - to - volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 2.8 - 3.2 g:1.3 - 1.7 g:0.25 - 0.35 g:0.08 - 0.12 g:100 - 120 mL; the pH value of the nanoparticle aqueous phase is adjusted with glacial acetic acid to pH 4.5 - 5.0; the volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase is 1:3.5 - 4.5.

[0012] For further optimization based on the above scheme, in step one, high - speed stirring and emulsification specifically means: at a rotation speed of 5000 - 6000 rpm for 10 - 15 min; homogenization specifically means: at a pressure of 140 - 160 MPa, circulating homogenization is carried out 4 times, with an interval of 2 - 4 min each time; purification specifically means: using a rotary evaporation process, at 38 - 42 °C and - 0.07 - 0.08 MPa, evaporating for 15 - 18 min to remove the solvent, and making up the volume with deionized water and storing it in the refrigerator for later use.

[0013] For further optimization based on the above scheme, in step two, the oil phase uses any one of liquid paraffin, petrolatum, and lanolin, and the emulsifier uses a mixture of glyceryl monostearate and Tween 80, and the mass ratio between glyceryl monostearate and Tween 80 is 0.35 - 1.56:1; during the preparation of the cream oil phase, the mixing temperature is 70 - 80 °C, the stirring rate is 300 - 500 rpm, and the stirring time is 20 - 30 min.

[0014] Based on the further optimization of the above - mentioned scheme, in step three, the humectant is a mixture of glycerol and hyaluronic acid, and the mass - to - volume ratio of glycerol to hyaluronic acid is 0.8 - 1.2 g: 1.8 - 2.2 mL; the preservative is a mixture of phenoxyethanol and methylparaben, and the mass ratio of phenoxyethanol to methylparaben is 0.55 - 0.65: 0.04 - 0.06; the volume ratio of deionized water to hyaluronic acid is 10:1; during the preparation of the cream aqueous phase, the mixing temperature is 70 - 80 °C, the stirring rate is 200 - 400 rpm, and the stirring time is 10 - 20 min.

[0015] Based on the further optimization of the above - mentioned scheme, in step four, the stirring rate is 750 - 850 rpm, the emulsification time is 14 - 16 min, and the cooling temperature of the primary emulsion matrix is 30 - 35 °C.

[0016] Based on the further optimization of the above - mentioned scheme, in step five, the stirring rate is 200 - 400 rpm and the stirring time is 10 - 30 min.

[0017] The following are the technical effects of the solution of the present invention: In the present invention, a composite carrier is obtained by cross - linking chitosan and sodium carboxymethylcellulose. The biodegradable polymer materials of the composite carrier and PLGA are mixed with fusidic acid to form a drug core layer, avoiding the long - term toxicity and accumulation risk of traditional polymers. At the same time, a water - soluble molecular polymer composed of PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate is wrapped around the periphery of the drug core layer to form a "core - shell" - structured drug encapsulation. First, the steric hindrance effect and electrostatic repulsion are used to hinder the aggregation of nanoparticles and improve the dispersibility of nanoparticles. Second, the specific surface area of the drug is significantly increased, enhancing the skin permeability. Third, a sustained - release property is provided, prolonging the action time of the drug at the skin local area and enhancing the drug retention. Fourth, the oxidation and degradation of the drug are inhibited, improving its stability. Then, by mixing the fusidic acid nanoparticles with the oil phase, emulsifier, humectant, and preservative, a fusidic acid cream is prepared, significantly improving its transdermal absorption rate and bioavailability, enhancing its antibacterial effect, having good biocompatibility and safety, and the overall process is simple and easy for industrial production. Detailed implementation manners

[0018] The technical scheme of the present invention will be clearly and completely described below through examples. Obviously, the described examples are only a part of the examples of the present invention, rather than all the examples, and do not limit the protection scope of the present invention.

[0019] Example 1: A preparation method of fusidic acid cream, comprising: The weight percentages of the components of fusidic acid cream are as follows: nanoparticle suspension 1%, oil phase 10%, emulsifier 3%, humectant 5%, preservative 0.1%, and the balance is deionized water.

[0020] Step 1. Preparation of fusidic acid nanoparticles: First, chitosan and sodium carboxymethyl cellulose are subjected to ionic crosslinking to obtain a composite carrier; specifically: First, chitosan is added to a 2% glacial acetic acid solution, and under magnetic stirring at 30 °C until completely dissolved (stirring rate 300 rpm, stirring time 40 min) to obtain solution A, and the mass-volume ratio of chitosan to glacial acetic acid solution is 0.75 g: 9.5 mL; then sodium carboxymethyl cellulose is added to deionized water, and stirred and dissolved in a water bath environment at 50 °C (stirring rate 300 rpm, stirring time 30 min), and cooled to room temperature to obtain solution B, the volume ratio of glacial acetic acid solution to deionized water is 9.5: 39.5, and the mass ratio of chitosan to sodium carboxymethyl cellulose is 7.5: 4.5; solution B is slowly dropped into solution A (dropping rate 1 mL / min), and stirred evenly (stirring rate 300 rpm, stirring time 10 min) to obtain a composite carrier solution. Finally, the composite carrier solution is dialyzed and freeze-dried to obtain a composite carrier powder; among them, dialysis is carried out using a dialysis bag with a molecular weight cut-off of 10 kDa, dialyzed in deionized water for 24 h, and the deionized water is changed every 4 h; freeze-drying specifically is: first cool the temperature to -60 °C and pre-freeze for 2 h, then under a vacuum degree of 10 Pa, rise to -20 °C at a heating rate of 0.5 °C / min, and carry out sublimation drying for 12 h, and then under a vacuum degree not greater than 10 Pa, rise to 30 °C at a heating rate of 0.5 °C / min, and carry out desorption drying for 6 h to complete freeze-drying.

[0021] Then, fusidic acid, PLGA (poly(lactic-co-glycolic acid)), and the composite carrier are added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 0.9 g: 1.5 g: 0.3 g: 12 mL. Mixing and stirring are carried out at 30 °C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during stirring, ultrasonic power 150 W) to obtain the oily phase of nanoparticles. After that, PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass-volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 2.8 g: 1.3 g: 0.25 g: 0.08 g: 100 mL. Mixing and stirring are carried out at 30 °C (stirring speed 300 rpm, stirring time 20 min). After cooling to room temperature, the pH is adjusted to 5.0 using glacial acetic acid to obtain the aqueous phase of nanoparticles. Finally, the oily phase of nanoparticles is slowly dropped into the aqueous phase of nanoparticles. The volume ratio between the oily phase of nanoparticles and the aqueous phase of nanoparticles is 1:3.5. Emulsification is carried out at a rotation speed of 5000 rpm for 15 min to achieve high-speed stirring emulsification (during the emulsification process, an ultrasonic emulsifier can be simultaneously turned on for ultrasonic treatment, the power of ultrasonic treatment is 200 W, and the frequency is 40 kHz). Then, it is homogenized and purified in sequence to obtain a nanoparticle suspension. Among them, homogenization specifically is: at a pressure of 140 MPa, cyclic homogenization is carried out 4 times, with an interval of 4 min each time; purification specifically is: using a rotary evaporation process, at 38 °C and -0.07 MPa, evaporation is carried out for 15 min to remove the solvent, and it is made up to volume with deionized water (made up to volume according to the actual usage amount) and refrigerated at 4 °C for standby.

[0022] Step 2: Preparation of the cream oily phase: Mix the oily phase and the emulsifier and stir evenly; the oily phase uses liquid paraffin, and the emulsifier uses a mixture of glyceryl monostearate and Tween 80, and the mass ratio between glyceryl monostearate and Tween 80 is 0.35:1; during the preparation of the cream oily phase, the mixing temperature is 70 °C, the stirring rate is 300 rpm, and the stirring time is 30 min.

[0023] Step 3: Preparation of the cream aqueous phase: Dissolve the humectant and the preservative in deionized water and stir evenly; the humectant uses a mixture of glycerol and hyaluronic acid, and the mass-volume ratio of glycerol and hyaluronic acid is 0.8 g: 1.8 mL; the preservative uses a mixture of phenoxyethanol and methylparaben, and the mass ratio of phenoxyethanol and methylparaben is 0.55:0.04; the volume ratio of deionized water to hyaluronic acid is 10:1; during the preparation of the cream aqueous phase, the mixing temperature is 70 °C, the stirring rate is 200 rpm, and the stirring time is 20 min.

[0024] Step 4. Emulsification: Slowly introduce the cream oil phase into the cream water phase, stir and emulsify to form a primary emulsion matrix, and cool it; the stirring rate is 750 rpm, the emulsification time is 16 min, and the cooling temperature of the primary emulsion matrix is 30 °C.

[0025] Step 5. Mixing: Add the nanoparticle suspension to the primary emulsion matrix, stir evenly, with a stirring rate of 200 rpm and a stirring time of 30 min to obtain the product.

[0026] Example 2: A method for preparing fusidic acid cream, comprising: The weight percentages of the components of the fusidic acid cream are as follows: nanoparticle suspension 3%, oil phase 15%, emulsifier 5.5%, humectant 7.5%, preservative 0.3%, and the rest is deionized water.

[0027] Step 1. Preparation of fusidic acid nanoparticles: First, perform ionic crosslinking on chitosan and sodium carboxymethylcellulose to obtain a composite carrier; specifically: First, add chitosan to a 2% glacial acetic acid solution, stir magnetically at 30 °C until completely dissolved (stirring rate 300 rpm, stirring time 40 min) to obtain solution A, and the mass-volume ratio of chitosan to glacial acetic acid solution is 0.8 g: 10 mL; then add sodium carboxymethylcellulose to deionized water, stir and dissolve in a water bath environment at 50 °C (stirring rate 300 rpm, stirring time 30 min), and cool to room temperature to obtain solution B. The volume ratio of glacial acetic acid solution to deionized water is 10:40, and the mass ratio of chitosan to sodium carboxymethylcellulose is 8:5; slowly drop solution B into solution A (dropping rate 1 mL / min), stir evenly (stirring rate 300 rpm, stirring time 10 min) to obtain a composite carrier solution. Finally, dialyze and lyophilize the composite carrier solution to obtain a composite carrier powder; among them, dialysis is carried out using a dialysis bag with a molecular weight cut-off of 10 kDa, dialyze in deionized water for 24 h, and change the deionized water every 4 h; the lyophilization is specifically as follows: first cool the temperature to -50 °C and pre-freeze for 3 h, then raise the temperature to -15 °C at a heating rate of 0.7 °C / min under a vacuum degree of 20 Pa for 15 h of sublimation drying, and then raise the temperature to 25 °C at a heating rate of 0.7 °C / min under a vacuum degree not greater than 10 Pa for 9 h of analytical drying to complete the lyophilization.

[0028] Next, fusidic acid, PLGA (polylactic acid-glycolic acid copolymer), and the composite carrier are added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 1 g: 1.6 g: 0.4 g: 12.5 mL. Mixing and stirring are carried out at 30°C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during stirring, ultrasonic power 150 W) to obtain the nanoparticle oil phase. After that, PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass-volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 3 g: 1.5 g: 0.3 g: 0.1 g: 110 mL. Mixing and stirring are carried out at 30°C (stirring speed 300 rpm, stirring time 20 min). After cooling to room temperature, the pH is adjusted to 4.7 with glacial acetic acid to obtain the nanoparticle aqueous phase. Finally, the nanoparticle oil phase is slowly dropped into the nanoparticle aqueous phase. The volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase is 1:4. Emulsification is carried out at a rotation speed of 5500 rpm for 13 min to achieve high-speed stirring emulsification (during the emulsification process, an ultrasonic emulsifier can be simultaneously turned on for ultrasonic treatment, ultrasonic treatment power 200 W, frequency 40 kHz), and then homogenization and purification are carried out in sequence to obtain the nanoparticle suspension. Among them, homogenization specifically is: at a pressure of 150 MPa, cyclic homogenization is carried out 4 times, with an interval of 3 min each time; purification specifically is: using the rotary evaporation process, at 40°C and -0.08 MPa, evaporation is carried out for 17 min to remove the solvent, and volume is fixed with deionized water (volume is fixed according to the actual usage amount), and it is refrigerated at 4°C for standby.

[0029] Step 2. Preparation of the cream oil phase: Mix the oil phase and the emulsifier and stir evenly; the oil phase uses petrolatum, and the emulsifier uses a mixture of glyceryl monostearate and Tween 80, and the mass ratio between glyceryl monostearate and Tween 80 is 0.95:1; during the preparation of the cream oil phase, the mixing temperature is 75°C, the stirring rate is 400 rpm, and the stirring time is 25 min.

[0030] Step 3. Preparation of the cream aqueous phase: Dissolve the humectant and the preservative in deionized water and stir evenly; the humectant uses a mixture of glycerol and hyaluronic acid, and the mass-volume ratio of glycerol to hyaluronic acid is 1 g: 2 mL; the preservative uses a mixture of phenoxyethanol and methylparaben, and the mass ratio of phenoxyethanol to methylparaben is 0.6: 0.05; the volume ratio of deionized water to hyaluronic acid is 10:1; during the preparation of the cream aqueous phase, the mixing temperature is 75°C, the stirring rate is 300 rpm, and the stirring time is 15 min.

[0031] Step 4. Emulsification: Slowly introduce the cream oil phase into the cream water phase, stir and emulsify to form a primary emulsion matrix, and cool; the stirring rate is 800 rpm, the emulsification time is 15 min, and the cooling temperature of the primary emulsion matrix is 33 °C.

[0032] Step 5. Mixing: Add the nanoparticle suspension to the primary emulsion matrix, stir evenly, the stirring rate is 300 rpm, and the stirring time is 20 min to obtain the product.

[0033] Example 3: A method for preparing fusidic acid cream, comprising: The weight percentages of the components of the fusidic acid cream are as follows: nanoparticle suspension 5%, oil phase 20%, emulsifier 8%, humectant 10%, preservative 0.5%, and the balance is deionized water.

[0034] Step 1. Preparation of fusidic acid nanoparticles: First, perform ionic cross-linking on chitosan and sodium carboxymethyl cellulose to obtain a composite carrier; specifically: First, add chitosan to a 2% glacial acetic acid solution, stir magnetically at 30 °C until completely dissolved (stirring rate 300 rpm, stirring time 40 min) to obtain solution A, and the mass-volume ratio of chitosan to glacial acetic acid solution is 0.85:10.5 mL; then add sodium carboxymethyl cellulose to deionized water, stir and dissolve in a water bath environment at 50 °C (stirring rate 300 rpm, stirring time 30 min), and cool to room temperature to obtain solution B. The volume ratio of glacial acetic acid solution to deionized water is 10.5:40.5, and the mass ratio of chitosan to sodium carboxymethyl cellulose is 8.5:5.5; slowly drop solution B into solution A (dropping rate 1 mL / min), stir evenly (stirring rate 300 rpm, stirring time 10 min) to obtain a composite carrier solution. Finally, dialyze and freeze-dry the composite carrier solution to obtain a composite carrier powder; among them, dialysis is carried out using a dialysis bag with a molecular weight cut-off of 10 kDa, dialyze in deionized water for 24 h, and change the deionized water every 4 h; freeze-drying is specifically: first cool the temperature to -40 °C and pre-freeze for 4 h, then raise the temperature to -10 °C at a heating rate of 1 °C / min under a vacuum degree of 30 Pa and carry out sublimation drying for 18 h, and then raise the temperature to 20 °C at a heating rate of 1 °C / min under a vacuum degree not greater than 10 Pa and carry out desorption drying for 12 h to complete freeze-drying.

[0035] Then, fusidic acid, PLGA (poly lactic-co-glycolic acid), and the composite carrier are added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 1.1 g: 1.7 g: 0.5 g: 13 mL. Mix and stir at 30 °C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during stirring, ultrasonic power 150 W) to obtain the oily phase of nanoparticles. After that, PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass-volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 3.2 g: 1.7 g: 0.35 g: 0.12 g: 120 mL. Mix and stir at 30 °C (stirring speed 300 rpm, stirring time 20 min), and adjust the pH to 4.5 with glacial acetic acid after cooling to room temperature to obtain the aqueous phase of nanoparticles. Finally, slowly drop the oily phase of nanoparticles into the aqueous phase of nanoparticles. The volume ratio between the oily phase of nanoparticles and the aqueous phase of nanoparticles is 1:4.5. Emulsify at a rotation speed of 6000 rpm for 10 min to achieve high-speed stirring emulsification (during the emulsification process, the ultrasonic emulsifier can be turned on synchronously for ultrasonic treatment, the power of ultrasonic treatment is 200 W, and the frequency is 40 kHz), and then successively go through homogenization and purification to obtain the nanoparticle suspension. Among them, homogenization is specifically: at a pressure of 160 MPa, circulate and homogenize 4 times, with an interval of 2 min each time; purification is specifically: adopt the rotary evaporation process, evaporate for 15 min at 42 °C and -0.08 MPa to remove the solvent, and make up the volume with deionized water (make up the volume according to the actual usage amount), and store in the refrigerator at 4 °C for standby.

[0036] Step 2: Preparation of the cream oily phase: Mix the oily phase and the emulsifier and stir evenly; the oily phase uses lanolin, and the emulsifier uses a mixture of glyceryl monostearate and Tween 80. The mass ratio between glyceryl monostearate and Tween 80 is 1.56:1; during the preparation of the cream oily phase, the mixing temperature is 80 °C, the stirring rate is 500 rpm, and the stirring time is 20 min.

[0037] Step 3: Preparation of the cream aqueous phase: Dissolve the humectant and the preservative in deionized water and stir evenly; the humectant uses a mixture of glycerol and hyaluronic acid, and the mass-volume ratio of glycerol and hyaluronic acid is 1.2 g: 2.2 mL; the preservative uses a mixture of phenoxyethanol and methylparaben, and the mass ratio of phenoxyethanol and methylparaben is 0.65:0.06; the volume ratio of deionized water to hyaluronic acid is 10:1; during the preparation of the cream aqueous phase, the mixing temperature is 80 °C, the stirring rate is 400 rpm, and the stirring time is 10 min.

[0038] Step 4. Emulsification: Slowly introduce the cream oil phase into the cream water phase, stir and emulsify to form a primary emulsion matrix, and then cool it; the stirring rate is 850 rpm, the emulsification time is 14 min, and the cooling temperature of the primary emulsion matrix is 35 °C.

[0039] Step 5. Mixing: Add the nanoparticle suspension to the primary emulsion matrix and stir evenly. The stirring rate is 400 rpm and the stirring time is 10 min to obtain the product.

[0040] The fusidic acid creams prepared in Examples 1 to 3 were respectively tested, and the test results are shown in Table 1 below: Table 1

[0041] It can be seen from Table 1 above that the fusidic acid cream prepared by the method of the present invention has the same quality as the commercially available product and is even better than the commercially available product.

[0042] Comparative Example 1: A preparation method of fusidic acid cream, comprising: The weight percentages of the components of the fusidic acid cream are as follows: nanoparticle suspension 3%, oil phase 15%, emulsifier 5.5%, humectant 7.5%, preservative 0.3%, and the rest is deionized water.

[0043] Step 1. Preparation of fusidic acid nanoparticles: Fusidic acid, PLGA (polylactic-co-glycolic acid copolymer), and chitosan were added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), chitosan, and absolute ethanol was 1 g: 1.6 g: 0.4 g: 12.5 mL. Mixing and stirring were carried out at 30 °C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation could be carried out synchronously during the stirring process, ultrasonic power 150 W) to obtain the nanoparticle oil phase. Then, PVA, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate were dissolved in deionized water respectively. The mass-volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water was 3 g: 1.5 g: 0.3 g: 0.1 g: 110 mL. Mixing and stirring were carried out at 30 °C (stirring speed 300 rpm, stirring time 20 min), and after cooling to room temperature, the pH was adjusted to 4.7 with glacial acetic acid to obtain the nanoparticle aqueous phase. Finally, the nanoparticle oil phase was slowly added dropwise to the nanoparticle aqueous phase, and the volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase was 1:4. Emulsification was carried out at a rotation speed of 5500 rpm for 13 min to achieve high-speed stirring emulsification (during the emulsification process, the ultrasonic emulsifier could be turned on synchronously for ultrasonic treatment, ultrasonic treatment power 200 W, frequency 40 kHz), and then homogenization and purification were carried out in sequence to obtain the nanoparticle suspension. Among them, the homogenization was specifically: at a pressure of 150 MPa, cyclic homogenization was carried out 4 times, with an interval of 3 min each time; the purification was specifically: using the rotary evaporation process, at 40 °C and -0.08 MPa, evaporation was carried out for 17 min to remove the solvent, and it was made up to volume with deionized water (made up to volume according to the actual usage amount) and refrigerated at 4 °C for standby.

[0044] Step 2. Preparation of the cream oil phase: The steps were the same as those in Example 2.

[0045] Step 3. Preparation of the cream aqueous phase: The steps were the same as those in Example 2.

[0046] Step 4. Emulsification: The steps were the same as those in Example 2.

[0047] Step 5. Mixing: The steps were the same as those in Example 2.

[0048] Comparative Example 2: A preparation method of fusidic acid cream, including: The weight percentages of the components of the fusidic acid cream were: nanoparticle suspension 3%, oil phase 15%, emulsifier 5.5%, humectant 7.5%, preservative 0.3%, and the rest was deionized water.

[0049] Step 1. Preparation of fusidic acid nanoparticles: First, chitosan and sodium carboxymethyl cellulose are ionically crosslinked to obtain a composite carrier. The preparation steps of the composite carrier are the same as those in Example 2.

[0050] Then, fusidic acid, PLGA (poly(lactic-co-glycolic acid)), and the composite carrier are added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 1 g: 1.6 g: 0.4 g: 12.5 mL. Mixing and stirring are carried out at 30 °C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during stirring, ultrasonic power 150 W) to obtain the nanoparticle oil phase. After that, PVA, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass-volume ratio of PVA (polyvinyl alcohol, molecular weight 8 - 15 kDa), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 3 g: 0.3 g: 0.1 g: 110 mL. Mixing and stirring are carried out at 30 °C (stirring speed 300 rpm, stirring time 20 min), and after cooling to room temperature, the pH is adjusted to 4.7 with glacial acetic acid to obtain the nanoparticle aqueous phase. Finally, the nanoparticle oil phase is slowly added dropwise to the nanoparticle aqueous phase. The volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase is 1:4. Emulsification is carried out at a rotation speed of 5500 rpm for 13 min to achieve high-speed stirring emulsification (during the emulsification process, an ultrasonic emulsifier can be simultaneously turned on for ultrasonic treatment, ultrasonic treatment power 200 W, frequency 40 kHz), and then homogenization and purification are carried out in sequence to obtain a nanoparticle suspension. Among them, homogenization specifically is: at a pressure of 150 MPa, cyclic homogenization is carried out 4 times, with an interval of 3 min each time; purification specifically is: using a rotary evaporation process, at 40 °C and -0.08 MPa, evaporation is carried out for 17 min to remove the solvent, and it is made up to volume with deionized water (made up to volume according to the actual usage amount) and refrigerated at 4 °C for standby.

[0051] Step 2. Preparation of the cream oil phase: The steps are the same as those in Example 2.

[0052] Step 3. Preparation of the cream aqueous phase: The steps are the same as those in Example 2.

[0053] Step 4. Emulsification: The steps are the same as those in Example 2.

[0054] Step 5. Mixing: The steps are the same as those in Example 2.

[0055] Comparative Example 3: A preparation method of fusidic acid cream, including: The weight percentages of the components of the fusidic acid cream are: nanoparticle suspension 3%, oil phase 15%, emulsifier 5.5%, humectant 7.5%, preservative 0.3%, and the rest is deionized water.

[0056] Step 1: Preparation of fusidic acid nanoparticles: First, chitosan and sodium carboxymethylcellulose are ionically crosslinked to obtain a composite carrier. The preparation steps of the composite carrier are the same as those in Example 2.

[0057] Then, fusidic acid, PLGA (polylactic acid - glycolic acid copolymer), and the composite carrier are added to absolute ethanol. The mass - volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 1 g: 1.6 g: 0.4 g: 12.5 mL. Mix and stir at 30 °C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during stirring, ultrasonic power 150 W) to obtain the nanoparticle oil phase. After that, PVP, sodium dodecyl glucoside sulfonate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass - volume ratio of PVP (polyvinylpyrrolidone, K30), sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate, and deionized water is 1.5 g: 0.3 g: 0.1 g: 110 mL. Mix and stir at 30 °C (stirring speed 300 rpm, stirring time 20 min), and adjust the pH to 4.7 with glacial acetic acid after cooling to room temperature to obtain the nanoparticle aqueous phase. Finally, the nanoparticle oil phase is slowly dropped into the nanoparticle aqueous phase. The volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase is 1:4, and emulsification is carried out at a rotation speed of 5500 rpm for 13 min to achieve high - speed stirring emulsification (during the emulsification process, an ultrasonic emulsifier can be turned on synchronously for ultrasonic treatment, ultrasonic treatment power 200 W, frequency 40 kHz), and then homogenization and purification are carried out in sequence to obtain a nanoparticle suspension. Among them, homogenization is specifically: at a pressure of 150 MPa, circulate and homogenize 4 times, with an interval of 3 min each time; purification is specifically: adopt the rotary evaporation process, evaporate at 40 °C and - 0.08 MPa for 17 min to remove the solvent, and make up the volume with deionized water (make up the volume according to the actual usage amount) and refrigerate at 4 °C for standby.

[0058] Step 2: Preparation of the cream oil phase: The same as the steps in Example 2.

[0059] Step 3: Preparation of the cream aqueous phase: The same as the steps in Example 2.

[0060] Step 4: Emulsification: The same as the steps in Example 2.

[0061] Step 5: Mixing: The same as the steps in Example 2.

[0062] Comparative Example 4: A preparation method of fusidic acid cream, including: The weight percentages of the components of fusidic acid cream are as follows: nanoparticle suspension 3%, oil phase 15%, emulsifier 5.5%, humectant 7.5%, preservative 0.3%, and the rest is deionized water.

[0063] Step 1. Preparation of fusidic acid nanoparticles: First, chitosan and sodium carboxymethyl cellulose are subjected to ionic crosslinking to obtain a composite carrier. The preparation steps of the composite carrier are the same as those in Example 2.

[0064] Then, fusidic acid, PLGA (poly(lactic-co-glycolic acid)), and the composite carrier are added to absolute ethanol. The mass-volume ratio of fusidic acid, PLGA (with a molecular weight of 10 kDa), the composite carrier, and absolute ethanol is 1 g: 1.6 g: 0.4 g: 12.5 mL. Mixing and stirring are carried out at 30°C (stirring rate 400 rpm, stirring time 30 min; meanwhile, ultrasonic oscillation can be carried out synchronously during the stirring process, ultrasonic power 150 W) to obtain the nanoparticle oil phase. After that, PVA, PVP, sodium dodecyl sulfate, and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water. The mass-volume ratio of PVA (polyvinyl alcohol, with a molecular weight of 8 - 15 kDa), PVP (polyvinylpyrrolidone, K30), sodium dodecyl sulfate, dipotassium ethylenediaminetetraacetate, and deionized water is 3 g: 1.5 g: 0.3 g: 0.1 g: 110 mL. Mixing and stirring are carried out at 30°C (stirring speed 300 rpm, stirring time 20 min). After cooling to room temperature, the pH is adjusted to 4.7 with glacial acetic acid to obtain the nanoparticle aqueous phase. Finally, the nanoparticle oil phase is slowly added dropwise to the nanoparticle aqueous phase. The volume ratio between the nanoparticle oil phase and the nanoparticle aqueous phase is 1:4. Emulsification is carried out at a rotation speed of 5500 rpm for 13 min to achieve high-speed stirring emulsification (during the emulsification process, an ultrasonic emulsifier can be synchronously turned on for ultrasonic treatment, ultrasonic treatment power 200 W, frequency 40 kHz), and then homogenization and purification are carried out in sequence to obtain the nanoparticle suspension. Among them, homogenization specifically is: under a pressure of 150 MPa, cyclic homogenization is carried out 4 times, with an interval of 3 min each time; purification specifically is: using a rotary evaporation process, evaporation is carried out at 40°C and -0.08 MPa for 17 min to remove the solvent, and volume is fixed with deionized water (volume is fixed according to the actual usage amount) and stored in a refrigerator at 4°C for standby.

[0065] Step 2. Preparation of the cream oil phase: The steps are the same as those in Step 2 of Example 2.

[0066] Step 3. Preparation of the cream aqueous phase: The steps are the same as those in Step 3 of Example 2.

[0067] Step 4. Emulsification: The steps are the same as those in Step 4 of Example 2.

[0068] Step 5. Mixing: The steps are the same as those in Step 5 of Example 2.

[0069] The transdermal rate, 24-hour cumulative penetration amount, inhibition zone diameter, skin retention amount, etc. of the fusidic acid cream prepared in Examples 1 to 3 and Comparative Examples 1 to 4 of the present invention were tested respectively; among them, the transdermal rate was determined by transdermal absorption, and the Franz diffusion cell method was used. Using excised rat skin as a barrier, the transdermal absorption rate, 24-hour cumulative penetration amount and the amount retained in the skin of the fusidic acid cream were measured respectively; the inhibition zone diameter was tested by an antibacterial activity experiment, and the agar diffusion method was used to measure the inhibition zone diameter of the fusidic acid cream against Staphylococcus aureus; the specific results are shown in Table 2 below: Table 2

[0070] Note: The data are the average values of three independent experiments ± standard deviation.

[0071] It can be seen from the above table that: the fusidic acid nanoparticles prepared preferentially in the present invention penetrate through the hair follicle bypass pathway and the intercellular lipid channel in a dual-pathway manner; at the same time, since the fusidic acid nanoparticles in Examples 1 to 3 have good dispersibility and are not easily agglomerated to form large particles, they are preferentially accumulated at the hair follicle opening and release the drug slowly, resulting in the transdermal rate, 24-hour cumulative penetration amount and skin retention amount in Examples 1 to 3 of the present invention being significantly higher than those in Comparative Examples 1 to 4; and due to the preparation of the fusidic acid nanoparticles, the transdermal rate, 24-hour cumulative penetration amount and skin retention amount of Comparative Examples 1 to 4 are due to the commercial products. At the same time, due to the excellent dispersibility of the nanoparticles, local high-concentration accumulation is caused, thereby breaking through the Staphylococcus aureus biofilm (thickness ≈ 20 μm), so that it is accelerated degradation at the infection site and targeted drug release is achieved, and further the inhibition zone diameter of the fusidic acid cream is significantly larger than that of Comparative Examples 1 to 4; and due to the preparation of the fusidic acid nanoparticles, the inhibition zone diameter of Comparative Examples 1 to 4 is significantly larger than that of the commercial products.

Claims

1. A method for preparing fusidic acid cream, characterized in that: include: Step 1, preparation of fusidic acid nanoparticles: firstly ionically cross-linking chitosan and sodium hydroxymethylcellulose to obtain a composite carrier; Fusidic acid, PLGA and the composite carrier are then added to anhydrous ethanol, mixed and stirred to obtain a nanoparticle oil phase; then, PVA, PVP, sodium dodecyl glucoside sulfonate and dipotassium ethylenediaminetetraacetate are respectively dissolved in deionized water, mixed and stirred, cooled to room temperature and the pH is adjusted to obtain a nanoparticle water phase; finally, the nanoparticle oil phase is slowly added dropwise to the nanoparticle water phase, stirred at high speed for emulsification, and homogenized and purified in sequence to obtain a nanoparticle suspension; Step 2, preparation of cream oil phase: mixing the oil phase with the emulsifier and stirring evenly; Step 3: Preparation of the aqueous phase of the cream: dissolving the moisturizer and preservative in deionized water and stirring evenly; Step 4, emulsification: slowly introduce the cream oil phase into the cream water phase, stir and emulsify to form colostrum matrix, and cool; Step 5: Mixing: Add the nanoparticle suspension into the colostrum matrix and stir evenly.

2. A method for preparing a fusidic acid cream according to claim 1, characterized in that: In the fusidic acid cream, the weight percentages of the components are: 1-5% of the nanoparticle suspension, 10-20% of the oil phase, 3-8% of the emulsifier, 5-10% of the moisturizer, 0.1-0.5% of the preservative, and the rest is deionized water.

3. A method for preparing a fusidic acid cream according to claim 1 or 2, characterized in that: The preparation method of the composite carrier is specifically as follows: first, chitosan is added to a 2% glacial acetic acid solution, and magnetically stirred until completely dissolved to obtain a solution A; then, sodium hydroxymethyl cellulose is added to deionized water, stirred in a water bath to dissolve, and cooled to room temperature to obtain a solution B; the solution B is slowly dripped into the solution A, and stirred evenly to obtain a composite carrier solution; finally, the composite carrier solution is dialyzed and freeze-dried to obtain a composite carrier powder.

4. The preparation method of a fusidic acid cream according to claim 1 or 3, characterized in that: The mass ratio of chitosan to sodium hydroxymethyl cellulose is 7.5-8.5:4.5-5.5; the mass volume ratio of chitosan to glacial acetic acid solution is 0.75-0.85 g:9.5-10.5 mL; the volume ratio of glacial acetic acid solution to deionized water is 9.5-10.5:39.5-40.

5.

5. A method for preparing a fusidic acid cream according to claim 1 or 3, characterized in that: The dialysis was performed using a dialysis bag with a molecular weight cutoff of 10 kDa in deionized water for 24 hours, with the deionized water being replaced every 4 hours.

6. A method for preparing fusidic acid cream according to claim 1, characterized in that: The mass volume ratio of fusidic acid, PLGA, composite carrier and anhydrous ethanol is 0.9-1.1g:1.5-1.7g:0.3-0.5g:12-13mL; the mass volume ratio of PVA, PVP, sodium dodecyl glucoside sulfonate, dipotassium ethylenediaminetetraacetate and deionized water is 2.8-3.2g:1.3-1.7g:0.25-0.35g:0.08-0.12g:100-120mL; glacial acetic acid is used to adjust the pH value of the nanoparticle water phase to 4.5-5.0; the volume ratio between the nanoparticle oil phase and the nanoparticle water phase is 1:3.5-4.

5.

7. A method for preparing fusidic acid cream according to claim 1, characterized in that: In the step 2, the oil phase adopts any one of liquid paraffin, vaseline, and lanolin, the emulsifier adopts a mixture of monostearate glyceryl and Tween 80, and the mass ratio of monostearate glyceryl to Tween 80 is 0.35-1.56:1; during the preparation of the cream oil phase, the mixing temperature is 70-80°C, the stirring rate is 300-500rpm, and the stirring time is 20-30min.

8. A method for preparing fusidic acid cream according to claim 1, characterized in that: In step 4, the stirring rate is 750-850 rpm, the emulsification time is 14-16 min, and the colostrum matrix cooling temperature is 30-35° C.

9. A method for preparing fusidic acid cream according to claim 1, characterized in that: In the step 5, the stirring rate is 200-400 rpm and the stirring time is 10-30 min.

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