A sodium fusidate ointment

Abstract

The application discloses a sodium fusidate ointment and belongs to the technical field of sodium fusidate pharmaceutical products. The sodium fusidate ointment contains 2% of sodium fusidate; the sodium fusidate is loaded in nano slurry containing DSPE-PEG2000-gamma-PGA, the DSPE-PEG2000-gamma-PGA accounts for 0.2%-0.3% of the mass of the nano slurry, and the nano slurry loaded with the sodium fusidate is uniformly dispersed in an ointment base. The application solves the technical problems that the existing commercially available ointment and traditional preparation have too much deep penetration of drugs, low skin retention and single adjustment of penetration enhancers cannot effectively improve local accumulation.

Description

Technical Field

[0001] This invention relates to the technical field of sodium fusidate pharmaceutical products, specifically to a sodium fusidate ointment. Background Technology

[0002] Sodium fusidate is a white crystalline powder, readily soluble in water, and its aqueous solution is a colorless, transparent liquid. Similar to fusidic acid, sodium fusidate exerts its bactericidal effect by inhibiting bacterial protein synthesis and exhibits strong antibacterial activity against Gram-positive bacteria. Current sodium fusidate ointments typically use lipid excipients such as lanolin, cetyl alcohol, liquid paraffin, and white petrolatum to construct an oily ointment base. This results in indiscriminate release on both normal and infected skin, potentially leading to skin flora imbalance and the risk of drug resistance. Furthermore, the use of such traditional ointment bases can result in low skin retention.

[0003] Therefore, we propose a sodium fusidate ointment. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a sodium fusidate ointment that overcomes these deficiencies. Its rational design solves the technical problems of excessive deep drug penetration, low skin retention, and the inability to effectively increase local accumulation by simply adjusting the penetration enhancer in existing commercially available ointments and traditional formulations.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A sodium fusidate ointment, wherein the sodium fusidate content in the ointment is 2% by mass; characterized in that: the sodium fusidate is loaded in a nano-slurry containing DSPE-PEG2000-γ-PGA (abbreviated as polyglutamic acid-polyethylene glycol 2000-phospholipid, full name 1,2-distearate-sn-glycerol-3-phosphoethanolamine-polyethylene glycol-γ-polyglutamic acid), wherein the DSPE-PEG2000-γ-PGA accounts for 0.2%–0.3% of the mass of the nano-slurry, and the nano-slurry loaded with sodium fusidate is uniformly dispersed in the ointment matrix.

[0007] Furthermore, the ointment base comprises liquid paraffin, glyceryl monostearate, cetearyl alcohol, and white petrolatum;

[0008] The ointment comprises the following ingredients by weight percentage:

[0009] Liquid paraffin 10.00%-15.00%;

[0010] Glyceryl stearate 3.00%-5.00%;

[0011] Cetearyl alcohol 5.00%-8.00%;

[0012] The nano-slurry loaded with sodium fusidate has a content of 8.00%-10.00%;

[0013] Antioxidant content: 0.10%-0.25%;

[0014] Preservatives: 0.10%-0.25%;

[0015] Remaining amount of white petroleum jelly.

[0016] Furthermore, the nano-slurry comprises the following raw materials by mass percentage:

[0017] Glyceryl stearate 1.50%-1.80%;

[0018] Medium-chain triglycerides: 1.00%-1.20%;

[0019] Cholesterol 0.50%-0.80%;

[0020] Polyethylene glycol 400: 1.50%-2.00%;

[0021] DSPE-PEG2000-γ-PGA0.20%-0.30%;

[0022] Poloxamer 0.50%-0.60%;

[0023] Phosphate buffer (pH 6.5-6.8) 3.00%-5.00%;

[0024] The remaining amount of purified water.

[0025] Furthermore, the nano-slurry comprises the following raw materials by mass percentage:

[0026] Glyceryl stearate 1.50%;

[0027] Medium-chain triglycerides 1.20%;

[0028] Cholesterol 0.60%;

[0029] Polyethylene glycol 400 2.00%;

[0030] DSPE-PEG2000-γ-PGA 0.25%;

[0031] Poloxamer 0.50%;

[0032] Phosphate buffer (pH 6.5-6.8) 4.00%;

[0033] The remaining amount of purified water.

[0034] Furthermore, the sodium fusidate is incorporated into the preparation process of the nano-slurry to achieve loading, including the following steps:

[0035] S1. Weigh out glyceryl monostearate, medium-chain triglycerides, cholesterol and DSPE-PEG2000-γ-PGA, mix them and place them in a water bath, heat to 70-75℃, stir evenly to obtain a molten lipid phase.

[0036] S2. Weigh poloxamer and dissolve it in purified water preheated to 70-75℃ to obtain a preheated hot water phase;

[0037] Maintain a shear rate of 8000-10000 rpm at 70-75℃, and inject the preheated hot water phase into the molten lipid phase at a rate of 2-5 mL / min. After the preheated hot water phase is completely injected, maintain this shear rate for 3-5 min to form the colostrum.

[0038] S3. Quickly transfer the colostrum to an ice-water bath and stir continuously at 200-400 rpm for 5-8 minutes. Then, use a high-pressure homogenizer at 10,000-12,000 psi for at least two cycles to obtain a blank lipid nanoparticle suspension.

[0039] S4. Add phosphate buffer and sodium fusidate to the above blank lipid nanoparticle suspension, stir well, and place in a constant temperature shaker at 40-50℃ and 200-400 rpm for 30-60 min.

[0040] S5. After incubation, add PEG400 to the system, stir at room temperature for 200-400 rpm for 15-20 min to obtain nano-slurry loaded with sodium fusidate.

[0041] Furthermore, the raw materials of the sodium fusidate ointment contain soy lecithin, which accounts for 0.1%-0.2% of the ointment's mass.

[0042] Preferably, the sodium fusidate ointment comprises the following ingredients by weight percentage:

[0043] Liquid paraffin 15.00%;

[0044] Glyceryl stearate 3.00%;

[0045] Cetearyl alcohol 5.00%;

[0046] The nano-slurry loaded with sodium fusidate had a content of 8.00%.

[0047] Antioxidant 0.10%;

[0048] Preservative 0.10%;

[0049] Soy lecithin 0.20%;

[0050] Remaining amount of white petroleum jelly.

[0051] Furthermore, the sodium fusidic acid ointment is prepared by the following method:

[0052] S1. Weigh out white petrolatum, liquid paraffin, glyceryl monostearate, cetearyl alcohol, and soybean lecithin according to the formula, add them to the oil phase pot, stir at 70-75℃ and 50-100 rpm for 10-15 minutes.

[0053] S2. Add antioxidants and preservatives to the oil phase pot, maintain the temperature at 70-75℃, stir at 50-100 rpm for 5 minutes;

[0054] S3. Keep stirring at 50-100 rpm and let it cool naturally to 40-45℃.

[0055] S4. Add the prepared nano-slurry loaded with sodium fusidate into the oil phase pot, stir at 40-45℃ and 300-500 rpm for 15-20 min.

[0056] S5. Transfer the system to a shear emulsifier and homogenize at 3000-5000 rpm for 5-10 min.

[0057] S6. Transfer the system to a vacuum degassing device, -0.06~-0.08MPa, 50-100rpm, degas for 10-15min, then keep stirring at low speed to allow the paste to cool to room temperature;

[0058] S7: Fill, seal, and label the ointment after it has cooled to room temperature.

[0059] Furthermore, the antioxidant is selected from vitamin E, vitamin C, propyl gallate, butyl anisole, citric acid, or combinations thereof.

[0060] Furthermore, the preservative is selected from methylparaben, ethylparaben, phenoxyethanol, or combinations thereof.

[0061] This invention provides a sodium fusidate ointment with the following beneficial effects: It introduces a nanocarrier system and endows it with pH-responsive properties, thereby achieving accelerated release and efficient utilization of the drug at the lesion site. Healthy skin has a slightly acidic pH, while the pH of the skin at the eczema lesion site reaches 6-7 or even becomes alkaline. In an environment above pH 6, the surface charge or spatial structure of the nanocarrier undergoes fine-tuning, further promoting the dissociation and release of drug molecules. This responsive characteristic ensures the stability of the drug during storage while maximizing bioavailability after application, achieving a technological leap from passive dispersion to active response.

[0062] Furthermore, this application constructs a semi-solid ointment matrix with high yield stress and appropriate thixotropy by adjusting the ratio of white petrolatum, cetearyl alcohol, and glyceryl monostearate (GMS). White petrolatum provides a basic rigid barrier, cetearyl alcohol imparts excellent thixotropic recovery properties to the matrix, and GMS constructs a uniform micro-thickening network within the matrix. When the nanoparticles release sodium fusidate in response to the pH of the epidermal microenvironment, the drug molecules must overcome the viscosity resistance and microscopic steric hindrance within the ointment matrix to diffuse to the skin surface and stratum corneum. This effectively avoids burst release of the drug, allowing it to be released continuously following zero-order or near-zero-order kinetics, thereby forming a stable and long-lasting drug reservoir in the epidermal layer. Detailed Implementation

[0063] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0064] Example 1

[0065] A sodium fusidate ointment, wherein the sodium fusidate content in the ointment is 2% by mass; the sodium fusidate is loaded in a nano-slurry containing DSPE-PEG2000-γ-PGA, wherein DSPE-PEG2000-γ-PGA accounts for 0.25% by mass of the nano-slurry, and the nano-slurry loaded with sodium fusidate is uniformly dispersed in the ointment matrix.

[0066] The nano-slurry comprises the following raw materials by mass percentage:

[0067] Glyceryl stearate 1.65%;

[0068] Medium-chain triglycerides 1.10%;

[0069] Cholesterol 0.65%;

[0070] Polyethylene glycol 400 1.75%;

[0071] DSPE-PEG2000-γ-PGA 0.25%;

[0072] Poloxamer 0.55%;

[0073] Phosphate buffer (using PB buffer, pH 6.8) 4.50%;

[0074] Add purified water to bring the volume to 100%.

[0075] In this embodiment 1 and subsequent embodiments 2 and 3,

[0076] DSPE-PEG2000-γ-PGA, where the molecular weight of γ-PGA is 5k-10kDa.

[0077] The preparation method of DSPE-PEG2000-γ-PGA is as follows:

[0078] S1. Weigh γ-polyglutamic acid, γ-PGA molecular weight is 8kDa, dissolve it in 20mM MES buffer at pH 6.0, stir well to obtain a γ-PGA solution with a concentration of 5mg / mL.

[0079] S2. Add EDC ((1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)) and NHS (N-hydroxysuccinimide) to the γ-PGA solution. The molar ratio of EDC, NHS and γ-PGA carboxyl groups is 5:10:2. Mix well, protect from light, and stir at 25°C for 30 min to activate some of the carboxyl groups on the γ-PGA chain segments, thereby obtaining an activated γ-PGA solution.

[0080] S3. Weigh DSPE-PEG2000-NH2 (commercially available or prepared by existing methods), dissolve it in a mixed solvent, which is anhydrous ethanol and dimethyl sulfoxide mixed in a volume ratio of 1:1, stir evenly to obtain a DSPE-PEG2000-NH2 solution with a concentration of 20 mg / mL.

[0081] S4. Add DSPE-PEG2000-NH2 solution dropwise to activated γ-PGA solution, with a molar ratio of DSPE-PEG2000-NH2 to γ-PGA carboxyl groups of 1:10. Adjust the pH of the reaction system to 6.8 and react for 16 hours under nitrogen protection to allow the amino group of DSPE-PEG2000-NH2 to undergo an amidation reaction with the carboxyl group of γ-PGA, forming crude DSPE-PEG2000-γ-PGA product.

[0082] S5. Place the crude DSPE-PEG2000-γ-PGA product in a dialysis bag with a molecular weight cutoff of 7.8kDa-12kDa, and dialyze it sequentially with 30% (v / v) ethanol solution and purified water for 48h to remove unreacted small molecule coupling agent and free DSPE-PEG2000-NH2.

[0083] S6. Freeze-dry the dialysis product to obtain DSPE-PEG2000-γ-PGA;

[0084] The sodium fusidate is incorporated into the nano-slurry during preparation to achieve loading, with a mass ratio of 2:7, and includes the following steps:

[0085] S1. Weigh out glyceryl monostearate, medium-chain triglycerides, cholesterol and DSPE-PEG2000-γ-PGA, mix them and place them in a water bath, heat to 72°C, stir evenly to obtain a molten lipid phase;

[0086] S2. Weigh poloxamer and dissolve it in purified water preheated to 72°C to obtain a preheated water phase;

[0087] Maintaining a shear rate of 10,000 rpm at 72°C, the preheated hot water phase was injected into the molten lipid phase at a rate of 5 mL / min. After the preheated hot water phase was completely injected, the shear rate was maintained for 3 min to form the colostrum.

[0088] S3. Quickly transfer the colostrum to an ice-water bath and stir continuously at 200 rpm for 8 min. Then, use a high-pressure homogenizer at 10,000 psi for 2 cycles to obtain a blank lipid nanoparticle suspension.

[0089] S4. Add PB buffer and sodium fusidate to the above blank lipid nanoparticle suspension, stir well, and place in a constant temperature shaker at 50°C and 200 rpm for 45 min.

[0090] S5. After incubation, add PEG400 to the system, stir at room temperature for 200 rpm for 20 min to obtain nano-slurry loaded with sodium fusidate.

[0091] Sodium fusidate ointment comprises the following ingredients by weight percentage:

[0092] Liquid paraffin 12.50%;

[0093] Glyceryl stearate 4.00%;

[0094] Cetearyl alcohol 6.00%;

[0095] The nano-slurry loaded with sodium fusidate was 9.00% (i.e., sodium fusidate was 2%, nano-slurry was 7%, and the ratio of the two was 2:7).

[0096] Soy lecithin 0.10%;

[0097] Antioxidant (Vitamin E) 0.18%;

[0098] Preservative (ethylparaben) 0.18%;

[0099] White petroleum jelly was added to bring the total to 100%.

[0100] This sodium fusidate ointment was prepared by the following method:

[0101] S1. Weigh out white petrolatum, liquid paraffin, glyceryl monostearate, cetearyl alcohol, and soybean lecithin according to the proportions, add them to the oil phase pot, and stir at 75°C and 50 rpm for 15 minutes.

[0102] S2. Add vitamin E and ethylparaben to the oil phase pot, keep the temperature at 75℃, stir at 50 rpm for 5 minutes;

[0103] S3. Keep stirring at 100 rpm and let it cool naturally to 40-45℃.

[0104] S4. Add the prepared nano-slurry loaded with sodium fusidate into the oil phase pot, and stir at 45°C and 300 rpm for 20 min.

[0105] S5. Transfer the system to a shear emulsifier and homogenize at 5000 rpm for 8 min.

[0106] S6. Transfer the system to a vacuum degassing device, degas at -0.08MPa, 50rpm for 10min, then keep stirring at low speed to allow the paste to cool to room temperature;

[0107] S7: Fill, seal, and label the ointment after it has cooled to room temperature.

[0108] Example 2

[0109] Nanoparticle slurry, comprising the following raw materials by mass percentage:

[0110] Glyceryl stearate 1.50%;

[0111] Medium-chain triglycerides 1.20%;

[0112] Cholesterol 0.60%;

[0113] Polyethylene glycol 400 2.00%;

[0114] DSPE-PEG2000-γ-PGA 0.25%;

[0115] Poloxamer 0.50%;

[0116] PB buffer (pH 6.8) 4.00%;

[0117] Add purified water to bring the volume to 100%.

[0118] The sodium fusidate is incorporated into the nano-slurry during preparation to achieve loading, with a mass ratio of 2:6, and includes the following steps:

[0119] S1. Weigh out glyceryl monostearate, medium-chain triglycerides, cholesterol and DSPE-PEG2000-γ-PGA, mix them and place them in a water bath, heat to 72°C, stir evenly to obtain a molten lipid phase;

[0120] S2. Weigh poloxamer and dissolve it in purified water preheated to 72°C to obtain a preheated water phase;

[0121] Maintaining a shear rate of 10,000 rpm at 72°C, the preheated hot water phase was injected into the molten lipid phase at a rate of 5 mL / min. After the preheated hot water phase was completely injected, the shear rate was maintained for 3 min to form the colostrum.

[0122] S3. Quickly transfer the colostrum to an ice-water bath and stir continuously at 200 rpm for 8 min. Then, use a high-pressure homogenizer at 10,000 psi for 2 cycles to obtain a blank lipid nanoparticle suspension.

[0123] S4. Add PB buffer and sodium fusidate to the above blank lipid nanoparticle suspension, stir well, and place in a constant temperature shaker at 50°C and 200 rpm for 45 min.

[0124] S5. After incubation, add PEG400 to the system, stir at room temperature for 200 rpm for 20 min to obtain nano-slurry loaded with sodium fusidate.

[0125] Sodium fusidate ointment comprises the following ingredients by weight percentage:

[0126] Liquid paraffin 15.00%;

[0127] Glyceryl stearate 3.00%;

[0128] Cetearyl alcohol 5.00%;

[0129] The nano-slurry loaded with sodium fusidate was 8.00% (i.e., sodium fusidate was 2%, nano-slurry was 6%, and the ratio of the two was 2:6).

[0130] Antioxidant (Vitamin E) 0.10%;

[0131] Preservative (ethylparaben) 0.10%;

[0132] Soy lecithin 0.20%;

[0133] White petroleum jelly was added to bring the total to 100%.

[0134] This sodium fusidate ointment was prepared by the following method:

[0135] S1. Weigh out white petrolatum, liquid paraffin, glyceryl monostearate, cetearyl alcohol, and soybean lecithin according to the proportions, add them to the oil phase pot, and stir at 75°C and 50 rpm for 15 minutes.

[0136] S2. Add vitamin E and ethylparaben to the oil phase pot, keep the temperature at 75℃, stir at 50 rpm for 5 minutes;

[0137] S3. Keep stirring at 100 rpm and let it cool naturally to 40-45℃.

[0138] S4. Add the prepared nano-slurry loaded with sodium fusidate into the oil phase pot, and stir at 45°C and 300 rpm for 20 min.

[0139] S5. Transfer the system to a shear emulsifier and homogenize at 5000 rpm for 8 min.

[0140] S6. Transfer the system to a vacuum degassing device, degas at -0.08MPa, 50rpm for 10min, then keep stirring at low speed to allow the paste to cool to room temperature;

[0141] S7: Fill, seal, and label the ointment after it has cooled to room temperature.

[0142] Example 3

[0143] Nanoparticle slurry, comprising the following raw materials by mass percentage:

[0144] Glyceryl stearate 1.80%;

[0145] Medium-chain triglycerides 1.00%;

[0146] Cholesterol 0.50%;

[0147] Polyethylene glycol 400 1.50%;

[0148] DSPE-PEG2000-γ-PGA 0.20%;

[0149] Poloxamer 0.60%;

[0150] PB buffer (pH 6.8) 3.00%;

[0151] Add purified water to bring the volume to 100%.

[0152] The sodium fusidate is incorporated into the nano-slurry during preparation to achieve loading, with a mass ratio of 2:8, and includes the following steps:

[0153] S1. Weigh out glyceryl monostearate, medium-chain triglycerides, cholesterol and DSPE-PEG2000-γ-PGA, mix them and place them in a water bath, heat to 72°C, stir evenly to obtain a molten lipid phase;

[0154] S2. Weigh poloxamer and dissolve it in purified water preheated to 72°C to obtain a preheated water phase;

[0155] Maintaining a shear rate of 10,000 rpm at 72°C, the preheated hot water phase was injected into the molten lipid phase at a rate of 5 mL / min. After the preheated hot water phase was completely injected, the shear rate was maintained for 3 min to form the colostrum.

[0156] S3. Quickly transfer the colostrum to an ice-water bath and stir continuously at 200 rpm for 8 min. Then, use a high-pressure homogenizer at 10,000 psi for 2 cycles to obtain a blank lipid nanoparticle suspension.

[0157] S4. Add PB buffer and sodium fusidate to the above blank lipid nanoparticle suspension, stir well, and place in a constant temperature shaker at 50°C and 200 rpm for 45 min.

[0158] S5. After incubation, add PEG400 to the system, stir at room temperature for 200 rpm for 20 min to obtain nano-slurry loaded with sodium fusidate.

[0159] Sodium fusidate ointment comprises the following ingredients by weight percentage:

[0160] Liquid paraffin 10.00%;

[0161] Glyceryl stearate 5.00%;

[0162] Cetearyl alcohol 8.00%;

[0163] The nano-slurry loaded with sodium fusidate was 10.00% (i.e., sodium fusidate was 2%, nano-slurry was 8%, and the ratio of the two was 2:8).

[0164] Soy lecithin 0.15%;

[0165] Antioxidant (Vitamin E) 0.25%;

[0166] Preservative (ethylparaben) 0.25%;

[0167] White petroleum jelly was added to bring the total to 100%.

[0168] This sodium fusidate ointment was prepared by the following method:

[0169] S1. Weigh out white petrolatum, liquid paraffin, glyceryl monostearate, cetearyl alcohol, and soybean lecithin according to the proportions, add them to the oil phase pot, and stir at 75°C and 50 rpm for 15 minutes.

[0170] S2. Add vitamin E and ethylparaben to the oil phase pot, keep the temperature at 75℃, stir at 50 rpm for 5 minutes;

[0171] S3. Keep stirring at 100 rpm and let it cool naturally to 40-45℃.

[0172] S4. Add the prepared nano-slurry loaded with sodium fusidate into the oil phase pot, and stir at 45°C and 300 rpm for 20 min.

[0173] S5. Transfer the system to a shear emulsifier and homogenize at 5000 rpm for 8 min.

[0174] S6. Transfer the system to a vacuum degassing device, degas at -0.08MPa, 50rpm for 10min, then keep stirring at low speed to allow the paste to cool to room temperature;

[0175] S7: Fill, seal, and label the ointment after it has cooled to room temperature.

[0176] Test Example 1: Analysis of Antibacterial Test

[0177] Experimental Group 1: Example 1: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer with a pH of 5.8.

[0178] Experimental Group 2: Example 2: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 5.8.

[0179] Experimental Group 3: Example 3: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 5.8.

[0180] Experimental Group 4: Example 1: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.0.

[0181] Experimental Group 5: Example 2: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.0.

[0182] Experimental Group 6: Example 3: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.0.

[0183] Experimental Group 7: Example 1: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.5.

[0184] Experimental Group 8: Example 2: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.5.

[0185] Experimental Group 9: Example 3: Sodium fusidic acid ointment. The buffer solution used in subsequent experiments was PB buffer solution with a pH of 6.5.

[0186] Positive control: Commercially available sodium fusidate ointment; the buffer solution used in subsequent experiments was PB buffer with a pH of 6.2.

[0187] Negative control: blank matrix, i.e., the nano-slurry loaded with sodium fusidate in Example 2 was replaced with an equal amount of white petrolatum.

[0188] Experimental steps:

[0189] S1. Spread 100 μL of 1×10⁻⁶ agar onto the cooled MH agar plate. 7 Staphylococcus aureus bacterial suspension at cfu / mL;

[0190] S2. Weigh 1.0g of the ointment product, add 10mL of sterile PB buffer, and stir in a 37℃ water bath at 100rpm for 30 minutes.

[0191] S3. Add 100 μL of ointment solution to the well of an agar plate, diffuse at 4°C for 2 hours, and then incubate at 35°C upside down for 24 hours.

[0192] The results are as follows:

[0193] The diameter of the inhibition zones in experimental groups 1-3 was 14.45-16.38 mm;

[0194] The diameter of the inhibition zone in experimental groups 4-6 was 21.75-23.49 mm;

[0195] The diameter of the inhibition zone in experimental groups 7-9 was 22.84-24.16 mm;

[0196] The diameter of the inhibition zone in the positive control group was 24.50 mm;

[0197] No obvious inhibition zone was observed in the negative control group.

[0198] The experimental results showed that the antibacterial effect of experimental groups 1-3, 4-6, and 7-9 increased sequentially. At pH 5.8, the inhibition zone of each experimental group was the smallest, indicating that the drug release was low and effectively avoiding ineffective distribution and waste of the drug on healthy tissue. As the pH value increased to 6.0, the diameter of the inhibition zone increased significantly, indicating that it could respond quickly and trigger drug release. When the pH reached 6.5, the increase in the diameter of the inhibition zone decreased significantly, gradually approaching that of the commercially available positive control ointment, indicating that its drug release rate was approaching the upper limit.

[0199] In addition, in other control experiments, in the above-mentioned preparation method of DSPE-PEG2000-γ-PGA, if the molecular weight of γ-PGA is 70kDa, the molar ratio of DSPE-PEG2000-NH2 to γ-PGA carboxyl groups is 1:5, and the pH is below 5.5; in the above-mentioned preparation method of DSPE-PEG2000-γ-PGA, if the molecular weight of PEG is 600Da (i.e., PEG600 is used), the molecular weight of γ-PGA is 12kDa, the molar ratio of DSPE-PEG600-NH2 to γ-PGA carboxyl groups is 1:25, and the pH of PB buffer is 7.0, the difference in the inhibition zone between the experimental group and the positive control is still 12.23%.

[0200] Test Example 2: Transdermal Test

[0201] 1. Experimental conditions

[0202] The area covered by the medicine was 1.77 cm². 2 A Franz diffusion cell with a receiving volume of 8 mL was used, with the skin of Bama miniature pigs (one month old) as the osmotic barrier, at a concentration of 10 mg / cm³. 2 The drug was applied at a dose of 17.7 mg, and the receiving solution was physiological saline for in vitro transdermal testing. The temperature was set at 32℃, the rotation speed at 600 rpm, and the sampling time points were 4, 8, 12, and 24 hours.

[0203] 2. Skin Selection

[0204] This experiment selected pig skin as the osmotic barrier.

[0205] 3. Skin source

[0206] Bama miniature pigs (one month old) should be frozen at -5℃ and used within two months.

[0207] 4. Skin treatment

[0208] Before use, place the whole piece of Bama miniature pig skin in physiological saline and thaw at room temperature. Then, cut along the spine of the pig skin from top to bottom towards the abdomen, cutting the skin into round pieces with a diameter of approximately 3cm. Place these pieces in physiological saline for later use. Ensure that adjacent pieces of skin are evenly distributed among the different preparations to guarantee relative consistency. Before applying the medication, blot the skin surface dry with absorbent paper and check the integrity and thickness of the skin.

[0209] 5. Percutaneous percutaneous penetration test of isolated porcine skin

[0210] Place the treated pig skin on clean absorbent paper with the stratum corneum facing upwards, and fix the quantitative loop in the center of the skin. Add 10 μL of PB buffer solution (pH 6.0) to the stratum corneum of the skin, let it stand for 2 minutes, and then use a suitable application tool to evenly spread the preparation on the stratum corneum of the skin. The amount of medication applied is 17.7 mg.

[0211] After drug application, the medicated skin was placed in the transdermal device, with the medicated layer facing upwards towards the sample cell and the unmedicated layer facing downwards towards the receiving cell. The receiving cell was filled with degassed receiving solution. The receiving cell was placed in a 32°C heating block, and a magnetic stirrer was turned on for continuous stirring at 600 rpm. All receiving solution was collected at 4, 8, 12, and 24 hours, and an equal volume of constant-temperature receiving solution was added. Transdermal diffusion apparatus parameters were set as follows: lubrication volume: 1.5 mL, filling volume: 1.5 mL, sampling volume: 5.0 mL, replenishment volume: 8.5 mL, and "Go to Waste" selected. The receiving solution was stored at 5°C for later processing and analysis. The experiment was terminated after 24 hours.

[0212] 6. Collection of residual samples from the skin

[0213] Follow the procedure described under “5. Percutaneous Permeation Test of Isolated Porcine Skin”. Use a pipette to transfer 1 mL of diluent (water:methanol:acetonitrile = 20:50:30) into the supply pool, and gently scrape the skin surface with a small spoon to dilute as much of the remaining ointment on the skin surface as possible into the diluent. Transfer the diluent containing the remaining ointment to a 50 mL volumetric flask and repeat the above cleaning operation 5 times.

[0214] Place the measuring loop in the corresponding numbered beaker, add diluent, vortex the beaker for 15 seconds, and use the same pipette to transfer the liquid from the beaker to a 50 mL volumetric flask. Repeat this process three times. Sonicate the volumetric flask for 30 minutes, remove it, add an appropriate amount of diluent to the beaker, and dilute to the mark with the diluent from the beaker. Filter using a 0.22 μm PTFE syringe filter, discard 2 mL of the initial filtrate, and collect the subsequent filtrate. Let it stand at room temperature until analysis.

[0215] 7. Extraction of drugs retained in the skin

[0216] Following the procedure described under "6. Collection of Residual Samples on Skin," blot away any residual solvent from the skin surface with absorbent paper after the test. Cut off the outer portion of the skin that did not directly contact the sample, retaining only the skin area equal to the pool opening size (i.e., 1.77 cm). 2 Weigh the treated skin, then cut it into strips and place it in a grinding cup. Freeze with liquid nitrogen for at least 1 hour.

[0217] After freezing, the skin was ground into powder using a cryo-abrasive, added to 25 mL of diluent, and sonicated for 5 minutes. The EP tube was then shaken up and down and sonicated again for 5 minutes. An appropriate amount was filtered through a 0.22 μm PTFE needle filter to obtain the skin extract, which was then ready for testing.

[0218] Ointment content test: Weigh approximately 17.7 mg of sample into a 10 mL EP tube, add 8 mL of diluent to dissolve, vortex for 2 min, and then transfer the solution to a 50 mL volumetric flask. Repeat the above washing operation 5 times. Then, dilute to the mark with diluent, shake well, sonicate for 10 min, filter using a 0.22 μm PTFE needle filter, discard 2 mL of the initial filtrate, and keep the subsequent filtrate at room temperature for later use.

[0219] The transdermal penetration rate of the sample in Example 1 was 4.15 μg / cm. 2 / h, the skin retention rate over 24 hours was 82.60%;

[0220] The transdermal penetration rate of the sample in Example 2 was 3.85 μg / cm. 2 / h, the skin retention rate over 24 hours was 85.29%;

[0221] The transdermal penetration rate of the sample in Example 3 was 4.22 μg / cm. 2 / h, the skin retention rate over 24 hours was 80.10%;

[0222] The transdermal penetration rate of commercially available products is 9.61 μg / cm. 2 / h, 24h skin retention rate 45.30%.

[0223] Permeation Control 1: Based on Example 2, sodium fusidate (2%) was used to replace the nano-slurry containing sodium fusidate, and the remainder was replaced with an equal amount of white petrolatum. The transdermal penetration rate was reduced to 2.10 μg / cm. 2 / h, and 24h skin retention 45.80%;

[0224] Permeation Control 2: The formulation is as follows: sodium fusidate 2.00%, liquid paraffin 18.00%, lanolin 8.00%, cetyl alcohol 5.00%, and white petrolatum to 100%. The transdermal penetration rate was 9.45 μg / cm. 2 / h, 24h skin retention rate 48.55%;

[0225] Permeation Control 3: The difference from Example 2 lies in the formulation of the ointment base. The nano-slurry loaded with sodium fusidate contained 8.00%, glyceryl monostearate 8.00%, cetearyl alcohol 12.00%, soybean lecithin 0.20%, vitamin E 0.10%, ethylparaben 0.10%, and white petrolatum to bring the total to 100%. The transdermal penetration rate decreased to 1.25 μg / cm³. 2 / h, 24h skin retention rate 35.27%;

[0226] Comparing Example 2 with Permeation Control 1, it can be seen that, with the ointment base system being exactly the same, free sodium fusidate alone performed poorly, with the 24-hour skin retention rate decreasing from 85.29% to 45.80%. This indicates that sodium fusidate must rely on a lipid fusion and epidermal anchoring mechanism mediated by nanoparticles to effectively lock the drug into the epidermal layer.

[0227] Comparing Example 2 with commercially available products and Penetration Control 2, it can be seen that although traditional oily ointments (containing lanolin to enhance penetration) have a fast transdermal penetration rate of 9.45 μg / cm³, 2 While the transdermal absorption rate is typically 1.5 μg / cm³, the drug readily penetrates the epidermis and enters the dermis and even the systemic circulation, resulting in less than 50% retention in the skin. This not only wastes the effective local concentration but also increases the potential risk of systemic absorption. The nano-formulation of this invention successfully reduces the transdermal absorption rate to 3.85 μg / cm³. 2 / h, while increasing the retention rate to 85.29%, achieving targeted delivery with high epidermal accumulation and low deep penetration.

[0228] Comparing Example 2 with Permeation Control 3, it is evident that even with the retention of the nanoparticle components, an imbalance in the matrix ratio, such as excessively increasing glyceryl monostearate and cetearyl alcohol while reducing white petrolatum, leads to an overly dense microstructure in the ointment. This dense microstructure locks the drug within the matrix, causing the transdermal penetration rate to decrease to 1.25 μg / cm³. 2 / h, the skin retention rate decreased to 35.27%.

[0229] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0230] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A sodium fusidate ointment, wherein the sodium fusidate content in the ointment is 2% by mass; characterized in that: The sodium fusidate is loaded into a nano-slurry containing DSPE-PEG2000-γ-PGA, wherein the DSPE-PEG2000-γ-PGA accounts for 0.2%–0.3% of the mass of the nano-slurry, and the nano-slurry loaded with sodium fusidate is uniformly dispersed in the ointment matrix.

2. The sodium fusidic acid ointment as described in claim 1, characterized in that: The nano-slurry comprises the following raw materials by mass percentage: Glyceryl stearate 1.50%-1.80%; Medium-chain triglycerides: 1.00%-1.20%; Cholesterol 0.50%-0.80%; Polyethylene glycol 400: 1.50%-2.00%; DSPE-PEG2000-γ-PGA0.20%-0.30%; Poloxamer 0.50%-0.60%; Phosphate buffer solution with pH 6.5-6.8, 3.00%-5.00%; The remaining amount of purified water.

3. The sodium fusidic acid ointment as described in claim 2, characterized in that: The nano-slurry comprises the following raw materials by mass percentage: Glyceryl stearate 1.50%; Medium-chain triglycerides 1.20%; Cholesterol 0.60%; Polyethylene glycol 400 2.00%; DSPE-PEG2000-γ-PGA 0.25%; Poloxamer 0.50%; 4.00% phosphate buffer solution with pH 6.5-6.8; The remaining amount of purified water.

4. A sodium fusidate ointment as described in claim 2 or 3, characterized in that: The sodium fusidic acid is incorporated into the nano-slurry during preparation to achieve loading, including the following steps: S1. Weigh out glyceryl monostearate, medium-chain triglycerides, cholesterol and DSPE-PEG2000-γ-PGA, mix them and place them in a water bath, heat to 70-75℃, stir evenly to obtain a molten lipid phase; S2. Weigh poloxamer and dissolve it in purified water preheated to 70-75℃ to obtain a preheated hot water phase; Maintain a shear rate of 8000-10000 rpm at 70-75℃, and inject the preheated hot water phase into the molten lipid phase at a rate of 2-5 mL / min. After the preheated hot water phase is completely injected, maintain this shear rate for 3-5 min to form the colostrum. S3. Quickly transfer the colostrum to an ice-water bath and stir continuously at 200-400 rpm for 5-8 minutes. Then, use a high-pressure homogenizer at 10,000-12,000 psi for at least two cycles to obtain a blank lipid nanoparticle suspension. S4. Add phosphate buffer and sodium fusidate to the above blank lipid nanoparticle suspension, stir well, and place in a constant temperature shaker at 40-50℃ and 200-400 rpm for 30-60 min. S5. After incubation, add PEG400 to the system, stir at room temperature for 200-400 rpm for 15-20 min to obtain nano-slurry loaded with sodium fusidate.

5. A sodium fusidic acid ointment as described in claim 2 or 3, characterized in that: The ointment base comprises liquid paraffin, glyceryl monostearate, cetearyl alcohol, and white petrolatum; The ointment comprises the following ingredients by weight percentage: Liquid paraffin 10.00%-15.00%; Glyceryl stearate 3.00%-5.00%; Cetearyl alcohol 5.00%-8.00%; The nano-slurry loaded with sodium fusidate has a content of 8.00%-10.00%; Antioxidant content: 0.10%-0.25%; Preservatives: 0.10%-0.25%; Remaining amount of white petroleum jelly.

6. The sodium fusidic acid ointment as described in claim 5, characterized in that: The ointment base contains soy lecithin, and the amount of soy lecithin added is 0.1%-0.2% of the ointment mass.

7. The sodium fusidic acid ointment as described in claim 6, characterized in that: The sodium fusidate ointment comprises the following ingredients by weight percentage: Liquid paraffin 15.00%; Glyceryl stearate 3.00%; Cetearyl alcohol 5.00%; The nano-slurry loaded with sodium fusidate had a content of 8.00%. Antioxidant 0.10%; Preservative 0.10%; Soy lecithin 0.20%; Remaining amount of white petroleum jelly.

8. The sodium fusidic acid ointment as described in claim 7, characterized in that: The antioxidant is selected from vitamin E, vitamin C, propyl gallate, butyl anisole, citric acid, or combinations thereof.

9. The sodium fusidic acid ointment as described in claim 7, characterized in that: The preservative is selected from methylparaben, ethylparaben, phenoxyethanol, or a combination thereof.

10. The sodium fusidic acid ointment as described in claim 7, characterized in that: This sodium fusidate ointment was prepared by the following method: S1. Weigh out white petrolatum, liquid paraffin, glyceryl monostearate, cetearyl alcohol and soybean lecithin according to the ratio, add them to the oil phase pot, stir at 70-75℃ and 50-100 rpm for 10-15 minutes. S2. Add antioxidants and preservatives to the oil phase pot, maintain the temperature at 70-75℃, stir at 50-100 rpm for 5 minutes; S3. Keep stirring at 50-100 rpm and let it cool naturally to 40-45℃. S4. Add the prepared nano-slurry loaded with sodium fusidate into the oil phase pot, stir at 40-45℃ and 300-500 rpm for 15-20 min. S5. Transfer the system to a shear emulsifier and homogenize at 3000-5000 rpm for 5-10 min. S6. Transfer the system to a vacuum degassing device, -0.06~-0.08MPa, 50-100rpm, degas for 10-15min, then keep stirring at low speed to allow the paste to cool to room temperature; S7: Fill, seal, and label the ointment after it has cooled to room temperature.