CN102727450B - Preparation method of Schisandrin C freeze-dried powder injection - Google Patents
Preparation method of Schisandrin C freeze-dried powder injection Download PDFInfo
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- CN102727450B CN102727450B CN 201210193280 CN201210193280A CN102727450B CN 102727450 B CN102727450 B CN 102727450B CN 201210193280 CN201210193280 CN 201210193280 CN 201210193280 A CN201210193280 A CN 201210193280A CN 102727450 B CN102727450 B CN 102727450B
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Abstract
The invention discloses a preparation method of a Schisandrin C freeze-dried powder injection. According to the invention, the freeze-dried formula adopts a combination of mannitol, trehalose and tert-butyl alcohol, accurate freeze-drying technological parameter control is combined, thus the problems of product collapse and pits caused by using indiscriminately routine freeze-dried formulas and technological parameters are solved; the obtained Schisandrin C dry powder has no adverse residue, good stability and rapid resumption of consumption of water, and meets the requirement of injecting powder injections; the addition of trehalose in the formula raises the room temperature stability of the Schisandrin C dry powder, and a small amount of the added tert-butyl alcohol can obviously change the shape of ice crystals, and the freeze-drying time can be reduced to about 70% of that of a contrast line without adding tert-butyl alcohol.
Description
One, technical field
The present invention relates to a kind of preparation method of schisandrin C lyophilized injectable powder, is to do excipient with mannitol, and adds freeze drying protectant trehalose and a small amount of tert-butyl alcohol, and the utilization vacuum freeze-drying technique obtains the high-purity schisandra third freezing-dried powder agent.
Two, background technology
The dry mature fruit of magnoliaceae schisandra contains multiple lignanoid composition; wherein Fructus Schisandrae Chinensis first, second element has certain protective role (Chinese medicine journal to hepatic injury; 2011,36 (6): 104-106), at the two drug effect, pharmacology and toxicological study carry out comparatively extensive.By comparison, schisandrin C (schisandrin C or wuweizisu C) correlational study is very deficient.Recently studies show that at mouse macrophage RAW 264.7 schisandrin C has significant antiinflammatory and anti-liver toxicity (biosci.biotechnol.biochem, 2010:74 (2) 285-291).Can predict, the pharmacology of schisandrin C and toxicologic study will further be carried out.Compare with oral medication, the advantage of injecting method is that drug effect is rapid by muscle or quiet notes, is the prefered method of being engaged in such research.Traditional aqueous injection stability is relatively poor usually, and lyophilized injectable powder exists with the glassy state powder form, have rapid-action, bioavailability is high, stability is high, be convenient to transportation storage, advantage such as easy to use, is the ideal substitute of aqueous injection.Present commercially available schisandrin C all occurs with crystal form, for ease of carrying out further pharmaceutical test, presses for and obtains its injection freeze-dried powder.
Complexity in view of the lyophilizing disperse system, want efficiently to obtain fast and satisfy the injectable powder not a duck soup that injection requires, so far do not form the ripe theory that the lyophilizing prescription is chosen as yet, all be with reference to the successful case of similar substance and determine after the experiment repeatedly at its lyophilizing prescription of different lyophilizing objects and lyophilizing program.Wherein excipient and the meeting of other additive and principal agent interact in the lyophilizing prescription, the kind of prescription and concentration can appreciable impact system freeze solidify and distillation dehydration behavior, as maximum Freeze concentration glass transition temperature (weighing the important indicator of whether subsiding when dry), minimum solidification point, rate of temperature fall, freeze annealing time etc.In addition, the time that the kind of additive and concentration also can the appreciable impact drying stages and the character of final products.Chinese patent 200910175342.6 discloses a kind of preparation method of Chinese medicine freeze dried injection, and it freezes minimum temperature can be-20 ~-40 ℃ of variations, and 2 ~ 5 hours pre-freeze time, the sublimation drying time, the adsorption stripping and dry stage was at 3 ~ 8 hours at 20 ~ 35 hours; Chinese patent 200510117539.6 discloses the preparation method of freeze dried pubescent holly powder for injection, it is to freezing speed and vacuum does not add explanation, be-40 ℃ of pre-freezes 12 hours, be warming up to-10 ℃ of drying under reduced pressure 10 hours, be warming up to 0 ℃ of drying under reduced pressure 6 hours, be warming up to 35 ℃ of drying under reduced pressure again 10 hours; Chinese patent 200310111036.9 discloses the preparation method of QINGKAILING DONGGANFENZHENJI, be sample to be cooled to-35 ℃ ~-60 ℃, kept 1 ~ 5 hour, open vacuum, vacuum is reached below the 30Pa, 0.5 ~ 2 ℃ speed slowly heats to goods by per hour raising, reach-5 ℃ ~-10 ℃ until products temperature, heat to goods by 2 ~ 5 ℃ the speed of per hour raising again, reach 21 ~ 30 ℃, kept 2 ~ 8 hours until products temperature.Therefrom be not difficult to find: its lyophilizing prescription of (1) different dry objects and technological process differ greatly, and lack the accurate explanation to technological parameter; (2) freeze-drying time is long, and is bigger as producing energy consumption in batches; (3) use mannitol as excipient usually; (4) be unique target all, promptly only pay close attention to medicine stability problem when reaching the lyophilizing end in the freeze-drying process, lack the holding conditions of lyophilized powder and the explanation of shelf-life with output dry powder.Owing to still retrieve less than freeze dried patent of schisandrin C and document at present, the inventor attempts applying mechanically the lyophilizing parameter that has similar medicine now and experimentizes, and its result is not ideal enough, and this specificity that this type of invention also is described is higher.
Three, summary of the invention
The present invention aims to provide a kind of preparation method of schisandrin C lyophilized injectable powder, and technical problem to be solved is to avoid the schisandrin C freeze-drying time to grow, subside, occur problems such as bubble hole and residual moisture content be not up to standard in preparation process.
The fat-soluble crystal of schisandrin C is water-soluble hardly, is soluble in organic solvents such as ethanol, but alcoholic acid freezing point is very low, and the cold-trap of freeze dryer can't be caught.It is higher that the tert-butyl alcohol has freezing point, and (Chinese journal of Practical Pharmacy, 2006:4 (3) 113-118), are expected to solve the dissolving and the slow problem of lyophilizing quick-freezing of schisandrin C to the characteristics such as fast noresidue that distil.In addition, its vitrification point of lyophilized powder that is in amorphous state is high more, and its stability is just good more under the identical storage temperature.And the vitrification point of mannitol commonly used is lower, is unfavorable for the stability under the room temperature.The present invention is with project of national nature science fund project (No.20803016, the glass transition rule and the research of structural relaxation rule of linear polyhydric alcohol and aqueous solution thereof) for relying on, utilize thermoanalysis technology accurately to measure lyophilizing disperse system heat chemistry parameter, and on this basis through experiment repeatedly, solved that to apply mechanically the freeze-drying time that existing conventional lyophilizing prescription causes long, lyophilized products is subsided, problems such as appearance bubble hole and residual moisture content are not up to standard, the lyophilizing prescription and the corresponding optimum parameters of freeze-drying process of a reasonable set have been provided, the final freeze-dried powder that meets the demands of efficiently preparing fast.
The preparation method of schisandrin C lyophilized injectable powder of the present invention comprises batch mixing, neutralization, adsorption-edulcoration, freezing and dry each unit process:
Described batch mixing be with schisandrin C, mannitol and trehalose according to the mixed of mass ratio 1:2-4:2-3 and to add the quality volumetric concentration be 15-30%(g/mL) tert-butyl alcohol aqueous solution be stirred to mannitol and trehalose and dissolve fully and obtain compound;
Described neutralization is to add NaOH solution to schisandrin C under stirring to dissolve fully in compound, obtains neutralizer with HCl solution adjust pH 7-8 then;
Described adsorption-edulcoration is that to add the quality volumetric concentration in neutralizer be 15-30%(g/mL) tert-butyl alcohol aqueous solution to make the quality volumetric concentration of schisandrin C be 0.5-1%(g/mL), add the needle-use activated carbon adsorption-edulcoration then, take off charcoal through micropore titanium filter decompression coarse filtration, after 0.22 μ m microporous filter membrane aseptic filtration, collect filtrate under the positive platen press 0.1MPa of reuse;
Described freezing be that filtrate is cooled to-45 ~-27 ℃ with the rate of temperature fall of 0.5-1 ℃/min, isothermal 2 hours presets condenser temperature-55 ~-38 ℃;
Described drying comprises sublimation drying and adsorption stripping and dry process; Described sublimation drying be keep dry pressure 13-36Pa, temperature-22 ~-13 ℃ of case dry 6-10 hour down; Described adsorption stripping and dry is behind the sublimation drying drying baker temperature to be warming up to 25-30 ℃, reduces to below the 1Pa approximately 12-16 hour until drying baker pressure; Taking out the back preserves in sealed under aseptic conditions.
Parameter when preparation condition is schisandrin C weak solution (0.5%) prescription:
The mass ratio 1:2:2 of schisandrin C, mannitol and trehalose in the batch mixing process, the quality volumetric concentration of tert-butyl alcohol aqueous solution is 15%(g/mL);
Adding the quality volumetric concentration in the adsorption-edulcoration process in neutralizer is 15%(g/mL) tert-butyl alcohol aqueous solution to make the quality volumetric concentration of schisandrin C be 0.5%(g/mL);
Be that filtrate is cooled to-45 ~-41 ℃ with the rate of temperature fall of 1 ℃/min in the refrigerating process, isothermal 2 hours presets condenser temperature-55 ~-51 ℃;
Keep dry in the sublimation drying process pressure 13-36Pa, temperature-22 ~-18 ℃ of case dry 8-10 hour down; In the adsorption stripping and dry process drying baker temperature is warming up to 25 ℃, reduces to below the 1Pa, take out the back and preserve in sealed under aseptic conditions until drying baker pressure;
Parameter when perhaps preparation condition is schisandrin C concentrated solution (1%) prescription:
The mass ratio 1:4:3 of schisandrin C, mannitol and trehalose in the batch mixing process, the quality volumetric concentration of tert-butyl alcohol aqueous solution is 30%(g/mL);
Adding the quality volumetric concentration in the adsorption-edulcoration process in neutralizer is 30%(g/mL) tert-butyl alcohol aqueous solution to make the quality volumetric concentration of schisandrin C be 1%(g/mL);
Be that filtrate is cooled to-33 ~-27 ℃ with the rate of temperature fall of 0.5 ℃/min in the refrigerating process, isothermal 2 hours presets condenser temperature-42 ~-38 ℃;
Keep dry in the sublimation drying process pressure 13-36Pa, temperature-17 ~-13 ℃ of case dry 6-8 hour down; In the adsorption stripping and dry process drying baker temperature is warming up to 30 ℃, reduces to below the 1Pa, take out the back and preserve in sealed under aseptic conditions until drying baker pressure;
The concentration of schisandrin C is between weak solution and concentrated solution the time, and the parameter of freezing, sublimation drying and adsorption stripping and dry is determined by linear interpolation method according to the parameter under schisandrin C weak solution and two kinds of limting concentration conditions of concentrated solution.
The present invention also adopts trehalose as freeze drying protectant except adopting mannitol as the excipient, and not only the low-temperature protection effect is obvious, and its vitrification point is higher 45 ℃ than sucrose, has guaranteed the storage-stable under the dry powder room temperature, makes it can normal temperature storage.Add a certain amount of tert-butyl alcohol in the prescription, not only has certain hydrotropy effect, and and the water mutual effect after acicular crystal distillation rapidly, the tubular structure that stays after the distillation is the better channels of adsorption stripping and dry stage steam, obviously shortened freeze-drying time, freeze-drying time can be reduced to and not add about 70% of tert-butyl alcohol control series, energy-saving and cost-reducing significant for what produce in batches.
The invention solves and apply mechanically product that existing parameters of freeze-drying process causes and subside, occur bubble and cheat and residual moisture content problem not up to standard, the lyophilized injectable powder quality is fluffy, rehydration is rapid, add the injection water shake up about 20 seconds both clear and bright liquid, as only using mannitol as excipient, the density of the lyophilized powder that obtains is bigger, still can observe particle in 3 minutes after the rehydration.It is residual that obtained freeze-drying powder of the present invention detects the no tert-butyl alcohol through gas chromatograph, meets the requirement of injection powder injection.
Four, the specific embodiment
Following embodiment is used to illustrate the preparation method of injection schisandrin C lyophilized powder of the present invention, includes but not limited to the following example.
Embodiment 1:
Lyophilized powder is formed: schisandrin C 2g, mannitol 4g, trehalose 4g.Prepare 180 bottles of injectable powder.
Preparation method:
1, taking by weighing schisandrin C, mannitol and trehalose, add 15%(g/mL) tert-butyl alcohol aqueous solution 80ml stirs.
2, the sodium hydroxide solution 45ml that adds 2M is stirred to dissolving fully, uses the hydrochloric acid solution adjust pH to 7.5 of 2M then, adds 15%(g/mL) tert-butyl alcohol aqueous solution is to 400ml, the concentration that makes schisandrin C is 0.5%(g/mL).
3, add 0.05%(g/mL) needle-use activated carbon, stirred 10 minutes, micropore titanium filter decompression coarse filtration, take off charcoal, after checking content and pH value (between 7-8), after 0.22 μ m microporous filter membrane terminal aseptic filtration, collect filtrate again, be sub-packed in the 10ml cillin bottle, every bottled 2-3ml, totally 180 bottles.
4, filtrate is cooled to-43 ℃ with the speed of 1 ℃/min, about 1 hour consuming time, shelf temperature keep-43 ℃ 2 hours, finish the ice crystal maturing process, to cold-trap cooling simultaneously, make it be cooled to-53 ℃ in the refrigerating process.
5, sublimation drying stage shelf temperature maintains-20 ℃, drying baker pressure maintains 36Pa, the distillation time is 8 hours, the shelf temperature to 30 that slowly raises afterwards ℃ carries out adsorption stripping and dry, freeze-drying process finishes after system pressure is reduced to 1Pa, about 12 hours consuming time, adds a cover plug under the aseptic condition, roll lid, room temperature is preserved.
Embodiment 2:
Lyophilized powder is formed: schisandrin C 2g, mannitol 8g, trehalose 6g.Prepare 80 bottles of injectable powder.
Preparation method:
1, taking by weighing schisandrin C, mannitol and trehalose, add 30%(g/mL) tert-butyl alcohol aqueous solution 80ml stirs.
2, the sodium hydroxide solution 45ml that adds 2M is stirred to dissolving fully, uses the hydrochloric acid solution adjust pH to 7.5 of 2M then, adds 30%(g/mL) tert-butyl alcohol aqueous solution is to 200ml, the concentration that makes schisandrin C is 1%(g/mL).
3, add 0.05%(g/mL) needle-use activated carbon, stirred 10 minutes, micropore titanium filter decompression coarse filtration, take off charcoal, after checking content and pH value (between 7-8), after 0.22 μ m microporous filter membrane terminal aseptic filtration, collect filtrate again, be sub-packed in the 10ml cillin bottle, every bottled 2-3ml, totally 80 bottles.
4, filtrate is cooled to-30 ℃ with the speed of 0.5 ℃/min, about 2 hours consuming time, shelf temperature keep-30 ℃ 2 hours, finish the ice crystal maturing process, to cold-trap cooling simultaneously, make it be cooled to-40 ℃ in the refrigerating process.
5, sublimation drying stage shelf temperature maintains-15 ℃, drying baker pressure maintains 20Pa, the distillation time is 8 hours, the shelf temperature to 30 that slowly raises afterwards ℃ carries out adsorption stripping and dry, freeze-drying process finishes after system pressure is reduced to 1Pa, about 20 hours consuming time, adds a cover plug under the aseptic condition, roll lid, room temperature is preserved.
Claims (3)
1. the preparation method of a schisandrin C lyophilized injectable powder comprises batch mixing, neutralization, adsorption-edulcoration, freezing and dry each unit process, it is characterized in that:
Described batch mixing is according to the mixed of mass ratio 1:2-4:2-3 and to add the quality volumetric concentration be that the tert-butyl alcohol aqueous solution of 15-30% is stirred to mannitol and trehalose and dissolves fully and obtain compound with schisandrin C, mannitol and trehalose;
Described neutralization is to add NaOH solution to schisandrin C under stirring to dissolve fully in compound, obtains neutralizer with HCl solution adjust pH 7-8 then;
Described adsorption-edulcoration is that to add the quality volumetric concentration in neutralizer be that to make the quality volumetric concentration of schisandrin C be 0.5-1% for the tert-butyl alcohol aqueous solution of 15-30%, add the needle-use activated carbon adsorption-edulcoration then, take off charcoal through micropore titanium filter decompression coarse filtration, after 0.22 μ m microporous filter membrane aseptic filtration, collect filtrate under the positive platen press 0.1MPa of reuse;
Described freezing be that filtrate is cooled to-45 ~-27 ℃ with the rate of temperature fall of 0.5-1 ℃/min, isothermal 2 hours presets condenser temperature-55 ~-38 ℃;
Described drying comprises sublimation drying and adsorption stripping and dry process; Described sublimation drying be keep dry pressure 13-36Pa, temperature-22 ~-13 ℃ of case dry 6-10 hour down; Described adsorption stripping and dry is behind the sublimation drying drying baker temperature to be warming up to 25-30 ℃, reduces to below the 1Pa 12-16 hour until drying baker pressure; Taking out the back preserves in sealed under aseptic conditions.
2. preparation method according to claim 1 is characterized in that:
Preparation condition is a schisandrin C weak solution prescription:
The mass ratio 1:2:2 of schisandrin C, mannitol and trehalose in the batch mixing process, the quality volumetric concentration of tert-butyl alcohol aqueous solution is 15%;
Adding the quality volumetric concentration in the adsorption-edulcoration process and be 15% tert-butyl alcohol aqueous solution in neutralizer, to make the quality volumetric concentration of schisandrin C be 0.5%;
Be that filtrate is cooled to-45 ~-41 ℃ with the rate of temperature fall of 1 ℃/min in the refrigerating process, isothermal 2 hours presets condenser temperature-55 ~-51 ℃;
Keep dry in the sublimation drying process pressure 13-36Pa, temperature-22 ~-18 ℃ of case dry 8-10 hour down; In the adsorption stripping and dry process drying baker temperature is warming up to 25 ℃, reduces to below the 1Pa, take out the back and preserve in sealed under aseptic conditions until drying baker pressure.
3. preparation method according to claim 1 is characterized in that:
Preparation condition is a schisandrin C concentrated solution prescription:
The mass ratio 1:4:3 of schisandrin C, mannitol and trehalose in the batch mixing process, the quality volumetric concentration of tert-butyl alcohol aqueous solution is 30%;
Adding the quality volumetric concentration in the adsorption-edulcoration process and be 30% tert-butyl alcohol aqueous solution in neutralizer, to make the quality volumetric concentration of schisandrin C be 1%;
Be that filtrate is cooled to-33 ~-27 ℃ with the rate of temperature fall of 0.5 ℃/min in the refrigerating process, isothermal 2 hours presets condenser temperature-42 ~-38 ℃;
Keep dry in the sublimation drying process pressure 13-36Pa, temperature-17 ~-13 ℃ of case dry 6-8 hour down; In the adsorption stripping and dry process drying baker temperature is warming up to 30 ℃, reduces to below the 1Pa, take out the back and preserve in sealed under aseptic conditions until drying baker pressure.
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| CN104771374A (en) * | 2015-04-20 | 2015-07-15 | 北京红太阳药业有限公司 | Preparation method of lactobionic acid azithromycin freeze-dried powder injection for injection and freeze-dried powder injection prepared by preparation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1544064A (en) * | 2003-11-19 | 2004-11-10 | 张晴龙 | Freeze-dried 'Shengmai' powder for injection and its preparing process |
| CN101116722A (en) * | 2006-08-01 | 2008-02-06 | 天津市轩宏医药技术有限公司 | Pharmaceutical formulations with the raw material containing panax, ophiopogon root and schisandra fruit, processes for their preparation, the raw material and the quality control method for the prepa |
| CN101879270A (en) * | 2009-05-07 | 2010-11-10 | 天津天士力之骄药业有限公司 | Chinese medicinal injectable powder and quality control method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1544064A (en) * | 2003-11-19 | 2004-11-10 | 张晴龙 | Freeze-dried 'Shengmai' powder for injection and its preparing process |
| CN101116722A (en) * | 2006-08-01 | 2008-02-06 | 天津市轩宏医药技术有限公司 | Pharmaceutical formulations with the raw material containing panax, ophiopogon root and schisandra fruit, processes for their preparation, the raw material and the quality control method for the prepa |
| CN101879270A (en) * | 2009-05-07 | 2010-11-10 | 天津天士力之骄药业有限公司 | Chinese medicinal injectable powder and quality control method thereof |
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