CN104146967A - Esomeprazole freeze-dried powder injection and preparation method thereof - Google Patents
Esomeprazole freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN104146967A CN104146967A CN201410331220.2A CN201410331220A CN104146967A CN 104146967 A CN104146967 A CN 104146967A CN 201410331220 A CN201410331220 A CN 201410331220A CN 104146967 A CN104146967 A CN 104146967A
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- esomeprazole
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Abstract
The invention discloses esomeprazole freeze-dried powder injection and a preparation method thereof. The preparation method comprises the following steps: preparing a main agent esomeprazole, auxiliary agents comprising a protective agent, a stabilizer and an excipient, a PH regulator and water for injection at a weight ratio of 1:(0.45-0.65):(0.25-0.5):50, arranging the components in a mixing tank, introducing inert gases, accelerating stirring until the mixture is foaming in a vacuum state, and performing filtering, split charging, pretreatment and freeze drying to obtain the finished esomeprazole freeze-dried powder injection. In the preparation process, a vacuum foaming technology is adopted, and the moisture in liquid medicine is greatly reduced, so that the freeze drying time of the liquid medicine is only 50 percent of that of an existing process, the specific surface area of the foamed materials is obviously enlarged, the properties of medicines are obviously improved, and the prepared finished powder injection is bulk in volume, difficult in agglomeration, high in re-dissolubility and high in clarity and has the advantage of high heat resistance. Moreover, the pharmacological activity of the medicines can be kept after injection, and the bioavailability of the medicines is greatly improved.
Description
Technical field
The invention belongs to a kind of pharmaceutical preparation, be specifically related to a kind of esomeprazole freeze-dried powder and preparation method thereof.
Background technology
Esomeprazole is the S-isomer of omeprazole, is that first can be used for the isomer proton pump inhibitor of clinical intravenous route administration in the world, and its effect is stronger.Its mechanism of action is protonated under acidulated condition, change into and there is the compound sulfenamide that suppresses H+/K+-ATP enzymatic activity, the sulfydryl of cysteine is combined and is formed disulfide bond on H+/K+-ATP enzyme rapidly, thereby make enzyme deactivation, thereby specificity suppresses H+/K+-ATP enzymatic activity gastric acid secretion inhibiting in parietal cell.Esomeprazole is a kind of proton pump inhibitor, has stronger more lasting gastric acid suppress ability compared with comparing of other, and metabolism individual variation and the side effect of esomeprazole are all less.Clinical practice shows, esomeprazole, controlling aspect the symptoms such as gastric and duodenal ulcers, gastro oesophageal reflux disease (GORD) and the caused epigastrium pain of reflux esophagitis, acid regurgitation and belch, has rapid-action, effect lasting stability, side effect is little, short treating period, the advantage such as curative effect is reliable.
CN102973524A discloses " a kind of esomeprazole lyophilized injectable powder and preparation method thereof ", and the weight ratio of the esomeprazole of this injection and disodium edetate and/or calcium disodium edetate is 1:0.01～0.1, and pH value is 9.5～11.5.Preparation method is that disodium edetate and/or calcium disodium edetate are dissolved in water for injection, it is 10.5～12.5 that sodium hydroxide is adjusted pH value, add esomeprazole to be stirred to dissolving, add water for injection to full dose and obtain medicinal liquid, adopt ultrafiltration except thermal source gained medicinal liquid again, the medicinal liquid after ultrafiltration obtains powder pin through aseptic filtration, fill lyophilizing.The method products obtained therefrom related substance is low, deposits that in process, related substance is without rising appreciably, and content is without obvious decline, but freeze-drying time reaches more than 20 hour, and esomeprazole own is insoluble in water, be lyophilized into after bulk and be more difficult to redissolve, after redissolving, clarity is difficult to ensure.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art and provide a kind of pharmacologically active of medicine strong, bioavailability is high, heat resistance is superior, and a kind of esomeprazole freeze-dried powder that freeze-drying time is short, energy resource consumption is low and preparation method thereof.
The object of the present invention is achieved like this: a kind of esomeprazole freeze-dried powder, comprise host esomeprazole, adjuvant, PH regulator and water for injection, it is characterized in that: the weight ratio of described host esomeprazole and adjuvant, PH regulator and water for injection is 1:0.45～0.65:0.25～0.5:50; Described esomeprazole freeze-dried powder is prepared as follows: host esomeprazole is dissolved in to water for injection and stirs to clarify; add adjuvant to comprise that protective agent, stabilizing agent and mixed with excipients stir and be placed in agitator tank; pass into noble gas and under vacuum state, accelerate to be stirred to foaming, subpackage, pretreatment, lyophilization obtain esomeprazole freeze-dried powder finished product after filtration.
Described host esomeprazole and adjuvant comprise that the percentage by weight of protective agent, stabilizing agent and excipient is: esomeprazole 60%～70%, protective agent 26%～30%, stabilizing agent 2%～4%, excipient 3%～6%.
Described protective agent is at least one in sucrose, Pluronic-F68, trehalose, sorbose, melezitose, sorbitol, stachyose, Raffinose, fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, glucose, mannitol, xylitol, threitol, glycerol.
Described stabilizing agent is at least one of gelatin, kollidon, ovalbumin, collagen protein, chondroitin sulfate, actin, myosin, dynein, kinetins, human serum albumin.
Described excipient is at least one of arginine, methionine, ethylenediaminetetraacetic acid and glycerol.
Described PH regulator is phosphate buffer, potassium phosphate, sodium phosphate, sodium acetate, histidine, sodium citrate, sodium succinate, the ammonium bicarbonate of 25mM pH7.2, the one of carbonate.
Described noble gas is N
2, CO
2, CH
4, H
2one.
Prepare a method for esomeprazole freeze-dried powder, it is characterized in that comprising the steps:
1. medicinal liquid preparation: the esomeprazole that takes weight portion is dissolved in 3/4ths water for injection, stirs to clarify under 25 DEG C of room temperature conditions, obtains medicinal liquid A; The adjuvant that takes weight portion comprises that protective agent, stabilizing agent and excipient add in medicinal liquid A, and mixing and stirring is adjusted PH to 4～10, adds water for injection to full dose, obtains medical liquid B;
2. vacuum foam: medical liquid B is placed in to vacuum stirring tank, the output frequency of vacuum pump is 35Hz, manual adjustments vacuum is 50Pa, stablize after 3～5 minutes and start to stir, in stirring, pass into noble gas, accelerate to be stirred to foaming, close manual modulation valve, vacuum in tank is dropped to rapidly below 10Pa, and temperature is down to 0～5 DEG C, obtains medicinal liquid C;
3. pretreatment: medicinal liquid C is filtered to subpackage, partly cover bottle stopper, be placed on freezer dryer dividing plate and carry out pretreatment, shelf temperature is set as 15 DEG C, and pretreatment time is 20～40 minutes;
4. lyophilization: primary drying regulates shelf temperature to-35～-45 DEG C, is warming up to 10 DEG C in 4 hours, continues dry 2～2.5 hours; Redrying is warming up to 25～31 DEG C by shelf temperature with 0.7 DEG C/min, continues dry 7.5～8.5 hours to obtain esomeprazole freeze-dried powder finished product.
The flow that described step passes into noble gas in is 2. 0.8～1.2m
3/ h, the time is 20～40 minutes.
The described step 2. middle speed of accelerating to stir is 1800～2200 revs/min
Compared with prior art, major advantage of the present invention is:
1, the present invention allocates protective agent in host esomeprazole, the adjuvant such as stabilizing agent and excipient, wherein select sucrose, Pluronic-F68, trehalose, sorbose, melezitose, sorbitol, stachyose, Raffinose, fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, glucose, mannitol, xylitol, threitol, one or more in glycerol are as protective agent, such protective agent can replace moisture to be centered around around bioactive materials in dry run, improve the intensity of material molecular structure, avoid material to be directly exposed in surrounding simultaneously, prevent material degeneration in dry run.One or more that select gelatin, kollidon, ovalbumin, collagen, chondroitin sulfate, actin, myosin, dynein, kinetins, human serum albumin are as stabilizing agent; in dry run, can strengthen the viscosity of material; make the foaming structure producing stablize, be difficult for breaking; provide protection to material, dried cystose medicine is still easy to rehydration and uses.Select the aminoacid such as arginine, methionine, glycerol, one or more of ethylenediaminetetraacetic acid are as excipient, aminoacid is because can remove Oxidation, desamidation, can stable protein structure, thereby the stability of raising bioactive materials, glycerol can be used as polyalcohols protective agent and the plasticiser of dried foam; Ethylenediaminetetraacetic acid can be removed the metal ion in solution, avoid metal ion to destroy radical reaction, glycerol can be used as surfactant simultaneously increases the dissolubility of other composition, can reduce the loss of activity that biomolecule causes due to surface tension in foaming process, the stability of reinforced foam, improve the rehydration performance of foam, contribute to the rehydration of medicine after foam-drying finishes to use.
2, the present invention adopts vacuum foam technology in preparation process, select and can not produce chemical reaction, the noble gas that can not change medicine character is as physical blowing agent, the medicinal liquid preparing is passed into while stirring under vacuum state to noble gas, make it expand into cystose, after filtration, after subpackage and pretreatment, under vacuum, heat one again, redrying, owing to can taking away large quantity of moisture in foaming process, therefore, primary drying temperature level can be far above the primary drying temperature level of traditional freeze-drying, significantly shorten drying time, it is only 50% of existing technique drying time.
3, the present invention adopts the specific surface area of the rear material of foam freeze drying process foaming to enlarge markedly, medicine character situation be improved significantly, the powder pin finished-product volume making is bulk, prevented from caking, solubility is good, and clarity is high, not only in heat resistance, has advantage, and can keep the pharmacologically active of medicine after injection, the bioavailability of medicine improves greatly.
Detailed description of the invention:
The present invention will be further described for following examples:
Embodiment 1:
Formula:
Preparation method:
1. medicinal liquid preparation: the esomeprazole that takes weight portion is dissolved in 3/4ths water for injection, stirs to clarify under 25 DEG C of room temperature conditions, obtains medicinal liquid A; The sucrose, Pluronic-F68, gelatin, arginine and the glycerol that take weight portion add in medicinal liquid A, and mixing and stirring, with the phosphate buffer adjusting PH to 4 of 25mM pH7.2, adds water for injection to full dose, obtains medical liquid B;
2. vacuum foam: medical liquid B is placed in to vacuum stirring tank, and the output frequency of vacuum pump is 35Hz, and manual adjustments vacuum is 50Pa, stablizes after 3 minutes and starts to stir, and in stirring, passes into noble gas N
2, the flow passing into is 0.8m
3/ h, time are 20 minutes, and mixing speed is 1800 revs/min, accelerate to be stirred to foaming, close manual modulation valve, and vacuum in tank is dropped to rapidly below 10Pa, and temperature is down to 0 DEG C, obtains medicinal liquid C;
3. pretreatment: medicinal liquid C is filtered to subpackage, partly cover bottle stopper, be placed on freezer dryer dividing plate and carry out pretreatment, shelf temperature is set as 15 DEG C, and pretreatment time is 20 minutes;
4. lyophilization: primary drying regulates shelf temperature to-35 DEG C, is warming up to 10 DEG C in 4 hours, continues dry 2 hours; Redrying is warming up to 25 DEG C by shelf temperature with 0.7 DEG C/min, continues dry 7.5 hours to obtain esomeprazole freeze-dried powder finished product.
Embodiment 2:
Formula:
Preparation method:
1. medicinal liquid preparation: the esomeprazole that takes weight portion is dissolved in 3/4ths water for injection, stirs to clarify under 25 DEG C of room temperature conditions, obtains medicinal liquid A; The lactose, sorbitol, ovalbumin, methionine and the glycerol that take weight portion add in medicinal liquid A, and mixing and stirring, with sodium phosphate adjusting PH to 7, adds water for injection to full dose and obtains medical liquid B;
2. vacuum foam: medical liquid B is placed in to vacuum stirring tank, and the output frequency of vacuum pump is 35Hz, and manual adjustments vacuum is 50Pa, stablizes after 4 minutes and starts to stir, and in stirring, passes into noble gas CO
2, the flow passing into is 1m
3/ h, time are 30 minutes, and mixing speed is 2000 revs/min, accelerate to be stirred to foaming, close manual modulation valve, and vacuum in tank is dropped to rapidly below 10Pa, and temperature is down to 2 DEG C, obtains medicinal liquid C;
3. pretreatment: medicinal liquid C is filtered to subpackage, partly cover bottle stopper, be placed on freezer dryer dividing plate and carry out pretreatment, shelf temperature is set as 15 DEG C, and pretreatment time is 30 minutes;
4. lyophilization: primary drying regulates shelf temperature to-40 DEG C, is warming up to 10 DEG C in 4 hours, continues dry 2.2 hours; Redrying is warming up to 28 DEG C by shelf temperature with 0.7 DEG C/min, continues dry 8 hours to obtain esomeprazole freeze-dried powder finished product.
Embodiment 3:
Preparation method:
1. medicinal liquid preparation: the esomeprazole that takes weight portion is dissolved in 3/4ths water for injection, stirs to clarify under 25 DEG C of room temperature conditions, obtains medicinal liquid A; The mannose, xylitol, collagen protein, ethylenediaminetetraacetic acid and the glycerol that take weight portion add in medicinal liquid A, and mixing and stirring, with ammonium bicarbonate adjusting PH to 10, adds water for injection to full dose, obtains medical liquid B;
2. vacuum foam: medical liquid B is placed in to vacuum stirring tank, and the output frequency of vacuum pump is 35Hz, and manual adjustments vacuum is 50Pa, stablizes after 5 minutes and starts to stir, and in stirring, passes into noble gas CH
4, the flow passing into is 1.2m
3/ h, time are 40 minutes, and mixing speed is 2200 revs/min, accelerate to be stirred to foaming, close manual modulation valve, and vacuum in tank is dropped to rapidly below 10Pa, and temperature is down to 5 DEG C, obtains the medicinal liquid C after foaming;
3. pretreatment: medicinal liquid C is filtered to subpackage, partly cover bottle stopper, be placed on freezer dryer dividing plate and carry out pretreatment, shelf temperature is set as 15 DEG C, and pretreatment time is 40 minutes;
4. lyophilization: primary drying regulates shelf temperature to-45 DEG C, is warming up to 10 DEG C in 4 hours, continues dry 2.5 hours; Redrying is warming up to 31 DEG C by shelf temperature with 0.7 DEG C/min, continues dry 8.5 hours to obtain esomeprazole freeze-dried powder finished product.
For character, ph, related substance and the content of checking product of the present invention, embodiment 1～3 product of preparation and character, ph, related substance and the content of commercial like product 1～3 have been carried out inspection contrast by present inventor, and it the results are shown in Table 1.
Table 1:
From table 1, assay shows, its character of embodiment of the present invention finished product, ph, related substance and content all conform to quality requirements.Meanwhile, the finished product that the inventor also prepares embodiment has carried out pharmacological evaluation, and its stimulation test and allergic experiment result are non-stimulated and allergic phenomena.
For the stability of checking product quality of the present invention, present inventor is placed in the sample of embodiment 1～3 and commercially available 1～3 similar sample the quality stability test of carrying out long-term 18 months under the condition of 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10% and investigates, and its investigation the results are shown in Table 2.The sample of the present invention 1～3 embodiment and commercially available 1～3 similar sample are placed in to the test of accelerating 6 months under the condition of 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 10% simultaneously and investigate, test is investigated and be the results are shown in Table 3.
Table 2:
Table 3:
From table 2, table 3, experimental result shows, the acceleration test in 6 months of carrying out under the condition of the test investigation in long-term 18 months of carrying out under the condition of 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10% and 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 10% is investigated and is all conformed to quality requirements, relatively commercially available 1～3 sample of its stability has had raising greatly, has increased the safety of medication.According to corresponding zest and anaphylaxis experiment, in use reduce the zest of medicine simultaneously, reduced the conflict of patient to medicine.
Claims (10)
1. an esomeprazole freeze-dried powder, comprise host esomeprazole, adjuvant, PH regulator and water for injection, it is characterized in that: the weight ratio of described host esomeprazole and adjuvant, PH regulator and water for injection is 1:0.45～0.65:0.25～0.5:50; Described esomeprazole freeze-dried powder is prepared as follows: host esomeprazole is dissolved in to water for injection and stirs to clarify; add adjuvant to comprise that protective agent, stabilizing agent and mixed with excipients stir and be placed in agitator tank; pass into noble gas and under vacuum state, accelerate to be stirred to foaming, subpackage, pretreatment, lyophilization obtain esomeprazole freeze-dried powder finished product after filtration.
2. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described host esomeprazole and adjuvant comprise that the percentage by weight of protective agent, stabilizing agent and excipient is: esomeprazole 60%～70%, protective agent 26%～30%, stabilizing agent 2%～4%, excipient 3%～6%.
3. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described protective agent is at least one of sucrose, Pluronic-F68, lactose, sorbitol, xylitol and glycerol.
4. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described stabilizing agent is at least one of gelatin, ovalbumin, collagen protein.
5. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described excipient is at least one of arginine, methionine, ethylenediaminetetraacetic acid and glycerol.
6. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described PH regulator is phosphate buffer, the sodium phosphate of 25mM pH7.2, the one of ammonium bicarbonate.
7. a kind of esomeprazole freeze-dried powder according to claim 1, is characterized in that described noble gas is N
2, CO
2, CH
4one.
8. a method of preparing esomeprazole freeze-dried powder described in claim 1, is characterized in that comprising the steps:
1. medicinal liquid preparation: the esomeprazole that takes weight portion is dissolved in 3/4ths water for injection, stirs to clarify under 25 DEG C of room temperature conditions, obtains medicinal liquid A; The adjuvant that takes weight portion comprises that protective agent, stabilizing agent and excipient add in medicinal liquid A, and mixing and stirring is adjusted PH to 4～10, adds water for injection to full dose, obtains medical liquid B;
2. vacuum foam: medical liquid B is placed in to vacuum stirring tank, the output frequency of vacuum pump is 35Hz, manual adjustments vacuum is 50Pa, stablize after 3～5 minutes and start to stir, in stirring, pass into noble gas, accelerate to be stirred to foaming, close manual modulation valve, vacuum in tank is dropped to rapidly below 10Pa, and temperature is down to 0～5 DEG C, obtains medicinal liquid C;
3. pretreatment: medicinal liquid C is filtered to subpackage, partly cover bottle stopper, be placed on freezer dryer dividing plate and carry out pretreatment, shelf temperature is set as 15 DEG C, and pretreatment time is 20～40 minutes;
4. lyophilization: primary drying regulates shelf temperature to-35～-45 DEG C, is warming up to 10 DEG C in 4 hours, continues dry 2～2.5 hours; Redrying is warming up to 25～31 DEG C by shelf temperature with 0.7 DEG C/min, continues dry 7.5～8.5 hours to obtain esomeprazole freeze-dried powder finished product.
9. a kind of method of preparing esomeprazole freeze-dried powder described in claim 1 according to claim 8, the flow that it is characterized in that passing into during described step 2. noble gas is 0.8～1.2m
3/ h, the time is 20～40 minutes.
10. a kind of method of preparing esomeprazole freeze-dried powder described in claim 1 according to claim 8, is characterized in that the speed of accelerating to stir during described step is 2. 1800～2200 revs/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410331220.2A CN104146967B (en) | 2014-07-11 | A kind of esomeprazole freeze-dried powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410331220.2A CN104146967B (en) | 2014-07-11 | A kind of esomeprazole freeze-dried powder and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104146967A true CN104146967A (en) | 2014-11-19 |
| CN104146967B CN104146967B (en) | 2016-11-30 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420660A (en) * | 2016-08-29 | 2017-02-22 | 海南合瑞制药股份有限公司 | Enteric-coated esomeprazole magnesium pellet |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319223A (en) * | 2011-09-21 | 2012-01-18 | 石药集团欧意药业有限公司 | Esomeprazole freeze-dried preparation and preparation method thereof |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319223A (en) * | 2011-09-21 | 2012-01-18 | 石药集团欧意药业有限公司 | Esomeprazole freeze-dried preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 施铭耀: "疫苗的泡沫冷冻干燥工艺研究", 《浙江大学硕士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420660A (en) * | 2016-08-29 | 2017-02-22 | 海南合瑞制药股份有限公司 | Enteric-coated esomeprazole magnesium pellet |
| CN106420660B (en) * | 2016-08-29 | 2019-09-03 | 海南合瑞制药股份有限公司 | A kind of esomeprazole enteric capsules |
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