CN102579374B - Preparation process of penehyclidine hydrochloride powder for injection - Google Patents
Preparation process of penehyclidine hydrochloride powder for injection Download PDFInfo
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- CN102579374B CN102579374B CN 201210094262 CN201210094262A CN102579374B CN 102579374 B CN102579374 B CN 102579374B CN 201210094262 CN201210094262 CN 201210094262 CN 201210094262 A CN201210094262 A CN 201210094262A CN 102579374 B CN102579374 B CN 102579374B
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Abstract
The invention discloses a preparation process of penehyclidine hydrochloride powder for injection, and belongs to the field of medical products. The process comprises the following steps: weighing penehyclidine hydrochloride and excipient; dissolving with injection water; regulating the pH value with hydrochloric acid solution; adding injection water to full dose; measuring the pH and content; filtering the liquid medicine through a 0.22mu m filter membrane, and subpackaging into aseptic penicillin bottles; and carrying out freeze drying; closing a butyl rubber stopper, and rolling an aluminum cap. The preparation prepared by the method has more stable pH value, related substances and content, and lower toxicity, so that the safety and efficiency of the penehyclidine hydrochloride and product quality are easier to be ensured.
Description
Technical field
The present invention relates to a kind of preparation technology of hydrochloride for injection amyl ethyl quin ether, be specifically related to the preparation technology of amyl ethyl quin ether hydrochloride injectable powder, belong to the medical drugs field.
Background technology
Amyl ethyl quin ether hydrochloride is the new selective anticholinergic agent, can enter in the brain by blood brain barrier.Its energy blockage of acetylcholine is to the agonism of M-ChR in the brain and nicotine receptor; Therefore, the maincenter poisoning symptom that preferably antagonism organophosphorus poison poisoning causes is such as convulsions, maincenter respiratory and circulatory failure and dysphoria etc.Simultaneously, stronger blockage of acetylcholine is also arranged to the agonism of m receptor in periphery; Thereby the muscarinic poisoning symptom that preferably antagonism organophosphorus poison (pesticide) poisoning causes is such as bronchial muscular spasm and secretions increase, perspiration, curtain coating, myosis and gastrointestinal smooth muscle spasm or contraction etc.It can also increase respiratory frequency and respiratory flow, but since this product to the M2 receptor without obvious effect, therefore heart rate is had no significant effect; To the periphery n receptor without obvious antagonism.
Amyl ethyl quin ether hydrochloride belongs to the raw material variety that Chengdu Lisite Pharmaceutical Co., Ltd. exclusively has, but only has at present a kind of dosage form of penehyclidine hydrochloride injection.Find through for many years producing and selling and use, penehyclidine hydrochloride injection exists pH value and related substance to raise the weak point of content decrease after high temperature sterilize or long-term storage.
Injectable powder is the dosage form of present comparative maturity, because medicine exists with solid forms, has reduced the chance of touching between drug molecule, thereby has reduced the response speed of labile drug, makes it more stable.
Freeze-drying is to produce one of injectable powder conventional route, and production equipment is numerous, and superior performance is suitable for large-scale production.But because different its processing parameters of kind is all not identical, therefore need to be by constantly groping just to provide its corresponding working condition.
For solving the unsettled problem of penehyclidine hydrochloride injection, find by long term test research, after amyl ethyl quin ether hydrochloride made injectable powder, its pH value, related substance and content all can keep stable in a long time, thereby have guaranteed stability and the efficacy of product.
Through retrieval, still find no the solution and the pertinent literature report that propose for the problems referred to above at present.
Summary of the invention
The present invention is intended to solve existing penehyclidine hydrochloride injection after high temperature sterilize or long-term storage, and its pH value and related substance raise, the problem of content decrease, and a kind of preparation technology of penehyclidine hydrochloride powder injection for injecting is provided.The hydrochloride for injection amyl ethyl quin ether product that is obtained by this process is more stable aspect pH, content and the related substance, and product quality and drug effect more easily are guaranteed.
For achieving the above object, the concrete technical scheme of the present invention's employing is:
A kind of preparation technology of penehyclidine hydrochloride powder injection for injecting is characterized in that: processing step is as follows:
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride and excipient, be dissolved in water for injection, add hydrochloric acid solution and regulate pH value to 4.0～8.0, then add the water injection water to full dose, add again pin an amount of with activated carbon, stir, first coarse filtration decarburization, use again the filtering with microporous membrane of 0.22 μ m to clear and bright, namely get the amyl ethyl quin ether hydrochloride medicinal liquid.
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; The condition of described sterilization and mode are: 180 ℃ of 1.5h or 320 ℃ of 5min of tunnel type dry heat sterilization.
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of sterilizations of steam 40min, 120 ℃ of oven dry, for subsequent use.
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization.
D, lyophilization: under gnotobasis, the condenser temperature of freeze dryer is opened to below-50 ℃ first, carry out pre-freeze, below eutectic temperature, carry out No. one time again vacuum drying, after 80% ~ 95% moisture is taken away, carry out again the secondary vacuum drying, behind dry the end, cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product.
The described excipient of steps A is one or more any mixture in mannitol, glycine, dextran, xylitol, polyvidone, the lactose.
The ratio of the described excipient of steps A and amyl ethyl quin ether hydrochloride is 100 ~ 200g:1g.
The described pre-freeze temperature of steps d is :-60 ℃～-20 ℃.
The described vacuum drying temperature of steps d is-40 ℃～-10 ℃.
The described secondary vacuum baking temperature of steps d is 10 ℃～50 ℃.
The invention has the advantages that:
With respect to prior art: because aseptic for guaranteeing in amyl ethyl quin ether hydrochloride injection production process, pass through high temperature sterilize, by aseptic filtration, therefore resulting product is all unstable because of its pH value, related substance and content after high temperature sterilize or long-term the placement, and makes product quality can not get effective assurance.
And adopt the inventive method in preparation penehyclidine hydrochloride powder injection for injecting process, owing to having avoided high temperature sterilize, the injectable powder that makes simultaneously exists with solid forms, thereby in long-term put procedure, effectively reduce the touch opportunity between material, thereby reduced the speed of reaction, guaranteed the stable of its pH value, related substance and content.
Show by effect experiment: the amyl ethyl quin ether hydrochloride injectable powder that the present invention makes is consistent with the drug effect of its injection; Toxicological test proves that also the acute toxicity of injectable powder is better than injection simultaneously.
The quality of safety, effectiveness and the product of the amyl ethyl quin ether hydrochloride powder ampoule agent for injection that is made by the inventive method more easily is guaranteed.
Below in conjunction with experiment the present invention made and to further specify:
Test 1: the contrast of content, related substance and pH value before and after the penehyclidine hydrochloride injection sterilization
Prescription: (specification: 1ml: 1mg)
Amyl ethyl quin ether hydrochloride 0.1g
Water for injection adds to 100ml
The preparation of test specimen: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, regulate pH=4.52 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.56, content=99.4%, related substance 0.02%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and the sealing compound sealing is for subsequent use.
Sterilize by following three conditions
1. 100 ℃, 30 minutes
2. 115 ℃, 20 minutes
3. 121 ℃, 15 minutes
The results are shown in Table 1
Table 1 high temperature sterilize is on the impact of penehyclidine hydrochloride injection quality
Note: the labelled amount that content refers to, its acceptability limit interval is 90%-110% of labelled amount.
The result: experimental study shows the raising along with sterilising conditions, and the penehyclidine hydrochloride injection pH value raises, content decrease, and related substance raises.
Test 2: penehyclidine hydrochloride injection and the contrast of aseptic powder injection stability
The hydrochloride for injection amyl ethyl quin ether sample of getting the preparation of penehyclidine hydrochloride injection and this law carries out accelerated test and long-term stable experiment.
The accelerated test condition: get test sample and put in the clean container, relative humidity 75% ± 5% was placed 6 months under 40 ℃ ± 2 ℃ temperature, in 1st month, 2 months, 3 months and 6th month pick test.
The long term test condition: 25% ± 2 ℃ of temperature, placed under the condition that relative humidity is 65% ± 10 ℃ 72 months, take a sample to check respectively at 12 months, 24 months, 36 months, 48 months, the result sees Table respectively 2, table 3
Table 2 accelerated test result
Table 3 long-term test results
Note: the labelled amount that content refers to, its acceptability limit interval is 90%-110% of labelled amount.
The result: be studies show that by stability experiment, variation is all occuring in passing penehyclidine hydrochloride injection in time aspect pH value, content and the related substance.And injection is all stable aspect pH value, content and related substance with amyl ethyl quin ether hydrochloride
Test 3: drug effect proves the concordance of this preparation and former preparation drug effect
The hydrochloride for injection amyl ethyl quin ether that adopts the present invention to produce is done pharmacological testing, injection all has obvious inhibitory action with amyl ethyl quin ether hydrochloride to the spontaneous contractions of the Guinea pig Gastric that exsomatizes, ileum, colon, gallbladder, bladder as a result, spastic contraction to above-mentioned isolated organ, anesthetized animal, the above-mentioned organ of sobering animal due to the acetylcholine (Ach) all has obvious relexation, in the spastic contraction to above-mentioned organ due to the Ach, ED during the relexation of stomach exsomatized
50Large than atropine, then strong than atropine to the in vitro bladder effect, all the other effects and atropine zero difference.But at anesthetized animal and sobering animal, the hydrochloride for injection amyl ethyl quin ether is strong than atropine to the relexation of stomach, ileum, colon, the spastic contraction of gallbladder.The relexation in the contraction of body cystospasm of in vitro bladder, anesthetized animal and sobering animal (intramuscular administration) obviously is better than atropine due to the Ach of hydrochloride for injection amyl ethyl quin ether.With penehyclidine hydrochloride injection without significant difference.
Show that this preparation technology does not affect drug effect, consistent with former injection drug effect.
Test 4: acute toxicity test shows that this preparation is better than former preparation
Behind rat, mice intramuscular injection hydrochloride for injection amyl ethyl quin ether or the penehyclidine hydrochloride injection, nervous, uneasy, activity minute occurring respectively at 3-5 minute, 15-20 increases, during the intramuscular injection larger dose, dyspnea and tic can occur, cyanosis occur individually and die from respiratory failure.The animal that dead animal and survival were put to death in 7 days afterwards, gross necropsy is showed no unusually, the results are shown in Table 4
The anxious malicious result of the test of table 4 penehyclidine hydrochloride injection and hydrochloride for injection amyl ethyl quin ether
Test shows: hydrochloride for injection amyl ethyl quin ether mice LD
50With rat LD
50Apparently higher than penehyclidine hydrochloride injection, show that acute toxicity is better than penehyclidine hydrochloride injection.
Test 5: long term toxicity test shows consistent with former preparation
Rat and Canis familiaris L. difference intramuscular injection hydrochloride for injection amyl ethyl quin ether or penehyclidine hydrochloride injection 0.68,3.28,13.50 and 0.015,0.9mg/kg, every day 1 time, continuous 12 all administrations, some common cholinolytic reactions appearred after 1 week, along with administration time prolongs, above-mentioned reaction is without obviously increasing the weight of, after drug withdrawal a couple of days to disappearing in 2 weeks, in the administration phase and behavioral activity, appetite and body weight, feces character, hematology and blood biochemistry checking, system's postmortem and histological examination after 1 week of drug withdrawal all without obvious change.Hydrochloride for injection amyl ethyl quin ether and penehyclidine hydrochloride injection long term toxicity test show without significant difference.
Test shows: hydrochloride for injection amyl ethyl quin ether and penehyclidine hydrochloride injection are consistent aspect the long term toxicity.
The specific embodiment
Embodiment 1
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride 0.1g and mannitol 10g, inject water 80ml, add hydrochloric acid solution and regulate pH value to 5.42, add water to 100ml, add again pin activated carbon 0.1g, stir, 60 ℃ of insulation absorption, elder generation's coarse filtration decarburization is again with the filtering with microporous membrane of the 0.22 μ m clear and bright amyl ethyl quin ether hydrochloride medicinal liquid that namely gets extremely.
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; Condition and the mode of sterilization are: 320 ℃ of 5min of tunnel type dry heat sterilization.
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of the pure steam 40min that sterilizes, 120 ℃ of oven dry, for subsequent use.
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization.
D, lyophilization: under gnotobasis, first the condenser temperature of freeze dryer is opened to-50 ℃, carried out pre-freeze, carry out vacuum drying No. one time at-20 ℃ again, after 48 hours, rising condenser temperature to 20 ℃ carries out the secondary vacuum drying, and after 24 hours, lyophilization finishes; Cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product.
Embodiment 2
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride 0.1g and mannitol 15g, inject water 80ml, add hydrochloric acid solution and regulate pH value to 5.36, add water to 100ml, add again pin activated carbon 0.1g, stir, 65 ℃ of insulation absorption, elder generation's coarse filtration decarburization is again with the filtering with microporous membrane of the 0.22 μ m clear and bright amyl ethyl quin ether hydrochloride medicinal liquid that namely gets extremely.
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; Condition and the mode of sterilization are: 180 ℃ of 1.5h of dry heat sterilization.
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of the pure steam 40min that sterilizes, 120 ℃ of oven dry, for subsequent use.
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization.
D, lyophilization: under gnotobasis, first the condenser temperature of freeze dryer is opened to-60 ℃, carried out pre-freeze, carry out vacuum drying No. one time at-25 ℃ again, after 48 hours, rising condenser temperature to 25 ℃ carries out the secondary vacuum drying, and after 24 hours, lyophilization finishes; Cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product.
Embodiment 3
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride 0.1g and xylitol 20g, inject water 80ml, add hydrochloric acid solution and regulate pH value to 8.0, add water to 100ml, add again pin activated carbon 0.1g, stir, 70 ℃ of insulation absorption, elder generation's coarse filtration decarburization is again with the filtering with microporous membrane of the 0.22 μ m clear and bright amyl ethyl quin ether hydrochloride medicinal liquid that namely gets extremely.
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; Condition and the mode of sterilization are: 320 ℃ of 5min of tunnel type dry heat sterilization.
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of the pure steam 40min that sterilizes, 120 ℃ of oven dry, for subsequent use.
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization.
D, lyophilization: under gnotobasis, first the condenser temperature of freeze dryer is opened to-50 ℃, carried out pre-freeze, carry out vacuum drying No. one time at-40 ℃ again, after 48 hours, rising condenser temperature to 10 ℃ carries out the secondary vacuum drying, and after 24 hours, lyophilization finishes; Cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product.
Embodiment 4
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride 0.1g and glycine 12g, inject water 80ml, add hydrochloric acid solution and regulate pH value to 4.0, add water to 100ml, add again pin activated carbon 0.1g, stir, 75 ℃ of insulation absorption, elder generation's coarse filtration decarburization is again with the filtering with microporous membrane of the 0.22 μ m clear and bright amyl ethyl quin ether hydrochloride medicinal liquid that namely gets extremely.
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; Condition and the mode of sterilization are: 320 ℃ of 5min of tunnel type dry heat sterilization.
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of the pure steam 40min that sterilizes, 120 ℃ of oven dry, for subsequent use.
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization.
D, lyophilization: under gnotobasis, first the condenser temperature of freeze dryer is opened to-50 ℃, carried out pre-freeze, carry out vacuum drying No. one time at-10 ℃ again, after 48 hours, rising condenser temperature to 50 ℃ carries out the secondary vacuum drying, and after 24 hours, lyophilization finishes; Cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product.
Claims (5)
1. the preparation technology of a penehyclidine hydrochloride powder injection for injecting, it is characterized in that: processing step is as follows:
The preparation of A, amyl ethyl quin ether hydrochloride sterile solution
Take by weighing amyl ethyl quin ether hydrochloride and excipient, be dissolved in water for injection, add hydrochloric acid solution and regulate pH value to 4.0～8.0, then add the water injection water to full dose, add again pin an amount of with activated carbon, stir, first coarse filtration decarburization, use again the filtering with microporous membrane of 0.22 μ m to clear and bright, namely get the amyl ethyl quin ether hydrochloride medicinal liquid;
The lyophilization of B, amyl ethyl quin ether hydrochloride sterile solution
A, vial process: with the vial ultrasonic waves for cleaning, after the pure water rinsing, wash with water for injection, 4 hours inner dryings and sterilization get clean, aseptic, dry, apyrogenic vial again; The condition of described sterilization and mode are: 180 ℃ of 1.5h or 320 ℃ of 5min of tunnel type dry heat sterilization;
B, plug process: with plug with dilute hydrochloric acid boil wash after, with the purified water flushing, again with the water for injection rinsing, thermal source is removed in silication after cleaning, then with 121 ℃ of sterilizations of steam 40min, 120 ℃ of oven dry, for subsequent use;
The bottling of c, medicinal liquid: after the medicinal liquid that steps A is made adopts volume quantitative, by quantitative medicinal liquid being divided in the vial of treated mistake of racking machine, simultaneously with the rubber plug cover of treated mistake on bottleneck, go to freeze dryer and prepare lyophilization;
D, lyophilization: under gnotobasis, the condenser temperature of freeze dryer is opened to below-50 ℃ first, carry out pre-freeze, below eutectic temperature, carry out No. one time again vacuum drying, after 80% ~ 95% moisture is taken away, carry out again the secondary vacuum drying, behind dry the end, cover tightly plug, roll aluminium lid, finally by lamp inspection, labeling, and sampling inspection after obtain product;
The described excipient of steps A is one or more any mixture in mannitol, glycine, dextran, xylitol, polyvidone, the lactose.
2. the preparation technology of described penehyclidine hydrochloride powder injection for injecting according to claim 1, it is characterized in that: the ratio of the described excipient of steps A and amyl ethyl quin ether hydrochloride is 100 ~ 200g:1g.
3. the preparation technology of described penehyclidine hydrochloride powder injection for injecting according to claim 1, it is characterized in that: the described pre-freeze temperature of steps d is :-60 ℃～-20 ℃.
4. the preparation technology of described penehyclidine hydrochloride powder injection for injecting according to claim 1, it is characterized in that: the described vacuum drying temperature of steps d is-40 ℃～-10 ℃.
5. the preparation technology of described penehyclidine hydrochloride powder injection for injecting according to claim 1, it is characterized in that: the described secondary vacuum baking temperature of steps d is 10 ℃～50 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101461807A (en) * | 2009-01-15 | 2009-06-24 | 成都力思特制药股份有限公司 | Application of penehyclidine hydrochloride in preparing medicament for treating haemorrhagic shock |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101461807A (en) * | 2009-01-15 | 2009-06-24 | 成都力思特制药股份有限公司 | Application of penehyclidine hydrochloride in preparing medicament for treating haemorrhagic shock |
Non-Patent Citations (4)
| Title |
|---|
| QIAO Jian-zhong等.study on pharmacokinetics of penehyclidine hydrochloride in mice.《Chinese Pharmaceutical Journal》.2003, |
| study on pharmacokinetics of penehyclidine hydrochloride in mice;QIAO Jian-zhong等;《Chinese Pharmaceutical Journal》;20031231;全文 * |
| 盐酸戊乙奎醚和阿托品对老年患者心率变异性及心率影响的比较;陈涌鸣等;《中华麻醉学杂志》;20051231(第1期);全文 * |
| 陈涌鸣等.盐酸戊乙奎醚和阿托品对老年患者心率变异性及心率影响的比较.《中华麻醉学杂志》.2005,(第1期),第59－60页. |
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