CN101199527B - Lafutidine lyophilized powder injection and preparing method thereof - Google Patents
Lafutidine lyophilized powder injection and preparing method thereof Download PDFInfo
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- CN101199527B CN101199527B CN2007101914838A CN200710191483A CN101199527B CN 101199527 B CN101199527 B CN 101199527B CN 2007101914838 A CN2007101914838 A CN 2007101914838A CN 200710191483 A CN200710191483 A CN 200710191483A CN 101199527 B CN101199527 B CN 101199527B
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Abstract
The invention relates to lafutidine freeze-dried injection, which can treat gastric ulcer, duodenal ulcer and ulcer on the anastomosed part. The lafutidine freeze-dried injection is composed of lafutidine and mannitol, wherein, the mass ratio of the lafutidine and the mannitol is 1 : 10 to 100; the preferable mass ratio is 1 : 20 to 50; and one or the mixture of sodium chloride and citrate can be added into the lafutidine freeze-dried injection so as to prevent the medicine bottle from exploding in the process of freeze-drying the lafutidine freeze-dried injection. The preparation processes are as following: the lafutidine is taken to be placed inside the aseptic container, and then the water for injection is added to be heated until the temperature reaches 70 DEG C so that the lafutidine can be dissolved in the water for injection; and then the mannitol is added to be mixed so that the mannitol can be dissolved and is mixed evenly; the content of the intermediate is measured; after the content of the intermediate is qualified, in the aseptic condition, the solution is filtered until to be clear by microporous membrane of 0.22 microns; the filtrate is filled inside the aseptic silin bottle; and part of the silin bottle is plugged by butyl rubber closure, with the posterior steps of tray filling, freeze-drying in the freeze dryer, tamponing, unpacking, mouth rolling, quality inspecting and packaging.
Description
Technical field
What the present invention relates to is a kind of Lafutidine lyophilized powder injection, can be used as the treatment of gastric ulcer, duodenal ulcer, anastomotic part ulcer by the Lafutidine lyophilized powder injection of technical solution of the present invention preparation; Can improve acute gastritis, the mucosa infection of the acute phase of cancerating of chronic gastritis (as rotten to the corn, hemorrhage, redness); Other can be used for preanesthetic medication.
Background technology
Peptic ulcer is a kind of commonly encountered diseases, frequently-occurring disease, and sickness rate accounts for 10% of population.According to " 98 years national medical medicining conditions " statistics, the 98 years ratios of the medicine hospital administration amount of money that act on digestive system increased by 74% in 97 years, and total amount reaches 72.5 hundred million yuan.
Lafutidine (lafutidine, 1) is the bisfentidine of being developed jointly by Japanese Fujiirebio and Taiho company, goes on the market in Japan first in 2000.Have lasting secretion inhibitor effect and potential mucous membrane protection effect, be mainly used in the treatment of gastric ulcer, duodenal ulcer and gastritis.
Ranitidine in the bisfentidine, famotidine and cimetidine occupy the front three of the single variety market share, and lafutidine obviously is better than said medicine as the curative effect of second filial generation bisfentidine, and be so market prospect is better, more competitive.Lafutidine can reduce the basal secretion amount of gastric acid, suppresses the gastric acid secretion of histamine, gastrin, urethane stimulation, has very strong gastric mucosal protective effect; The gastric mucosa injury healing acceleration be can make, the gastric mucosa thickness that recovers attenuation and the parietal cell quantity of minimizing comprised; Can promote gastric mucosa regeneration, increase gastric mucosal blood flow, increase the gastric mucus effect.Be applicable to gastric ulcer, duodenal ulcer, anastomotic part ulcer; Can improve acute gastritis, the mucosa infection of the acute phase of cancerating of chronic gastritis (as rotten to the corn, hemorrhage, redness); Other can be used for preanesthetic medication.
Existing lafutidine preparation all is oral formulations, because lafutidine is water insoluble, oral onset is slow, and bioavailability is low, makes the bioavailability that injection can improve lafutidine greatly.And onset is rapid, but lafutidine is water insoluble, can't be prepared into injection with commonsense method.Chinese patent 02135960.1 adopts the method that adds surfactant and organic solvent to prepare injection, because most of surfactants and organic solvent all have certain hemolytic, can increase the zest of injection to human body, what have also can cause severe anaphylactic reaction, have defective, other known technologies also all do not propose to improve the suggestion of these defectives.
Summary of the invention
The objective of the invention is provides a kind of Lafutidine lyophilized powder injection at above weak point, Lafutidine lyophilized powder injection by the technical solution of the present invention preparation, do not need to add surfactant and organic solvent, do not need to improve the lafutidine dissolubility with excessive acid yet, have minimum human body zest and maximum clinical drug safety, adopt non-terminally sterilised aseptic filtration technology as aseptic guarantee, do not need high temperature sterilize, can under hot conditions, not make the lafutidine degraded yet, clinical easy to use, redissolve rapidly, good stability can not separated out.
The chemical name of lafutidine is: (±)-2-(furfuryl sulfinyl)-N-{4-[4-(1-piperidine methyl)-2-pyridyloxy]-suitable-crotyl } acetamide, chemical structural formula is:
Lafutidine is because dissolubility is relatively poor, find by test, adopt appropriate heating (heating-up temperature is normally about 70 ℃), adopt suitable concentration (the normally following concentration of 1mg/ml), can guarantee the fine dissolving of lafutidine and in pouring process, can not separate out, but lafutidine was just almost all separated out before the solution full solidification in the freeze-drying process, and is shapeless after the lyophilizing, adds 20ml water for injection and also can't redissolve.Further test is found, add a large amount of mannitol solutions and can play Stabilization, slow down even prevent that lafutidine from separating out from solution, add a kind of or its mixture in sodium chloride and the citric acid simultaneously in order to prevent Lafutidine lyophilized powder injection fried bottle in freeze-drying process.By test, we put lafutidine in the sterile chamber, add water for injection, be heated to 70 ℃ and make its dissolving, add mannitol again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic cillin bottle, part is butyl rubber bung beyond the Great Wall, freeze dryer is opened in sabot in advance, utilizes conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when reaching 0 ℃, the product temperature begins the phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 30 ℃ the beginning parsing-desiccations, vacuum is not controlled, kept this temperature 3～5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.Do not have in the lafutidine freeze-dried powder freeze-drying process of gained and separate out, the lyophilizing postforming is good, has obtained the good crystal formation of the more conventional lyophilizing crystallization of solubility property, thereby add water for injection and redissolve rapidly, has thoroughly solved the problems referred to above that lafutidine prepares injection.
A kind of Lafutidine lyophilized powder injection is made up of lafutidine and mannitol, and the mass ratio of lafutidine and mannitol is 1: 10～100.
Described a kind of Lafutidine lyophilized powder injection, the mass ratio of lafutidine and mannitol be preferably 1: 20～and 50.
Described a kind of Lafutidine lyophilized powder injection can also add a kind of or its mixture in sodium chloride and the citric acid.
Described a kind of Lafutidine lyophilized powder injection, the mass ratio of a kind of or its mixture and mannitol in sodium chloride and the citric acid is 1: 10～100.
The preparation method of described a kind of Lafutidine lyophilized powder injection, its preparation process is:
Getting lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make its dissolving, add mannitol again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 3～5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing.
The preparation method of described a kind of Lafutidine lyophilized powder injection, the mass ratio of lafutidine and mannitol are 1: 10～100.
The preparation method of described a kind of Lafutidine lyophilized powder injection, getting lafutidine in preparation process puts in the sterile chamber, add water for injection, be heated to 70 ℃ make its dissolving after, can also add a kind of or its mixture in sodium chloride and the citric acid when adding mannitol: the mass ratio of a kind of or its mixture and mannitol in sodium chloride and the citric acid is 1: 10～100.
A kind of Lafutidine lyophilized powder injection of the present invention, do not need to add hemolytic and the anaphylaxis that surfactant and organic solvent bring by this scheme, do not need to improve the lafutidine dissolubility yet, avoided adding too much sour releasing stimulus and pain with excessive acid.Because what adopt all is the injection-grade auxiliary material that the most conventional safety has abundant assurance, thereby minimum human body zest and maximum clinical drug safety are arranged.Adopt non-terminally sterilised aseptic filtration technology as aseptic guarantee, do not need high temperature sterilize, avoided the degraded of the lafutidine that high temperature sterilize brings.Adopt special freeze-dry process, do not have in the freeze-drying process and separate out, the lyophilizing postforming is good, has obtained the good crystal formation of the more conventional lyophilizing crystallization of solubility property, redissolve rapidly, and good stability, the transfusion of redissolving can not separated out, and is clinical easy to use.The Lafutidine lyophilized powder injection its related substances that the present invention prepares gained is low, and the quality stable homogeneous is stored and transport convenient.Preparation technology of the present invention is simple, convenient feasible, good reproducibility is easy to realize industrialized great production, and freeze-drying time is short, percent defective is low, lamp inspection inspection rejects difficulty is low, saves manpower, short production cycle, lower percent defective and lower human cost, production cost is reduced significantly, can produce considerable economic and social benefit.
The specific embodiment
Further specify the present invention below by embodiment.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:
Prescription
Lafutidine 10g
Mannitol 100g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 3 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Analyse lafutidine by observation window discovery nothing before pre-freeze stage solution full solidification and go out in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 2:
Prescription
Lafutidine 10g
Mannitol 1000g
Sodium chloride 20g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol and sodium chloride again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 4 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
In freeze-drying process, find by observation window that lafutidine does not have before pre-freeze stage solution full solidification and separate out that gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 3:
Prescription
Lafutidine 10g
Mannitol 200g
Sodium chloride 5g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol and sodium chloride again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 4 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Find that by observation window no lafutidine is separated out before pre-freeze stage solution full solidification in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 4:
Prescription
Lafutidine 10g
Mannitol 500g
Sodium chloride 5g
Citric acid 10g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol again, sodium chloride and citric acid, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reaches-40 ℃, stop board is cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 4 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Find that by observation window no lafutidine is separated out before pre-freeze stage solution full solidification in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 5:
Prescription
Lafutidine 10g
Mannitol 300g
Citric acid 30g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol and citric acid again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Find that by observation window no lafutidine is separated out before pre-freeze stage solution full solidification in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 6:
Prescription
Lafutidine 10g
Mannitol 600g
Sodium chloride 6g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol and sodium chloride again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Find that by observation window no lafutidine is separated out before pre-freeze stage solution full solidification in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Embodiment 7:
Prescription
Lafutidine 10g
Mannitol 400g
Sodium chloride 5g
Citric acid 5g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Getting the recipe quantity lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make dissolving, add recipe quantity mannitol again, sodium chloride and citric acid, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 25ml cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reaches-40 ℃, stop board is cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lafutidine lyophilized powder injection.
Find that by observation window no lafutidine is separated out before pre-freeze stage solution full solidification in freeze-drying process, gained Lafutidine lyophilized powder injection profile is good after the lyophilizing, adds 10ml water for injection and redissolves rapidly.
Claims (4)
1. a Lafutidine lyophilized powder injection is characterized in that being made up of lafutidine and mannitol, and the mass ratio of lafutidine and mannitol is 1: 10～100;
The preparation method of described Lafutidine lyophilized powder injection is:
Getting lafutidine puts in the sterile chamber, add water for injection, be heated to 70 ℃ and make its dissolving, add mannitol again, stirring makes its dissolving and mix homogeneously, measure intermediate content, qualified back is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic cillin bottle, part is butyl rubber bung beyond the Great Wall, sabot, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃, rapidly the lafutidine solution of fill in aseptic cillin bottle is sent into freeze dryer until the flaggy temperature, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reached-40 ℃, stop board was cold, the open cold condenser, utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, opens vacuum system, insulation begins the distillation that heats up stage by stage after finishing, the phase I distillation rises to the flaggy temperature-10 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches-20 ℃, begin second stage distillation, rapidly the flaggy temperature is risen to 10 ℃, therebetween with preceding case vacuum control between 15～20Pa, when the product temperature reaches 0 ℃, begin phase III distillation, rapidly the flaggy temperature is risen to 35 ℃, therebetween with preceding case vacuum control between 10～15Pa, begin parsing-desiccations when the product temperature reaches 30 ℃, vacuum is not controlled, and keeps this temperature 3～5 hours, after the case vacuum does not have after the obvious decline before valve in closing, tamponade, outlet rolls mouth, quality inspection, packing.
2. a kind of Lafutidine lyophilized powder injection according to claim 1; the chemical name that it is characterized in that lafutidine is: (±)-2-(furfuryl sulfinyl)-N-{4-[4-(1-piperidine methyl)-2-pyridyloxy]-suitable-crotyl } acetamide, chemical structural formula is:
3. a kind of Lafutidine lyophilized powder injection according to claim 1, the mass ratio that it is characterized in that described lafutidine and mannitol is 1: 20～50.
4. the described a kind of Lafutidine lyophilized powder injection of claim 1 is characterized in that also adding a kind of or its mixture in sodium chloride and the citric acid;
The preparation method of described Lafutidine lyophilized powder injection is: get lafutidine and put in the sterile chamber in preparation process, add water for injection, be heated to 70 ℃ make its dissolving after, when adding mannitol, also add a kind of or its mixture in sodium chloride and the citric acid; The mass ratio of a kind of or its mixture and mannitol in described sodium chloride and the citric acid is 1: 10～100.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101914838A CN101199527B (en) | 2007-12-20 | 2007-12-20 | Lafutidine lyophilized powder injection and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2007101914838A CN101199527B (en) | 2007-12-20 | 2007-12-20 | Lafutidine lyophilized powder injection and preparing method thereof |
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| CN101199527A CN101199527A (en) | 2008-06-18 |
| CN101199527B true CN101199527B (en) | 2010-09-15 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018677A (en) * | 2010-12-28 | 2011-04-20 | 哈药集团三精制药股份有限公司 | Roxatidine acetate hydrochloride used for injection and preparation method thereof |
| CN102716083B (en) * | 2012-06-29 | 2014-02-26 | 海南美兰史克制药有限公司 | Lafutidine liposome solid preparation and preparing method thereof |
| CN103550170A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Lafutidine composition freeze-dried powder injection for injection |
| CN105362237A (en) * | 2015-12-08 | 2016-03-02 | 哈药集团三精制药有限公司 | Preparation method of roxatidine acetate hydrochloride for injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1421204A (en) * | 2002-12-04 | 2003-06-04 | 黄振华 | Lafutidine injecta and its prepn |
| CN1562972A (en) * | 2004-03-30 | 2005-01-12 | 四川科伦药业股份有限公司 | Medicinal compound for curing disease of gastrointestinal tract, preparation method and relevant medication |
| CN1649590A (en) * | 2002-04-30 | 2005-08-03 | Ucb公司 | Therapeutic agent comprising lafutidine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649590A (en) * | 2002-04-30 | 2005-08-03 | Ucb公司 | Therapeutic agent comprising lafutidine |
| CN1421204A (en) * | 2002-12-04 | 2003-06-04 | 黄振华 | Lafutidine injecta and its prepn |
| CN1562972A (en) * | 2004-03-30 | 2005-01-12 | 四川科伦药业股份有限公司 | Medicinal compound for curing disease of gastrointestinal tract, preparation method and relevant medication |
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| CN101199527A (en) | 2008-06-18 |
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Address after: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |
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