CN102440965B - Esomeprazole sodium composition used for injection and its preparation method - Google Patents
Esomeprazole sodium composition used for injection and its preparation method Download PDFInfo
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- CN102440965B CN102440965B CN 201010505392 CN201010505392A CN102440965B CN 102440965 B CN102440965 B CN 102440965B CN 201010505392 CN201010505392 CN 201010505392 CN 201010505392 A CN201010505392 A CN 201010505392A CN 102440965 B CN102440965 B CN 102440965B
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Abstract
The invention provides an Esomeprazole sodium composition used for injection and its preparation method, the Esomeprazole sodium composition is prepared by the following steps: 1) liquid preparation: selecting esomeprazole sodium and ethylenediamine tetraacetic acid or ethylenediamine tetraacetic acid salt as raw materials, wherein the weight ratio of esomeprazole sodium to ethylenediamine tetraacetic acid or ethylenediamine tetraacetic acid salt is 1:0.01-0.1, weighting a proper amount of raw materials into a preparation tank, and adding water for injection to the weight of 23.47-234.7 times of esomeprazole sodium, stirring and uniformly mixing the solution, adjusting the pH value of 10.0-12.5; 2) activated carbon finishing; 3) adsorbing; 4) sterile filtrating and split charging; 5) vacuum freeze-drying to obtain the esomeprazole sodium composition used for injection. The esomeprazole sodium composition used for injection and the preparation method are capable of ensuring the heat source, visible foreign matter and insoluble particulate to accord with the requirements of the injection for the injection preparations such as esomeprazole sodium preparation liquid with high pH value.
Description
Technical field
The present invention relates to a kind of Esomeprazole sodium composition and method of making the same of injection, belong to medical preparing technical field.
Background technology
((S)-((4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl) sulfinyl-1 H-benzimidazole sodium, structural formula is Esomeprazole sodium chemistry 5-methoxyl group-2-by name
Esomeprazole sodium is used for the treatment of gastro oesophageal reflux disease (GORD) (GERD)-erosive reflux esophagitis clinically.The long term maintenance treatment that the esophagitis patient who has cured prevents from recurring.The symptom control of gastro oesophageal reflux disease (GORD) (GERD).With suitable antimicrobial therapy drug combination eradicate helicobacter pylori, and-healing and helicobacter pylorus infect the recurrent peptic ulcer that relevant duodenal ulcer-prevent is correlated with helicobacter pylori.
Esomeprazole sodium is unstable under sour environment, the sour environment Esomeprazole sodium is very easily degraded on the one hand, impurity increases and occurs the change of solution colour, on the other hand, the fastness of Esomeprazole sodium salify is poor, very easily separates out with the form of esomeprazole under acid and weak basic condition, cause the transfusion drug effect to descend, more harmful is that esomeprazole is separated out microgranule and entered human body, causes capillary embolism and granuloma.For reducing above quality risk, to the injection of Esomeprazole sodium, in process for preparation, all adopted higher pH value (usually more than 9.5), to improve the physics and chemistry stability of Esomeprazole sodium obtain solution.
Based on the consideration of clinical drug safety, thermal source is to be the heaviest point of weight that injection production is paid close attention to always, and thermal source exceeds standard and often causes serious clinical application accident, even jeopardizes patient's life.Usually adopt the mode of activated carbon adsorption or ultrafiltration to remove thermal source in the injection production, ultrafiltration needs special and expensive equipment and ultrafilter membrane, and ultrafiltration time while is longer, is unfavorable for the control of production process.The activated carbon adsorption cost is low, speed is fast, can also play the effect of absorption foreign pigment simultaneously, is used widely in the production of esomeprazole sodium injection.But in the esomeprazole sodium injection, use the activated carbon adsorption thermal source that its defective is also arranged, active carbon is to be fired by simple process by timber to obtain, inevitably there is a large amount of impurity, in esomeprazole sodium injection production process, active carbon has also been introduced new impurity in absorption thermal source and coloring matter, bring the significantly reduction of visible foreign matters and particulate matter control level, this situation is along with the raising of Esomeprazole sodium obtain solution pH value is obvious all the more, Esomeprazole sodium obtain solution pH value is higher, take off the impurity that active carbon discharges in the charcoal process also more, these impurity filter link at 0.22 μ m filter and can't remove, thereby be retained in the middle of the final preparation, so that preparation finished product visible foreign matters and particulate matter inspection are defective, cause scrapping of entire block.In addition, active carbon batch between the mass discrepancy quality of also can appreciable impact taking off product behind the charcoal, the active carbon of different batches, because how many differences of impurity content own, the degree that discharges when taking off charcoal is also different, and these impacts all can't be expected, and brings great hidden danger for the product final mass.
And existing technology is all less than the suggestion that above defective is proposed improve: Chinese patent CN200380101430.2 discloses a kind of method for preparing omeprazole or esomeprazole take piconol as raw material via pyrmethyl chloride and Pyrmetazole, does not solve above-mentioned technological deficiency.Chinese patent CN200810004014.5 discloses a kind of method for preparing omeprazole or esomeprazole take piconol as raw material via pyrmethyl chloride and Pyrmetazole, it is characterized in that whole course of reaction is in the situation that do not separate or purify intermediates is carried out, and does not solve above-mentioned technological deficiency.Chinese patent CN200810111831.0 discloses a kind of for gastro oesophageal reflux disease (GORD): the treatment of erosive reflux esophagitis, the long term maintenance treatment that the esophagitis patient who has cured prevents from recurring, the symptom control of gastro oesophageal reflux disease (GORD); Also be used for and suitable antimicrobial therapy drug combination eradicate helicobacter pylori, and healing is infected relevant duodenal ulcer with helicobacter pylorus, prevent the pharmaceutical preparation of the recurrent peptic ulcer relevant with helicobacter pylori, be particularly related to a kind of oral slow-releasing preparation that is prepared from take esomeprazole magnesium as raw material, do not solve above-mentioned technological deficiency.Chinese patent CN200780020611.0 discloses the method for the quaternary ammonium salt of preparation esomeprazole, does not solve above-mentioned technological deficiency.Chinese patent CN200810228898.2 discloses a kind of pipe esomeprazole magnesium esomeprazole magnesium injection liquid that can treat gastro oesophageal reflux disease (GORD), mainly contain esomeprazole magnesium or its officinal salt and solvent for injection, do not solve above-mentioned technological deficiency.
Therefore, to the higher injection of Esomeprazole sodium this class preparating liquid pH, can guarantee simultaneously that in the urgent need to a kind of product thermal source, visible foreign matters and particulate matter meet the technical scheme of injection requirement.
Summary of the invention
Purpose of the present invention overcomes the deficiencies in the prior art part, provides a kind of product thermal source, visible foreign matters and particulate matter of can guaranteeing simultaneously to meet the esomeprazole composition of sodium of injection requirement.
The esomeprazole composition of sodium of injection of the present invention is to be prepared from by following method:
1) medicinal liquid preparation: choosing Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is raw material, wherein the part by weight of Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is 1: 0.01～0.1, taking by weighing an amount of raw material puts in the preparing tank, inject water to solution weight and be 23.47～234.7 times of Esomeprazole sodium weight, stirring makes dissolving and mix homogeneously, and the regulator solution pH value is 10.0～12.5;
2) active carbon arrangement:
A, by the step poly-1) medicinal liquid weight 0.05%～0.5% takes by weighing active carbon, the water for injection that adds 50 times of active carbon weight, stirring makes and is uniformly dispersed, the regulator solution pH value is 10.0～12.5, be heated to 60～70 ℃ and be incubated 30 minutes, while hot Insta-Char be delivered to titanium rod filter and take off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, make the step poly-1) medicinal liquid of preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will go on foot poly-3) obtain through the absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
Preferably,
In the esomeprazole composition of sodium of described injection, the part by weight of said Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is 1: 0.02～0.05;
In the esomeprazole composition of sodium of described injection, said edetate is selected from disodiumedetate or calcium disodium edathamil.
In the esomeprazole composition of sodium of described injection, the material of said adjusting pH value is sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium citrate.
More preferably,
In the esomeprazole composition of sodium of described injection, also comprise mannitol, lactose, dextran or glucose as excipient in the said composition material.
The principle of technical solution of the present invention is: put in order by the active carbon that the absorption medicinal liquid is used, and adopt suitable absorption to take off charcoal technique, even if when Esomeprazole sodium preparating liquid pH is very high, can guarantee simultaneously that also product thermal source, visible foreign matters and particulate matter meet the injection requirement.The present invention effectively the elimination activity charcoal batch between mass discrepancy on the impact of esomeprazole sodium injection end product quality.
At first, take by weighing active carbon (this ratio is the optimum ratio that active carbon is removed thermal source and coloring matter) in preparating liquid weight 0.05%～0.5%, the water for injection that adds 50 times of active carbon weight, stirring makes and is uniformly dispersed, the regulator solution pH value is 10.0～12.5, be heated to 60～70 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal, in this process, the present invention has created first the high alkalinity environment of a simulation esomeprazole sodium injection obtain solution, and auxiliary and heater means, so that as much as possible the discharging of easy release impurity in the active carbon, owing to only having used the water for injection of a small amount of pH adjusting agent and suitable weight (50 times of active carbon weight), this process is on the almost not impact of absorbability of active carbon.By this process, contain still less and to be collected by titanium rod filter after the active carbon of impurity level takes off charcoal while hot, take off charcoal for follow-up active carbon arrangement and absorption and get ready.
Secondly, active carbon with the collection of water for injection flushing titanium rod filter, until pH value is less than 8, taking away with water for injection in the active carbon in the impurity so that the active carbon pH that titanium rod filter is collected reduces, to guarantee the stable of ethylenediaminetetraacetic acid in the subsequent operation and to remove the efficient of residue trace impurity in the active carbon.
Again, the active carbon of the ethylenediaminetetraacetic acid circulation flushing titanium rod filter collection by 0.1% 30 minutes, the residue trace impurity is also removed in the active carbon.
At last, the active carbon of collecting with water for injection flushing titanium rod filter 30 minutes, guaranteeing does not have ethylenediaminetetraacetic acid residual in the active carbon of arrangement.
Active carbon by said method arrangement can discharge impurity hardly when the higher injection of Esomeprazole sodium this class preparating liquid pH is taken off charcoal, and fabulous elimination active carbon criticize a mass discrepancy to taking off the impact of charcoal product quality.
In addition, not that the active carbon that will put in order falls and takes off charcoal after the into the liquid stirring, but connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes, this is creationary to take off charcoal technique so that the solution uniformity after taking off charcoal is better, thermal source control level and better reliability.
The Esomeprazole sodium composition and method of making the same of injection of the present invention, to the higher injection of Esomeprazole sodium this class preparating liquid pH, the present invention can guarantee simultaneously that product thermal source, visible foreign matters and particulate matter meet the injection requirement.Can make in the Esomeprazole sodium injection preparation process active carbon in absorption thermal source and coloring matter, can not introduce new impurity by the method, avoid bringing the significantly reduction of visible foreign matters and particulate matter control level, even if when Esomeprazole sodium obtain solution pH value is very high, also can prevent active carbon in the anti-avulsion charcoal process discharge make new advances impurity, so that preparation finished product visible foreign matters and particulate matter control level can not be subject to the impact that activated carbon adsorption and pH are heightened, simultaneously fabulous elimination active carbon criticize a mass discrepancy to taking off the impact of charcoal product quality, avoided to greatest extent scrapping of product, reduced even eliminated esomeprazole sodium injection visible foreign matters and the underproof phenomenon of particulate matter fully.Thereby need not because a large amount of waste product removings have increased lamp inspection workload and lamp inspection human cost, yield rate significantly improves in addition, and production cost is reduced, and has also avoided because of visible foreign matters and the defective hidden danger of bringing to the patient clinical safe medication of particulate matter.
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.
Be guarantee test result's concordance, the embodiment of the invention has been used identical raw material, adjuvant, cillin bottle and plug, and has adopted consistent vacuum freeze-drying technique to prepare the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of reference examples 1 preparation injection
Prescription:
Esomeprazole sodium 426g
Ethylenediaminetetraacetic acid 4.26g
Water for injection adds to 20Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 20Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 12.0;
2) absorption: take by weighing the 10g active carbon, join in the above-mentioned Esomeprazole sodium obtain solution, stirring makes and is uniformly dispersed, and continues to stir 30 minutes, is delivered to titanium rod filter and takes off charcoal;
3) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 1ml/ is sub-packed in the cillin bottle, partly jumps a queue;
4) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of reference examples 2 preparation injections
Prescription:
Esomeprazole sodium 426g
Disodiumedetate 8.52g
Mannitol 500g
Water for injection adds to 50Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, mannitol and disodiumedetate and put in the preparing tank, inject water to 50Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.0;
2) absorption: take by weighing the 50g active carbon, join in the above-mentioned Esomeprazole sodium obtain solution, stirring makes and is uniformly dispersed, and continues to stir 30 minutes, is delivered to titanium rod filter and takes off charcoal;
3) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
4) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of reference examples 3 preparation injections
Prescription:
Esomeprazole sodium 852g
Lactose 500g
Ethylenediaminetetraacetic acid 42.6g
Water for injection adds to 80Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, lactose and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 80Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.8;
2) absorption: take by weighing the 320g active carbon, join in the above-mentioned Esomeprazole sodium obtain solution, stirring makes and is uniformly dispersed, and continues to stir 30 minutes, is delivered to titanium rod filter and takes off charcoal;
3) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 4ml/ is sub-packed in the cillin bottle, partly jumps a queue;
4) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of reference examples 4 preparation injections
Place ten thousand:
Esomeprazole sodium 852g
Mannitol 1Kg
Calcium disodium edathamil 85.2g
Water for injection adds to 100Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, mannitol and calcium disodium edathamil and put in the preparing tank, inject water to 100Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.6;
2) absorption: take by weighing the 50g active carbon, join in the above-mentioned Esomeprazole sodium obtain solution, stirring makes and is uniformly dispersed, and continues to stir 30 minutes, is delivered to titanium rod filter and takes off charcoal;
3) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
4) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 1 preparation injection
Prescription:
Esomeprazole sodium 426g
Ethylenediaminetetraacetic acid 4.26g
Water for injection adds to 20Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 20Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 12.0;
2) active carbon arrangement:
A, take by weighing the 10g active carbon, add the water for injection of 500g, stir to make and be uniformly dispersed, the regulator solution pH value is 12.0, is heated to 60 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 1ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 2 preparation injections
Prescription:
Esomeprazole sodium 426g
Disodiumedetate 8.52g
Mannitol 500g
Water for injection adds to 50Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, mannitol and disodiumedetate and put in the preparing tank, inject water to 50Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.0;
2) active carbon arrangement:
A, take by weighing the 50g active carbon, add the water for injection of 2.5g, stir to make and be uniformly dispersed, the regulator solution pH value is 10.0, is heated to 65 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 3 preparation injections
Prescription:
Esomeprazole sodium 852g
Lactose 500g
Ethylenediaminetetraacetic acid 42.6g
Water for injection adds to 80Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, lactose and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 80Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.8;
2) active carbon arrangement:
A, take by weighing the 320g active carbon, add the water for injection of 16Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 10.8, is heated to 60 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 4ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 4 preparation injections
Prescription:
Esomeprazole sodium 852g
Mannitol 1Kg
Calcium disodium edathamil 85.2g
Water for injection adds to 100Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, mannitol and calcium disodium edathamil and put in the preparing tank, inject water to 100Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 10.6;
2) active carbon arrangement:
A, take by weighing the 50g active carbon, add the water for injection of 2.5Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 10.6, is heated to 70 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 5 preparation injections
Prescription:
Esomeprazole sodium 426g
Mannitol 500g
Ethylenediaminetetraacetic acid 42.6g
Water for injection adds to 40Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, mannitol and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 40Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 11.3;
2) active carbon arrangement:
A, take by weighing the 200g active carbon, add the water for injection of 10Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 11.3, is heated to 70 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 6 preparation injections
Prescription:
Esomeprazole sodium 426g
Lactose 1Kg
Calcium disodium edathamil 21.3g
Water for injection adds to 100Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, lactose and calcium disodium edathamil and put in the preparing tank, inject water to 100Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 11.6;
2) active carbon arrangement:
A, take by weighing the 200g active carbon, add the water for injection of 10Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 11.6, is heated to 68 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 7 preparation injections
Place ten thousand:
Esomeprazole sodium 852g
Glucose 1Kg
Ethylenediaminetetraacetic acid 17.04g
Water for injection adds to 40Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, glucose and ethylenediaminetetraacetic acid and put in the preparing tank, inject water to 40Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 11.8;
2) active carbon arrangement:
A, take by weighing the 200g active carbon, add the water for injection of 10Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 11.8, is heated to 63 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
The esomeprazole composition of sodium of embodiment 8 preparation injections
Prescription:
Esomeprazole sodium 852g
Dextran 5 00g
Disodiumedetate 8.52g
Water for injection adds to 20Kg
1) medicinal liquid preparation: take by weighing Esomeprazole sodium, dextran and disodiumedetate and put in the preparing tank, inject water to 20Kg, stir and make dissolving and mix homogeneously, the regulator solution pH value is 12.5;
2) active carbon arrangement:
A, take by weighing the 40g active carbon, add the water for injection of 2Kg, stir to make and be uniformly dispersed, the regulator solution pH value is 12.5, is heated to 64 ℃ and be incubated 30 minutes, while hot Insta-Char is delivered to titanium rod filter and takes off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, will through absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, the loading amount of propping up by 1ml/ is sub-packed in the cillin bottle, partly jumps a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
Foreign body and particulate matter contrast in embodiment 9 reference examples 1～4 and embodiment 1～8 compositions
Respectively prepare respectively the esomeprazole composition of sodium of injection by reference examples 1～4 and embodiment 1～8, check respectively visible foreign matters, particulate matter, content and related substance again, it the results are shown in Table 1.
The esomeprazole composition of sodium check result of table 1 injection
As can be seen from Table 1, technical scheme of the present invention (embodiment 1～8) is more secure than prior art (reference examples 1～4) visible foreign matters and particulate matter, and content and related substance are without significant change.
Foreign body and particulate matter stabilizing effect contrast in embodiment 10 reference examples 1～4 and embodiment 1～8 compositions
Each prepares respectively the esomeprazole composition of sodium of injection by reference examples 1～4 and embodiment 1～8, puts under the room temperature lucifuge condition and carries out study on the stability, checks respectively visible foreign matters and particulate matter again, and it the results are shown in Table 2, table 3.
The esomeprazole composition of sodium visible foreign matters study on the stability result of table 2 injection
The esomeprazole composition of sodium particulate matter study on the stability result of table 3 injection
Can find out from table 2 and table 3, technical scheme of the present invention (embodiment 1～8) is better than prior art (reference examples 1～4) visible foreign matters and particulate matter stability, has clear superiority.
Claims (5)
1. the esomeprazole composition of sodium of an injection is characterized in that, said composition is to be prepared from by following method:
1) medicinal liquid preparation: choosing Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is raw material, wherein the part by weight of Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is 1:0.01～0.1, taking by weighing an amount of raw material puts in the preparing tank, inject water to solution weight and be 23.47～234.7 times of Esomeprazole sodium weight, stirring makes dissolving and mix homogeneously, and the regulator solution pH value is 10.0～12.5;
2) active carbon arrangement:
A, take by weighing active carbon by step 1) medicinal liquid weight 0.05%～0.5%, the water for injection that adds 50 times of active carbon weight, stirring makes and is uniformly dispersed, and the regulator solution pH value is 10.0～12.5, be heated to 60～70 ℃ and be incubated 30 minutes, while hot Insta-Char be delivered to titanium rod filter and take off charcoal;
B, the active carbon of then collecting with water for injection flushing titanium rod filter are until pH value is less than 8;
C, the active carbon collected with 0.1% ethylenediaminetetraacetic acid circulation flushing titanium rod filter again 30 minutes;
D, the active carbon collected with water for injection flushing titanium rod filter at last 30 minutes namely get the active carbon through arrangement;
3) absorption: connect preparing tank and titanium rod filter, the medicinal liquid that makes the step 1) preparation was circulation absorption in the active carbon of arrangement 30 minutes;
4) aseptic filtration, packing: close circulation, with step 3) obtain through the absorption medicinal liquid with 0.22 μ m filter aseptic filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
5) vacuum lyophilization namely gets the esomeprazole composition of sodium of injection.
2. the esomeprazole composition of sodium of injection according to claim 1 is characterized in that, the part by weight of said Esomeprazole sodium and ethylenediaminetetraacetic acid or edetate is 1:0.02～0.05.
3. injection esomeprazole composition of sodium according to claim 2 is characterized in that, said edetate is selected disodiumedetate and calcium disodium edathamil.
4. the esomeprazole composition of sodium of injection according to claim 1 is characterized in that, the material of said adjusting pH value is sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium citrate.
5. the esomeprazole composition of sodium of any one described injection in 4 according to claim 1 is characterized in that, also comprises mannitol, lactose, dextran or glucose as excipient in the said composition material.
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| CN102746273A (en) * | 2012-05-29 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Esomeprazole sodium polymorph and application of esomeprazole sodium polymorph in drugs for injection |
| CN102702172B (en) * | 2012-06-15 | 2013-09-04 | 孙威 | Esomeprazole sodium preparation method |
| CN102973524A (en) * | 2012-11-30 | 2013-03-20 | 深圳海王药业有限公司 | Esomeprazole sodium lyophilized powder injection and preparation method thereof |
| CN105055339A (en) * | 2015-07-31 | 2015-11-18 | 苏州汇和药业有限公司 | Injection esomeprazole composition and method for preparing same |
| CN105001202B (en) * | 2015-08-09 | 2017-11-07 | 朗天药业(湖北)有限公司 | A kind of Esomeprazole sodium compound and its pharmaceutical composition |
| CN107773529B (en) * | 2016-08-24 | 2020-06-16 | 华仁药业股份有限公司 | Esomeprazole sodium and sodium chloride injection and preparation method thereof |
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| ATE490247T1 (en) * | 2006-06-07 | 2010-12-15 | Astrazeneca Ab | NEW PROCESS FOR PRODUCING AMMONIUM SALTS OF ESOMEPRAZOLE |
| CN1857200A (en) * | 2006-06-08 | 2006-11-08 | 周华英 | Medicinel liquid containing proton pump inhibitor |
| CN101513387A (en) * | 2008-11-20 | 2009-08-26 | 李铁军 | Esomeprazole magnesium injection liquid |
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