CN101313894A - Freeze-dried injection of proton pump inhibitor - Google Patents
Freeze-dried injection of proton pump inhibitor Download PDFInfo
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- CN101313894A CN101313894A CNA2008101227604A CN200810122760A CN101313894A CN 101313894 A CN101313894 A CN 101313894A CN A2008101227604 A CNA2008101227604 A CN A2008101227604A CN 200810122760 A CN200810122760 A CN 200810122760A CN 101313894 A CN101313894 A CN 101313894A
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- pump inhibitor
- proton pump
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Abstract
The invention relates to a proton pump inhibitor frozen powder injection agent and a preparation method thereof. The proton pump inhibitor frozen powder injection agent prepared by the method can be taken as a medicine for treating gastric ulcer, duodenal ulcer, erosive gastroesophageal reflux disease, helicobacter pylori and Zollinger-Ellison Syndrome. The proton pump inhibitor frozen powder injection agent is prepared through taking a proton pump inhibitor as an active ingredient, adopting crystallized filtration, freezing and drying. The preparation process comprises the following steps of: adding water for injection and alkali to the proton pump inhibitor, stirring to dissolve and mix uniformly; performing the crystallized filtration; after measuring the content, adjusting pH value of filtrate; using the water for injection for fixing volume and a millipore filter with 0.22 mu m for filtration; filling, partially arranging corks, arranging in trays, freezing out, pressing the corks, taking out from boxes, rolling openings, checking quality and packaging. The prepared proton pump inhibitor frozen powder injection agent has excellent re-dissolving performance, is more stable when used together with transfusion in clinical use, can not separate out, and has better inspection result for visible foreign matters and insoluble particles.
Description
Technical field
What the present invention relates to is a kind of preparation method of lyophilized injectable powder of proton pump inhibitor, can be used as the medicine of gastric ulcer, duodenal ulcer, erosive stomach-esophageal reflux disease, helicobacter pylori, tall and erect Emhorn (Zollimger-ellison) syndrome by the Lansoprazole freeze-dried injection of this method preparation.
Background technology
The digestive system disease is one of common frequently-occurring disease, and wherein Peptic Ulcers is for the most common, and its total incidence accounts for 10～12% of population, and main age of onset is 30～50 years old.The U.S. has 400,000 person-times to suffer from peptic ulcers every year, mainly because smoking, drink, nervous, medicine irritation (as ASP, indometacin, piroxicam etc.) causes that U.S. male sickness rate is 10%, the women is 5%.Japan's gastrointestinal tract sickness rate is 5～10%, and Germany is 12.3%.China is 11.43% according to minority ground finding, and Shanghai resident's prevalence is up to 30.23% (Beijing, Sichuan, Liaoning Province are 23.66%), and wherein the sick sickness rate of digestive tract ulcer is 4.54%.From global marketing market, according to the MIDS system statistics of IMS HEALTH, treatment Peptic Ulcers medicine is sure to occupy global marketing volume first place always.
Nearly more than ten years anti-ulcer medicament research has trended towards the excretory medicine of energy selectivity gastric acid inhibitory, proton pump inhibitor (the PPI)-H of the exploitation listing eighties
+/ K
+-APT enzyme inhibitor, because of its mechanism of action uniqueness, effect specificity height, action intensity is big and the time is long, is widely used in sour relevant various disorder diseases to be favored day by day.
The kind of the domestic and international exploitation of proton pump inhibitor at present mainly contains Omeprazole Sodium, S-Omeprazole Sodium, Pantoprazole Sodium, S-Pantoprazole Sodium, lansoprazole, RABEPRAZOLE SODIUM, leminoprazole and Tenatoprazole etc.
Because proton pump inhibitor is very easily degraded in sour environment; so common proton pump inhibitor oral formulations all adopts the mode of enteric coating to prevent that active component from degrading in gastric acid; enteric coating makes also that in the protection active component acid effect that presses down of proton pump inhibitor is postponed; be unfavorable for treatment in time and remove patient's misery rapidly; thereby it need be prepared into injection; but because the proton pump inhibitor stability of solution is poor; and can not high temperature sterilize, can only adopt freeze-drying to prepare its injection.In development process, find, adopt the proton pump inhibitor lyophilized injectable powder redissolution back visible foreign matters and the particulate matter check result of the preparation of ordinary preparation method undesirable, when particularly adopting clinical use to infuse compatibility, there are a large amount of fine particles to occur, diameter can block blood flow by pulmonary capillary the time at 5-20 micron and above granule, thereby cause as pulmonary infarction complication even worried dead, exogenous granule also can form phlebitis in the injection site, may cause that also vein blood vessel blocks and patient's injury, have a strong impact on clinical drug safety.The lansoprazole of U.S.'s listing (
) injection adds when proposing clinical use that to join micropore size be that 1.2 μ m disposable filters come the above-mentioned fine particles of filtering, but fundamentally do not address the aforementioned drawbacks, and improved the cost of preparation greatly, increase financial burden to the patient, the aseptic safeguard level of disposable filter has also strengthened the risk of microbiological contamination, is not ideal solution; Commercially available omeprazole freeze-dried powder injection and freeze-dried powder injection of pantoprazole sodium adopt the way that is equipped with dedicated solvent, but have brought trouble for clinical use and packed and transported, and other known technologies do not improve the suggestion of above defective yet.
Summary of the invention
The objective of the invention is to provide a kind of preparation method of proton pump inhibitor lyophilized injectable powder at above weak point, can significantly improve proton pump inhibitor lyophilizing redissolution performance by this method, and it is more stable during clinical use with the transfusion compatibility, can not separate out, visible foreign matters and particulate matter check result are better, improved the safety of clinical use greatly, need not to be equipped with micropore size is that 1.2 μ m disposable filter preparation costs are low, can not increase financial burden to the patient, also need not to be equipped with dedicated solvent, reduced the trouble of packed and transported and clinical use.
A kind of proton pump inhibitor lyophilized injectable powder is to be active component with the proton pump inhibitor, and adopts crystallize filtration preparation postlyophilization to be prepared from.
A kind of proton pump inhibitor lyophilized injectable powder, described proton pump inhibitor comprise a kind of in omeprazole, S-omeprazole, pantoprazole, S-pantoprazole, lansoprazole, rabeprazole, leminoprazole, Tenatoprazole and the salt thereof.
A kind of proton pump inhibitor lyophilized injectable powder, the filtering compound method of described crystallize is: earlier proton pump inhibitor is added alkali dissolution and be mixed with concentrated solution in water for injection, be 9.8～10.3 by adding the anti-accent of acid solution pH value again, make it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of proton pump inhibitor lyophilized injectable powder, the filtering compound method of described crystallize can also for: earlier proton pump inhibitor is added alkali dissolution and in water for injection, is mixed with concentrated solution, make it crystallize by freeze thawing again, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of proton pump inhibitor lyophilized injectable powder, the filtering compound method of described crystallize can also for: earlier proton pump inhibitor is added alkali dissolution and in water for injection, is mixed with concentrated solution, be 9.8～10.3 by adding the anti-accent of acid solution pH value again, and freeze thawing makes it crystallize, to separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of preparation method of proton pump inhibitor lyophilized injectable powder is to adopt following scheme to realize:
Get proton pump inhibitor and put in the container, add the water for injection of cumulative volume 10～50%, add the alkali stirring and make its dissolving and mix homogeneously make the proton pump inhibitor concentrated solution, crystallize filters, and measures the content of proton pump inhibitor in the solution, and regulating the filtrate pH value according to measurement result is 10.5～12.0, and be settled to full dose with water for injection, under aseptic condition, with 0.22 μ m filtering with microporous membrane to clear and bright, the filtrate fill is in aseptic cillin bottle, part is butyl rubber bung beyond the Great Wall, and freeze dryer is sent in sabot, 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-35～-40 ℃, continued freezing 2～4 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2～4 hours, tamponade, outlet rolls mouth, quality inspection, packing.
A kind of preparation method of proton pump inhibitor lyophilized injectable powder, the filtering method of described crystallize is: by adding the anti-modified sub-pump inhibitor concentrated solution pH value of acid is 9.8～10.3, make it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of preparation method of proton pump inhibitor lyophilized injectable powder, the filtering method of described crystallize is: by the freeze thawing of proton pump inhibitor concentrated solution is made it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of preparation method of proton pump inhibitor lyophilized injectable powder, the filtering method of described crystallize is: by adding the anti-modified sub-pump inhibitor concentrated solution pH value of acid is 9.8～10.3, and freeze thawing makes it crystallize, to separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
A kind of preparation method of proton pump inhibitor lyophilized injectable powder also adds adjuvant in the described process for preparation, adjuvant comprises a kind of or its mixture in mannitol, lactose, dextran, the glucose.
A kind of proton pump inhibitor lyophilized injectable powder of the present invention, undesirable at the proton pump inhibitor lyophilized injectable powder redissolution back visible foreign matters and the particulate matter check result that adopt the preparation of ordinary preparation method, when particularly adopting clinical use to infuse compatibility, there are a large amount of fine particles to occur, have a strong impact on the defective of clinical drug safety, by in preparation process, adopting the filtering compound method of crystallize to obtain better proton pump inhibitor solution of stability, the proton pump inhibitor lyophilized injectable powder that this solution makes after lyophilization has excellent redissolution performance, and it is more stable during clinical use with the transfusion compatibility, can not separate out, visible foreign matters and particulate matter check result are better, improved the safety of clinical use greatly, need not to be equipped with micropore size is 1.2 μ m disposable filters, the preparation cost is low, can not increase financial burden to the patient, the microbiological contamination risk that does not also have the aseptic safeguard level difference of disposable filter to bring, aseptic safeguard level is higher, also need not to be equipped with dedicated solvent, reduced the trouble of packed and transported and clinical use.Improved simultaneously the stability of proton pump inhibitor dry freeze powder injection in preparation process greatly, the proton pump inhibitor lyophilized injectable powder its related substances of preparation gained is low, steady quality, moisture drying is thorough, makes the proton pump inhibitor lyophilized injectable powder more stable in storage and transportation.Preparation technology of the present invention is simple, and convenient feasible, good reproducibility is easy to realize industrialized great production, 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 Lansoprazole freeze-dried injection (30mg specification)
Prescription
Lansoprazole 30g
Mannitol 50g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Get the recipe quantity lansoprazole and put in the container, add the water for injection of cumulative volume 80% amount, add the alkali stirring and make its dissolving and mix homogeneously, add recipe quantity mannitol again, stir and make its dissolving and mix homogeneously, add water for injection behind the content of lansoprazole in the mensuration solution and be settled to full dose, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-35 ℃, continues freezing 3 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 2:
Commonsense method prepares Lansoprazole freeze-dried injection (15mg specification)
Prescription
Lansoprazole 15g
Mannitol 25g
Water for injection adds to 1500ml
Make 1000 bottles altogether
Get the recipe quantity lansoprazole and put in the container, add the water for injection of cumulative volume 80% amount, add the alkali stirring and make its dissolving and mix homogeneously, add recipe quantity mannitol again, stir and make its dissolving and mix homogeneously, add water for injection behind the content of lansoprazole in the mensuration solution and be settled to full dose, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-35 ℃, continues freezing 2 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 3:
Prescription
Lansoprazole 30g
Mannitol 50g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 30%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.3 of transferring of acid, leave standstill and make the solution crystallize, to separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, and regulate filtrate pH value to 11.5 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-40 ℃, continues freezing 4 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 4:
Prescription
Lansoprazole 15g
Mannitol 25g
Water for injection adds to 1500ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 10%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 9.8 of transferring of acid, leave standstill and make it crystallize, to separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, and regulate filtrate pH value to 11.6 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-35 ℃, continues freezing 2 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 2 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 5:
Prescription
Lansoprazole 30g
Lactose 80g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 50%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add lactose again, stirring makes its dissolving and mix homogeneously, put in-30 ℃ of environment and freezed 3 hours, taking-up is put and is made it under the room temperature to melt, to separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, and regulate filtrate pH value to 10.5 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-40 ℃, continues freezing 2 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 4 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 6:
Prescription
Lansoprazole 15g
Glucose 60g
Water for injection adds to 2000ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 20%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add glucose again, stirring makes its dissolving and mix homogeneously, put in-35 ℃ of environment and freezed 5 hours, taking-up is put and is made it under the room temperature to melt, to separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, and regulate filtrate pH value to 11.8 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-40 ℃, continues freezing 3 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 7:
Prescription
Lansoprazole 30g
Dextran 30g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 20%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add dextran again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.3 of transferring of acid, put in-35 ℃ of environment and freezed 3 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, regulate filtrate pH value to 12.0 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 3 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 4 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 8:
Prescription
Lansoprazole 15g
Mannitol 100g
Water for injection adds to 2500ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 25%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.0 of transferring of acid, put in-35 ℃ of environment and freezed 2 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, regulate filtrate pH value to 11.4 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 2 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 9:
Prescription
Lansoprazole 30g
Water for injection adds to 2000ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 30%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, stirring makes its dissolving and mix homogeneously, put in-35 ℃ of environment and freezed 4 hours, taking-up is put and is made it under the room temperature to melt, to separate out crystal with microporous filter membrane filters out, measure the content of lansoprazole in the solution, regulate filtrate pH value to 11.3 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 3 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 3 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 10:
Prescription
Lansoprazole 15g
Mannitol 25g
Glucose sugar 25g
Water for injection adds to 2500ml
Make 1000 bottles altogether
Getting lansoprazole puts in the container, the water for injection that adds cumulative volume 10%, adding the alkali stirring makes its dissolving and mix homogeneously make the lansoprazole concentrated solution, add mannitol and glucose sugar again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.0 of transferring of acid, leave standstill and make it crystallize, to separate out crystal with microporous filter membrane and filter out, measure the content of lansoprazole in the solution, and regulate filtrate pH value to 11.7 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-35 ℃, continues freezing 2 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 2 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets Lansoprazole freeze-dried injection.
Embodiment 11:
Prescription
Omeprazole 20g
Mannitol 40g
Water for injection adds to 2000ml
Make 1000 bottles altogether
Getting omeprazole puts in the container, the water for injection that adds cumulative volume 20%, adding the alkali stirring makes its dissolving and mix homogeneously make the omeprazole concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.2 of transferring of acid, put in-35 ℃ of environment and freezed 3 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of omeprazole in the solution, regulate filtrate pH value to 11.8 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 2 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets the omeprazole lyophilized injectable powder.
Embodiment 12:
Prescription
Omeprazole Sodium 42.6g
Glucose 30g
Water for injection adds to 2000ml
Make 1000 bottles altogether
Getting Omeprazole Sodium puts in the container, the water for injection that adds cumulative volume 30%, stirring makes its dissolving and mix homogeneously make the Omeprazole Sodium concentrated solution, add glucose again, stirring makes its dissolving and mix homogeneously, put in-35 ℃ of environment and freezed 5 hours, taking-up is put and is made it under the room temperature to melt, to separate out crystal with microporous filter membrane and filter out, measure the content of Omeprazole Sodium in the solution, and regulate filtrate pH value to 1 1.5 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-40 ℃, continues freezing 3 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 3 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets omeprazole freeze-dried powder injection.
Embodiment 13:
Prescription
Pantoprazole Sodium 44.3g
Mannitol 40g
Water for injection adds to 2000ml
Make 1000 bottles altogether
Getting Pantoprazole Sodium puts in the container, the water for injection that adds cumulative volume 30%, stirring makes its dissolving and mix homogeneously make the Pantoprazole Sodium concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 9.9 of transferring of acid, leave standstill and make it crystallize, to separate out crystal with microporous filter membrane and filter out, measure the content of Pantoprazole Sodium in the solution, and regulate filtrate pH value to 11.5 and be settled to full dose with water for injection according to measurement result, under aseptic condition, to clear and bright, the filtrate fill is in aseptic cillin bottle with 0.22 μ m filtering with microporous membrane, 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 reaches-35 ℃, continues freezing 2 hours, stop board is cold, the open cold condenser when condenser temperature reaches below-45 ℃, is opened vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keeps this temperature after 2 hours, tamponade, outlet, roll mouth, quality inspection, packing promptly gets freeze-dried powder injection of pantoprazole sodium.
Embodiment 14:
Prescription
RABEPRAZOLE SODIUM 21.3g
Mannitol 100g
Water for injection adds to 2500ml
Make 1000 bottles altogether
Getting RABEPRAZOLE SODIUM puts in the container, the water for injection that adds cumulative volume 20%, stirring makes its dissolving and mix homogeneously make the RABEPRAZOLE SODIUM concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.2 of transferring of acid, put in-35 ℃ of environment and freezed 2 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of RABEPRAZOLE SODIUM in the solution, regulate filtrate pH value to 11.4 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 2 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets sodium rebeprazole freeze-dried injection.
Embodiment 15:
Prescription
S-omeprazole 20g
Mannitol 80g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Getting the S-omeprazole puts in the container, the water for injection that adds cumulative volume 25%, adding the alkali stirring makes its dissolving and mix homogeneously make S-omeprazole concentrated solution, add mannitol again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.1 of transferring of acid, put in-35 ℃ of environment and freezed 2 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of S-omeprazole in the solution, regulate filtrate pH value to 11.6 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 2 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets S-omeprazole lyophilized injectable powder.
Embodiment 16:
Prescription
Leminoprazole 20g
Dextran 30g
Water for injection adds to 4000ml
Make 1000 bottles altogether
Getting leminoprazole puts in the container, the water for injection that adds cumulative volume 20%, adding the alkali stirring makes its dissolving and mix homogeneously make the leminoprazole concentrated solution, add dextran again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.3 of transferring of acid, put in-35 ℃ of environment and freezed 4 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of leminoprazole in the solution, regulate filtrate pH value to 12.0 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 3 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 3 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets the leminoprazole lyophilized injectable powder.
Embodiment 17:
Prescription
Tenatoprazole 20g
Dextran 30g
Water for injection adds to 3000ml
Make 1000 bottles altogether
Getting Tenatoprazole puts in the container, the water for injection that adds cumulative volume 20%, adding the alkali stirring makes its dissolving and mix homogeneously make the Tenatoprazole concentrated solution, add dextran again, stirring makes its dissolving and mix homogeneously, add the anti-solution pH value to 10.3 of transferring of acid, put in-35 ℃ of environment and freezed 3 hours, taking-up is put and is made it under the room temperature to melt, and will separate out crystal with microporous filter membrane and filter out, measure the content of Tenatoprazole in the solution, regulate filtrate pH value to 11.8 and be settled to full dose according to measurement result with water for injection, 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, and freeze dryer is sent in sabot, 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 ℃, continued freezing 3 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 4 hours, tamponade, outlet rolls mouth, quality inspection, packing promptly gets the Tenatoprazole lyophilized injectable powder.
Embodiment 18:
Proton pump inhibitor lyophilized injectable powder visible foreign matters is checked
Get the proton pump inhibitor lyophilized injectable powder,, check according to visible foreign matters inspection technique (Chinese Pharmacopoeia 2005 version two ones) with 0.9% sodium chloride transfusion 10ml dissolving, should be up to specification.
Embodiment 19:
Proton pump inhibitor lyophilized injectable powder particulate matter is checked
Get the proton pump inhibitor lyophilized injectable powder,, check according to particulate matter inspection technique (Chinese Pharmacopoeia 2005 version two ones) with 0.9% sodium chloride transfusion 100ml dissolving, should be up to specification.
Embodiment 20:
Respectively prepare the proton pump inhibitor lyophilized injectable powder respectively by embodiment 1～17, check its character, visible foreign matters and particulate matter more respectively, add up above-mentioned assay, it the results are shown in Table 1.
Table 1
Claims (10)
1, a kind of proton pump inhibitor lyophilized injectable powder is characterized in that with the proton pump inhibitor being active component, and adopts crystallize filtration preparation postlyophilization to be prepared from.
2, proton pump inhibitor lyophilized injectable powder according to claim 1 is characterized in that described proton pump inhibitor comprises a kind of in omeprazole, S-omeprazole, pantoprazole, S-pantoprazole, lansoprazole, rabeprazole, leminoprazole, Tenatoprazole and the salt thereof.
3, proton pump inhibitor lyophilized injectable powder according to claim 1, it is characterized in that the filtering compound method of described crystallize is: earlier proton pump inhibitor is added alkali dissolution and in water for injection, be mixed with concentrated solution, be 9.8～10.3 by adding the anti-accent of acid solution pH value again, make it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
4, proton pump inhibitor lyophilized injectable powder according to claim 1, it is characterized in that the filtering compound method of described crystallize can also for: earlier proton pump inhibitor is added alkali dissolution and in water for injection, is mixed with concentrated solution, make it crystallize by freeze thawing again, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
5, proton pump inhibitor lyophilized injectable powder according to claim 1, it is characterized in that the filtering compound method of described crystallize can also for: earlier proton pump inhibitor is added alkali dissolution and in water for injection, is mixed with concentrated solution, be 9.8～10.3 by adding the anti-accent of acid solution pH value again, and freeze thawing makes it crystallize, to separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
6, a kind of preparation method of proton pump inhibitor lyophilized injectable powder is characterized in that preparation process is:
Get proton pump inhibitor and put in the container, add the water for injection of cumulative volume 10～50%, add the alkali stirring and make its dissolving and mix homogeneously make the proton pump inhibitor concentrated solution, crystallize filters, and measures the content of proton pump inhibitor in the solution, and regulating the filtrate pH value according to measurement result is 10.5～12.0, and be settled to full dose with water for injection, under aseptic condition, with 0.22 μ m filtering with microporous membrane to clear and bright, the filtrate fill is in aseptic cillin bottle, part is butyl rubber bung beyond the Great Wall, and freeze dryer is sent in sabot, 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-35～-40 ℃, continued freezing 2～4 hours, stop board is cold, the open cold condenser, when condenser temperature reaches below-45 ℃, open vacuum system, begin the distillation that heats up, final drying temperature product temperature is 30 ℃, keep this temperature after 2～4 hours, tamponade, outlet rolls mouth, quality inspection, packing.
7, the preparation method of proton pump inhibitor lyophilized injectable powder according to claim 6, it is characterized in that the filtering method of described crystallize is: by adding the anti-modified sub-pump inhibitor concentrated solution pH value of acid is 9.8～10.3, make it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
8, the preparation method of proton pump inhibitor lyophilized injectable powder according to claim 6, it is characterized in that the filtering method of described crystallize is: by the freeze thawing of proton pump inhibitor concentrated solution is made it crystallize, and will separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
9, the preparation method of proton pump inhibitor lyophilized injectable powder according to claim 6, it is characterized in that the filtering method of described crystallize is: by adding the anti-modified sub-pump inhibitor concentrated solution pH value of acid is 9.8～10.3, and freeze thawing makes it crystallize, to separate out crystal with microporous filter membrane and filter out, adding to the full amount of water for injection at last obtains better proton pump inhibitor solution of stability.
10, the preparation method of proton pump inhibitor lyophilized injectable powder according to claim 6 is characterized in that also adding in the described process for preparation adjuvant, and adjuvant comprises a kind of or its mixture in mannitol, lactose, dextran, the glucose.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085190A (en) * | 2011-01-28 | 2011-06-08 | 海南锦瑞制药股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
| CN103565747A (en) * | 2012-08-06 | 2014-02-12 | 江苏奥赛康药业股份有限公司 | Esomeprazole composition and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085190A (en) * | 2011-01-28 | 2011-06-08 | 海南锦瑞制药股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
| CN102085190B (en) * | 2011-01-28 | 2012-07-25 | 海南锦瑞制药股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
| CN103565747A (en) * | 2012-08-06 | 2014-02-12 | 江苏奥赛康药业股份有限公司 | Esomeprazole composition and preparation method thereof |
| CN103565747B (en) * | 2012-08-06 | 2015-07-08 | 江苏奥赛康药业股份有限公司 | Esomeprazole composition and preparation method thereof |
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