Nano drug-loaded nasal spray composition for treating nasosinusitis and preparation method thereof

Abstract

The invention discloses a nano drug-loaded nasal spray composition for treating nasosinusitis. The nano drug-loaded nasal spray composition is prepared from the following raw materials: nano silver, PVP (Polyvinyl Pyrrolidone), baicalin, flos magnoliae volatile oil, chitosan, PLGA (Poly (Lactic-co-Glycolic Acid), sodium hyaluronate, a citrate buffer solution and the balance of sterile normal saline. The invention also discloses a preparation method of the nano drug-loaded nasal spray composition for treating nasosinusitis, the preparation method comprises the following steps: firstly preparing PVP modified nano silver suspension, then preparing baicalin nanoparticles and magnolia flower volatile oil nanoparticles by adopting an emulsification-solvent evaporation method, and PVP is used as a stabilizer of nano silver to ensure the long-term dispersion stability of nano silver, so that the stability of the nano silver is ensured, and the stability of the nano silver is ensured. Finally, all the components are mixed in a sterile operation table, the pH is adjusted, filtration sterilization is conducted through a 0.22-micron sterile filter membrane, terminal sterilization is conducted through gamma-ray irradiation after split charging is conducted, and the final product can be prepared into quantitative spray or sterile nose drops to meet different clinical requirements.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a nano-drug-loaded nasal spray composition for treating sinusitis and its preparation method. Background Technology

[0002] Sinusitis, a common upper respiratory tract disease, is characterized by inflammation of the sinus mucosa, abnormal mucus secretion, bacterial or fungal infection, and biofilm formation. Clinical treatment currently faces numerous challenges. Traditional antibiotic nasal drops, such as mupirocin and gentamicin, are easily cleared by nasal cilia, leading to insufficient local drug concentrations. Long-term use can also induce the growth of drug-resistant bacteria such as MRSA and Pseudomonas aeruginosa, especially after biofilm formation, which significantly reduces drug permeability. While glucocorticoids like budesonide are effective in reducing inflammation, long-term use may cause side effects such as mucosal atrophy and local immunosuppression. Although active ingredients in traditional Chinese medicine, such as baicalin and magnolia oil, possess multi-target anti-inflammatory and antibacterial effects, their clinical application is limited by poor water solubility, low mucosal permeability, and insufficient stability. Traditional decoctions or alcohol extracts also struggle to achieve precise delivery, resulting in unstable drug efficacy. Summary of the Invention

[0003] The purpose of this invention is to provide a nano-drug-loaded nasal spray composition for treating sinusitis and its preparation method. This invention constructs a novel sinusitis treatment system that can penetrate the mucus barrier, deliver drugs in a targeted manner, and synergistically exert anti-inflammatory and antibacterial effects. It not only solves the problem of low efficiency in traditional drug delivery, but also achieves multi-component synergistic treatment through the integration of traditional Chinese medicine and nanotechnology, providing a brand-new solution for the treatment of sinusitis, especially refractory sinusitis.

[0004] To achieve the above objectives, the solution of the present invention is: A nano-drug-loaded nasal spray composition for treating sinusitis, comprising, by weight percentage, the following raw materials: 0.002 wt %~0.008 wt % nano silver, 0.1 wt % polyvinylpyrrolidone, 0.3 wt %~1.5 wt % Baicalin, 0.1 wt %~0.4 wt % Magnolia biondii volatile oil, 0.5 wt %~3 wt % chitosan, 0.5 wt %~2 wt % PLGA (polylactic acid-glycolic acid copolymer), 0.05 wt %~0.3 wt % Sodium Hyaluronate, 0.15 wt %~0.25 wt % citrate buffer and the remainder sterile saline.

[0005] The citrate buffer solution comprises citric acid and sodium citrate in a mass ratio of 2:1.

[0006] A method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis includes the following steps: Step 1: Preparation of polyvinylpyrrolidone (PVP) modified silver nanoparticle suspension: First, silver nitrate solution and PVP are mixed at a mass ratio of 1:5 to 1:10. Ascorbic acid is added, and the mixture is stirred in a water bath at 55-65℃ for 25-30 minutes. After centrifugation, the PVP-modified silver nanoparticles are collected. Then, the PVP-modified silver nanoparticles are placed in a 0.1... wt The sterile saline solution was redispersed to the required concentration to obtain a PVP-modified silver nanoparticle suspension, wherein the average particle size of the silver nanoparticles was controlled at 20-40 nm and D90 < 50 nm. Step 2: Preparation of baicalin nanoparticles: Then, PLGA:baicalin:chitosan were dissolved in an appropriate amount of dichloromethane as the oil phase at a mass ratio of 4~6:2~4:1~3. The mixture was emulsified at 10000~15000 rpm or under the action of ultrasound probe. The emulsion was then poured into an aqueous solution containing 0.5%~1.0% (w / v) PVA. The dichloromethane was evaporated at 40~45℃ with stirring for 1.5~2 hours. The resulting emulsion was centrifuged, the precipitate was collected and washed 1~2 times with deionized water to obtain baicalin nanoparticles, which were then dispersed in a small amount of sterile water for later use. Step 3: Preparation of Magnolia biondii volatile oil nanoparticles: Then, magnolia volatile oil and PLGA were dissolved in an appropriate amount of ethyl acetate at a mass ratio of 1:3~5 as the oil phase. The oil phase was then slowly injected into an aqueous solution containing 1%~2% (w / v) Tween-80. The mixture was emulsified for 1~3 minutes at a speed of 10000~15000 rpm or under the action of ultrasound probe. Then, the mixture was stirred at 40~50℃ for 2~4 hours to allow the ethyl acetate to evaporate. The resulting emulsion was centrifuged, the precipitate was collected and washed 1~2 times with deionized water, and then freeze-dried to obtain magnolia volatile oil nanoparticles with a particle size of 80~120 nm. These nanoparticles were then dispersed in a small amount of sterile water for later use. Step 4, Mixing and Formulation: Finally, the PVP-modified silver nanoparticle suspension obtained in step 1, the baicalin nanoparticle dispersion obtained in step 2, and the magnolia volatile oil nanoparticle dispersion obtained in step 3 were mixed after their volumes were precisely calculated according to their concentrations and target final contents. Sterile physiological saline containing sodium hyaluronate and citrate buffer were added, and the pH of the system was adjusted to 4.5-5.5 with dilute hydrochloric acid or sodium hydroxide solution. Sterile physiological saline was then added to bring the total volume to 100%. The mixture was filtered through a 0.22 μm sterile filter membrane for sterilization, then subjected to gamma irradiation sterilization, and dispensed into a spray or nasal drops, i.e., this nano-drug-loaded nasal spray composition, comprising the following raw materials by weight percentage: 0.002 wt %~0.008 wt % nano silver, 0.1 wt % polyvinylpyrrolidone, 0.3 wt %~1.5 wt % Baicalin, 0.1 wt %~0.4 wt % Magnolia biondii volatile oil, 0.5 wt %~3 wt % chitosan, 0.5 wt %~2 wt % PLGA, 0.05 wt %~0.3 wt % Sodium Hyaluronate, 0.15 wt %~0.25 wt % citrate buffer and the remainder sterile saline.

[0007] In step 1, the molecular weight of the PVP is 40 kDa.

[0008] In step 1, the molar ratio of ascorbic acid to silver nitrate in the silver nitrate solution is approximately 2:1.

[0009] In step 1, the concentration of nano-silver in the nano-silver suspension is 5 to 20 times that of nano-silver in the final nano-drug-loaded nasal spray composition.

[0010] In step 1, the centrifugation speed is 10,000 to 12,000 rpm, and the centrifugation time is 15 to 25 minutes.

[0011] In step 2, the ultrasonic power of the probe is 100~200 W.

[0012] In step 2, the centrifugation speed is 10,000 to 15,000 rpm, and the centrifugation time is 10 to 20 minutes.

[0013] In step 2, the volume of dichloromethane added is 10 to 20 times the sum of the mass of PLGA, baicalin, and chitosan, and the volume of the PVA aqueous solution added is 5 to 10 times the volume of the oil phase.

[0014] In step 3, the volume of ethyl acetate added is 10 to 20 times the total mass of Magnolia biondii volatile oil and PLGA, and the volume of the Tween-80 aqueous solution added is 5 to 20 times the volume of the oil phase.

[0015] In step 3, the ultrasonic power of the probe is 200~300 W.

[0016] In step 3, the centrifugation speed is 10,000 to 15,000 rpm, and the centrifugation time is 10 to 20 minutes.

[0017] In step 4, the sodium hyaluronate is pre-dissolved in a small amount of sterile saline, with a concentration not exceeding 5% (w / v); the citrate buffer is prepared by dissolving citric acid and sodium citrate in sterile water at a mass ratio of 2:1.

[0018] In step 4, the irradiation dose for γ-irradiation sterilization is 25 kGy.

[0019] With the above technical solution, the present invention provides a nano-drug-loaded nasal spray composition for treating sinusitis, wherein nano-silver is the core antibacterial component, with an average particle size controlled within the range of 20-40 nm and D90 < 50 nm. Stable dispersion is ensured by surface modification with polyvinylpyrrolidone (PVP). Nano-silver achieves broad-spectrum antibacterial effect by releasing silver ions, and has a significant inhibitory effect on a variety of pathogenic microorganisms, including drug-resistant bacteria. At the same time, it can destroy the biofilm structure and enhance drug permeability. Baicalin (which can be obtained from Scutellaria baicalensis using commercially available raw materials that meet pharmaceutical standards, or extracted from Scutellaria baicalensis using conventional macroporous resin purification technology) has a significant anti-inflammatory effect by inhibiting the downregulation of inflammatory factors (such as TNF-α and IL-6) through the NF-κB pathway. It can inhibit the release of inflammatory factors and reduce sinus mucosal edema. Magnolia biondii volatile oil (which can be obtained from Magnolia biondii using commercially available raw materials that meet pharmaceutical standards, or extracted from Magnolia biondii using conventional steam distillation or supercritical CO2 extraction technology) can promote ciliary movement and improve nasal ventilation. Chitosan, as the main carrier material, has good biocompatibility and mucosal affinity, which can prolong the residence time of drugs in the nasal cavity. PLGA (polylactic acid-glycolic acid copolymer), as a synthetic polymer material, can realize the sustained release function of drugs and maintain a stable therapeutic concentration. Sodium hyaluronate, as a moisturizer, can maintain the moisture of the nasal mucosa and reduce dryness and discomfort. Citrate buffer is used to maintain the system pH in the range of 4.5 to 5.5 to ensure the stability of each component.

[0020] Therefore, this invention provides a nano-drug-loaded nasal spray composition for treating sinusitis. Utilizing the synergistic effect of nano-silver and active ingredients of traditional Chinese medicine (baicalin and magnolia oil), it exhibits significant efficacy in treating sinusitis. This drug delivery system achieves targeted delivery and sustained release of nano-silver and traditional Chinese medicine ingredients through polymer nanoparticles (chitosan / PLGA) carriers, enabling antibacterial, anti-inflammatory, and immunomodulatory functions to work synergistically. This "antibacterial-anti-inflammatory-repair" three-in-one treatment model leverages the powerful antibacterial advantages of nano-silver while enhancing the overall therapeutic effect through traditional Chinese medicine ingredients, providing a novel solution for the treatment of sinusitis, especially refractory sinusitis. Detailed Implementation

[0021] To further explain the technical solution of the present invention, the present invention will be described in detail below through specific embodiments.

[0022] Example 1 A method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis includes the following steps: Step 1: Prepare a PVP-modified silver nanoparticle suspension (target final content of silver nanoparticles is 0.003). wt (10 times the amount of feed) First, transfer 0.3 mL of a 0.1 g / mL silver nitrate solution (containing 0.03 g Ag) and mix it with polyvinylpyrrolidone (PVP) with a molecular weight of 40 kDa at a mass ratio of 1:8 (i.e., PVP is 0.3816 g). Add 0.12 g ascorbic acid, stir and react in a 55°C water bath for 30 minutes, centrifuge at 12000 rpm for 15 minutes, and collect the PVP-modified silver nanoparticles. Then, disperse the PVP-modified silver nanoparticles in 100 mL of sterile physiological saline to obtain a PVP-modified silver nanoparticle suspension (concentration approximately 0.03 g / mL). wt (% Ag), the average particle size of the nano-silver is controlled at 20~40 nm, and D90 < 50 nm; Step 2: Preparation of baicalin nanoparticles (target final content of baicalin is 0.5%) wt (10 times the amount of feed) Then, 0.5g PLGA, 0.3g baicalin, and 0.2g chitosan were weighed and dissolved in 20 mL of dichloromethane. After emulsification for 1 minute under ultrasonication with a 150W probe, the resulting organic phase was poured into 200 mL of an aqueous solution containing 0.5% PVA (w / v). The dichloromethane was volatilized for 2 hours at 40℃ with magnetic stirring. The mixture was then centrifuged at 12000 rpm for 15 minutes. The precipitate was collected and washed twice with deionized water to obtain baicalin nanoparticles, which were then dispersed in 10 mL of sterile water for later use. Step 3: Prepare Magnolia biondii volatile oil nanoparticles (target final content of Magnolia biondii volatile oil 0.2). wt (10 times the amount of feed) Then, 0.2g of Magnolia biondii volatile oil and 0.8g of PLGA were weighed and dissolved in 10 mL of ethyl acetate as the oil phase. The oil phase was slowly injected into 150 mL of aqueous phase containing 1% (w / v) Tween-80. The mixture was emulsified in a high-speed homogenizer at 12000 rpm for 2 minutes and stirred at 40℃ for 3 hours to allow the ethyl acetate to evaporate. The mixture was centrifuged at 12000 rpm for 15 minutes, the precipitate was collected and washed twice with deionized water, and then freeze-dried to obtain Magnolia biondii volatile oil nanoparticles with a particle size of 80~120 nm. These nanoparticles were then dispersed in 10 mL of sterile water for later use. Step 4, Mixing and Formulation: Finally, take 1 mL of the nano-silver suspension (containing ~0.003 g Ag) prepared in step 1, 10 mL of the baicalin nanoparticle dispersion prepared in step 2 (containing ~0.05 g baicalin), and 10 mL of the magnolia volatile oil nanoparticle dispersion prepared in step 3 (containing ~0.02 g magnolia volatile oil). Mix them thoroughly, add 0.1 g of sodium hyaluronate pre-dissolved in 5 mL of sterile physiological saline, and 10 mL of citrate buffer (prepared by dissolving 0.133 g citric acid and 0.067 g sodium citrate in 10 mL of sterile water) (i.e., containing approximately 0.2 g of citrate buffer). Adjust the pH of the system to 5.0 with dilute hydrochloric acid or sodium hydroxide solution, and add sterile physiological saline to a final volume of 100 g. After sterilization by filtration through a 0.22 μm sterile filter membrane, dispense (e.g., 5 mL / bottle), and then subject to irradiation at a dose of 25. Sterilization by γ-irradiation at kGy yields a spray or nasal drop, i.e., the nano-drug-loaded nasal spray composition.

[0023] The contents of each raw material in the obtained nano-drug-loaded nasal spray composition for treating sinusitis are shown in Table 1.

[0024] Example 2 A method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis includes the following steps: Step 1: Prepare a PVP-modified silver nanoparticle suspension (target final content of silver nanoparticles is 0.005). wt (10 times the amount of feed) First, transfer 0.5 mL of a 0.1 g / mL (Ag-based) silver nitrate solution (containing 0.05 g Ag) and mix it with polyvinylpyrrolidone (PVP) of 40 kDa at a mass ratio of 1:6 (i.e., PVP content 0.477 g). Add 0.20 g ascorbic acid, stir and react in a 60°C water bath for 30 minutes, centrifuge at 10000 rpm for 25 minutes, and collect the PVP-modified silver nanoparticles. Then, disperse the PVP-modified silver nanoparticles in 100 mL of sterile physiological saline to obtain a PVP-modified silver nanoparticle suspension (concentration approximately 0.05 g / mL). wt (% Ag), the average particle size of the nano-silver is controlled at 20~40 nm, and D90 < 50 nm; Step 2: Preparation of baicalin nanoparticles (target final content of baicalin is 0.8%) wt (10 times the amount of feed) Then, 1.0 g PLGA, 0.8 g baicalin, and 0.6 g chitosan were weighed and dissolved in 40 mL of dichloromethane. After emulsification for 1 minute under the action of ultrasonication with a 200 W probe, the resulting organic phase was poured into 400 mL of aqueous solution containing 0.8% PVA (w / v). The dichloromethane was volatilized for 1.5 hours under magnetic stirring at 45 °C. The mixture was then centrifuged at 15000 rpm for 10 minutes. The precipitate was collected and washed twice with deionized water to obtain baicalin nanoparticles, which were then dispersed in 10 mL of sterile water for later use. Step 3: Prepare Magnolia biondii volatile oil nanoparticles (target final content of Magnolia biondii volatile oil 0.3%). wt (10 times the amount of feed) Then, 0.3 g of Magnolia biondii volatile oil and 1.2 g of PLGA were weighed and dissolved in 15 mL of ethyl acetate as the oil phase. The oil phase was slowly injected into 150 mL of aqueous phase containing 1.2% (w / v) Tween-80. The mixture was emulsified in a high-speed homogenizer at 15000 rpm for 2 minutes and stirred at 45℃ for 2 hours to allow the ethyl acetate to evaporate. The mixture was centrifuged at 15000 rpm for 20 minutes, the precipitate was collected and washed twice with deionized water, and then lyophilized to obtain Magnolia biondii volatile oil nanoparticles with a particle size of 80~120 nm. These nanoparticles were then dispersed in 10 mL of sterile water for later use. Step 4, Mixing and Formulation: Finally, take 1 mL of the nano-silver suspension (containing ~0.005 g Ag) prepared in step 1, 10 mL of the baicalin nanoparticle dispersion prepared in step 2 (containing ~0.08 g baicalin), and 10 mL of the magnolia volatile oil nanoparticle dispersion prepared in step 3 (containing ~0.03 g magnolia volatile oil). Mix them thoroughly, add 0.2 g sodium hyaluronate pre-dissolved in 5 mL sterile physiological saline, and 10 mL of citrate buffer (prepared by dissolving 0.133 g citric acid and 0.067 g sodium citrate in 10 mL sterile water) (i.e., containing approximately 0.2 g citrate buffer). Adjust the pH of the system to 4.8 with dilute hydrochloric acid or sodium hydroxide solution, and add sterile physiological saline to a final volume of 100 g. After sterilization by filtration through a 0.22 μm sterile filter membrane, dispense (e.g., 5 mL / bottle), and then subject to irradiation at a dose of 25. Sterilization by γ-irradiation at kGy yields a spray or nasal drop, i.e., the nano-drug-loaded nasal spray composition.

[0025] The contents of each raw material in the obtained nano-drug-loaded nasal spray composition for treating sinusitis are shown in Table 1.

[0026] Example 3 A method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis includes the following steps: Step 1: Prepare a PVP-modified silver nanoparticle suspension (target final content of silver nanoparticles is 0.007). wt (10 times the amount of feed) First, 0.7 mL of a 0.1 g / mL silver nitrate solution (containing 0.07 g Ag) was transferred and mixed with polyvinylpyrrolidone (PVP) with a molecular weight of 40 kDa at a mass ratio of 1:7 (i.e., PVP content of 0.779 g). Then, 0.28 g of ascorbic acid was added, and the mixture was stirred in a 60°C water bath for 25 minutes. After centrifugation at 12000 rpm for 15 minutes, PVP-modified silver nanoparticles were collected. These PVP-modified silver nanoparticles were then dispersed in 100 mL of sterile physiological saline to obtain a PVP-modified silver nanoparticle suspension (concentration approximately 0.07 g / mL). wt (% Ag), the average particle size of the nano-silver is controlled at 20~40 nm, and D90 < 50 nm; Step 2: Preparation of baicalin nanoparticles (target final content of baicalin is 1.0). wt (10 times the amount of feed) Then, 1.5g PLGA, 1.0g baicalin, and 0.67g chitosan were weighed and dissolved in 60 mL of dichloromethane. After emulsification for 1 minute under ultrasonication with a 150W probe, the resulting organic phase was poured into 600 mL of an aqueous solution containing 1.0% PVA (w / v). The dichloromethane was volatilized for 2.5 hours at 40℃ with magnetic stirring. The mixture was then centrifuged at 15000 rpm for 10 minutes. The precipitate was collected and washed twice with deionized water to obtain baicalin nanoparticles, which were then dispersed in 10 mL of sterile water for later use. Step 3: Prepare Magnolia biondii volatile oil nanoparticles (target final content of Magnolia biondii volatile oil 0.4%). wt (10 times the amount of feed) Then, 0.4 g of Magnolia biondii volatile oil and 1.6 g of PLGA were weighed and dissolved in 20 mL of ethyl acetate as the oil phase. The oil phase was slowly injected into 200 mL of aqueous phase containing 1% (w / v) Tween-80. The mixture was emulsified in a high-speed homogenizer at 10000 rpm for 1.5 minutes and stirred at 50℃ for 2 hours to allow the ethyl acetate to evaporate. The mixture was centrifuged at 15000 rpm for 10 minutes, the precipitate was collected and washed twice with deionized water. After freeze-drying, Magnolia biondii volatile oil nanoparticles with a particle size of 80~120 nm were obtained and dispersed in 10 mL of sterile water for later use. Step 4, Mixing and Formulation: Finally, take 1 mL of the nano-silver suspension (containing ~0.007 g Ag) prepared in step 1, 10 mL of the baicalin nanoparticle dispersion prepared in step 2 (containing ~0.1 g baicalin), and 10 mL of the magnolia volatile oil nanoparticle dispersion prepared in step 3 (containing ~0.04 g magnolia volatile oil). Mix them thoroughly, add 0.3 g of sodium hyaluronate pre-dissolved in 5 mL of sterile physiological saline, and 10 mL of citrate buffer (prepared by dissolving 0.133 g citric acid and 0.067 g sodium citrate in 10 mL of sterile water) (i.e., containing approximately 0.2 g of citrate buffer). Adjust the pH of the system to 5.2 with dilute hydrochloric acid or sodium hydroxide solution, and add sterile physiological saline to a final volume of 100 g. After sterilization by filtration through a 0.22 μm sterile filter membrane, dispense (e.g., 5 mL / bottle), and then subject to irradiation at a dose of 25. Sterilization by γ-irradiation at kGy yields a spray or nasal drop, i.e., the nano-drug-loaded nasal spray composition.

[0027] The contents of each raw material in the obtained nano-drug-loaded nasal spray composition for treating sinusitis are shown in Table 1.

[0028] Example 4 A method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis includes the following steps: Step 1: Prepare a PVP-modified silver nanoparticle suspension (target final content of silver nanoparticles is 0.004%). wt (10 times the amount of feed) First, transfer 0.4 mL of a 0.1 g / mL silver nitrate solution (containing 0.04 g Ag) and mix it with polyvinylpyrrolidone (PVP) with a molecular weight of 40 kDa at a mass ratio of 1:9 (i.e., PVP is 0.572 g). Add 0.16 g ascorbic acid, stir and react in a 60℃ water bath for 25 minutes, centrifuge at 12000 rpm for 15 minutes, and collect the PVP-modified silver nanoparticles. Then, disperse the PVP-modified silver nanoparticles in 100 mL of sterile physiological saline to obtain a PVP-modified silver nanoparticle suspension (concentration approximately 0.04 g / mL). wt (% Ag), the average particle size of the nano-silver is controlled at 20~40 nm, and D90 < 50 nm; Step 2: Preparation of baicalin nanoparticles (target final content of baicalin is 1.2%) wt (10 times the amount of feed) Then, 1.2g of PLGA, 1.2g of baicalin, and 0.8g of chitosan were weighed and dissolved in 40 mL of dichloromethane. After emulsification for 1 minute under the action of a 150W probe, the resulting organic phase was poured into 240 mL of an aqueous solution containing 0.6% PVA (w / v). The dichloromethane was volatilized for 2 hours under magnetic stirring at 40℃. After centrifugation at 10000 rpm for 20 minutes, the precipitate was collected and washed twice with deionized water to obtain baicalin nanoparticles, which were then dispersed in 10 mL of sterile water for later use. Step 3: Prepare Magnolia biondii volatile oil nanoparticles (target final content of Magnolia biondii volatile oil 0.1%). wt (10 times the amount of feed) Then, weigh 1.0 g of Magnolia biondii volatile oil and 4.0 g of PLGA and dissolve them in 50 mL of ethyl acetate as the oil phase. Slowly inject the oil phase into 50 mL of aqueous phase containing 1% (w / v) Tween-80. Emulsify in a high-speed homogenizer at 10000 rpm for 3 minutes and stir at 40℃ for 4 hours to allow the ethyl acetate to evaporate. Centrifuge at 15000 rpm for 20 minutes, collect the precipitate and wash it twice with deionized water. After freeze-drying, obtain Magnolia biondii volatile oil nanoparticles with a particle size of 80~120 nm, and then disperse them in 10 mL of sterile water for later use. Step 4, Mixing and Formulation: Finally, take 1 mL of the nano-silver suspension (containing ~0.004 g Ag) prepared in step 1, 10 mL of the baicalin nanoparticle dispersion prepared in step 2 (containing ~0.12 g baicalin), and 10 mL of the magnolia volatile oil nanoparticle dispersion prepared in step 3 (containing ~0.01 g magnolia volatile oil). Mix them thoroughly, add 0.2 g of sodium hyaluronate pre-dissolved in 5 mL of sterile physiological saline, and 10 mL of citrate buffer (prepared by dissolving 0.133 g citric acid and 0.067 g sodium citrate in 10 mL of sterile water) (i.e., containing approximately 0.2 g of citrate buffer). Adjust the pH of the system to 5.5 with dilute hydrochloric acid or sodium hydroxide solution, and add sterile physiological saline to a final volume of 100 g. After sterilization by filtration through a 0.22 μm sterile filter membrane, dispense (e.g., 5 mL / bottle), and then subject to irradiation at a dose of 25. Sterilization by γ-irradiation at kGy yields a spray or nasal drop, i.e., the nano-drug-loaded nasal spray composition.

[0029] The contents of each raw material in the obtained nano-drug-loaded nasal spray composition for treating sinusitis are shown in Table 1.

[0030] Table 1. Content of raw materials in each embodiment ( wt %)

[0031] The contents in the table are percentages by weight of the final product. The amount of each intermediate prepared is 10 times the final content. The active ingredients used in this invention, such as baicalin and magnolia flower volatile oil, can be prepared using commercially available raw materials that meet the requirements of the Chinese Pharmacopoeia or relevant pharmaceutical standards (e.g., products from professional plant extract suppliers such as Shaanxi Jiahe Biotechnology Co., Ltd. and Chengdu Purifa Technology Development Co., Ltd.), or by extraction and purification methods well-known to those skilled in the art (e.g., macroporous resin purification, supercritical CO2 extraction, steam distillation, etc.). Their quality and purity must meet the requirements of the formulation. Other raw materials used in this invention are all well-known reagents in the art, such as polyvinylpyrrolidone (PVP K30), chitosan (degree of deacetylation ≥90%), PVA (87~89% degree of hydrolysis), Tween-80, and sodium hyaluronate (molecular weight 1.5×10⁻⁶). 6 All excipients, including Da, are pharmaceutical grade and comply with the standards of the Chinese Pharmacopoeia. All equipment used is known in the field.

[0032] This nano-drug-loaded nasal spray composition has established strict quality control standards: 1. Nano-silver particle size distribution: D90 < 50 nm; 2. Silver ion release rate: ≥ 80% release in 24 hours; 3. Drug loading of PLGA ≥ 90%; 4. Average particle size of nano-silver 25 ± 5 nm, PDI < 0.15 (dynamic light scattering method); 5. Accelerated stability test at 40℃ / 75%RH for 3 months, no stratification or precipitation (visual observation); 6. Baicalin content (HPLC determination, RSD < 2%), volatile oil content of Magnolia biondii (GC method detection, eucalyptol ≥ 0.05 wt%, RSD < 5%), bacterial endotoxin detection (< 0.5 EU / ml), and in vitro release experiment (pH = 5.0 phosphate buffer) show that PLGA nanoparticles release 75% of baicalin in 24 hours, meeting the zero-order kinetic model (R = 0.98) and other indicators, ensuring the safety and efficacy of the product; 7. Sterility test: meets the requirements of the sterility test method in the Chinese Pharmacopoeia.

[0033] The characteristics and usage of the nano-drug-loaded nasal spray compositions in each embodiment are described below: Example 1 (Applicable to mild outpatient cases) Target patients: Mild acute bacterial sinusitis with normal immune function Basis: The content of nano-silver is 0.003. wt %, PVP modification ensures rapid dispersion, suitable for the early stage of acute infection. Chitosan is modified with thiolation (-SH content ≥200 μmol / g), which enhances mucosal adhesion through disulfide bonds. The diameter of the inhibition zone against MRSA reaches 18 mm (agar diffusion method), which is superior to traditional nasal drops (12 mm).

[0034] Antibacterial effect: The MIC value of the composition against Staphylococcus aureus (including MRSA) was 0.5 μg / mL, as determined by the micro-broth dilution method, which is significantly lower than that of traditional antibiotics (such as mupirocin MIC=4 μg / mL).

[0035] Anti-inflammatory effect: ELISA showed that baicalin could inhibit LPS-induced IL-6 release in RAW264.7 macrophages (inhibition rate 78.3%, p<0.01).

[0036] Mucus permeability: Franz diffusion cell experiments showed that chitosan nanoparticles increased the drug permeation efficiency in artificial mucus layers by 2.3 times.

[0037] Example 2 (Applicable to moderate to severe cases during hospitalization) Target patients: Moderate to severe infections accompanied by systemic symptoms Based on the results: the bacterial clearance rate was 91.7% (n=48), with the best clearance effect against Pseudomonas aeruginosa. Scanning electron microscopy (SEM) showed that nano-silver (0.005%) could destroy the biofilm structure of Pseudomonas aeruginosa (reducing the biofilm thickness by 62%). Combined with the PLGA sustained-release system, the in vitro release curve showed that the silver ion release reached 85% in 24 hours and the cumulative release in 72 hours was >95%.

[0038] Features: The addition of 1.0% PLGA enables continuous nighttime drug administration and maintains stable blood drug concentrations.

[0039] Example 3 (Applicable to difficult-to-heal postoperative cases) Target patients: Patients after functional endoscopic sinus surgery Basis: An in vitro porcine nasal mucosa adhesion experiment showed that the preparation containing 2.0% chitosan remained on the mucosal surface for more than 6 hours (compared to only 3 hours for the control group containing 0.5% chitosan).

[0040] Features: 2.0 wt Chitosan forms a protective film, reducing postoperative adhesions; PLGA nanoparticles are surface-modified with TAT peptide (sequence YGRKKRRQRRR), which increases the penetration efficiency of sinus epithelial cells by 5 times (verified by flow cytometry).

[0041] Example 4 (Special Allergic Type) Target patients: Patients with allergic rhinitis complicated by secondary infection Based on the following: the improvement rate of the Nasal Symptom Score (TNSS) was 83.5%, and the average decrease in IgE levels was 42%.

[0042] Features: 1.2% baicalin specifically inhibits mast cell degranulation.

[0043] The above embodiments are not intended to limit the product form and style of the present invention. Any appropriate changes or modifications made by those skilled in the art should be considered as not departing from the patent scope of the present invention.

Claims

1. A nano-drug-loaded nasal spray composition for treating sinusitis, characterized by the following by weight percentage: The raw materials include the following dosage: 0.002 wt %~0.008 wt % nano silver, 0.1 wt %PVP, 0.3 wt %~1.5 wt % Baicalin, 0.1 wt %~0.4 wt % Magnolia biondii volatile oil, 0.5 wt %~3 wt % chitosan, 0.5 wt %~2 wt % PLGA, 0.05 wt %~0.3 wt % Sodium Hyaluronate, 0.15 wt %~0.25 wt The mixture contains % citrate buffer and the remainder sterile saline, wherein the citrate buffer comprises citric acid and sodium citrate in a mass ratio of 2:

1.

2. A method for preparing the nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 1, characterized in that: Includes the following steps: Step 1: Preparation of PVP-modified silver nanoparticle suspension: First, silver nitrate solution and PVP are mixed at a mass ratio of 1:5 to 1:

10. Ascorbic acid is added, and the mixture is stirred in a water bath at 55-65℃ for 25-30 minutes. After centrifugation, the PVP-modified silver nanoparticles are collected. Then, the PVP-modified silver nanoparticles are placed in a 0.1... wt The sterile saline solution was redispersed to the required concentration to obtain a PVP-modified silver nanoparticle suspension, wherein the average particle size of the silver nanoparticles was controlled at 20-40 nm and D90 < 50 nm. Step 2: Preparation of baicalin nanoparticles: Then, PLGA:baicalin:chitosan were dissolved in an appropriate amount of dichloromethane as the oil phase at a mass ratio of 4~6:2~4:1~3. The mixture was emulsified at 10000~15000 rpm or under the action of ultrasound probe. The emulsion was then poured into an aqueous solution containing 0.5%~1.0% (w / v) PVA. The dichloromethane was evaporated at 40~45℃ with stirring for 1.5~2 hours. The resulting emulsion was centrifuged, the precipitate was collected and washed 1~2 times with deionized water to obtain baicalin nanoparticles, which were then dispersed in a small amount of sterile water for later use. Step 3: Preparation of Magnolia biondii volatile oil nanoparticles: Then, the volatile oil of Magnolia biondii and PLGA were dissolved in an appropriate amount of ethyl acetate at a mass ratio of 1:3~5 as the oil phase. The oil phase was then slowly injected into an aqueous solution containing 1%~2% (w / v) Tween-80. The mixture was emulsified for 1~3 minutes at a speed of 10000~15000 rpm or under the action of ultrasound probe. Then, the mixture was stirred at 40~50℃ for 2~4 hours to allow the ethyl acetate to evaporate. The resulting emulsion was centrifuged, the precipitate was collected and washed 1~2 times with deionized water, and then freeze-dried to obtain Magnolia biondii volatile oil nanoparticles with a particle size of 80~120 nm. The nanoparticles were then dispersed in a small amount of sterile water for later use. Step 4, Mixing and Formulation: Finally, the PVP-modified silver nanoparticle suspension obtained in step 1, the baicalin nanoparticle dispersion obtained in step 2, and the magnolia volatile oil nanoparticle dispersion obtained in step 3 were mixed after their volumes were precisely calculated according to their concentrations and target final contents. Sterile physiological saline containing sodium hyaluronate and citrate buffer were added, and the pH of the system was adjusted to 4.5-5.5 with dilute hydrochloric acid or sodium hydroxide solution. Sterile physiological saline was then added to bring the total volume to 100%. The mixture was filtered through a 0.22 μm sterile filter membrane for sterilization, then subjected to gamma irradiation sterilization, and dispensed into a spray or nasal drops, i.e., this nano-drug-loaded nasal spray composition, comprising the following raw materials by weight percentage: 0.002 wt %~0.008 wt % nano silver, 0.1 wt %PVP, 0.3 wt %~1.5 wt % Baicalin, 0.1 wt %~0.4 wt % Magnolia biondii volatile oil, 0.5 wt %~3 wt % chitosan, 0.5 wt %~2 wt % PLGA, 0.05 wt %~0.3 wt % Sodium Hyaluronate, 0.15 wt %~0.25 wt % citrate buffer and the remainder sterile saline.

3. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 1, the molecular weight of the PVP is 40 kDa, the molar ratio of the ascorbic acid to the silver nitrate in the silver nitrate solution is close to 2:1, and the concentration of the nano-silver in the nano-silver suspension is 5 to 20 times that of the nano-silver in the final nano-drug-loaded nasal spray composition.

4. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 1, the centrifugation speed is 10,000 to 12,000 rpm, and the centrifugation time is 15 to 25 minutes.

5. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 2, the ultrasonic power of the probe is 100~200 W, the centrifugation speed is 10000~15000 rpm, and the centrifugation time is 10~20 minutes.

6. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 2, the volume of dichloromethane added is 10 to 20 times the total mass of PLGA, baicalin, and chitosan, and the volume of the PVA aqueous solution added is 5 to 10 times the volume of the oil phase.

7. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 3, the volume of ethyl acetate added is 10 to 20 times the total mass of Magnolia biondii volatile oil and PLGA, and the volume of the Tween-80 aqueous solution added is 5 to 20 times the volume of the oil phase.

8. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 3, the ultrasonic power of the probe is 200~300 W, the centrifugation speed is 10000~15000 rpm, and the centrifugation time is 10~20 minutes.

9. The method for preparing a nano-drug-loaded nasal spray composition for treating sinusitis as described in claim 2, characterized in that: In step 4, the sodium hyaluronate is pre-dissolved in a small amount of sterile saline, with a concentration not exceeding 5% (w / v); the citrate buffer is prepared by dissolving citric acid and sodium citrate in sterile water at a mass ratio of 2:1; and the irradiation dose for γ-irradiation sterilization is 25 kGy.

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