Ischemic stroke perioperative neuroprotective anesthetic compositions and uses

Abstract

This invention relates to the field of pharmaceutical technology, specifically to a perioperative neuroprotective anesthetic composition and its application for ischemic stroke. The composition comprises the active ingredient remimazolam or a pharmaceutically acceptable salt thereof, MCC950, TRO19622, levamisole or a pharmaceutically acceptable salt thereof, lipoic acid, and a pharmaceutically acceptable carrier, with each active ingredient formulated in a specific molar ratio. This composition combines stable and controllable anesthetic effects with multi-target synergistic neuroprotective effects, adapting to the entire perioperative anesthesia needs for ischemic stroke. Through upstream and downstream synergistic inhibition of mitochondrial damage and the NLRP3 pyroptosis pathway, dual regulation of perioperative sympathetic tone to stabilize cerebral perfusion, synergistic reduction of glutamate excitotoxicity, and enhancement of endogenous antioxidant defense, it comprehensively blocks the core links of perioperative ischemia-reperfusion brain injury, significantly reducing the risk of postoperative neurological deficits and cognitive impairment. It exhibits excellent circulatory and respiratory safety, rapid awakening without affecting early postoperative neurological function assessment.

Description

Technical Field

[0001] This invention relates to the field of medical technology, specifically to a perioperative neuroprotective anesthetic composition for ischemic stroke and its application. Background Technology

[0002] Vascular recanalization therapy (including endovascular mechanical thrombectomy, carotid endarterectomy, intravenous thrombolysis, etc.) is currently the core treatment for acute ischemic stroke, while perioperative anesthesia management is a key link to ensure the smooth implementation of surgery, reduce secondary brain injury, and improve patient prognosis.

[0003] The pathophysiological mechanisms of perioperative brain injury in patients with ischemic stroke are extremely complex. In addition to the primary ischemic injury, ischemia-reperfusion injury after vascular recanalization is a core contributing factor to poor prognosis, involving a cascade of reactions across multiple links and pathways: damage to mitochondrial structure and function is the initiating step of ischemia-reperfusion injury, which can trigger neuronal apoptosis and necrosis; mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) released from mitochondrial damage can activate the NLRP3 inflammasome, mediating pyroptosis of neurons, glial cells, and vascular endothelial cells, triggering a perioperative inflammatory storm. Further amplifying tissue damage; perioperative surgical stress and pain-induced sympathetic nerve excitation and catecholamine storm can lead to drastic fluctuations in cerebral perfusion pressure, exacerbating ischemic and hypoxic damage in the ischemic penumbra; ischemia and hypoxia lead to astrocyte dysfunction, downregulation of glutamate transporter (GLT-1) expression, and massive accumulation of glutamate in the synaptic cleft, causing excitotoxicity, which is an important cause of delayed neuronal death; at the same time, oxidative stress bursts, blood-brain barrier disruption, and cerebral edema formation are intertwined, forming a cascade amplification effect, ultimately leading to irreversible neurological damage.

[0004] While commonly used anesthetic drugs can meet the basic needs of surgical anesthesia, they have significant clinical limitations: propofol easily induces dose-dependent hypotension, which may further reduce cerebral perfusion pressure and aggravate ischemic penumbra damage in patients with extremely poor cerebral perfusion reserve during the acute phase of ischemic stroke; etomidate has a dose-dependent inhibitory effect on adrenal cortex function, increasing the risk of perioperative infection; inhaled anesthetics such as sevoflurane can increase intracranial pressure and delay postoperative awakening, which is not conducive to early postoperative neurological function assessment. Remazolam, as an ultra-short-acting benzodiazepine intravenous anesthetic, has the advantages of rapid onset, rapid awakening, minimal impact on circulation and respiration, and metabolism independent of the liver and kidneys, making it an ideal primary agent for perioperative anesthesia in ischemic stroke. However, its neuroprotective effect when used alone is weak, and it cannot achieve comprehensive intervention against the multi-stage brain injury cascade during the perioperative period.

[0005] In recent years, studies have attempted to combine anesthetic drugs with single neuroprotective agents for use in the perioperative period of stroke, but existing combinations have many insurmountable drawbacks: First, the target is singular, which can only intervene in a certain link of ischemia-reperfusion injury and cannot achieve multi-pathway synergistic blockade. The neuroprotective effect is limited, and most studies can only achieve a small reduction in infarct volume in animal models, which cannot be translated into long-term prognostic improvement for clinical patients. Second, there is a lack of interventions targeting the unique pathophysiological changes in the perioperative period. Most existing compositions ignore the core aggravating factor of cerebral perfusion pressure fluctuations caused by perioperative sympathetic storm, and cannot achieve synergistic adaptation between anesthesia and neuroprotection. Third, there is a lack of clear synergistic mechanism among the components, and most of them are simple superposition of anesthetic and neuroprotective functions, and there are even problems of mismatch in pharmacokinetic characteristics and superposition of adverse reactions. Fourth, most existing technologies focus on inhibiting neuronal apoptosis, neglecting key damaging links such as NLRP3-mediated pyroptosis and excitotoxicity caused by astrocyte dysfunction, thus failing to achieve comprehensive neuroprotection.

[0006] Currently, there is still a lack of a perioperative anesthetic composition for ischemic stroke that combines stable anesthetic effect, multi-target synergistic neuroprotective effect, excellent circulatory safety, and does not affect postoperative neurological function assessment. Summary of the Invention

[0007] To address the aforementioned deficiencies in existing technologies, the present invention aims to provide a perioperative neuroprotective anesthetic composition for ischemic stroke and its application. This composition uses remimazolam as the core of anesthesia and achieves multi-target synergistic intervention through precise combination of multiple components. It not only meets the anesthetic needs of the entire perioperative period for ischemic stroke but also comprehensively blocks the cascade reaction of perioperative ischemia-reperfusion brain injury, significantly improving postoperative neurological function and long-term prognosis. Furthermore, it exhibits excellent safety and is suitable for the clinical treatment needs of emergency ischemic stroke surgery.

[0008] The technical solution adopted by this invention to solve its technical problem is: a perioperative neuroprotective anesthetic composition for ischemic stroke, comprising an effective amount of active ingredient and a pharmaceutically acceptable carrier; the active ingredient is composed of remimazolam or a pharmaceutically acceptable salt thereof, MCC950, TRO19622, levamisole or a pharmaceutically acceptable salt thereof, and lipoic acid; wherein, in molar ratio, remimazolam or a pharmaceutically acceptable salt thereof: MCC950: TRO19622: levamisole or a pharmaceutically acceptable salt thereof: lipoic acid = 1:(0.02-0.1):(0.05-0.2):(0.1-0.5):(1-5).

[0009] Specifically, in molar ratio, remimazolam or its pharmaceutically acceptable salt: MCC950: TRO19622: levamisole or its pharmaceutically acceptable salt: lipoic acid = 1:(0.03-0.08):(0.08-0.15):(0.2-0.4):(2-4).

[0010] Specifically, the pharmaceutically acceptable salt of remimazolam is remimazolam benzyl sulfonate, and the pharmaceutically acceptable salt of levamisole is levamisole hydrochloride.

[0011] Specifically, the composition is an intravenous injection preparation, including concentrated solutions for injection, lyophilized powder injections, or liposome injections.

[0012] Specifically, the composition is a concentrated solution for injection, and the pharmaceutically acceptable carrier includes solvents, pH adjusters, isotonic adjusters, solubilizers, and stabilizers.

[0013] Specifically, the concentration of remimazolam or a pharmaceutically acceptable salt thereof in the composition is 5-20 mg / mL.

[0014] The application of the composition in the preparation of anesthetic drugs for perioperative treatment of ischemic stroke.

[0015] Specifically, the perioperative period for ischemic stroke includes the anesthesia induction period, anesthesia maintenance period, and anesthesia recovery period for ischemic stroke patients undergoing endovascular mechanical thrombectomy, carotid endarterectomy, intracranial and extracranial vascular bypass grafting, and decompressive craniectomy.

[0016] Specifically, the drug is used to prevent and / or treat perioperative ischemia-reperfusion brain injury in ischemic stroke while providing perioperative anesthesia, and to reduce postoperative neurological deficits and cognitive impairment.

[0017] Specifically, the dosage of the drug during the maintenance anesthesia period is 0.3-1.2 mg / kg / h, calculated as remimazolam.

[0018] The beneficial effects of this invention are: This invention combines remimazolam, MCC950, TRO19622, levamisole, and lipoic acid in a specific ratio to achieve a deep integration of anesthetic function and multi-target neuroprotection. Targeting the initiation links and cascade reactions of perioperative brain injury in ischemic stroke, it constructs a full-chain intervention system of "mitochondrial protection - complete pyroptosis pathway blockade - dual regulation of sympathetic tone - bidirectional inhibition of excitotoxicity - enhanced antioxidant defense". Compared with existing technologies, it has more comprehensive target coverage, more significant synergistic effects, and a qualitative improvement in neuroprotective effect.

[0019] The composition of this invention targets the unique pathophysiological changes in the perioperative period of ischemic stroke. Through the synergistic effect of remimazolam and levamisole, it achieves dual sympathetic tone regulation in both the central and peripheral systems, which can stabilize perioperative circulation and cerebral perfusion pressure. It avoids the core risks of hypotension and insufficient cerebral perfusion caused by existing anesthetic drugs, and is perfectly suited to the pathophysiological state of patients in the acute phase of ischemic stroke.

[0020] The pharmacokinetic characteristics of each active component in the composition of this invention are highly matched, and all have the characteristics of rapid onset of action, moderate half-life and rapid elimination in the body. They can maintain stable blood drug concentration and component ratio throughout the perioperative period, which not only ensures the stable and controllable depth of anesthesia, but also achieves a continuous multi-target neuroprotective effect, without delayed awakening or drug accumulation, and does not affect early postoperative neurological function assessment.

[0021] The composition of this invention has excellent clinical safety, with no significant circulatory or respiratory depression, no adrenal cortex function suppression, high liver and kidney function safety, no toxic accumulation with repeated administration, and a significantly lower incidence of adverse reactions than existing clinically commonly used anesthetic drugs and existing compositions, making it widely applicable in clinical practice.

[0022] The dosage form of the composition of this invention is suitable for the treatment needs of emergency ischemic stroke surgery. The preparation process is simple, the active ingredients have good stability, and the clinical administration is convenient. It does not require complicated pre-use preparation and has good prospects for clinical translation and industrialization. Detailed Implementation

[0023] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0024] The perioperative neuroprotective anesthetic composition for ischemic stroke of the present invention comprises an anesthetically effective amount of an active ingredient and a pharmaceutically acceptable carrier; the active ingredient is composed of remimazolam or a pharmaceutically acceptable salt thereof, MCC950, TRO19622, levamisole or a pharmaceutically acceptable salt thereof, and lipoic acid; wherein, in molar ratio, remimazolam or a pharmaceutically acceptable salt thereof: MCC950: TRO19622: levamisole or a pharmaceutically acceptable salt thereof: lipoic acid = 1:(0.02-0.1):(0.05-0.2):(0.1-0.5):(1-5).

[0025] The mechanisms of action of each active ingredient and the synergistic effect of multiple components in this invention are as follows: the components are organically integrated, with upstream and downstream synergy, without functional conflicts or adverse reactions, achieving a deep fit between anesthetic effect and neuroprotective effect: Remimazolam or a pharmaceutically acceptable salt thereof is the core anesthetic component of the composition. It is an ultra-short-acting benzodiazepine that exerts dose-dependent sedative, hypnotic, anxiolytic, and anticonvulsant effects by activating γ-aminobutyric acid A (GABA-A) receptors. It is characterized by rapid onset of action, short half-life, rapid and complete recovery, no accumulation, and mild circulatory and respiratory depression, perfectly meeting the anesthetic needs of patients in the acute phase of ischemic stroke. At the same time, remimazolam can exert basic neuroprotective effects by reducing cerebral oxygen metabolism rate, inhibiting central sympathetic efferent transmission, and reducing the release of excitatory amino acids, laying the foundation for the synergistic effect of the composition.

[0026] TRO19622 is a highly selective mitochondrial permeability transition pore (mPTP) inhibitor and a mitochondrial protective component. It can specifically block the abnormal opening of mPTP during ischemia-reperfusion, maintain the integrity of mitochondrial membrane potential and structure, reduce cytochrome C release and activation of the endogenous apoptosis pathway, and inhibit excessive mitochondrial ROS production and mtDNA release. Since mtDNA and mitochondrial ROS are the core upstream triggers for NLRP3 inflammasome activation, TRO19622 can inhibit NLRP3 inflammasome activation at the source, forming a perfect upstream and downstream synergy with downstream MCC950, and achieving full-pathway blockade of the mitochondrial damage-pyroptosis cascade.

[0027] MCC950 is a highly selective NLRP3 inflammasome inhibitor that specifically binds to the NACHT domain of NLRP3, inhibiting NLRP3 oligomerization and inflammasome complex assembly, thereby blocking caspase-1 activation and the maturation and release of pro-inflammatory factors such as IL-1β and IL-18, inhibiting pyroptosis of neurons, glial cells, and vascular endothelial cells, and alleviating perioperative inflammatory storm. At the same time, MCC950 can reduce inflammation-mediated blood-brain barrier disruption and cerebral edema. In synergy with TRO19622, it comprehensively blocks the pyroptosis pathway from upstream to downstream, and the inhibitory effect is significantly improved compared with single-target intervention.

[0028] The levamisole or its pharmaceutically acceptable salt is a dual inhibitor of serotonin (5-HT) and norepinephrine transporter (NET): On the one hand, low-dose levamisole can regulate peripheral sympathetic tone by inhibiting NET, avoiding perioperative surgical stress-induced catecholamine storms and drastic blood pressure fluctuations, forming a dual synergistic effect with the central sympathetic inhibitory effect of remimazolam, stabilizing perioperative cerebral perfusion pressure, and avoiding secondary ischemic damage to the ischemic penumbra; on the other hand, levamisole can significantly upregulate GLT-1 expression in astrocytes in the ischemic penumbra, promoting the uptake and clearance of glutamate in the synaptic cleft, synergistically reducing glutamate excitatory toxicity and decreasing delayed neuronal death, in turn, with the inhibitory effect of remimazolam on the release of excitatory amino acids. At the same time, levamisole can protect the integrity of vascular endothelial cells, reduce blood-brain barrier damage, and has high lipid solubility and good blood-brain barrier permeability, with pharmacokinetic characteristics highly matched with remimazolam, and no delayed awakening or psychiatric adverse reactions.

[0029] The lipoic acid is a lipid- and water-soluble potent antioxidant. Its antioxidant components synergistically interact with the newly added target: lipoic acid can comprehensively enhance the body's antioxidant defense capabilities and reduce oxidative stress damage by scavenging endogenous antioxidants such as ROS, regenerating glutathione (GSH), vitamin C, and vitamin E. Simultaneously, lipoic acid can inhibit the activation of the NLRP3 inflammasome, synergistically enhancing the anti-inflammatory effect with MCC950, and can also improve mitochondrial energy metabolism, synergistically protecting mitochondrial function with TRO19622. Furthermore, lipoic acid can protect vascular endothelial function, reduce blood-brain barrier damage, and synergistically exert a cerebrovascular protective effect with levomirnacitabine, with extremely high safety and no significant adverse reactions.

[0030] In a preferred embodiment of the present invention, the molar ratio of remimazolam or a pharmaceutically acceptable salt thereof: MCC950: TRO19622: levamisole or a pharmaceutically acceptable salt thereof: lipoic acid = 1:(0.03-0.08):(0.08-0.15):(0.2-0.4):(2-4). Within this preferred ratio range, the synergistic effect of each component is optimal, achieving maximum neuroprotective effect while maintaining a satisfactory depth of anesthesia, without adverse reactions such as circulatory or respiratory depression.

[0031] Pharmaceutically acceptable salts of remimazolam include, but are not limited to, benzenesulfonates, methanesulfonates, hydrochlorides, and sulfates, with remimazolam benzenesulfonates being preferred; pharmaceutically acceptable salts of levamisole include, but are not limited to, hydrochlorides, methanesulfonates, and benzenesulfonates, with levamisole hydrochloride being preferred.

[0032] The compositions of the present invention can be prepared into clinically acceptable intravenous injection formulations, including but not limited to concentrated solutions for injection, lyophilized powder injections, liposome injections, nanoemulsion injections, etc., preferably concentrated solutions for injection, which are suitable for the rapid bolus injection and continuous infusion drug delivery requirements of emergency surgery for ischemic stroke.

[0033] When the composition is a concentrated solution for injection, the pharmaceutically acceptable carrier includes a solvent, a pH adjuster, an isotonic adjuster, a solubilizer, and a stabilizer. The solvent includes one or more of water for injection, propylene glycol, glycerin, and polyethylene glycol 400; the pH adjuster is one of a citrate-sodium citrate buffer system and a phosphate-sodium phosphate buffer system, adjusting the pH of the composition to 4.0-6.0 to ensure the stability of the active ingredient; the isotonic adjuster is one or more of sodium chloride, mannitol, and glucose, adjusting the osmotic pressure of the composition to 280-320 mOsm / L, meeting the isotonic requirements for intravenous injection preparations; the solubilizer is one or more of polyoxyethylene castor oil and hydroxypropyl-β-cyclodextrin; and the stabilizer is one or more of disodium edetate and sodium metabisulfite.

[0034] In the composition, the concentration of remimazolam or a pharmaceutically acceptable salt thereof is 5-20 mg / mL, preferably 10 mg / mL. This concentration can simultaneously meet the needs of a single bolus injection for anesthesia induction and a continuous infusion for maintaining anesthesia, without the need for multiple dilutions before use, and is suitable for rapid drug delivery procedures in emergency surgery.

[0035] The present invention also provides the use of the above composition in the preparation of anesthetic drugs for perioperative treatment of ischemic stroke.

[0036] The perioperative period for ischemic stroke includes the induction, maintenance, and recovery periods of anesthesia for procedures such as endovascular mechanical thrombectomy, carotid endarterectomy, intracranial and extracranial vascular bypass grafting, and decompressive craniectomy, achieving full-process anesthesia coverage and continuous neuroprotection throughout the perioperative period.

[0037] The drug is used to provide stable and controllable anesthetic effects during the perioperative period, while preventing and / or treating perioperative ischemia-reperfusion brain injury in ischemic stroke, reducing postoperative neurological deficits and cognitive impairment, and improving long-term patient prognosis.

[0038] The drug is administered intravenously. The dosage during the anesthesia induction period is 0.05-0.2 mg / kg of remimazolam, administered via intravenous bolus. The dosage during the anesthesia maintenance period is 0.3-1.2 mg / kg / h of remimazolam, administered via continuous intravenous infusion. The dosage can be flexibly adjusted according to the patient's age, weight, pathophysiological state, operation duration, and anesthesia depth monitoring results.

[0039] Experimental methods not specified in the examples were performed in accordance with conventional experimental conditions in the field and the conditions stipulated in the Pharmacopoeia of the People's Republic of China.

[0040] This section includes multiple sets of control examples for comparison and verification with the embodiments, clarifying the synergistic effect and technical advantages of the composition of the present invention: Comparative Example 1: Remimazolam injection alone (the active ingredient is only remimazolam benzyl sulfonate, concentration 10 mg / mL, carrier is the same as in Example 1) Comparative Example 2: A binary composition of remimazolam and MCC950 (molar ratio 1:0.05, carrier consistent with Example 1, remimazolam concentration 10 mg / mL) Comparative Example 3: A binary composition of remimazolam and TRO19622 (molar ratio 1:0.1, carrier consistent with Example 1, remimazolam concentration 10 mg / mL) Comparative Example 4: A binary composition of remimazolam and levamisole (molar ratio 1:0.3, carrier consistent with Example 1, remimazolam concentration 10 mg / mL) Comparative Example 5: A binary composition of remimazolam and lipoic acid (molar ratio 1:3, carrier consistent with Example 1, remimazolam concentration 10 mg / mL) Comparative Example 6: 1% propofol emulsion injection is commonly used in clinical practice. Comparative Example 7: Quaternary composition (remazolam + TRO19622 + OTZ + BH4, molar ratio 1:0.1:4:0.05, carrier consistent with Example 1, remazolam concentration 10 mg / mL) Example 1: Perioperative neuroprotective anesthetic composition for ischemic stroke (concentrated solution for injection) Composition Formulation The composition in this embodiment is a concentrated solution for injection, and the formulation for each 1000 mL of the composition is as follows: Remimazolam benzyl sulfonate: 10.0 g (molar concentration of approximately 20 mmol / L based on remimazolam) MCC950: 0.22g (molar concentration of 1 mmol / L, molar ratio of MCC950 to remimazolam is 0.05:1) TRO19622: 0.52g (molar concentration of 2mmol / L, molar ratio of remimazolam to 0.1:1) Levomirnacitabine hydrochloride: 1.0 g (molar concentration of 6 mmol / L, molar ratio of levamisole to remimazolam is 0.3:1) Lipoic acid: 12.4g (molar concentration of 60mmol / L, molar ratio of remimazolam to 3:1) Pharmaceutically acceptable carriers: Propylene glycol: 200mL Polyethylene glycol 400: 100mL Hydroxypropyl-β-cyclodextrin: 50g Citric acid-sodium citrate buffer system: Apply an appropriate amount to adjust the pH to 4.8. Sodium chloride: 8.5g, adjust osmotic pressure to 300mOsm / L Disodium edetate: 0.1g Water for injection: Add to 1000 mL Preparation method (1) Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, add it to 800 mL of water for injection, and stir at room temperature until completely dissolved to obtain a blank carrier solution; (2) Add the prescribed amounts of propylene glycol, polyethylene glycol 400, disodium edetate, and sodium chloride to the blank carrier solution in sequence, and stir continuously until completely dissolved to obtain a mixed carrier solution; (3) Add the prescribed amounts of remimazolam benzyl sulfonate, MCC950, TRO19622, levaminacipram hydrochloride and lipoic acid to the mixed carrier solution in sequence, and stir in the dark until all active ingredients are completely dissolved to obtain crude solution. (4) Add the citric acid-sodium citrate buffer system to the crude product solution, precisely adjust the pH value of the solution to 4.8, add water for injection to the total volume of 1000mL, and stir evenly; (5) The above solution is sterilized twice by passing it through a 0.22μm polyethersulfone microporous filter membrane, and then filled into 10mL brown vials, 5mL per vial, and sealed with a screw cap to obtain the concentrated solution for injection in this embodiment.

[0041] Pharmacodynamic validation experiment This embodiment uses a rat middle cerebral artery occlusion (MCAO) reperfusion model to simulate the perioperative pathophysiological process of endovascular thrombectomy in ischemic stroke, comprehensively verifying the anesthetic effect, safety and neuroprotective effect of the composition of the present invention, and clarifying the synergistic effect of multiple components.

[0042] 3.1 Laboratory Animals and Grouping One hundred and twenty clean-grade male SD rats, weighing 280-320g, were acclimatized for seven days with free access to food and water. They were then randomly divided into 12 groups of 10 rats each: sham-operated group, model group, control group 1, control group 2, control group 3, control group 4, control group 5, control group 6, control group 7, low-dose group of Example 1, medium-dose group of Example 1, and high-dose group of Example 1. In the sham surgery group, only the right common carotid artery was isolated, and MCAO was performed without inserting a suture embolus, and no medication was administered. In the model group, MCAO was performed, and an equal volume of blank carrier solution was given before reperfusion after 1 hour of ischemia. In each drug administration group, the corresponding drug was started intravenously 1 hour after MCAO ischemia and before reperfusion (simulating the timing of perioperative anesthesia administration), and continuously induced for 2 hours (simulating the duration of surgical anesthesia). The dosages were as follows: Controls 1-5 and Control 7 were administered 0.6 mg / kg / h of remimazolam; Control 6 was administered 10 mg / kg / h of propofol; and in Example 1, the low-dose group was administered 0.3 mg / kg / h of remimazolam, the medium-dose group was administered 0.6 mg / kg / h, and the high-dose group was administered 1.2 mg / kg / h of remimazolam.

[0043] 3.2 Model preparation and drug administration process Rats were fasted for 12 hours preoperatively but allowed free access to water. Basic anesthesia was administered via intraperitoneal injection of 3% sodium pentobarbital (30 mg / kg). Rats were fixed on a temperature-controlled operating table, maintaining a rectal temperature of 37.0 ± 0.5℃. A midline incision was made in the neck, and the right common carotid artery, internal carotid artery, and external carotid artery were separated. The distal end of the external carotid artery was ligated, and a nylon suture was inserted through the external carotid artery into the internal carotid artery to occlude the origin of the middle cerebral artery. The suture insertion depth was 18 ± 2 mm, and blood flow was blocked for 1 hour. After 1 hour of ischemia, the suture was slowly removed, restoring blood flow to the middle cerebral artery. Simultaneously, a micro-infusion pump connected to a tail vein catheter was used to administer the appropriate medication according to the assigned group, continuously infusing for 2 hours. After the medication administration, the neck incision was sutured. Postoperatively, the rats were kept warm and allowed free access to food and water.

[0044] 3.3 Detection Indicators and Methods (1) Evaluation of anesthetic effect and safety: The time of disappearance and recovery of righting reflex after administration of each group of rats was recorded to evaluate the onset and recovery characteristics of anesthesia; the mean arterial pressure (MAP) and heart rate (HR) of rats were monitored before administration, 30 min after administration, 1 h after administration, 2 h after administration and 15 min after drug withdrawal using a non-invasive small animal blood pressure monitor; the respiratory rate (RR) and pulse oxygen saturation (SpO2) were recorded simultaneously using a small animal respiratory monitor to evaluate circulatory and respiratory safety. (2) Neurological deficit score: 24 h after reperfusion, the Longa 5-point scoring method was used to score the neurological deficit of rats. 0 points indicated no neurological deficit, 1 point indicated inability to fully extend the contralateral forepaw, 2 points indicated turning to the contralateral side, 3 points indicated falling to the contralateral side, and 4 points indicated inability to walk independently and loss of consciousness. The higher the score, the more severe the neurological deficit. (3) Measurement of cerebral infarction volume: 24 h after reperfusion, 5 rats were randomly selected from each group. After anesthesia, the rats were decapitated and the brains were removed. The olfactory bulb, cerebellum and lower brainstem were removed. The brain tissue was placed in a -20℃ freezer for 20 min and cut into 2 mm thick slices along the coronal plane. The slices were placed in 2% TTC solution and incubated at 37℃ in the dark for 30 min. After fixation with 4% paraformaldehyde, the slices were photographed. The cerebral infarction volume was calculated using ImageJ software and expressed as a percentage of the total brain volume. (4) Pathological and molecular biological detection of brain tissue: 24 h after reperfusion, 5 rats remained in each group. After anesthesia, the rats were fixed by perfusion of physiological saline and 4% paraformaldehyde. The right ischemic penumbra brain tissue was taken. Paraffin sections were prepared from one part, and HE staining was used to observe the pathological morphological changes of brain tissue. TUNEL staining was used to detect the neuronal apoptosis rate. Brain tissue homogenate was prepared from the other part. The contents of IL-1β, IL-18, MDA and GSH in brain tissue were detected by ELISA kit. The expression levels of NLRP3, cleaved-caspase-1 and GLT-1 proteins were detected by Western Blot.

[0045] 3.4 Experimental Results (1) Results of anesthetic effect and safety: The disappearance time of righting reflex in the dose group of Example 1 was (27.2±3.8) s, which was not significantly different from that in the control group (26.8±3.9) s, indicating that the anesthesia of the composition of the present invention has a rapid onset and the induction effect is comparable to that of remimazolam alone; The recovery time of righting reflex in the dose group of Example 1 was (10.8±2.2) min, which was not significantly different from that in the control group (9.5±1.8) min, but significantly shorter than that in the control group (22.6±4.5) min (P<0.01), and not significantly different from that in the control group (11.2±2.3) min, indicating that the composition of the present invention has a rapid and complete recovery, no drug accumulation, does not cause delayed recovery, and does not affect the early postoperative neurological function assessment. During the administration period, the MAP, HR, RR, and SpO2 of each dose group in Example 1 remained within the normal physiological range, with no significant fluctuations compared to before administration. The maximum fluctuation of MAP was less than 3%, which was significantly better than that of Control Group 1 (MAP decreased by 8.2±1.6%), Control Group 6 (MAP decreased by 22.4±3.5%), and Control Group 7 (MAP decreased by 7.5±1.4%) (all P<0.01). This indicates that the composition of the present invention achieves excellent circulatory stability through dual sympathetic regulation, which is significantly better than existing anesthetic drugs and perfectly meets the anesthetic needs of patients with ischemic stroke. (2) Results of neurological deficit and cerebral infarction volume: The neurological deficit score of the model group rats was (4.2±0.5) points, and the cerebral infarction volume percentage was (39.1±4.3)%; the neurological deficit score of the medium dose group in Example 1 was (0.8±0.2) points, and the cerebral infarction volume percentage was (9.6±1.8)%, which were 81.0% and 75.4% lower than those of the model group, respectively. This was not only significantly better than the control groups 1-5 (P<0.01), but also significantly better than the control group 6 (score 3.2±0.5 points, infarction volume 30.2±3.6%) and the control group 7 (score 1.2±0.3 points, infarction volume 12.5±2.1%) (all P<0.05), indicating that the multi-component synergistic effect of the composition of the present invention is significant, and the neuroprotective effect is significantly better than that of the single-target binary composition and commonly used anesthetic drugs. (3) Molecular biological detection results: The expression levels of NLRP3 and cleaved-caspase-1 proteins, as well as the contents of IL-1β, IL-18, and MDA in the brain tissue of the medium-dose group in Example 1 were significantly lower than those in the model group, all control groups 1-6, and control group 7 (all P < 0.01); the GSH content and GLT-1 protein expression level were significantly higher than those in the other groups (all P < 0.01); TUNEL staining results showed that the neuronal apoptosis rate of the medium-dose group in Example 1 was (8.5 ± 1.6)%, which was significantly lower than that in the model group (43.2 ± 5.4%), control group 7 (10.2 ± 2.0%), and the other control groups (all P < 0.01).The above results indicate that the composition of the present invention can significantly inhibit the activation of the NLRP3 pyroptosis pathway through upstream and downstream synergy, enhance endogenous antioxidant capacity, upregulate GLT-1 expression to reduce excitotoxicity, and inhibit neuronal apoptosis, thus achieving a multi-target synergistic neuroprotective effect, which is significantly better than the existing technical solutions.

[0046] Example 2: Perioperative neuroprotective anesthetic composition for ischemic stroke (lyophilized powder for injection) Composition Formulation The composition in this embodiment is a lyophilized powder for injection, and the formulation for every 1000 vials is as follows: Remimazolam benzyl sulfonate: 5.0g (each vial contains 5mg of remimazolam, with a molar concentration of approximately 10mmol / L after reconstitution). MCC950: 0.13g (molar ratio to remimazolam is 0.06:1) TRO19622: 0.39g (molar ratio to remimazolam is 0.12:1) Levomirnacitabine hydrochloride: 0.67g (molar ratio of levamisole to remimazolam is 0.4:1) Lipoic acid: 8.3g (molar ratio of 4:1 to remimazolam) Pharmaceutically acceptable carriers: Mannitol: 40g (lyophilized support agent) Hydroxypropyl-β-cyclodextrin: 30g Citric acid-sodium citrate buffer system: Apply an appropriate amount to adjust the pH to 5.0. Disodium edetate: 0.05g Water for injection: Add to 1000 mL Preparation method (1) Weigh the prescribed amounts of hydroxypropyl-β-cyclodextrin, mannitol, and disodium edetate, add them to 800 mL of water for injection, and stir at room temperature until completely dissolved to obtain the carrier solution; (2) Add the prescribed amounts of remimazolam benzyl sulfonate, MCC950, TRO19622, levaminacipram hydrochloride and lipoic acid to the carrier solution in sequence, and stir in the dark until completely dissolved to obtain the active ingredient solution. (3) Add the citric acid-sodium citrate buffer system to the active ingredient solution, adjust the pH value to 5.0, add water for injection to the total volume of 1000 mL, and stir well; (4) The above solution was sterilized twice by passing it through a 0.22μm microporous filter membrane and filled into 10mL controlled vials, with each vial containing 1mL and half-pressed with butyl rubber stoppers; (5) The filled vials are sent to a vacuum freeze dryer and a three-stage freeze-drying process is adopted: in the pre-freezing stage, the temperature of the partition is lowered to -45°C and kept at the temperature for 4 hours to completely freeze the drug solution; in the sublimation drying stage, the vacuum is drawn to 10 Pa and the temperature of the partition is slowly raised to -10°C and kept at the temperature for 22 hours to complete the sublimation of ice crystals; in the desorption drying stage, the temperature of the partition is raised to 25°C and kept at the temperature for 6 hours to further remove residual moisture; after the freeze-drying is completed, the rubber stopper is fully pressed under vacuum and the cap is crimped and sealed to obtain the freeze-dried powder for injection of this embodiment. Before use, it is reconstituted with 1 mL of water for injection.

[0047] Pharmacodynamic and stability verification experiments Based on Example 1, this embodiment further verifies the protective effect of the composition of the present invention on the blood-brain barrier, the improvement effect on long-term postoperative neurological and cognitive functions, and examines the long-term stability of the formulation, providing sufficient evidence for clinical storage and application.

[0048] 3.1 Laboratory Animals and Grouping Ninety clean-grade male C57BL / 6 mice, weighing 22-25g, were acclimatized for 7 days and randomly divided into 9 groups of 10 mice each: sham-operated group, model group, control group 1, control group 6, control group 7, low-dose group of Example 2, medium-dose group of Example 2, high-dose group of Example 2, and accelerated stability group of Example 2. The accelerated stability group was administered the lyophilized powder injection of Example 2, which had been stored at 40℃ and 75% relative humidity for 6 months, after reconstitution. The dosing regimens for the other groups were the same as in Example 1: the medium-dose group was 0.6 mg / kg / h of remimazolam, the low-dose group was 0.3 mg / kg / h, and the high-dose group was 1.2 mg / kg / h.

[0049] 3.2 Model Preparation and Detection Indicators A mouse MCAO model using the suture occlusion method was employed, followed by reperfusion after 1 hour of ischemia, with the drug administration method identical to that in Example 1. The detection indicators are as follows: (1) Detection of blood-brain barrier permeability and cerebral edema: 24 h after reperfusion, 5 mice in each group were randomly selected and injected with 2% Evans blue (EB) saline solution via tail vein at a dose of 5 mL / kg. After 2 h of injection, the mice were anesthetized and perfused with saline solution into the right atrium. Clear fluid flowed out. The mice were decapitated and the brain was removed. The left and right cerebral hemispheres were separated, weighed, and placed in formamide solution. The mixture was incubated in a 60°C water bath for 48 h. The supernatant was collected by centrifugation, and the absorbance at 620 nm was measured using an ELISA reader. The EB content in the brain tissue was calculated according to the standard curve to evaluate the blood-brain barrier permeability. At the same time, the water content of the brain tissue was detected by the wet-dry weight method. The ischemic cerebral hemisphere was taken, the wet weight was measured, and the mixture was dried in an oven at 105°C until constant weight. The dry weight was measured. The water content of the brain tissue (%) = (wet weight - dry weight) / wet weight × 100%. (2) Long-term evaluation of neurological and cognitive functions: The modified neurological deficit score (mNSS) was used to score the neurological function of mice at 3, 7, 14 and 28 days after reperfusion. The score covers motor, sensory, reflex and balance abilities, with a total score of 18 points. The higher the score, the more severe the neurological deficit. At 22-28 days after reperfusion, the Morris water maze test was used to test the learning and memory abilities of mice. The escape latency and the number of times the mice crossed the platform were recorded to evaluate the improvement effect of postoperative cognitive dysfunction. (3) Accelerated stability test: The lyophilized powder injection of Example 2 was placed in a constant temperature and humidity chamber at 40°C and 75% relative humidity for 6 months. Samples were taken at 0, 3 and 6 months. The appearance, reconstitution time, pH value, content of active ingredients, related substances, sterility and bacterial endotoxins of the preparation were tested according to the pharmacopoeia standard to evaluate the stability of the preparation. (4) Pharmacodynamic verification of accelerated stability samples: The same dosing regimen as the medium dose group was used to test the neuroprotective effect of the samples after 6 months of accelerated storage and compared with the fresh samples after 0 months.

[0050] 3.3 Experimental Results (1) Results of blood-brain barrier protection and improvement of cerebral edema: The EB content in the ischemic side of the model group was (13.2±1.9) μg / g, and the water content in the brain tissue was (86.8±1.3)%; the EB content in the medium dose group of Example 2 was (2.5±0.4) μg / g, and the water content in the brain tissue was (78.5±0.7)%, which were reduced by 81.1% and 9.6% respectively compared with the model group, and significantly lower than that of the control group (EB 7.8±1.2 μg / g). The results showed that the composition of the present invention could significantly reduce blood-brain barrier damage caused by ischemia-reperfusion, reduce blood-brain barrier permeability, and reduce vasogenic cerebral edema, with significantly better effects than existing anesthetic drugs. The results also showed that the composition of the present invention could significantly reduce blood-brain barrier damage caused by ischemia-reperfusion, reduce blood-brain barrier permeability, and reduce vasogenic cerebral edema. (2) Long-term neurological and cognitive function results: At 3, 7, 14 and 28 days after reperfusion, the mNSS scores of the dose group in Example 2 were significantly lower than those of the model group, control group 1, control group 6 and control group 7 (all P < 0.05). At 28 days after reperfusion, the mNSS score of the dose group in Example 2 was (2.1 ± 0.4) points, which was close to the normal level, while the score of control group 7 was (3.5 ± 0.6) points and the score of model group was (8.6 ± 1.2) points. The Morris water maze test results showed that at 28 days after reperfusion, the escape latency of mice in the dose group in Example 2 was significantly shorter than that of the other treatment groups and the model group, and the number of times they crossed the platform was significantly more than that of the other groups (all P < 0.05). This indicates that the composition of the present invention can not only improve acute neurological deficits, but also significantly improve long-term neurological and cognitive functions after ischemia-reperfusion, effectively reducing the risk of postoperative cognitive impairment. (3) Accelerated stability test results: After 6 months of accelerated storage, the appearance of the lyophilized powder injection of Example 2 was still a white, loose, blocky substance without collapse or shrinkage. The reconstitution time was less than 10 seconds, the pH value was maintained between 4.9 and 5.1, the content of each active ingredient remained above 98.5% of the labeled amount, there was no significant increase in related substances, and the sterility and bacterial endotoxin tests met the pharmacopoeia requirements, indicating that the lyophilized powder injection of the present invention has excellent stability and can meet the needs of long-term storage and clinical application. (4) Pharmacodynamic results of accelerated stability samples: The neuroprotective effect of the composition of Example 2 after 6 months of accelerated storage was not significantly different from that of the fresh sample after 0 months. The infarct volume, neurological function score, blood-brain barrier permeability and other indicators did not change significantly, indicating that the active ingredients of the composition of the present invention are stable during storage, the efficacy does not decrease, and it has good clinical application value.

[0051] Example 3: Perioperative neuroprotective anesthetic composition for ischemic stroke (liposome injection) Composition Formulation The composition in this embodiment is a liposome injection solution, and the formulation per 1000 mL of the composition is as follows: Remimazolam benzyl sulfonate: 15.0 g (molar concentration of approximately 30 mmol / L based on remimazolam) MCC950: 0.20g (molar ratio with remimazolam is 0.03:1) TRO19622: 0.39g (molar ratio to remimazolam is 0.05:1) Levomirnacitabine hydrochloride: 0.50g (molar ratio of 0.1:1 to remimazolam) Lipoic acid: 6.2g (molar ratio of 1:1 to remimazolam) Liposome carrier: Soy lecithin: 100g Cholesterol: 25g Vitamin E: 2g Other pharmaceutically acceptable carriers: Sucrose: 90g (isotonic regulator) Phosphate-sodium phosphate buffer system: Appropriate amount, adjust pH to 5.5. Water for injection: Add to 1000 mL Preparation method The liposome injection solution was prepared using a thin-film dispersion-high pressure homogenization method, and the specific steps are as follows: (1) Weigh out the prescribed amount of soybean lecithin, cholesterol and vitamin E, add them to 500 mL of anhydrous ethanol, stir in a 35 °C water bath until completely dissolved, and obtain a lipid material solution; (2) Transfer the lipid material solution to a rotary evaporator and remove anhydrous ethanol by rotary evaporation under reduced pressure at 40°C. A uniform and transparent lipid film is formed on the inner wall of the flask. Continue vacuum drying for 2 hours to remove residual ethanol. (3) Add 500 mL of water for injection to the eggplant-shaped flask, and hydrate by shaking in a water bath at 40°C for 30 min to obtain a blank liposome suspension; (4) The blank liposome suspension was transferred to a high-pressure homogenizer and homogenized 5 times at 800 bar pressure to obtain a blank liposome solution with uniform particle size and good dispersibility. (5) Weigh the prescribed amounts of remimazolam benzyl sulfonate, MCC950, TRO19622, levaminapril hydrochloride, thioctic acid, and sucrose, add them to 400 mL of water for injection, stir in the dark until completely dissolved, and obtain the active ingredient solution. Adjust the pH value to 5.5 using a phosphate-sodium phosphate buffer system. (6) Mix the blank liposome solution with the active ingredient solution evenly, and incubate in a water bath at 60°C in the dark for 30 min to allow the active ingredient to be fully loaded into the liposome bilayer and the inner aqueous phase; (7) The above liposome suspension was sterilized by filtering through a 0.22 μm microporous membrane, and water for injection was added to bring the total volume to 1000 mL. The solution was then filled into 10 mL brown ampoules and sealed to obtain the liposome injection solution of this embodiment. Testing showed that the average particle size of the liposomes in this embodiment was 112 nm, and the encapsulation efficiency was greater than 85%, meeting the quality requirements for intravenous liposome injection.

[0052] Pharmacokinetics and Large Animal Safety Validation Experiments This embodiment uses healthy adult Beagle dogs as experimental animals to evaluate the anesthetic effect, pharmacokinetic characteristics, clinical safety, and impact on cerebral blood flow of the composition of the present invention in large animals, providing sufficient non-clinical experimental evidence for clinical translation.

[0053] 3.1 Laboratory Animals and Grouping Twenty-four healthy adult Beagle dogs (half male and half female), weighing 10-12 kg, were acclimatized for 14 days and randomly divided into eight groups of three dogs each: Control Group 1, Control Group 6, Control Group 7, Low-dose group (Example 3), Medium-dose group (Example 3), High-dose group (Example 3), Repeated-dose group (Example 3), and Surgical Model group (Example 3). Dosage regimen: All groups received intravenous induction followed by continuous infusion maintenance. The anesthesia induction dose was 0.15 mg / kg remimazolam, administered via slow intravenous bolus. The anesthesia maintenance dose was 0.8 mg / kg / h for the medium-dose group, 0.4 mg / kg / h for the low-dose group, and 1.2 mg / kg / h for the high-dose group, administered via continuous infusion for 2 hours, simulating the duration of clinical surgical anesthesia. The repeated-dose group received the medium-dose composition daily for three consecutive days to evaluate the long-term safety of repeated administration. The surgical model group used a Beagle dog carotid endarterectomy model, receiving the medium-dose composition to simulate the perioperative medication scenario in clinical practice.

[0054] 3.2 Detection Indicators and Methods (1) Evaluation of anesthetic effect: The time of disappearance of righting reflex, eyelash reflex and jaw relaxation of the dog after induction drug administration were recorded to evaluate the speed and stability of anesthetic induction; the depth of anesthesia was monitored throughout the process using a bispectral index (BIS) monitor and the stability of BIS value maintained between 40 and 60 was recorded to evaluate the controllability of the depth of anesthesia; after the infusion was stopped, the recovery time of righting reflex, the recovery time of command response and the time of complete awakening were recorded to evaluate the awakening characteristics. (2) Pharmacokinetic assay: Forelimb venous blood was collected at 1 min, 5 min, 15 min, 30 min, 1 h, 2 h (after administration), 2 h 5 min, 2 h 15 min, 2 h 30 min, 3 h, 4 h, and 6 h after induction administration. The blood plasma was separated by centrifugation at 4 °C. The plasma concentrations of remimazolam, MCC950, TRO19622, levamisole, and thioctic acid were detected by LC-MS / MS. The pharmacokinetic parameters of each active ingredient were calculated using DAS 3.0 pharmacokinetic software to evaluate the pharmacokinetic matching of each component. (3) Clinical safety evaluation: MAP, HR, ECG, RR, and SpO2 of dogs were monitored throughout the administration process using a multi-functional animal monitor before administration, 30 min after administration, 1 h after administration, 2 h after administration, 15 min after administration, and 30 min after administration to evaluate circulatory and respiratory safety. Venous blood was collected before administration and 24 h and 48 h after administration to detect blood routine, liver and kidney function (ALT, AST, BUN, Cr), electrolytes, and serum cortisol levels to evaluate the effects on liver and kidney function and adrenal cortex function. After repeated administration for 3 consecutive days, the above indicators were tested. At the same time, after euthanasia, gross dissection and histopathological examination of the heart, liver, spleen, lung, kidney, and brain tissues were performed to evaluate the long-term toxicity of repeated administration. (4) Cerebral blood flow monitoring: Local cerebral blood flow (rCBF) changes in dogs were monitored through the cranial window during administration using a laser Doppler flowmeter. rCBF values ​​were recorded before administration, 1 h after administration, and 2 h after administration to evaluate the effect of the composition on cerebral perfusion.

[0055] 3.3 Experimental Results (1) Results of anesthetic effect: In Example 3, the disappearance time of the righting reflex in the dose group was (21.5±3.2) s, and the disappearance time of the eyelash reflex was (34.2±3.8) s, which were not significantly different from those in Control Group 1, indicating that the anesthesia induction of the composition of the present invention was rapid and stable, with no excitation phenomenon during the induction period; During the administration period, the BIS value of the dose group in Example 3 remained stable between 42 and 58, with a fluctuation range of less than 6%, which was significantly lower than that of Control Group 1 (fluctuation range 13%), Control Group 6 (fluctuation range 16%), and Control Group 7 (fluctuation range 1). 0%), indicating that the anesthetic depth of the composition of the present invention is highly controllable and stable, which can meet the needs of surgical anesthesia; after stopping the administration, the righting reflex recovery time of the dose group in Example 3 was (11.8±2.3) min, and the complete awakening time was (14.5±2.6) min, which was not significantly different from the control group 1, significantly shorter than the control group 6 (29.2±4.8) min, and not significantly different from the control group 7, indicating that the composition of the present invention provides rapid and complete awakening, without drug accumulation, without awakening delay, and does not affect the early postoperative neurological function assessment. (2) Pharmacokinetic results: In the composition of Example 3, the pharmacokinetic parameters of each active ingredient are highly matched: the peak time Tmax of remimazolam is 1.1±0.2 min, and the elimination half-life t1 / 2 is 41.8±6.5 min; The Tmax of MCC950 is 1.3±0.3 min, and the t1 / 2 is 43.5±6.8 min; The Tmax of TRO19622 was 1.2 ± 0.3 min, and the t1 / 2 was 44.2 ± 7.1 min. The Tmax of levomirtanil was 1.2 ± 0.2 min, and the t1 / 2 was 40.5 ± 6.2 min. The Tmax of lipoic acid was 1.3±0.3 min, and the t1 / 2 was 39.8±6.0 min. The results showed that the onset time, peak time, and elimination half-life of the five active ingredients in the composition of the present invention were highly consistent, and a stable blood drug concentration ratio could be maintained during perioperative administration, ensuring the continuous synergistic effect of anesthetic and multi-target neuroprotective effects, avoiding effect fluctuations caused by pharmacokinetic mismatch, and laying a good pharmacokinetic foundation for clinical application. (3) Clinical safety results: During the administration period, the MAP, HR, RR, and SpO2 of each dose group in Example 3 were maintained within the normal physiological range, with no obvious dose-dependent decrease, and no significant difference from before administration; while the MAP of the control group 6 showed a significant dose-dependent decrease, with a maximum decrease of 26%, and the HR was significantly slowed down, which was extremely significantly different from the group in Example 3 (P<0.01); the control groups 1 and 7 also showed a slight decrease in MAP, with decreases of 9% and 8% respectively, which were significantly higher than those in the group in Example 3 (P<0.05). Before and after administration, there were no significant changes in blood routine tests, liver and kidney function, and electrolytes in all groups of Example 3, and serum cortisol levels remained within the normal physiological range. However, serum cortisol levels in the control group 6 showed a significant decrease (P < 0.05), indicating that the composition of the present invention has no inhibitory effect on adrenal cortex function and excellent safety in liver and kidney function. After repeated administration for 3 days, all hematological indicators in the Example 3 group were normal, and gross anatomical and histopathological examinations showed no obvious pathological changes in the heart, liver, spleen, lungs, kidneys, and brain tissues, indicating that the composition of the present invention does not accumulate toxicity with repeated administration and has good long-term safety. (4) Results of cerebral blood flow monitoring: During the administration period, the rCBF of the dose group in Example 3 increased by (16.8±2.6)% compared with that before administration, while there was no significant change in rCBF of the control group 1 and control group 7. The rCBF of the control group 6 decreased by (9.2±1.8)% compared with that before administration, and the rCBF of the surgical model group increased by (18.2±3.1)% compared with that before administration. This indicates that the composition of the present invention can significantly improve cerebral blood flow and increase cerebral perfusion. Especially in the perioperative scenario of carotid endarterectomy, it can effectively maintain cerebral perfusion, avoid ischemic injury, and perfectly meet the pathophysiological needs of the perioperative period of ischemic stroke.

[0056] The foregoing has shown and described 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 to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of protection claimed by the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A perioperative neuroprotective anesthetic composition for ischemic stroke, characterized in that, The product comprises an anesthetically effective amount of an active ingredient and a pharmaceutically acceptable carrier; the active ingredient is composed of remimazolam or a pharmaceutically acceptable salt thereof, MCC950, TRO19622, levaminacipran or a pharmaceutically acceptable salt thereof, and lipoic acid; wherein, in molar ratio, remimazolam or a pharmaceutically acceptable salt thereof: MCC950: TRO19622: levaminacipran or a pharmaceutically acceptable salt thereof: lipoic acid = 1:(0.02-0.1):(0.05-0.2):(0.1-0.5):(1-5).

2. The perioperative neuroprotective anesthetic composition for ischemic stroke according to claim 1, characterized in that: On a molar ratio, remimazolam or its pharmaceutically acceptable salt: MCC950: TRO19622: levamisole or its pharmaceutically acceptable salt: lipoic acid = 1:(0.03-0.08):(0.08-0.15):(0.2-0.4):(2-4).

3. The perioperative neuroprotective anesthetic composition for ischemic stroke according to claim 1, characterized in that: The pharmaceutically acceptable salt of remimazolam is remimazolam benzyl sulfonate, and the pharmaceutically acceptable salt of levaminacipran is levaminacipran hydrochloride.

4. The perioperative neuroprotective anesthetic composition for ischemic stroke according to claim 1, characterized in that: The composition is an intravenous injection preparation, including concentrated solutions for injection, lyophilized powder injections, or liposome injections.

5. The perioperative neuroprotective anesthetic composition for ischemic stroke according to claim 4, characterized in that: The composition is a concentrated solution for injection, and the pharmaceutically acceptable carrier includes solvents, pH adjusters, isotonic adjusters, solubilizers, and stabilizers.

6. The perioperative neuroprotective anesthetic composition for ischemic stroke according to claim 1, characterized in that: In the composition, the concentration of remimazolam or a pharmaceutically acceptable salt thereof is 5-20 mg / mL.

7. The use of the composition according to any one of claims 1-6 in the preparation of a perioperative anesthetic for ischemic stroke.

8. The application according to claim 7, characterized in that: The perioperative period for ischemic stroke includes the induction, maintenance, and recovery periods of anesthesia for procedures such as endovascular mechanical thrombectomy, carotid endarterectomy, intracranial and extracranial vascular bypass grafting, and decompressive craniectomy.

9. The application according to claim 7, characterized in that: The drug is used to provide perioperative anesthesia while preventing and / or treating perioperative ischemia-reperfusion brain injury in ischemic stroke, and to reduce postoperative neurological deficits and cognitive impairment.

10. The application according to claim 7, characterized in that: The dosage of the drug during the maintenance anesthesia period is 0.3-1.2 mg / kg / h, calculated as remimazolam.