Muscle relaxation antagonist for reversing benzylisoquinoline muscle relaxants

Abstract

The invention provides a muscle relaxation antagonist for reversing benzylisoquinoline muscle relaxants, particularly provides a preparation method and application of a safer and more effective muscle relaxation antagonist preparation for reversing benzylisoquinoline muscle relaxants, and more particularly provides a preparation method and application of the muscle relaxation antagonist preparation for reversing benzylisoquinoline muscle relaxants. The invention provides omekasone sodium as a substitute for neostigmine for reversing muscle relaxation of a benzylisoquinoline muscle relaxation drug cisatracurium besylate. In the process of remnant neuromuscular block after muscle relaxation induced by a muscle relaxation agent cisatracurium, the omekasone sodium can replace neostigmine, and the omekasone sodium is remarkably superior to neostigmine in the aspects of heart rate maintenance and the like under the condition that the antagonistic drug effect is maintained to be equivalent. The invention also provides the Omexone sodium and a compound pharmaceutical preparation thereof, the Omexone sodium is prepared into freeze-dried powder injection or injection, and the Omexone sodium is suitable for being applied to preparation of antagonistic muscle relaxation drugs.

Description

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 drug 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 an important component of general anesthesia drugs. They can provide surgeons with a clearer surgical field, ensure that patients do not move during surgery, and reduce the occurrence of complications during surgery. Cisatracurium is a newer medium-acting non-depolarizing muscle relaxant and one of the isomers of atracurium. It is mainly degraded by Hofmann clearance at physiological pH and body temperature, and is independent of liver and kidney metabolism. It has the characteristics of no accumulation, fast recovery, and strong effect in clinical practice. In particular, its low histamine release and small effect on cardiovascular function make it widely used in clinical practice. At present, medium-acting non-depolarizing muscle relaxants, such as cisatracurium, rocuronium, and vecuronium, are widely used in clinical practice. The three occupy almost more than 98% of the entire muscle relaxant market. Among them, cisatracurium occupies the largest share and can be said to be the leader in the muscle relaxant market.

[0004] Incomplete metabolism of muscle relaxants often leads to respiratory insufficiency after extubation, and residual muscle relaxants after surgery can prevent the recovery of laryngeal muscle function, causing an increase in the incidence of postoperative aspiration, dysphagia, and upper airway obstruction. If the patient's breathing is suppressed, hypoxemia will occur. This residual muscle relaxant effect can increase postoperative complications and mortality in patients and prolong the time of in-hospital treatment. Literature reports that even in the United States and Canada, where muscle relaxant monitoring is more commonly used today, the incidence of residual muscle relaxant effects reached 64.7% and 63.5% when the tube was extubated after surgery. There are also literature reports that the use of non-depolarizing muscle relaxant cisatracurium in general anesthesia according to conventional methods found that 12% of patients still had 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 tube was removed after surgery.

[0005] At present, the commonly used muscle relaxant antagonists in clinical practice are anticholinesterase drugs, which work by inhibiting cholinesterase to reduce the decomposition of acetylcholine (Ach). The most commonly used anticholinesterase drug in clinical practice is neostigmine, which antagonizes the muscle relaxant effect and also produces obvious muscarinic effects, especially the effect on heart rate, which can induce bradycardia and can cause cardiac arrest in severe cases, resulting in many patients in clinical practice needing to prohibit or use the 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 antagonize the residual muscle relaxant effect, and the two drugs are usually mixed. However, because atropine takes effect quickly and neostigmine takes effect relatively slowly, there will be a significant increase in heart rate at the beginning. This hemodynamic change will cause the occurrence of perioperative myocardial ischemia, which will cause more serious effects or consequences for some patients with more severe heart disease. Some researchers suggest that atropine be administered 2-4 minutes after neostigmine, but the anesthesia recovery room is busy and it is difficult to ensure that the drug is administered at the prescribed time every time. If atropine is injected too late, it may cause the risk of excessive bradycardia. In addition, atropine easily crosses the blood-brain barrier and is a risk factor for postoperative cognitive dysfunction, and may even cause delirium, which is a huge risk for elderly patients.

[0006] Olmecton sodium is a safer alternative to neostigmine for antagonizing the muscle relaxant cisatracurium besylate. Olmecton sodium is a small molecule drug developed by our company and is a Class I Chinese chemical drug. Currently, the highest research and development stage of this drug is clinical phase III, which is used for the reversal of neuromuscular blockade.

[0007] Sugammadex sodium, with the trade name Bridion, is the only registered product of the same class as the drug omepromazine sodium described in the present invention. As a new type of muscle relaxant antagonist, it is a specific antagonist of rocuronium bromide (steroidal muscle relaxant). Sugammadex sodium does not bind to succinylcholine or benzylisoquinoline neuromuscular blockers (such as mivacurium, atracurium and cisatracurium); on the contrary, after administration of sugammadex sodium, the neuromuscular blockade induced by cisatracurium takes effect faster and the block level is deeper. The earliest research report on sugammadex sodium and atracurium was published in 2006 by HD de Boer et al. in the British Journal of Anaesthesia, which found that sugammadex sodium was ineffective in reversing atracurium-induced neuromuscular blockade, but had no effect on blood pressure and heart rate. The 2023 American Society of Anesthesiologists' Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade also pointed out that benzylisoquinoline neuromuscular blocking drugs are ineffective for antagonism with sugammadex sodium. In addition, sugammadex sodium has certain hidden dangers in terms of safety. It was rejected by the US FDA three times due to allergic reactions, prolonged cardiac Qt, and bleeding risks. It took 7 years before it was 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 disorders, cardiovascular system side effects, bronchospasm and laryngeal spasm, and other adverse reactions such as postoperative nausea, prolonged renal excretion time, neuronal apoptosis, and abnormal metallic taste. Therefore, cholinesterase inhibitors and cholinesterase inhibitors plus anticholinergics have not yet met clinical needs, and there is an urgent need to provide patients with muscle relaxant antagonists that are both effective and safe in antagonizing muscle relaxation. Summary of the invention

[0008] The present invention aims to provide a use of omexin sodium in preparing a pharmaceutical composition for reversing neuromuscular tissue blockade induced by benzylisoquinoline muscle relaxants (such as atracurium besylate).

[0009] In a first aspect of the present invention, there is provided a use of omexin sodium, which can be used to prepare a pharmaceutical composition for reversing muscle relaxation caused by benzylisoquinoline muscle relaxants (such as atracurium besylate).

[0010] The use as described in 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.

[0011] The use as described in the first aspect of the present invention, wherein the pharmaceutical composition is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation, wherein the adverse reactions are selected from the following group: decreased heart rate, decreased blood pressure, and gastrointestinal discomfort.

[0012] 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 of a drug that antagonizes muscle relaxation. In the embodiment, the second therapeutic component is neostigmine.

[0013] The second aspect of the present invention provides an olmixone sodium preparation, comprising: a therapeutically effective amount of olmixone sodium, mannitol, and the balance of water for injection.

[0014] The preparation as described in 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.

[0015] The preparation as described in the second aspect of the present invention 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.

[0016] The preparation according to the second aspect of the present invention, wherein the preparation is used to reverse the muscle relaxation caused by cisatracurium besylate;

[0017] In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation;

[0018] In another preferred embodiment, the preparation is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation.

[0019] The third aspect of the present invention provides an olmixone sodium preparation, wherein the preparation is a freeze-dried powder injection, and the preparation comprises: a therapeutically effective amount of olmixone sodium, sodium hydroxide or hydrochloric acid, and the balance of water for injection.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The preparation according to the third aspect of the present invention, wherein the preparation is used to reverse muscle relaxation caused by cisatracurium besylate;

[0024] In another preferred embodiment, the preparation is used to reverse the residual neuromuscular blocking effect after cisatracurium-induced muscle relaxation;

[0025] In another preferred embodiment, the preparation is also used to improve adverse reactions in the process of antagonizing cisatracurium-induced muscle relaxation.

[0026] The fourth aspect of the present invention also provides a compound injection preparation, wherein the preparation comprises: a therapeutically effective amount of omexin sodium and neostigmine methylsulfate;

[0027] Preferably, the preparation further comprises: mannitol, an antibacterial agent, a pH regulator, and the remainder of water for injection.

[0028] In another preferred embodiment, the antibacterial agent is phenol.

[0029] In another preferred embodiment, the pH adjuster is sodium hydroxide or hydrochloric acid.

[0030] As described in the fourth aspect of the present invention, the compound injection 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 antibacterial agent, an appropriate amount of pH regulator, and the remainder of water for injection; and the volume of the preparation is 2 mL.

[0031] In another preferred embodiment, the pH of the preparation is 6-9.

[0032] The present invention is beneficial in that:

[0033] (1) The results of animal model experiments strongly proved that omexin sodium has the effect of antagonizing the depolarizing muscle relaxant cisatracurium. Specifically, omexin sodium at a dose of 10 mg / kg can significantly shorten the recovery time of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium. With the increase of omexin sodium dosage, the 20 and 40 mg / kg dose groups of omexin sodium showed better acceleration of muscle relaxation recovery, and showed a certain dose-effect relationship. The 40 mg / kg omexin sodium high-dose group, the 0.0625 mg / kg neostigmine positive control group and the combined group (omexin sodium: 10 mg / kg; neostigmine: 0.03125 mg / kg) had the same effect on the recovery of residual muscle relaxation in the guinea pig muscle relaxation model, and the effects were all very significant. There was no significant difference among the three, indicating that the activity of omexin sodium in antagonizing cisatracurium is equivalent to the antagonistic effect of neostigmine.

[0034] (2) It was also surprisingly found 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 hazard. The heart rate reduction effect of the animals in the combination group was slowed down after the drug was given, but it was still not fully recovered. The administration of 10, 20, and 40 mg / kg doses 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.

[0035] (3) Olmectonamide 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 the use of antagonizing cisatracurium is successfully developed, its clinical application range will be further broadened, the muscarinic effect of neostigmine will be resolved, and safety concerns about the combined use of atropine and neostigmine will be overcome, namely: the heart rate is not stable enough, there are tachycardia and arrhythmia, and postoperative cognitive impairment and other safety issues. Olmectonamide successfully replaces neostigmine combined with atropine, which will benefit a wider range of patients undergoing general anesthesia surgery.

[0036] 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 embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The following are the muscle relaxation monitoring patterns of guinea pigs in each group. Figure 1 As shown, (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 group of the test article; (D) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the medium-dose group of the test article; (E) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the high-dose group of the test article; (F) is the muscle relaxation monitoring spectrum of each of the 10 guinea pigs in the combination group. DETAILED DESCRIPTION

[0038] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0039] Example 1 Risk Assessment of Compound-Induced Sensitization (Safety Screening 1)

[0040] 1. Experimental process

[0041] Wild-type AB zebrafish at 2 days post fertilization (2 dpf) were randomly selected and placed in a 24-well plate. Six replicate wells were set up in each group, and 10 zebrafish were treated in each well. (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 (Omexone 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 Omexone sodium, Compounds 2-6 were Omexone sodium analogs, and Compound 7 was Sugammadex sodium; The volume of each well was 1 mL, and each experimental group was given BAPNA (mast cell degranulation specific detection reagent) in water.

[0042] Table 1 Structural formula of compounds 1-7

[0043]

[0044] After 1 day of treatment at 28°C, the liquid was transferred to a 96-well plate, 200 μL / well, and the relative absorbance value (OD value) of the tryptase expression level of each experimental group was detected by an ELISA instrument. The sensitization risk of the sample was evaluated by the statistical analysis results of the OD value. SPSS software was used for statistical analysis, and p<0.05 indicated a significant difference.

[0045]

[0046] 2. Test results

[0047] Table 2 Sensitization risk of each compound

[0048]

[0049] Note: The data listed in the table are mean ± standard deviation (mean ± SE). *: P < 0.05; ***: P < 0.001 vs normal control group.

[0050] 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 compound 1 (olmethoxazole sodium) experimental group and the compound 2 experimental group were 0.060 and 0.052, respectively, which were similar to the normal control group (0.054), and there was almost no risk of sensitization. The OD value of the compound 7 (sugammadex sodium) experimental group was 0.079, which was slightly higher than that of the normal control group (0.054), and had a certain risk of sensitization. There were more deaths of zebrafish in the compound 3, compound 4, compound 5 and compound 6 experimental groups, so they were not evaluated.

[0051] 3. Experimental conclusion

[0052] Among the tested compounds, the sensitization risk of compound 1 (olmethoxazole sodium), compound 2, and compound 7 (sugammadex sodium) were significantly lower than that of the positive control. Among them, compound 2 and compound 1 (olmethoxazole sodium) had no or essentially no sensitization risk and were suitable for subsequent drug development; compound 7 (sugammadex sodium) had a low sensitization risk.

[0053] Example 2 Effects of Olmec Sodium, Sugammadex Sodium, and Neostigmine on Immunoinflammatory Activity (Safety Screening II)

[0054] 1. Experimental process

[0055] Antibody chip is a kind of protein chip, which is characterized by 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 Fluor 555-streptavidin was used to detect the signal.

[0056] In this experiment, ICR mice were randomly divided into a blank group, an omekesone sodium (1g / kg) group, a sugammadex sodium (1g / mg) group, and a neostigmine (0.3mg / kg) group, with 2 mice in each group. Each group of mice was given the corresponding dose of compound via the tail vein once a day for 5 consecutive days. After the last day of administration, the plasma of the two animals was mixed and tested using the Ary028 immune chip kit. The specific detection steps are as follows:

[0057] (1) Determination of sample volume: 200μl serum sample for each Array unit. (2) Blocking protein chip: Each membrane needs to be blocked with 2ml 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 1.5ml per membrane, added to the corresponding Array unit, and incubated with the Array protein membrane at 4℃ overnight. (4) Wash the membrane three times with the corresponding Wash buffer, add the diluted detection antibody, and incubate at room temperature for 1h. (5) Wash the membrane three times with the corresponding Wash buffer, add streptavidin-HRP, incubate for 30min, and shake on a shaker at room temperature. (6) Wash the membrane three times with the corresponding Wash buffer, add 1ml of chemical colorimetric reagent to each well, and develop the color on a chemiluminescent imager. (7) The relative concentration of the corresponding protein is represented by fluorescence intensity.

[0058] 2. Test results

[0059] Table 3 Comparison of fluorescence intensity of hypersensitivity-related factors

[0060]

[0061]

[0062] Note: "No detection" means the protein concentration in serum is lower than the minimum detection limit

[0063] Table 4 Comparison of fluorescence intensity of inflammatory related factors

[0064]

[0065]

[0066] Note: "No detection" means the protein concentration in serum is lower than the minimum detection limit

[0067] 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 serum were all below the minimum detection limit in the blank group. Compared with the sugammadex sodium group and the neostigmine group, the detection levels of each hypersensitivity-related factor 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 the induction of immune inflammation in mice, followed by sugammadex sodium, and neostigmine was the most serious.

[0068] 3. Experimental conclusion

[0069] The results of this experiment analyzing the effects of three muscle relaxant antagonists, namely, omexin sodium, sugammadex sodium and neostigmine, on the immune-inflammatory effects in mice showed that omexin sodium had the smallest effect on the induction of immune-inflammatory effects 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 effects; sugammadex sodium had the second largest effect on the induction of immune-inflammatory effects in mice, indicating that the drug has average safety in terms of immune-inflammatory effects; and neostigmine had the most serious effect on the induction of immune-inflammatory effects in mice, resulting in increased secretion of most hypersensitivity reactions and inflammatory-related factors, indicating that the drug has great hidden dangers in terms of safety in terms of immune-inflammatory effects.

[0070] Example 3 Effect of Olmecton Sodium on Residual Muscle Relaxant Antagonism in Anesthetized Guinea Pigs after Administration of Muscle Relaxant Cisatracurium (Pharmacological Efficacy Experiment)

[0071] 1. Experimental process

[0072] 90 male Hartley guinea pigs that passed the quarantine were obtained. 60 of them were divided into 6 experimental groups according to body weight using stratified random method, namely negative control group, positive control group, low-dose, medium-dose and high-dose test sample groups and combination group, 10 animals in each group (n=10), and the remaining animals were used as spare. The negative control group was given 0.9% sodium chloride, the positive control group was given 0.0625 mg / kg neostigmine methylsulfate (referred to as neostigmine), the low-dose test sample group was given 10 mg / kg omexin sodium, the medium-dose test sample group was given 20 mg / kg omexin sodium, the high-dose test sample group was given 40 mg / kg omexin sodium, and the combination group was given 10 mg / kg omexin sodium and 0.03125 mg / kg neostigmine. The administration volume for all groups was 1 mL / kg.

[0073] After the quarantine, adaptive feeding was carried out. On the day of the experiment, the guinea pigs were weighed, and anesthetic drugs (10 mg / kg sodium pentobarbital and 1000 mg / kg urethane) were injected intraperitoneally after intramuscular injection of atropine 0.1 mg / kg. After the animals were fixed, the trachea was intubated and connected to the small animal ventilator. The external jugular veins on both sides and the right carotid artery were separated for intubation. 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 used a multi-channel physiological signal acquisition and processing system to continuously monitor arterial blood pressure and heart rate. Electrode patches were pasted subcutaneously behind the left femur and tibia of the guinea pig, and the two stimulating electrodes of the muscle relaxation monitor were fixed on the two electrode patches respectively. The left hind foot was fixed on a homemade 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 on the flat part of the skin. First, use the 1Hz mode for continuous single stimulation. After the twitch is highly stable, change to 4 series stimulation modes (TOF mode, stimulation current 5mA, frequency 2Hz, wave width 0.2ms, interval between series 15s) for continuous stimulation for at least 5min. Then calibrate with calibration mode 2, and then stimulate with TOF mode. After obtaining a stable stimulation response for at least 2min, start intravenous injection of cisatracurium solution with a dual-channel microinjection pump, and record the start time of the injection. When the cisatracurium solution is continuously injected until T4 / T1 (TOFr) disappears and T1 is below 15%, the muscle relaxation model is considered successful, and then the injection of cisatracurium solution is stopped. After stopping the injection, the neuromuscular function is allowed to recover spontaneously. When the neuromuscular function recovers moderately, the test substance is injected intravenously. After the neuromuscular function is fully recovered, the administration time ( Figure 1 ). The time when neuromuscular function spontaneously recovered to moderate (TOF50) was taken as the zero point, and the time for the animal's neuromuscular function to recover from TOF50 to TOF75, TOF75 to TOF90, and 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 were recorded before the bolus injection of cisatracurium solution, when the bolus injection of cisatracurium solution was stopped, when the neuromuscular function recovered moderately, and when the neuromuscular function recovered completely (Table 3-7). The data were expressed as Mean±SD, and the SPSS software was used for statistical T test to evaluate the differences in blood pressure, heart rate and residual muscle relaxation recovery time. P<0.05 was considered statistically significant.

[0074] 2. Test results

[0075] (1) Effect of omexin sodium on the recovery time of residual muscle relaxation in muscle relaxation model animals

[0076] Table 5 Effect of omexin sodium antagonizing cisatracurium on the recovery time of residual muscle relaxation in muscle relaxation model animals

[0077]

[0078]

[0079] Note: The data listed in the table are all mean ± standard deviation. *: P < 0.05; **: P < 0.01 vs. negative control group. There are 10 guinea pigs in each group.

[0080] 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 was completely restored. 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 group of the test sample were significantly shortened (P<0.05), and the residual muscle relaxation recovery time tTOF50-90 of the medium-dose group of the test sample was significantly shortened. The residual muscle relaxation recovery time tTOF75-90 and tTOF50-90 of the high-dose group of the test sample were significantly shortened (P<0.01), and the residual muscle relaxation recovery time tTOF50-75, tTOF75-90 and tTOF50-90 of the combination group were significantly shortened (P<0.05-0.01), indicating that under the conditions of this experiment, different doses of omexin sodium can significantly shorten the residual muscle relaxation recovery time of the guinea pig muscle relaxation model induced by cisatracurium. The residual muscle relaxation recovery time tTOF50-90 values ​​of the animals in 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 was 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 omexin 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 omexin sodium and neostigmine.

[0081] (2) Effect of omexin sodium on the ratio of residual muscle relaxation to recovery time in muscle relaxation model animals

[0082] Taking into account the possible differences in muscle relaxation recovery time tTOF0-50 between different guinea pigs before administration of the test substance, 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.

[0083] Table 6 Effect of omexin sodium antagonizing cisatracurium on the ratio of residual muscle relaxation recovery time in muscle relaxation model animals

[0084]

[0085]

[0086] Note: The data listed in the table are all mean ± standard deviation. *: P < 0.05; **: P < 0.01 vs. negative control group. There are 10 guinea pigs in each group.

[0087] 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 in 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 in the low and medium dose groups were significantly reduced (P<0.05), and the high dose group was significantly reduced. 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 were significantly reduced (P<0.05). The above results showed that different doses of omepromazine sodium can significantly accelerate the induced by cisatracurium under the experimental conditions. 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-, high-dose groups of the test sample 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.

[0088] (3) Effects of omexin sodium on blood pressure in muscle relaxation model animals

[0089] Table 7 Effect of omexin sodium antagonizing cisatracurium on the average systolic blood pressure of muscle relaxation model animals

[0090]

[0091]

[0092] Note: The data listed in the table are all mean ± standard deviation. There was no significant difference in the indicators of each group, P>0.05 vs negative control group. There were 10 guinea pigs in each group.

[0093] Table 8 Effect of omexin sodium antagonizing cisatracurium on the mean diastolic blood pressure of muscle relaxation model animals

[0094]

[0095] Note: The data listed in the table are all mean ± standard deviation. There was no significant difference in the indicators of each group, P>0.05 vs negative control group. There were 10 guinea pigs in each group.

[0096] Table 9 Effect of omexin sodium on the mean arterial pressure of muscle relaxation model animals by antagonizing cisatracurium

[0097]

[0098] Note: The data listed in the table are all mean ± standard deviation. There was no significant difference in the indicators of each group, P>0.05 vs negative control group. There were 10 guinea pigs in each group.

[0099] Table 10 The effect of omexin sodium antagonizing cisatracurium on the mean pulse pressure difference of muscle relaxation model animals

[0100]

[0101] Note: The data listed in the table are all mean ± standard deviation. There was no significant difference in the indicators of each group, P>0.05 vs negative control group. There were 10 guinea pigs in each group.

[0102] 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-, medium-, high-dose groups and combination groups before administration of cisatracurium solution, when the push injection of cisatracurium solution was stopped, when neuromuscular function recovered moderately and when neuromuscular function recovered completely (P>0.05).

[0103] (4) Effects of omexin sodium on the heart rate of muscle relaxation model animals

[0104] Table 11 Omexin sodium antagonizes the effect of cisatracurium on the heart rate of muscle relaxation model animals

[0105]

[0106] Note: The data listed in the table are all mean ± standard deviation. **: P < 0.01; ***: P < 0.001 vs. negative control group. There are 10 guinea pigs in each group.

[0107] 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 of omexin sodium had no significant effect on the heart rate during the moderate neuromuscular recovery and the complete recovery of neuromuscular function, and the drug was very safe in terms of its effect on heart rate.

[0108] Compared with the animals in the negative control group, there was no significant difference in the heart rate of the animals in the positive control group and the combined group before the administration of cisatracurium solution and when the bolus injection of cisatracurium solution 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 the muscle relaxation was completely recovered (the heart rate decrease when the muscle relaxation was completely recovered = (heart rate at the beginning of muscle relaxation - heart rate at complete 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 the muscle relaxation was completely recovered (the heart rate decrease when the muscle relaxation was completely recovered = (heart rate at the beginning of muscle relaxation - heart rate at complete recovery) / heart rate at the beginning of muscle relaxation), indicating that the heart rate lowering effect of omexin sodium and neostigmine was improved after the combination of drugs, but could not be completely restored.

[0109] 3. Experimental conclusion

[0110] Under the conditions of this experiment, omexin sodium at a dose of 10 mg / kg can significantly shorten the recovery time of residual muscle relaxation in the guinea pig muscle relaxation model induced by cisatracurium, and the effect is equivalent to that of 0.0625 mg / kg neostigmine. After 10, 20, and 40 mg / kg of omexin sodium was given to guinea pigs with cisatracurium muscle relaxation model, there was no effect on the blood pressure and heart rate of the animals, while 0.0625 mg / kg of neostigmine had a significant side effect of lowering the heart rate, indicating that omexin sodium is significantly safer than neostigmine in protecting heart rate.

[0111] As mentioned in the background technology of the specification, sugammadex sodium does not bind to atracurium and cisatracurium; on the contrary, after administration of sugammadex sodium, the neuromuscular blockade induced by cisatracurium takes effect faster and the blockade level is deeper. As early as 2006, HDde Boer et al. also found that sugammadex sodium was ineffective in reversing atracurium-induced neuromuscular blockade. Considering its clinical side effects such as hypersensitivity, allergic reaction, and QT interval prolongation, sugammadex sodium was not used as a control group in this experiment.

[0112] Based on the fact that cisatracurium occupies more than 70% of the market share in the domestic muscle relaxant market and also occupies a relatively high market share abroad, but its antagonist is only neostigmine, which has obvious limitations and side effects and cannot meet clinical needs. The omexin sodium of the present invention is not inferior to neostigmine in terms of efficacy, and no adverse reactions similar to neostigmine are found. As a new generation of products in this field, it can meet clinical needs and fill market gaps, and has very important significance.

[0113] Example 4 Preparation of injection

[0114] Table 12 Recipe

[0115]

[0116] Weigh mannitol according to the prescription amount, add about 80% of the total amount of water for injection, and stir until dissolved; then, add the prescribed amount of omexin sodium, stir until dissolved, add water for injection to the full amount, use a 0.2μm microporous filter membrane for sterilization filtration, and package in medium-borosilicate glass ampoules, each containing 2ml, fill with nitrogen, seal, and sterilize at 121℃ for 15 minutes to obtain omexin sodium injection.

[0117] Example 5 Preparation of compound injection

[0118] Table 13 Recipe

[0119]

[0120] Weigh mannitol and sodium acetate according to the prescription amount, add about 80% of the total amount of water for injection, and stir until dissolved; add the prescription amount of omexin sodium and neostigmine methylsulfate, and stir until dissolved; then add the prescription 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, use a 0.2μm microporous filter membrane for sterilization and filtration, use medium borosilicate glass vials to package, each containing 2ml, fill with nitrogen, seal, and sterilize at 121℃ for 15 minutes to obtain the omexin sodium and neostigmine methylsulfate compound injection.

[0121] Example 6 Preparation of freeze-dried powder injection

[0122] Table 14 Recipe

[0123]

[0124] Put the prescribed amount of omexin sodium into 80% of the prescribed amount of water for injection, stir and dissolve; add water for injection to the prescribed amount. Add activated carbon (0.1-0.5%) to the above liquid medicine, stir for dozens of minutes; decolorize with activated carbon, filter and decarbonize; use sodium hydroxide solution or hydrochloric acid solution to adjust the pH value of the liquid medicine to 6-9. Take samples for semi-finished product testing. Filter twice through a 0.22μm filter and fill. Freeze-dry, plug, cap and package according to the set freeze-drying parameters.

[0125] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. 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 claims attached to this application.

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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