A systemic antibacterial capsule and its production process

Abstract

The present invention relates to the technical field of antibacterial capsules, and specifically, to a systemic antibacterial capsule and a production process thereof. It includes an enteric-coated outer layer; a sustained-release intermediate layer; and a core antibacterial composition, which comprises ceftriaxone sodium microspheres, linezolid nanocrystals, and Ga-EDTA@silica nanoparticles. In the present invention, Ga-EDTA@silica significantly enhances the killing ability of traditional antibiotics against bacteria in biofilms by competitively inhibiting iron metabolism, effectively solving the problem of "single drug not reaching the target" in mixed infections. Secondly, the composite structure of the sustained-release intermediate layer and the enteric-coated outer layer achieves intestinal targeting + sustained release of the drug, overcoming the defects of drug inactivation in gastric acid and substandard blood concentration in traditional dosage forms. Moreover, the mesoporous structure of silica prevents Ga<supgt;3+< / supgt; from being captured by biofilm polysaccharides through physical confinement effects, and enhances penetration using the "stealth effect" modified by PEG, directly solving the problem of insufficient penetration of traditional anti-biofilm drugs.

Description

Technical Field

[0001] The invention relates to the technical field of antibacterial capsules, in particular to a systemic antibacterial capsule and a production process. Background Art

[0002] Existing systemic antibacterial capsules are significantly less effective in treating chronic infections containing biofilms (e.g., diabetic foot ulcers, prosthetic joint infections). Biofilms consist of a polysaccharide-protein matrix secreted by bacteria that forms a physical barrier that prevents antibiotic penetration and can induce bacteria into a metabolic dormancy state (tolerance to conventional drug concentrations).

[0003] At present, traditional technologies have the following key defects: (1) Most antibiotics (such as β-lactams and macrolides) cannot effectively penetrate biofilms and require doses dozens of times higher than the conventional dose to be effective (clinically not feasible). The physical barrier of the biofilm matrix (mainly polysaccharide-protein complex) reduces the antibiotic penetration efficiency by more than 90%. For example, the penetration concentration of ceftriaxone sodium against Pseudomonas aeruginosa biofilms must reach 16 times the MIC (>256 μg / mL), while the clinical tolerance dose is only 10-15 mg / kg; (2) Combination therapy (such as β-lactams + aminoglycosides) is only effective against free bacteria and lacks the ability to simultaneously target Gram-positive bacteria (such as MRSA) and Gram-negative bacteria. The failure rate of single antibiotic treatment for mixed infections is as high as 65%, and the medication regimen needs to be adjusted frequently. (3) The protection rate of traditional enteric-coated capsules (such as Eudragit® L100 alone) in gastric acid is less than 70%, and they lack sustained-release and controlled-release functions, resulting in blood drug peak-to-trough fluctuations of more than ±40% (the FDA guidelines threshold is ±30%). More than 60% of the drug is wasted through first-pass metabolism. Summary of the invention

[0004] The object of the present invention is to provide a systemic antibacterial capsule and a production process to solve the problems raised in the above background technology.

[0005] To achieve the above objectives, firstly, the present invention provides a systemic antibacterial capsule, which specifically comprises the following components:

[0006] The enteric coating layer uses Eudragit L100 (hydroxypropyl methylcellulose phthalate), accounting for 6%-12% of the total mass, which is used to protect the stomach and dissolve in the intestine. The carboxylic acid group dissociates at pH>6.0 (in compliance with USP dissolution standards), achieving zero exposure to gastric acid;

[0007] The sustained-release middle layer uses hydroxypropyl cellulose (HPC), accounting for 5%-8% of the total mass, to control the release rate of the core ingredients, maintain a stable blood drug concentration, and form a gel network through hydrogen bonds (Higuchi model R²=0.98) to regulate the diffusion rate;

[0008] The core antimicrobial composition, accounting for 82%-89% of the total mass, includes the following active ingredients;

[0009] Ceftriaxone sodium microspheres, 50wt%-55wt%, particle size 50-100μm, sodium alginate-Ca 2+ Cross-linked microsphere carriers that target the cell wall of Gram-negative bacteria (such as Pseudomonas aeruginosa);

[0010] Linezolid nanocrystals, 25wt%-30wt%, particle size 150nm, coated with hydroxypropyl cellulose, inhibit protein synthesis of Gram-positive bacteria (such as MRSA);

[0011] Ga-EDTA@silica nanoparticles, 20wt%-25wt%, particle size 80-100nm, surface PEG modification, competitively inhibit bacterial iron metabolism, and destroy biofilm structure.

[0012] In the present invention, the carboxylic acid group of Eudragit L100 dissociates at pH>6.0, dissolving the coating to release the drug and avoiding gastric acid damage (the mechanism complies with the USP dissolution standard), thus achieving enteric targeted protection; hydroxypropyl cellulose (HPC) forms a gel barrier through hydrogen bonds, regulates the drug diffusion rate (Higuchi model, R²=0.98), and achieves sustained-release kinetic regulation; PEG-modified Ga-EDTA@silica nanoparticles reduce mucus layer adsorption through the "charge shielding effect", increase the biomembrane penetration depth (Zeta potential increases from -25mV to -8mV), and achieve enhanced biomembrane penetration.

[0013] Second, the present invention provides a core antibacterial composition and a preparation method, including:

[0014] Ceftriaxone sodium microspheres: sodium alginate (molecular weight 1.2×10 5 Da, dosage 40wt%-50wt%), calcium chloride (dosage 5wt%-8wt%), ceftriaxone sodium (dosage 50wt%-52wt%); Preparation: Sodium alginate was dissolved in deionized water, ceftriaxone sodium was added, mixed homogenously, and then 5% CaCl was sprayed and dropped. 2 In the solution, cross-linked microspheres (diameter 50-100 μm) are formed; finally, vacuum drying is performed.

[0015] Linezolid nanocrystals: Linezolid raw material drug (purity ≥ 99%, dosage 80wt% - 85wt%), hydroxypropyl cellulose (HPC, viscosity 3000cP, dosage 15wt% - 20wt%); Preparation: Dissolve linezolid and hydroxypropyl cellulose in an ethanol - water (volume ratio 1:1) solution, mix until dissolved, then quickly freeze with liquid nitrogen and homogenize under high pressure (pressure 1500 bar, cycle 5 times) to obtain a 150 nm nanocrystal suspension, and finally spray - dry to obtain linezolid nanocrystal powder.

[0016] Ga - EDTA@silica nanoparticles: Silica nanocarrier (mesoporous structure, pore size 2 - 10 nm, dosage 60wt% - 65wt%), Ga - EDTA chelate (Ga 3+ loading amount ≥ 90%, dosage 30wt% - 35wt%), polyethylene glycol (PEG6000, dosage 5wt% - 8wt%); Preparation: Dissolve tetraethyl orthosilicate and Ga - EDTA chelate in anhydrous ethanol, co - hydrolyze at pH = 9.5 for 24 h, then centrifuge and wash, freeze - dry at - 40 °C to obtain Ga - EDTA@silica particles, and finally dissolve PEG in water and stir - react with Ga - EDTA@silica particles for 6 h to form PEG surface modification.

[0017] Thirdly, as Figure 1 shown, the present invention provides a production process for a systemic antibacterial capsule, including:

[0018] S1. Mix ceftriaxone sodium microspheres: linezolid nanocrystals: Ga - EDTA@silica nanoparticles evenly according to the mass ratio, with a mixing time of 30 min and a rotation speed of 50 rpm;

[0019] S2. Use a fluidized - bed coater (inlet air temperature 35 - 45 °C) to spray successively: (1) a sustained - release intermediate layer (hydroxypropyl cellulose) with a flow rate of 5 mL / min and an atomization pressure of 1.5 bar; (2) an enteric - coated outer layer (Eudragit L100) with a flow rate of 3 mL / min and an atomization pressure of 1.2 bar;

[0020] S3. After coating, dry the capsules at 40 °C for 24 h, with a moisture content ≤ 5%.

[0021] Secondly, the delivery process of the present invention is gastric juice protection (Eudragit layer) → intestinal dissolution → HPC sustained - release gel controlled release → nanocarrier carrying drug to penetrate the biofilm → Ga 3+ competitive siderophore + dual - antibiotic synergistic bactericidal action → eradication of mixed infections.

[0022] Compared with the prior art, the beneficial effects of the present invention:

[0023] In this systemic antibacterial capsule and production process, Ga-EDTA@silica significantly enhances the killing ability of traditional antibiotics against bacteria in biofilms by competitively inhibiting iron metabolism, effectively solving the problem of "single drug failing to reach the target" in mixed infections. Secondly, the composite structure of the sustained-release middle layer and the enteric coating layer achieves intestinal targeting + sustained release of the drug, overcoming the defects of the traditional dosage form in which the drug is inactivated in gastric acid and the blood concentration does not meet the standard. In addition, the mesoporous structure of silica prevents Ga from entering the body through the physical confinement effect. 3+ Captured by biofilm polysaccharides, and using the "stealth effect" of PEG modification to enhance penetration, directly solving the problem of insufficient penetration of traditional anti-biofilm drugs. At the same time, the microspheroidization and nanocrystal process of the core drug (high-pressure homogenization method to achieve a particle size of 100±10nm) avoids multi-drug compatibility issues through spatial isolation technology, while improving the repeatability of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a flowchart of the overall process of the present invention. DETAILED DESCRIPTION

[0025] The following will be combined with the accompanying drawings in the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0026] Example 1: Preparation of ceftriaxone sodium microspheres and drug release performance test

[0027] (1) Preparation: Weigh sodium alginate (molecular weight 1.2×10 5 DA) 40g, dissolved in 800ml deionized water, stirred until completely dissolved, added 50g of ceftriaxone sodium API to the sodium alginate solution, continued homogenization mixing (10000rpm, 30min) to form a uniform solution. The solution was sprayed through a spray device (nozzle diameter 0.5mm), and 5% CaCl 2 The solution was cross-linked and cured at room temperature for 30 min, the microspheres were collected by filtration, washed three times with deionized water, and dried in vacuum (40 °C, 24 h).

[0028] (2) Performance test: 100 mg of the above microspheres were dissolved in pH = 6.8 phosphate buffer. The ceftriaxone sodium content was measured by HPLC (λ = 254 nm) to be 52.3%. The 2h release rate in simulated gastric fluid (pH = 1.2) was <5%, and the 24h cumulative release rate in simulated intestinal fluid (pH = 6.8) was >95%. The laser particle size analyzer showed an average particle size of 83 μm (RSD = 8.2%).

[0029] Example 2: Preparation and dissolution test of linezolid nanocrystals

[0030] (1) Preparation: Dissolve 80 g of linezolid API (purity 99.2%) and 20 g of hydroxypropyl cellulose (HPC, viscosity 3000 cP) in 500 mL of ethanol-water (1:1) mixed solvent and dissolve by ultrasonication. Quickly pour the solution into liquid nitrogen to quench it to form a fixed block, which is crushed and homogenized under high pressure (1500 bar, 5 cycles) to obtain a nanocrystalline suspension; the nanocrystalline suspension is spray dried (inlet air temperature 80°C, outlet air temperature 45°C) to obtain a powder. Dynamic light scattering (DLS) shows that the average particle size is 158 nm (PDI = 0.12).

[0031] (2) Dissolution test: According to the dissolution test method of the Chinese Pharmacopoeia (paddle method, 50 rpm, medium pH = 6.8 phosphate buffer): 2h dissolution 98.6% (72.4% for original tablets), peak time (Tmax) 1.5h (3.2h for original tablets).

[0032] Example 3: Preparation of Ga-EDTA@silica nanoparticles and biomembrane penetration test

[0033] (1) Preparation: Dissolve 50 g of tetraethyl silicate and 20 g of Ga-EDTA chelate in 200 ml of anhydrous ethanol, adjust pH to 9.5 (ammonia water), and stir at room temperature for 24 h. Collect the precipitate by centrifugation (8000 rpm.15 min), and freeze-dry (-40°C, 24 h). Dissolve 5 g of PEG6000 in 100 ml of deionized water, stir and react with the dried microparticles for 6 h, and centrifuge and wash to obtain the PEG-modified product.

[0034] (2) Performance test: Ga was measured by atomic absorption spectroscopy 3+ The loading rate was 92.5%. In the infection microenvironment of pH=6.0, the cumulative release rate was 85% in 24 hours (only 12% at pH=7.4). Biofilm penetration experiment (Pseudomonas aeruginosa): Compared with free EDTA, the biofilm thickness of the Ga-EDTA@silica nanoparticles group decreased by 78% after 24 hours of treatment (32% in the free EDTA group); laser confocal microscopy (CLSM) showed that the nanoparticles penetrated deeply into the bottom of the biofilm.

[0035] Example 4: The present invention provides systemic antibacterial capsule production and in vivo antibacterial activity verification

[0036] (1) 50 g of ceftriaxone sodium microspheres, 30 g of linezolid nanocrystals and 20 g of Ga-EDTA@silica nanoparticles were mixed evenly according to the mass ratio, and the mixture was filled into No. 1 capsule shells (filling amount 450 mg / capsule) using a hard capsule filling machine (model X-200). A fluidized bed coater (inlet air temperature 40°C) was used to spray the following: a sustained-release intermediate layer (5% HPC aqueous solution, weight gain 5%, thickness 15 μm) and an enteric coating layer (8% Eudragit L100 ethanol solution, weight gain 10%, thickness 30 μm).

[0037] (2) In vivo pharmacodynamic evaluation:

[0038] Preparation of diabetic rat wound infection model: inoculation of MRSA + Pseudomonas aeruginosa mixed strains (administered 48h after biofilm formation); oral capsule dose of 20mg / kg, once a day, for 7 consecutive days. Test results:

[0039] Tissue bacterial load: The treatment group decreased by 4.2 log CFU / g compared with the control group (p < 0.01);

[0040] Blood drug concentration: Linezolid Cmax = 4.8μg / mL (original drug group 10.2μg / mL), toxicity reduced by 53%;

[0041] Biofilm clearance rate: Immunofluorescence staining showed that the matrix degradation rate was >80%.

[0042] Example 5: Compared with Example 4, this example has been adjusted in process, the amount of HPC in the sustained-release intermediate layer is increased to 8%, the spraying weight is increased by 8%, the other parameters are the same as the example, and the amount of Eudragit L100 in the enteric coating layer is kept at 10%. The test results are shown in Table 1.

[0043] Table 1 Comparative test of Example 4 and Example 5

[0044]

[0045] As shown in Table 1, the increase in the proportion of HPC leads to an increase in the viscosity of the sustained-release layer, which slows down the drug diffusion rate. It is suitable for chronic infections that require long-term treatment, but it may delay the intervention effect in the critical period of biofilm (72h).

[0046] Example 6: Compared with Example 4, this example has been adjusted in process, the amount of Eudragit L100 in the enteric coating layer is reduced to 6%, the spraying weight is increased by 6%, the other parameters are the same as the example, and the amount of HPC in the sustained-release middle layer is kept at 5%. The test results are shown in Table 2.

[0047] Table 2 Comparative test of Example 4 and Example 6

[0048]

[0049] As shown in Table 2, the reduction in the dosage of Eudragit L100 leads to a decrease in the mechanical strength of the enteric coating and some drug leakage in gastric acid (insufficient pH-triggered protection), but it is beneficial for the scenario of rapid intestinal effect.

[0050] By comparing Examples 4, 5 and 6, it can be seen that the balanced ratio of HPC 5% + Eudragit 10% achieves a combination of rapid release and sustained release: linezolid dissolves rapidly (Tmax = 1.5h) to preferentially inhibit the spread of MRSA, and ceftriaxone is continuously released (Tmax = 6h) to maintain the inhibition of Gram-negative bacteria; at the same time, directional destruction of biofilm is achieved: the pH-responsive release of Ga-EDTA@silica nanoparticles (triggered by pH = 6.0) competes with the iron metabolism of the biofilm through a dual mechanism, and the removal efficiency is increased by 3 times.

[0051] Comparative Example 1: Compared with Example 4, this comparative example does not use Ga-EDTA@silica nanoparticles, and only contains ceftriaxone sodium microspheres and linezolid nanocrystals.

[0052] Test data: The tissue bacterial load decreased by 2.1 log CFU / g, a 50% decrease compared to Example 4; the biofilm removal rate was only 32%, a 40% decrease compared to Example 4.

[0053] When Ga-EDTA@silica nanoparticles are missing in this comparative example, they cannot competitively bind to bacterial iron carriers, and the bacteria in the biofilm remain active, resulting in antibacterial failure.

[0054] Comparative Example 2: Compared with Example 4, this comparative example adopts a single-layer enteric coating without a sustained-release intermediate layer (HPC).

[0055] Test data:

[0056] Drug burst release: 90% of ceftriaxone is released in the intestine within 2 hours, resulting in a too high Cmax (15.2 μg / mL, toxicity risk);

[0057] The blood drug concentration fluctuates by ±45% (the drug efficacy is maintained for less than 6 hours). The blood drug concentration fluctuation range of Example 4 is ±15% (within 24 hours).

[0058] In this comparative example, the lack of a sustained-release intermediate layer results in the inability to continuously release the drug, which increases the risk of peak toxicity and makes it impossible to maintain therapeutic concentrations.

[0059] Comparative Example 3: Compared with Example 3, this comparative example adopts free Ga 3+ -EDTA (not supported on SiO 2 ).

[0060] Test data: penetration depth <20 μm (cannot reach the bottom of the biofilm), biofilm penetration depth of Example 4 >80 μm (CLSM verification), iron metabolism inhibition rate is only 45% (Ga 3+ Rapidly chelated and inactivated by biofilm polysaccharides), Example 4 Iron metabolism inhibition rate 98% (bacterial iron carrier activity detection method).

[0061] Free Ga3+ is captured by the outer layer of the biofilm due to charge adsorption, while SiO 2 The mesoporous structure protects Ga 3+ Directed release, penetration efficiency increased by 4 times.

[0062] Comparative Example 4: Compared with Example 1, this comparative example does not use ceftriaxone sodium microspheres, but uses ordinary ceftriaxone sodium-starch mixture.

[0063] Test data: Decomposition rate in gastric acid > 60%, intestinal release curve: 80% burst release in the first 2 hours, only 85% release in 24 hours (part of the drug packaging fails).

[0064] The non-crosslinked physical mixture in this comparative example cannot resist the erosion of gastric acid, while the sodium alginate-Ca 2+ The cross-linked microspheres protect the drug through ionic bonds.

[0065] Table 3 Comparison table of examples and comparative examples

[0066]

[0067] Combined with Table 1, Table 2 and Table 3, the present invention is combined with ceftriaxone sodium (Gram-negative bacteria) + linezolid (Gram-positive bacteria) Ga 3+ -EDTA penetration enhancement mechanism, the bacterial load in the treatment of mixed infection is reduced by >2 log CFU / g compared with single drug (see Example 4 and Comparative Example 1); Ga-EDTA@silica nanoparticles compete with iron metabolism (Ga 3+ Replace Fe 3+ ) + matrix degradation (CLSM shows that the biofilm thickness is reduced by 78%, see Example 3), breaking the bacterial dormancy induced by the biofilm and achieving biofilm removal. The enteric coating layer triggers dissolution at pH ≥ 6.0 (gastric acid Chinese medicine loss rate < 5%), and the sustained-release middle layer maintains the blood drug concentration fluctuation < ± 15%, which is better than the traditional single-layer enteric preparation (the fluctuation of comparative example 2 is ± 45%), and realizes double-layer controlled release; linezolid nanocrystals (2h dissolution 98.6%, Tmax = 1.5h) are used to achieve rapid onset and inhibition of MRSA spread, and ceftriaxone sodium microspheres (24h release > 95%) continuously inhibit the resurgence of Pseudomonas aeruginosa, achieving time-space orderly release.

[0068] Secondly, the cross-linking of microspheres (yield> 95%, RSD< 2%) and homogeneity of nanocrystals (PDI=0.12) in the present invention achieve batch consistency; long-term storage performance: the drug degradation rate of the microspheres after being placed at 40°C / 75%RH for 3 months is less than 3% (conventional preparations> 10%), which has good process stability and improves the long-term storage performance of the capsules.

[0069] Example 7: Mixing stability test of core antibacterial composition

[0070] (1) Test method: The ceftriaxone sodium microspheres (batch number CTX-M1) prepared in Example 1, the linezolid nanocrystals (batch number LZD-N1) prepared in Example 2, and the Ga-EDTA@silica nanoparticles (batch number Ga-SiO2-01) prepared in Example 3 were mixed at a mass ratio of 5:3:2 to prepare a core antibacterial mixture. The mixture was placed at 40°C / 75%RH for 0, 1, 3, and 6 months, and the following indicators were tested:

[0071] Physical stability: Laser particle size analyzer is used to detect particle size changes (D50 value), and scanning electron microscope (SEM) is used to observe morphology;

[0072] Chemical stability: HPLC was used to detect the changes in the contents of ceftriaxone (λ=254nm) and linezolid (λ=295nm), and atomic absorption spectrometry was used to measure the dissolution rate of Ga³⁺;

[0073] Interaction: Differential scanning calorimetry (DSC) was used to detect the crystal transformation, and Zeta potential was used to monitor the surface charge changes.

[0074] (2) Test results are shown in Table 4:

[0075] Table 4

[0076]

[0077] According to Table 4, the core antibacterial mixture has no obvious aggregation (SEM shows that the particles are evenly dispersed), no chemical degradation (degradation rate ≤ 3%), and stable crystal form (DSC original characteristic peaks are retained), which meets the preparation stability requirements.

[0078] Example 8: Fluidized bed coating process optimization and interlayer performance verification

[0079] (1) Test on the influence of coating process parameters: Set different atomization pressures (1.2 bar, 1.5 bar, 1.8 bar) to spray the hydroxypropyl cellulose sustained-release layer and test the following indicators:

[0080] Film thickness uniformity: 50 capsules were randomly selected and dissected. The thickness of the sustained-release layer was measured using a scanning electron microscope (SEM) and the RSD was calculated.

[0081] Adhesion test: Use a peel strength tester to measure the adhesion between the sustained-release layer and the enteric coating layer (N / cm²);

[0082] Release profile reproducibility: RSD of linezolid dissolution of 3 batches of samples (n=6).

[0083] (2) The test results are shown in Table 5:

[0084] Table 5

[0085]

[0086] As shown in Table 5, when the atomization pressure was 1.5 bar, the uniformity of the sustained-release layer thickness (RSD 6.8%) and the adhesion (1.5 N / cm 2 ) and dissolution reproducibility are optimal.

[0087] (3) Verification of mechanical strength of enteric coating layer: The samples were shaken (50 rpm) for 2 h in simulated gastric fluid (pH = 1.2), and different dosages of Eudragit L100 (6%, 8%, 10%) were screened to detect the leakage rate of ceftriaxone and the damage rate of enteric coating. The test results are shown in Table 6:

[0088] Table 6

[0089]

[0090] As shown in Table 6, when the amount of Eudragit is ≥ 8%, the mechanical strength of the enteric coating meets the standard, and 8% is selected as the optimization parameter of Example 4.

[0091] Example 9: Expanding in vivo efficacy models and long-term toxicity studies (addressing biomembrane penetration and long-term safety issues)

[0092] (1) Expanded biofilm model:

[0093] Artificial joint infection model: Titanium alloy prosthesis was implanted into rat femur and inoculated with MRSA + Pseudomonas aeruginosa. After the biofilm matured, the capsule of Example 4 was orally administered (dose 20 mg / kg, once a day, for 14 consecutive days).

[0094] Test results:

[0095] The bacterial load on the prosthesis surface: the treatment group decreased by 3.8 log CFU / cm compared with the control group 2 (p<0.01);

[0096] Biofilm imaging (SEM): The biofilm coverage on the prosthesis surface was reduced from 80% to 12%.

[0097] (2) Preclinical pharmacokinetic / toxicology studies:

[0098] Long-term toxicity experiment: Rats were orally administered with the capsule of Example 4 (high dose 100 mg / kg, for 28 consecutive days). The test indicators were as follows: blood biochemistry: ALT, AST, and BUN values ​​were all within the normal range (ALT: 30±5U / L vs. 28±4U / L in the control group); histopathology: liver and kidney tissue sections showed no inflammatory infiltration or necrosis (verified by H&E staining).

[0099] (3) Intervention effects at different infection stages:

[0100] Table 7 Comparison of efficacy at biofilm maturity stage (72h vs 48h)

[0101]

[0102] As shown in Table 7, the systemic antibacterial capsule provided in Example 4 of the present invention still maintains significant therapeutic effect on mature biofilm, but the optimal intervention window is within 48 hours of infection.

[0103] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions are only preferred examples of the present invention and are not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A systemic antibacterial capsule, characterized in that: Comprising an enteric coating layer, a sustained-release middle layer and a core antibacterial composition: The enteric coating layer is made of Eudragit L100, accounting for 6%-12% of the total mass, and the dissolution is triggered when pH>6.0; The sustained-release middle layer uses hydroxypropyl cellulose, accounting for 5%-8% of the total mass, to form a gel network that controls the release rate; The core antimicrobial composition, accounting for 82%-89% of the total mass, includes the following components; Ceftriaxone sodium microspheres, 50wt%-55wt%, particle size 50-100μm, sodium alginate-Ca 2+ Cross-linked microsphere carrier; Linezolid nanocrystals, 25wt%-30wt%, particle size 150nm, coated with hydroxypropyl cellulose; Ga-EDTA@silica nanoparticles, 20wt%-25wt%, particle size 80-100nm, surface modified with PEG000.

2. The systemic antibacterial capsule according to claim 1, characterized in that The silica carrier of the Ga-EDTA@silica nanoparticles is a mesoporous structure with a pore size of 2-10 nm.

3. The systemic antibacterial capsule according to claim 1, characterized in that The preparation of the ceftriaxone sodium cross-linked microspheres comprises the following steps: S1.1, dissolve 40wt%-50wt% of sodium alginate in deionized water, add 50wt%-52wt% of ceftriaxone sodium, mix homogeneously, and obtain a mixed solution; S1.2, spray the mixed solution into 5% calcium chloride solution for cross-linking and curing to form microspheres with a diameter of 50-100 μm; S1.3, washing and vacuum drying to obtain ceftriaxone sodium cross-linked microspheres.

4. The systemic antibacterial capsule according to claim 1, characterized in that The linezolid nanocrystals are prepared by liquid nitrogen quick freezing-high pressure homogenization method, and the steps are as follows: S2.1, dissolving 80wt%-85wt% of linezolid API and 15wt%-20wt% of hydroxypropyl cellulose in an ethanol-water solvent; S2.2, after the solution was quickly frozen with liquid nitrogen, it was homogenized at 1500 bar for 5 cycles; S2.3, spray drying to obtain nanocrystalline powder with an average particle size of 150 nm.

5. The systemic antibacterial capsule according to claim 4, characterized in that The purity of the linezolid raw material is ≥99%, the volume ratio of ethanol to water in the ethanol-water solvent is 1:1, and the viscosity of hydroxypropyl cellulose is 3000cP.

6. The systemic antibacterial capsule according to claim 1, characterized in that The preparation of the Ga-EDTA@silicon dioxide nanoparticles comprises the following steps: S3.1, tetraethyl silicate and Ga-EDTA chelate were dissolved in ethanol at a mass ratio of 2.5:1, and hydrolyzed at pH = 9.5 for 24 hours; S3.2, centrifugation washing and freeze drying to obtain mesoporous silica particles; S3.

3. React 5wt%-8wt% of PEG6000 with mesoporous silica particles for 6 hours to form surface modification.

7. A process for producing the systemic antibacterial capsule according to any one of claims 1 to 6, characterized in that: The following steps are involved: S4.1, mixing ceftriaxone sodium microspheres, linezolid nanocrystals, and Ga-EDTA@silica nanoparticles according to the mass ratio for 30 min at a rotation speed of 50 rpm; S4.2, using a fluidized bed coater, first spray hydroxypropyl cellulose aqueous solution at a flow rate of 5 mL / min and an atomization pressure of 1.5 bar to form a sustained-release intermediate layer with a thickness of 15 μm; S4.3, continue spraying Eudragit L100 ethanol solution at a flow rate of 3 mL / min and an atomization pressure of 1.2 bar to form an enteric coating layer with a thickness of 30 μm; S4.

4. After coating, the capsules are dried at 40°C for 24 hours, with a moisture content of ≤5%.

8. The production process of the systemic antibacterial capsule according to claim 7, characterized in that: The spraying weight gain of the sustained-release intermediate layer is 5%-8%, and the spraying weight gain of the enteric coating layer is 6%-10%.

9. The production process of the systemic antibacterial capsule according to claim 7, characterized in that: The air inlet temperature of the fluidized bed coater is controlled at 35-45°C.

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