CN101074202A - Production of injecting reductive glutathione - Google Patents
Production of injecting reductive glutathione Download PDFInfo
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- CN101074202A CN101074202A CN 200610054295 CN200610054295A CN101074202A CN 101074202 A CN101074202 A CN 101074202A CN 200610054295 CN200610054295 CN 200610054295 CN 200610054295 A CN200610054295 A CN 200610054295A CN 101074202 A CN101074202 A CN 101074202A
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Abstract
Production of injection reducing glutathione is carried out by pre-freezing for reducing glutathione solution and freeze-drying. It's simple, cheap, has stable product quality and less water content and related substances and can be used for industrial production.
Description
Technical field
The present invention relates to field of medicine preparations, more particularly, is a kind of preparation method of glutathione for injection.
Background technology
Gsh is distributed widely in Mammals, plant and the microorganism cells, be topmost, content is the abundantest contains the sulfydryl low molecular active peptide, is the important antioxidant component of biochemical system, in the liver biochemistry metabolism, play an important role.Clinical medicine mainly as detoxifcation, antioxygenation, control tumour patient chemotherapy and medicamentous liver lesion, the chronic fatty liver of treatment, treatment viral hepatitis and liver cirrhosis etc.
Reduced glutathion is responsive to ratio of specific heat, and instability and viscosity are big in the aqueous solution, and more oxidized, and above situation all easily causes related substances to raise.Therefore to take stable Technology aborning, avoid the too high detrimentally affect of airborne oxygen, moisture and temperature product.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of glutathione for injection, to solve the problem that moisture and related substance easily exceed standard in the currently available products.
The inventor adopts nitrogen protection at the glutathione for injection all round process, has solved the problem of the easy oxidation of reduced glutathion.And on practical basis for many years, freeze-dry process has been carried out a large amount of explorations, summed up unique reduced glutathion cryodesiccated freeze-drying curve of being applicable to, greatly degree avoided the too high detrimentally affect of airborne oxygen, moisture and freeze-drying process temperature to product, the moisture and the related substance of product is controlled at lower level.
In freeze-drying process, the inventor finds that the reduced glutathion soltion viscosity is bigger, and surface solution forms a vitrified amorphous structure on the surface of freezing product because speed of freezing is too slow, and whole structure of freezing product is homogeneous no longer.In the process of distillation, because the existence of the amorphism structure of surface vitrification will increase the upwards mobile resistance of overflowing of water vapor, distillation is obstructed.Product tends to that thin film or shell are arranged more or less on the surface, and spray dish phenomenon occurs.The random loose passage of product section, tending to has vitreous state tomography or blister cavity in the centre, all be in higher level through the product moisture and the related substance of this explained hereafter, and quality product is had considerable influence.
The present invention adopted before operation freeze-drying program, carried out pre-freeze earlier, can address this problem well.The pre-freeze stage kept 3 hours at-30～-20 ℃ earlier, was raised to-5～-1 ℃ in 2 hours, kept 1 hour, dropped to-42 ℃ then in 1.5 hours again, kept 2 hours, vacuumized again.This pre-freeze process effect is: the eutectic point of reduced glutathion solution is about-20 ℃, allow products temperature slowly drop to-20 ℃ earlier, when solution temperature is lower than apparent freezing point, part in the solution can be separated out in crystallization, and remaining strength of solution will rise, and the apparent freezing point temperature descends along with the increase of strength of solution, then continue cooling, ice crystal increases along with cooling, and remaining strength of solution increases thereupon, and dense solute forms dispersion comparatively uniformly around ice crystal under-20 ℃.Elevated temperature again, when beginning to freeze near 0 ℃, ice crystal is the hexagonal symmetric figure, grows forward at six major axes orientations, simultaneously, also some countershafts can occur, and all ice crystals couple together, and form a network structure in solution.The process that kept 1 hour can make this structure slowly firm, comparatively fast drops to-42 ℃ again, makes the strong solution of not freezing form fine-grain, highly meticulous small vesicular structure occurs, the regular and homogeneous of entire structure.During sublimation drying, moisture is overflowed from loose passage smoothly, and this pre-freeze process can make soup form loose preferably skeleton, helps the distillation of moisture.The product section is cellular uniformly after the freeze-drying, and moisture and related substance all can be in lower level.
Preparation method's whole process of glutathione for injection of the present invention is:
(1) gets recipe quantity sodium hydroxide, add an amount of cooling water for injection and be mixed with sodium hydroxide solution.
(2) get an amount of water for injection, cooling feeds aseptic nitrogen adds recipe quantity after 15～20 minutes gsh and is made into suspension.
(3) all feed under aseptic nitrogen and the airtight condition at sodium hydroxide solution and suspension, sodium hydroxide solution is slowly added in the gsh suspension pH value to 5.2 of regulator solution～5.4.
(4) add to the full amount of water for injection, continue to feed aseptic nitrogen, stir sterile filtration.
(5) be filled in the freeze-drying tray, formerly kept 1.5 hours, in 2 hours, be raised to-5～-1 ℃, kept 1 hour at-30～-20 ℃, in 2 hours, drop to-42 ℃ then again, kept 2 hours, vacuumize, be warming up to 50～53 ℃, be incubated 13～14 hours, freeze-drying finishes.
(6) outlet, crushing screening divides the aseptic film bag of packing into.Adopt the high velocity air portioning machine cillin bottle of packing into, tamponade is rolled lid and is promptly got glutathione for injection of the present invention.
The reduced glutathion steady quality that adopts present method to make, moisture and related substances all meet the effect phase internal control quality standard of glutathione for injection, far below statutory standards (National Drug Administration's drug standard (trying) WS-449 (X-400)-2001 (2)), see Table 1 with the contrast of the technology of not carrying out pre-freeze.This product is in storage, and moisture and related substance can slowly rise, and therefore, for guaranteeing this product (2 years) up-to-standard before the deadline, the inner quality standard of dispatching from the factory of product is moisture≤3.0%, related substance≤2.8%.
The sample quality detected result of two kinds of freeze-dry process preparations of table 1
| Test item | Statutory standards | Adopt the sample of pre-freeze prepared | Do not adopt the sample of pre-freeze prepared | |||
| 040401 | 040402 | 040403 | 040404 | 040405 | ||
| Proterties | Should be white porous block or powder | White powder | White powder | White powder | White powder | White powder |
| Moisture | ≤5.0％ | 1.4％ | 1.4％ | 1.5％ | 2.8％ | 2.9％ |
| Related substance | ≤4.0％ | 1.6％ | 1.8％ | 1.7％ | 3.7％ | 3.8％ |
| Content | Should be 92.0%～110.0% of labelled amount | 99.9％ | 99.5％ | 99.6％ | 95.9％ | 94.5％ |
Adopt glutathione for injection that this pre-freeze technology makes under 40 ℃ ± 2 ℃, relative humidity 75 ± 5% conditions, to carry out accelerated test, the result shows every index and did not relatively have considerable change in 0 month, the effect phase internal control quality standard that all meets glutathione for injection is far below statutory standards (seeing Table 2); Carry out long-term stable experiment under 20 ℃ ± 2 ℃, relative humidity 75 ± 10% conditions, the result shows every index and did not relatively have considerable change in 0 month, all meets the effect phase internal control quality standard of glutathione for injection, far below statutory standards (seeing Table 3).
Table 2 040401 batch sample accelerated test result
| Test item | Statutory standards | 0 month | January | February | March | June |
| Proterties | Should be white porous block or powder | White powder | White powder | White powder | White powder | White powder |
| Visible foreign matters | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
| Weight loss on drying | ≤5.0％ | 1.5％ | 1.5％ | 1.6％ | 1.8％ | 1.8％ |
| Related substance | ≤4.0％ | 1.7％ | 1.8％ | 2.0％ | 2.1％ | 2.4％ |
| PH value | 4.8～5.8 | 5.1 | 5.1 | 5.2 | 5.1 | 5.3 |
| Content | Should be 92.0%～110.0% of labelled amount | 99.8％ | 98.9％ | 98.2％ | 98.5％ | 97.9％ |
Table 3 040401 batch sample permanent stability result
| Test item | Statutory standards | 0 month | March | June | September | December | 18 months | 24 months |
| Proterties | Should be white porous block or powder | White powder | White powder | White powder | White powder | White powder | White powder | White powder |
| Visible foreign matters | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
| Weight loss on drying | ≤5.0％ | 1.6％ | 1.5％ | 1.5％ | 1.6％ | 1.7％ | 1.7％ | 1.9％ |
| Related substance | ≤4.0％ | 1.7％ | 1.7％ | 1.9％ | 1.8％ | 2.1％ | 2.3％ | 2.3％ |
| PH value | 4.8～5.8 | 5.2 | 5.2 | 5.2 | 5.3 | 5.2 | 5.2 | 5.2 |
| Content | Should be 92.0%～110.0% of labelled amount | 99.8％ | 99.5％ | 99.7％ | 98.8％ | 97.9％ | 97.5％ | 97.3％ |
Compared with prior art, the present invention has following beneficial effect:
1, the present invention carries out pre-freeze earlier before the freeze-drying program, has guaranteed that the moisture of glutathione for injection and related substance are controlled at lower level.Constant product quality, method is simple, and easy handling is suitable for industrialized production.
2, in freeze-drying process, soup height homogeneous, the temperature transmission is even, and moisture is easily overflowed from loose passage, phenomenons such as the too high or local spray dish of local temperature can not occur.
3, adopt nitrogen protection in the production whole process, product has no chance to contact with oxygen in the air, has avoided the oxidation of product.
Embodiment
The present invention is described further by following examples.
Embodiment 1
Get 1.6kg sodium hydroxide, add an amount of cooling water for injection and be mixed with sodium hydroxide solution.Get an amount of water for injection, cooling feeds aseptic nitrogen and adds the 12kg gsh after 15～20 minutes and be made into suspension.All feed under aseptic nitrogen and the airtight condition at sodium hydroxide solution and suspension, sodium hydroxide solution is slowly added in the gsh suspension pH value to 5.2～5.4 of regulator solution.Add to the full amount of water for injection, continue to feed aseptic nitrogen, stir sterile filtration.Be filled in the freeze-drying tray, every dish is irritated 7kg, keeps 3 hours at-20 ℃ earlier, is raised to-5 ℃ again in 2 hours,-5 ℃ kept 1 hour, in 1.5 hours, drop to-42 ℃ then again, kept 2 hours, vacuumize, be warming up to 50～53 ℃, be incubated 13～14 hours, freeze-drying finishes, and feeds the aseptic nitrogen of exsiccant and presses again.Outlet, crushing screening divides the aseptic film bag of packing into.Adopt the high velocity air portioning machine cillin bottle of packing into, tamponade is rolled lid and is promptly got glutathione for injection of the present invention.
Embodiment 2
Get 1.6kg sodium hydroxide, add an amount of cooling water for injection and be mixed with sodium hydroxide solution.Get an amount of water for injection, cooling feeds aseptic nitrogen and adds the 12kg gsh after 15～20 minutes and be made into suspension.All feed under aseptic nitrogen and the airtight condition at sodium hydroxide solution and suspension, sodium hydroxide solution is slowly added in the gsh suspension pH value to 5.2 of regulator solution～5.4.Add to the full amount of water for injection, continue to feed aseptic nitrogen, stir sterile filtration.Be filled in the freeze-drying tray, every dish is irritated 7kg, keeps 3 hours at-30 ℃ earlier, is raised to-5 ℃ again in 2 hours,-5 ℃ kept 1 hour, in 1.5 hours, drop to-42 ℃ then again, kept 2 hours, vacuumize, be warming up to 50～53 ℃, be incubated 13～14 hours, freeze-drying finishes, and feeds the aseptic nitrogen of exsiccant and presses again.Outlet, crushing screening divides the aseptic film bag of packing into.Adopt the high velocity air portioning machine cillin bottle of packing into, tamponade is rolled lid and is promptly got glutathione for injection of the present invention.
Embodiment 3
Get 1.6kg sodium hydroxide, add an amount of cooling water for injection and be mixed with sodium hydroxide solution.Get an amount of water for injection, cooling feeds aseptic nitrogen and adds the 12kg gsh after 15～20 minutes and be made into suspension.All feed under aseptic nitrogen and the airtight condition at sodium hydroxide solution and suspension, sodium hydroxide solution is slowly added in the gsh suspension pH value to 5.2 of regulator solution～5.4.Add to the full amount of water for injection, continue to feed aseptic nitrogen, stir sterile filtration.Be filled in the freeze-drying tray, every dish is irritated 7kg, keeps 3 hours at-20 ℃ earlier, is raised to-1 ℃ again in 2 hours,-1 ℃ kept 1 hour, in 1.5 hours, drop to-42 ℃ then again, kept 2 hours, vacuumize, be warming up to 50～53 ℃, be incubated 13～14 hours, freeze-drying finishes, and feeds the aseptic nitrogen of exsiccant and presses again.Outlet, crushing screening divides the aseptic film bag of packing into.Adopt the high velocity air portioning machine cillin bottle of packing into, tamponade is rolled lid and is promptly got glutathione for injection of the present invention.
Claims (3)
1, a kind of preparation method of glutathione for injection is characterized in that elder generation with reduced glutathion sodium solution pre-freeze, the freeze-drying program of reruning.
2, preparation method as claimed in claim 1 is characterized in that the program of pre-freeze is: kept 3 hours at-30～-20 ℃ earlier, be raised to-5～-1 ℃ again in 2 hours, kept 1 hour.
3, preparation method as claimed in claim 1 is characterized in that freeze dried program is: dropped to-42 ℃ after the pre-freeze in 1.5 hours, kept 2 hours, vacuumize, be warming up to 50～53 ℃, be incubated 13～14 hours, freeze-drying finishes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100542956A CN101074202B (en) | 2006-05-16 | 2006-05-16 | Production of injecting reductive glutathione |
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| CN2006100542956A CN101074202B (en) | 2006-05-16 | 2006-05-16 | Production of injecting reductive glutathione |
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| CN101074202A true CN101074202A (en) | 2007-11-21 |
| CN101074202B CN101074202B (en) | 2012-08-08 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101647783B (en) * | 2009-07-24 | 2010-12-22 | 上海复旦复华药业有限公司 | Prefreezing method in preparing injection-used reduced glutathione with freeze drying method |
| CN102151251A (en) * | 2011-01-11 | 2011-08-17 | 山东绿叶制药有限公司 | Method for freeze-drying reducing glutathione for injection |
| CN102335411A (en) * | 2011-09-22 | 2012-02-01 | 山东金城医药化工股份有限公司 | Novel process for preparing reduced glutathione monosodium salt preparation for injection |
| CN102670523A (en) * | 2011-03-18 | 2012-09-19 | 海南中化联合制药工业股份有限公司 | Method for preparing injection reduced glutathione freeze-dried powder |
| CN105434368A (en) * | 2014-11-27 | 2016-03-30 | 广州白云山明兴制药有限公司 | Reduced glutathione for injection and pre-freezing method thereof |
| CN107531751A (en) * | 2015-03-31 | 2018-01-02 | 公立大学法人大阪市立大学 | The crystal of reduced glutathione |
| CN108567970A (en) * | 2018-05-25 | 2018-09-25 | 福安药业集团湖北人民制药有限公司 | High stable glutathione for injection |
| CN113398280A (en) * | 2020-03-16 | 2021-09-17 | 武汉广行科学研究有限公司 | Ligand-bound copper clusters, compatibility of ligand-bound copper clusters and application of ligand-bound copper clusters in treatment of liver cirrhosis |
-
2006
- 2006-05-16 CN CN2006100542956A patent/CN101074202B/en active Active
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101647783B (en) * | 2009-07-24 | 2010-12-22 | 上海复旦复华药业有限公司 | Prefreezing method in preparing injection-used reduced glutathione with freeze drying method |
| CN102151251A (en) * | 2011-01-11 | 2011-08-17 | 山东绿叶制药有限公司 | Method for freeze-drying reducing glutathione for injection |
| CN102670523A (en) * | 2011-03-18 | 2012-09-19 | 海南中化联合制药工业股份有限公司 | Method for preparing injection reduced glutathione freeze-dried powder |
| CN102335411A (en) * | 2011-09-22 | 2012-02-01 | 山东金城医药化工股份有限公司 | Novel process for preparing reduced glutathione monosodium salt preparation for injection |
| CN102335411B (en) * | 2011-09-22 | 2014-03-26 | 山东金城医药化工股份有限公司 | Novel process for preparing reduced glutathione monosodium salt preparation for injection |
| CN105434368A (en) * | 2014-11-27 | 2016-03-30 | 广州白云山明兴制药有限公司 | Reduced glutathione for injection and pre-freezing method thereof |
| CN107531751A (en) * | 2015-03-31 | 2018-01-02 | 公立大学法人大阪市立大学 | The crystal of reduced glutathione |
| JPWO2016159317A1 (en) * | 2015-03-31 | 2018-02-01 | 公立大学法人大阪市立大学 | Crystals of reduced glutathione |
| EP3279208A4 (en) * | 2015-03-31 | 2018-11-14 | Osaka City University | Crystal of reduced glutathione |
| US10640532B2 (en) | 2015-03-31 | 2020-05-05 | University Public Corporation Osaka | Crystal of reduced glutathione |
| CN108567970A (en) * | 2018-05-25 | 2018-09-25 | 福安药业集团湖北人民制药有限公司 | High stable glutathione for injection |
| CN108567970B (en) * | 2018-05-25 | 2021-09-24 | 福安药业集团湖北人民制药有限公司 | Preparation method of reduced glutathione for injection |
| CN113398280A (en) * | 2020-03-16 | 2021-09-17 | 武汉广行科学研究有限公司 | Ligand-bound copper clusters, compatibility of ligand-bound copper clusters and application of ligand-bound copper clusters in treatment of liver cirrhosis |
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| Publication number | Publication date |
|---|---|
| CN101074202B (en) | 2012-08-08 |
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