CN101810588B - Pantoprazole sodium freeze-drying medicinal composition for injection and preparation method thereof - Google Patents
Pantoprazole sodium freeze-drying medicinal composition for injection and preparation method thereof Download PDFInfo
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- CN101810588B CN101810588B CN2009102239181A CN200910223918A CN101810588B CN 101810588 B CN101810588 B CN 101810588B CN 2009102239181 A CN2009102239181 A CN 2009102239181A CN 200910223918 A CN200910223918 A CN 200910223918A CN 101810588 B CN101810588 B CN 101810588B
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Abstract
The invention relates to a pantoprazole sodium freeze-drying medicinal composition for injection and a preparation method thereof. The pantoprazole sodium freeze-drying medicinal composition for injection comprises the following components in part by weight: 1 part of pantoprazole sodium, 0.01 to 0.1 part of mannitol, 0.02 to 0.03 part of natrium adetate, 0.07 to 0.10 part of sodium sulfite and 0 to 0.1 part of sodium citrate. In the method, the stability of the solution of the pantoprazole sodium is improved, related matters of the solution of the pantoprazole sodium in the process of preparation, packaging or freeze-drying during preparation are not increased obviously, the content of the related matters is not reduced obviously; the prepared pantoprazole sodium freeze-drying powder injection is good in stability in the process of transportation and storage; solution mixed with the injection during clinical use can be placed for a long time, so that the clinical use is more convenient; and simultaneously, hidden troubles of the medication safety of patients due to the increase of impurities (related matters) and the problem of the curative effect on the patients due to content reduction are reduced greatly.
Description
Technical field
The present invention relates to a kind of pantoprazole sodium freeze-drying medicinal composition for injection and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Pantoprazole Sodium (Pantoprazole Sodium), chemical name is: 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridine radicals) methyl]-sulfinyl-1H-benzimidazole sodium salt.Pantoprazole Sodium is a proton pump inhibitor class antiulcerative.The pantoprazole sodium injection is mainly used in digestive ulcerative bleeding, under acute gastric mucosa damage that nonsteroidal antiinflammatory drug causes and the stress state after ulcer massive hemorrhage and general anesthesia or the major operation and weak comatose patient prevent treatment of conditions such as regurgitation of gastric juice and aspiration pneumonitis.The poor stability of Pantoprazole Sodium, all very sensitive to light, heat, oxygen, water etc., especially when acid condition, the destructive variation can take place in its chemical constitution, variable color and polymerism occur, thereby is unsuitable for making water agent for injecting, is fit to make lyophilized injectable powder.
In the patent documentation in the past, the report of existing many relevant freeze-dried powder injection of pantoprazole sodium, such as in Chinese patent " pantoprazole sodium freeze-drying preparation and pantoprazole injection " (publication number CN1476335A, open day on February 18th, 2004), having disclosed " the aqueous solution lyophilization of Pantoprazole Sodium, ethylenediaminetetraacetic acid and/or its suitable salt and sodium hydroxide and/or sodium carbonate " made lyophilized formulations; But the preparation stability with the preparation of this technical scheme is bad, and when it is dissolved in the injection, intensive amount will descend in 2 to 4 hours, affected the treatment.At Chinese patent " freeze-dried pantoprazole injectable powder and preparation method " (publication number CN1235018A, open day on November 17th, 1999) disclosed a kind of method for preparing freeze-dried powder injection of pantoprazole sodium in, its prescription is made up of Pantoprazole Sodium (1 part), frozen-dried supporting agent (1-5 part), complexing of metal ion agent (0.05-2 part) and pH regulator agent.The used pharmaceutic adjuvant amount of this technical scheme is bigger, thereby brings some side effect.
In sum, at the characteristics of Pantoprazole Sodium to light, heat, oxygen and water unstable, common solution is that Pantoprazole Sodium is prepared into lyophilized injectable powder, but we find, even if be prepared into the stability that lyophilized formulations can not guarantee its preparation, transportation and storage process, the content of its preparation still has obvious decline and related substance obviously increases, and preparation and infusion time is had harsh requirement during clinical use, extremely inconvenience and patient's drug safety brought hidden danger.
Summary of the invention
The objective of the invention is provides a kind of pantoprazole sodium freeze-drying medicinal composition for injection and preparation method thereof at above weak point, can improve the stability of pantoprazole sodium solution greatly by this method, no matter be preparation during preparation, packing still is that the related substance of pantoprazole sodium solution in the freeze-drying process does not all have obvious increase, content does not have obvious decline yet, the freeze-dried powder injection of pantoprazole sodium of preparation having good stability in transportation and storage process, compatibility solution can be placed the long period during clinical use, make clinical use become convenient, also having reduced greatly simultaneously increases the curative effect problem of descending and bringing to the patient for hidden danger that patient's drug safety brings and content because of impurity (related substance).
The present invention at first provides a kind of pantoprazole sodium freeze-drying medicinal composition for injection, and the side effect of this freeze-drying medicinal composition is little, and the having good stability of this freeze-drying medicinal composition.
The present invention adopts following technical scheme:
A kind of pantoprazole sodium freeze-drying medicinal composition for injection, wherein, described freeze-drying medicinal composition comprises following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.01-0.1 weight portion
Disodium edetate 0.02-0.03 weight portion
Sodium sulfite 0.07-0.10 weight portion
Sodium citrate 0-0.1 weight portion.
Preferably, freeze-drying medicinal composition of the present invention comprises following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.05-0.1 weight portion
Disodium edetate 0.02-0.025 weight portion
Sodium sulfite 0.07-0.08 weight portion
Sodium citrate 0.05-0.1 weight portion.
Preferred, freeze-drying medicinal composition of the present invention comprises following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.1 weight portion
Disodium edetate 0.02 weight portion
Sodium sulfite 0.07 weight portion
Sodium citrate 0.05 weight portion.
Secondly, the present invention is in the preparation method that a kind of pantoprazole sodium freeze-drying medicinal composition for injection is provided, this method simple possible, and the injection pantoprazole sodium freeze-drying compositions side effect of preparation is little, has good stability.
The present invention adopts following technical scheme:
A kind of preparation method of pantoprazole sodium freeze-drying medicinal composition for injection of the present invention, wherein, described preparation method comprises the steps:
1) mannitol and disodium edetate are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value of sodium hydrate regulator solution is to alkalescence;
2) add sodium sulfite and sodium citrate in sterile chamber, stirring and dissolving gets solution A;
3) in solution A, add Pantoprazole Sodium again, stir and make dissolving, obtain solution B;
4) in solution B, add needle-use activated carbon, stirring and adsorbing, filtering decarbonization, benefit adds to the full amount of water for injection, and crosses microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the pH value described in the step 1) to alkalescence is 11.0-11.5 for pH value.
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the temperature of solution A is controlled between 2-8 ℃ when adding Pantoprazole Sodium in the step 3).
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, be to add needle-use activated carbon in the step 4) by the 0.01-0.05% of solution amount.
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the stirring and adsorbing described in the step 4) is 10～20 ℃ of following stirring and adsorbing 20～30 minutes.
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the stirring and adsorbing described in the step 4) is 15 ℃ of following stirring and adsorbing 20～30 minutes.
Preparation method according to aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the described lyophilization of step 4) is: be cooled to-50～-45 ℃ earlier, pre-freeze 1.5～2.5h, evacuation then, and be warming up to-5～-15 ℃ by 2.5～3.5 ℃ of h-1, be warming up to 25～35 ℃ by 4.5～5.5 ℃ of h-1 afterwards, insulation 1.5～2.5h.
Below be detailed description of the present invention:
Pantoprazole Sodium is all unstable to light, heat, oxygen and water, can not satisfy the requirement of injection.In the prior art, the report of existing many relevant freeze-dried powder injection of pantoprazole sodium.But these disclosed freeze-dried powder injection of pantoprazole sodium or stability are bad, or the pharmaceutic adjuvant large usage quantity, thereby bring some side effect.
One aspect of the present invention is exactly to provide that a kind of side effect is little, the pantoprazole sodium freeze-drying medicinal composition for injection of good stability.
Freeze-drying medicinal composition provided by the present invention comprises following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.01-0.1 weight portion
Disodium edetate 0.02-0.03 weight portion
Sodium sulfite 0.07-0.10 weight portion
Sodium citrate 0-0.1 weight portion.
Because the easy oxidation of Pantoprazole Sodium, added a certain amount of sodium sulfite among the present invention to prevent pharmaceutical preparation generation oxidation reaction, because metal ion can play catalytic action, add the metal ion chelation agent disodium edetate in the prescription of the present invention simultaneously, can increase the stability of solution.
The present invention adds a spot of lyophilizing caffolding agent for the outward appearance that makes freeze-dried powder is more attractive in appearance.The present invention selects for use mannitol as the lyophilizing caffolding agent, and except as the pharmaceutic adjuvant, itself also has pharmacological action, if can improve plasma osmotic pressure, produces dehydration, can be used for prophylaxis of acute renal failure and treatment glaucoma and cerebral edema etc. clinically.Because mannitol has its oneself pharmacological action, human body should be taken in as far as possible less, so should be to add a spot of mannitol as far as possible in pharmaceutical preparation.The present invention is by the improvement to prescription, adds the adjuvant of minute quantity and reaches the preparation that meets medicinal standard.
Simultaneously, the present invention has also taken into full account the stability problem of making behind the preparation.In prescription of the present invention, can add a certain amount of sodium citrate, can certainly not add.But preferably add a certain amount of sodium citrate, in the present invention, select for use sodium citrate, not only can guarantee its stability in normal saline, and find having good stability of this pharmaceutical composition as stabilizing agent.
On the other hand, the invention provides a kind of preparation method of pantoprazole sodium freeze-drying medicinal composition for injection of the present invention, wherein, described preparation method comprises the steps:
1) mannitol and disodium edetate are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value of sodium hydrate regulator solution is to alkalescence;
2) add sodium sulfite and sodium citrate in sterile chamber, stirring and dissolving gets solution A;
3) in solution A, add Pantoprazole Sodium again, stir and make dissolving, obtain solution B;
4) in solution B, add needle-use activated carbon, stirring and adsorbing, filtering decarbonization, benefit adds to the full amount of water for injection, and crosses microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.
Pantoprazole Sodium is unstable to acid, stable to alkali, because it is acid that the disodium edetate solution of recipe quantity shows, dissolve together if directly main Pantoprazole Sodium is added in the disodium edetate solution or with principal agent and disodium edetate, place a period of time, the impurity of principal agent Pantoprazole Sodium increases, content slightly descends, and earlier with sodium hydroxide the pH value of disodium edetate solution is transferred to alkalescence, adds the principal agent Pantoprazole Sodium again, stirring makes its dissolving, can significantly increase its stability.
In the preparation method of the present invention, wherein, the pH value described in the step 1) to alkalescence is 11.0-11.5 for pH value.
The present invention finds can significantly increase its stability when the pH value of solution is 11.0-11.5.
In the preparation method of the present invention, wherein, the temperature of solution A is controlled between 2-8 ℃ when adding Pantoprazole Sodium in the step 3).
The present invention is directed to Pantoprazole Sodium to heat-labile characteristics, when adding Pantoprazole Sodium, the stable of sterile chamber is controlled between 2-8 ℃, thereby made a stable cryogenic solution environmental, thereby guaranteed Pantoprazole Sodium stablizing from be formulated into the whole process of fill.
Wherein, be to add needle-use activated carbon in the step 4) by the 0.01-0.05% of solution amount.
The adding proper amount of active carbon can improve the clarity of injection, can adsorb thermal source, pigment again, but active carbon also has adsorption to Pantoprazole Sodium simultaneously.The inventor adopts the content of spectrophotometry Pantoprazole Sodium, has investigated the influence to pantoprazole sodium content in the injection pantoprazole sodium pharmaceutical composition of active carbon, temperature, adsorption time.The result shows, activated carbon dosage be solution amount 0.01%～0.05%, 10～20 ℃ of absorption 20～30 minutes down, effect is preferable, again with in 15 ℃ of absorption 20～30 minutes down, best results.
According to the preparation method of aforesaid pantoprazole sodium freeze-drying medicinal composition for injection, wherein, the described lyophilization of step 4) is: be cooled to-50～-45 ℃ earlier, and pre-freeze 1.5～2.5h, evacuation then, and by 2.5～3.5 ℃ of h
-1Be warming up to-5～-15 ℃, afterwards by 4.5～5.5 ℃ of h
-1Be warming up to 25～35 ℃, insulation 1.5～2.5h.
The present invention has carried out strict control to freeze drying process, has guaranteed that not only the profile of product is full, but also has improved the stability of product.
Compared with prior art, the present invention has following advantage:
(1) the present invention by to adjuvant select meticulously and to the strictness of each supplementary product consumption restriction, minimizing big and stability problem may produce the patient because of the adjuvant addition side effect and curative effect problem, drug safety is provided, when reaching medicinal standard, further improved stability of drug;
(2) the inventive method can improve the stability of pantoprazole sodium solution greatly, no matter be that the related substance of pantoprazole sodium solution does not all have obvious increase, content and do not have obvious decline yet in preparation, packing or the freeze-drying process during preparation, the freeze-dried powder injection of pantoprazole sodium of preparation having good stability in transportation and storage process, compatibility solution can be placed the long period during clinical use, make clinical use become convenient, also having reduced greatly simultaneously increases the curative effect problem of descending and bringing to the patient for hidden danger that patient's drug safety brings and content because of impurity (related substance).
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
Prescription:
Pantoprazole Sodium 20g
Mannitol 2g
Disodium edetate 0.4g
Sodium sulfite 1.4g
Sodium citrate 1g
Make 1000 bottles
Preparation technology:
1) mannitol 2g and disodium edetate 0.4g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value of sodium hydrate regulator solution is to alkalescence;
2) add sodium sulfite 1.4g and sodium citrate 1g in sterile chamber, stirring and dissolving gets solution A;
3) in solution A, add Pantoprazole Sodium 20g again, stir and make dissolving, obtain solution B;
4) in solution B, add needle-use activated carbon, stirring and adsorbing, filtering decarbonization is added water for injection to 1000ml, crosses microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.
Embodiment 2
Prescription:
Pantoprazole Sodium 20g
Mannitol 2g
Disodium edetate 0.4g
Sodium sulfite 1.4g
Sodium citrate 1g
Make 1000 bottles
Preparation technology:
1) mannitol 2g and disodium edetate 0.4g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value to 11.0 of sodium hydrate regulator solution;
2) add sodium sulfite 1.4g and sodium citrate 1g in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled at 2 ℃, adds Pantoprazole Sodium 20g in solution A, stirs and makes dissolving, obtains solution B;
4) add needle-use activated carbon by 0.01% of solution amount in solution B, 10 ℃ of following stirring and adsorbing 20 minutes, filtering decarbonization was added water for injection to 1000ml, crossed microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.Wherein said lyophilization is: be cooled to-50 ℃ earlier, and pre-freeze 2.5h, evacuation then, and by 2.5 ℃ of h
-1Be warming up to-5 ℃, afterwards by 5.5 ℃ of h
-1Be warming up to 25 ℃, insulation 1.5h.
Embodiment 3
Prescription:
Pantoprazole Sodium 20g
Mannitol 1g
Disodium edetate 0.5g
Sodium sulfite 1.4g
Sodium citrate 1g
Make 1000 bottles
Preparation technology:
1) mannitol 1g and disodium edetate 0.5g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value to 11.5 of sodium hydrate regulator solution;
2) add sodium sulfite 1.4g and sodium citrate 1g in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled at 8 ℃, adds Pantoprazole Sodium 20g in solution A, stirs and makes dissolving, obtains solution B;
4) add needle-use activated carbon by 0.05% of solution amount in solution B, 20 ℃ of following stirring and adsorbing 30 minutes, filtering decarbonization was added water for injection to 1000ml, crossed microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.Wherein said lyophilization is: be cooled to-45 ℃ earlier, and pre-freeze 1.5h, evacuation then, and by 3.5 ℃ of h
-1Be warming up to-15 ℃, afterwards by 4.5 ℃ of h
-1Be warming up to 35 ℃, insulation 2.5h.
Embodiment 4
Prescription:
Pantoprazole Sodium 20g
Mannitol 0.2g
Disodium edetate 0.4g
Sodium sulfite 2.0g
Sodium citrate 2.0g
Make 1000 bottles
Preparation technology:
1) mannitol 0.2g and disodium edetate 0.4g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value to 11.3 of sodium hydrate regulator solution;
2) add sodium sulfite 2.0g and sodium citrate 2.0g in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled at 5 ℃, adds Pantoprazole Sodium 20g in solution A, stirs and makes dissolving, obtains solution B;
4) add needle-use activated carbon by 0.02% of solution amount in solution B, 15 ℃ of following stirring and adsorbing 25 minutes, filtering decarbonization was added water for injection to 1000ml, crossed microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.Wherein said lyophilization is: be cooled to-48 ℃ earlier, and pre-freeze 2.0h, evacuation then, and by 3.0 ℃ of h
-1Be warming up to-10 ℃, afterwards by 4.8 ℃ of h
-1Be warming up to 30 ℃, insulation 2.0h.
Embodiment 5
Prescription:
Pantoprazole Sodium 20g
Mannitol 1.6g
Disodium edetate 0.6g
Sodium sulfite 1.6g
Sodium citrate 0.4g
Make 1000 bottles
Preparation technology:
1) mannitol 1.6g and disodium edetate 0.6g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value to 11.5 of sodium hydrate regulator solution;
2) add sodium sulfite 1.6g and sodium citrate 0.4g in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled at 4 ℃, adds Pantoprazole Sodium 20g in solution A, stirs and makes dissolving, obtains solution B;
4) add needle-use activated carbon by 0.02% of solution amount in solution B, 18 ℃ of following stirring and adsorbing 25 minutes, filtering decarbonization was added water for injection to 1000ml, crossed microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.Wherein said lyophilization is: be cooled to-46 ℃ earlier, and pre-freeze 1.8h, evacuation then, and by 2.6 ℃ of h
-1Be warming up to-7 ℃, afterwards by 5.2 ℃ of h
-1Be warming up to 26 ℃, insulation 1.6h.
Embodiment 6
Prescription:
Pantoprazole Sodium 20g
Mannitol 1.6g
Disodium edetate 0.6g
Sodium sulfite 1.6g
Make 1000 bottles
Preparation technology:
1) mannitol 1.6g and disodium edetate 0.6g are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value to 11.5 of sodium hydrate regulator solution;
2) add sodium sulfite 1.6g and sodium citrate 0.4g in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled at 4 ℃, adds Pantoprazole Sodium 20g in solution A, stirs and makes dissolving, obtains solution B;
4) add needle-use activated carbon by 0.02% of solution amount in solution B, 18 ℃ of following stirring and adsorbing 25 minutes, filtering decarbonization was added water for injection to 1000ml, crossed microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.Wherein said lyophilization is: be cooled to-46 ℃ earlier, and pre-freeze 1.8h, evacuation then, and by 2.6 ℃ of h
-1Be warming up to-7 ℃, afterwards by 5.2 ℃ of h
-1Be warming up to 26 ℃, insulation 1.6h.
Test example 1
This test example be to investigate different caffolding agents to the influence of freeze-dried powder injection of pantoprazole sodium quality to screen suitable caffolding agent.
Table 1, freeze-dried powder injection of pantoprazole sodium caffolding agent The selection result
| Caffolding agent | Consumption (g/1000 props up) | Color and luster | Outward appearance | pH | Clarity |
| Sodium chloride | 1.9 | White | Loose block | 10.86 | Clear and bright |
| Glucose | 2.3 | Yellow | Loose block | 10.23 | Clear and bright |
| Lactose | 1.8 | Yellow | Loose block | 10.56 | Clear and bright |
| Mannitol | 2 | White | Loose block | 10.75 | Clear and bright |
Table 2, different support agent system freeze-dried powder injection of pantoprazole sodium and common infusion fluid compatibility result (2h)
By table 1 and table 2 as can be known, caffolding agent has certain influence to the quality of finished product.As caffolding agent, the finished product color and luster that obtains is relatively poor with glucose and lactose; As caffolding agent, when clinical compatibility, be prone to muddiness with sodium chloride; Finished product is found that along with the prolongation of time, liquid color is with flavescence when containing the transfusion compatibility of glucose, and this mainly is because the higher less stable of glucose that causes of pH value of preparation causes.Result to sum up, the present invention finally selects the caffolding agent of mannitol as lyophilized injectable powder for use.
Test example 2
This test example is to investigate the influence to pantoprazole sodium content in the injection of activated carbon dosage, temperature, adsorption time.
1, the preparation of Pantoprazole Sodium sample solution: precision takes by weighing the about 0.68g of Pantoprazole Sodium, puts in the 5000ml volumetric flask, is diluted with water to scale, shakes up, and measures content, as reserve liquid.
2, different time and different amounts active carbon are to the influence of Pantoprazole Sodium absorption: get reserve liquid 100ml25 part respectively, per 5 parts is one group, adds active carbon 0 respectively, 0.01,0.05,0.10,0.15g, in every group 5 parts stir 15,20,25,30 respectively in 30 ℃ of thermostat water baths, 35min, be cooled to 10-15 ℃, filter, get subsequent filtrate and measure trap according to containing quantifier below method, calculate content, the results are shown in Table 3:
Table 3. active carbon different amounts and of the influence (%) of different mixings time to the pantoprazole sodium content
3, temperature is to the influence of pantoprazole sodium content: get reserve liquid 100ml6 part respectively, add the 0.05g active carbon successively, under 5,10,15,20,25,30 ℃ of conditions, stir 20min respectively, be cooled to the 15-20 after-filtration, get subsequent filtrate and measure trap according to method under the assay item, calculate content, the results are shown in Table 4:
Table 4. temperature is to the influence of pantoprazole sodium content
| Temperature (℃) | 5 | 10 | 15 | 20 | 25 | 30 |
| Content (%) | 100.42 | 94.89 | 99.87 | 95.41 | 92.26 | 88.54 |
From table a as can be seen, the consumption of active carbon was greater than 0.05% o'clock, and the content of Pantoprazole Sodium obviously descends, adsorption time is long more, content descends obvious more, and therefore activated carbon dosage is between 0.01%～0.05% in preparation process, and adsorption time was advisable at 20～30 minutes.
From table b as can be seen, along with the rising of temperature, the activated carbon adsorption effect is obvious more, so adsorption temp is advisable the best when being 15 ℃ at 10 ℃～20 ℃.
Test example 3
Prescription of the present invention is reduced to minimum limit through repeatedly experiment with the addition of adjuvant in the prescription.And reaching Clinical Application by experiment confirms, this prescription that contains the adjuvant of minute quantity has good stability, injection freeze-dried powder injection of pantoprazole sodium of the present invention mixes back color, clarity, content and related substance in 4 hours significant change does not take place with the 100mL0.9%NaCl injection, concrete outcome sees Table 5.
Table 5
Claims (8)
1. a pantoprazole sodium freeze-drying medicinal composition for injection is characterized in that, described freeze-drying medicinal composition is made up of following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.01-0.1 weight portion
Disodium edetate 0.02-0.03 weight portion
Sodium sulfite 0.07-0.10 weight portion
Sodium citrate 0-0.1 weight portion;
The preparation method of described freeze-drying medicinal composition comprises the steps:
1) mannitol and disodium edetate are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value of sodium hydrate regulator solution is to 11.0-11.5;
2) add sodium sulfite and sodium citrate in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled between 2-8 ℃, adds Pantoprazole Sodium again in solution A, stirs and makes dissolving, obtains solution B;
4) in solution B, add needle-use activated carbon, stirring and adsorbing, filtering decarbonization, benefit adds to the full amount of water for injection, and crosses microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.
2. pantoprazole sodium freeze-drying medicinal composition for injection according to claim 1 is characterized in that, described freeze-drying medicinal composition is made up of following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.05-0.1 weight portion
Disodium edetate 0.02-0.025 weight portion
Sodium sulfite 0.07-0.08 weight portion
Sodium citrate 0.05-0.1 weight portion.
3. freeze-drying medicinal composition according to claim 2 is characterized in that, described pharmaceutical composition is made up of following component:
Pantoprazole Sodium 1 weight portion
Mannitol 0.1 weight portion
Disodium edetate 0.02 weight portion
Sodium sulfite 0.07 weight portion
Sodium citrate 0.05 weight portion.
4. the preparation method of any described pantoprazole sodium freeze-drying medicinal composition for injection of claim 1-3 is characterized in that, described preparation method comprises the steps:
1) mannitol and disodium edetate are put in the sterile chamber, the water for injection that adds total liquid measure 80% makes it dissolving, uses 0.1molL
-1The pH value of sodium hydrate regulator solution is to 11.0-11.5;
2) add sodium sulfite and sodium citrate in sterile chamber, stirring and dissolving gets solution A;
3) temperature with solution A is controlled between 2-8 ℃, adds Pantoprazole Sodium again in solution A, stirs and makes dissolving, obtains solution B;
4) in solution B, add needle-use activated carbon, stirring and adsorbing, filtering decarbonization, benefit adds to the full amount of water for injection, and crosses microporous filter membrane, measure content after, fill in glass tube vial, every 1mL;
5) fill is good sample is inserted in the freezer dryer, promptly gets injection pantoprazole sodium freeze-drying compositions through lyophilization, after rolling the cap seal mouth.
5. the preparation method of pantoprazole sodium freeze-drying medicinal composition for injection according to claim 4 is characterized in that, in the step 4) is to add needle-use activated carbon by the 0.01-0.05% of solution amount.
6. the preparation method of pantoprazole sodium freeze-drying medicinal composition for injection according to claim 4 is characterized in that, the stirring and adsorbing described in the step 4) is 10～20 ℃ of following stirring and adsorbing 20～30 minutes.
7. the preparation method of pantoprazole sodium freeze-drying medicinal composition for injection according to claim 6 is characterized in that, the stirring and adsorbing described in the step 4) is 15 ℃ of following stirring and adsorbing 20～30 minutes.
8. according to the preparation method of any described pantoprazole sodium freeze-drying medicinal composition for injection of claim 4-7, it is characterized in that the described lyophilization of step 4) is: be cooled to-50～-45 ℃ earlier, pre-freeze 1.5～2.5h, evacuation then, and by 2.5～3.5 ℃ of h
-1Be warming up to-5～-15 ℃, afterwards by 4.5～5.5 ℃ of h
-1Be warming up to 25～35 ℃, insulation 1.5～2.5h.
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| CN102225063B (en) * | 2011-05-10 | 2012-10-10 | 江苏奥赛康药业股份有限公司 | Pantoprazole sodium composition for injection |
| CN102525960B (en) * | 2012-01-16 | 2013-03-20 | 湖北济生医药有限公司 | Pantoprazole sodium medicinal composition and preparation method thereof |
| CN105193745A (en) * | 2015-09-18 | 2015-12-30 | 康普药业股份有限公司 | Pantoprazole sodium freeze-drying medicine composition for injection and preparation method thereof |
| CN112587486B (en) * | 2020-12-29 | 2022-05-13 | 南京健友生化制药股份有限公司 | Pantoprazole sodium freeze-dried powder injection for injection and preparation method thereof |
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