A muscle relaxant antagonist for reversing benzylisoquinoline muscle relaxants

Abstract

This invention provides a neuromuscular antagonist for reversing the effects of benzylisoquinoline-based neuromuscular relaxants. Specifically, this invention provides a safer and more effective method for preparing a neuromuscular antagonist formulation for reversing the effects of benzylisoquinoline-based neuromuscular relaxants, and its application. More specifically, this invention provides omeprazole sodium as an alternative to neostigmine for reversing the neuromuscular blockade caused by the benzylisoquinoline-based neuromuscular relaxant atracurium besylate. In reversing the residual neuromuscular blockade effect induced by the neuromuscular relaxant atracurium besylate, omeprazole sodium can replace neostigmine, and while maintaining comparable antagonistic efficacy, it is significantly superior to neostigmine in terms of heart rate maintenance. This invention also provides omeprazole sodium and its compound formulations, wherein omeprazole sodium is prepared as a lyophilized powder for injection or a solution, suitable for use in the preparation of neuromuscular antagonist drugs.

Description

A muscle relaxation antagonist for reversing benzylisoquinoline muscle relaxants Field of the Invention The present invention relates to the field of medicine. Specifically, the present invention relates to a method for preparing a safer and more effective muscle relaxation antagonist preparation for reversing benzylisoquinoline muscle relaxants (such as atracurium besylate) and its application. Background of the Invention With the continuous development and progress of surgery and minimally invasive medicine, and the increasing requirements of patients for surgical comfort and safety, general anesthesia accounts for an increasingly large proportion of clinical surgical anesthesia, and in some hospitals, it even reaches more than 90%. Muscle relaxation drugs are an important part of general anesthetic drugs, which can provide a clearer surgical field for surgeons, ensure that patients do not have body movement during the operation, and reduce the occurrence of intraoperative complications. Cisatracurium is a relatively new intermediate-acting non-depolarizing muscle relaxant, which is one of the isomers of atracurium. It is mainly degraded by Hofmann elimination occurring at physiological pH and body temperature, and does not depend on liver and kidney metabolism. Clinically, it has the characteristics of no accumulation, rapid recovery, strong action, etc. In particular, its low histamine release and small impact on cardiovascular function make it widely used clinically. Currently, the most commonly used clinically are intermediate-acting non-depolarizing muscle relaxants, such as cisatracurium, rocuronium, vecuronium, etc. The three almost occupy more than 98% of the entire muscle relaxant market share. Among them, cisatracurium occupies the largest share and can be said to be the leader in the muscle relaxant market. Incomplete metabolism of muscle relaxation drugs often leads to respiratory insufficiency in patients after extubation. Moreover, the residual muscle relaxation drugs after surgery can prevent the recovery of laryngeal muscle function, leading to an increase in the incidence of postoperative aspiration, dysphagia, and upper airway obstruction in patients. If it inhibits the patient's respiration, it will lead to the occurrence of hypoxemia. This residual muscle relaxation effect can increase the postoperative complications and mortality rate of patients and prolong the in-hospital treatment time of patients. Literature reports that even in the United States and Canada where muscle relaxation monitoring is relatively common today, the incidence of residual muscle relaxation effects reaches 64.7% and 63.5% respectively when extubating after surgery. There are also literature reports that when using the non-depolarizing muscle relaxant cisatracurium according to the conventional method during general anesthesia, it is found that 12% of the patients still have the hidden danger of residual muscle relaxant effects (TOFr < 0.9; TOFr: the ratio of the fourth muscle twitch to the first muscle twitch T4 / T1) when the tracheal catheter is removed at the end of the operation. Currently, the commonly used muscle relaxant antagonists in clinical practice are anticholinesterase drugs, which exert their effects by inhibiting cholinesterase and reducing the decomposition of acetylcholine (Ach). The most commonly used anticholinesterase drug in clinical practice is neostigmine. While antagonizing muscle relaxation, it also produces obvious muscarinic effects, especially on heart rate, inducing bradycardia, and in severe cases, cardiac arrest, resulting in many patients in clinical practice having to avoid or use this drug with caution. Atropine is an anticholinergic drug that can increase heart rate and antagonize the bradycardia caused by neostigmine. Clinically, the two drugs are usually combined to exert the effect of antagonizing residual muscle relaxation, and usually the two drugs are used in combination. However, because atropine takes effect quickly while neostigmine takes effect relatively slowly, there will be an obvious process of increased heart rate at the beginning. This hemodynamic change will cause the occurrence of perioperative myocardial ischemia, which will have a more serious impact or consequence on some patients with more severe heart diseases. Some researchers have suggested using atropine 2 - 4 minutes after neostigmine, but the work in the anesthesia recovery room is busy, and it is very difficult to ensure that the drug is administered at the specified time each time. If atropine is injected too late, it may cause the risk of excessive bradycardia. In addition, atropine easily passes through the blood-brain barrier and is a risk factor for postoperative cognitive dysfunction, and may even cause delirium, which poses a great risk to elderly patients. Orgmetrine sodium is a safer muscle relaxation antagonist invented by the present invention to replace neostigmine for antagonizing cisatracurium besylate, a muscle relaxant. Orgmetrine sodium is a small molecule drug developed by our company and belongs to Class I of Chinese chemical drugs. Currently, the highest R & D stage of this drug is Phase III clinical trial for the reversal of neuromuscular block. Sugammadex sodium, with the trade name Bridion, is the only currently registered product of the same kind as the drug omadex sodium described in the present invention. As a new type of muscle relaxant antagonist, it is a specific antagonist of rocuronium (a steroidal muscle relaxant). Sugammadex sodium does not bind to succinylcholine or benzylisoquinoline neuromuscular blockers (such as mivacurium, atracurium, and cisatracurium); on the contrary, after the administration of sugammadex sodium, the onset of cisatracurium-induced neuromuscular blockade is faster and the level of blockade is deeper. The earliest research reports on sugammadex sodium and atracurium were published in 2006 by H. D. de Boer et al. in the British Journal of Anaesthesia, which found that sugammadex sodium was ineffective in reversing atracurium-induced neuromuscular blockade, but it had no effect on blood pressure and heart rate. The 2023 American Society of Anesthesiologists' Practice Guidelines for the Monitoring and Antagonism of Neuromuscular Blockade also pointed out that sugammadex sodium was ineffective in antagonizing benzylisoquinoline neuromuscular blockers. In addition, sugammadex sodium has certain safety concerns and has been rejected by the US FDA three times due to allergic reactions, cardiac Qt prolongation, and bleeding risks. It took 7 years to be approved for marketing; in recent years, there have been more and more potential adverse reactions to sugammadex sodium, including common and serious adverse reactions such as residual postoperative muscle relaxation, allergic reactions and hypersensitivity reactions, coagulation dysfunction, cardiovascular system side effects, bronchospasm and laryngospasm, etc., as well as other adverse reactions such as postoperative nausea, prolonged renal excretion time, neuronal apoptosis, and abnormal taste of metallic taste. Therefore, cholinesterase inhibitors and cholinesterase inhibitors combined with anticholinergic drugs have not yet met the clinical needs, and there is an urgent need to provide patients with a muscle relaxant antagonist treatment drug that can effectively antagonize muscle relaxation and is safe. Summary of the Invention The object of the present invention is to provide a use of omadex sodium in the preparation of a pharmaceutical composition for reversing neuromuscular tissue blockade induced by benzylisoquinoline muscle relaxants (such as atracurium besylate). In the first aspect of the present invention, there is provided a use of omadex sodium, which can be used in the preparation of a pharmaceutical composition for reversing muscle relaxation caused by benzylisoquinoline muscle relaxants (such as atracurium besylate). The use as described in the first aspect of the present invention, wherein the pharmaceutical composition is further used for reversing the residual neuromuscular blockade after cisatracurium-induced muscle relaxation. The use as described in the first aspect of the present invention, wherein the pharmaceutical composition is further used for improving the adverse reactions during the process of antagonizing cisatracurium-induced muscle relaxation. The adverse reactions are selected from the following group: decreased heart rate, decreased blood pressure, gastrointestinal discomfort reactions. The use as described in the first aspect of the present invention, wherein the pharmaceutical composition further comprises a second therapeutic component, and the second therapeutic component is an active ingredient for antagonizing muscle relaxant drugs. In the examples, the second therapeutic component is neostigmine. The second aspect of the present invention provides a formulation of ormeloxifene sodium, which includes: a therapeutically effective amount of ormeloxifene sodium, mannitol, and the balance of water for injection. The formulation according to the second aspect of the present invention includes: 2-5 parts by weight of ormeloxifene sodium, 0.1-1 part by weight of mannitol, and 15-30 parts by weight of water for injection. The formulation according to the second aspect of the present invention includes: 0.2-0.5 g / dose of ormeloxifene sodium, 0.01-0.1 g / dose of mannitol, and the balance of water for injection; and the volume of the formulation is 2 mL. The formulation according to the second aspect of the present invention is used to reverse the muscle relaxation caused by cisatracurium besylate; in another preferred example, the formulation is used to reverse the residual neuromuscular blockade after cisatracurium-induced muscle relaxation; in another preferred example, the formulation is also used to improve the adverse reactions during the antagonism of cisatracurium-induced muscle relaxation. The third aspect of the present invention provides a formulation of ormeloxifene sodium, wherein the formulation is a freeze-dried powder for injection, and the formulation includes: a therapeutically effective amount of ormeloxifene sodium, sodium hydroxide or hydrochloric acid, and the balance of water for injection. In another preferred example, the formulation includes: 1-5 parts by weight of ormeloxifene sodium, 15-30 parts by weight of water for injection, and an appropriate amount of sodium hydroxide or hydrochloric acid. In another preferred example, the formulation includes: 0.1-0.5 g / dose of ormeloxifene sodium, an appropriate amount of sodium hydroxide or hydrochloric acid, and the balance of water for injection; and the volume of the formulation is 2 mL. In another preferred example, the formulation is prepared by the following method: mixing a therapeutically effective amount of ormeloxifene sodium with the prescribed amount of water for injection, adjusting the pH value to 6-9 using sodium hydroxide or hydrochloric acid, and then performing freeze-drying treatment to obtain the freeze-dried powder for injection formulation. The formulation according to the third aspect of the present invention is used to reverse the muscle relaxation caused by cisatracurium besylate; in another preferred example, the formulation is used to reverse the residual neuromuscular blockade after cisatracurium-induced muscle relaxation; in another preferred example, the formulation is also used to improve the adverse reactions during the antagonism of cisatracurium-induced muscle relaxation. The fourth aspect of the present invention further provides a compound injection formulation, wherein the formulation includes: a therapeutically effective amount of ormeloxifene sodium and neostigmine methylsulfate; preferably, the formulation further includes: mannitol, bacteriostatic agent, pH regulator, and the balance of water for injection. In another preferred example, the bacteriostatic agent is phenol. In another preferred example, the pH regulator is sodium hydroxide or hydrochloric acid. The compound injection preparation as described in the fourth aspect of the present invention, wherein the preparation comprises: 2-5 parts by weight of sodium omadacycline, 6-22 parts by weight of neostigmine methylsulfate, 0.1-1 part by weight of mannitol, 0.01-0.1 part by weight of bacteriostatic agent, an appropriate amount of pH regulator, and the balance of injection water; and the volume of the preparation is 2 mL. In another preferred example, the pH of the preparation is 6-9. The beneficial effects of the present invention are as follows: (1) The results of animal model test studies strongly prove that sodium omadacycline has the effect of antagonizing the depolarizing muscle relaxant cisatracurium. Specifically, sodium omadacycline can significantly shorten the recovery time of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium at a dose of 10 mg / kg. As the dosing dose of sodium omadacycline increases, the 20 and 40 mg / kg dose groups of sodium omadacycline show a better effect of accelerating muscle relaxation recovery, and show a certain dose-effect relationship. The high-dose group of sodium omadacycline at 40 mg / kg, the positive control group of neostigmine at 0.0625 mg / kg, and the combination group (sodium omadacycline: 10 mg / kg; neostigmine: 0.03125 mg / kg) have the same effect on the recovery of residual muscle relaxation in the guinea pig muscle relaxation model, and the effects are all very significant. There is no significant difference among the three, indicating that the activity of sodium omadacycline in antagonizing cisatracurium is equivalent to the antagonistic effect of neostigmine. (2) At the same time, it is also surprisingly found that in terms of heart rate protection, the safety of sodium omadacycline is significantly better than that of neostigmine. Specifically, after the positive control group was given 0.0625 mg / kg of neostigmine, the heart rate decreased significantly, with a decrease amplitude of up to about 30%, presenting a safety hazard. The heart rate reduction effect in the combination group of animals was slowed down after administration of the drug, but it still could not be fully restored. Administration of sodium omadacycline at doses of 10, 20, and 40 mg / kg had no obvious effect on the blood pressure and heart rate of the guinea pig muscle relaxation model. Therefore, sodium omadacycline has the potential to be developed into a clinical drug that can antagonize the depolarizing muscle relaxant cisatracurium. (3) The indication of sodium omadacycline is to antagonize various degrees of neuromuscular blockade caused by steroidal non-depolarizing muscle relaxants such as rocuronium during general anesthesia surgery. Currently, the phase III clinical research in China has been completed. If the development of the use of antagonizing cisatracurium is successful, it will further broaden its clinical application scope, solve the muscarinic effect of neostigmine, and overcome the safety concerns of the combined use of atropine and neostigmine, that is, the heart rate performance is not stable enough, there are tachycardia and arrhythmia, and safety problems such as postoperative cognitive impairment. The successful replacement of neostigmine combined with atropine by sodium omadacycline will benefit a wider range of patients undergoing general anesthesia surgery. It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed Description of the Preferred Embodiment The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. Example 1 Evaluation of the Risk of Compound-Induced Sensitization ( Safety Screening I ) 1. Test Procedure Wild-type AB strain zebrafish at 2 days post-fertilization (2 dpf) were randomly selected and placed in 24-well plates, with 6 replicate wells in each group and 10 zebrafish in each well. The following groups were set up respectively: (1) normal control group; (2) positive control group (the drug used was the mast cell sensitizer C48 / 80 at a concentration of 1.5 μg / mL); (3) experimental group of Compound 1 (orgometrexine sodium); (4) experimental group of Compound 2; (5) experimental group of Compound 3; (6) experimental group of Compound 4; (7) experimental group of Compound 5; (8) experimental group of Compound 6; (9) experimental group of Compound 7 (sugammadex); in each experimental group, Compound 1 was orgometrexine sodium, Compounds 2-6 were orgometrexine sodium analogs, and Compound 7 was sugammadex; the volume of each well was 1 mL, and BAPNA (a specific reagent for detecting mast cell degranulation) was administered by water solution to each experimental group. Table 1 Structural Formulas of Compounds 1-7 After treatment at 28°C for 1 day, the liquid was transferred to 96-well plates, 200 μL per well, and the relative absorbance value (OD value) of the expression level of tryptase in each experimental group was detected using an enzyme-labeled instrument. The sensitization risk of the samples was evaluated based on the statistical analysis results of the OD values. Statistical analysis was performed using SPSS software, and p < 0.05 indicated a significant difference. 2. Test Results Table 2 Sensitization Risks of Compounds Note: The data listed in the table are all mean ± standard deviation (mean ± SE). *: P < 0.05; ***: P < 0.001 vs normal control group. The results showed that the OD value of the positive control group was 0.099, which was significantly higher than that of the normal control group (0.054), indicating that under the experimental concentration conditions, the positive drug C48 / 80 had a high risk of sensitization. The OD values of the experimental groups of Compound 1 (orgasmex sodium) and Compound 2 were 0.060 and 0.052 respectively, which were similar to that of the normal control group (0.054), with almost no risk of sensitization. The OD value of the experimental group of Compound 7 (sugammadex sodium) was 0.079, which was slightly higher than that of the normal control group (0.054), indicating a certain risk of sensitization. In the experimental groups of Compound 3, Compound 4, Compound 5 and Compound 6, many zebrafish died, so no evaluation was carried out. 3. Test conclusion Among the tested compounds, the sensitization risks of Compound 1 (orgasmex sodium), Compound 2 and Compound 7 (sugammadex sodium) were significantly lower than that of the positive control. Among them, Compound 2 and Compound 1 (orgasmex sodium) had no or basically no risk of sensitization and were suitable for subsequent drug development; Compound 7 (sugammadex sodium) had a low risk of sensitization. Example 2 Effects of Orgasmex Sodium, Sugammadex Sodium and Neostigmine on Immune Inflammation of Organisms ( Safety Screening II ) 1. Test procedure Antibody microarray is a type of protein microarray, which has the characteristics of miniaturization, integration and high throughput, and can be used to detect the expression abundance of proteins related to a specific physiological or pathological process. The principle is mainly to arrange the capture antibodies on the membrane or glass slide, add the sample for incubation, then add the biotin-labeled antibody of the target protein. Finally, HRP-streptavidin or fluorescein-streptavidin is used to detect the signal of the microarray. Finally, chemiluminescence or HiLyte™ Fluor 555-streptavidin is used to detect the signal. In this experiment, ICR mice were randomly divided into a blank group, a sugammadex (1 g / kg) group, a sugammadex (1 g / mg) group, and a neostigmine (0.3 mg / kg) group, with 2 mice in each group. Mice in each group were given the corresponding dose of the compound via tail vein once a day for 5 consecutive days. After the last dose, plasma from 2 animals was mixed and detected using the Ary028 immunochip kit. The specific detection steps are as follows: (1) Sample volume determination: 200 μl of serum sample for each Array unit. (2) Blocking the protein chip: Each membrane needs to be blocked with 2 ml of the corresponding Array Buffer and incubated on a shaker for 1 hour. (3) Sample treatment: The sample needs to be diluted with the corresponding Array Buffer to a volume of 1.5 ml per membrane, added to the corresponding Array unit, and incubated with the Array protein membrane overnight at 4°C. (4) Wash the membrane three times with the corresponding Wash buffer, add the diluted detection antibody, and incubate at room temperature for 1 h. (5) Wash the membrane three times with the corresponding Wash buffer, add streptavidin-HRP, and incubate for 30 min with shaking on a shaker at room temperature. (6) Wash the membrane three times with the corresponding Wash buffer, add 1 ml of the chemiluminescent reagent to each well, and develop the color on a chemiluminescent imaging instrument. (7) The relative concentration of the corresponding protein is represented by the fluorescence intensity. 2. Experimental results Table 3 Comparison of fluorescence intensities of hypersensitivity reaction-related factors Note: "Not detected" means that the protein concentration in the serum is lower than the lowest detection limit Table 4 Comparison of fluorescence intensities of inflammation-related factors Note: "Not detected" means that the protein concentration in the serum is lower than the lowest detection limit A total of 11 hypersensitivity reaction-related factors and 45 inflammation-related factors were detected this time. Among them, as shown in Table 3 and Table 4, the detection amounts of 11 hypersensitivity reaction-related factors and 37 inflammation-related factors in the serum were lower than the lowest detection limit in the blank group. Compared with the sugammadex group and the neostigmine group, the detection amounts of various hypersensitivity reaction and inflammation-related factors in the sugammadex group were the lowest or lower than the lowest detection limit, indicating that sugammadex had the least impact on inducing immune inflammation in mice, followed by sugammadex, and neostigmine was the most serious. 3. Experimental conclusion The results of analyzing the effects of three muscle relaxant antagonists, sodium omadacycline, sugammadex sodium, and neostigmine, on immune inflammation in mice through this experiment showed that sodium omadacycline had the least inducing effect on immune inflammation in mice. Many hypersensitivity reactions and inflammation-related factors were not induced and were below the lowest detection limit, indicating that the drug had good safety in terms of immune inflammation. The inducing effect of sugammadex sodium on immune inflammation in mice was the second, indicating that the drug had general safety in terms of immune inflammation. Neostigmine had the most serious inducing effect on immune inflammation in mice, resulting in an increase in the secretion of the vast majority of hypersensitivity reactions and inflammation-related factors, indicating that the drug had great potential safety hazards in terms of immune inflammation. Example 3 Effect of sodium omadacycline on residual muscle relaxant antagonism after administration of the muscle relaxant cisatracurium to anesthetized guinea pigs ( Pharmacodynamic experiment ) 1. Test procedure Ninety Hartley guinea pigs that passed quarantine, male. Sixty of these animals were grouped using stratified randomization according to body weight into six test groups, namely a negative control group, a positive control group, low, medium, and high dose groups of the test article, and a combination group, with 10 animals in each group (n = 10). The remaining animals were used as spares. The negative control group was given 0.9% sodium chloride, the positive control group was given 0.0625 mg / kg neostigmine methylsulfate (abbreviated as neostigmine), the low dose group of the test article was given 10 mg / kg sodium omadacycline, the medium dose group of the test article was given 20 mg / kg sodium omadacycline, the high dose group of the test article was given 40 mg / kg sodium omadacycline, and the combination group was given 10 mg / kg sodium omadacycline and 0.03125 mg / kg neostigmine. The dosing volume for all groups was 1 mL / kg. After the quarantine ended, adaptive feeding was carried out. On the day of the experiment, the guinea pigs were weighed, and after intramuscular injection of atropine 0.1 mg / kg, anesthetic drugs were intraperitoneally injected (sodium pentobarbital 10 mg / kg, urethane 1000 mg / kg). After the animals were fixed, tracheal intubation was performed, and they were connected to a small animal ventilator. The external jugular veins on both sides and the right common carotid artery were separated for intubation. The left vein was used for injecting cisatracurium solution, the right vein was used for injecting different test substances, and the carotid artery was continuously monitored for arterial blood pressure and heart rate using a multi-channel physiological signal acquisition and processing system. Electrode patches were pasted subcutaneously behind the left femur and tibia of the guinea pigs, and two stimulating electrodes of the neuromuscular monitor were fixed on the two electrode patches respectively. The left hind foot was fixed on a self-made platform. The sensor was fixed on the skin surface of the gastrocnemius muscle of the left hind limb of the guinea pig, and the skin temperature probe was fixed at a flat skin area. First, continuous single stimulation was performed in the 1 Hz mode. After the twitch height was stable, it was changed to the train-of-four stimulation mode (TOF mode, stimulation current 5 mA, frequency 2 Hz, pulse width 0.2 ms, inter-train interval 15 s) for continuous stimulation for at least 5 min. Then, calibration was performed using calibration mode 2, and then stimulation was performed in the TOF mode. After at least 2 min of stable stimulation response was obtained, cisatracurium solution was intravenously injected using a dual-channel micro-injection pump, and the start time of the injection was recorded. When continuous injection of cisatracurium solution led to the disappearance of T4 / T1 (TOFr) and T1 was below 15%, the muscle relaxation model was considered successful, and then the injection of cisatracurium solution was stopped. After the injection was stopped, the neuromuscular function was allowed to spontaneously recover. When the neuromuscular function was moderately recovered, the test substance preparation was intravenously injected, and when the neuromuscular function was completely recovered, the administration time was recorded (Figure 1). Taking the time when the neuromuscular function spontaneously recovered to moderate (TOF50) as zero point, the time for the animal's neuromuscular function to recover from TOF50 to TOF75, from TOF75 to TOF90, and from TOF50 to TOF90 was calculated respectively (Table 1-2). The arterial blood pressure (including systolic blood pressure, diastolic blood pressure, mean arterial pressure) and heart rate at before injecting cisatracurium solution, when stopping injecting cisatracurium solution, when the neuromuscular function was moderately recovered, and when the neuromuscular function was completely recovered were recorded (Table 3-7). The data were expressed as Mean±SD, and statistical T-test using SPSS software was used to evaluate the differences in blood pressure, heart rate, and the recovery time of residual muscle relaxation. P<0.05 was considered statistically significant. 2. Test results (1) Effect of ormexolone sodium on the recovery time of residual muscle relaxation in animals with muscle relaxation model Table 5 Effect of ormexolone sodium on antagonizing cisatracurium and the recovery time of residual muscle relaxation in animals with muscle relaxation model Note: The data listed in the table are all mean±standard deviation. *: P<0.05; **: P<0.01 vs negative control group. The number of guinea pigs in each group was 10. The results showed that there were no significant differences in the tTOF0-50 values among the groups compared with the negative control group (P>0.05), indicating that the spontaneous recovery of neuromuscular function before administration of the test article preparation was basically the same. After the spontaneous recovery of neuromuscular function reached moderate level, the test article preparation was administered, and the neuromuscular function recovered completely. The residual muscle relaxation recovery times tTOF50-75, tTOF75-90, and tTOF50-90 in the positive control group were significantly shortened (P<0.05-0.01). The residual muscle relaxation recovery times tTOF75-90 and tTOF50-90 in the low-dose test article group were significantly shortened (P<0.05). The residual muscle relaxation recovery time tTOF50-90 in the medium-dose test article group was significantly shortened (P<0.05). The residual muscle relaxation recovery times tTOF75-90 and tTOF50-90 in the high-dose test article group were significantly shortened (P<0.01). The residual muscle relaxation recovery times tTOF50-75, tTOF75-90, and tTOF50-90 in the combination group were significantly shortened (P<0.05-0.01), indicating that sodium omadex can significantly shorten the residual muscle relaxation recovery time of the cisatracurium-induced guinea pig muscle relaxation model under the conditions of this experiment. The tTOF50-90 values of the residual muscle relaxation recovery times of the animals in the negative control group, positive control group, low-, medium-, and high-dose test article groups, and combination group were (455±201) s, (188±86) s, (248±139) s, (279±123) s, (201±131) s, and (174±108) s, respectively. After administration of the drugs in the positive control group, low-, medium-, and high-dose test article groups, and combination group, tTOF50-90 was shortened by 58.7%, 45.5%, 38.7%, 55.8%, and 61.8% respectively (the degree of shortening of tTOF50-90 time = (tTOF50-90 value of the negative control group - tTOF50-90 value of the experimental group) / tTOF50-90 value of the negative control group), indicating that low-, medium-, and high-dose sodium omadex have a significant effect on the recovery of residual muscle relaxation in the cisatracurium-induced guinea pig muscle relaxation model, and are close to the effect of neostigmine administration or the combined administration of sodium omadex and neostigmine. (2) Effect of sodium omadex on the ratio of residual muscle relaxation recovery time in the muscle relaxation model animals Considering the possible differences in the muscle relaxation recovery time tTOF0-50 before administration of the test article among different guinea pig individuals, the ratios RtTOF50-75 / 0-50, RtTOF75-90 / 0-50, and RtTOF50-90 / 0-50 of the residual muscle relaxation recovery times tTOF50-75, tTOF75-90, and tTOF50-90 to the muscle relaxation recovery time tTOF0-50 were used as the observation indexes. Table 6 Effect of sodium omadex on antagonizing cisatracurium on the ratio of residual muscle relaxation recovery time in the muscle relaxation model animals Note: The data listed in the table are all mean ± standard deviation. *: P < 0.05; **: P < 0.01 vs negative control group. The number of guinea pigs in each group was 10. The results showed that compared with the negative control group, the ratios of residual muscle relaxation recovery time RtTOF50-75 / 0-50, RtTOF75-90 / 0-50, and RtTOF50-90 / 0-50 in the positive control group were significantly decreased (P < 0.05 - 0.01). The ratios of residual muscle relaxation recovery time RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 in the low and medium dose groups of the test article were significantly decreased (P < 0.05). The ratios of residual muscle relaxation recovery time RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 in the high dose group of the test article were significantly decreased (P < 0.01). The ratios of residual muscle relaxation recovery time RtTOF50-75 / 0-50, RtTOF75-90 / 0-50, and RtTOF50-90 / 0-50 in the combination group were significantly decreased (P < 0.05). The above results indicated that under the experimental conditions, omadex sodium at different doses could significantly accelerate the recovery of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium, and showed a certain dose-effect relationship. Compared with the positive control group, there was no significant difference in the ratios of residual muscle relaxation recovery time RtTOF50-75 / 0-50, RtTOF75-90 / 0-50, and RtTOF50-90 / 0-50 in the low, medium, and high dose groups of the test article (P > 0.05), indicating that the combination group, each dose group of the test article and the positive control group had similar effects on the recovery of residual muscle relaxation in the muscle relaxation model animals. The RtTOF50-90 / 0-50 of the negative control group, positive control group, low, medium, and high dose groups of the test article, and combination group were (0.42 ± 0.22), (0.18 ± 0.09), (0.23 ± 0.13), (0.22 ± 0.08), (0.16 ± 0.11), and (0.17 ± 0.17) respectively. The results showed that the RtTOF50-90 / 0-50 of each drug administration group was significantly decreased, and the effects of the combination group, each dose group of the test article and the positive control group on the recovery of residual muscle relaxation were basically the same. (3) Effect of omadex sodium on the blood pressure of muscle relaxation model animals Table 7 Effect of omadex sodium on antagonizing cisatracurium on the mean systolic blood pressure of muscle relaxation model animals Note: The data listed in the table are all mean ± standard deviation. There was no significant difference in each group index, P > 0.05 vs negative control group. The number of guinea pigs in each group was 10. Table 8 Effect of omadex sodium on antagonizing cisatracurium on the mean diastolic blood pressure of muscle relaxation model animals Note: The data listed in the table are all mean ± standard deviation. There were no significant differences in the indicators among the groups, P > 0.05 vs negative control group. The number of guinea pigs in each group was 10. Table 9 Effects of Orgemonium Sodium on Mean Arterial Pressure in Muscle Relaxation Model Animals Antagonizing Cisatracurium Note: The data listed in the table are all mean ± standard deviation. There were no significant differences in the indicators among the groups, P > 0.05 vs negative control group. The number of guinea pigs in each group was 10. Table 10 Effects of Orgemonium Sodium on Mean Pulse Pressure Difference in Muscle Relaxation Model Animals Antagonizing Cisatracurium Note: The data listed in the table are all mean ± standard deviation. There were no significant differences in the indicators among the groups, P > 0.05 vs negative control group. The number of guinea pigs in each group was 10. The results showed that compared with the animals in the negative control group, there were no significant differences in the mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean pulse pressure difference among the animals in the positive control group, the low, medium, and high dose groups of the test article, and the combination group before administration of cisatracurium solution, when the injection of cisatracurium solution was stopped, at moderate neuromuscular recovery, and at complete neuromuscular function recovery (P > 0.05). (4) Effects of Orgemonium Sodium on Heart Rate in Muscle Relaxation Model Animals Table 11 Effects of Orgemonium Sodium on Heart Rate in Muscle Relaxation Model Animals Antagonizing Cisatracurium Note: The data listed in the table are all mean ± standard deviation. **: P < 0.01; ***: P < 0.001 vs negative control group. The number of guinea pigs in each group was 10. The results showed that compared with the animals in the negative control group, there were no significant differences in the heart rate among the animals in the low, medium, and high dose groups of the test article before administration of cisatracurium solution, when the injection of cisatracurium solution was stopped, at moderate neuromuscular recovery, and at complete neuromuscular function recovery (P > 0.05), indicating that the low, medium, and high doses of Orgemonium Sodium test article had no obvious effect on the heart rate at moderate neuromuscular recovery and at complete neuromuscular function recovery, and the drug had good safety in terms of its effect on heart rate. Compared with the animals in the negative control group, there were no significant differences in the heart rates of the animals in the positive control group and the combination group before the administration of cisatracurium solution and when the injection of cisatracurium solution was stopped (P > 0.05). However, compared with the animals in the negative control group, significant differences in heart rates were observed in the positive control group during moderate recovery of neuromuscular function and complete recovery of neuromuscular function (P < 0.01 or 0.001). The decrease in heart rate at complete recovery of muscle relaxation was 35% (the decrease in heart rate at complete recovery of muscle relaxation = (heart rate at the start of muscle relaxation - heart rate at complete recovery) / heart rate at the start of muscle relaxation), indicating that neostigmine had obvious side effects in terms of affecting heart rate; significant differences in heart rates were also observed in the combination group during moderate recovery of neuromuscular function and complete recovery of neuromuscular function (P < 0.01). The decrease in heart rate at complete recovery of muscle relaxation was 21% (the decrease in heart rate at complete recovery of muscle relaxation = (heart rate at the start of muscle relaxation - heart rate at complete recovery) / heart rate at the start of muscle relaxation), indicating that the combination of sugammadex sodium and neostigmine improved the effect of reducing heart rate, but could not completely restore it. 3. Test conclusion Under the conditions of this experiment, sugammadex sodium at a dose of 10 mg / kg could significantly shorten the recovery time of residual muscle relaxation in the cisatracurium-induced guinea pig muscle relaxation model, and the effect was equivalent to that of 0.0625 mg / kg neostigmine. After administration of 10, 20, and 40 mg / kg of sugammadex sodium to the guinea pigs in the cisatracurium muscle relaxation model, no effects on the blood pressure and heart rate of the animals were observed, while after administration of 0.0625 mg / kg neostigmine, there were obvious side effects of decreased heart rate, indicating that sugammadex sodium was significantly safer than neostigmine in terms of protecting heart rate. As already mentioned in the background art of the specification, sugammadex sodium does not bind to atracurium and cisatracurium; on the contrary, after administration of sugammadex sodium, the onset of cisatracurium-induced neuromuscular blockade is faster and the blockade level is deeper. As early as 2006, H. D. de Boer et al. also found that sugammadex sodium was ineffective in reversing atracurium-induced neuromuscular blockade. Considering its clinical side effects such as hypersensitivity reaction, allergic reaction, and QT interval prolongation, sugammadex sodium was not used as a control group in this experiment. Based on the fact that cisatracurium occupies more than 70% of the domestic muscle relaxant drug market share and also has a relatively high market share abroad, but its antagonist is only neostigmine, which has obvious limitations in its effects and side effects and cannot meet the clinical needs. The sugammadex sodium of the present invention is non-inferior to neostigmine in terms of drug efficacy, and at the same time, no adverse reactions similar to neostigmine have been found. As a new generation product in this field, it can meet the clinical needs and fill the market gap, which has very important significance. Examples 4 Preparation of injection Table 12 Formulation table Weigh mannitol according to the prescription amount, add about 80% of the total amount of water for injection, stir until dissolved; then, add the prescription amount of sodium omeclozanide, stir until dissolved, make up the volume to the total amount with water for injection, filter through a 0.2 μm microporous membrane for sterilization, fill into medium-borosilicate glass ampoules, 2 ml per vial, fill with nitrogen, seal by melting, and sterilize at 121 °C for 15 minutes to obtain sodium omeclozanide injection. Example 5 Compound Preparation of Compound InjectionTable 13 Formulation Table Weigh mannitol and sodium acetate according to the prescription amount, add about 80% of the total amount of water for injection, stir until dissolved; add the prescription amount of sodium omeclozanide and neostigmine methylsulfate, stir until dissolved; then add the prescription amount of phenol, stir until dissolved; adjust the pH to 5.5 ± 0.5 with an appropriate amount of acetic acid solution or sodium hydroxide solution; make up the volume to the total amount with water for injection, filter through a 0.2 μm microporous membrane for sterilization, fill into medium-borosilicate glass vials, 2 ml per vial, fill with nitrogen, seal by melting, and sterilize at 121 °C for 15 minutes to obtain compound injection of sodium omeclozanide and neostigmine methylsulfate. Example 6 Preparation of Freeze-dried Powder for InjectionTable 14 Formulation Table Put the prescription amount of sodium omeclozanide into 80% of the prescription amount of water for injection, stir to dissolve; add water for injection to the prescription amount. Add activated carbon (0.1 - 0.5%) to the above-mentioned liquid medicine, stir for dozens of minutes; decolorize with activated carbon and filter to remove carbon; adjust the pH value of the liquid medicine to 6 - 9 with sodium hydroxide solution or hydrochloric acid solution. Take samples for semi-finished product inspection. Filter twice through a 0.22 μm filter and fill. Carry out freeze-drying, plugging, capping, and packaging according to the set freeze-drying parameters. All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the scope of the patent application attached to this application. (None) Figure 1 shows the muscle relaxation monitoring spectra of each group of guinea pigs. As shown in Figure 1, (A) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the negative control group; (B) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the positive control group; (C) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the low-dose test article group; (D) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the medium-dose test article group; (E) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the high-dose test article group; (F) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the combination group. (None)

Claims

1. A use of sodium omeprazole, characterized in that it is used to prepare a pharmaceutical composition for reversing muscle relaxation caused by benzyl isoquinoline muscle relaxants; wherein the benzyl isoquinoline muscle relaxant is cisatracurium.

2. As claimed in claim 1, the pharmaceutical composition is also used to reverse residual neuromuscular blockade following muscle relaxation induced by benzylisoquinoline muscle relaxants.

3. As claimed in claim 1, the pharmaceutical composition is also used to improve adverse reactions during the antagonism of cisatracurium-induced muscle relaxation.

4. As described in claim 3, the adverse reactions are selected from the group consisting of: decreased heart rate, decreased blood pressure, and gastrointestinal discomfort.

5. The use as claimed in claim 1, wherein the pharmaceutical composition further comprises a second therapeutic component, and the second therapeutic component is an active ingredient of a muscle relaxant drug; wherein the second therapeutic component is neostigmine.

6. The use of an omeprazole sodium formulation for reversing muscle relaxation induced by atracurium besylate, characterized in that the formulation comprises: 2-5 parts by weight of sodium omeprazole, 0.1-1 parts by weight of mannitol, and 15-30 parts by weight of water for injection.

7. The use of an omeprazole sodium formulation for reversing muscle relaxation induced by atracurium besylate, characterized in that the omeprazole sodium formulation is a lyophilized powder for injection, and the lyophilized powder for injection is obtained by lyophilizing a formulation comprising: 1-5 parts by weight of sodium omeprazole, pH adjuster, and 15-30 parts by weight of water for injection; The pH adjuster is sodium hydroxide or hydrochloric acid.

8. A compound injectable formulation, characterized in that the formulation comprises: Sodium omeprazole and neostigmine methyl sulfate; The formulation comprises: 2-5 parts by weight of sodium omeprazole, 6-22 parts by weight of neostigmine methylsulfate, 0.1-1 parts by weight of mannitol, 0.01-0.1 parts by weight of antibacterial agent, an appropriate amount of pH adjuster, and the remainder being water for injection; and the volume of the formulation is 2 mL; wherein the antibacterial agent is phenol; the pH adjuster includes sodium hydroxide, hydrochloric acid, acetic acid, or sodium acetate; and the pH of the formulation is 6-9.

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