A fusidic acid cream composition and preparation method thereof

Abstract

The invention discloses a fusidic acid cream composition, comprising fusidic acid, an oil phase matrix, a wetting agent, an emulsifier, an antioxidant, a pH regulator and water, wherein the oil phase matrix is ​​one of cetyl alcohol or white vaseline; the wetting agent is one of propylene glycol or glycerol; the emulsifier is one of caprylic acid glyceride or ethylhexylglycerol; the antioxidant is butylated hydroxyanisole, and no additional preservative is added to the composition; the invention also discloses a preparation method of the fusidic acid cream composition; compared with the prior art, the preparation process of the invention uses negative pressure combined with nitrogen pressure maintenance, which is beneficial to sample properties and improves stability; no additional preservative is added, a specific emulsifier is screened out, and combined with high temperature and filtration and sterilization reduction technology, the skin irritation, allergy or hypersensitivity reaction caused by the preservative is reduced; the raw materials adopt a pre-dispersion process, which significantly reduces the risk of uneven mixing caused by raw material agglomeration.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to an external cream composition containing fusidic acid and a preparation method thereof. Background Art

[0002] Fusidic acid cream is an antibiotic topical drug widely used to treat skin infections caused by Staphylococcus, Streptococcus, Propionibacterium acnes, Corynebacterium minium and other bacteria sensitive to fusidic acid. Its main indications include impetigo, furuncle, carbuncle, paronychia, traumatic infection, acne barbae, hidradenitis, erythrasma, folliculitis, acne vulgaris and other diseases. Although fusidic acid cream has a significant antibacterial effect, there are the following adverse reactions in actual application: local skin reactions at the site of application, including dermatitis (contact dermatitis, eczema), rash (pustule, blister, maculopapular rash, papule), itching, erythema, skin allergic reaction, etc., and there may even be irritation or pain (such as skin burning) at the site of application. In addition, fusidic acid is prone to yellowing, thinning viscosity, poor stability, uneven drug release and other problems during the preparation process or after long-term storage. On the one hand, these problems may be related to the excipients of fusidic acid cream, which may have an adverse effect on the safety and efficacy of the drug; on the other hand, they may be due to the heat-labile chemical properties of fusidic acid, which is easily oxidatively degraded and hydrolyzed during high-temperature preparation and storage, thereby increasing the complexity and difficulty of the preparation process.

[0003] CN115721602A discloses a prescription composition of a fusidic acid cream, wherein the aqueous phase comprises glycerol with a volume fraction of 85%, potassium sorbate (preservative) and purified water, and the oil phase comprises hexadecanol, white vaseline, polysorbate 60, liquid paraffin and butylated hydroxyanisole; the cream is prepared by the following method: the aqueous phase and the oil phase are mixed and then subjected to a first homogenization to obtain a mixture, and then a fusidic acid raw material is added to the mixture for a second homogenization and cooling to obtain the fusidic acid cream.

[0004] CN117180179A provides a method for preparing a fusidic acid cream, wherein the auxiliary materials include an emulsifier, a moisturizer, an oil phase matrix, potassium sorbate (preservative), an antioxidant, a pH regulator and water; in the method, firstly, an aqueous solvent system is formed with part of the aqueous components in the cream auxiliary materials, or an oily solvent system is formed with part of the oily components in the cream auxiliary materials, and the fusidic acid raw material is dispersed in the above-mentioned solvent system to form a fusidic acid dispersion, and the remaining aqueous components and the remaining oily components in the auxiliary materials except for the aqueous solvent system or the oily solvent system and the pH regulator for dispersing the fusidic acid raw material are used to prepare the aqueous phase and the oil phase respectively, and the aqueous phase and the oil phase are mixed and emulsified to form an cream matrix, and finally the fusidic acid dispersion is introduced to form the final fusidic acid cream. The preparation method has complicated steps and needs to be prepared multiple times.

[0005] In order to reduce skin irritation, allergic or hypersensitivity reactions caused by the use of potassium sorbate and improve the safety of fusidic acid cream, it is urgent to develop a new fusidic acid cream formulation and preparation method that does not use potassium sorbate or uses safer types of preservatives to replace the antibacterial effect of potassium sorbate to ensure the product quality, stability, uniformity of drug release and therapeutic effect of the cream. Summary of the invention

[0006] In the prior art, there are reports of adverse reactions of fusidic acid cream during use, and it is easy to be oxidatively degraded and hydrolyzed during preparation and storage, resulting in poor stability of the cream and uneven drug release. Therefore, in order to solve the above problems, the present invention provides a preservative-free fusidic acid cream composition and a preparation method thereof, which improves the quality and stability of the product to reduce the incidence of adverse reactions, and effectively solves the problems existing in the prior art.

[0007] The first aspect of the present invention provides a fusidic acid cream composition, comprising the following components: fusidic acid, an oil phase matrix, a wetting agent, an emulsifier, an antioxidant, a pH regulator and water, wherein the oil phase matrix is ​​one of cetyl alcohol or white vaseline; the wetting agent is one of propylene glycol or glycerol; the emulsifier is one of caprylic acid glyceride or ethylhexylglycerol; the antioxidant is butylated hydroxyanisole, and no additional preservative is added to the composition.

[0008] The emulsifier of the present invention uses caprylic acid glyceryl or ethylhexylglycerol to replace the polysorbate 60 and polysorbate 80 (Tween 60 or Tween 80) emulsifiers which are more easily oxidized.

[0009] As an embodiment of the present invention, the fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 12%-20% oil phase matrix, 20%-40% wetting agent, 4%-8% emulsifier, 0.001%-0.5% antioxidant, and the remaining components are purified water.

[0010] As an embodiment of the present invention, in the fusidic acid cream composition, the mass ratio of the oil phase matrix: wetting agent: emulsifier is 1-5:4-6:1. The mass ratio of the oil phase matrix: wetting agent: emulsifier can further be 2.5:5:1 or 2.7:5:1 or 3:5:1.

[0011] As an embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 20%-40% propylene glycol, 12%-20% cetyl alcohol, 4%-8% caprylic acid glyceride, 0.001%-0.5% butylated hydroxyanisole, and the balance is water. No additional preservatives are added to the composition.

[0012] As an embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 20%-40% propylene glycol, 12%-20% cetyl alcohol, 4%-8% ethylhexylglycerol, 0.001%-0.5% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition.

[0013] As an embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 20%-40% glycerol, 12%-20% cetyl alcohol, 4%-8% caprylic acid glyceride, 0.001%-0.5% butylated hydroxyanisole, and the balance is water. No additional preservatives are added to the composition.

[0014] As an embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 20%-40% glycerol, 12%-20% cetyl alcohol, 4%-8% ethylhexylglycerol, 0.001%-0.5% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition.

[0015] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% hexadecanol, 6% caprylic acid glyceride, 0.1% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition. The mass ratio of hexadecanol: propylene glycol: caprylic acid glyceride is 2.7: 5: 1.

[0016] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% hexadecanol, 6% ethylhexylglycerol, 0.1% butylated hydroxyanisole, and the balance is water, and no additional preservative is added to the composition. The mass ratio of hexadecanol: propylene glycol: ethylhexylglycerol is 2.7: 5: 1.

[0017] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 30% glycerol, 16% hexadecanol, 6% caprylic acid glyceride, 0.1% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition. The mass ratio of hexadecanol: propylene glycol: caprylic acid glyceride is 2.7: 5: 1.

[0018] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 30% glycerol, 16% hexadecanol, 6% ethylhexylglycerol, 0.1% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition. The mass ratio of hexadecanol: propylene glycol: ethylhexylglycerol is 2.7: 5: 1.

[0019] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 40% propylene glycol, 20% hexadecanol, 8% caprylic acid glyceride, 0.5% butylated hydroxyanisole, and the balance is water, and no additional preservative is added to the composition. The mass ratio of the hexadecanol: propylene glycol: caprylic acid glyceride is 2.5:5:1.

[0020] As a specific embodiment of the present invention, the fusidic acid cream composition includes the following components by weight: 2% fusidic acid, 20% propylene glycol, 12% hexadecanol, 4% caprylic acid glyceride, 0.001% butylated hydroxyanisole, and the balance is water, and no additional preservative is added to the composition. The mass ratio of the hexadecanol: propylene glycol: caprylic acid glyceride is 3:5:1.

[0021] The second aspect of the present invention provides a method for preparing the above-mentioned fusidic acid cream composition, comprising the following steps:

[0022] Step 1, prepare the aqueous phase: after mixing water and wetting agent, adjust pH, under nitrogen protection, heat at high temperature first, then cool, filter and set aside.

[0023] Step 2, preparing the oil phase: mixing the oil phase matrix, emulsifier and antioxidant, heating until the oil phase is melted, heating and then cooling under nitrogen protection, filtering and setting aside.

[0024] Step 3: Mixing the two phases: Mix the water phase and the oil phase, stir and emulsify under heat preservation and negative pressure conditions to prepare a mixed solution. This step can ensure the smooth flow of the mixed solution.

[0025] Step 4, raw material dispersion: disperse the micronized fusidic acid raw material in part of the mixed liquid to obtain a raw material dispersion, mix the raw material dispersion with the remaining mixed liquid under a negative pressure condition, stir and emulsify; stop emulsification after cooling, and reduce the stirring rate. After the emulsification stops, reducing the stirring rate can ensure the fluidity of the cream and facilitate subsequent filling.

[0026] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0027] As an embodiment of the present invention, the preparation method comprises the following steps:

[0028] Step 1, prepare the water phase: add purified water and wetting agent into the container, adjust the pH to 4.5-5.5 with pH adjuster, heat to 121°C under nitrogen protection, keep for at least 12 minutes, cool to 60-65°C, pass through a sterilizing filter with a maximum pore size of 0.45 μm, and put into a mixing tank for later use.

[0029] Step 2, prepare the oil phase: add the oil phase matrix, emulsifier and antioxidant into the container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, keep for at least 10 minutes, cool to 60-65°C, and filter through a filter with a maximum pore size of 10μm under nitrogen protection to a mixing tank.

[0030] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep the temperature at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure, start stirring and emulsification, the emulsification parameter is not less than 6000rpm / min, the stirring parameter is 40-200rpm / min (to ensure the smooth flow of the mixed liquid), and the time is controlled at 15-30min to prepare the mixed liquid.

[0031] Step 4, raw material dispersion: transfer part of the mixed liquid (60-65) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 2000-4000rpm / min, and keep the stirring parameter at 80-200rpm / min, cool down while stirring, and keep the cooling rate at 1-3℃ / min. When the temperature drops below 30℃, turn off the emulsification and reduce the stirring rate to 40-60rpm / min (to ensure the flow of the cream).

[0032] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0033] As a more specific embodiment of the present invention, in the preparation method of the fusidic acid cream composition of the present invention, the prescription of the composition comprises the following components by weight: 2% fusidic acid, 20%-40% propylene glycol, 12%-20% cetyl alcohol, 4%-8% caprylic glyceride, 0.001%-0.5% butylated hydroxyanisole, and the balance is water, and no additional preservatives are added to the composition.

[0034] As a more specific embodiment of the present invention, the specific preparation method comprises the following steps:

[0035] Step 1, prepare the water phase: add pure water and 20%-40% propylene glycol into a container, and adjust the pH to 4.5-5.5 with a pH adjuster, heat to 121°C under nitrogen protection, keep it for at least 12 minutes, cool it to 60-65°C, and pass it through a sterilizing filter with a maximum pore size of 0.45μm to a mixing tank.

[0036] Step 2, preparing the oil phase: adding 12%-20% of cetyl alcohol, 4%-8% of caprylic acid glyceride, and 0.001%-0.5% of butylated hydroxyanisole into a container, heating at 60-65°C until the oil phase is completely melted, heating to 90-95°C under nitrogen protection, maintaining for at least 10 minutes, cooling to 60-65°C, and filtering through a filter with a maximum pore size of 10 μm under nitrogen protection to a mixing tank.

[0037] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep the temperature at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure, start stirring and emulsification, the emulsification parameter is not less than 6000rpm / min, the stirring parameter is 40-200rpm / min (to ensure the smooth flow of the mixed liquid), and the time is controlled at 15-30min to prepare the mixed liquid.

[0038] Step 4, raw material dispersion: transfer 1-2L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the mixing tank under negative pressure, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 2000-4000rpm / min, and keep the stirring parameter at 80-200rpm / min, cool down while stirring, and keep the cooling rate at 1-3°C / min. When the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 40-60rpm / min (to ensure the flow of the cream).

[0039] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0040] Compared with the prior art, the fusidic acid cream composition and preparation method thereof provided by the present invention have the following beneficial effects:

[0041] 1. Improve quality: Negative pressure protection is used in the liquid preparation process, and high-purity nitrogen is used to maintain pressure in the filling process, so that the bubbles generated can be eliminated to a certain extent, reducing the contact between oxygen and liquid medicine, reducing the oxygen content in the product, which is beneficial to the stability of sample properties and loading volume during filling, and improving product quality and stability during storage.

[0042] 2. No need to add additional preservatives, reduce the types of auxiliary materials, and by screening out specific emulsifiers and combining high temperature and filtration sterilization processes in the liquid preparation process, skin irritation, allergies or hypersensitivity reactions caused by preservatives are reduced, while ensuring that the microbial limits within the product life cycle meet regulations.

[0043] 3. The drug is released evenly, and the raw materials are pre-dispersed, which significantly reduces the risk of uneven mixing caused by raw material agglomeration. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 : Microscopic observation of the fusidic acid cream obtained in Example 1.

[0045] Figure 2 : Microscopic observation of the fusidic acid cream obtained in Comparative Example 3.

[0046] Figure 3 : Microscopic observation of the reference preparation. DETAILED DESCRIPTION

[0047] The exemplary embodiments of the present disclosure will be described in more detail below. However, it should be understood that the present disclosure can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present disclosure and to enable the scope of the present disclosure to be fully communicated to those skilled in the art.

[0048] The particle size distribution determination method (D 90 ) Refer to the first method (microscope method) in the "General Rules 0982 of the 2020 Edition of the Chinese Pharmacopoeia"; the method for determining mixing uniformity refers to the high performance liquid chromatography method in the "General Rules 0512 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia".

[0049] Embodiment 1:

[0050] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% caprylic glyceride, 0.1% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0051] The specific preparation method is as follows:

[0052] Step 1, prepare the aqueous phase: add pure water and 30% propylene glycol into a container, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-60-65°C, and filter through a 0.45um sterilizing filter into a mixing tank.

[0053] Step 2, prepare the oil phase: add 16% of cetyl alcohol, 6% of caprylic acid glyceride, and 0.1% of butyl hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, maintain for 10 minutes, cool to 60-65°C, and pass through a 10 μm filter under nitrogen protection to a mixing tank.

[0054] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min, the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0055] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and stir quickly to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0056] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0057] Embodiment 2:

[0058] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% ethylhexylglycerol, 0.1% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0059] The specific preparation method is as follows:

[0060] Step 1, prepare the aqueous phase: add pure water and 30% propylene glycol into a container, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45μm sterilizing filter into a mixing tank.

[0061] Step 2, prepare the oil phase: add 16% of cetyl alcohol, 6% of caprylic acid glyceride, and 0.1% of butyl hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, maintain for 10 minutes, cool to 60-65°C, and pass through a 10 μm filter under nitrogen protection to a mixing tank.

[0062] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min, the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0063] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and stir quickly to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0064] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0065] Embodiment 3:

[0066] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% glycerol, 16% cetyl alcohol, 6% caprylic acid glyceride, 0.1% butyl hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0067] The specific preparation method is as follows:

[0068] Step 1, prepare the aqueous phase: add pure water and 30% glycerol into a container, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45μm sterilizing filter to a mixing tank when necessary.

[0069] Step 2, preparing the oil phase: adding 16% of cetyl alcohol, 6% of caprylic acid glyceride and 0.1% of butyl hydroxyanisole into a container, heating at 60-65°C until the oil phase is completely melted, heating to 90-95°C under nitrogen protection, maintaining for 10 minutes, cooling to 60-65°C, and passing through a 10 μm filter under nitrogen protection to a mixing tank when necessary.

[0070] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min, the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0071] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and stir quickly to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0072] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0073] Embodiment 4:

[0074] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% glycerol, 16% cetyl alcohol, 6% ethylhexylglycerol, 0.1% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0075] The specific preparation method is as follows:

[0076] Step 1, prepare the aqueous phase: add pure water and 30% glycerol into a container, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45μm sterilizing filter to a mixing tank when necessary.

[0077] Step 2, preparing the oil phase: adding 16% of cetyl alcohol, 6% of caprylic acid glyceride and 0.1% of butyl hydroxyanisole into a container, heating at 60-65°C until the oil phase is completely melted, heating to 90-95°C under nitrogen protection, maintaining for 10 minutes, cooling to 60-65°C, and passing through a 10 μm filter under nitrogen protection to a mixing tank when necessary.

[0078] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min and the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0079] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and stir quickly to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0080] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0081] Embodiment 5:

[0082] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 40% propylene glycol, 20% cetyl alcohol, 8% caprylic acid glyceride, 0.5% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0083] The specific preparation method is as follows:

[0084] Step 1, prepare the aqueous phase: add pure water and 40% propylene glycol into a container, and adjust the pH to 5.3±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45μm sterilizing filter into a mixing tank.

[0085] Step 2, prepare the oil phase: add 20% of cetyl alcohol, 8% of caprylic acid glyceride, and 0.5% of butylated hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, maintain for 10 minutes, cool to 60-65°C, and filter through a 10 μm pore size filter under nitrogen protection to a mixing tank.

[0086] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min and the stirring parameter is 200rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 15min, and the mixed liquid is prepared.

[0087] Step 4, raw material dispersion: transfer 2L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 4000rpm / min, and keep the stirring parameter at 200rpm / min, cool down while stirring, and keep the cooling rate at 3°C / min. When the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 60rpm / min (to ensure the flow of the cream).

[0088] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0089] Embodiment 6:

[0090] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 20% propylene glycol, 12% cetyl alcohol, 4% caprylic glyceride, 0.001% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

[0091] The specific preparation method is as follows:

[0092] Step 1, prepare the aqueous phase: add pure water and 20% propylene glycol into a container, and adjust the pH to 4.7±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45μm sterilizing filter into a mixing tank.

[0093] Step 2, prepare the oil phase: add 12% of cetyl alcohol, 4% of caprylic acid glyceride, and 0.001% of butyl hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, maintain for 10 minutes, cool to 60-65°C, and pass through a 10 μm filter under nitrogen protection to a mixing tank.

[0094] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min and the stirring parameter is 40rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 15min, and the mixed liquid is prepared.

[0095] Step 4, raw material dispersion: transfer 1L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure condition of the mixing tank, add the raw material dispersion into the mixing tank while hot, start emulsification, keep the emulsification speed at 2000rpm / min, and keep the stirring parameter at 80rpm / min, cool down while stirring, and keep the cooling rate at 1°C / min. When the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 40rpm / min (to ensure the flow of the cream).

[0096] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0097] Comparative Example 1: (adding preservative)

[0098] Compared with Example 1, Comparative Example 1 adds potassium sorbate as a preservative.

[0099] A fusidic acid cream composition comprises the following components by weight: 2% of fusidic acid, 30% of propylene glycol, 16% of cetyl alcohol, 6% of caprylic glyceride, 0.1% of butylated hydroxyanisole, 0.25% of potassium sorbate, and the balance is water.

[0100] The specific preparation method is as follows:

[0101] Step 1, prepare the aqueous phase: add pure water, 30% propylene glycol, and 0.25% potassium sorbate into a container, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-60-65°C, and filter through a 0.45um sterilizing filter into a mixing tank.

[0102] Step 2, prepare the oil phase: add 16% of cetyl alcohol, 6% of caprylic acid glyceride, and 0.1% of butyl hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C under nitrogen protection, maintain for 10 minutes, cool to 60-65°C, and filter through a 10 μm pore size filter under nitrogen protection to a mixing tank.

[0103] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min, the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0104] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and stir quickly to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the negative pressure of the mixing tank, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0105] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0106] Comparative Example 2: (Tween 60, nitrogen flushing)

[0107] A fusidic acid cream composition is provided, wherein Tween 60 is used to replace the emulsifier caprylic acid glyceryl in Example 1, and the rest of the formula is the same as that of Example 1 by weight, as shown in detail below.

[0108] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% Tween 60, 0.1% butylated hydroxyanisole, and the balance is water.

[0109] The preparation method is as follows:

[0110] The specific preparation method is as follows:

[0111] Step 1, prepare the aqueous phase: add pure water and 30% propylene glycol into a container and stir to completely dissolve the potassium sorbate, and adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C under nitrogen protection, maintain for 12 minutes, cool to 60-65°C, and pass through a 0.45 μm sterilizing filter to a mixing tank when necessary.

[0112] Step 2, preparing the oil phase: adding 16% hexadecanol, 6% Tween 60, and 0.1% butylated hydroxyanisole into a container, heating at 60-65°C until the oil phase is completely melted, heating to 90-95°C under nitrogen protection, maintaining for 10 minutes, cooling to 60-65°C, and passing through a 10 μm filter under nitrogen protection to a mixing tank when necessary.

[0113] Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep it warm at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is 6000rpm / min and the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), the time is controlled at 25min, and the mixed liquid is prepared.

[0114] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the mixing tank under negative pressure, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, keep the cooling rate at 2°C / min, and when the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm (to ensure the flow of the cream).

[0115] Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

[0116] Comparative Example 3: (Raw materials are not premixed)

[0117] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% caprylic glyceride, 0.1% butylated hydroxyanisole, and the balance is water.

[0118] The preparation method thereof refers to Example 1 except that the raw materials in step 4 are directly mixed with the entire mixed solution obtained in step 3.

[0119] Comparative Example 4: (Emulsifier is Tween 60, preservative is added, and nitrogen flushing is not performed)

[0120] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% Tween 60, 0.25% potassium sorbate, 0.1% butylated hydroxyanisole, and the balance is water.

[0121] The specific preparation method is as follows:

[0122] Step 1, prepare the aqueous phase: add pure water, 30% propylene glycol, and 0.25% potassium sorbate into a container and stir until completely dissolved, then adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C, maintain for 12 minutes, cool to 60-65°C, and filter through a 0.45 μm sterilizing filter into a mixing tank.

[0123] Step 2, prepare the oil phase: add 16% hexadecanol, 6% Tween 60, and 0.1% butylated hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C, maintain for 10 minutes, cool to 60-65°C, and filter through a 10 μm filter to a mixing tank.

[0124] Step 3, two-phase mixing: add the water phase and the oil phase into the mixing tank, keep warm at 60-65°C, start stirring and emulsification, emulsification parameter 6000rpm / min, stirring parameter 100rpm / min (to ensure smooth flow of the mixed liquid), time control within 25min, to prepare the mixed liquid.

[0125] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, stir quickly to disperse and obtain a raw material dispersion; add the raw material dispersion to the mixing tank while it is hot, start emulsification, maintain the emulsification speed at 3000rpm / min, and maintain the stirring parameter at 100rpm / min, cool down while stirring, and maintain the cooling rate at 2°C / min. When the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0126] Step 5: Filling: Use clean air to pressurize and fill into the aluminum tube and seal the tube.

[0127] Comparative Example 5: (without preservatives and without nitrogen flushing)

[0128] A fusidic acid cream composition comprises the following components by weight: 2% fusidic acid, 30% propylene glycol, 16% cetyl alcohol, 6% caprylic glyceride, 0.1% butyl hydroxyanisole, and the balance is water.

[0129] The preparation method is as follows

[0130] Step 1, prepare the aqueous phase: add pure water and 30% propylene glycol into a container, stir until completely dissolved, adjust the pH to 5.0±0.2 with pH adjuster hydrochloric acid, heat to 121°C, maintain for 12 minutes, cool to 60-65°C, and filter through a 0.45μm sterilizing filter into a mixing tank.

[0131] Step 2, prepare the oil phase: add 16% of cetyl alcohol, 6% of caprylic acid glyceride, and 0.1% of butyl hydroxyanisole into a container, heat at 60-65°C until the oil phase is completely melted, heat to 90-95°C, maintain for 10 minutes, cool to 60-65°C, and filter through a 10 μm pore size filter to a mixing tank.

[0132] Step 3, two-phase mixing: add the water phase and the oil phase into the mixing tank, keep warm at 60-65°C, start stirring and emulsification, the emulsification parameter is 6000rpm / min, the stirring parameter is 100rpm / min (to ensure the smooth flow of the mixed liquid), and the time is controlled within 25min to prepare the mixed liquid.

[0133] Step 4, raw material dispersion: transfer 1.5L of the mixed liquid (60-65°C) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, stir quickly to disperse and obtain a raw material dispersion, add the raw material dispersion to the mixing tank while it is hot, start emulsification, keep the emulsification speed at 3000rpm / min, and keep the stirring parameter at 100rpm / min, cool down while stirring, and keep the cooling rate at 2°C / min. When the temperature drops below 30°C, turn off the emulsification and reduce the stirring rate to 50rpm / min (to ensure the flow of the cream).

[0134] Step 5: Filling: Use clean air to pressurize and fill into the aluminum tube and seal the tube.

[0135] 0-day sample quality comparison

[0136] The properties, appearance, acidity, particle size, viscosity, content, related substances and microbial limits of the fusidic acid creams prepared in Examples 1-6 and Comparative Examples 1-5 were respectively measured. The results are shown in Table 1.

[0137] Table 1: Summary of samples tested on day 0

[0138]

[0139]

[0140] Stability comparison

[0141] The fusidic acid creams prepared in Example 1-6 and Comparative Example 1-5 were sealed and placed at an upper storage temperature of 30° C. for 6 months for quality comparison. The results are shown in Table 2.

[0142] Table 2: Summary of sample testing at 30℃-6 months

[0143]

[0144] in conclusion:

[0145] ① Comparing the microbial limit results of Examples 1-6 with Comparative Examples 1 and 2, the microbial limits of Examples 1-6 without adding additional preservatives and Comparative Example 1 with adding preservatives all meet the regulations after 6 months, while the microbial limits of Comparative Example 2, in which Tween 60 was selected as the emulsifier to prepare the sample, did not meet the regulations without adding additional preservatives. Using caprylic acid glyceryl or ethylhexylglycerol instead of Tween 60 as the emulsifier can improve the antibacterial effect of the product.

[0146] ② By comparing the particle size of Examples 1-6 with that of Comparative Example 3, the process properties of the raw materials after pre-dispersion meet the requirements. Figure 1 and Figure 2 .from Figure 1 It can be seen that the particle size of the API is always kept <10 μm; Figure 2 It can be seen that the particle size of the raw material is large, the distribution is uneven, and agglomerates appear. Figure 3 It can be seen that the reference preparation (Leo Pharma A / S, trade name Fucidin, specification 2%), the reference preparation and the raw materials in Example 1 are uniformly dispersed in the cream matrix, and there is no raw material agglomeration. ③ Using raw materials with the same impurity level to prepare samples according to different prescriptions and processes, comparing the 0-day and accelerated 6-month related substances of Examples 1-6 with those of Comparative Examples 4 and 5, the emulsifier is selected from caprylic acid glyceryl or ethylhexylglycerol relative to Tween 60, the impurity growth is less, and the stability of the nitrogen flushing process samples is significantly better than that of the non-nitrogen flushing samples.

[0147] Skin allergy test

[0148] Test method: 40 patients with moderate acne vulgaris, aged between 15 and 35 years old, were selected and divided into 2 groups, with 20 people in each group.

[0149] Inclusion criteria: Meet the diagnostic criteria for acne vulgaris, meet grade II and III according to the international modified grading system, with a total number of 30-100 lesions; no anti-infective drugs have been used within 2 weeks.

[0150] Treatment method: Before using the medicine, clean the affected area first; after the skin is dry, evenly apply lidocaine cream on the skin lesions to form a thin film; gently rub after applying the medicine to promote drug absorption; then wash hands with soap. Each group was applied with lidocaine cream of Examples 1-6 and Comparative Example 1, twice a day, and the efficacy was observed after 4 weeks of medication.

[0151] Efficacy evaluation criteria:

[0152] Cured: All rashes disappear, leaving only pigmentation, no new rashes appear, and no recurrence within 3 months; Significantly effective: All acne disappears, but recurrence within 3 months or acne is reduced by more than 50%;

[0153] Effective: Acne reduced by more than 30%;

[0154] Ineffective: No significant changes before and after treatment.

[0155] Adverse reactions: Local skin reactions at the medication site, including dermatitis (contact dermatitis, eczema), rash (pustules, blisters, maculopapular rash, papules), itching, erythema, skin allergic reactions, etc., and even irritation or pain at the medication site.

[0156] Total effective rate = (number of cured cases + number of markedly effective cases + number of effective cases) / number of cases in each group.

[0157] Adverse reaction rate = number of adverse reactions / number of cases in each group.

[0158] The treatment results are shown in Table 3 below:

[0159] Table 3: Statistical table of treatment effects of Example 1 and Comparative Example 1

[0160]

[0161] It can be seen from Table 3 that the adverse reaction rate of Example 1 is significantly lower than that of Comparative Example 1. Therefore, the fusidic acid cream composition prepared by the present invention, without adding additional preservatives, screens a specific emulsifier to replace the conventional preservatives, greatly reduces the incidence of adverse reactions, and achieves unexpected technical effects.

Claims

1. A fusidic acid cream composition, characterized in that, The invention comprises the following components: fusidic acid, an oil phase matrix, a wetting agent, an emulsifier, an antioxidant, a pH regulator and water, wherein the oil phase matrix is ​​one of cetyl alcohol and white vaseline; the wetting agent is one of propylene glycol and glycerol; the emulsifier is one of caprylic acid glyceride and ethylhexylglycerol; the antioxidant is butylated hydroxyanisole, and no additional preservative is added to the composition.

2. The fusidic acid cream composition according to claim 1, characterized in that The invention comprises the following components by weight: 2% of fusidic acid, 12%-20% of oil phase base, 20%-40% of wetting agent, 4%-8% of emulsifier, 0.001%-0.5% of antioxidant, and the remaining components are purified water.

3. The fusidic acid cream composition according to claim 1, characterized in that The mass ratio of the oil phase matrix:wetting agent:emulsifier is 1-5:4-6:1, and the mass ratio of the oil phase matrix:wetting agent:emulsifier can further be 2.5:5:1 or 2.7:5:1 or 3:5:

1.

4. The fusidic acid cream composition according to claim 2, characterized in that The composition comprises the following components by weight: 2% of fusidic acid, 30% of propylene glycol, 16% of cetyl alcohol, 6% of caprylic acid glyceryl or 6% of ethylhexylglyceryl, 0.1% of butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

5. The fusidic acid cream composition according to claim 2, characterized in that, The composition comprises the following components by weight: 2% of fusidic acid, 30% of glycerol, 16% of cetyl alcohol, 6% of caprylic acid glyceride or 6% of ethylhexylglycerol, 0.1% of butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

6. The fusidic acid cream composition according to claim 2, characterized in that The composition comprises the following components by weight: 2% fusidic acid, 40% propylene glycol, 20% cetyl alcohol, 8% caprylic acid glyceride, 0.5% butylated hydroxyanisole, and the balance is water. No additional preservative is added to the composition.

7. The fusidic acid cream composition according to claim 2, characterized in that The composition comprises the following components by weight: 2% fusidic acid, 20% propylene glycol, 12% cetyl alcohol, 4% caprylic acid glyceride, 0.001% butylated hydroxyanisole, and the balance is water. No additional preservatives are added to the composition.

8. The method for preparing the fusidic acid cream composition according to any one of claims 1 to 7, characterized in that: The steps include: Step 1, prepare the aqueous phase: mix water and wetting agent, adjust pH, heat at high temperature and then cool under nitrogen protection, filter and set aside; Step 2, preparing the oil phase: mixing the oil phase matrix, emulsifier and antioxidant, heating until the oil phase melts, heating and then cooling under nitrogen protection, filtering and setting aside; Step 3, two-phase mixing: mixing the water phase and the oil phase, stirring and emulsifying under heat preservation and negative pressure conditions to prepare a mixed solution; Step 4, raw material dispersion: dispersing the micronized fusidic acid raw material in part of the mixed solution to obtain a raw material dispersion, mixing the raw material dispersion with the remaining mixed solution under a negative pressure condition, stirring and emulsifying; after cooling, stop emulsification and reduce the stirring rate; Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

9. The method for preparing the fusidic acid cream composition according to claim 8, wherein: The steps include: Step 1, prepare the water phase: add purified water and wetting agent into the container, adjust the pH to 4.7-5.3 with pH adjuster, heat to 121°C under nitrogen protection, keep for at least 12 minutes, cool to 60-65°C, filter through a 0.45 μm sterilizing filter into a mixing tank for standby use; Step 2, preparing the oil phase: adding the oil phase matrix, emulsifier and antioxidant into a container, heating at 60-65°C until the oil phase is completely melted, heating to 90-95°C under nitrogen protection, maintaining for at least 10 minutes, cooling to 60-65°C, and passing through a filter with a pore size of 10 μm under nitrogen protection to a mixing tank; Step 3, two-phase mixing: add the water phase and the oil phase to the mixing tank, keep the temperature at 60-65°C, turn on the vacuum pump, keep the mixing tank under negative pressure and start stirring and emulsification, the emulsification parameter is not less than 6000rpm / min, the stirring parameter is 40-200rpm / min, and the time is controlled at 15-30min to prepare a mixed solution; Step 4, raw material dispersion: transfer part of the mixed liquid (60-65) from the mixing tank, premix the fusidic acid raw material (micronized to make the average particle size of the mixed raw materials ≤10 microns) in the mixed liquid, and quickly stir to disperse to obtain a raw material dispersion; turn on the vacuum pump, keep the mixing tank under negative pressure, add the raw material dispersion to the mixing tank while hot, start emulsification, keep the emulsification speed at 2000-4000rpm / min, and keep the stirring parameter at 80-200rpm / min, cool down while stirring, keep the cooling rate at 1-3℃ / min, and when the temperature drops below 30℃, turn off the emulsification and reduce the stirring rate to 40-60rpm / min; Step 5: Filling: Use high-purity nitrogen to add liquid and fill into the aluminum tube, and seal the tube.

10. The method for preparing the fusidic acid cream composition according to claim 8, characterized in that: The prescription of the composition comprises the following components by weight: 2% fusidic acid, 20%-40% propylene glycol, 12%-20% cetyl alcohol, 4%-8% caprylic acid glyceride, 0.001%-0.5% butylated hydroxyanisole, and the balance is water. No additional preservatives are added to the composition.

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