Muscle relaxant antagonist for reversal for benzylisoquinoline muscle relaxant

Abstract

The present invention provides a muscle relaxant antagonist for reversal for a benzylisoquinoline muscle relaxant. Specifically, the present invention provides a preparation method for a safer and more effective muscle relaxant antagonist pharmaceutical preparation for reversing a benzylisoquinoline muscle relaxant, and a use. More specifically, the present invention provides adamgammadex sodium serving as an alternative to neostigmine to reverse muscle relaxation by a benzylisoquinoline muscle relaxant cisatracurium besylate. During reversal of residual neuromuscular blockade after muscle relaxation induced by the muscle relaxant cisatracurium besylate, adamgammadex sodium can serve as an alternative to neostigmine, demonstrating significant superiority over neostigmine in terms of heart rate maintenance while maintaining comparable antagonist efficacy. The present invention also provides adamgammadex sodium and a compound pharmaceutical preparation thereof. Adamgammadex sodium is prepared into a freeze-dried powder injection or liquid injection and is applicable to the preparation of a muscle relaxant antagonist.

Description

A muscle relaxant antagonist for reversing the effects of benzylisoquinoline muscle relaxants Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a method for preparing a safer and more effective muscle relaxant antagonist pharmaceutical preparation for reversing benzylisoquinoline muscle relaxants (such as atracurium besylate) and its application. Background Art

[0002] With the continuous development and progress of surgery and minimally invasive medicine, patients' requirements for surgical comfort and safety have increased, and general anesthesia has accounted for an increasingly large proportion of clinical surgical anesthesia, even reaching more than 90% in some hospitals.

[0003] Muscle relaxants are a crucial component of general anesthesia. They provide the surgeon with a clearer operative field, prevent patient movement during surgery, and reduce the risk of complications. Cisatracurium is a relatively new, intermediate-acting, non-depolarizing muscle relaxant and one of the isomers of atracurium. It is primarily degraded by Hofmann clearance at physiological pH and body temperature, independent of liver and kidney metabolism. Its clinical benefits include a lack of accumulation, rapid recovery, and potent effects. Its low histamine release and minimal impact on cardiovascular function have led to its widespread clinical use. Currently, intermediate-acting, non-depolarizing muscle relaxants, such as cisatracurium, rocuronium, and vecuronium, are the most widely used in clinical practice. These three drugs together account for over 98% of the muscle relaxant market. Cisatracurium holds the largest market share, making it a leading player in the muscle relaxant market.

[0004] Incomplete metabolism of muscle relaxants often leads to respiratory insufficiency after extubation. Furthermore, residual muscle relaxants after surgery can impede recovery of laryngeal muscle function, leading to increased rates of postoperative aspiration, dysphagia, and upper airway obstruction. Suppressing respiration can also lead to hypoxemia. This residual muscle relaxant effect can increase postoperative complications and mortality, and prolong hospitalization time. Literature reports indicate that even in the United States and Canada, where muscle relaxant monitoring is now widely used, the incidence of residual muscle relaxant effects at the time of extubation after surgery reaches 64.7% and 63.5%, respectively. Other literature reports suggest that the potential risk of residual muscle relaxant effects (TOFr < 0.9; TOFr: the ratio of the fourth twitch to the first twitch, T4 / T1) persists in 12% of patients after extubation following surgery, even with the routine use of the non-depolarizing muscle relaxant cisatracurium during general anesthesia.

[0005] Currently, the most commonly used muscle relaxant antagonists in clinical practice are anticholinesterase drugs, which work by inhibiting cholinesterase, thereby reducing the breakdown of acetylcholine (ACh). Neostigmine, the most commonly used anticholinesterase drug in clinical practice, not only antagonizes muscle relaxants but also produces significant muscarinic effects, particularly on heart rate, which can induce bradycardia and, in severe cases, cardiac arrest. This has led to many patients being prohibited from using this drug or using it with caution. Atropine, an anticholinergic drug, can increase heart rate and antagonize the bradycardia induced by neostigmine. Clinically, these two drugs are often combined to antagonize the residual muscle relaxant effects, and the two drugs are often used together. However, because atropine has a rapid onset of action, while neostigmine is slower, there is a significant initial increase in heart rate. This hemodynamic alteration can contribute to perioperative myocardial ischemia, with more severe consequences for some patients with more severe heart disease. Some researchers recommend administering atropine 2-4 minutes after neostigmine, but the busy schedule of anesthesia recovery rooms makes it difficult to ensure that medication is administered at the prescribed time. If atropine is injected too late, it can cause excessive bradycardia. Furthermore, atropine readily crosses the blood-brain barrier, posing a risk factor for postoperative cognitive impairment and even delirium, a significant risk for elderly patients.

[0006] Olmethasone sodium is a safer alternative to neostigmine for the muscle relaxant cisatracurium besylate. Olmethasone sodium is a small molecule drug developed by our company and is a Class I Chinese chemical drug. Currently, the drug is in Phase III clinical trials for the reversal of neuromuscular blockade.

[0007] Sugammadex sodium, also known as Bridion, is the only currently registered counterpart to the drug omepromazine sodium described in this invention. As a novel muscle relaxant antagonist, it is a specific antagonist of rocuronium bromide (a steroidal muscle relaxant). Sugammadex sodium does not bind to succinylcholine or benzylisoquinoline neuromuscular blockers (such as mivacurium, atracurium, and cisatracurium); instead, after administration of sugammadex sodium, cisatracurium-induced neuromuscular blockade develops more rapid onset and deeper levels of blockade. The earliest study on sugammadex sodium and atracurium was published in 2006 by HD de Boer et al. in the British Journal of Anaesthesia. The study found that sugammadex sodium was ineffective in reversing atracurium-induced neuromuscular blockade, but had no effect on blood pressure or heart rate. The 2023 American Society of Anesthesiologists' Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade also state that sugammadex sodium is ineffective for antagonism of benzylisoquinoline neuromuscular blocking agents. Furthermore, sugammadex sodium presents certain safety concerns. It was rejected three times by the US FDA due to allergic reactions, cardiac Qt prolongation, and bleeding risks, and was finally approved for marketing seven years later. In recent years, reports of potential adverse reactions to sugammadex sodium have increased, including common and serious adverse reactions such as residual postoperative muscle relaxation, allergic and hypersensitivity reactions, coagulopathy, cardiovascular side effects, bronchospasm and laryngospasm, as well as other adverse reactions such as postoperative nausea, prolonged renal excretion time, neuronal apoptosis, and metallic taste abnormalities. Therefore, cholinesterase inhibitors and cholinesterase inhibitors combined with anticholinergics have yet to meet clinical needs. There is an urgent need to provide patients with effective and safe muscle relaxant antagonists.

[0008] Summary of the Invention

[0009] The present invention aims to provide a use of olmethasone sodium in preparing a pharmaceutical composition for reversing neuromuscular blockade induced by benzylisoquinoline muscle relaxants (such as atracurium besylate).

[0010] In a first aspect, the present invention provides a use of olmethasone sodium, which can be used to prepare a pharmaceutical composition for reversing muscle relaxation caused by benzylisoquinoline muscle relaxants (such as atracurium besylate).

[0011] The use according to the first aspect of the present invention, wherein the pharmaceutical composition is also used to reverse the residual neuromuscular blocking effect after muscle relaxation induced by cisatracurium.

[0012] The use according to the first aspect of the present invention, wherein the pharmaceutical composition is further used to improve adverse reactions during antagonism of cisatracurium-induced muscle relaxation, wherein the adverse reactions are selected from the group consisting of decreased heart rate, decreased blood pressure, and gastrointestinal discomfort.

[0013] According to the use of the first aspect of the present invention, the pharmaceutical composition further comprises a second therapeutic component, and the second therapeutic component is an active ingredient of a muscle relaxant antagonist. In the embodiment, the second therapeutic component is neostigmine.

[0014] The second aspect of the present invention provides an olmethasone sodium preparation, comprising: a therapeutically effective amount of olmethasone sodium, mannitol, and the balance water for injection.

[0015] The preparation according to the second aspect of the present invention comprises: 2-5 parts by weight of omexin sodium, 0.1-1 parts by weight of mannitol, and 15-30 parts by weight of water for injection.

[0016] The preparation according to the second aspect of the present invention comprises: 0.2-0.5 g / dose of olmixone sodium, 0.01-0.1 g / dose of mannitol, and the balance of water for injection; and the volume of the preparation is 2 mL.

[0017] The preparation according to the second aspect of the present invention, wherein the preparation is used to reverse muscle relaxation caused by cisatracurium besylate;

[0018] In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation;

[0019] In another preferred embodiment, the preparation is also used to improve adverse reactions during antagonizing cisatracurium-induced muscle relaxation.

[0020] The third aspect of the present invention provides an olmexone sodium preparation, wherein the preparation is a lyophilized powder injection, and the preparation comprises: a therapeutically effective amount of olmexone sodium, sodium hydroxide or hydrochloric acid, and the balance water for injection.

[0021] In another preferred embodiment, the preparation comprises: 1-5 parts by weight of omexin sodium, 15-30 parts by weight of water for injection, and an appropriate amount of sodium hydroxide or hydrochloric acid.

[0022] In another preferred embodiment, the preparation comprises: 0.1-0.5 g / dose of omexin sodium, an appropriate amount of sodium hydroxide or hydrochloric acid, and the balance of water for injection; and the volume of the preparation is 2 mL.

[0023] In another preferred embodiment, the preparation is prepared by the following method: mixing a therapeutically effective amount of omecam sodium with a prescribed amount of water for injection, adjusting the pH value to 6-9 using sodium hydroxide or hydrochloric acid, and then freeze-drying to obtain the freeze-dried powder injection preparation.

[0024] The preparation according to the third aspect of the present invention, wherein the preparation is used to reverse muscle relaxation caused by cisatracurium besylate;

[0025] In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation;

[0026] In another preferred embodiment, the preparation is also used to improve adverse reactions during antagonizing cisatracurium-induced muscle relaxation.

[0027] The fourth aspect of the present invention also provides a compound injection preparation, wherein the preparation comprises: a therapeutically effective amount of omecam sodium and neostigmine methylsulfate;

[0028] Preferably, the preparation further comprises: mannitol, an antibacterial agent, a pH regulator, and the balance water for injection.

[0029] In another preferred embodiment, the antibacterial agent is phenol.

[0030] In another preferred embodiment, the pH adjuster is sodium hydroxide or hydrochloric acid.

[0031] As described in the fourth aspect of the present invention, the compound injection preparation comprises: 2-5 parts by weight of omecamyl sodium, 6-22 parts by weight of neostigmine methylsulfate, 0.1-1 parts by weight of mannitol, 0.01-0.1 parts by weight of an antibacterial agent, an appropriate amount of a pH regulator, and the balance water for injection; and the volume of the preparation is 2 mL.

[0032] In another preferred embodiment, the pH of the preparation is 6-9.

[0033] The present invention is beneficial in that:

[0034] (1) The results of animal model experiments strongly proved that omepromazine sodium has the effect of antagonizing the depolarizing muscle relaxant cisatracurium. Specifically, omepromazine sodium at a dose of 10 mg / kg can significantly shorten the recovery time of residual muscle relaxation in the cisatracurium-induced guinea pig muscle relaxation model. As the dose of omepromazine sodium increases, the 20 and 40 mg / kg dose groups of omepromazine sodium show better acceleration of muscle relaxation recovery, and a certain dose-effect relationship is shown. The 40 mg / kg high-dose omepromazine sodium group, the 0.0625 mg / kg neostigmine positive control group and the combined group (omepromazine sodium: 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 groups, indicating that the activity of omepromazine sodium in antagonizing cisatracurium is equivalent to the antagonistic effect of neostigmine.

[0035] (2) We were also surprised to find that in terms of heart rate protection, the safety of omepromazine sodium was 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 of about 30%, which poses a safety risk. The heart rate reduction effect of the animals in the combined group was slowed down after the drug was given, but it still could not be fully restored. The administration of 10, 20, and 40 mg / kg of omepromazine sodium had no significant effect on the blood pressure and heart rate of the guinea pig muscle relaxation model. Therefore, omepromazine sodium has the potential to be developed into a clinical drug that can antagonize the depolarizing muscle relaxant cisatracurium.

[0036] (3) Olmecton sodium is indicated for antagonizing various degrees of neuromuscular blockade caused by steroidal non-depolarizing muscle relaxants such as rocuronium during general anesthesia surgery. Phase III clinical studies in China have been completed. If its use as an antagonist of cisatracurium is successfully developed, it will further broaden its clinical application scope, address the muscarinic effects of neostigmine, and overcome safety concerns regarding the combined use of atropine and neostigmine, namely, safety issues such as unstable heart rate, tachycardia and arrhythmia, and postoperative cognitive impairment. Olmecton sodium's successful replacement of neostigmine combined with atropine will benefit a wider range of patients undergoing general anesthesia surgery.

[0037] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 shows the muscle relaxation monitoring patterns of guinea pigs in each group. As shown in Figure 1, (A) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the negative control group; (B) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the positive control group; (C) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the low-dose test article group; (D) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the medium-dose test article group; (E) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the high-dose test article group; and (F) is the muscle relaxation monitoring pattern of each of the 10 guinea pigs in the combination group. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0040] Example 1 Risk Assessment of Compound-Induced Sensitization (Safety Screening 1)

[0041] 1. Experimental process

[0042] Wild-type AB zebrafish at 2 days post fertilization (dpf) were randomly selected and plated in a 24-well plate. Six replicate wells were set up in each group, and 10 zebrafish were treated in each well. The following groups were set up: (1) normal control group; (2) positive control group (the drug used was mast cell sensitizer C48 / 80, 1.5 μg / mL concentration); (3) compound 1 (olmethionine sodium) experimental group; (4) compound 2 experimental group; (5) compound 3 experimental group; (6) compound 4 experimental group; (7) compound 5 experimental group; (8) compound 6 experimental group; (9) compound 7 (sugammadex sodium) experimental group. In each experimental group, compound 1 was olmethionine sodium, compounds 2-6 were olmethionine sodium analogs, and compound 7 was sugammadex sodium. The volume of each well was 1 mL, and each experimental group was given water-soluble BAPNA (mast cell degranulation specific detection reagent).

[0043] Table 1 Structural formula of compounds 1-7

[0044] After one day of treatment at 28°C, the solution was transferred to a 96-well plate at 200 μL / well. The relative absorbance (OD) of tryptase expression in each experimental group was measured using a microplate reader. Statistical analysis of the OD values ​​was used to assess the sensitization risk of the samples. Statistical analysis was performed using SPSS software; a p < 0.05 indicated a significant difference.

[0045] 2. Test results

[0046] Table 2 Sensitization risk of each compound Note: The data listed in the table are mean ± standard deviation (mean ± SE). *: P < 0.05; ***: P < 0.001 vs. normal control group.

[0047] 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 the positive drug C48 / 80 had a high risk of sensitization under the experimental concentration conditions. The OD values ​​of the experimental group of compound 1 (olmethoxazole sodium) and the experimental group of compound 2 were 0.060 and 0.052, respectively, which were similar to the normal control group (0.054), indicating 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. Many zebrafish died in the experimental groups of compound 3, compound 4, compound 5, and compound 6, so they were not evaluated.

[0048] 3. Experimental conclusion

[0049] Among the tested compounds, Compound 1 (Omexone sodium), Compound 2, and Compound 7 (Sugammadex sodium) all had significantly lower allergy-causing risks than the positive control. Compounds 2 and 1 (Omexone sodium) had no or essentially no allergy-causing risk and are suitable for subsequent drug development; Compound 7 (Sugammadex sodium) had a low allergy-causing risk.

[0050] Example 2 Effects of Olmecton Sodium, Sugammadex Sodium, and Neostigmine on Immunoinflammatory Function (Safety Screening II)

[0051] 1. Experimental process

[0052] Antibody chip is a type of protein chip with the characteristics of miniaturization, integration and high throughput. It can be used to detect the expression abundance of proteins related to a specific physiological or pathological process. The principle is to arrange the capture antibody on a membrane or glass slide, add the sample for incubation, then add the biotin-labeled antibody of the target protein, and finally, HRP-streptavidin or fluorescein-streptavidin is used to detect the chip signal. Finally, chemical light or HiLyte TM The signal was detected using Fluor 555-streptavidin.

[0053] In this study, ICR mice were randomly divided into a blank group, an olmethionine sodium (1g / kg) group, a sugammadex sodium (1g / mg) group, and a neostigmine (0.3mg / kg) group, with two mice in each group. Each group of mice was administered the corresponding dose of compound via the tail vein once daily for five consecutive days. After the final day of dosing, plasma from both animals was pooled and assayed using the Ary028 Immunochip Kit. The specific assay steps are as follows:

[0054] (1) Sample volume determination: 200 μl serum sample per Array unit. (2) Blocking 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 processing: 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 at 4°C overnight. (4) Wash the membrane three times with the corresponding Wash buffer, add the diluted detection antibody, and incubate at room temperature for 1 hour. (5) Wash the membrane three times with the corresponding Wash buffer, add streptavidin-HRP, incubate for 30 minutes, and shake at room temperature. (6) Wash the membrane three times with the corresponding Wash buffer, add 1 ml of chemical color reagent to each well, and develop the color on a chemiluminescence imager. (7) The relative concentration of the corresponding protein is expressed as fluorescence intensity.

[0055] 2. Test results

[0056] Table 3 Comparison of fluorescence intensity of hypersensitivity reaction-related factors Note: “Not detected” means the protein concentration in serum is below the minimum detection limit

[0057] Table 4 Comparison of fluorescence intensity of inflammatory related factors Note: “Not detected” means the protein concentration in serum is below the minimum detection limit

[0058] A total of 11 hypersensitivity-related factors and 45 inflammatory-related factors were detected. As shown in Tables 3 and 4, the detection levels of 11 hypersensitivity-related factors and 37 inflammatory-related factors in the serum of the blank group were all below the minimum detection limit. Compared with the sugammadex sodium and neostigmine groups, the detection levels of each hypersensitivity-related and inflammatory-related factor in the omepromazine sodium group were the lowest or below the minimum detection limit, indicating that omepromazine sodium had the least effect on inducing immune inflammation in mice, followed by sugammadex sodium, and neostigmine had the most severe effect.

[0059] 3. Experimental conclusion

[0060] The results of this experiment analyzing the effects of three muscle relaxant antagonists, namely, olmethionine sodium, sugammadex sodium, and neostigmine, on immune-inflammatory activity in mice showed that olmethionine sodium had the least effect on inducing immune-inflammatory activity in mice, and many hypersensitivity reactions and inflammatory-related factors were not induced, which was below the minimum detection limit, indicating that the drug has good safety in terms of immune-inflammatory activity; sugammadex sodium had the second worst effect on inducing immune-inflammatory activity in mice, indicating that the drug has average safety in terms of immune-inflammatory activity; and neostigmine had the most serious effect on inducing immune-inflammatory activity in mice, leading to increased secretion of most hypersensitivity reactions and inflammatory-related factors, indicating that the drug has great safety risks in terms of immune-inflammatory activity.

[0061] Example 3 Effect of Olmectonide Sodium on Residual Muscle Relaxation Antagonism after Administration of the Muscle Relaxant Cisatracurium in Anesthetized Guinea Pigs (Pharmacological Efficacy Experiment)

[0062] 1. Experimental process

[0063] Ninety male Hartley guinea pigs that passed quarantine were obtained. Sixty of these animals were randomly divided into six experimental groups based on body weight using a stratified randomization method: a negative control group, a positive control group, low-, medium-, and high-dose test article groups, and a combination group, with 10 animals in each group (n=10). The remaining animals were kept as backup. The negative control group was given 0.9% sodium chloride, the positive control group was given 0.0625 mg / kg of neostigmine methylsulfate (abbreviated as neostigmine), the low-dose test article group was given 10 mg / kg of omepromazine sodium, the medium-dose test article group was given 20 mg / kg of omepromazine sodium, the high-dose test article group was given 40 mg / kg of omepromazine sodium, and the combination group was given 10 mg / kg of omepromazine sodium and 0.03125 mg / kg of neostigmine. The dosing volume for all groups was 1 mL / kg.

[0064] After quarantine, adaptive feeding was performed. On the day of the experiment, the guinea pigs were weighed and injected intramuscularly with atropine 0.1 mg / kg, followed by an intraperitoneal injection of anesthetic drugs (pentobarbital sodium 10 mg / kg, urethane 1000 mg / kg). After the animals were immobilized, they were intubated and connected to a small animal ventilator. The external jugular veins on both sides and the right carotid artery were isolated and cannulated. The left vein was used for bolus injection of cisatracurium solution, and the right vein was used for injection of different test substances. 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 attached subcutaneously to the posterior femur and tibia of the guinea pig's left side, and the two stimulating electrodes of the muscle relaxation monitor were fixed to the two electrode patches respectively. The left hind foot was fixed on a homemade platform. The sensor was fixed to the skin surface of the gastrocnemius muscle of the guinea pig's left hind limb, and the skin temperature probe was fixed to a flat part of the skin. First, continuous single stimulation was performed using the 1Hz mode. Once the twitch was highly stable, the stimulation was switched to a train-of-four stimulation mode (TOF mode, stimulation current 5mA, frequency 2Hz, pulse width 0.2ms, inter-train interval 15s) for at least 5 minutes. After that, calibration was performed using calibration mode 2, and then stimulation was resumed using the TOF mode. After obtaining a stable stimulation response for at least 2 minutes, intravenous bolus injection of cisatracurium solution was started using a dual-channel microinjection pump, and the bolus start time was recorded. When the cisatracurium solution was continuously bolused until the T4 / T1 (TOFr) disappeared and T1 was below 15%, the muscle relaxation model was considered successful, and the bolus injection of cisatracurium solution was then stopped. After the bolus injection was stopped, the neuromuscular function was allowed to recover spontaneously. When the neuromuscular function recovered moderately, the test substance was intravenously injected. After the neuromuscular function was fully restored, the administration time was recorded (Figure 1). The time from TOF50 to TOF75, TOF75 to TOF90, and TOF50 to TOF90 was calculated, with the time of spontaneous recovery of neuromuscular function (TOF50) as the zero point (Table 1-2). Arterial blood pressure (including systolic, diastolic, and mean arterial pressure) and heart rate were recorded before the bolus injection of cisatracurium solution, at the time of cessation of the bolus injection of cisatracurium solution, at the time of moderate neuromuscular recovery, and at the time of complete neuromuscular recovery (Table 3-7). Data are expressed as mean ± SD. T-tests were performed using SPSS software to evaluate differences in blood pressure, heart rate, and time to recovery of residual muscle relaxation. P < 0.05 was considered statistically significant.

[0065] 2. Test results

[0066] (1) Effect of omexin sodium on the recovery time of residual muscle relaxation in muscle relaxation model animals

[0067] Table 5 Effect of omecamylamine sodium antagonizing cisatracurium on the recovery time of residual muscle relaxation in muscle relaxation model animals Note: Data listed in the table are mean ± SD. *: P < 0.05; **: P < 0.01 vs. negative control group. There were 10 guinea pigs in each group.

[0068] The results showed that compared with the negative control group, there was no significant difference in the tTOF0-50 values ​​of each group (P>0.05), indicating that the spontaneous recovery of neuromuscular function was basically the same before the administration of the test preparation. After the neuromuscular function spontaneously recovered to moderate, the test preparation was administered, and the neuromuscular function recovered completely. The residual muscle relaxation recovery time tTOF50-75, tTOF75-90 and tTOF50-90 of the positive control group were significantly shortened (P<0.05-0.01), the residual muscle relaxation recovery time tTOF75-90 and tTOF50-90 of the low-dose test group were significantly shortened (P<0.05), and the residual muscle relaxation recovery time tTOF50-90 of the medium-dose test group was significantly shortened (P<0.05). The results showed that the time of recovery of residual muscle relaxation tTOF75-90 and tTOF50-90 in the high-dose group of the test sample was significantly shortened (P<0.01), and the time of recovery of residual muscle relaxation tTOF50-75, tTOF75-90 and tTOF50-90 in the combination group was significantly shortened (P<0.05-0.01), indicating that different doses of omepromazine sodium can significantly shorten the time of recovery of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium under the conditions of this experiment. The residual muscle relaxation recovery time tTOF50-90 values ​​of the negative control group, positive control group, low-dose, medium-dose, high-dose groups and combination group were (455±201) seconds, (188±86) seconds, (248±139) seconds, (279±123) seconds, (201±131) seconds and (174±108) seconds, respectively. After administration of drugs to the positive control group, low-dose, medium-dose, high-dose groups and combination group, tTOF50-90 values ​​were shortened by 58.7% , 45.5%, 38.7%, 55.8% and 61.8% (the degree of shortening of tTOF50-90 time = (tTOF50-90 value of negative control group - tTOF50-90 value of experimental group) / tTOF50-90 value of negative control group), indicating that low, medium and high doses of omepromazine sodium had significant effects on the recovery of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium, and the effects were close to those of neostigmine administration or the combined administration of omepromazine sodium and neostigmine.

[0069] (2) Effect of omepromazine sodium on the ratio of residual muscle relaxation to recovery time in muscle relaxation model animals

[0070] Taking into account the possible differences in muscle relaxation recovery time tTOF0-50 before administration of the test substance among different guinea pigs, the ratios of residual muscle relaxation recovery time tTOF50-75, tTOF75-90 and tTOF50-90 to muscle relaxation recovery time tTOF0-50 (RtTOF50-75 / 0-50, RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50) were used as evaluation indicators.

[0071] Table 6 Effects of omecamyl sodium antagonizing cisatracurium on the ratio of residual muscle relaxation recovery time in muscle relaxation model animals Note: Data listed in the table are mean ± SD. *: P < 0.05; **: P < 0.01 vs. negative control group. There were 10 guinea pigs in each group.

[0072] The results showed that compared with the negative control group, the residual muscle relaxation recovery time ratios RtTOF50-75 / 0-50, RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 of the positive control group were significantly reduced (P<0.05-0.01), the residual muscle relaxation recovery time ratios RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 of the low and medium dose groups were significantly reduced (P<0.05), and the high dose group was significantly The residual muscle relaxation recovery time ratios RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 of the group A were significantly reduced (P<0.01), and the residual muscle relaxation recovery time ratios RtTOF50-75 / 0-50, RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 of the combined group A were significantly reduced (P<0.05). The above results showed that different doses of omepromazine sodium can significantly accelerate the recovery of cisatracurium-induced The residual muscle relaxation of the guinea pig muscle relaxation model was restored, and a certain dose-effect relationship was shown. Compared with the positive control group, there was no significant difference in the residual muscle relaxation recovery time ratios RtTOF50-75 / 0-50, RtTOF75-90 / 0-50 and RtTOF50-90 / 0-50 of the low, medium and high doses of the test article (P>0.05), indicating that the combined group, the test article dose groups and the positive control group had similar effects on the recovery of residual muscle relaxation in the muscle relaxation model animals; the negative control group 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 control group, low-, medium-, and high-dose test sample groups, and the 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 medication group was significantly reduced, and the combination group, each dose group of the test sample, and the positive control group had basically the same effect on the recovery of residual muscle relaxation.

[0073] (3) Effects of omepromazine sodium on blood pressure in muscle relaxation model animals

[0074] Table 7 Effect of omepromazine sodium on the antagonism of cisatracurium on the average systolic blood pressure of muscle relaxation model animals Note: Data listed in the table are mean ± SD. No significant differences were observed between groups (P > 0.05 vs. negative control group). Each group consisted of 10 guinea pigs.

[0075] Table 8 Effect of omecamylamine sodium on the antagonism of cisatracurium on the mean diastolic blood pressure of muscle relaxation model animals Note: Data listed in the table are mean ± SD. No significant differences were observed between groups (P > 0.05 vs. negative control group). Each group consisted of 10 guinea pigs.

[0076] Table 9 Effect of omepromazine sodium on the mean arterial pressure of muscle relaxation model animals by antagonizing cisatracurium Note: Data listed in the table are mean ± SD. No significant differences were observed between groups (P > 0.05 vs. negative control group). Each group consisted of 10 guinea pigs.

[0077] Table 10 Effect of omepromazine sodium antagonizing cisatracurium on the mean pulse pressure difference of muscle relaxation model animals Note: Data listed in the table are mean ± SD. No significant differences were observed between groups (P > 0.05 vs. negative control group). Each group consisted of 10 guinea pigs.

[0078] 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, low-dose, medium-dose and high-dose test sample groups and the combination group before administration of cisatracurium solution, when the injection of cisatracurium solution was stopped, when neuromuscular function recovered moderately and when neuromuscular function recovered completely (P>0.05).

[0079] (4) Effects of omepromazine sodium on the heart rate of muscle relaxation model animals

[0080] Table 11 Oxamethylenetetramine antagonizes the effect of cisatracurium on the heart rate of muscle relaxation model animals Note: Data listed in the table are mean ± SD. **: P < 0.01; ***: P < 0.001 vs. negative control group. There were 10 guinea pigs in each group.

[0081] The results showed that compared with the animals in the negative control group, there was no significant difference in the heart rate of the animals in the low, medium and high dose groups of the test sample before administration of cisatracurium solution, when the push injection of cisatracurium solution was stopped, when the neuromuscular function was moderately recovered and when the neuromuscular function was fully recovered (P>0.05), indicating that the low, medium and high doses of the test sample omepromazine sodium had no significant effect on the heart rate when the neuromuscular function was moderately recovered and when the neuromuscular function was fully recovered, and the drug was very safe in terms of its effect on heart rate.

[0082] Compared with the negative control group, there was no significant difference in the heart rate of the positive control group and the combined group before administration of cisatracurium solution and when the cisatracurium solution injection was stopped (P>0.05). However, compared with the animals in the negative control group, the heart rates of the positive control group showed significant differences at the time of moderate neuromuscular recovery and complete recovery of neuromuscular function (P<0.01 or 0.001), and the heart rate decreased by 35% when muscle relaxation was fully recovered (the decrease in heart rate when muscle relaxation was fully recovered = (heart rate at the beginning of muscle relaxation - heart rate at full recovery) / heart rate at the beginning of muscle relaxation), indicating that neostigmine has obvious side effects in affecting heart rate; the heart rates of the animals in the combination group showed significant differences at the time of moderate neuromuscular recovery and complete recovery of neuromuscular function (P<0.01), and the heart rate decreased by 21% when muscle relaxation was fully recovered (the decrease in heart rate when muscle relaxation was fully recovered = (heart rate at the beginning of muscle relaxation - heart rate at full recovery) / heart rate at the beginning of muscle relaxation), indicating that the heart rate-lowering effect of omepromazine sodium and neostigmine was improved after combination, but could not be completely restored.

[0083] 3. Experimental conclusion

[0084] Under the conditions of this study, olmethasone sodium at a dose of 10 mg / kg significantly shortened the recovery time of residual muscle relaxation in the cisatracurium-induced guinea pig muscle relaxation model, demonstrating comparable efficacy to 0.0625 mg / kg of neostigmine. In the cisatracurium-induced muscle relaxation model, administration of olmethasone sodium at doses of 10, 20, or 40 mg / kg did not affect blood pressure or heart rate in guinea pigs. However, administration of 0.0625 mg / kg of neostigmine significantly reduced heart rate, demonstrating that olmethasone sodium is significantly safer than neostigmine in protecting heart rate.

[0085] As mentioned in the background section of the specification, sugammadex sodium does not bind to atracurium and cisatracurium; rather, after administration of sugammadex sodium, cisatracurium-induced neuromuscular blockade has a faster onset and deeper level of blockade. As early as 2006, HD 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 reactions, allergic reactions, and QT interval prolongation, sugammadex sodium was not used as a control group in this study.

[0086] Cisatracurium holds over 70% of the domestic muscle relaxant market and also holds a high market share abroad. However, its only antagonist is neostigmine, which has significant limitations and side effects and fails to meet clinical needs. Olmectonide sodium of the present invention is non-inferior to neostigmine in efficacy and is free of the adverse reactions associated with neostigmine. As a new generation product in this field, it can meet clinical needs and fill a market gap, thus having significant significance.

[0087] Example 4 Preparation of injection

[0088] Table 12 Recipe

[0089] Weigh mannitol according to the prescribed amount, add about 80% of the total amount of water for injection, and stir until dissolved; then, add the prescribed amount of omepromazine sodium, stir until dissolved, add more water for injection to the full amount, sterilize and filter through a 0.2μm microporous filter membrane, and package into medium-borosilicate glass ampoules, each containing 2ml, fill with nitrogen, seal, and sterilize at 121℃ for 15 minutes to obtain omepromazine sodium injection.

[0090] Example 5 Preparation of compound injection

[0091] Table 13 Recipe

[0092] Weigh mannitol and sodium acetate according to the prescribed amount, add about 80% of the full amount of water for injection, and stir until dissolved; add the prescribed amount of omepromazine sodium and neostigmine methylsulfate, and stir until dissolved; then add the prescribed amount of phenol, and stir until dissolved; use an appropriate amount of acetic acid solution or sodium hydroxide solution to adjust the pH to 5.5±0.5; add water for injection to the full amount, sterilize and filter with a 0.2μm microporous filter membrane, and package in medium-borosilicate glass vials, each containing 2ml, fill with nitrogen, seal, and sterilize at 121°C for 15 minutes to obtain the omepromazine sodium and neostigmine methylsulfate compound injection.

[0093] Example 6 Preparation of freeze-dried powder injection

[0094] Table 14 Recipe

[0095] Dissolve the prescribed amount of omepromazine sodium in 80% of the prescribed amount of water for injection, stirring to dissolve. Add water for injection to the prescribed volume. Add activated carbon (0.1-0.5%) to the solution and stir for several dozen minutes. Decolorize with the activated carbon and filter to remove carbon. Adjust the pH of the solution to 6-9 using sodium hydroxide solution or hydrochloric acid. Take a sample for semi-finished product testing. Filter again through a 0.22μm filter and fill. Freeze-dry, stopper, cap, and package according to the specified freeze-drying parameters.

[0096] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A use of omexin sodium, characterized in that: The invention is used for preparing a pharmaceutical composition for reversing muscle relaxation caused by benzylisoquinoline muscle relaxants.

2. The use according to claim 1, characterized in that The pharmaceutical composition is also used to reverse the residual neuromuscular blocking effect after muscle relaxation induced by benzylisoquinoline muscle relaxants; In another preferred embodiment, the benzylisoquinoline muscle relaxant is cisatracurium.

3. The use according to claim 1, characterized in that The pharmaceutical composition is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation.

4. The use according to claim 3, characterized in that The adverse reactions are selected from the following group: decreased heart rate, decreased blood pressure, and gastrointestinal discomfort.

5. The use according to claim 1, characterized in that The pharmaceutical composition further comprises a second therapeutic component, and the second therapeutic component is an active ingredient of a drug that antagonizes muscle relaxation.

6. The use according to claim 5, characterized in that The second therapeutic component is neostigmine.

7. An omexin sodium preparation, characterized in that: The preparation comprises: a therapeutically effective amount of omexin sodium, mannitol, and the balance of water for injection; In another preferred embodiment, the preparation comprises: 2-5 parts by weight of omexin sodium, 0.1-1 parts by weight of mannitol, and 15-30 parts by weight of water for injection; In another preferred embodiment, the preparation comprises: 0.2-0.5 g / dose of omexin sodium, 0.01-0.1 g / dose of mannitol, and the balance of water for injection; and the volume of the preparation is 2 mL.

8. The preparation according to claim 7, characterized in that The preparation is used to reverse the muscle relaxation caused by cisatracurium besylate; In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation; In another preferred embodiment, the preparation is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation.

9. An omexin sodium preparation, characterized in that: The preparation is a freeze-dried powder injection, and the preparation comprises: a therapeutically effective amount of omexin sodium, a pH regulator, and the remainder of water for injection; In another preferred embodiment, the preparation comprises: 1-5 parts by weight of omexin sodium, 15-30 parts by weight of water for injection, and an appropriate amount of a pH adjuster; preferably, the pH adjuster is sodium hydroxide or hydrochloric acid; In another preferred embodiment, the preparation comprises: 0.1-0.5 g / dose of omexin sodium, an appropriate amount of sodium hydroxide or hydrochloric acid, and the balance of water for injection; and the volume of the preparation is 2 mL; In another preferred embodiment, the preparation is prepared by the following method: mixing a therapeutically effective amount of omexin sodium with a prescribed amount of water for injection, adjusting the pH value to 6-9 using sodium hydroxide or hydrochloric acid, and then freeze-drying to obtain the freeze-dried powder injection preparation.

10. The preparation according to claim 9, characterized in that The preparation is used to reverse the muscle relaxation caused by cisatracurium besylate; In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation; In another preferred embodiment, the preparation is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation.

11. A compound injection preparation, characterized in that: The preparation comprises: a therapeutically effective amount of omexin sodium and neostigmine methylsulfate; Preferably, the preparation further comprises: mannitol, an antibacterial agent, a pH regulator, and the remainder of water for injection; In another preferred embodiment, the antibacterial agent is phenol; In another preferred embodiment, the pH adjuster is sodium hydroxide or hydrochloric acid.

12. The compound injection preparation according to claim 11, characterized in that: The preparation comprises: 2-5 parts by weight of omexin sodium, 6-22 parts by weight of neostigmine methylsulfate, 0.1-1 parts by weight of mannitol, 0.01-0.1 parts by weight of an antibacterial agent, an appropriate amount of a pH regulator, and the remainder of water for injection; and the volume of the preparation is 2 mL; In another preferred embodiment, the pH of the preparation is 6-9.

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