CN102670524B - Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof - Google Patents
Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof Download PDFInfo
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- CN102670524B CN102670524B CN 201210135474 CN201210135474A CN102670524B CN 102670524 B CN102670524 B CN 102670524B CN 201210135474 CN201210135474 CN 201210135474 CN 201210135474 A CN201210135474 A CN 201210135474A CN 102670524 B CN102670524 B CN 102670524B
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Abstract
The invention relates to a pantoprazole sodium freeze-dried preparation for injection and a preparation method thereof. The freeze-dried preparation is formed by preparing components containing the following parts by weight into liquor for freeze drying after dissolving into water for injection: 60 to 80 parts of pantoprazole sodium, 100 to 300 parts of glycocoll, 50 to 100 parts of glucose and aright amount of sodium hydroxide. According to the pantoprazole sodium freeze-dried preparation for the injection, which is disclosed by the invention, the problem of stability of a preparation is solved; and moreover, an adverse reaction existing in a traditional product is lowered.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains Pantoprazole Sodium, particularly a kind of injection pantoprazole sodium freeze-drying preparation and preparation method thereof belongs to the Western medicine preparation technical field.
Background technology
(Pantoprazole Sodium PAN-Na) is proton pump inhibitor behind omeprazole, lansoprazole to Pantoprazole Sodium, in the gastric mucosa parietal cell, reduces H in the cell by specific effect
+-K
+The activity of/ATP enzyme, thereby the secretion of gastric acid inhibitory are used for the treatment of acutes hemorrhage of upper gastrointestinal tract such as duodenal ulcer, gastric ulcer, AGML, plyability gastric ulcer.
The injection Pantoprazole Sodium is at present domestic to have the Duo Jia pharmaceutical factory to produce listing, mainly adopts clinically to join in 0.9% sodium chloride injection after the dedicated solvent dissolving and does intravenous drip.In addition, as follows about the bibliographical information of pantoprazole sodium freeze-drying powder injection formulation:
CN101011397A discloses a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.This freeze-dried powder injection of pantoprazole sodium, pH value are 9.5-11.5, and its prescription comprises following components by weight portion: 1 part of Pantoprazole Sodium, and proppant 0.5-1 part, weak acid strong alkali salt 0-0.06 part, inorganic base is an amount of.Its preparation method may further comprise the steps: 1) get material by following parts by weight proportioning: proppant 0.5-1 part, weak acid strong alkali salt 0-0.06 part, 1 part of Pantoprazole Sodium; 2) proppant and weak acid strong alkali salt are dissolved with water for injection, transfer pH value to 9.5-11.5 with inorganic base, add Pantoprazole Sodium, the dissolving back transfers pH value to 9.5-11.5 with inorganic base; 3) filter; 4) lyophilizing obtains freeze-dried powder injection of pantoprazole sodium.
CN101810588A discloses a kind of pantoprazole sodium freeze-drying medicinal composition for injection and preparation method thereof.This pantoprazole sodium freeze-drying medicinal composition for injection 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 and sodium citrate 0-0.1 weight portion.
CN1679563A discloses a kind of freeze-dried powder injection of pantoprazole sodium, counts by weight, and its composition comprises: 1 part of Pantoprazole Sodium, and excipient 0-0.125 part, weak acid strong alkali salt 0.075-0.125 part, disodium edetate 0.025-0.0375 part, inorganic base is an amount of.
Although the freeze-dried powder injection of pantoprazole sodium of above-mentioned bibliographical information has solved the problem of preparation stability, yet because the adjuvant that adds is too much, might cause the side effect that other are unknown, influence patient's drug safety.In addition, there are the untoward reaction such as diarrhoea of persistence in the injection Pantoprazole Sodium that has gone on the market at present.Therefore, reduce the diarrhoea untoward reaction that Pantoprazole Sodium produces by preparation research, medication interdependence and the therapeutic effect of patient in clinical all had positive facilitation.
Summary of the invention
In view of the deficiencies in the prior art, the objective of the invention is to carry out a large amount of screening test researchs by prescription and technology to the injection Pantoprazole Sodium, a kind of injection pantoprazole sodium freeze-drying preparation and preparation method thereof is provided.The inventor is surprised to find that this injection pantoprazole sodium freeze-drying preparation has not only solved the problem of preparation stability, and has reduced the diarrhoea untoward reaction that existing product exists.
First purpose of the present invention is achieved in that
A kind of injection pantoprazole sodium freeze-drying preparation is dissolved in by the component that contains following weight portion and is mixed with the medicinal liquid lyophilizing behind the water for injection and forms:
First purpose of the present invention can also realize like this:
Described injection pantoprazole sodium freeze-drying preparation is dissolved in by the component that contains following weight portion and is mixed with the medicinal liquid lyophilizing behind the water for injection and forms:
Described injection pantoprazole sodium freeze-drying preparation is dissolved in by the component that contains following weight portion and is mixed with the medicinal liquid lyophilizing behind the water for injection and forms:
In preferred embodiment of the present invention, described injection pantoprazole sodium freeze-drying preparation is dissolved in by the component of following weight portion and is mixed with the medicinal liquid lyophilizing behind the water for injection and forms:
In another preferred embodiment of the present invention, described injection pantoprazole sodium freeze-drying preparation is dissolved in by the component of following weight portion and is mixed with the medicinal liquid lyophilizing behind the water for injection and forms:
Second purpose of the present invention is achieved in that
The preparation method of described injection pantoprazole sodium freeze-drying preparation comprises the steps:
(1) measures the water for injection that cumulative volume 70%-85% measures, when treating that temperature is down to below 40 ℃, successively add glucose, the glycine of recipe quantity, be stirred to dissolving; The Pantoprazole Sodium that adds recipe quantity then while stirring stirs and makes its dissolving;
(2) with 1mol/L sodium hydroxide solution regulator solution pH=10.5-10.8, add injection water standardize solution, stir evenly;
(3) take by weighing in the needle-use activated carbon adding solution of amount of preparation 0.1%, stirring and adsorbing 15min filters decarburization, with 0.45 μ m microporous filter membrane coarse filtration, with 0.22 μ m microporous filter membrane fine straining;
(4) liquid drug under the aseptic condition, lyophilization in the freeze dryer is sent in sabot.
Preferably, the preparation method of described lyophilized injectable powder, wherein freezing dry process is as follows: the sample inlet, sample temperature is down to insulation below-40 ℃ 1-2 hour; The open cold condenser is down to below-50 ℃ temperature, and vacuum is evacuated to below the 10Pa in the case, distils after 0.8-1.2 hour, sample is warming up to-15 ± 1 ℃, sublimation drying 8-9 hour; In 2.8-3.2 hour, sample is warming up to-5 ± 1 ℃ from-15 ± 1 ℃ then, in 4-6 hour, is warming up to 35 ± 1 ℃ from-5 ± 1 ℃, keep vacuum 3-5Pa at last, be incubated and fill nitrogen after 3-4 hour, tamponade, outlet.
Compared with prior art, injection pantoprazole sodium freeze-drying preparation that the present invention relates to and preparation method thereof has following advantage and marked improvement: (1) untoward reaction reduces.Find that by animal experiment pantoprazole sodium freeze-drying preparation of the present invention can significantly reduce the diarrhoea untoward reaction that existing product exists, this is indicating that its interdependence and therapeutic effect to patient's medication all has positive facilitation.(2) stability is high.Find that by accelerated test checking back pantoprazole sodium freeze-drying preparation of the present invention is under acceleration environment, its molding is good, and skeleton is loose, redissolves effective.In addition, its basicity, clarity, related substance and content are the generation significant change.The injection Pantoprazole Sodium of this explanation the present invention preparation has good stability.
The specific embodiment
Form is described in further detail foregoing of the present invention again by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment 1 injection Pantoprazole Sodium
Prescription is formed:
Preparation technology:
(1) measures the water for injection of cumulative volume 2500ml, when treating that temperature is down to below 40 ℃, successively add glucose, the glycine of recipe quantity, be stirred to dissolving; The Pantoprazole Sodium that adds recipe quantity then while stirring stirs and makes its dissolving;
(2) with 1mol/L sodium hydroxide solution regulator solution pH=10.5-10.8, add the injection water and be settled to 3000ml, stir evenly;
(3) take by weighing in the needle-use activated carbon adding solution of amount of preparation 0.1%, stirring and adsorbing 15min filters decarburization, with 0.45 μ m microporous filter membrane coarse filtration, with 0.22 μ m microporous filter membrane fine straining;
(4) liquid drug under the aseptic condition, lyophilization in the freeze dryer is sent in sabot.
Wherein, described freezing dry process is as follows: the sample inlet, sample temperature is down to insulation below-40 ℃ 1.5 hours; The open cold condenser is down to below-50 ℃ temperature, and vacuum is evacuated to below the 10Pa in the case, distils after 1 hour, sample is warming up to about-15 ℃ sublimation drying 8.5 hours; In 3 hours, sample is warming up to about-5 ℃ from-15 ℃ then, in 5 hours, is warming up to about 35 ℃ from-5 ℃, keep vacuum 4Pa at last, be incubated and fill nitrogen after 3.5 hours, tamponade, outlet.
The preparation of embodiment 2 injection Pantoprazole Sodiums
Prescription is formed:
Preparation technology:
(1) measures the water for injection of cumulative volume 2400ml, when treating that temperature is down to below 40 ℃, successively add glucose, the glycine of recipe quantity, be stirred to dissolving; The Pantoprazole Sodium that adds recipe quantity then while stirring stirs and makes its dissolving;
(2) with 1mol/L sodium hydroxide solution regulator solution pH=10.5-10.8, add the injection water and be settled to 3000ml, stir evenly;
(3) take by weighing in the needle-use activated carbon adding solution of amount of preparation 0.1%, stirring and adsorbing 15min filters decarburization, with 0.45 μ m microporous filter membrane coarse filtration, with 0.22 μ m microporous filter membrane fine straining;
(4) liquid drug under the aseptic condition, lyophilization in the freeze dryer is sent in sabot.
Wherein, described freezing dry process is as follows: the sample inlet, sample temperature is down to insulation below-40 ℃ 1.5 hours; The open cold condenser is down to below-50 ℃ temperature, and vacuum is evacuated to below the 10Pa in the case, distils after 1 hour, sample is warming up to about-15 ℃ sublimation drying 8.5 hours; In 3 hours, sample is warming up to about-5 ℃ from-15 ℃ then, in 5 hours, is warming up to about 35 ℃ from-5 ℃, keep vacuum 4Pa at last, be incubated and fill nitrogen after 3.5 hours, tamponade, outlet.
The preparation of embodiment 3 injection Pantoprazole Sodiums
Prescription is formed:
Preparation technology: with embodiment 1.
The preparation of embodiment 4 injection Pantoprazole Sodiums
Prescription is formed:
Preparation technology: with embodiment 1.
The preparation of comparative example's 1 injection Pantoprazole Sodium
Prescription is formed:
Pantoprazole Sodium 60g (Pantoprazole Sodium is in free acid)
Mannitol 60g
Sodium hydroxide is regulated described medicinal liquid pH=10.5-10.8.
Preparation technology:
(1) measures the water for injection of cumulative volume 1800ml, when treating that temperature is down to below 40 ℃, successively add the mannitol of recipe quantity, be stirred to dissolving; The Pantoprazole Sodium that adds recipe quantity then while stirring stirs and makes its dissolving;
(2) with 1mol/L sodium hydroxide solution regulator solution pH=10.5-10.8, add the injection water and be settled to 2000ml, stir evenly;
(3) take by weighing in the needle-use activated carbon adding solution of amount of preparation 0.1%, stirring and adsorbing 15min filters decarburization, with 0.45 μ m microporous filter membrane coarse filtration, with 0.22 μ m microporous filter membrane fine straining;
(4) liquid drug under the aseptic condition, lyophilization in the freeze dryer is sent in sabot.
Wherein, described freezing dry process is as follows: the sample inlet, sample temperature is down to insulation below-40 ℃ 1.5 hours;
The open cold condenser is down to below-50 ℃ temperature, and vacuum is evacuated to below the 10Pa in the case, distils after 1 hour, sample is warming up to about-15 ℃ sublimation drying 8.5 hours; In 3 hours, sample is warming up to about-5 ℃ from-15 ℃ then, in 5 hours, is warming up to about 35 ℃ from-5 ℃, keep vacuum 4Pa at last, be incubated and fill nitrogen after 3.5 hours, tamponade, outlet.
Embodiment 5 injection Pantoprazole Sodium stability of formulation are investigated test
Injection pantoprazole sodium sample according to the preparation of the formulation and technology of embodiment 1-4 packs with cillin bottle, is placed on following 12 months of the environment of 40 ℃ of temperature, humidity 75%, carries out the accelerated test of preparation.Accelerated test result shows that its molding is good, and skeleton is loose, redissolves effective.In addition, its basicity, clarity, related substance and content are the generation significant change.The injection Pantoprazole Sodium of this explanation the present invention preparation has good stability.
Get each 1 bottle of the injection Pantoprazole Sodium of embodiment 1 preparation respectively, place 0.9% sodium chloride solution 100ml, shake up, respectively at 0,1,2,3 hour sampling and measuring content, pH value, related substance, and check outward appearance and clarity.Result of the test sees Table 1.
Result's (60 ℃) is investigated in table 1 hot test
The result shows that the freeze-dried powder injection of pantoprazole sodium of the present invention's preparation is in 0.9% sodium chloride injection, and internal stability was good in 3 hours.
Embodiment 6 freeze-dried powder injection of pantoprazole sodium cause the experimental study of rat diarrhoea incidence rate
40 of healthy SD rats, male, body weight (180 ± 20) g is divided into normal control group (10), test A group (15), test B group (15) at random.Wherein:
Test A group: joined the freeze-dried powder injection of pantoprazole sodium of doing above-mentioned comparative example's 1 preparation of intravenous drip in 0.9% sodium chloride injection in continuous 7 days, dosage is 10mg Pantoprazole Sodium/(kgd);
Test B group: continuous 7 join the freeze-dried powder injection of pantoprazole sodium of doing 1 preparation of the intravenous drip embodiment of the invention in 0.9% sodium chloride injection, and dosage is 10mg Pantoprazole Sodium/(kgd);
Normal control group: continuous 2 days intravenous drip normal saline 100ml/ (kgd).
Administration places metabolic cage with rat after finishing, and spreads white filter paper at the bottom of the cage to observe the stool situation, and every day, observed and recorded was 2 times.Its diarrhoea methods of marking is:
0 minute: stool was normal;
1 minute: laxativeness, stool is visible slight wet soft;
2 minutes: moderate diarrhoea, stool were wet and shapeless, and have slight crissum painted;
3 minutes: severe diarrhoea, watery stool was also painted with the severe crissum.
(3) test results and analysis
Behind the rat injection freeze-dried powder injection of pantoprazole sodium, can be observed the diarrhoea untoward reaction, it is 2 as follows that the appraisal result of diarrhoea sees Table.
Table 2 is respectively organized rat diarrhoea situation relatively
Compare with test A group,
*P＜0.05,
*P＜0.01.
According to the result of the test of table 2 as can be seen, freeze-dried powder injection of pantoprazole sodium diarrhoea incidence rate of the present invention is starkly lower than 1 group of comparative example (P＜0.05 or P＜0.01), and this is indicating that its medication interdependence and therapeutic effect to the patient all has positive facilitation.
Claims (7)
1. injection pantoprazole sodium freeze-drying preparation is characterized in that: be dissolved in by the component of following weight portion and be mixed with the medicinal liquid lyophilizing behind the water for injection and form:
2. injection pantoprazole sodium freeze-drying preparation according to claim 1 is characterized in that: be dissolved in by the component of following weight portion and be mixed with the medicinal liquid lyophilizing behind the water for injection and form:
3. injection pantoprazole sodium freeze-drying preparation according to claim 1 is characterized in that: be dissolved in by the component of following weight portion and be mixed with the medicinal liquid lyophilizing behind the water for injection and form:
4. injection pantoprazole sodium freeze-drying preparation according to claim 2 is characterized in that: be dissolved in by the component of following weight portion and be mixed with the medicinal liquid lyophilizing behind the water for injection and form:
5. injection pantoprazole sodium freeze-drying preparation according to claim 3 is characterized in that: be dissolved in by the component of following weight portion and be mixed with the medicinal liquid lyophilizing behind the water for injection and form:
6. the preparation method of each described injection pantoprazole sodium freeze-drying preparation of claim 1-5 comprises the steps:
(1) measures the water for injection that cumulative volume 70%-85% measures, when treating that temperature is down to below 40 ℃, successively add glucose, the glycine of recipe quantity, be stirred to dissolving; The Pantoprazole Sodium that adds recipe quantity then while stirring stirs and makes its dissolving;
(2) with 1mol/L sodium hydroxide solution regulator solution pH=10.5-10.8, add injection water standardize solution, stir evenly;
(3) take by weighing in the needle-use activated carbon adding solution of amount of preparation 0.1%, stirring and adsorbing 15min, filtering decarbonization is with 0.45 μ m microporous filter membrane coarse filtration, with 0.22 μ m microporous filter membrane fine straining;
(4) liquid drug under the aseptic condition, lyophilization in the freeze dryer is sent in sabot.
7. according to the preparation method of the described injection pantoprazole sodium freeze-drying of claim 6 preparation, it is characterized in that: described freezing dry process is as follows: the sample inlet is incubated 1-2 hour with sample temperature Jiang Zhi – below 40 ℃; The open cold condenser makes temperature Jiang Zhi – below 50 ℃, and vacuum is evacuated to below the 10Pa in the case, distils after 0.8-1.2 hour, sample is Shenged 15 ± 1 ℃ of Wen Zhi –, sublimation drying 8-9 hour; 15 ± 1 ℃ of sample Cong – are Shenged 5 ± 1 ℃ of Wen Zhi – then in 2.8-3.2 hour, Cong – is warming up to 35 ± 1 ℃ for 5 ± 1 ℃ Nei 4-6 hour, keeps vacuum 3-5Pa at last, is incubated to fill nitrogen after 3-4 hour, tamponade, outlet.
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| CN104998267B (en) * | 2014-04-21 | 2018-02-23 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition of Esomeprazole sodium |
| CN104188924B (en) * | 2014-09-01 | 2019-12-27 | 山东绿叶制药有限公司 | Pantoprazole sodium pharmaceutical composition for injection |
| CN110693821A (en) * | 2019-09-26 | 2020-01-17 | 无锡凯夫制药有限公司 | Method for preparing pantoprazole sodium for injection |
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| CN1235018A (en) * | 1999-04-22 | 1999-11-17 | 沈阳东宇药业有限公司 | Preparation of freeze-dried pantoprazole injection and preparing method thereof |
| CN101961309B (en) * | 2010-09-15 | 2012-06-27 | 河南辅仁怀庆堂制药有限公司 | Process for preparing pantoprazole sodium for injection |
| CN102000034B (en) * | 2010-10-13 | 2011-12-21 | 江苏奥赛康药业股份有限公司 | S-pantoprazole sodium composite for 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 |
| 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 |
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Inventor after: Cai Xiaofang Inventor before: Yuan Hongbo Inventor before: Cai Xiaofang |