CN101199851A - Preparing method of lyophilized powder injection via high solid amount mannite accessory - Google Patents
Preparing method of lyophilized powder injection via high solid amount mannite accessory Download PDFInfo
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- CN101199851A CN101199851A CNA2007101914857A CN200710191485A CN101199851A CN 101199851 A CN101199851 A CN 101199851A CN A2007101914857 A CNA2007101914857 A CN A2007101914857A CN 200710191485 A CN200710191485 A CN 200710191485A CN 101199851 A CN101199851 A CN 101199851A
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Abstract
The invention relates to a lyophilized powder for injection which uses high-solid-content mannitol as excipient. The invention is characterized in that the invention is prepared by lyophilizing the water solution containing active medical ingredient, mannitol and hydrogen-bond-inhibited compound, wherein, the concentration of mannitol in water solution is 25-200mg/ml; the hydrogen-bond-inhibited bond can be sodium chloride or citric acid or the mixture of sodium chloride and citric acid, with the concentration in water solution being 0.25-20mg/ml. Citric acid can be added to adjust the power of hydrogen of the water solution. The preparation includes the following steps: active medical ingredient is put into a container; 80%of injection-used water is added; the compound is stirred for dissolution and mixed evenly; mannitol and hydrogen-bond-inhibited compound are added; the compound is stirred for dissolution and mixed evenly; the content of intermediate is determined; if the determination is passed, injection-used water is added to total amount for constant volume; under the sterile condition, a microporous membrane of 0.22um is used for filtering the compound to clarification; the filtered compound is put into a sterile penicillin bottle, partly plugged by a butyl rubber closure, tray-filled, sent to lyophilizer for lyophilizing, closure-pressed, taken out from the lyophilizer, encapsulated, quality-tested and packed.
Description
Technical field
What the present invention relates to is to be the lyophilized injectable powder of adjuvant with high solids content mannitol, and is that the lyophilized injectable powder of adjuvant can be used as the technology personal care medicine by technical solution of the present invention preparation with high solids content mannitol.
Background technology
The skeleton agent that lyophilized injectable powder is commonly used has lactose and mannitol, because lactose exists in the part crowd and do not tolerate, domestic in addition injection stage lactose supplier is less and do not have statutory standards of injection stage lactose, usually with mannitol as first-selected skeleton agent.Simultaneously relatively poor for dissolubility, fill volume greatly and the medicine of easily separating out, adding mannitol can play Stabilization to solution to a certain extent, and can obtain good preparation outward appearance.But mannitol itself also has its shortcoming, that is exactly to have higher fried bottle ratio in the production process of the bigger lyophilized injectable powder of the higher and canned volume of some mannitol solid content, greatly reduce the product yield, production capacity, supplementary material and inner packaging material have been caused very big waste, and because some drugs toxicity is bigger, the medicine that leaks with fried bottle damages the operator probably, also clears out a gathering place to production and has brought difficulty, has increased the risk of cross-contamination.Based on above shortcoming, prior art is generally come seeking solution by strict even harsh lyophilizing parameter control and prolongation freeze-drying time, and effect is all undesirable, waste energy, and poor reproducibility.Other known technologies also all do not propose to improve the suggestion of above defective.
Summary of the invention
The objective of the invention is to provide a kind of at above weak point is the lyophilized injectable powder of adjuvant with high solids content mannitol, reducing greatly even eliminated with high solids content mannitol fully by technical solution of the present invention is the phenomenon of exploding bottle in the lyophilized injectable powder freeze-drying process of adjuvant, improved yield, saved the energy, and lyophilizing parameter control that need not be harsh has improved the efficient of producing greatly.
Adopting high solids content mannitol is that the human medicine of the lyophilized injectable powder of adjuvant comprises: oxaliplatin, carboplatin, palonosetron Hcl, mitoxantrone hydrochloride, octreotide acetate, lafutidine, topotecan hydrochloride, thunder for song account for, along atracurium besilate, lornoxicam, zoledronic acid etc.
These medicines or since dissolubility relatively poor, fill volume is separated out greatly and easily, add mannitol and can play Stabilization to solution to a certain extent, perhaps because labelled amount is little, the lyophilizing postforming is poor, add mannitol and can obtain full good preparation outward appearance, often need to add the mannitol of higher solid content and adopt bigger canned volume, in the lyophilized injectable powder production process, have higher fried bottle ratio.Discover by TMA (thermodynamic analysis) and DSC (difference formula scanning calorimetry), mannitol is the fracture of hydrogen bond collective when heating up, volume sharply enlarges (the expansion multiple is 30 times of glass), thereby when fill volume is big, fried bottle very easily takes place, and test shows, when the Osmitrol of filling 3%, adopt similar temperature-rise period, have the bottle about 30% to burst.
A kind of is the lyophilized injectable powder of adjuvant with high solids content mannitol, aqueous solution lyophilizing by the chemical compound that contains active pharmaceutical ingredient, mannitol and inhibition hydrogen bond makes, the concentration of mannitol in aqueous solution is 25～200mg/ml, and the concentration of chemical compound in aqueous solution that suppresses hydrogen bond is 0.25～20mg/ml; Described active pharmaceutical ingredient comprise oxaliplatin, carboplatin, palonosetron Hcl, mitoxantrone hydrochloride, octreotide acetate, lafutidine, topotecan hydrochloride, thunder for bently account for, a kind of along in atracurium besilate, lornoxicam, the zoledronic acid.
Described a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, the concentration of mannitol in aqueous solution is 50～150mg/ml.
Described a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, the chemical compound that suppresses hydrogen bond is a kind of or its mixture in sodium chloride and the citric acid.
Described a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, the concentration of chemical compound in aqueous solution that suppresses hydrogen bond is 0.25～10mg/ml.
Described a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, can also add sodium citrate to regulate the acid-base value of aqueous solution in the aqueous solution of chemical compound of hydrogen bond containing active pharmaceutical ingredient, mannitol and suppress.
Described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, its preparation process is:
Get active pharmaceutical ingredient and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, the chemical compound that adds mannitol and inhibition hydrogen bond again stirs and makes its dissolving and mix homogeneously, measures intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, when sample reaches-40 ℃, stop board is cold, the open cold condenser when condenser temperature reaches-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing.
Described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, the concentration of mannitol in aqueous solution is 25～200mg/ml, the concentration of chemical compound in aqueous solution that suppresses hydrogen bond is 0.25～20mg/ml.
Described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, can also add sodium citrate to regulate the acid-base value of aqueous solution in the aqueous solution of chemical compound of hydrogen bond containing active pharmaceutical ingredient, mannitol and suppress.
The present invention is a kind of to be lyophilized injectable powder of adjuvant and preparation method thereof with high solids content mannitol, by add the chemical compound that suppresses hydrogen bond in prescription is formed is a kind of or its mixture in sodium chloride and the citric acid, the hydrogen bond that reduces greatly in the Osmitrol forms, thereby avoided with high solids content mannitol be the lyophilized injectable powder of adjuvant in preparation process because mannitol hydrogen bond collective fracture when heating up, volume sharply enlarges the fried bottle that (the expansion multiple is 30 times of glass) causes, improved the product yield, reduced production capacity, the waste of supplementary material and inner packaging material, the injury of having avoided the bigger active pharmaceutical ingredient of the toxicity of leaking to cause the operator with fried bottle, reduced and produced the difficulty of clearing out a gathering place, reduced the risk of cross-contamination.Do not need simultaneously harsh lyophilizing parameter control, need not prolong freeze-drying time, energy savings, and favorable reproducibility.Owing to broken through fried bottle to mannitol solid content and filled with solution quantitative limitation, can adopt the more solution of high solids content, the lyophilized injectable powder outward appearance of gained is better, fill larger volume solution also becomes possibility in less volumetrical cillin bottle, help with the lyophilized injectable powder employing less packaging volume of big specification medicine, and then help saving packing and cost of transportation as active component.Preparation technology of the present invention is simple, and is convenient feasible, good reproducibility, be easy to realize industrialized great production,, improved production efficiency greatly owing to when guaranteeing extremely low fried bottle rate, need not prolong freeze-drying time, production cost reduces significantly, thereby 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:
Commonsense method prepares oxaliplatin freeze-dried powder (50mg specification)
Prescription
Oxaliplatin 50g
Mannitol 300g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, fried bottle rate is 25.8%.
Embodiment 2:
Commonsense method prepares oxaliplatin freeze-dried powder (100mg specification)
Prescription
Oxaliplatin 100g
Mannitol 600g
Water for injection adds to 20000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 30ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, fried bottle rate is 43.1%.
Embodiment 3:
Oxaliplatin 50g
Mannitol 300g
Citric acid 20g
Sodium citrate 41.7g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, citric acid and sodium citrate stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, fried bottle rate is 0.2%.
Embodiment 4:
Oxaliplatin 100g
Mannitol 600g
Citric acid 40g
Sodium citrate 83.4g
Water for injection adds to 20000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, citric acid and sodium citrate stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 30ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, fried bottle rate is 0.5%.
Embodiment 5:
Prescription
Oxaliplatin 50g
Mannitol 500g
Citric acid 40g
Sodium citrate 83.4g
Water for injection adds to 20000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, citric acid and sodium citrate stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 30ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 6:
Prescription
Oxaliplatin 100g
Mannitol 960g
Citric acid 160g
Sodium citrate 333.6g
Water for injection adds to 16000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, citric acid and sodium citrate stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 30ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 7:
Prescription
Oxaliplatin 50g
Mannitol 1600g
Citric acid 160g
Sodium citrate 333.6g
Water for injection adds to 8000ml
Make 1000 bottles altogether
Get oxaliplatin and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol again, citric acid and sodium citrate stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 3 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 8:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 9:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 10:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 11:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 12:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 13:
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, does not have fried bottle, adds 10ml water for injection and redissolves rapidly.
Embodiment 14:
Prescription
Carboplatin 100g
Mannitol 500g
Sodium chloride 2.5g
Water for injection adds to 10000ml
Make 1000 bottles altogether
Card taking platinum is put in the container, adds the water for injection of 80% amount, stirs to make its dissolving and mix homogeneously, add mannitol and sodium chloride again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 4 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 15:
Prescription
Lornoxicam 8g
Mannitol 300g
Sodium chloride 1.5g
Water for injection adds to 6000ml
Make 1000 bottles altogether
Get lornoxicam and put in the container, add the water for injection of 80% amount, stirring is regulated pH value down and is made its dissolving and mix homogeneously, add mannitol and sodium chloride again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 10ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 4 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 16:
Prescription
Palonosetron Hcl 0.25g
Mannitol 200g
Sodium chloride 2.5g
Water for injection adds to 5000ml
Make 1000 bottles altogether
Get palonosetron Hcl and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, add mannitol and sodium chloride again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 10ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 4 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Embodiment 17:
Prescription
Thunder accounts for 2g for song
Mannitol 250g
Citric acid 6g
Water for injection adds to 6000ml
Make 1000 bottles altogether
Get thunder and account for and put in the container for song, add the water for injection of 80% amount, stirring is regulated pH value down and is made its dissolving and mix homogeneously, add mannitol and citric acid again, stir and make its dissolving and mix homogeneously, measure intermediate content, qualified back is settled to full dose with water for injection, and is under aseptic condition, extremely clear and bright with 0.22 μ m filtering with microporous membrane, the filtrate fill is in aseptic 10ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, and when sample reached-40 ℃, stop board was cold, the open cold condenser, when condenser temperature reaches-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keep this temperature after 4 hours, tamponade, outlet, roll mouth, do not have fried bottle.
Claims (8)
1. one kind is the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that making by the aqueous solution lyophilizing of the chemical compound that contains active pharmaceutical ingredient, mannitol and inhibition hydrogen bond, the concentration of mannitol in aqueous solution is 25～200mg/ml, and the concentration of chemical compound in aqueous solution that suppresses hydrogen bond is 0.25～20mg/ml; Described active pharmaceutical ingredient comprise oxaliplatin, carboplatin, palonosetron Hcl, mitoxantrone hydrochloride, octreotide acetate, lafutidine, topotecan hydrochloride, thunder for bently account for, a kind of along in atracurium besilate, lornoxicam, the zoledronic acid.
2. according to claim 1 a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that the concentration of described mannitol in aqueous solution is 50～150mg/ml.
3. according to claim 1 a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, the chemical compound that it is characterized in that described inhibition hydrogen bond is a kind of or its mixture in sodium chloride and the citric acid.
4. according to claim 1 a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that the concentration of chemical compound in aqueous solution of described inhibition hydrogen bond is 0.25～10mg/ml.
5. according to claim 1 a kind of be the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that can also adding sodium citrate to regulate the acid-base value of aqueous solution in the aqueous solution of chemical compound of hydrogen bond containing active pharmaceutical ingredient, mannitol and suppress.
Claim 1 described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that preparation process is:
Get active pharmaceutical ingredient and put in the container, add the water for injection of 80% amount, stir and make its dissolving and mix homogeneously, the chemical compound that adds mannitol and inhibition hydrogen bond again stirs and makes its dissolving and mix homogeneously, measures intermediate content, qualified back is settled to full dose with water for injection, and 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, and part is butyl rubber bung beyond the Great Wall, sabot, send into freeze dryer, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, the product relaxing the bowels with purgatives of warm nature of making falls, when sample reaches-40 ℃, stop board is cold, the open cold condenser when condenser temperature reaches-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 35 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing.
7. according to claim 6 described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that the concentration of mannitol in aqueous solution is 25～200mg/ml, the concentration of chemical compound in aqueous solution that suppresses hydrogen bond is 0.25～20mg/ml.
8. according to claim 6 described a kind of be the preparation method of the lyophilized injectable powder of adjuvant with high solids content mannitol, it is characterized in that can also adding sodium citrate to regulate the acid-base value of aqueous solution in the aqueous solution of chemical compound of hydrogen bond containing active pharmaceutical ingredient, mannitol and suppress.
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| CNA2007101914857A CN101199851A (en) | 2007-12-20 | 2007-12-20 | Preparing method of lyophilized powder injection via high solid amount mannite accessory |
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| CNA2007101914857A CN101199851A (en) | 2007-12-20 | 2007-12-20 | Preparing method of lyophilized powder injection via high solid amount mannite accessory |
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| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
| CN102416001A (en) * | 2011-12-09 | 2012-04-18 | 重庆煜澍丰医药有限公司 | Octreotide acetate freeze-dried powder injection for injection and preparation method thereof |
| CN102475685A (en) * | 2010-11-29 | 2012-05-30 | 天津市汉康医药生物技术有限公司 | Sitafloxacin medicament composition for injection and preparation method thereof |
| CN102526700A (en) * | 2011-12-31 | 2012-07-04 | 江苏奥赛康药业股份有限公司 | Octreotide acetate freeze-dried combination for injection and preparation method thereof |
| CN102048705B (en) * | 2009-11-10 | 2012-07-18 | 齐鲁制药有限公司 | Palonosetron hydrochloride orally disintegrating tablet and preparation method thereof |
| CN102846558A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Lornoxicam freeze-drying preparation and preparation method thereof |
| CN103070832A (en) * | 2012-10-27 | 2013-05-01 | 江苏华泰晨光药业有限公司 | Cisatracurium besylate lyophilized preparation composition stable at room temperature and preparation method thereof |
| CN103932996A (en) * | 2014-05-15 | 2014-07-23 | 严白双 | Injection octreotide acetate lyophilized composition and preparation method thereof |
| CN104274827A (en) * | 2013-07-01 | 2015-01-14 | 上海贺普药业股份有限公司 | He Pula peptide preparation |
| CN111135148A (en) * | 2019-10-22 | 2020-05-12 | 健进制药有限公司 | Preparation method of topotecan hydrochloride freeze-dried preparation for injection |
| CN111346214A (en) * | 2020-05-13 | 2020-06-30 | 吉林吉力生物技术研究有限公司 | Octreotide acetate freeze-dried powder injection for animal injection and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
| CN102048705B (en) * | 2009-11-10 | 2012-07-18 | 齐鲁制药有限公司 | Palonosetron hydrochloride orally disintegrating tablet and preparation method thereof |
| CN102475685A (en) * | 2010-11-29 | 2012-05-30 | 天津市汉康医药生物技术有限公司 | Sitafloxacin medicament composition for injection and preparation method thereof |
| CN102416001A (en) * | 2011-12-09 | 2012-04-18 | 重庆煜澍丰医药有限公司 | Octreotide acetate freeze-dried powder injection for injection and preparation method thereof |
| CN102416001B (en) * | 2011-12-09 | 2013-06-05 | 重庆煜澍丰医药有限公司 | Octreotide acetate freeze-dried powder injection for injection and preparation method thereof |
| CN102526700A (en) * | 2011-12-31 | 2012-07-04 | 江苏奥赛康药业股份有限公司 | Octreotide acetate freeze-dried combination for injection and preparation method thereof |
| CN102846558B (en) * | 2012-09-20 | 2014-08-20 | 浙江亚太药业股份有限公司 | Lornoxicam freeze-drying preparation and preparation method thereof |
| CN102846558A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Lornoxicam freeze-drying preparation and preparation method thereof |
| CN103070832A (en) * | 2012-10-27 | 2013-05-01 | 江苏华泰晨光药业有限公司 | Cisatracurium besylate lyophilized preparation composition stable at room temperature and preparation method thereof |
| US10603352B2 (en) | 2013-07-01 | 2020-03-31 | Shanghai Hep Pharmaceutical Co., Ltd. | Formulations of hepalatide |
| CN104274827A (en) * | 2013-07-01 | 2015-01-14 | 上海贺普药业股份有限公司 | He Pula peptide preparation |
| CN104274827B (en) * | 2013-07-01 | 2020-07-14 | 上海贺普药业股份有限公司 | Formulations of He Pula peptide |
| CN103932996B (en) * | 2014-05-15 | 2015-12-02 | 南京正宽医药科技有限公司 | A kind of Octreotide acetate freeze-dried combination for injection and preparation method thereof |
| CN103932996A (en) * | 2014-05-15 | 2014-07-23 | 严白双 | Injection octreotide acetate lyophilized composition and preparation method thereof |
| CN111135148A (en) * | 2019-10-22 | 2020-05-12 | 健进制药有限公司 | Preparation method of topotecan hydrochloride freeze-dried preparation for injection |
| CN111346214A (en) * | 2020-05-13 | 2020-06-30 | 吉林吉力生物技术研究有限公司 | Octreotide acetate freeze-dried powder injection for animal injection and preparation method and application thereof |
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