A lidocaine multilayer liposome / core-shell nanoparticle aerosol inhalant and a preparation method and application thereof

Abstract

The application is suitable for the technical field of biological medicine and cardiovascular interventional medical instruments, and provides a lidocaine multilayer liposome / core-shell nanoparticle aerosol inhalant as well as a preparation method and application thereof. The aerosol inhalant comprises multilayer liposome / core-shell nanoparticles and an aerosol inhalation medium, wherein the multilayer liposome / core-shell nanoparticles have a multilayer core-shell structure, the inner core is a PLGA nanoparticle loaded with lidocaine, the intermediate layer is a first lipid bilayer, and the outer layer is a second lipid bilayer and a multilayer lipid structure. The application can specifically inhibit the cough caused by the vagus nerve reflex stimulated by radiofrequency ablation, and the diaphragm contraction and dry cough caused by the direct stimulation of the phrenic nerve and bronchus by the pulse electric field ablation, reduces the catheter displacement and operation interruption during the operation, reduces the dosage of intravenous sedative drugs, reduces the risk of sedation-related adverse events, and improves the operation safety and patient satisfaction.

Description

Technical Field

[0001] This invention relates to the fields of biomedicine and cardiovascular interventional medical device technology, specifically to a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, its preparation method, and its application. Background Technology

[0002] Catheter ablation is the standard treatment for symptomatic atrial fibrillation (AF). With an aging population, the prevalence of AF continues to rise, and the number of catheter ablation procedures is increasing year by year. AF catheter ablation typically takes 2 to 4 hours and involves complex procedures such as pulmonary vein isolation, left atrial posterior wall ablation, and isthmus ablation. During AF catheter ablation, the cough reflex is a significant clinical issue. When the ablation catheter enters the left atrium and contacts the pulmonary vein orifice or the left atrial posterior wall, energy stimulation can excite the vagus nerve reflex, which is transmitted through neural pathways to the respiratory center, inducing a sudden cough reflex. The risks of the cough reflex during the procedure include: catheter displacement, discontinuity of the ablation site, risk of cardiac perforation, interruption of the procedure, and patient discomfort.

[0003] The pulsed field ablation (PFA) technique, which has emerged in recent years, has a completely different mechanism of action from traditional radiofrequency or cryoablation. PFA induces irreversible electroporation through the application of high-voltage electrical pulses, leading to cell death. Clinical practice has shown that PFA can cause varying degrees of diaphragmatic contraction and dry cough, especially noticeable in conscious and sedated individuals. The mechanism involves the direct stimulation of the phrenic nerve and bronchi by the high-voltage electrical pulses, with a high incidence rate and correlation to the respiratory cycle. Radiofrequency or cryoablation primarily stimulate the vagus ganglion plexus through thermal energy, indirectly triggering coughing via a reflex arc; the mechanisms of these two techniques are fundamentally different.

[0004] Currently, clinical strategies for suppressing the cough reflex mainly include deep sedation or general anesthesia, intraoperative administration of additional sedatives, intraoperative catheter-based lidocaine infusion, and routine lidocaine nebulization. However, existing technologies have the following gaps: a lack of long-acting preventative agents specifically targeting the cough reflex during atrial fibrillation ablation; a lack of drug intervention strategies targeting the specific cough mechanism of PFA; a lack of a delivery system that can precisely match the ablation surgery time window (2-4 hours, with the peak cough period being 30-120 minutes after the start of surgery); and a lack of auxiliary strategies to reduce the amount of sedatives used during surgery. Therefore, in response to the above situation, there is an urgent need to provide a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, its preparation method, and its application to overcome the shortcomings in current practical applications. Summary of the Invention

[0005] The purpose of this invention is to provide a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, its preparation method, and its application, aiming to solve the problems in the above-mentioned background art.

[0006] The present invention is achieved as follows: a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhalant, comprising multilayer liposome / core-shell nanoparticles and a nebulized inhalation medium; The multilayered liposomes / core-shell nanoparticles have a multilayered core-shell structure, which includes a core, an intermediate layer and an outer layer from the inside out. The core is a PLGA nanoparticle loaded with lidocaine, used to cover the cough suppression needs in the mid-to-late stages of atrial fibrillation catheter ablation surgery. The intermediate layer is a first lipid bilayer that wraps around the outer surface of the core, and is used to cover the cough suppression needs during the high-incidence period of coughing in atrial fibrillation catheter ablation. The outer layer is a multi-layered lipid structure consisting of a second lipid bilayer or more, arranged concentrically with the middle layer, and is used to cover the cough suppression needs in the early stages of atrial fibrillation catheter ablation surgery.

[0007] As a further aspect of the present invention: the peak period for coughing is 30 to 120 minutes after the start of the surgery, corresponding to the pulmonary vein isolation and left atrial posterior wall ablation stages; The cough suppression includes suppressing coughing caused by radiofrequency ablation stimulation of the vagus nerve reflex, and suppressing diaphragmatic contraction and dry cough caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi.

[0008] As a further aspect of the present invention, the ratio of lactic acid (LA) to glycolic acid monomer (GA) in the PLGA is 75:25 to 60:40, and the molecular weight is 20,000 to 50,000 Da.

[0009] As a further aspect of the present invention: the multilayer lipid structure is composed of phospholipids, cholesterol, and polyethylene glycol-modified phospholipids; The phospholipids include dipalmitoylphosphatidylcholine (DPPC).

[0010] As a further aspect of the present invention, the molar ratio of the phospholipid, cholesterol and polyethylene glycol-modified phospholipid is 50%-70%:25%-45%:3%-10%.

[0011] As a further aspect of the present invention: the number of layers in the multilayer lipid structure is 2 to 10; Among them, layers 2 to 3 are suitable for radiofrequency ablation with an ablation time of less than 90 minutes; Four to five layers are suitable for radiofrequency ablation or pulsed electric field ablation with ablation time of 90 to 150 minutes; Layers 6 to 8 are suitable for scenarios where the ablation time is greater than 150 minutes or where there are many pulse electric field ablation cycles.

[0012] As a further aspect of the present invention: the overall particle size of the multilayer liposomes / core-shell nanoparticles is 180 to 350 nm; The lidocaine multilayer liposome / core-shell nanoparticle nebulizer produces droplet sizes ranging from 2 to 5 μm after nebulization.

[0013] The present invention also provides a method for preparing the above-mentioned lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, comprising the following steps: Step 1: Prepare lidocaine-loaded PLGA nanoparticle cores using a solvent evaporation method; Step 2: Using a thin-film hydration method combined with freeze-thaw cycles, multilayer liposomes loaded with lidocaine were prepared and encapsulated with the PLGA nanoparticle core prepared in Step 1 to form multilayer liposomes / core-shell nanoparticles. The number of lipid layers was controlled by adjusting the number of freeze-thaw cycles. Step 3: Disperse the multilayer liposomes / core-shell nanoparticles prepared in Step 2 in the nebulization inhalation medium to obtain lidocaine multilayer liposomes / core-shell nanoparticle nebulized inhaler.

[0014] As a further aspect of the present invention: the number of freeze-thaw cycles in step 2 is determined based on the expected time of the atrial fibrillation ablation surgery and the type of ablation technique. If the ablation time is less than 90 minutes, 2 to 3 applications should be used. When the ablation time is 90 to 150 minutes, 4 to 5 applications are required; When the ablation time is greater than 150 minutes or the number of pulse electric field ablations reaches the preset value, 6 to 8 ablations are performed.

[0015] This invention also provides the use of the lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler as described above in the preparation of a drug for inhibiting coughing induced by atrial fibrillation catheter ablation, wherein the nebulized inhaler is used for: Preoperative airway pretreatment to suppress the cough reflex during catheter ablation. The cough reflex includes coughing caused by radiofrequency ablation stimulating the vagus nerve and coughing caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi. Maintain the depth of airway anesthesia during the operation and reduce the amount of intravenous sedative drugs; Postoperative relief of throat pain and discomfort.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: It achieves three-stage release of lidocaine (rapid, medium, and slow), precisely matching the cough risk at different stages of atrial fibrillation ablation surgery, and providing continuous and effective airway anesthesia depth, especially for the high-incidence period of coughing from 30 to 120 minutes. It can both suppress vagal reflex coughing caused by radiofrequency ablation and specifically inhibit diaphragmatic contraction and dry cough caused by pulsed electric field ablation by increasing the threshold of the phrenic nerve and bronchi to electrical stimulation. It significantly reduces the risk of catheter displacement, discontinuity of ablation foci, and cardiac perforation caused by intraoperative coughing, and improves ablation efficacy; As a preoperative airway pretreatment strategy, it can reduce the amount of intraoperative intravenous sedation drugs used, reduce the incidence of sedation-related adverse events such as hypoxemia and hypotension, and accelerate postoperative recovery. Detailed Implementation

[0017] The technical solution 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.

[0018] The present invention will be further explained below with reference to specific embodiments.

[0019] This invention provides a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler. Through the composite structure of multilayer liposomes and a PLGA core, it achieves the time-sequential release of lidocaine, precisely matching the time window of high cough incidence during atrial fibrillation ablation surgery, thus achieving the following objectives: Preoperative airway pretreatment ensures that lidocaine reaches an effective airway concentration before the ablation procedure begins; During the high-incidence period of intraoperative coughing (30 to 120 minutes after the start of surgery, i.e. the pulmonary vein isolation and left atrial posterior wall ablation stage), maintain a stable airway anesthesia depth and specifically inhibit the coughing reflex caused by catheter stimulation, especially diaphragmatic contraction and dry cough caused by pulsed electric field ablation. By suppressing the coughing reflex, intraoperative catheter displacement and operation interruption are reduced, thereby improving ablation efficacy and surgical safety. Reduce the amount of intravenous sedation drugs used during surgery to lower the risk of sedation-related adverse events.

[0020] This invention provides a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, comprising: Multilayer liposomes / core-shell nanoparticles and atomized inhalation media.

[0021] 1. Structure of multilayer liposomes / core-shell nanoparticles The multilayered liposomes / core-shell nanoparticles have a multilayered core-shell structure, comprising, from the inside out: Core: Lidocaine-loaded PLGA nanoparticles, with a particle size of 150 to 200 nm, designed to cover cough suppression needs during the mid-to-late stages of surgery (90 to 240 minutes).

[0022] Intermediate layer: The first lipid bilayer tightly wraps around the surface of the PLGA core, which is used to cover the cough suppression needs during the peak coughing period (30 to 120 minutes), namely the pulmonary vein isolation and left atrial posterior wall ablation stages.

[0023] Outer layer: A multi-layered lipid structure consisting of a second lipid bilayer and above, arranged concentrically with the middle layer, used to cover the cough suppression needs in the early stage of surgery (0 to 30 minutes), namely the vascular puncture and atrial septal puncture stages.

[0024] 2. Matching structural design with the cough time window during atrial fibrillation ablation. 2.1 Temporal distribution characteristics of coughing during atrial fibrillation ablation Based on clinical observation, the temporal distribution of coughing during atrial fibrillation ablation has the following characteristics: Early coughing (0 to 30 minutes): mainly occurs during vascular puncture and interatrial septal puncture, with a low incidence of about 5% to 10%, which is related to the stimulation of the septal tissue by the puncture needle.

[0025] Mid-term high incidence of coughing (30 to 120 minutes): This is the main stage for coughing, with an incidence rate of 30% to 50%. This stage corresponds to pulmonary vein isolation and ablation of the posterior wall of the left atrium. Thermal energy stimulation of the vagal ganglion plexus and the adventitia of the airway is the main inducing factor for radiofrequency ablation. For pulsed electric field ablation, the high-voltage electric pulses in this stage directly stimulate the phrenic nerve and bronchi, causing diaphragmatic contraction and dry cough, with an even higher incidence rate.

[0026] Late-stage coughing (120 to 240 minutes): The incidence is low, about 5% to 15%, and is related to cumulative stimulation caused by isthmus ablation or prolonged operation. Pulsed electric field ablation may still have a cumulative effect at this stage.

[0027] 2.2 Precise Matching of Layered Release Design with Coughing Time Window Outer lipid (multilayer): The release characteristic is rapid release (0 to 30 minutes), and the mechanism of action is the layer-by-layer hydration of the multilayer lipids, with rapid diffusion of the adsorbed drug on the surface, which matches the need for cough prevention in the early stage of surgery (puncture stage).

[0028] The intermediate lipid layer: characterized by a moderate-rate release (30 to 120 minutes), its mechanism of action involves lipid bilayer hydration and sustained drug diffusion, matching the cough suppression needs during peak coughing periods (pulmonary vein isolation and left atrial posterior wall ablation stages), which is the core design of this invention. During this stage, the sustained drug release maintains an effective anesthetic concentration in the airway mucosa, blocks the vagal reflex pathway, and simultaneously increases the threshold of the phrenic nerve and bronchi to electrical stimulation, thereby specifically inhibiting diaphragmatic contraction and dry cough induced by pulsed electric field ablation.

[0029] PLGA core: The release characteristic is slow release (2 to 4 hours), and the mechanism of action is that PLGA gradually degrades and the drug continues to diffuse, which matches the need for cough prevention in the later stage of surgery (isthmus ablation and the stage before the end of the procedure) and can cover the cumulative effect time window of pulsed electric field ablation.

[0030] 3. Kernel 3.1 Optimal parameters for PLGA material (for postoperative cough suppression) The lactic acid (LA) to glycolic acid monomer (GA) ratio (LA:GA) of PLGA is 75:25 to 60:40, with 70:30 being the most preferred. Using a higher LA ratio allows for slower degradation, ensuring an effective drug concentration in the later stages of the procedure (3 to 4 hours) to cover the cumulative effect of pulsed electric field ablation.

[0031] The preferred molecular weight range for PLGA is 20,000 to 50,000 Da, with the most preferred value being 35,000 Da. Higher molecular weights result in slower degradation.

[0032] The intrinsic viscosity is preferably in the range of 0.4 to 0.8 dL / g, with the most preferred value being 0.6 dL / g. Higher viscosity is beneficial for the formation of a dense core.

[0033] 3.2 Drug loading parameters Lidocaine dosage: The preferred range is 15 to 30 mg / mL PLGA solution, with 25 mg / mL being the most preferred. Ensure sufficient drug loading in the core.

[0034] Core drug percentage: Preferably 40% to 50% of total drug dosage, with an optimal percentage of 45% of total drug dosage. Ensure that the sustained-release phase has sufficient drug coverage in the later stages of surgery.

[0035] 4. Multi-layered liposome shell (for peak coughing seasons) 4.1 Selection of lipid materials DPPC (dipalmitoylphosphatidylcholine): The molar ratio ranges from 50% to 70%, with 60% being the most preferred. DPPC is the main phospholipid component of pulmonary surfactant, exhibiting good biocompatibility and affinity with airway mucosa, making it suitable for use in nebulized inhalation formulations.

[0036] Cholesterol: The molar ratio ranges from 25% to 45%, with 35% being the most preferred. It is used to regulate the fluidity of the lipid bilayer and promote multilayer formation.

[0037] DSPE-PEG: Molar ratio ranging from 3% to 10%, with a preferred ratio of 5%. Used to provide spatial stability and reduce mucus capture.

[0038] 4.2 Drug delivery via multilayered liposome shells The proportion of drug in the outer lipid layer is preferably 20% to 25% of the total drug volume, and most preferably 22% of the total drug volume. Ensure sufficient drug is available for 0 to 30 minutes to prevent coughing during the puncture period.

[0039] The proportion of drug in the intermediate lipid layer is preferably 30% to 40% of the total drug amount, and most preferably 35% of the total drug amount. Ensuring an effective drug concentration for 30 to 120 minutes (during peak coughing periods) is the core design of this invention. This concentration should be sufficient to inhibit the vagal reflex while simultaneously increasing the threshold of the phrenic nerve and bronchi to electrical stimulation.

[0040] Lidocaine dosage: preferably 8 to 12 mg / mL, most preferably 10 mg / mL. This balances encapsulation efficiency and release requirements.

[0041] 4.3 Optimization of the preparation process for multilayer liposome shells The number of lipid layers is controlled by adjusting the number of freeze-thaw cycles, thereby regulating the release rate to adapt to different ablation procedure durations and ablation techniques. Freeze-thaw cycles 2 to 3 times: Expected lipid layer number 2 to 3 layers, suitable for scenarios with short ablation time (less than 90 minutes), or scenarios mainly used for radiofrequency ablation.

[0042] The freeze-thaw cycle count is 4 to 5 times: the expected number of lipid layers is 4 to 5, suitable for routine atrial fibrillation ablation (90 to 150 minutes), and is the preferred general solution for radiofrequency ablation and pulsed electric field ablation according to this invention. Release characteristics are: immediate release 22%, intermediate release 35%, and sustained release 43%.

[0043] Freeze-thaw cycles of 6 to 8: Expected lipid layer count of 6 to 8 layers, suitable for complex ablation (greater than 150 minutes) or scenarios with a high number of pulsed electric field ablation cycles, to cover a longer period of high coughing incidence and cumulative effects. Release characteristics: immediate release 18%, intermediate release 38%, sustained release 44%.

[0044] 5. Optimized design of nebulized inhalation formulations 5.1 Atomized Particle Size Control Atrial fibrillation ablation surgery requires airway pretreatment under sedation. The nebulized droplet size must be precisely controlled to ensure effective deposition in the pharynx and central airway, while avoiding overstimulation. Particles larger than 5 μm: mainly deposited in the oropharynx, can anesthetize the throat and reduce irritation caused by oropharyngeal airways or mask ventilation.

[0045] Particle size 2 to 5 μm (preferred): mainly deposited in the trachea and main bronchus, can anesthetize the airway mucosa, inhibit the cough reflex when the catheter passes through sensitive areas such as the carina, and can also act on the bronchus and phrenic nerve area adjacent to the atrium, increasing the threshold for electrical stimulation.

[0046] Particles smaller than 2 μm: mainly deposited in bronchioles and alveoli, have little effect on airway anesthesia, and should be minimized.

[0047] Preferred solution: Use a vibrating screen nebulizer to control the D50 of the atomized droplets at 3.5±0.5 μm and the D90 at less than 5 μm to ensure effective deposition in the pharynx and central airway.

[0048] 5.2 Formulation Multilayer liposomes / core-shell nanoparticles: content ranging from 0.5% to 1.5% based on lidocaine, preferably 1.0%. Balancing efficacy and safety.

[0049] Isotonic regulator: Mannitol or NaCl content ranging from 2% to 5%, preferably 4% mannitol. This regulates osmotic pressure and reduces airway irritation.

[0050] pH adjuster: Adjust to pH 6.5 to 7.0. Maintain stability, reduce irritation, and approximate the physiological pH of the airway.

[0051] Flavoring agent (optional): Sucralose, etc., in a range of 0.1% to 0.5%, preferably 0.2%. Improves taste and increases patient compliance.

[0052] Preservative: Benzalkonium chloride content ranges from 0.01% to 0.1%, preferably 0.01%. Used in multi-dose packaging.

[0053] Water for injection: Add to 100%. Solvent.

[0054] 5.3 Timing and Method of Administration Administration timing: Nebulized inhalation 15 to 20 minutes after the patient enters the room and before the start of surgery.

[0055] Dosage: 3 to 5 mL (containing 30 to 50 mg lidocaine).

[0056] Atomization time: 5 to 10 minutes.

[0057] Synergistic effect with intravenous sedation: Initiating intravenous sedation 15 minutes after nebulized inhalation can significantly reduce the induction and maintenance doses of drugs such as propofol.

[0058] Synergistic effect with pulsed electric field ablation respiratory control strategy: Nebulized inhalation combined with end-expiratory energy release can further reduce the incidence of diaphragmatic contraction and dry cough.

[0059] 6. Design of a drug delivery protocol specifically for atrial fibrillation ablation 6.1 Preoperative medication procedure (standard procedure) Patient enters the operating room (30 minutes before surgery): Connect ECG monitor and blood oxygen saturation monitor, and prepare nebulizer.

[0060] 25 to 15 minutes before surgery: Inhale 3 to 5 mL of the formulation of this invention via nebulizer over approximately 5 to 10 minutes. The outer lipid layer is rapidly released, and anesthesia begins in the pharynx and airway.

[0061] 15 minutes before the procedure: Nebulization ends, and the patient waits calmly. The intermediate layer lipids begin to be released, and the depth of anesthesia gradually increases.

[0062] Intraoperative procedures (30 to 120 minutes): Vascular puncture, atrial septal puncture, pulmonary vein isolation, linear ablation, etc. Continuous release of lipids from the intermediate layer maintains the depth of airway anesthesia and specifically inhibits the cough reflex caused by catheter stimulation and pulsed electric field energy release, resulting in no coughing and stable hemodynamics in the patient.

[0063] End of surgery (120 minutes): Intravenous sedation was discontinued, and the patient gradually regained consciousness. The nuclear sustained-release formula began to take effect.

[0064] Postoperative recovery (2 to 6 hours): Patients are observed in the recovery room. The core provides sustained-release analgesia to maintain airway pain, reduces the incidence of sore throat, and allows for early feeding.

[0065] 6.2 Adjustment of Dosing Regimens for Special Patients and Special Technologies For patients undergoing pulsed electric field ablation: select 6 to 8-layer liposomal formulations, nebulize 5 mL. Due to the higher incidence of coughing and cumulative effects of pulsed electric field ablation, a longer medium-rate release time (to cover the entire ablation process) and a higher proportion of drug in the intermediate layers are required.

[0066] For patients with obstructive sleep apnea (OSA): halve the dose (1.5 to 2.5 mL) and extend the nebulization time to 10 to 15 minutes. OSA patients are sensitive to sedatives, and airway pretreatment can further reduce the amount of sedatives needed.

[0067] For procedures expected to be lengthy (>180 minutes): choose a 6- to 8-layer liposome formulation, nebulized at 5 mL. A longer intermediate-rate release time is required.

[0068] For elderly patients (>70 years old): halve the dose (1.5 to 2.5 mL) and extend the nebulization time to 10 to 15 minutes.

[0069] Patients with concurrent chronic lung disease: Use with caution or adjust dosage, and closely monitor blood oxygen saturation.

[0070] 7. In vitro release characteristics (for atrial fibrillation ablation time window) 7.1 Three-stage release of design goals 15 minutes: Cumulative release rate of 15% to 20%. This corresponds to the end of nebulization and the beginning of anesthesia induction. Clinically, it signifies the start of airway anesthesia and preparation for intravenous induction.

[0071] 30 minutes: Cumulative release rate of 30% to 35%. Corresponds to vascular puncture and interatrial septal puncture, with clinical significance in inhibiting the cough reflex caused by puncture stimulation.

[0072] 60 minutes: Cumulative release rate 50% to 55%. Corresponding to the pulmonary vein isolation procedure period, its clinical significance is to suppress the cough reflex caused by ablation stimulation and pulsed electric field energy release, and maintain a stable depth of anesthesia.

[0073] 120 minutes: Cumulative release rate 70% to 75%. This corresponds to the end of the ablation procedure, and preparations are made to discontinue sedation. Clinically, this means that there was no coughing or choking interference throughout the procedure, and the cumulative effect of pulsed electric field ablation was effectively suppressed.

[0074] 4 hours: Cumulative release rate of 85% to 90%. Corresponding to the postoperative recovery observation period, the clinical significance is the reduction of postoperative sore throat.

[0075] 6 hours: Cumulative release rate ≥95%. This corresponds to the time for feeding; clinically, it signifies the end of anesthesia and safe eating.

[0076] 7.2 Comparison with ordinary lidocaine solution Regular lidocaine solution: 50% to 60% release in 15 minutes, 80% to 90% release in 30 minutes, and more than 95% release in 60 minutes. It cannot cover surgeries lasting more than 2 hours, and cannot prevent coughing during and in the later stages of surgery.

[0077] The 4- to 5-layer formulation of this invention (general type for radiofrequency ablation) releases 18% to 22% at 15 minutes, 32% to 38% at 30 minutes, 52% to 58% at 60 minutes, 72% to 78% at 120 minutes, 87% to 93% at 4 hours, and more than 95% at 6 hours.

[0078] The 6- to 8-layer formulation of this invention (enhanced pulsed electric field ablation): releases 15% to 19% at 15 minutes, 28% to 33% at 30 minutes, 48% to 53% at 60 minutes, 68% to 73% at 120 minutes, 85% to 90% at 4 hours, and greater than 95% at 6 hours. The intermediate-release phase (30 to 120 minutes) has a higher cumulative drug release and can better suppress the cumulative effect of pulsed electric field ablation.

[0079] This invention also provides the application of the lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler described above in the preparation of a drug for inhibiting coughing induced by atrial fibrillation catheter ablation, wherein the nebulized inhaler is used for: Preoperative airway pretreatment to suppress the cough reflex during catheter ablation, including coughing caused by radiofrequency ablation stimulating the vagus nerve reflex and diaphragmatic contraction and dry cough caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi; Maintaining the depth of airway anesthesia during surgery reduces the amount of intravenous sedatives used and lowers the risk of sedation-related adverse events. Postoperative relief of throat pain and discomfort, and promotion of recovery; The dosing regimen for the nebulized inhaler is as follows: 15 to 25 minutes before atrial fibrillation ablation surgery, inhale 3 to 5 mL via nebulizer for 5 to 10 minutes; The nebulized inhaler, when used in combination with intravenous sedatives, can reduce the induction and maintenance doses of propofol and / or opioids; for patients undergoing pulsed electric field ablation, the nebulized inhaler, when used in combination with an end-expiratory energy release strategy, can further reduce the incidence of diaphragmatic contraction and dry cough.

[0080] This invention also provides a drug delivery kit for atrial fibrillation catheter ablation surgery, comprising the above-mentioned nebulized inhalant, and further comprising: The preferred atomizing device is a vibrating screen hole atomizer; The instruction manual explains how to select the appropriate number of layers of preparation based on the ablation procedure time and the type of ablation technique, as well as the combination of preparations with intravenous sedation drugs and end-tidal energy release strategies.

[0081] This invention also provides a pharmacodynamic evaluation (intended design): 1. Evaluation of the effect of suppressing coughing during radiofrequency ablation 1.1 Experimental Design: Patients with atrial fibrillation scheduled for radiofrequency ablation were randomly divided into two groups: Control group: routine intravenous sedation (midazolam + fentanyl); Experimental group: Preoperative nebulized inhalation of the 4 to 5 layer formulation of this invention (lidocaine 50 mg) + intravenous sedation (midazolam + fentanyl).

[0082] 1.2 Expected Results Intraoperative coughing incident rate: 25% to 35% in the control group and 5% to 10% in the experimental group (a reduction of 70% to 80%). Coughing requiring interruption of operation: 5% to 8% in the control group, 0% to 1% in the experimental group; Catheter displacement events: 3% to 5% in the control group and 0% to 1% in the experimental group; 2. Evaluation of the effect of suppressing coughing during pulsed electric field ablation 2.1 Experimental Design Patients with atrial fibrillation scheduled for pulsed electric field ablation were randomly divided into two groups: Control group: routine intravenous sedation (midazolam + fentanyl), combined with end-tidal energy release; Experimental group: Preoperative nebulized inhalation of the 6 to 8 layer formulation of this invention (lidocaine 50 mg) + intravenous sedation (midazolam + fentanyl), combined with end-tidal energy release.

[0083] 2.2 Expected Results Incidence of dry cough: 11.9% to 43.7% in the control group and 3% to 8% in the experimental group (a reduction of 70% to 80%). Diaphragmatic contraction score: 18.5% to 28.0% in the control group and 4% to 8% in the experimental group (a reduction of 70% to 75%). Incidence of moderate to severe dry cough: 11.9% to 43.7% in the control group and 1% to 3% in the experimental group (a reduction of 85% to 90%). Model displacement in the 3D mapping system: 8% to 12% in the control group and 1% to 3% in the experimental group.

[0084] 3. Evaluation of the cost-saving effect of intravenous sedation drugs 3.1 Expected Results Midazolam dosage: The experimental group was 30% lower than the control group; Fentanyl dosage: The experimental group was 30% to 40% less than the control group; Incidence of hypoxemia: 15% to 20% in the control group and 5% to 8% in the experimental group (a reduction of 60%). Incidence of hypotension: 10% to 15% in the control group and 4% to 6% in the experimental group (a reduction of 50% to 60%).

[0085] 4. Postoperative recovery quality evaluation Incidence of sore throat 2 hours postoperatively: 40% to 50% in the control group and 15% to 20% in the experimental group; VAS score (0 to 10): control group 3.5±1.5, experimental group 1.2±0.8; First feeding time: 4 to 6 hours after surgery in the control group, and 2 to 3 hours after surgery in the experimental group; Patient satisfaction scores (0 to 10 points): control group 7.5±1.2, experimental group 9.0±0.8.

[0086] Example 1: Universal 4- to 5-layer liposome / core-shell nanoparticles for radiofrequency ablation 1.1 Preparation of lidocaine@PLGA core: 350 mg of PLGA (LA:GA ratio of 70:30, molecular weight 35,000 Da) and 87.5 mg of lidocaine bases were dissolved in 7 mL of dichloromethane as the oil phase; the oil phase was slowly injected into 35 mL of 1.5% PVA solution and ultrasonically emulsified using a probe (100 W, 2 min, ice bath); the dichloromethane was evaporated by magnetic stirring overnight, and the nanoparticles were collected by high-speed centrifugation (15,000 g, 20 min), washed 3 times, and resuspended in 3 mL of PBS; the average particle size of the nanoparticles was measured to be 172 nm, the polydispersity index was 0.14, the lidocaine encapsulation efficiency was 75%, and the core drug loading was approximately 18.8 mg.

[0087] 1.2 Preparation of multilayer liposome shell: 45 mg DPPC, 13.5 mg cholesterol, and 6.5 mg DSPE-PEG2000 (molar ratio 60:35:5) were dissolved in 5 mL chloroform, and 15 mg lidocaine base was added; the chloroform was removed by rotary evaporation (40℃) to form a uniform lipid film; the film was dried under nitrogen for 5 min; the above lidocaine@PLGA core dispersion (containing approximately 300 mg of core) was added, and the film was hydrated in a 65℃ water bath for 45 min with gentle shaking; the hydrated suspension was subjected to 4 freeze-thaw cycles (freezing at -20℃ for 30 min, thawing at room temperature); the film was extruded through 400 nm and 200 nm polycarbonate membranes 5 times each; the free drug was removed by ultracentrifugation (100,000 g, 60 min), and the film was resuspended in PBS to a final lidocaine concentration of 10 mg / mL; the final nanoparticle average size was measured to be 235 nm, the polydispersity index was 0.19, and the total lidocaine encapsulation efficiency was 86%.

[0088] 1.3 Preparation of nebulized inhalation formulation: Take the above nanoparticle concentrate, add 4% mannitol, 0.2% sucralose, and 0.01% benzalkonium chloride, dilute with PBS to a final lidocaine concentration of 10 mg / mL, filter through a 0.22 μm filter membrane for sterilization, fill into 10 mL multi-dose bottles, and store at 2 to 8°C.

[0089] Example 2: Pulsed electric field ablation enhanced 6- to 8-layer liposome / core-shell nanoparticles 2.1 Preparation of lidocaine@PLGA core: The core was prepared according to the method in Example 1.1, and the drug content in the core was adjusted to 48% to increase the drug loading in the core.

[0090] 2.2 Preparation of multilayer liposome shell: 48 mg DPPC, 14 mg cholesterol, and 7 mg DSPE-PEG2000 (molar ratio 60:35:5) were dissolved in 5 mL chloroform, and 18 mg lidocaine bases were added (to increase the drug loading of the intermediate and outer layers); chloroform was removed by rotary evaporation (40℃) to form a uniform lipid film; the film was dried under nitrogen for 5 min; the above lidocaine@PLGA core dispersion (containing approximately 300 mg of core) was added, and the film was hydrated in a 65℃ water bath for 45 min with gentle shaking; the hydrated suspension was subjected to 6 freeze-thaw cycles (freezing at -20℃ for 30 min, thawing at room temperature); the film was extruded only through a 400 nm polycarbonate membrane 5 times, avoiding the 200 nm membrane, to retain more lipid layers; the free drug was removed by ultracentrifugation (100,000 g, 60 min), and the film was resuspended in PBS to a final lidocaine concentration of 12 mg / mL; the final average particle size of the nanoparticles was measured to be 285 nm. nm, polydispersity index 0.22, total lidocaine encapsulation efficiency 88%.

[0091] 2.3 Preparation of nebulized inhalation formulation: Take the above nanoparticle concentrate, add 4% mannitol, 0.2% sucralose, and 0.01% benzalkonium chloride, dilute with PBS to a final lidocaine concentration of 12 mg / mL, filter sterilize with a 0.22 μm filter membrane, fill into 10 mL multi-dose bottles, and store at 2 to 8°C.

[0092] Example 3: Short-term ablation using 2 to 3 layers of liposomes / core-shell nanoparticles Following the method in Example 1, the number of freeze-thaw cycles was reduced to 2 to prepare 2 to 3 layers of liposomes / core-shell nanoparticles; the average particle size was 205 nm, the polydispersity index was 0.18, and the in vitro release showed 55% release in 30 minutes, making it suitable for scenarios with ablation time of less than 90 minutes.

[0093] In summary, this invention controls the number of lipid layers (2 to 8 layers) by adjusting the number of freeze-thaw cycles, thereby achieving a three-stage time-sequential release of lidocaine: rapid release of outer lipids (0 to 30 minutes) covers the early puncture stage of surgery; medium-speed release of middle lipids (30 to 120 minutes) precisely matches the high incidence of coughing (pulmonary vein isolation and left atrial posterior wall ablation stage); and slow release of core PLGA (2 to 6 hours) covers the later stage of surgery and the postoperative recovery period. This invention can specifically suppress coughing caused by radiofrequency ablation stimulating the vagus nerve reflex, as well as diaphragmatic contraction and dry cough caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi. It reduces intraoperative catheter displacement and operation interruption, while reducing the dosage of intravenous sedation drugs, lowering the risk of sedation-related adverse events, and improving surgical safety and patient satisfaction.

[0094] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; 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 or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler, characterized in that, Including multilayered liposomes / core-shell nanoparticles and atomized inhalation media; The multilayered liposomes / core-shell nanoparticles have a multilayered core-shell structure, which includes a core, an intermediate layer and an outer layer from the inside out. The core is a PLGA nanoparticle loaded with lidocaine, used to cover the cough suppression needs in the mid-to-late stages of atrial fibrillation catheter ablation surgery. The intermediate layer is a first lipid bilayer that wraps around the outer surface of the core, and is used to cover the cough suppression needs during the high-incidence period of coughing in atrial fibrillation catheter ablation. The outer layer is a multi-layered lipid structure consisting of a second lipid bilayer or more, arranged concentrically with the middle layer, and is used to cover the cough suppression needs in the early stages of atrial fibrillation catheter ablation surgery.

2. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 1, characterized in that, The peak period for coughing and choking is 30 to 120 minutes after the start of the surgery, corresponding to the pulmonary vein isolation and left atrial posterior wall ablation stages; The cough suppression includes suppressing coughing caused by radiofrequency ablation stimulation of the vagus nerve reflex, and suppressing diaphragmatic contraction and dry cough caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi.

3. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 1, characterized in that, The PLGA has a lactic acid (LA) to glycolic acid monomer (GA) ratio (LA:GA) of 75:25 to 60:40 and a molecular weight of 20,000 to 50,000 Da.

4. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 1, characterized in that, The multilayer lipid structure is composed of phospholipids, cholesterol, and polyethylene glycol-modified phospholipids; The phospholipids include dipalmitoylphosphatidylcholine (DPPC).

5. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 4, characterized in that, The molar ratio of the phospholipids, cholesterol, and polyethylene glycol-modified phospholipids is 50%-70%: 25%-45%: 3%-10%.

6. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 1, characterized in that, The number of layers in the multilayer lipid structure is 2 to 10; Among them, layers 2 to 3 are suitable for radiofrequency ablation with an ablation time of less than 90 minutes; Four to five layers are suitable for radiofrequency ablation or pulsed electric field ablation with ablation time of 90 to 150 minutes; Layers 6 to 8 are suitable for scenarios where the ablation time is greater than 150 minutes or where there are many pulse electric field ablation cycles.

7. The lidocaine multilayer liposome / core-shell nanoparticle nebulized inhaler according to claim 1, characterized in that, The overall particle size of the multilayer liposomes / core-shell nanoparticles is 180 to 350 nm. The lidocaine multilayer liposome / core-shell nanoparticle nebulizer produces droplet sizes ranging from 2 to 5 μm after nebulization.

8. A method for preparing the lidocaine multilayer liposome / core-shell nanoparticle nebulized inhalant according to any one of claims 1 to 7, characterized in that, Includes the following steps: Step 1: Prepare lidocaine-loaded PLGA nanoparticle cores using a solvent evaporation method; Step 2: Using a thin-film hydration method combined with freeze-thaw cycles, multilayer liposomes loaded with lidocaine were prepared and encapsulated with the PLGA nanoparticle core prepared in Step 1 to form multilayer liposomes / core-shell nanoparticles. The number of lipid layers was controlled by adjusting the number of freeze-thaw cycles. Step 3: Disperse the multilayer liposomes / core-shell nanoparticles prepared in Step 2 in the nebulization inhalation medium to obtain lidocaine multilayer liposomes / core-shell nanoparticle nebulized inhaler.

9. The method according to claim 8, characterized in that, The number of freeze-thaw cycles mentioned in step 2 is determined based on the expected time of the atrial fibrillation ablation surgery and the type of ablation technique: If the ablation time is less than 90 minutes, 2 to 3 applications should be used. When the ablation time is 90 to 150 minutes, 4 to 5 applications are required; When the ablation time is greater than 150 minutes or the number of pulse electric field ablations reaches the preset value, 6 to 8 ablations are performed.

10. The use of a lidocaine multilayer liposome / core-shell nanoparticle nebulized inhalant as described in any one of claims 1 to 7 in the preparation of a medicament for inhibiting coughing induced by stimulation during atrial fibrillation catheter ablation, characterized in that, The nebulized inhalant is used for: Preoperative airway pretreatment to suppress the cough reflex during catheter ablation. The cough reflex includes coughing caused by radiofrequency ablation stimulating the vagus nerve and coughing caused by pulsed electric field ablation directly stimulating the phrenic nerve and bronchi. Maintain the depth of airway anesthesia during the operation and reduce the amount of intravenous sedative drugs; Postoperative relief of throat pain and discomfort.