CN107519136B - Succinylcholine chloride freeze-dried preparation and preparation method thereof - Google Patents

Succinylcholine chloride freeze-dried preparation and preparation method thereof Download PDF

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CN107519136B
CN107519136B CN201710694540.8A CN201710694540A CN107519136B CN 107519136 B CN107519136 B CN 107519136B CN 201710694540 A CN201710694540 A CN 201710694540A CN 107519136 B CN107519136 B CN 107519136B
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acid
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CN107519136A (en
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陈涛
卢伍党
顾相应
刘玺
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Xian Libang Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Abstract

The invention provides a freeze-dried preparation of succinylcholine chloride and a preparation method thereof. The preparation comprises: the main drug is succinylcholine chloride, and the excipient is mainly one of amino acid, oligopeptide, lactose, sucrose, mannose, maltose, mannitol, dextran or a mixture of the amino acid, the oligopeptide, the lactose, the sucrose, the mannose, the maltose, the mannitol and the dextran; the formulation vehicle comprises: one, two or more than two mixtures of physiological saline, water for injection, glucose aqueous solution, acetate, dibasic phosphate, carbonate, citrate, tartrate and maleate; also comprises one or a mixture of two or more of acetic acid-acetate buffer solution, dihydrogen phosphate-hydrogen phosphate buffer solution, bicarbonate-carbonate buffer solution, citric acid-citrate buffer solution, tartaric acid-tartrate buffer solution and maleic acid-maleate buffer solution.

Description

Succinylcholine chloride freeze-dried preparation and preparation method thereof
Technical Field
The invention belongs to anesthetic drugs, and relates to an ultrashort-effect polarized muscle relaxant, in particular to a freeze-dried pharmaceutical preparation for injection. In particular to a freeze-dried preparation of succinylcholine chloride taking excipient such as amino acid buffer pair, organic salt buffer pair, inorganic salt buffer pair and the like as a carrier and a preparation method thereof.
Background
Suxamethonium Chloride (Suxamethonium Chloride) belongs to depolarized muscle relaxant, is a synthetic substitute of tubocurarine, can be rapidly combined with nicotinic receptors to generate stable depolarization effect, and causes skeletal muscle relaxation; after taking effect, the intermediate metabolite succinyl monocholine muscle relaxant is quickly hydrolyzed by the pseudocholinesterase in the blood and is generated by decompositionThe action is weak, and the metabolite with no muscle relaxation is further metabolized and then discharged out of the body. The muscle relaxation effect is 60-90 s effective, the effect is maintained for about 10min, the half-life period of plasma is 2-4 min, and the effect can be prolonged by repeated intravenous injection or continuous instillation. Therefore, the succinylcholine chloride has the characteristics of quick response, short duration and easy control of muscle relaxation effect, and is very suitable for trachea intubation and small surgical operation[1-5]. At present, no depolarizing muscle relaxant clinically has the advantages of succinylcholine chloride and no adverse reaction. Therefore, the succinylcholine chloride is used up to now and becomes the muscle relaxant which is used for the longest time, and is the only muscle relaxant selected at present when the intubation is difficult and the intubation is urgent.
At present, research results prove that the choline chloride succinate is extremely unstable in aqueous solution, particularly when the choline chloride succinate is sterilized at high temperature and is stored in an aqueous solution medicament preparation for a long time, the choline chloride succinate can be hydrolyzed to generate a series of substances such as choline chloride, succinic acid and the like (as shown in figure 1), and further causes a series of adverse reactions, for degradation products, the limit of the current foreign products is specified to be 7%, the limit of the domestic products is 10%, in actual measurement, the choline chloride is degraded more greatly, and the degradation is more than 10% after the choline chloride is placed for more than 12 months. In order to overcome the hydrolysis of the succinylcholine chloride, the succinylcholine chloride is prepared by foreign sterilization with very low solution acidity (pH 3.5). The product needs to be stored at low temperature of 2-8 ℃. The domestic injection in China adopts propylene glycol as a solution, the hydrolysis of the succinylcholine cannot be completely stopped due to the completely anhydrous propylene glycol and the low acidity, the hydrolysis speed can only be reduced, and meanwhile, the succinylcholine chloride injection taking the propylene glycol as a solvent has very high viscosity, and the filling precision in the preparation process is not easy to control. In addition, currently, the injection of succinylcholine chloride on the market has many adverse reactions, such as: too low a pH or aqueous propylene glycol solution can cause local (vascular) irritation, bradycardia, nodal arrhythmia, and cardiac arrest. The clinical use safety of the medicine is seriously influenced. There are reports that[7-8]It is pointed out that the hydrolysis of the succinylcholine chloride may further increase the pH of the injection solution of succinylcholine chloride, thereby aggravating the pain response of the succinylcholine chloride。
Aiming at the problems, the invention provides a novel prescription of a freeze-dried preparation of succinylcholine chloride. Firstly, the freeze-dried preparation enables the medicine to exist in a solid form, avoids the characteristic of easy degradation of the medicine in a solution state, and ensures the purity of the main medicine; secondly, adopting amino acid or oligopeptide, mannitol, trehalose and the like as excipients, adjusting the pH value to 3.5-5, and using inorganic salt or organic salt or a buffer pair thereof as a solvent, wherein the solvent comprises an aqueous solution of acetate, dibasic phosphate, carbonate, citrate, tartrate, maleate, sodium chloride and glucose; also comprises acetic acid-acetate buffer solution, dihydrogen phosphate-hydrogen phosphate dibasic buffer solution, bicarbonate-carbonate buffer solution, citric acid-citrate buffer solution, tartaric acid-tartrate buffer solution, and maleic acid-maleate buffer solution. On one hand, the freeze-dried preparation enables the choline chloride to exist more stably, on the other hand, the special solvent can effectively control the acidity of the redissolved solution to be in a physiological pH range, the stimulation of the medicine to blood vessels is reduced, and in addition, the stable pH range enables the preparation system to be in a stable state for a long time, the medicine degradation is inhibited, the content of the main medicine is ensured, and then the medication safety is ensured. In addition, reasonable pH and removal of propylene glycol avoids injection pain and vascular inflammation.
[1] Li Da Cheng, Wu Xiwen, clinical application of Succinylcholine chloride [ J ]. Shandong biomedical engineering, 2000,19(2):1.
[2] The medicament-substitute and pharmacodynamics of the plum-hydrozyl-succinylcholine [ J ]. International Anesthesia and Resuscitation journal, 1994(5):276 + 278.
[3]PHarmGKB summary:succinylcholine pathway,pHarmacokinetics/pHarmacodynamics. PHarmacogenetics and genomics,2015,25(12),622-630.
[4] Pharmacodynamic and pharmacokinetic studies on succinylcholine chloride made in Zhang Qian, Wan Junke, China [ J ] Jiangsu medicine, 2006,32(6): 588-589.
[5] Application of Liyan, Xionglize, Yangbo, etc. Succinylcholine chloride in neurosurgical anesthesia [ J ] China journal of neurosurgical disease research, 2005,4(4): 353-.
[6] Yanfeng, Vila, unique clock, domestic succinylcholine chloride muscle relaxation effect and cardiovascular effects [ J ] Xinjiang medicine, 2007,37(6): 69-70.
[7]Sally C,Palmon M D,Aaron T,et al.The effect of needle gauge andlidocaine pH on pain during intradermal injection[J].Anesth Analg,1998,86:379-381.
[8]D Han,B Koo,S Choi,et al.Neutralized rocuronium(pH 7.4)beforeadministration prevents injection pain in awake patients:a randomizedprospective trial[J].Journal of Clinical Anesthesia, 2007,19(6):418-423.
Disclosure of Invention
The invention provides a freeze-dried preparation of succinylcholine chloride with amino acid buffer pair as excipient and a preparation method thereof, and the preparation have the following two main characteristics: firstly, the stability of the pharmaceutical preparation can be obviously improved, and the generation of impurities can be reduced; secondly, the buffer salt used by the preparation can control the pH value of the preparation within a physiological range, thereby reducing the stimulation of the succinylcholine chloride to blood vessels and the injection pain; thirdly, the properties of the freeze-dried preparation are obviously improved.
The freeze-dried preparation of the succinylcholine chloride provided by the invention is stored in a freeze-dried preparation form before clinical use, so that the problem of rapid degradation of an aqueous solution is solved.
The invention aims to provide a freeze-dried succinylcholine chloride combined preparation.
The freeze-dried combined preparation consists of a freeze-dried preparation and a solvent, wherein the freeze-dried preparation and the solvent are independently packaged. The freeze-dried preparation consists of succinylcholine chloride and a freeze-dried excipient, the pH value of a liquid medicine obtained after the freeze-dried preparation is added with a solvent for redissolving is 5.5-7.0, wherein the freeze-dried excipient is one or a mixture of more than two of water-soluble amino acid, oligopeptide, lactose, sucrose, mannose, maltose, mannitol, trehalose and dextran.
Wherein the weight ratio of the succinylcholine chloride to the freeze-drying excipient in the freeze-drying preparation is 1.0: 0.0-1.0: 10.0, and preferably 1: 1.
Wherein, the pH value of the freeze-dried preparation is adjusted by weak acid or weak acid salt in the preparation process, and the pH range is 3.5-5.
Wherein the water-soluble amino acid is selected from: weakly acidic amino acids, neutral amino acids, basic amino acids, or oligopeptides formed by free bonding of two or more amino acids; the freeze-drying excipient can be any one, two or a mixture of more than two of the amino acids and the oligopeptides;
wherein the water-soluble amino acid is a neutral amino acid selected from the group consisting of glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine, and hydroxyproline; or an acidic amino acid selected from aspartic acid, glutamic acid; or basic amino acids selected from lysine, arginine, and histidine. The amino acid and oligopeptide are human existing substances and are used as excipients, so that the stability and safety of the preparation can be guaranteed to the greatest extent.
The solvent provided by the invention plays a role in dissolving and regulating acidity and alkalinity, and is selected from the following components: the water solution of acetate, dibasic phosphate, carbonate, citrate, tartrate, maleate, sodium chloride and glucose can be one of them, or the mixture of two or more of them; or one or a mixture of two or more of acetic acid-acetate buffer, dihydrogen phosphate-hydrogen phosphate buffer, bicarbonate-carbonate buffer, citric acid-citrate buffer, tartaric acid-tartrate buffer, and maleic acid-maleate buffer.
Among them, the solvent is preferably: the water solution of dibasic phosphate, citrate, tartrate, maleate, sodium chloride and glucose can be one of, two of or a mixture of more than two of; or one, two or more of dihydrogen phosphate-dihydrogen phosphate buffer solution, citric acid-citrate buffer solution, tartaric acid-tartrate buffer solution, and maleic acid-maleate buffer solution.
Wherein, the solvent or excipient can be one or a mixture of sodium salt, calcium salt and zinc salt.
The acid, weak acid and weak acid salt for adjusting the pH value can be aqueous solutions of amino acid, acetate, dibasic acid phosphate, carbonate, citrate, tartrate, maleate, sodium chloride and glucose, and can be a mixture of one, two or more of the amino acid, acetate, dibasic acid phosphate, carbonate, citrate, tartrate, maleate, sodium chloride and glucose; or one or a mixture of two or more of acetic acid-acetate buffer, dihydrogen phosphate-hydrogen phosphate buffer, bicarbonate-carbonate buffer, citric acid-citrate buffer, tartaric acid-tartrate buffer, and maleic acid-maleate buffer;
the freeze-dried preparation of the succinylcholine chloride provided by the invention can be matched with a corresponding solvent, so that the pH of the finally dissolved medicine is 5.5-7.0, the preparation is required for quick muscle relaxation, the preparation is stable within 4 hours after being dissolved, and the dissolved medicine can be used as soon as possible in clinic, so that the pH range can meet the clinical requirement;
the invention can also directly adopt amino acid buffer solution, acetic acid-acetate buffer solution, dihydrogen phosphate-dibasic phosphate buffer solution, bicarbonate-carbonate buffer solution, citric acid-citrate buffer solution, tartaric acid-tartrate buffer solution, maleic acid-maleate buffer solution and the like, directly adjust the pH value of the freeze-dried stock solution to be between 5.5 and 7.0, then subpackage and freeze-dry, the impurity content of the freeze-dried preparation is slightly higher than that of the succinylcholine chloride freeze-dried preparation containing weak acid auxiliary materials, and the corresponding normal saline or glucose aqueous solution solvent is prepared at the same time, but compared with the aqueous solution, the impurity content of the preparation is obviously lower;
further, a novel freeze-dried preparation of succinylcholine chloride is prepared by the following representative formula:
Figure GDA0002489249500000031
Figure GDA0002489249500000041
furthermore, the effect and amount of each material in the formulation is listed in the representative formulation, but is not fixed, wherein in addition to the choline chloride being an essential formulation ingredient, other excipients such as pH buffering agents may be added or not or partially added.
By adjusting the formulation of the preparation, the pH (5.5-7.0) of the freeze-dried preparation is close to the pH level of blood, so that a pH regulator does not need to be added into a solvent, and the solvent is an isotonic injection, such as physiological saline for injection or glucose injection. Or, for example, if no amino acid is used in the lyophilized excipient, a pH buffering component, such as an inorganic/organic salt buffer, an inorganic/organic salt or a weakly basic amino acid, may be added to the special vehicle. The prescribed amount is merely an example of an invention and is not a control amount of the claims.
The specific formula can be as follows:
Figure GDA0002489249500000042
the specific formula can be as follows:
Figure GDA0002489249500000043
the specific formula can be as follows:
Figure GDA0002489249500000044
the specific formula can be as follows:
Figure GDA0002489249500000045
the specific formula can be as follows:
Figure GDA0002489249500000051
the specific formula can be as follows:
Figure GDA0002489249500000052
the specific formula can be as follows:
Figure GDA0002489249500000053
the specific formula can be as follows:
Figure GDA0002489249500000054
the specific formula can be as follows:
Figure GDA0002489249500000055
the specific formula can be as follows:
Figure GDA0002489249500000056
Figure GDA0002489249500000061
the specific formula can be as follows:
Figure GDA0002489249500000062
the specific formula can be as follows:
Figure GDA0002489249500000063
the specific formula can be as follows:
Figure GDA0002489249500000064
the specific formula can be as follows:
Figure GDA0002489249500000065
it is another object of the present invention to provide a method for preparing a lyophilized combination preparation.
General procedure 1 preparation: dissolving succinylcholine chloride with appropriate amount of injectable water completely, adding lyophilized excipient, mixing at 25 deg.C, stirring, measuring pH to 3.5-5, sterile filtering, packaging, lyophilizing, pressing, capping, packaging, and storing at 2-8 deg.C; dissolving the auxiliary materials in the prescription amount completely with water for injection, filtering, subpackaging, corking and capping.
For the preparation of the product of method 1: the pH value of the prepared liquid medicine is 5-7, and the pH value is realized by adjusting the formula dosage of a freeze-drying excipient and a pH buffering agent in a corresponding solvent;
also, the lyophilization step in the above process employs conventional lyophilization techniques. The freeze-drying process parameters are as follows: the pre-freezing temperature is-21 to-60 ℃, and the pre-freezing time is 1 to 10 hours; the primary sublimation temperature is-30-0 ℃, and the drying time is 12-48 hours; the secondary sublimation temperature is 0-30 ℃, and the time is 6-12 hours.
General procedure 2 preparation: dissolving succinylcholine chloride with appropriate amount of injectable water completely, adding freeze-drying excipient (buffer), mixing at 25 deg.C, stirring to obtain solution with pH of 5-7, sterile filtering, packaging, lyophilizing, pressing, capping, packaging, and storing at 2-8 deg.C; solvent, normal saline, water for injection, glucose solution, and buffered saline solution with pH 5-7.
For the preparation of the product of method 2: the stability of the stock solution in the lyophilization process is an important point.
The advantageous effects of the present invention are further illustrated by the following experiments.
Experiment 1: improvement of related substance and content determination method of succinylcholine chloride preparation
Regarding related substances, related substances of domestic succinylcholine chloride preparations are controlled by T L C (ChP, which is not more than 10%), related substances are controlled by Japanese Pharmacopoeia (JP) only at abroad (which is not more than 7%), and related substances of the type are not regulated by other mainstream countries by adopting a method of T L C.
In terms of content, the content determination methods of the existing preparations of the succinylcholine chloride are largely inconsistent at home and abroad, wherein the method of HP L C is adopted for USP38, and the volumetric method is adopted for BP2010(EP7.0), JP15, ChP2015 and the like.
In view of the advantages of high sensitivity and high precision of the HP L C method, the method is combined with the raw materials USP38 and EP7.0 and pharmacopoeia methods of other countries to solve the interference of preparation auxiliary materials, and a HP L C determination method for related substances and content of the freeze-dried preparation of the succinylcholine chloride is preferred.
Chromatographic conditions chromatographic column, alltima 88056C18(4.6mm X250 mm, 5um), mobile phase buffer solution acetonitrile (950: 50) degassing, flow rate 1.0m L. min-1(ii) a Detection wavelength: 214 nm; column temperature: 25 ℃; record to 45 min.
Under the condition of experimental chromatography, the retention time of the main drug, namely the choline chloride succinoxide is 21.15min, the retention time of the monocholine chloride succinoxide is 11.16min, and the retention time of the succinic acid is 4.87 min; the chromatogram of the crude drug and the impurity standard under the above conditions is shown in FIG. 2. The separation degree of each impurity in the succinylcholine chloride, three possible impurities can be well separated from the main drug (see table 1).
TABLE 1 degrees of separation of various impurities of succinylcholine chloride
Figure GDA0002489249500000071
Experiment 2: investigation of preparation temperature of lyophilized stock solution
The succinylcholine chloride intermediate solution is prepared under a certain temperature condition, so that the influence of temperature on the stability of the intermediate solution needs to be examined to determine the temperature of the preparation agent and the time for which the intermediate solution can be continuously stabilized, and data accumulation is also carried out for industrial production. We examined the stability of the lyophilized stock solutions of Table 2 below at different temperatures, and examined the conditions of the relevant substances at 25 deg.C, 40 deg.C, and 55 deg.C for 0h, 2h, 4h, 6h, 8h, and 24h (Table 3).
Table 2: temperature research formula
Figure GDA0002489249500000081
Table 3: effect of temperature on the stability of the intermediate solution
Figure GDA0002489249500000082
The test results show that: the content of related substances in the intermediate solution is gradually increased within 8 hours at 25 ℃, 40 ℃ and 55 ℃, wherein the intermediate solution at 25 ℃ is better and preliminarily meets the production and clinical requirements, so that the temperature is lower in the preparation process, and the production is facilitated.
Experiment 3: determination of the pH Range
The formulation of table 2 is taken as an example, the prepared intermediate solution is adjusted to different pH values by using a pH regulator (0.1mol/ml hydrochloric acid or sodium hydroxide solution), and related substances and content conditions of the freeze-dried preparation prepared by the method are examined according to the process time so as to determine the proper pH range of the intermediate solution. The pH of the intermediate solution was adjusted to 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, and 10.5, respectively, and changes in the substances of the prepared lyophilized formulation of succinylcholine chloride were examined (table 4).
Table 4: influence of pH range of intermediate solution on related substances and content of lyophilized preparation
Examination index (pH) 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
Related substance (%) 0.80 0.42 0.31 0.38 0.40 0.43 0.44 0.50
Examination index (pH) 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
Related substance (%) 0.53 0.79 0.85 1.03 1.38 1.43 1.44 1.98
The test result shows that the change of related substances is small when the pH value is between 3.5 and 7, on the basis, the related substances are gradually increased along with the increase or decrease of the pH value, so that the support can be provided for clinical application, and the change of the related substances is basically not changed when the pH value of the solution is between 3.5 and 5.0, so that the support can be provided for a freeze-drying preparation process.
Experiment 4: ratio of freeze-dried excipient to main drug and determination of buffer pair addition in special solvent
According to the invention, the addition amount of the freeze-drying excipient is determined according to the pH requirement of the intermediate solution. Since the aqueous solution of succinylcholine chloride is acidic, the lyophilized excipient selected in the present invention is neutral or slightly acidic, and the amount of excipient added is determined according to the experiment in order to make the pH according to the theory of acid-base neutralization preferable (3.5-5.0) in experiment 2. Taking the formulation process of example 1 as an example, 0%, 25%, 50%, 75%, 100%, 125%, 150% of lyophilized excipients as the main drugs were added, and the addition amount was determined by measuring the pH of the intermediate solution (table 6).
Table 5: freeze-dried excipient research formula
Figure GDA0002489249500000091
TABLE 6 Effect of different amounts of lyophilized excipients added on the pH of the intermediate solution
Figure GDA0002489249500000092
The experimental results show that: the lyophilized excipient in the formulation of table 5, when added in an amount of 100% of the base drug, gives a better product appearance and satisfactory solution pH.
The addition amount of the buffer in the special solvent needs to be determined according to the pH value of the freeze-dried preparation, and the pH value of the final liquid medicine needs to be 6-7, so that the proper pH value of the special solvent needs to be determined through experiments. Taking still example 1 as an example, on the basis of the results determined in table 6, the pH of the solvent is adjusted to 7.0, 7.5, 8.0, 8.5, 9.0 by adding a buffer, and a special solvent is prepared according to the preparation process, the prepared freeze-dried preparation is reconstituted with the solvent, the pH of the liquid medicine is measured, and if the pH is within 5 to 7, the addition amount of the buffer in the corresponding solvent is the appropriate addition amount (table 8).
TABLE 7 vehicle formulation
Figure GDA0002489249500000093
TABLE 8 determination of the pH of the vehicle
Figure GDA0002489249500000094
As shown in Table 8, the pH of the special solvent in example 1 is preferably adjusted to 7.5-8.0.
The amounts of lyophilized excipient and buffer in the vehicle were also determined according to the methods of tables 6 and 8.
Experiment 5: study of Freeze drying Process
In order to reduce the freeze-drying period, improve the freeze-drying efficiency and consider the thermal stability of the main drug, the freeze-drying process parameters are investigated. Taking the succinylcholine chloride intermediate solution prepared in any one of the embodiments 1, and carrying out a freeze-drying experiment according to the following scheme to prepare a finished product, namely, the succinylcholine chloride freeze-dried powder:
step 1: pre-freezing to reduce the temperature of the product to below-20 ℃, preserving heat for a period of time until the temperature of the probe is below-5 ℃ (freezing), recording the heat preservation time (preferably 1-10 hours), and vacuumizing;
step 2: primary sublimation: setting the temperature to be-30-0 ℃, preserving heat for 2-4 hours after the temperature of the temperature control plate reaches the set temperature, gradually increasing the temperature (adding 1-2 ℃ every 2 hours) until the temperature of all products is 0 ℃, continuously preserving heat for 2-6 hours, and carrying out sublimation and termination once, wherein the total required time is 12-48 hours;
and step 3: secondary sublimation: setting the temperature to be 0-30 ℃, keeping the temperature for 6-12 hours when the temperature curve of the temperature control plate is parallel to the temperature curve of the product and the vacuum degree is not obviously changed, finishing the secondary sublimation and finishing the freeze-drying process.
Experiment 6: stability comparison of lyophilized preparation with Succinylcholine chloride injection
In order to prove that the novel freeze-dried preparation of the succinylcholine chloride has a remarkable stability advantage compared with the currently marketed injection of the succinylcholine chloride, the following experiment is designed:
taking a plurality of parts of a commercially packaged succinylcholine chloride freeze-dried powder sample in the embodiment 1 of the invention as an experimental group, and taking a plurality of parts of a commercially available succinylcholine chloride injection (produced by Xian Hanfeng pharmaceutical industry, Limited liability company) as a control group; since the commercially available injection has an expiration date of 12 months and is stored under refrigeration, the experimental and control samples were stored for 30 days at 40 ℃. + -. 2 ℃ and 70%. + -. 5% humidity, respectively, and the changes of the relevant substances and contents were examined (Table 9).
TABLE 9 comparison of the stability of the lyophilized formulation of the present invention with the commercially available succinylcholine chloride injection
Figure GDA0002489249500000101
As can be seen from Table 9, after the commercially available succinylcholine chloride injection is stored for 30 days at 40 ℃, the related substances are obviously increased to more than 8 percent, and the content of the main drug is obviously reduced; after the freeze-dried preparation is stored for 30 days at 40 ℃, related substances hardly change and the content does not change obviously. Obviously, the stability of the freeze-dried preparation in the invention is greatly higher than that of the injection preparation of the market.
Experiment 7: stability comparison of lyophilized formulation of succinylcholine chloride containing different excipients
TABLE 10 different excipient formulations
Figure GDA0002489249500000102
Figure GDA0002489249500000111
Experimental protocol, materials of interest methods referring to test 1, the sample was stored at 40 ℃ ± 2 ℃ and humidity at 70% ± 5% at measured time points of 0d, 5d, 10d, 20d, 30d, 60d, and the results are shown in the following table:
TABLE 11 stability results for different excipient formulations
Numbering 0d 5d 10d 20d 30d 60d
Composition
1 0.18 0.21 0.23 0.28 0.35 0.57
Composition 2 0.20 0.25 0.27 0.30 0.34 0.52
Composition 3 0.16 0.22 0.28 0.33 0.42 0.68
Composition 4 0.18 0.18 0.22 0.26 0.31 0.44
Composition 5 0.21 0.24 0.26 0.29 0.38 0.59
Composition 6 0.22 0.24 0.27 0.32 0.39 0.58
Composition 7 0.19 0.20 0.21 0.26 0.31 0.42
Composition 8 0.18 0.20 0.26 0.32 0.40 0.63
Composition 9 0.19 0.23 0.26 0.29 0.37 0.58
Composition 10 0.21 0.25 0.27 0.29 0.34 0.52
Composition 11 0.21 0.24 0.28 0.30 0.33 0.51
Composition 12 0.17 0.25 0.29 0.32 0.39 0.64
Composition 13 0.20 0.23 0.26 0.28 0.36 0.58
The results show that: the main drug, succinylcholine chloride, has good compatibility with different excipients, and compared with the impurities in the succinylcholine chloride injection in the test 6, the impurities are obviously reduced. Compared among the 13 groups of excipient formula groups, the stability of the excipient formula groups is slightly different, wherein the stability is better when the excipient is added than when the excipient is not added; the amino acid is used as an excipient, and the acidic amino acid has better formula stability than neutral or basic amino acid; mannitol is the preferred formulation because it has the slowest impurity growth.
Experiment 8: compared with the irritation caused by the choline chloride injection preparation, the novel freeze-dried preparation of the choline chloride is relatively more irritant
8.1 vein administration of blood vessels and injection site stimulation test
The irritation of the blood vessel by a single intravenous injection administration of the novel lyophilized formulation of succinylcholine chloride of the present invention and a commercially available injection of succinylcholine chloride was investigated using New Zealand rabbits.
The method comprises the following steps of taking 8 healthy rabbits, dividing the rabbits into 2 groups, wherein each group comprises 4 rabbits, and the rabbits are female and male in half, and performing self-contrast on the left side and the right side of the same body. A group of the novel succinylcholine chloride lyophilized preparation (6.5mg kg-1) of the invention in example 20 was administered to the right ear by intravenous injection, the formulation of experiment 4 was administered to the left ear, and the same volume of sodium chloride injection was administered to the left ear; the other group was administered with a commercially available succinylcholine chloride injection (Seisan Hanfeng pharmaceutical Co., Ltd.; batch No.: 1503291) (6.5 mg. kg-1) in the right ear and the same volume of sodium chloride injection in the left ear intravenously. Single administration. The administration time is about 30s, rabbit reactions during administration are recorded, 2 animals are sacrificed in each group after 1h of administration, the animals are half female and half male, ear edge tissues are respectively cut from an injection part and two parts of the ear edge vein near the heart, the stimulation reaction condition of the injection part is observed by naked eyes, 10% neutral formalin is fixed, and histopathology examination is carried out on conventional tissue sections.
The animals generally were in good condition and did not die during the test period; during each administration, rabbits in the lyophilized preparation group are calm when injected into the right ear, rabbits in the injection liquid group are slightly obvious in reaction when injected into the right ear, and rabbits in the two groups are calm when injected into the left ear; after the administration, the administration part is observed by naked eyes, the right ear of the freeze-dried group has no obvious abnormality, while the right ear of the injection group has slight red swelling and congestion, and the left ear of the two groups has no obvious abnormality. Histopathological examination results show that no obvious drug-stimulated histopathological change is seen in the right ear of the freeze-dried group, no obvious drug-stimulated histopathological change is seen in the right ear of the injection group, and no obvious drug-stimulated histopathological change is seen in the left ear of the two groups.
Conclusion under the test conditions, no vascular irritation was observed when the novel freeze-dried formulation of succinylcholine chloride of the present invention was intravenously administered to New Zealand rabbits, whereas the commercially available aqueous injection formulation of succinylcholine chloride had a certain vascular irritation.
8.2 stimulation experiments with intramuscular administration
The novel lyophilized formulation of succinylcholine chloride of the present invention and the commercially available succinylcholine chloride injection were administered to the muscle at the administration site using a single intramuscular injection of a New Zealand rabbit.
The method comprises dividing 8 healthy rabbits into 2 groups, each group having half male and female, and performing homomorphic left and right self-contrast. The animals were first cut with electric hair clippers, the quadriceps femoris muscles on the left and right sides were exposed, and the hair was removed from the right and left sides of each rabbit by aseptic technique. A group of the novel succinylcholine chloride lyophilized preparation (6.5 mg. kg-1) of the invention in example 20 was administered to the right side of the intramuscular injection, the formulation of experimental example 4 was used as the vehicle, and the same volume of sodium chloride injection was administered to the left side of the intramuscular injection; another group was administered with a commercial succinylcholine chloride injection (Xian Hanfeng pharmaceuticals, Inc., lot number: 1503291) by intramuscular injection on the right side and with the same volume of sodium chloride injection by intramuscular injection on the left side. Single administration. Each group of 2 animals was sacrificed 2h after administration, and the sex was half each, the quadriceps femoris muscle was dissected out, longitudinally cut, visually observed the stimulation response status of the muscle tissue at the injection site and scored accordingly, 10% neutral formalin was fixed, and histopathological examination was performed on the conventional tissue sections.
Results the animals generally worked well during the test period and did not die abnormally; before administration, no obvious abnormality is observed at the administration part by naked eye observation; no abnormality was found in the right and left sides of the lyophilized group 1 hour after administration, while the right muscles of the injection group showed red swelling and congestion, and the left muscles did not show abnormality. Histopathological examination results show that: no drug-stimulated histopathological changes were observed on either the left or right side of the lyophilized group, while slight drug-stimulated histopathological changes were observed on the right side of the injection group and no drug-stimulated histopathological changes were observed on the left side.
Conclusion under the test conditions, the irritation test of the novel freeze-dried preparation of the succinylcholine chloride provided by the invention in a single intramuscular injection of New Zealand rabbits has no irritation, and the injection of commercially available succinylcholine chloride has certain muscle irritation.
Drawings
FIG. 1, the hydrolysis process and products of succinylcholine chloride
FIG. 2, standard HP L C pattern of succinylcholine chloride and its possible impurities
A. Succinic acid (succinic acid) B, succinyl-1-cholinechloride (succininyl-1-cholinechloride) as main impurity
C. Succinylcholine chloride D, HP L C system adaptive separation degree spectrogram
Detailed Description
For a more clear understanding of the present invention, the following preparation examples of the novel lyophilized formulation of succinylcholine chloride are given to further describe the present invention in detail, but not to limit the present invention.
Example 1:
prescription:
Figure GDA0002489249500000131
the preparation process comprises the following steps: accurately weighing succinylcholine chloride, adding 60% of injection water, dissolving completely, adding glycine (freeze-drying excipient) according to the prescription amount, mixing and dissolving at about 25 ℃, adding injection water according to the prescription amount, stirring uniformly, measuring the pH of the solution to be 4.51, performing sterile filtration, subpackaging, freeze-drying, tamponade, capping, packaging and storing at room temperature; the special solvent is used for completely dissolving histidine according to the prescription amount by using injection water according to the prescription amount, measuring the pH value to be 8.06, adding sodium chloride to adjust the osmotic pressure to be isotonic, filtering, subpackaging, pressing a plug and rolling a cover. Wherein, the freeze-drying parameters and conditions are as follows: the pre-freezing temperature is-20 to-60 ℃ during freeze-drying, and the pre-freezing time is 1 to 10 hours; the primary sublimation temperature is-30-0 ℃, and the drying time is 12-48 hours; the secondary sublimation temperature is 0-30 ℃, and the time is 6-18 hours.
Example 2
Prescription:
Figure GDA0002489249500000132
Figure GDA0002489249500000141
the formulation process was the same as in example 1. The pH of the intermediate solution was the same as that of example 1, and the pH of the special solvent was adjusted to 7.58. The pH of the re-dissolved liquid medicine is 6.73.
Example 3
Prescription:
Figure GDA0002489249500000142
the formulation process was the same as in example 1. The pH of the intermediate solution was the same as that of example 1, and the pH of the special solvent was adjusted to 8.12. The pH of the re-dissolved liquid medicine is 6.85.
Example 4
Prescription:
Figure GDA0002489249500000143
the formulation process was the same as in example 1. The pH of the intermediate solution was the same as that of example 1, and the pH of the special solvent was adjusted to 7.32. The pH of the re-dissolved liquid medicine is 6.76.
Example 5
Prescription:
Figure GDA0002489249500000144
the formulation process was the same as in example 1. The pH of the intermediate solution was the same as that of example 1, and the pH of the special solvent was adjusted to 7.43. The pH of the re-dissolved liquid medicine is 6.68.
Example 6
Prescription:
Figure GDA0002489249500000151
the formulation process was the same as in example 1. The pH of the intermediate solution was the same as that of example 1, and the pH of the special solvent was adjusted to 7.56. The pH of the re-dissolved liquid medicine is 6.59.
Example 7
Prescription:
Figure GDA0002489249500000152
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.25, and the pH of the special solvent is adjusted to 7.58.
Example 8
Prescription:
Figure GDA0002489249500000153
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.25, and the pH value of the special solvent is adjusted to 7.32.
Example 9
Prescription:
Figure GDA0002489249500000154
Figure GDA0002489249500000161
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.25, and the pH of the special solvent is adjusted to 7.56.
Example 10
Prescription:
Figure GDA0002489249500000162
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 8.06.
Example 11
Prescription:
Figure GDA0002489249500000163
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 7.58.
Example 12
Prescription:
Figure GDA0002489249500000164
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 7.32.
Example 13
Prescription:
Figure GDA0002489249500000165
Figure GDA0002489249500000171
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 7.56.
Example 14
Prescription:
Figure GDA0002489249500000172
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 8.12.
Example 15
Prescription:
Figure GDA0002489249500000173
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.08, and the pH value of the special solvent is adjusted to 8.06.
Example 16
Prescription:
Figure GDA0002489249500000174
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.48, and the pH value of the special solvent is adjusted to 7.58.
Example 17
Prescription:
Figure GDA0002489249500000175
Figure GDA0002489249500000181
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.048, and the pH of the special solvent is adjusted to 7.32.
Example 18
Prescription:
Figure GDA0002489249500000182
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.48, and the pH value of the special solvent is adjusted to 7.56.
Example 19
Prescription:
Figure GDA0002489249500000183
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.48, and the pH value of the special solvent is adjusted to 8.12.
Example 20
Prescription:
Figure GDA0002489249500000184
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.58, and the pH value of the special solvent is adjusted to 8.06.
Example 21
Prescription:
Figure GDA0002489249500000185
Figure GDA0002489249500000191
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.58, and the pH value of the special solvent is adjusted to 7.58.
Example 22
Prescription:
Figure GDA0002489249500000192
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.58, and the pH value of the special solvent is adjusted to 7.32.
Example 23
Prescription:
Figure GDA0002489249500000193
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.58, and the pH of the special solvent is adjusted to 7.56.
Example 24
Prescription:
Figure GDA0002489249500000194
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.58, and the pH value of the special solvent is adjusted to 8.12.
Example 25
Prescription:
Figure GDA0002489249500000195
Figure GDA0002489249500000201
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.63, and the pH value of the special solvent is adjusted to 8.06.
Example 26
Prescription:
Figure GDA0002489249500000202
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.63, and the pH of the special solvent is adjusted to 7.58.
Example 27
Prescription:
Figure GDA0002489249500000203
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.63, and the pH value of the special solvent is adjusted to 7.32.
Example 28
Prescription:
Figure GDA0002489249500000204
the formulation process was the same as in example 1. Wherein, the pH of the intermediate solution is 4.63, and the pH of the special solvent is adjusted to 7.56.
Example 25
Prescription:
Figure GDA0002489249500000205
Figure GDA0002489249500000211
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.63, and the pH value of the special solvent is adjusted to 8.06.
Example 26
Prescription:
Figure GDA0002489249500000212
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.57, and the pH value of the special solvent is adjusted to 7.58.
Example 27
Prescription:
Figure GDA0002489249500000213
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.57, and the pH value of the special solvent is adjusted to 7.32.
Example 28
Prescription:
Figure GDA0002489249500000214
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 4.57, and the pH value of the special solvent is adjusted to 7.56.
Example 29
Prescription:
Figure GDA0002489249500000215
Figure GDA0002489249500000221
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.68, and the special solvent is normal saline for injection.
Example 30
Prescription:
Figure GDA0002489249500000222
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.68, and the special solvent is glucose injection.
Example 31
Prescription:
Figure GDA0002489249500000223
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.65, and the special solvent is normal saline for injection.
Example 32
Prescription:
Figure GDA0002489249500000224
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.65, and the special solvent is glucose injection.
Example 33
Prescription:
Figure GDA0002489249500000231
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.59, and the special solvent is normal saline for injection.
Example 34
Prescription:
Figure GDA0002489249500000232
the formulation process was the same as in example 1. Wherein, the pH value of the intermediate solution is 6.59, and the special solvent is normal saline for injection.

Claims (6)

1. The freeze-dried succinylcholine chloride combined preparation is characterized by consisting of a freeze-dried preparation and a solvent which are both independently packaged, wherein the freeze-dried preparation consists of succinylcholine chloride and a freeze-dried excipient, the pH value of a liquid medicine obtained after the freeze-dried preparation is added with the solvent for redissolution is 5.5-7.0, and the freeze-dried excipient is selected from one or a mixture of more than two of water-soluble amino acid and mannitol;
the weight ratio of the succinylcholine chloride to the freeze-drying excipient in the freeze-dried preparation is 1: 1;
adjusting pH value of the lyophilized preparation with weak acid or weak acid salt during preparation process, wherein the water-soluble amino acid is neutral amino acid selected from glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline; or an acidic amino acid selected from aspartic acid, glutamic acid;
wherein, the menstruum is selected from: one, two or more than two of acetate, dibasic phosphate, carbonate, citrate, tartrate, maleate, sodium chloride and glucose aqueous solution; or one or a mixture of two or more of acetic acid-acetate buffer, dihydrogen phosphate-hydrogen phosphate buffer, bicarbonate-carbonate buffer, citric acid-citrate buffer, tartaric acid-tartrate buffer, and maleic acid-maleate buffer.
2. The lyophilized combination formulation of claim 1, wherein the vehicle is selected from the group consisting of: one, two or more than two of dibasic phosphate, citrate, tartrate, maleate, sodium chloride and glucose aqueous solution; or one or a mixture of two or more of a dihydrogen phosphate-dihydrogen phosphate buffer solution, a citric acid-citrate buffer solution, a tartaric acid-tartrate buffer solution and a maleic acid-maleate buffer solution.
3. The lyophilized combination formulation according to claim 1, wherein the vehicle is a sodium salt.
4. The freeze-dried succinylcholine chloride combined preparation is characterized by consisting of a freeze-dried preparation and a solvent, wherein the freeze-dried preparation and the solvent are independently packaged, the pH value of a liquid medicine obtained after the freeze-dried preparation is added with the solvent for redissolution is 5.5-7.0, and the freeze-dried preparation comprises the following components in formula: succinylcholine chloride, 200 mg; mannitol, 250 mg; tartaric acid, 30 mg; 40mg of sodium tartrate, and the pH value of the freeze-dried preparation is adjusted by weak acid or weak acid salt in the preparation process, and the pH range is 3.5-5.
5. The freeze-dried succinylcholine chloride combined preparation is characterized by consisting of a freeze-dried preparation and a solvent, wherein the freeze-dried preparation and the solvent are independently packaged, the pH value of a liquid medicine obtained after the freeze-dried preparation is added with the solvent for redissolution is 5.5-7.0, the pH value of the freeze-dried preparation is adjusted by weak acid or weak acid salt in the preparation process, the pH range is 3.5-5, and the freeze-dried preparation specifically comprises the following components:
freeze-drying preparation: 20g of succinylcholine chloride, 20g of glycine, and preparation specification: 200 mg/count;
solvent, histidine 8.5g and proper amount of sodium chloride, water for injection is added to 400m L, the specification of the solvent is 10 ml/branch,
or
Freeze-drying preparation: 20g of succinylcholine chloride, 10g of glycine, 2g of sodium dihydrogen phosphate, and the specification of the preparation: 200 mg/count;
the solvent is proper amount of sodium chloride, the water for injection is added to 400m L, the specification of the solvent is 10 ml/branch,
or
Freeze-drying preparation: 20g of succinylcholine chloride, 10g of glycine, 2g of sodium dihydrogen phosphate, and the specification of the preparation: 200 mg/count;
solvent including histidine 5g, disodium hydrogen phosphate 2g, water for injection added to 400m L, solvent specification of 10 ml/branch,
or
Freeze-drying preparation: 20g of succinylcholine chloride, 25g of mannitol, 1g of maleic acid, and the specification of the preparation: 200 mg/count;
5g of sodium maleate as solvent, 400m of L of water for injection, 10 ml/branch of solvent,
or
Freeze-drying preparation: 20g of succinylcholine chloride, 10g of proline, 20g of serine, and the specification of the preparation: 200 mg/count;
solvent of 1g tartaric acid and 5g sodium tartrate, and water for injection of 400m L, wherein the specification of the solvent is 10 ml/branch.
6. A method of preparing a lyophilized combination preparation according to claim 1, comprising the steps of:
a) freeze-drying preparation: dissolving the freeze-dried excipient with a proper amount of water for injection completely, adding the succinylcholine chloride with a prescription amount, uniformly mixing and dissolving at the temperature of below 25 ℃, stirring uniformly, measuring the pH value of the solution to be 3.5-5, performing sterile filtration, subpackaging, freeze-drying, corking, capping, packaging and storing at the temperature of 2-8 ℃;
b) dissolving the auxiliary materials in the prescription amount completely with water for injection, filtering, subpackaging, corking and capping.
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