CN103585018A - New freeze-drying method for reduced glutathione for injection - Google Patents
New freeze-drying method for reduced glutathione for injection Download PDFInfo
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- CN103585018A CN103585018A CN201310533779.9A CN201310533779A CN103585018A CN 103585018 A CN103585018 A CN 103585018A CN 201310533779 A CN201310533779 A CN 201310533779A CN 103585018 A CN103585018 A CN 103585018A
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Abstract
The invention discloses a new freeze-drying method for reduced glutathione for injection. The method comprises the steps that tert butyl alcohol is added into a glutathione preparation solution at first, and then freeze drying is conducted. According to the new freeze-drying method for reduced glutathione for injection, the prepared reduced glutathione is qualified in quality, and freeze-drying time is greatly shortened.
Description
Technical field
What the present invention relates to is field of medicaments, more specifically a kind of new freeze-dry process method that shortens the freeze-drying time of glutathione for injection.
Background technology
Glutathion is a kind of natural activity peptide with important physiological function, and it is comprised of glutamic acid, cysteine and glycine.It is the important antioxidant content in biosystem, and plays a significant role in liver biochemistry metabolism.There is clinically removing toxic substances, antioxidation curative effect, be mainly used in prevention and treatment Chemotherapy of Tumor Patients and Drug hepar damnification, treat various hepatitis.
Reduced glutathion is because existing active sulfydryl unstable and to thermo-responsive, therefore generally adopt aseptic manipulation to make freeze-dried powder injection for clinical in water.But the viscosity of reduced glutathion aqueous solution is large, surface solution is because freezing speed forms the glazed amorphous structure of a kind of class slowly on surface, cause in product lyophilization process, the resistance increment that steam upwards flows and overflows, water sublimed difficulty, it is large that freeze-drying process is controlled difficulty, lyophilization cycle is long, and specification is larger, product water solution concentration is larger, and its lyophilizing difficulty is also larger.And, the eutectic point lower (between-20～-30 ℃) of reduced glutathion, during primary drying, cold drying for a long time, also causes lyophilization cycle significant prolongation.Therefore, guaranteeing that, under the prerequisite of product quality, shortening freeze-drying time is a problem demanding prompt solution.
Open or authorize, in patent about reduced glutathion freeze-dry process (application number 200610054295.6,200610023149.7,201110004370.9), although once and/or the technique of redrying there are differences, but substantially all adopt the method for rising again in pre-freeze process, to guarantee to form the microcrystal grain of homogeneous, avoid surperficial glass amorphous structure, or the formation of coarse crystal, thereby reach the object that shortens lyophilization cycle.
The tert-butyl alcohol is a kind of alternative good non-water freezing solvent.Because tert-butyl alcohol freezing point is high, the pure tert-butyl alcohol at room temperature (25 ℃) just can freeze, therefore adopt tertiary butanol and water as freezing solvent system, can improve the eutectic point of medicine in this solvent system.In addition, the vapour pressure of the tert-butyl alcohol is higher, high distillation, the saving freeze-drying time of being conducive to of vapour pressure.And tert-butyl alcohol toxicity is low, as medicinal adjuvant, the toxicity of the tert-butyl alcohol is very low, and in freeze-drying process, most of tert-butyl alcohol can be in the distillation of primary drying stage, and in preparation, residual quantity is very low, can safe producing for preparation.
Summary of the invention
The inventor studies discovery by experiment: when adopting aqueous solution as freeze-drying system, and adopt general lyophilisation condition, the lyophilization cycle of reduced glutathion (0.6g and 1.2g) reaches 80 hours.Surprisingly, when adopting tertiary butanol and water freezing solvent system, if and only if wherein the content of the tert-butyl alcohol between 5-40%, while adopting following freeze-dry process program, the product of producing has loose, full outward appearance, structure homogeneous, redissolution is rapid, lyophilizing moisture entrapment is low, the feature of excellent in stability, and lyophilization cycle shortens greatly, between 19-54 hour.
In the present invention, the detailed preparation technology of reduced glutathion lyophilized formulations is as follows:
(1) weigh appropriate sodium hydroxide, add appropriate water for injection to be mixed with 20% aqueous solution, cooling.
(2) get approximately 50% water for injection, and the 5-40% tert-butyl alcohol, cooling, pass into nitrogen, add recipe quantity reduced glutathion.
(3) add above-mentioned sodium hydroxide solution, between regulator solution pH to 5.2-5.7, add water for injection cumulative volume, continue to stir, until obtain clarifying homogeneous solution
(4) continue to pass into aseptic nitrogen, filtration, packing, half tamponade.
(5) pre-freeze, lowers the temperature rapidly (2-3 hour) with the speed of 25-50 ℃/h, then at-35～-50 ℃, maintains 1～3 hour.
(6) after pre-freeze is finished, evacuation, after vacuum <10Pa, is warming up to-25～-15 ℃, insulation 5-18 hour.Continue to be warming up to 45-55 ℃, be incubated 5 hours.
(7) under the state of vacuum, product is pressed to full plug, outlet.
Under the above condition, lyophilization cycle is between 19-54 hour.Compared with reach 80 hours of traditional handicraft, lyophilization cycle at least shortens more than 30%.
In reduced glutathion freeze-dried products of the present invention, specification is respectively 0.3g, 0.6g, 1.2g and 1.8g.These four kinds of specifications all can adopt cillin bottle carry out lyophilizing and obtain.And in current production scale technique, because the large required freeze-drying time of specification reduced glutathion freeze-dried products is longer, therefore aseptic subpackaged production model after the lyophilizing of most of employing crude drug pallet, additional pulverizing and fill, brought extra pollution risk.Therefore, adopt freeze-dry process described in the invention, not only can shorten lyophilization cycle, save Financial cost, can also improve the safety of pharmaceutical preparation.In key index that prepared freeze-dried products is carried out is evaluated, moisture, related substance, content, visible foreign matters etc. are all far below statutory standards, and with the corresponding data disclosed in other patent quite (number of patent application 200610054295.6).
The specific embodiment
The present invention further sets forth explanation by following examples and test example, but the present invention is not limited to this.
Embodiment 1: preparation 0.3g glutathione for injection
Weigh appropriate sodium hydroxide, add appropriate water for injection to be mixed with 20% aqueous solution, cooling, get 500ml water for injection, and different content (5-40%) tert-butyl alcohol, cooling, pass into nitrogen, add recipe quantity reduced glutathion 300g, add above-mentioned sodium hydroxide solution, between regulator solution pH to 5.2-5.7, benefit injects water to 1L, continue to stir, until obtain clarifying homogeneous solution, continue to pass into aseptic nitrogen, analyze qualified after, medicinal liquid first filters with 0.45 μ m filter, use again 0.22 μ m filtering with microporous membrane degerming, after filtrate checks that visible foreign matters is qualified, be sub-packed in 10ml glass tube vial, every bottle of 0.3g/1ml packing, 1000 bottles of fills.After fill finishes, half tamponade pre-freeze, to-45 ℃, is incubated 2 hours with the 2-3 hour baffle temperature that lands vertically.After pre-freeze is finished, evacuation, after vacuum 10Pa, is warming up to-25～-15 ℃ in 3 hours, and insulation 5-8 hour, carries out sublimation drying one time.After primary drying completes, continue to be warming up to 45 ℃ in 3 hours, be incubated 5 hours, carry out redrying.Under the state of vacuum, product is pressed to full plug, outlet, rolls lid.Adopt the freeze-drying prods indices of different tert-butyl alcohol volumes as following table, meet quality standard.
| T butanol content | 5% | 10% | 15% | 20% | 40% |
| Primary drying temperature | -25℃ | -23℃ | -19℃ | -16℃ | -15℃ |
| A freeze-drying time | 8h | 7h | 6.5h | 6h | 5h |
| Loss on drying | 1.4% | 1.2% | 1.5% | 1.4% | 1.0% |
| The tert-butyl alcohol is residual | 0.05% | 0.07% | 0.11% | 0.15% | 0.19% |
| Character | White powder | White powder | White powder | White powder | White powder |
| Dissolve the time limit | 10 seconds | 10 seconds | 8 seconds | 5 seconds | 6 seconds |
| Content | 99.9% | 99.8% | 99.5% | 99.7% | 99.1% |
| Related substance | 1.61% | 1.66% | 1.75% | 1.82% | 1.83% |
| Visible foreign matters | Qualified | Qualified | Qualified | Qualified | Qualified |
Whole freeze-drying time is at 19-22 hour.
Embodiment 2: preparation 0.6g glutathione for injection
Weigh appropriate sodium hydroxide, add appropriate water for injection to be mixed with 20% aqueous solution, cooling, get about 1L water for injection, and different content (5-40%) tert-butyl alcohol, cooling, pass into nitrogen, add recipe quantity reduced glutathion 600g, add above-mentioned sodium hydroxide solution, between regulator solution pH to 5.2-5.7, benefit injects water to 2L, continue to stir, until obtain clarifying homogeneous solution, continue to pass into aseptic nitrogen, analyze qualified after, medicinal liquid first filters with 0.45 μ m filter, use again 0.22 μ m filtering with microporous membrane degerming, after filtrate checks that visible foreign matters is qualified, be sub-packed in 10ml glass tube vial, every bottle of 0.6g/2ml packing, 1000 bottles of fills.After fill finishes, half tamponade pre-freeze, to-45 ℃, is incubated 2 hours with the 2-3 hour baffle temperature that lands vertically.After pre-freeze is finished, evacuation, after vacuum 10Pa, is warming up to-25～-15 ℃ in 3 hours, and insulation 8-12 hour, carries out sublimation drying one time.After primary drying completes, continue to be warming up to 45 ℃ in 3 hours, be incubated 5 hours, carry out redrying.Under the state of vacuum, product is pressed to full plug, outlet, rolls lid.Adopt the freeze-drying prods indices of different tert-butyl alcohol volumes as following table, meet quality standard.
| T butanol content | 5% | 10% | 15% | 20% | 40% |
| Primary drying temperature | -25℃ | -23℃ | -19℃ | -16℃ | -15℃ |
| The primary drying time | 12h | 10h | 9h | 8h | 8h |
| Loss on drying | 1.2% | 1.4% | 1.1% | 1.0% | 0.8% |
| The tert-butyl alcohol is residual | 0.06% | 0.07% | 0.14% | 0.15% | 0.21% |
| Character | White powder | White powder | White powder | White powder | White powder |
| Dissolve the time limit | 12 seconds | 10 seconds | 9 seconds | 8 seconds | 9 seconds |
| Content | 99.8% | 100.2% | 100.3% | 99.9% | 100.1% |
| Related substance | 1.63% | 1.59% | 1.71% | 1.75% | 1.86% |
| Visible foreign matters | Qualified | Qualified | Qualified | Qualified | Qualified |
Whole freeze-drying time is at 22-26 hour.
Embodiment 3: preparation 1.2g glutathione for injection
Weigh appropriate sodium hydroxide, add appropriate water for injection to be mixed with 20% aqueous solution, cooling, get about 2L water for injection, and different content (5-40%) tert-butyl alcohol, cooling, pass into nitrogen, add recipe quantity reduced glutathion 1.2kg, add above-mentioned sodium hydroxide solution, between regulator solution pH to 5.2-5.7, benefit injects water to 4L, continue to stir, until obtain clarifying homogeneous solution, continue to pass into aseptic nitrogen, analyze qualified after, medicinal liquid first filters with 0.45 μ m filter, use again 0.22 μ m filtering with microporous membrane degerming, after filtrate checks that visible foreign matters is qualified, be sub-packed in 10ml glass tube vial, every bottle of 1.2g/4ml packing.After fill finishes, half tamponade pre-freeze, to-45 ℃, is incubated 3 hours with the 2-3 hour baffle temperature that lands vertically.After pre-freeze is finished, evacuation, after vacuum 10Pa, is warming up to-25～-15 ℃ in 3 hours, and insulation 10-16 hour, carries out sublimation drying one time.After primary drying completes, continue to be warming up to 45 ℃ in 3 hours, be incubated 5 hours, carry out redrying.Under the state of vacuum, product is pressed to full plug, outlet, rolls lid.Adopt the selected primary drying temperature and time of freeze-drying prods of different tert-butyl alcohol volumes as following table, indices all meets quality standard.
Whole freeze-drying time is at 24-30 hour.
By present application example 1-3 comparison, with t butanol content, increase, freeze-drying time shortens.The freeze-dry process that adopts the application to provide is prepared the glutathione for injection of same specification.Freeze-drying time shortens greatly, up-to-standard.
Claims (3)
1. a new freeze drying process for glutathione for injection, is characterized in that: first glutathion is prepared into the solution containing the 5-40% tert-butyl alcohol, then through pre-freeze program, completes once and redrying program.
2. new freeze drying process as claimed in claim 1, is characterized in that: described pre-freeze program is: the speed with 25-50 ℃/h is lowered the temperature rapidly, then at-35～-50 ℃, maintains 1～3 hour.
3. new freeze drying process as claimed in claim 1, is characterized in that: describedly with redrying program be once: after pre-freeze is finished, evacuation, after vacuum 10Pa, is warming up to-25～-15 ℃, insulation 5-18 hour.Continue to be warming up to 45-55 ℃, be incubated 5 hours.
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| CN201310533779.9A CN103585018A (en) | 2013-11-01 | 2013-11-01 | New freeze-drying method for reduced glutathione for injection |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106643005A (en) * | 2015-07-29 | 2017-05-10 | 广西梧州制药（集团）股份有限公司 | Application of tert butyl alcohol to freeze drying process of panax notoginseng saponins or composition of panax notoginseng saponins |
| CN106749332A (en) * | 2016-12-02 | 2017-05-31 | 河北联合制药有限公司 | The production technology of ampicillin sodium crystal |
| CN110314221A (en) * | 2019-06-29 | 2019-10-11 | 四川汇宇制药有限公司 | A kind of lyophilized technique of injection bortezomib |
-
2013
- 2013-11-01 CN CN201310533779.9A patent/CN103585018A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106643005A (en) * | 2015-07-29 | 2017-05-10 | 广西梧州制药（集团）股份有限公司 | Application of tert butyl alcohol to freeze drying process of panax notoginseng saponins or composition of panax notoginseng saponins |
| CN106749332A (en) * | 2016-12-02 | 2017-05-31 | 河北联合制药有限公司 | The production technology of ampicillin sodium crystal |
| CN110314221A (en) * | 2019-06-29 | 2019-10-11 | 四川汇宇制药有限公司 | A kind of lyophilized technique of injection bortezomib |
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