CN107519136A - A kind of Choline Chloride Succinate lyophilized formulations and preparation method thereof - Google Patents
A kind of Choline Chloride Succinate lyophilized formulations and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of Choline Chloride Succinate lyophilized formulations and preparation method thereof.Said preparation includes：Main ingredient is Choline Chloride Succinate, and excipient is mainly one of amino acid, oligopeptides, lactose, sucrose, mannose, maltose, mannitol, dextran or their mixture；Preparation solvent includes：One of physiological saline, water for injection, D/W, acetate, phosphoric acid hydrogen disalt, carbonate, citrate, tartrate, maleate, two or more mixture；Also one of acetic acid acetate buffer, the salt buffer of dihydric phosphate phosphoric acid hydrogen two, bicarbonate carbonate buffer solution, citric acid citrate buffer, tartaric acid tartrate buffer, maleic acid maleate buffers, two or more mixture are included.
Description
Technical field
The invention belongs to narcotics, is related to a kind of ultrashort effect polarization muscle relaxant, particularly injectable drug lyophilized formulations.
It is exactly a kind of buffered with amino acid to, organic salt buffer to, the chlorination amber that inorganic salt buffer equity excipient is carrier
Choline lyophilized formulations and preparation method thereof.
Background technology
Choline Chloride Succinate (Suxamethonium Chloride) belongs to depolarising type muscle relaxant, is the conjunction of tubocurarine
Into substitute, it can be combined rapidly with nicotinic receptor, produced stable depolarization effect, caused skeletal muscle relaxation；After action, again
Hydrolyzed by pseudocholinesterase in blood rapidly, it is very weak to decompose the intermediate metabolites succinylcholine Muscle relaxation of generation, enters one
Step is metabolized into the metabolin of no Muscle relaxation, is excreted therewith.60~90s of Muscle relaxation works, and maintains 10min left
The right side, plasma half-life are 2~4min, and prolonged action can be made by repeating intravenous or persistent instillation.Therefore Choline Chloride Succinate has flesh loose
The characteristics of onset of action is fast, the duration is short, easily controllable, it is highly suitable for trachea cannula and surgery minor operation[1-5].Mesh
Before, it clinically there is no a kind of depolarizing relaxant to possess the advantages of Choline Chloride Succinate completely and go its adverse reaction.So
Choline Chloride Succinate using so far, turns into the most long muscle relaxant of usage time always, and when difficult intubation and emergency intubation, mesh
The preceding muscle relaxant being uniquely selected.
At present, result of study proves, Choline Chloride Succinate is extremely unstable in aqueous, particularly high-temperature sterilization and water-soluble
When liquid medicine preparation preserves for a long time, Choline Chloride Succinate can hydrolyze the choline of generation chlorination amber one, Choline Chloride, butanedioic acid etc.
A series of materials (such as Fig. 1), and then cause a series of adverse reaction, for catabolite, external product limit provides at present
For 7%, home products limit is 10%, and in the measure of reality, Choline Chloride Succinate is degraded more very, is placed more than 12 months
Degraded is more than 10%.In order to overcome the hydrolysis of Choline Chloride Succinate, foreign countries are removed using low-down solution acidity (pH 3.5)
It is prepared by bacterium.Product needs 2-8 DEG C of Cord blood.The domestic parenteral solution in China uses propane diols as solution, due to completely anhydrous
Propane diols and relatively low acidity can not prevent the hydrolysis of Scoline completely, be merely capable of reducing hydrolysis rate, while with the third two
Alcohol is very high for the viscosity of the in-situ chlorination graft of solvent, and the filling accuracy of preparation process is difficult to control.In addition, mesh
Preceding in-situ chlorination graft adverse reaction on sale is numerous, such as：PH value is too low or the aqueous solution of propane diols can cause
The side effect such as part (blood vessel) excitant, bradycardia, nodal arrhythmia and sudden arrest of heart beat.The medicine is had a strong impact on
Clinical practice security.Have been reported that[7-8]Point out that Choline Chloride Succinate hydrolyzes, it is also possible to further Choline Chloride Succinate injection
The pH of liquid, and then aggravate the pain reaction of Choline Chloride Succinate.
The present invention is directed to problem above, proposes that new Choline Chloride Succinate lyophilized formulations are newly formulated.First, the lyophilized formulations
Medicine is existed in solid form, avoid its characteristic easily degraded in solution state, ensure that the purity of main ingredient；Its
It is secondary, excipients are used as using amino acid or oligopeptides, mannitol, trehalose etc., and pH value is adjusted to 3.5-5, solvent is with inorganic salts
Or organic salt or its buffering pair, including acetate, phosphoric acid hydrogen disalt, carbonate, citrate, tartrate, maleic acid
Salt, sodium chloride, the aqueous solution of glucose；Also include acetic acid-acetate buffer, the dihydric phosphate-salt buffer of phosphoric acid hydrogen two,
Carbonate-hydrogen carbonate buffer solution, acid-citrate buffer solution, tartaric acid-tartrate buffer, maleic acid-Malaysia
Phthalate buffer.On the one hand, lyophilized formulations enable the more stable presence of Choline Chloride Succinate, and on the other hand, special is molten
Matchmaker can effectively control the acidity for redissolving solution to be in physiological pH range, reduce stimulation of the medicine to blood vessel, also have, stable pH models
Enclosing can make said preparation system be chronically at stable state, it is suppressed that drug degradation, ensure drug content and then cause drug safety.
In addition, after rational pH and removal propane diols, injection pain and vascular inflammation are avoided.
[1] Li great Cheng, clinical practice [J] the Shandong biomedical engineering of Wu's tin text Choline Chloride Succinates, 2000,19
(2):1.
[2] pharmacokinetics of Li Yan Scolines and pharmacodynamics [J] world anesthesiologys and recovery magazine, 1994 (5):276-
278.
[3]PHarmGKB summary:succinylcholine pathway,pHarmacokinetics/
pHarmacodynamics. PHarmacogenetics and genomics,2015,25(12),622-630.
[4] the domestic Choline Chloride Succinate pharmacodynamics of Zhang Qian, Wang Jun section and pharmacokinetic [J] Jiangsu medicine,
2006,32(6): 588-589.
[5] Li Yang, bear Lize, Yang Bo, application [J] China nerve of the Choline Chloride Succinates in neurosurgery anesthesia is waited
Surgical disease research magazine, 2005,4 (4):353-356.
[6] Yang Feng, Wella, the domestic Choline Chloride Succinate flesh pine effects of the unique of clock and cardiovascular effect [J] Xinjiang medical science,
2007,37(6): 69-70.
[7]Sally C,Palmon M D,Aaron T,et al.The effect of needle gauge and
lidocaine 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)before
administration prevents injection pain in awake patients:a randomized
prospective trial[J].Journal of Clinical Anesthesia, 2007,19(6):418-423.
The content of the invention
The present invention provide it is a kind of with buffered with amino acid to for the Choline Chloride Succinate lyophilized formulations of excipient and its preparation side
Method, mainly there are two the characteristics of the formula and formulation：First, the stability of pharmaceutical preparation can be significantly improved, reduces impurity
Produce；Second, its buffer salt used may be such that in the pH value control physiological range of preparation, so as to reduce Choline Chloride Succinate
Stimulation and injection pain to blood vessel；3rd, hence it is evident that improve lyophilized formulations character.
Choline Chloride Succinate lyophilized formulations provided by the present invention, it is protected before Clinical practice in the form of lyophilized formulations
Deposit, solve the problems, such as aqueous solution fast degradation.
It is an object of the invention to provide a kind of Choline Chloride Succinate to freeze combination preparation.
The lyophilized combination preparation is made up of lyophilized formulations and solvent, and lyophilized formulations and solvent are all independent packagings.Wherein, freeze
Dry preparation is made up of Choline Chloride Succinate, freeze-dried excipient, and lyophilized formulations add the decoction pH value after solvent redissolves in 5.5-7.0
Between, wherein, freeze-dried excipient is selected from water miscible amino acid, oligopeptides, lactose, sucrose, mannose, maltose, mannitol, sea
Mixture more than one or both of algae sugar, dextran.
Wherein, the weight of Choline Chloride Succinate and lyophilized excipients ratio scope is 1.0 in lyophilized formulations:0.0~1.0:
10.0, preferably 1:1.
Wherein, for lyophilized formulations with weak acid or faintly acid salt regulation pH value in preparation process, pH scopes are 3.5-5.
Wherein, water miscible amino acid is selected from：Weak acid acidic amino acid, neutral amino acid, basic amino acid, or by two kinds
Or the oligopeptides that two or more amino acid freely bonds together to form；Lyophilized excipients can be any in above-mentioned amino acid and oligopeptides
Kind, two kinds or two or more mixtures；
Wherein, water miscible amino acid is neutral amino acid, selected from glycine, alanine, leucine, isoleucine, figured silk fabrics
Propylhomoserin, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, egg
Propylhomoserin and hydroxyproline；Or be acidic amino acid, selected from aspartic acid, glutamic acid；Or be basic amino acid, selected from bad ammonia
Acid, arginine, histidine.Amino acid, oligopeptides are human body existence matter, using it as excipient, can ensure preparation to the full extent
Stability and security.
Wherein, solvent provided by the present invention plays dissolving and acid-base modifier effect, and solvent is selected from：Acetate, phosphoric acid
Hydrogen disalt, carbonate, citrate, tartrate, maleate, sodium chloride, the aqueous solution of glucose, can be wherein it
First, two or more mixture；Can also be acetic acid-acetate buffer, the dihydric phosphate-salt buffer of phosphoric acid hydrogen two
Liquid, carbonate-hydrogen carbonate buffer solution, acid-citrate buffer solution, tartaric acid-tartrate buffer, maleic acid-
One of maleate buffers, two or more mixture.
Wherein, solvent is preferred：Phosphoric acid hydrogen disalt, citrate, tartrate, maleate, sodium chloride, the water of glucose
Solution can be one of them, two or more mixture；It can also be dihydric phosphate-salt buffer of phosphoric acid hydrogen two
Liquid, acid-citrate buffer solution, tartaric acid-tartrate buffer, maleic acid-maleate buffers, can be it
One of, two or more mixture.
Wherein, solvent or excipient, can be mixtures one or more of in sodium salt, calcium salt, zinc salt.
Wherein, the present invention regulation pH value acid, weak acid, faintly acid salt, can be amino acid, acetate, phosphoric acid hydrogen disalt,
Carbonate, citrate, tartrate, maleate, sodium chloride, the aqueous solution of glucose can be one of them, two kinds or
Two or more mixtures；Can also be acetic acid-acetate buffer, the dihydric phosphate-salt buffer of phosphoric acid hydrogen two, bicarbonate
Salt-carbonate buffer solution, acid-citrate buffer solution, tartaric acid-tartrate buffer, maleic acid-maleate delay
One of fliud flushing, two or more mixture；
Choline Chloride Succinate lyophilized formulations provided by the present invention, can be furnished with corresponding solvent so that the medicine after final dissolving
The pH of thing is between 5.5-7.0, and said preparation is that quick flesh pine needs, more stable within 4h after formulation dissolution, after dissolving
Medicine can clinically use as early as possible, and therefore, the pH scopes can meet clinical demand；
The present invention's can also directly use buffered with amino acid liquid, acetic acid-acetate buffer, dihydric phosphate-phosphoric acid
The salt buffer of hydrogen two, carbonate-hydrogen carbonate buffer solution, acid-citrate buffer solution, tartaric acid-Tartrate buffer
Liquid, maleic acid-maleate buffers etc., directly the pH value of lyophilized stoste is adjusted between 5.5-7.0, then packing and jelly
Dry, the impurity content of such lyophilized formulations is slightly above the Choline Chloride Succinate lyophilized formulations of the auxiliary material containing faintly acid, while is equipped with phase
Answer with physiological saline or D/W solvent, still, such preparation compared with the aqueous solution, impurity content substantially compared with
It is low；
Further, a kind of new Choline Chloride Succinate lyophilized formulations, representative prescription are：
Further, effect and dosage of each material in prescription are enumerated in representative prescription, but it is also not solid
It is fixed, wherein in addition to Choline Chloride Succinate is necessary formulation ingredients, other auxiliary materials such as pH buffer can add can also be not added with or
Person part adds.
By adjusting pharmaceutical formulation so that the pH (5.5~7.0) of lyophilized formulations close to blood pH level, then without
PH adjusting agent is added in solvent, solvent is isotonic parenteral solution, such as injection physiological saline or glucose injection.Or
Such as unused amino acid in freeze-dried excipient, then it must add people's pH buffer compositions in special solvent, such as the buffering of inorganic/organic salt
Liquid, inorganic/organic salt or weak base acidic amino acid.Prescription dosage is as just inventive embodiments, and the control of non-claimed is used
Amount.
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
Specific formula can be：
It is another object of the present invention to provide the preparation method of lyophilized combination preparation.
Prepare universal method 1：Recipe quantity Choline Chloride Succinate is dissolved completely with appropriate water for injection, adds prescription
The lyophilized excipients measured, less than 25 DEG C mix dissolving, stir, and measure the PH of solution in 3.5-5, aseptic filtration, packing, jelly
Dry, tamponade, roll lid, packaging, 2-8 DEG C of storage；Solvent, the auxiliary material of recipe quantity water for injection is dissolved completely, filter, dispense,
Tamponade, roll lid.
For the product of preparation method 1：The pH of the decoction finally prepared is 5~7, is by adjusting freeze-dried excipient and phase
The prescription dosage of pH buffer in solvent is answered to realize；
Further, as above the step of freeze drying in technique uses normal freeze-drying technology.Parameters of freeze-drying process is：Pre-freezing temperature
For -21~-60 DEG C, the pre-freeze time is 1~10 hour；Sublimation temperature is -30~0 DEG C, and drying time is 12~48 small
When；Secondary sublimation temperature is 0~30 DEG C, and the time is 6~12 hours.
Prepare universal method 2：Recipe quantity Choline Chloride Succinate is dissolved completely with appropriate water for injection, adds prescription
The lyophilized excipients (buffer) of amount, less than 25 DEG C mix dissolving, stir, and measure the PH of solution in 5-7, aseptic filtration,
Packing, lyophilized, tamponade, roll lid, packaging, 2-8 DEG C of storage；Solvent, physiological saline, water for injection, glucose solution, PH5-7's
Buffer salt solution.
For the product of preparation method 2：The stability of stoste is emphasis in lyophilized technique.
Beneficial effects of the present invention are further illustrated by following experiment.
Experiment 1：The relevant material of Sux-Cert and the Measuring method improvement of content
In terms of relevant material, (ChP, must not mistake using TLC controls for the relevant material of domestic Sux-Cert at present
10%), external only Japanese Pharmacopoeia (JP) is controlled relevant material and (must not cross 7%), use and TLC method,
Other main flow countries do not make regulation to the relevant material of the veriety.
In terms of content, the content assaying method of the existing preparation of Choline Chloride Succinate is also made great difference both at home and abroad, wherein USP38
Using HPLC method, BP2010 (EP7.0), JP15, ChP2015 etc. use volumetric method.
In view of high sensitivity and high precision advantage that HPLC methods have, we combine raw material USP38 and EP7.0 and
The official method of other countries, solve pharmaceutical adjunct interference, the relevant material of preferably a set of Choline Chloride Succinate lyophilized formulations and
The HPLC determination methods of content.
Chromatographic condition chromatographic column：Alltima 88056C18 (4.6mm x 250mm, 5um)；Mobile phase：Cushioning liquid：Second
Nitrile (950：50) deaerate；Flow velocity：1.0mL·min-1；Detection wavelength：214nm；Column temperature：25℃；Record to 45min.
In the case where testing chromatographic condition, the retention time of main ingredient Choline Chloride Succinate is 21.15min, chlorination amber list choline
Retention time be 11.16min, the retention time of butanedioic acid is 4.87min；Bulk drug and contamination levels product are in above-mentioned condition
Chromatogram is shown in Fig. 2.Each impurity separating degree in Choline Chloride Succinate, three kinds of possible impurity can separate very well with main ingredient (to be shown in Table
2).
Each impurity separating degree of the Choline Chloride Succinate of table 2
Experiment 2：Lyophilized stoste is prepared temperature and investigated
Choline Chloride Succinate midbody solution can be formulated under the conditions of certain temperature, then need to investigate temperature centering
The influence of mesosome stability of solution, also it is industry to determine time that the temperature of ingredients and midbody solution can be continual and steady
Data accumulation is done in metaplasia production.We are investigated the stability of the lyophilized stoste to different temperatures table 3 below, respectively 25 DEG C,
40 DEG C, 0h, 2h, 4h, 6h, 8h, 24h relevant material situation (table 4) is investigated under 55 DEG C of temperature conditionss.
Table 3：Temperature studies formula
Table 4：Influence of the temperature to intermediate stability of solution
Result of the test is shown：Midbody solution respectively at 25 DEG C, 40 DEG C, 55 DEG C, in 8h relevant content of material progressively on
Rise, wherein, 25 DEG C are preferably, and preliminary to meet production and clinical requirement, therefore, in preparation process, temperature is relatively low to be advantageous to produce.
Experiment 3：The determination of pH value range
Choline Chloride Succinate is more sensitive to pH, by taking the formula of table 3 as an example, the midbody solution pH adjusting agent prepared
(0.1mol/ml hydrochloric acid or sodium hydroxide solution), regulation are arrived different pH, arranged according to the process time, to this
The relevant material and content situation of manufactured lyophilized formulations are investigated, to determine the advantageous pH range of midbody solution.Respectively
By the pH of midbody solution regulation 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,
9.5th, 10.0,10.5, investigate the situation of change (table 4) of the relevant material for the Choline Chloride Succinate lyophilized formulations prepared.
Table 5：Midbody solution pH scopes are to influence of the lyophilized formulations about material and content
| Inspection target (pH) | 3.0 | 3.5 | 4.0 | 4.5 | 5.0 | 5.5 | 6.0 | 6.5 |
| Relevant material (%) | 0.80 | 0.42 | 0.31 | 0.38 | 0.40 | 0.43 | 0.44 | 0.50 |
| Inspection target (pH) | 7.0 | 7.5 | 8.0 | 8.5 | 9.0 | 9.5 | 10.0 | 10.5 |
| Relevant material (%) | 0.53 | 0.79 | 0.85 | 1.03 | 1.38 | 1.43 | 1.44 | 1.98 |
Result of the test shows that pH relevant material changes between 3.5~7 are smaller, on this basis, as pH value must increase
Or reduce, relevant material incrementally increases, can be for that can provide support for clinical practice, and the pH of solution is relevant between 3.5~5.0
Material change is substantially unchanged, can provide support for lyophilized formulations technique.
Experiment 4：Determination of the buffering to addition in freeze-dried excipient and main ingredient ratio and special solvent
The present invention, a kind of new Choline Chloride Succinate lyophilized formulations, the addition of freeze-dried excipient are molten according to intermediate
The pH of liquid is required to determine.Because the Choline Chloride Succinate aqueous solution is in acidity, the freeze-dried excipient selected in of the invention is in neutrality
Or slant acidity, it is theoretical according to acid-base neutralization, to cause pH to meet in experiment 2 institute preferably (3.5~5.0), then be according to reality
Test to determine to add the amount of excipient.We are separately added into main ingredient 0% by taking the formulation and technology of embodiment 1 as an example, and 25%, 50%,
75%, 100%, 125%, 150% freeze-dried excipient, addition (table 5) is determined by determining the pH of midbody solution.
Table 3：Freeze-dried excipient research formula
Influence of the freeze-dried excipient difference addition of table 5 to intermediate pH value of solution
Test result indicates that：When freeze-dried excipient in the formula of table 3 adds 100% amount of main ingredient, preferably production can be obtained
Product outward appearance and satisfactory pH value of solution.
Buffer addition needs to be determined according to the pH of lyophilized formulations in special solvent, because the pH requirements of final decoction
It must be 6~7, therefore the suitable pH of special solvent need to be determined by testing.By still by taking embodiment 1 as an example, in the knot that table 5 determines
On the basis of fruit, the pH of solvent is adjusted to 7.0,7.5,8.0,8.5,9.0 respectively by adding buffer and prepared according to preparation technology
Into special solvent, the lyophilized formulations standard prepared has solvent redissolution, determines decoction pH, if being met the requirements between 5~7,
Now the addition of buffer is suitable addition (table 6) in corresponding solvent.
The solvent formula of table 6
The pH value of the special solvent of table 7 determines
As seen from Table 6, the pH of the special solvent in embodiment 1 needs to adjust to being advisable between 7.5~8.0.
The addition of buffer in the addition and special solvent of freeze-dried excipient in the present invention in other embodiment
And it is determined according to the method for table 5 and table 6.
Experiment 5：The research of lyophilized technique
To reduce lyophilization cycle, lyophilized efficiency is improved, and takes into account the heat endurance of main ingredient, investigates parameters of freeze-drying process.Take
The Choline Chloride Succinate midbody solution of any preparation in embodiment 1, freeze-drying experiment is carried out by following scheme, is prepared into
Product, i.e. Choline Chloride Succinate freeze-dried powder：
Step 1：Pre-freeze, products temperature is set to be down to less than -20 DEG C, insulation a period of time so that probe temperature is shown as -5
Untill (freezing real) below DEG C, soaking time (being advisable for 1~10 hour) is recorded, is vacuumized；
Step 2：Once distil：Design temperature is -30~0 DEG C, after temperature control disk temperature reaches design temperature, insulation 2~
4h, temperature (every 2h plus 1~2 DEG C) is stepped up, until all products temperatures cross 0 DEG C, continue 2~6h of insulation, once rise
China terminates, and required time is 12~48 hours altogether；
Step 3：Secondary distillation：Design temperature is 0~30 DEG C, when temperature control disk temperature curve and products temperature oriented parallel,
And vacuum without significant change when, continue insulation 6~12 hours, secondary distillation terminates, and freeze-drying process terminates.
Experiment 6：Lyophilized formulations are compared with the stability of in-situ chlorination graft
In order to prove the present invention, a kind of new Choline Chloride Succinate lyophilized formulations, more presently commercially available Choline Chloride Succinate
Parenteral solution has significant stability advantage, and then we design following experiment：
The commercially available back Choline Chloride Succinate freeze-dried powder sample several pieces of the embodiment of the present invention 1 are taken separately to be taken as experimental group
Several pieces are as a control group for commercially available in-situ chlorination graft (Xi'an Hanfeng Pharmaceutical Co., Ltd.'s production)；Due to commercially available
The effect phase of parenteral solution is 12 months and is stored refrigerated, therefore this experiment is in 40 DEG C ± 2 DEG C of temperature, bar of the humidity 70% ± 5%
Experimental group and control sample are deposited 30 days respectively under part, investigate its situation of change (table 7) about material and content.
7 lyophilized formulations of the present invention of table are compared with the stability of commercially available in-situ chlorination graft
As can be seen from Table 7, after commercially available 40 DEG C of in-situ chlorination graft storage 30 days, relevant material substantially increases
Greatly, more than 8% is reached, drug content substantially reduces；And after the storage 30 days of 40 DEG C of the lyophilized formulations in the present invention, relevant material is several
Without significant change, content is also without significant change.It will be apparent that the lyophilized formulations stability in the present invention be much higher than it is commercially available
This product injection formulation.
Experiment 7：Choline Chloride Succinate lyophilized formulations stability containing different excipient compares
The different excipient prescriptions of table 8
Experimental program, relevant substance method reference test 1, Sample storage environment are 40 DEG C ± 2 DEG C, humidity 70% ±
5%, the time point of measure is 0d, 5d, 10d, 20d, 30d, 60d, and result of study is as shown in the table：
Table 9, different excipient prescription stability results
| Numbering | 0d | 5d | 10d | 20d | 30d | 60d |
| Prescription 1 | 0.18 | 0.21 | 0.23 | 0.28 | 0.35 | 0.57 |
| Prescription 2 | 0.20 | 0.25 | 0.27 | 0.30 | 0.34 | 0.52 |
| Prescription 3 | 0.16 | 0.22 | 0.28 | 0.33 | 0.42 | 0.68 |
| Prescription 4 | 0.18 | 0.18 | 0.22 | 0.26 | 0.31 | 0.44 |
| Prescription 5 | 0.21 | 0.24 | 0.26 | 0.29 | 0.38 | 0.59 |
| Prescription 6 | 0.22 | 0.24 | 0.27 | 0.32 | 0.39 | 0.58 |
| Prescription 7 | 0.19 | 0.20 | 0.21 | 0.26 | 0.31 | 0.42 |
| Prescription 8 | 0.18 | 0.20 | 0.26 | 0.32 | 0.40 | 0.63 |
| Prescription 9 | 0.19 | 0.23 | 0.26 | 0.29 | 0.37 | 0.58 |
| Prescription 10 | 0.21 | 0.25 | 0.27 | 0.29 | 0.34 | 0.52 |
| Prescription 11 | 0.21 | 0.24 | 0.28 | 0.30 | 0.33 | 0.51 |
| Prescription 12 | 0.17 | 0.25 | 0.29 | 0.32 | 0.39 | 0.64 |
| Prescription 13 | 0.20 | 0.23 | 0.26 | 0.28 | 0.36 | 0.58 |
As a result show：Compatibility is good between main ingredient Choline Chloride Succinate and different excipient, with experiment 6 in chlorination amber
Impurity compares in amber choline injection, and impurity substantially reduces.Compare between above-mentioned 13 groups of excipient prescription group, its stability is slightly
Difference, wherein, it is better than being added without excipient stability to add excipient；Amino acid is as excipient, and acidic amino acid is than neutral
Or the prescription stability of basic amino acid is good；The growth of mannitol prescription impurity is most slow, is preferable prescription.
Experiment 8：New Choline Chloride Succinate lyophilized formulations are compared with excitant caused by Choline Chloride Succinate hydro-acupuncture preparation
8.1 intravenously administrable blood vessels and injection site irritation experiment
Using new zealand rabbit have studied single intravenous injection give the present invention new Choline Chloride Succinate lyophilized formulations and
Excitant of the commercially available in-situ chlorination graft to blood vessel.
The rabbit 8 of health is taken, is divided into 2 groups, every group 4, equal male and female half and half, androgynous left and right sides Self-control method.One group
New Choline Chloride Succinate lyophilized formulations (6.5mgkg-1) the solvent experiment of the embodiment of the present invention 20 is given in auris dextra intravenous injection
Prescription in example 4, left ear give the sodium chloride injection of same volume；Another group of auris dextra gives commercially available Choline Chloride Succinate note
Penetrate liquid (Xi'an Hanfeng Pharmaceutical Co., Ltd., lot number：1503291) (6.5mgkg-1), left ear vein give same volume
Sodium chloride injection.Single-dose.Administration time about 30s, record administration when rabbit reaction, administration terminate 1h after every group it is each
2 animals are put to death, male and female half and half, clip ear-edge tissue is distinguished at injection site, auricular vein proximal part two, is visually observed
Injection site irritation reaction condition, 10% neutral formalin are fixed, and conventional organization section carries out histopathological examination.
Animal general state is good during experiment, does not occur death；Every time during administration, family when lyophilized formulations group auris dextra is injected
Rabbit is more tranquil, and the reaction of rabbit is slightly obvious during the injection of parenteral solution group auris dextra, and two groups of left ears are tranquiler when injecting；Administration knot
It is local that administration is visually observed after beam, lyophilized group auris dextra is shown no obvious abnormalities, and parenteral solution group auris dextra shows slightly red and swollen and congested, two groups
Left ear is showed no obvious abnormalities.Histopathological examination result shows that lyophilized group auris dextra has no obvious medicine irritation tissue disease
Neo-Confucianism changes, and parenteral solution group auris dextra has obvious medicine irritation tissue pathologies change, and two groups of left ears are showed no obvious medicine
Excitant tissue pathologies change.
Under this experimental condition of conclusion, the new Choline Chloride Succinate lyophilized formulations of the present invention are given in new zealand rabbit intravenous injection
Blood vessel irritation is had no, and commercially available Choline Chloride Succinate hydro-acupuncture preparation has certain blood vessel irritation.
8.2 the stimulation test of intramuscular delivery
The new Choline Chloride Succinate lyophilized formulations of the present invention and commercially available chlorine are given using new zealand rabbit single intramuscular injection
Change excitant of the Scoline parenteral solution to medicine-feeding part muscle.
Method takes the rabbit 8 of health, is divided into 2 groups, every group of male and female half and half, androgynous left and right sides Self-control method.Animal is first
With electric hair cutter cropping, exposure left and right sides quadriceps muscle of thigh, lost hair or feathers with aseptic manipulation in every rabbit right, left both sides.One group right
The injection of pleural muscle meat gives new Choline Chloride Succinate lyophilized formulations (6.5mgkg-1) solvent of the embodiment of the present invention 20 using real
The prescription tested in example 4, left muscles inject the sodium chloride injection for giving same volume；City is given in another group of right muscles injection
Sell in-situ chlorination graft (Xi'an Hanfeng Pharmaceutical Co., Ltd., lot number：1503291), left muscles injection is given
The sodium chloride injection of same volume.Single-dose.Every group of 2h respectively puts to death 2 animals, male and female half and half after administration, and stock is taken out in dissection
Musculus quadriceps, it is longitudinally slit, visually observe the stimulate the reaction situation of injection site musculature and scored accordingly, in 10%
Property formalin fix, conventional organization section carry out histopathological examination.
As a result animal general state is good during testing, and does not occur abnormal growth；Medicine-feeding part is visually observed before administration not
See obvious exception；1h after administration, lyophilized group is right, left side is showed no exception, and flesh appearance is red and swollen, congested on the right side of parenteral solution group, left
Pleural muscle meat is showed no exception.Histopathological examination result shows：Lyophilized group left and right sides is showed no medicine irritation histopathology
Learn and change, and the slight change of medicine irritation histopathology then occur on the right side of parenteral solution group, left side has no medicine irritation
Tissue pathologies change.
Under this experimental condition of conclusion, new zealand rabbit single intramuscular injection gives the lyophilized system of new Choline Chloride Succinate of invention
Agent irritation test has no excitant, and giving commercially available Choline Chloride Succinate liquid drugs injection has certain muscle irritation.
Brief description of the drawings
Fig. 1, the hydrolytic process of Choline Chloride Succinate and product
Fig. 2, Choline Chloride Succinate and its possible impurity standard items HPLC collection of illustrative plates
A, butanedioic acid (succinic acid) B, major impurity chlorination amber list choline (succinyl-1-choline
chloride)
C, Choline Chloride Succinate (succinylcholine chloride) D, HPLC system adaptability separating degree spectrogram
Embodiment
For a clearer understanding of the present invention, the preparation embodiment pair of new Choline Chloride Succinate lyophilized formulations given below
The present invention is described in further detail, but is not construed as limiting the invention.
Embodiment 1：
Prescription：
Preparation technology：Accurately Choline Chloride Succinate being weighed to be added in the water for injection of recipe quantity 60%, dissolving is complete, then
The glycine (freeze-dried excipient) of recipe quantity is added, 25 DEG C or so mix dissolving, and benefit injects water to recipe quantity, and stirring is equal
Even, the PH for measuring solution is 4.51, is sterile filtered, packing, lyophilized, tamponade, rolls lid, packs, room temperature storage；Special solvent, will
The water for injection dissolving of the histidine recipe quantity of recipe quantity is complete, and it is 8.06 to measure pH, adds sodium chloride regulation infiltration and is depressed into
It is isotonic, filtering, packing, tamponade, roll lid.Wherein, parameter and condition are freezed：Pre-freezing temperature is -20~-60 DEG C when lyophilized, pre-freeze
Time is 1~10 hour；Sublimation temperature is -30~0 DEG C, and drying time is 12~48 hours；Secondary sublimation temperature be 0~
30 DEG C, the time is 6~18 hours.
Embodiment 2
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is constant still same as Example 1, the pH of special solvent
It is adjusted to 7.58.Decoction pH after redissolution is 6.73.
Embodiment 3
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is constant still same as Example 1, the pH of special solvent
It is adjusted to 8.12.Decoction pH after redissolution is 6.85.
Embodiment 4
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is constant still same as Example 1, the pH of special solvent
It is adjusted to 7.32.Decoction pH after redissolution is 6.76.
Embodiment 5
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is constant still same as Example 1, the pH of special solvent
It is adjusted to 7.43.Decoction pH after redissolution is 6.68.
Embodiment 6
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is constant still same as Example 1, the pH of special solvent
It is adjusted to 7.56.Decoction pH after redissolution is 6.59.
Embodiment 7
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.25, and the pH of special solvent is adjusted to 7.58.
Embodiment 8
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.25, and the pH of special solvent is adjusted to 7.32.
Embodiment 9
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.25, and the pH of special solvent is adjusted to 7.56.
Embodiment 10
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 8.06.
Embodiment 11
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 7.58.
Embodiment 12
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 7.32.
Embodiment 13
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 7.56.
Embodiment 14
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 8.12.
Embodiment 15
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.08, and the pH of special solvent is adjusted to 8.06.
Embodiment 16
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.48, and the pH of special solvent is adjusted to 7.58.
Embodiment 17
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.048, and the pH of special solvent is adjusted to 7.32.
Embodiment 18
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.48, and the pH of special solvent is adjusted to 7.56.
Embodiment 19
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.48, and the pH of special solvent is adjusted to 8.12.
Embodiment 20
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.58, and the pH of special solvent is adjusted to 8.06.
Embodiment 21
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.58, and the pH of special solvent is adjusted to 7.58.
Embodiment 22
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.58, and the pH of special solvent is adjusted to 7.32.
Embodiment 23
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.58, and the pH of special solvent is adjusted to 7.56.
Embodiment 24
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.58, and the pH of special solvent is adjusted to 8.12.
Embodiment 25
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.63, and the pH of special solvent is adjusted to 8.06.
Embodiment 26
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.63, and the pH of special solvent is adjusted to 7.58.
Embodiment 27
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.63, and the pH of special solvent is adjusted to 7.32.
Embodiment 28
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.63, and the pH of special solvent is adjusted to 7.56.
Embodiment 25
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.63, and the pH of special solvent is adjusted to 8.06.
Embodiment 26
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.57, and the pH of special solvent is adjusted to 7.58.
Embodiment 27
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.57, and the pH of special solvent is adjusted to 7.32.
Embodiment 28
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 4.57, and the pH of special solvent is adjusted to 7.56.
Embodiment 29
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.68, and special solvent is injection physiological saline.
Embodiment 30
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.68, and special solvent is glucose injection.
Embodiment 31
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.65, and special solvent is injection physiological saline.
Embodiment 32
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.65, and special solvent is glucose injection.
Embodiment 33
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.59, and special solvent is injection physiological saline.
Embodiment 34
Prescription：
Preparation process is the same as embodiment 1.Wherein, the pH of midbody solution is 6.59, and special solvent is injection physiological saline.
Claims (10)
1. a kind of Choline Chloride Succinate freezes combination preparation, it is characterised in that the combination preparation is made up of lyophilized formulations and solvent,
Both at independent packaging, wherein, lyophilized formulations are made up of Choline Chloride Succinate, freeze-dried excipient, and lyophilized formulations add solvent
Decoction pH value after redissolution between 5.5-7.0, wherein, freeze-dried excipient be selected from water miscible amino acid, oligopeptides, lactose, sugarcane
Mixture more than one or both of sugar, mannose, maltose, mannitol, trehalose, dextran.
2. lyophilized combination preparation according to claim 1, it is characterised in that Choline Chloride Succinate and lyophilized in lyophilized formulations
The weight ratio of excipients is 1.0:0.0~1.0:10.0, preferably 1:1.
3. lyophilized combination preparation according to claim 1, it is characterised in that lyophilized formulations in preparation process with weak acid,
Or faintly acid salt regulation pH value, pH scopes are 3.5-5.
4. lyophilized combination preparation according to claim 1, it is characterised in that water miscible amino acid is neutral amino acid,
Selected from glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, silk ammonia
Acid, phenylalanine, tyrosine, tryptophan, proline, methionine and hydroxyproline；Or be acidic amino acid, selected from asparagus fern ammonia
Acid, glutamic acid；Or be basic amino acid, selected from lysine, arginine, histidine.
5. lyophilized combination preparation according to claim 1, it is characterised in that solvent is selected from：Acetate, phosphoric acid hydrogen disalt,
Carbonate, citrate, tartrate, maleate, sodium chloride, the aqueous solution of glucose can be one of them, two kinds or
Two or more mixtures；Can also be acetic acid-acetate buffer, the dihydric phosphate-salt buffer of phosphoric acid hydrogen two, bicarbonate
Salt-carbonate buffer solution, acid-citrate buffer solution, tartaric acid-tartrate buffer, maleic acid-maleate delay
One of fliud flushing, two or more mixture.
6. lyophilized combination preparation according to claim 1, it is characterised in that solvent is selected from：Phosphoric acid hydrogen disalt, citric acid
Salt, tartrate, maleate, sodium chloride, the aqueous solution of glucose can be one of them, two or more mixed
Compound；Can also be dihydric phosphate-salt buffer of phosphoric acid hydrogen two, acid-citrate buffer solution, tartaric acid-tartaric acid
Salt buffer, maleic acid-maleate buffers can be one of them, two or more mixture.
7. lyophilized combination preparation according to claim 1, it is characterised in that solvent or excipient, can be sodium salt, calcium
One or more of mixture in salt, zinc salt.
8. lyophilized combination preparation according to claim 1, it is characterised in that the formula composition of lyophilized formulations is as follows：Chlorination
Scoline, 200mg mannitol, 250mg；Tartaric acid, 30mg；Sodium tartrate, 40mg.
9. lyophilized combination preparation according to claim 1, it is characterised in that formula composition is as follows：
Lyophilized formulations：Choline Chloride Succinate 20g, glycine 20g, preparation specification：200mg/ branch；
Solvent：Histidine 8.5g, appropriate sodium chloride, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, glycine 10g, sodium dihydrogen phosphate 2g, preparation specification：200mg/ branch；
Solvent：Appropriate sodium chloride, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, glycine 10g, sodium dihydrogen phosphate 2g, preparation specification：200mg/ branch；
Solvent：Histidine 5g, disodium hydrogen phosphate 2g, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, glutamic acid 8g, citric acid 2g, preparation specification：200mg/ branch；
Solvent：Disodium hydrogen phosphate 4g, sodium dihydrogen phosphate 1g, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, citric acid 2g, preparation specification：200mg/ branch；
Solvent：Sodium citrate 5g, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, mannitol 25g, maleic acid 1g, preparation specification：200mg/ branch；
Solvent：Sodium maleate 5g, water for injection add to 400mL, solvent specification：10ml/ branch, or
Lyophilized formulations：Choline Chloride Succinate 20g, proline 10g, serine 20g, preparation specification：200mg/ branch；
Solvent：Tartaric acid 1g, sodium tartrate 5g, water for injection add to 400mL, solvent specification：10ml/ branch.
10. the preparation method of the lyophilized combination preparation described in claim 1, it is characterised in that comprise the following steps：
1) lyophilized formulations：Recipe quantity is freezed into excipients to be dissolved completely with appropriate water for injection, adds the chlorination of recipe quantity
Scoline, less than 25 DEG C mix dissolving, stir, and measure the pH of solution in 3.5-5, aseptic filtration, packing, lyophilized, pressure
Fill in, roll lid, packaging, 2-8 DEG C of storage；
2) solvent, the auxiliary material of recipe quantity is dissolved with water for injection complete, filtering, packing, tamponade, rolls lid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108663456A (en) * | 2018-06-15 | 2018-10-16 | 安徽医科大学 | The detection method of Choline Chloride Succinate in a kind of peripheral blood |
| CN110698355A (en) * | 2019-11-13 | 2020-01-17 | 上海旭东海普药业有限公司 | Refining method of succinylcholine chloride |
| CN113368065A (en) * | 2021-06-29 | 2021-09-10 | 上海轩耘生物医药科技有限公司 | Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof |
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| WO2007061529A1 (en) * | 2005-11-18 | 2007-05-31 | Scidose Llc. | Lyophilization process and products obtained thereby |
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| WO2007061529A1 (en) * | 2005-11-18 | 2007-05-31 | Scidose Llc. | Lyophilization process and products obtained thereby |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108663456A (en) * | 2018-06-15 | 2018-10-16 | 安徽医科大学 | The detection method of Choline Chloride Succinate in a kind of peripheral blood |
| CN108663456B (en) * | 2018-06-15 | 2020-10-30 | 安徽医科大学 | Method for detecting succinylcholine chloride in peripheral blood |
| CN110698355A (en) * | 2019-11-13 | 2020-01-17 | 上海旭东海普药业有限公司 | Refining method of succinylcholine chloride |
| CN110698355B (en) * | 2019-11-13 | 2021-02-19 | 上海旭东海普药业有限公司 | Refining method of succinylcholine chloride |
| CN113368065A (en) * | 2021-06-29 | 2021-09-10 | 上海轩耘生物医药科技有限公司 | Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof |
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