CN102106833A - Pemetrexed disodium freeze-dried powder injection and preparation method thereof - Google Patents
Pemetrexed disodium freeze-dried powder injection and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medication, and in particular relates to a pemetrexed disodium freeze-dried powder injection and a preparation method thereof. The pemetrexed disodium freeze-dried powder injection consists of pemetrexed disodium and mannitol, wherein the mass ratio of the mannitol to the pemetrexed disodium is (0.6-2.0):1. The preparation method comprises the following steps: adding injecting water into a liquid preparation tank; adding the pemetrexed disodium weighted according to the formula; stirring until the pemetrexed disodium completely dissolved; adding the mannitol; regulating the pH by utilizing a hydrochloric acid solution or a sodium hydroxide solution; adding activated carbon for decoloration; filtering to remove the carbon; finely filtering with a filter membrane; subpackaging; and freezing and drying. The pemetrexed disodium freeze-dried powder injection has excellent moldability; the appearance of the solution before freezing is clear; the frozen and dry product has good re-dissolubility; and the re-dissolved product has the advantages of good clarity, low impurity content, low moisture content, good stability and controllable quality.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of pemetrexed disodium freeze-dried injection and preparation method thereof.
Background technology
Pemetrexed disodium, its chemical name is: N-[4-[2-(2-amino-4,7-dihydro-4-carbonyl-1H-pyrroles [2,3-d]-pyrimidine-5-yl) ethyl] benzoyl]-L disodium glutamate salt 2.5 hydrates.Molecular formula is: C
20H
19N
5Na
2O
62.5H
2O, molecular weight are 516.38, its chemical structural formula:
Pemetrexed is to contain the folic acid resisting preparation of core for pyrroles's pyrimidine group on a kind of structure, by destroying the dependent homergy process of folic acid in the cell, suppresses cellular replication, thereby suppresses growth of tumor.In vitro study shows, pemetrexed can suppress the activity of thymidylate synthetase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, these enzymes all are the synthetic necessary enzymes of folic acid, participate in the biological resynthesis process of thymidylic acid and purine nucleotides.Pemetrexed enters in the cell by the carrier of delivery folic acid and the folic acid-binding protein transportation system on the cell membrane.In case pemetrexed enters in the cell, it just is converted into the form of many glutamic acid under the effect of the many glutamate synthetases of leaf acyl.Many glutamic acid retain in the inhibitor that becomes thymidylate synthetase and glycinamide ribonucleotide formyl transferase in the cell.Many glutamic acidization is presentative time-concentration dependent process in tumor cell, and concentration is very low in normal structure.The half-life of many glutamic acidization metabolite in tumor cell prolongs, thereby also just prolonged the action time of medicine in tumor cell.
Preclinical study shows that pemetrexed is external and suppresses mesothelioma cell line (MSTO-211H, growth NCI-H2052).Mesothelioma cell line MSTO-211H studies show that out pemetrexed and cisplatin combined synergism is arranged.The pemetrexed combination with cisplatin is used for the treatment of the malignant pleural mesothelioma that can't perform the operation.
Infer that from the mechanism of action of pemetrexed it should be a kind of broad-spectrum anti-cancer drug.Also show that with the clinical research result except that 2 indications of approved, pemetrexed also has certain curative effect to other multiple solid tumor before clinical.And pemetrexed and multiple other anticarcinogen coupling all have synergistic function, and can reduce toxicity, and this suffers from the available patient of no suitable drug because of the drug resistance problem for some and has brought hope.
The less stable of pemetrexed disodium, under high temperature, oxidizing condition, easily degrade, generation may cause the impurity of toxic and side effects, be not suitable for making the injection that needs high temperature sterilize, thereby pemetrexed disodium is made lyophilized injectable powder usually, but existing pemetrexed disodium freeze-dried injection is in the process of transportation and storage, Chang Yinwei temperature control is strict and cause that impurity content obviously increases in the lyophilized injectable powder yet, and prior art and common practise are not also openly improved the suggestion of above-mentioned defective.
CN200810234188.0 discloses a kind of pemetrexed disodium freeze-dried injection and preparation method thereof, this pemetrexed disodium freeze-dried injection is by pemetrexed disodium, mannitol and sodium sulfite are formed, sodium sulfite is antioxidant commonly used, has stronger chemism, can with some aldoketones medicine generation additive reaction, and can produce certain influence to the effectiveness of principal agent, in addition, since human body to freeze-dried powder require high, and the kind of the adjuvant in this freeze-dried powder is more, not only increase the kind and the content of impurity in the freeze-dried powder, also increased the risk that impurity brought in the adjuvant, the impurity content of this freeze-dried powder is 0.72%～0.85%; Moreover this freeze-dried powder is cooled to goods-40 ℃ earlier in freeze-drying process, continued freezing 2-4 hour, evacuation is warming up to 35 ℃ with 2-4 ℃ the speed of per hour raising then, this freeze-dry process is coarse, lyophilizing finishes the moisture height of back finished product, and the moisture of this freeze-dried powder is 4.8%～5.8%, in addition, in the exsiccant process, heating rate is too slow, and it is excessive to produce required energy consumption, and economic benefit is low.
Given this, the special the technical program that proposes.
Summary of the invention
The object of the present invention is to provide a kind of pemetrexed disodium freeze-dried injection, this pemetrexed disodium freeze-dried injection good forming ability, solution appearance clarification before freezing, the dried frozen aquatic products solubility is good, and the clarity after the redissolution is good, and impurity content is low, moisture is low, and good stability is quality controllable.
Another object of the present invention is to provide a kind of preparation method of pemetrexed disodium freeze-dried injection.
In order to realize first purpose of the present invention, the technical solution used in the present invention is:
A kind of pemetrexed disodium freeze-dried injection, this pemetrexed disodium freeze-dried injection is made up of pemetrexed disodium and mannitol, and the mass ratio of described mannitol and pemetrexed disodium is 0.6～2.0: 1.
Among the present invention, through the prescription screening test, the mass ratio of mannitol and pemetrexed disodium is preferably 0.8～1.6 in the pemetrexed disodium freeze-dried injection: 1, most preferably be 1.2: 1.
Among the present invention, the impurity content of freshly prepd pemetrexed disodium freeze-dried injection is not higher than 0.28%, and moisture is not higher than 1.59%.
From the screening of prescription, in the selection of adjuvant, the inventor follows and can prepare on the basis of stable and controllable for quality, the product that meets clinical needs the few more good more principle of the kind of adjuvant, consumption; This is because supplementary product kind is few more, can simplify batching step greatly when meaning production technology; The kind and the content of the impurity that adjuvant brings have simultaneously also been reduced, the side effect that is difficult to expect of avoiding various adjuvants to bring.Therefore, a kind of excipient is only used in final decision of the present invention; Comparing glucose, sodium chloride, dextran and mannitol respectively after the appearance as filler, the effect of finding mannitol is better, in addition, and again because when lyophilization, mannitol has higher disintegrate temperature, so the present invention adopts a kind of excipient of mannitol.Through a large amount of experiments, find when the mass ratio of pemetrexed disodium and mannitol is 1: 0.6～2.0, the outward appearance of product is loose block, impurity content is low, and solubility has also reached requirement, when the mass ratio of pemetrexed disodium and mannitol is 1: 0.8～1.6, the full not atrophy of the outward appearance of product, color and luster homogeneous, solubility, clarity reach good, consider the composite factor of cost and quality, and most preferably the two ratio is 1: 1.2.
Prescription and technology are the key factors of decision pemetrexed disodium freeze-dried powder quality, because the used adjuvant of this product is simple, the content of adjuvant is low, this brings certain influence will for lyophilized injectable powder outward appearance, solubility, the present invention has done test and research repeatedly to each link in the preparation process of pemetrexed disodium freeze-dried injection, by improving the preparation technology of freeze-dried powder, overcome composition with the content relative less defective brought of pemetrexed disodium freeze-dried injection, improved the quality of pemetrexed disodium freeze-dried injection because of adjuvant.
In order to realize another object of the present invention, a kind of preparation method of pemetrexed disodium freeze-dried injection is provided, described preparation method is:
(a) in Agitation Tank, add water for injection earlier, add the pemetrexed disodium of recipe quantity again, be stirred to dissolving fully;
(b) in Agitation Tank, add the mannitol of recipe quantity again, continue to stir and make medicinal liquid become clear and bright solution, regulate the medicinal liquid pH value, replenish water for injection, stir with hydrochloric acid solution or sodium hydroxide solution;
(c) add medicinal carbon, stirring and adsorbing adopts decarburization limit, limit circulation mode to take off charcoal, aseptic filtration;
(d) with the solution packing of step (c) gained, the false add plug carries out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: behind the evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5～0.55 ℃/min afterwards again to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-45 ℃ with the speed of 0.72 ℃/min again, be incubated 3～5 hours, it is 10pa that last evacuation makes the interior vacuum of case;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.44～0.51 ℃/min, treats that temperature rises to-3～-1 ℃, continues insulation 3～5 hours;
The redrying stage: shelf temperature is risen to 17～19 ℃ with the speed of 0.50～0.63 ℃/min, be incubated 1 hour, shelf continues to rise to 38～42 ℃ with the speed of 0.18～0.22 ℃/min, treat that temperature of articles in the redrying reaches 33～37 ℃ after, continue insulation after 3 hours;
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet.
In the above-mentioned preparation method, when adding pemetrexed disodium in the step (a), the solution temperature in the Agitation Tank is controlled between 0～10 ℃.
In the above-mentioned preparation method, in the step (b), regulate medicinal liquid pH value to 7.0～7.5 with the hydrochloric acid solution of 0.1mol/L or the sodium hydroxide solution of 0.1mol/L.
In the above-mentioned preparation method, in the step (c), the amount that adds active carbon is the 0.2%g/ml of medicinal liquid cumulative volume, and stirring and adsorbing was filtered and 0.22 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.22 μ m after 30 minutes.
In the above-mentioned preparation method, the preferred version of step (d) is:
The pre-freeze stage: behind the evacuation, inflated with nitrogen is to normal pressure, afterwards shelf temperature is reduced to-3 ℃ with the speed of 0.5 ℃/min, be incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, the speed with 0.72 ℃/min is cooled to-45 ℃ again.
The primary drying stage: the heating rate of shelf is 0.48 ℃/min.
The redrying stage: shelf temperature is risen to 15 ℃ with the speed of 0.57 ℃/min, be incubated 1 hour, shelf continues to rise to 40 ℃ with the speed of 0.2 ℃/min, is incubated 3 hours.
Process conditions in the inventive method play crucial effects to the quality that guarantees product, the inventor screens its prescription, to the amount of the scope of the consumption of mannitol, dosing temperature, pH value, active carbon and adsorption time, decarburization mode, freeze-dry process or the like, by selecting only amounts of components proportioning, optimizing production technology, clarity after resulting dried frozen aquatic products redissolves is good, impurity content is low, and low, the good stability of moisture is quality controllable.
The pemetrexed disodium less stable, at high temperature, oxidizing condition is easily degraded down, generation can cause the impurity of toxic and side effects, the present invention is directed to these characteristics of pemetrexed disodium, in the process of preparating liquid, make one 0～10 ℃ cryogenic solution environmental earlier, then pemetrexed disodium is added in the water for injection of Agitation Tank and stir and make its dissolving, pemetrexed disodium is emitted heat of solution when dissolving, heat of solution will in time be discharged in a large amount of cryogenic waters for injection apace, the heat of solution that discharges can not bring any influence to pemetrexed disodium itself, add adjuvant mannitol afterwards again and regulate pH value, guaranteed that pemetrexed disodium dry powder injection is in the stable environment in the overall process of solution preparation, the adverse effect of having avoided the heat of solution of pemetrexed disodium and mannitol abrupt release in course of dissolution that pemetrexed disodium itself is brought.
The present invention studies the consumption and the using method of active carbon, the activated carbon dosage of 0.2% (g/ml) promptly guarantees to adsorb fully pyrogen in the medicinal liquid, impurity etc., improve the purity and the yield rate of product, can the content of principal agent in the medicinal liquid not exerted an influence again; Adopt the limit to take off charcoal limit circulation method, make active carbon attached on the filter stick, make the absorbability of active carbon obtain reinforcement, guarantee once, not stopping up of secondary 0.2 μ m degerming filter membrane and successfully finish filtering liquid medicine, make its aseptic filtration effect reach splendid state; Dissolubility is better after having improved the clarity, lyophilizing of filtering liquid medicine.
Pemetrexed disodium is easily degraded under high temperature, oxidizing condition, generation may cause the impurity of toxic and side effects, generally can in the prescription of pemetrexed disodium freeze-dried injection, add antioxidant, as sodium sulfite, but sodium sulfite has stronger chemism, can with some aldoketones medicine generation additive reaction, can produce certain influence to the effectiveness of pemetrexed disodium.In order to reduce the unpredictable toxic and side effects that lyophilized injectable powder brings human body, the present invention only selects a kind of adjuvant for use, employing mannitol is excipient, does not add any antioxidant, solves the problem that degraded easily takes place pemetrexed disodium by production technology under high temperature, oxidizing condition.The present invention is first evacuation before freeze-dry process, and inflated with nitrogen carries out whole freeze-drying process in the environment of anaerobic, solves the problem that degraded easily takes place pemetrexed disodium by improving preparation technology under oxidizing condition.
Afterwards, during pre-freeze, earlier shelf temperature is reduced to eutectic point with the speed of 0.5～0.55 ℃/min and be about-3 ℃, be incubated 0.5 hour, to eliminate the temperature difference and the medicinal liquid temperature inside gradient between medicinal liquid and the shelf, rate of temperature fall in this step considers that the fast power consumption of cooling is high, the slow efficient of cooling is low, so select the rate of temperature fall of 0.5～0.55 ℃/min.When the temperature of medicinal liquid is lower than-3 ℃ of continuation coolings, if rate of temperature fall is big more, the degree of supercooling of solution and degree of supersaturation are bigger, critical crystalline granularity is then little, and nucleation rate is fast more, forms the less thin crystalline substance of the more size of granule easily, thereby after the ice crystal distillation, the pore-size that forms in the material is less, and dry rate can be lower, but solubility is good after the lyophilizing; On the contrary, slow freezing forms oarse-grained ice crystal easily, and the aqueous vapor discharge channel size that ice crystal distillation back forms is bigger, help improving dry rate, but it is poor to do the back rehydration.So lyophilized injectable powder all adopts refrigerating process comparatively fast in the pre-freeze stage, but in the preparation process of reality, in the pre-freeze stage,, easily cause some crystal seed to be analysed to come out if temperature decline is too fast; If it is too slow that temperature descends, easily make a part of raw material form crystal formation.The present invention adopts the program of cooling again that afterwards heats up of lowering the temperature earlier in the pre-freeze stage, in the pre-freeze process according to the rate of temperature fall of 0.70～0.74 ℃/min elder generation fast cooling to-30 ℃, stop cooling, be incubated 1 hour, pre-freeze makes the filtrate of packing form the less thin crystalline substance of the more size of granule fast, analyse to come out for avoiding some crystal seed, make shelf temperature slowly be warming up to-5 ℃ again, be incubated 1 hour, speed with 0.70～0.74 ℃/min is cooled to-43～-47 ℃ again, at this moment, crystal seed in the filtrate goods can not only all be separated out, and forms an ideal structure of freezing, and solute wherein can be evenly distributed in the ice crystal after whole the freezing, and high-precision small loose structure appears, whole ice crystal freezes the tactical rule homogeneous.The present invention cools the temperature to-43～-47 ℃ when pre-freeze, guarantee that the medicinal liquid goods are thoroughly frozen, and do not waste energy and the time.
Because during primary drying, vacuum in the case is 10pa, vacuum is very low, so ice crystal is very slow to the conduction of heat of internal layer by skin, and along with the continuous intensification of shelf, the temperature difference of shelf temperature and ice crystal can constantly increase, and ice crystal is also constantly increased by the inside temperature difference of skin, ice crystal is heated inhomogeneous, when reaching ice crystal and cave in temperature, porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause rehydration, stability and clarity is variation simultaneously.The primary drying stage of the present invention adopts staged to heat up, intensification-insulation hockets, every intensification 10 minutes, then be incubated 5 minutes, the temperature difference between elimination shelf and the ice crystal and the temperature difference of ice crystal inside, the ice crystal of guaranteeing the primary drying stage is heated evenly, moisture evenly distils in the ice crystal, with overcome ice crystal in temperature rise period since the inhomogeneous rate of sublimation that brings that heats up slow down, problems such as downgrade, guarantee that ice crystal keeps the full not atrophy of profile in the process that once heats up, the color and luster homogeneous, and the dried finished products solubility is good, and owing to ice crystal in the staged temperature-rise period is heated evenly, the moisture of the ice crystal innermost layer and the bottom also can distil unobstructedly, and this has reduced last temperature retention time in temperature rise period, after shelf is rising to-3～-1 ℃, only need insulation 3～5 hours, improved distillation efficient.
Also there are a lot of tiny ice crystals behind the primary drying in the goods, because tiny ice crystal has very high surface energy, if the heating rate of redrying is slower, then little ice crystal easily mutually combines and forms big ice crystal, if the heating rate of redrying is very fast, dry insufficient phenomenon then may appear, and pemetrexed disodium is heat-labile material, so the present invention adopts and is rapidly heated earlier, shelf temperature is risen to 14～16 ℃ with the fast speed of 0.5～0.63 ℃/min, be incubated 1 hour, make moisture elder generation rapid evaporation in the little ice crystal behind the primary drying, avoid between the little ice crystal because of the big ice crystal of formation that mutually combines slowly that heats up, afterwards, consider the unstability of pemetrexed disodium in pyritous environment, the higher factors such as (being 40 ℃) of temperature when exsiccant effect and redrying are incubated at last, again with the speed of 0.18～0.22 ℃ slower/min drying that slowly heats up, and reduced the time that is incubated in the redrying final stage, after treating that temperature of articles in the redrying reaches 35 ℃, continue insulation 3 hours, promptly guaranteed the exsiccant effect of pemetrexed disodium freeze-dried injection, guaranteed that again the maintenance of pemetrexed disodium in dry run is stable.
In the process conditions of the present invention, the control of temperature, time and speed during particularly to pre-freeze and drying has effectively improved the crystalline state of crude drug and the aeration of manufactured goods.Simultaneously steam can be appeared smoothly, makes the full not atrophy of profile of product, and the color and luster homogeneous, dry fully, moisture is low, and kept medicine good stable and porous, the clarity after dried frozen aquatic products redissolves is very good.
Compared with prior art, a kind of pemetrexed disodium freeze-dried injection provided by the invention and preparation method thereof has following advantage:
(1) pemetrexed disodium freeze-dried injection provided by the invention only contains a kind of adjuvant, and prescription is simple, and is little to the side effect of human body, safe and reliable; The full homogeneous of pemetrexed disodium freeze-dried injection outward appearance, solubility is good, impurity content is few, moisture is low, good stability, helps stably transporting and storing.
(2) the present invention is directed to the characteristics of pemetrexed disodium,, optimize production technology, improved the stability and the quality of pemetrexed disodium by formulating rational prescription; In addition, pemetrexed disodium freeze-dried injection preparation technology provided by the invention is simple, and is convenient feasible, good reproducibility, percent defective (variable color) is low, lamp inspection inspection rejects difficulty is low, saves manpower, and each link is controlled, short production cycle, lower percent defective and lower human cost, production cost is reduced significantly, can produce considerable economic and social benefit, can realize industrialization production.
The specific embodiment
Below by specific embodiment summary of the invention of the present invention is described further, but does not therefore limit content of the present invention.
Embodiment 1
Add water for injection 2244ml in Agitation Tank, the temperature of Agitation Tank is 5 ℃, adds the 80g pemetrexed disodium again, stirring and dissolving.Add 96g mannitol again, stirring makes medicinal liquid become clear and bright solution; Regulate liquid PH value to 7.3 with the hydrochloric acid solution of 0.1mol/L and/or the sodium hydroxide solution of 0.1mol/L, add water for injection 396ml, mixing.
0.20% (g/ml) medicinal carbon that in clear and bright solution, adds the dosing total amount, after the stirring and adsorbing 30 minutes, filter and 0.2 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.2 μ m, gained filtrate is used for fill to the medicinal liquid bottle.
The filtrate packing, the false add plug is put into freeze dryer and is carried out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: evacuation, inflated with nitrogen are reduced to-3 ℃ with shelf temperature with the speed of 0.5 ℃/min again to normal pressure, be incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-45 ℃ with the speed of 0.72 ℃/min again, after filtrate products temperature to be packed is reduced to-35 ℃, continue insulation 4 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.48 ℃/min, treats that temperature rises to-3 ℃, continues insulation 4 hours;
The redrying stage: shelf temperature is risen to 15 ℃ with the speed of 0.57 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.2 ℃/min, continues insulation 3 hours.
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet, and the impurity content of freeze-dried powder is not higher than 0.28%, and moisture is not higher than 1.59%.
Embodiment 2
Add water for injection 3060ml in Agitation Tank, the temperature of Agitation Tank is 0 ℃, adds the 80g pemetrexed disodium again, stirring and dissolving.Add 160g mannitol again, stirring makes medicinal liquid become clear and bright solution; Regulate liquid PH value to 7.0 with the hydrochloric acid solution of 0.1mol/L and/or the sodium hydroxide solution of 0.1mol/L, add water for injection 540ml, mixing.
0.20% (g/ml) medicinal carbon that in clear and bright solution, adds the dosing total amount, after the stirring and adsorbing 30 minutes, filter and 0.2 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.2 μ m, gained filtrate is used for fill to the medicinal liquid bottle.
The filtrate packing, the false add plug is put into freeze dryer and is carried out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.55 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.70 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-43 ℃ with the speed of 0.70 ℃/min again, continue insulation 3 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.44 ℃/min, treats that temperature rises to-1 ℃, continues insulation 3 hours;
The redrying stage: shelf temperature is risen to 14 ℃ with the speed of 0.50 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.18 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet, and the impurity content of freeze-dried powder is not higher than 0.28%, and moisture is not higher than 1.59%.
Embodiment 3
Add water for injection 2652ml in Agitation Tank, the temperature of Agitation Tank is 10 ℃, adds the 80g pemetrexed disodium again, stirring and dissolving.Add 128g mannitol again, stirring makes medicinal liquid become clear and bright solution; Regulate liquid PH value to 7.54 with the hydrochloric acid solution of 0.1mol/L and/or the sodium hydroxide solution of 0.1mol/L, add water for injection 468ml, mixing.
0.20% (g/ml) medicinal carbon that in clear and bright solution, adds the dosing total amount, after the stirring and adsorbing 30 minutes, filter and 0.2 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.2 μ m, gained filtrate is used for fill to the medicinal liquid bottle.
The filtrate packing, the false add plug is put into freeze dryer and is carried out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.53 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.74 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-47 ℃ with the speed of 0.74 ℃/min again, continue insulation 5 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.51 ℃/min, treats that temperature rises to-1 ℃, continues insulation 5 hours;
The redrying stage: shelf temperature is risen to 16 ℃ with the speed of 0.63 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.22 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet, and the impurity content of freeze-dried powder is not higher than 0.28%, and moisture is not higher than 1.59%.
Embodiment 4
Add water for injection 1836ml in Agitation Tank, the temperature of Agitation Tank is 5 ℃, adds the 80g pemetrexed disodium again, stirring and dissolving.Add 64g mannitol again, stirring makes medicinal liquid become clear and bright solution; Regulate liquid PH value to 7.2 with the hydrochloric acid solution of 0.1mol/L and/or the sodium hydroxide solution of 0.1mol/L, add water for injection 324ml, mixing.
0.20% (g/ml) medicinal carbon that in clear and bright solution, adds the dosing total amount, after the stirring and adsorbing 30 minutes, filter and 0.2 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.2 μ m, gained filtrate is used for fill to the medicinal liquid bottle.
The filtrate packing, the false add plug is put into freeze dryer and is carried out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.55 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.73 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-45 ℃ with the speed of 0.73 ℃/min again, continue insulation 4 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.48 ℃/min, treats that temperature rises to-2 ℃, continues insulation 4 hours;
The redrying stage: shelf temperature is risen to 15 ℃ with the speed of 0.60 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.21 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet, and the impurity content of freeze-dried powder is not higher than 0.28%, and moisture is not higher than 1.59%.
Embodiment 5
Add water for injection 1632ml in Agitation Tank, the temperature of Agitation Tank is 10 ℃, adds the 80g pemetrexed disodium again, stirring and dissolving.Add 48g mannitol again, stirring makes medicinal liquid become clear and bright solution; Regulate liquid PH value to 7.5 with the hydrochloric acid solution of 0.1mol/L and/or the sodium hydroxide solution of 0.1mol/L, add water for injection 288ml, mixing.
0.20% (g/ml) medicinal carbon that in clear and bright solution, adds the dosing total amount, after the stirring and adsorbing 30 minutes, filter and 0.2 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.2 μ m, gained filtrate is used for fill to the medicinal liquid bottle.
The filtrate packing, the false add plug is put into freeze dryer and is carried out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-47 ℃ with the speed of 0.72 ℃/min again, continue insulation 4 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.48 ℃/min, treats that temperature rises to-1 ℃, continues insulation 3 hours;
The redrying stage: shelf temperature is risen to 16 ℃ with the speed of 0.63 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.18 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Whole freeze-drying process finishes, and feeds nitrogen, and the total head plug detects qualified back outlet, and the impurity content of freeze-dried powder is not higher than 0.28%, and moisture is not higher than 1.59%.
For verifying the reasonability of injection pemetrexed disodium injection prescription of freeze-drying powder of the present invention and preparation method thereof, the inventor once tested in a large number, and it is as follows now to enumerate part:
Experimental example 1
Determining of acidity scope
PH value scope according to injection pemetrexed disodium quality standard (import drugs registered standard JX20040040) is 6.6～7.8, the quality control clearance of the pH value of medicinal liquid when the inventor determines that by following test this preparation is produced.
Test method: precision takes by weighing the pemetrexed disodium and the mannitol of each recipe quantity in the table 1, place beaker respectively, 85% the water for injection that adds recipe quantity, stirring makes is dissolved into clear and bright solution, regulate each medicinal liquid pH value (the results are shown in Table 1) with the sodium hydroxide solution of 0.1mol/L hydrochloric acid solution or 0.1mol/L respectively, replenish water for injection more respectively to 15ml, stir, with 0.45 μ m filtering with microporous membrane decarburization, 0.2 germ tight filter of μ m filters and 0.2 μ m secondary terminals aseptic filtration, each subsequent filtrate is filled in the injection bottle by 3ml/ bottle branch, vacuum freeze-drying technique by embodiment 1 makes sample, behind the sample outlet, detect the pH value of quadrat sampling product (concentration is the pH value of the sample of 25mg/ml under the injection water as solvent) everywhere.
Definite result of the test of table 1pH value
By each sample pH value of solution value analysis result as can be known, after the lyophilizing sample solution pH value than lyophilizing before the medicinal liquid pH value all descend slightly to some extent, but change not obvious.
Acidity scope according to above-mentioned process of the test, data result, import registration quality standard, and in conjunction with the toleration influence factor of human body, when the inventor determines to produce, the pH value of medicinal liquid is adjusted to 7.0～7.5, with the sodium hydroxide solution of the hydrochloric acid solution of 0.1mol/L or 0.1mol/L pH value regulator as this preparation medicinal liquid.
Experimental example 2
Determining of the adsorption time of activated carbon dosage and active carbon
(1) adopts active carbon depyrogenation and decolouring adsorption to be arranged,, investigate the consumption of medicinal carbon therefore by following experiment to the solution Chinese medicine.
Test method: prescription proportioning and the medicinal liquid compound method preparation pemetrexed disodium solution of pressing embodiment 1, be divided into 4 equal portions, wherein 3 parts add respectively and account for 0.10% of medicinal liquid cumulative volume, 0.20%, 0.3% (g/ml) medicinal carbon, another part is made not adsorbent solution, all in 10 ℃ of following stirring and adsorbing 30min, filter carbon removal, get each filtrate and not adsorbent solution carry out analyzing and testing, investigate the pemetrexed disodium medicinal liquid through the relative amount (relatively solution absorption before) of variable concentrations medicinal carbon in identical adsorption time, the clarity of solution, color, pH value and bacterial endotoxin the results are shown in Table 2.
Table 2 medicinal carbon absorption result
By experimental data as can be known: concentration of activated carbon 0.10%～0.30% (g/ml) does not all have tangible absorption to principal agent; Along with the medicinal carbon consumption increases, sample solution clarity has clear improvement, adsorbent solution and the clarity of solution after 0.10% (g/ml) activated carbon adsorption all do not reach clarification, and the clarity behind 0.20% and 0.30% (g/ml) activated carbon adsorption solution reaches requirement; And along with activated carbon dosage is big more, the sample solution color is deepened slightly to some extent, and the solution pH value increases to some extent, and the medicinal liquid bacterial endotoxin after absorption is all up to specification.Consider the influence after the activated carbon adsorption, selecting concentration of activated carbon is the adsorption concentration of 0.20% (g/ml) as this medicinal liquid.
The investigation of (2) 0.20% medicinal carbon adsorption times
According to above result of the test, following test through different adsorption times, is investigated the absorption situation of active carbon to pemetrexed disodium by adding same concentrations (0.20%) active carbon.
Test method: prescription proportioning and the medicinal liquid compound method preparation pemetrexed disodium medicinal liquid of pressing embodiment 1, be divided into 4 equal portions, the medicinal carbon that adds 0.20% (g/ml) that account for each medicinal liquid cumulative volume respectively, all stir 0min, 20min, 30min, 40min down in 10 ℃, the medical filtration carbon removal, get each filtrate again and carry out analyzing and testing, investigate pemetrexed disodium solution through the influence of taking off relative amount, clarity, color, pH value and bacterial endotoxin after charcoal is handled of the medicinal charcoal of same concentrations, the results are shown in Table 3 at different adsorption times.
The investigation of table 3 medicinal carbon adsorption time
(annotate: the pH value before the medicinal liquid absorption is 7.21)
Analysis of experiments result shows: in identical medicinal carbon concentration 0.2% (g/ml), adsorption time 20～40min, active carbon is to not significantly absorption of principal agent, and yellow green is all clarified, is shallower than to solution No. 2, bacterial endotoxin is all up to specification, does not have significant change before and after the absorption of medicinal liquid pH value.Consider the influence of medicinal carbon absorption back to each index, this preparation medicine is used the activated carbon adsorption time, selects stirring and adsorbing 30min under the room temperature.
According to above two result of the tests, in this preparation medicinal liquid when preparation,, it is 0.20% medicinal charcoal that consumption is selected in medicinal carbon absorption for use, stirring and adsorbing 30min under the room temperature.
Experimental example 4
Determining of parameters of freeze-drying process
Adopt prescription proportioning and the above-mentioned definite dosing method of embodiment 1, preparation pemetrexed disodium solution is divided into 3 parts, every part contains pemetrexed disodium 0.1g, each technological parameter of design carries out vacuum lyophilization in the according to the form below 4, analyzes prepared sample respectively, the results are shown in following table 5.Determine to be fit to the parameters of freeze-drying process of this preparation (every bottle contains pemetrexed disodium 0.1g specification).
Table 4 parameters of freeze-drying process
Table 5 sample analysis result
More than in the sample of 5 freeze-dry process preparation, loose, full, the homogeneous of the outward appearance of sample 4 and sample 5 is better than sample 1,2 and 3; In addition, sample 4 and 5 impurity content are lower than sample 1,2 and 3, and the result of all other indexs of sample is all better, but totally it seems, sample 4 and every index of 5 be all owing to other, therefore tentatively determine that the freeze-dry process basic parameter of this preparation is as follows:
Freeze-dry process:
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5～0.55 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.70～0.74 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-43～-47 ℃ with the speed of 0.70～0.74 ℃/min again, continue insulation 3～5 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.44～0.51 ℃/min, treats that temperature rises to-3～-1 ℃, continues insulation 3～5 hours;
The redrying stage: shelf temperature is risen to 14～16 ℃ with the speed of 0.50～0.63 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.18～0.22 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Consider the factors such as quality of production cycle, power consumption and dried frozen aquatic products, determine that the most preferred freeze-dry process of the present invention is as follows:
The pre-freeze stage: evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-45 ℃ with the speed of 0.72 ℃/min again, continue insulation 4 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.48 ℃/min, treats that temperature rises to-3 ℃, continues insulation 4 hours;
The redrying stage: shelf temperature is risen to 15 ℃ with the speed of 0.57 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.20 ℃/min, treat that temperature of articles in the redrying reaches 35 ℃ after, continue insulation 3 hours.
Experimental example 5
The pemetrexed disodium freeze-dried injection stability study
(1) influence factor's test
Test sample: the pemetrexed disodium freeze-dried injection that adopts the process preparation of embodiment 1
This product is got in hot test, (sample segment was uprightly placed in 10 days in placement under 60 ℃ of conditions, sample segment makes medicine fully contact with plug the content broken back upside down of shaking), respectively at the 5th day and sampling in the 10th day, character to sample, the redissolution time, the clarity of solution and color, acid-base value, moisture, visible foreign matters, particulate matter, impurity, D-isomer and content are investigated and (are at first investigated the sample of upside down, when the sample of upside down is investigated the sample that result and 0 day are no longer investigated upright placement when more constant, when the sample of upside down checks that item relatively had significant change with 0 day, cut-off stands up the sample of putting and investigates this with method, is the variation or the incompatible variation that causes with plug of medicine of medicine self with differentiation).
This product is got in the strong illumination test, remove label, under the condition of intensity of illumination 4500lx, place 10 days (traverse), respectively at the 5th day and the 10th day sampling, clarity and color, acid-base value, moisture, visible foreign matters, particulate matter, impurity, D-isomer and the content of the character of sample, redissolution time, solution are investigated.
This product is got in the high humility test, under the condition of 25 ℃ of temperature, relative humidity 92.5%, placed 10 days, respectively at the 5th day and the 10th day sampling, clarity and color, acid-base value, moisture, visible foreign matters, particulate matter, plug and seal of vessel, impurity, D-isomer and the content of the character of sample, plug outward appearance, redissolution time, solution are investigated.
Table 6 influence factor result of the test
As seen from the experiment, except that hot test 10 days and 10 days sample impurity of strong illumination test slightly increase, the investigation result of sundry item and more all do not have significant change in 0 day, sample character under high temperature (60 ℃), high light (intensity of illumination 4500lx) and high humility (25 ℃ of temperature, RH92.5%) condition is all stable; What hot test was investigated is the sample of upside down, and the result shows that the medicine and the packaging material compatibility are good, and this product prescription is reasonable, preparation technology is feasible.
(2) accelerated test
Adopt three batches of pemetrexed disodium freeze-dried injections of the process preparation of embodiment 1, lot number: 091101,091102,091103, (XiLin is bottled for the simulation commercially available back, add the papery capsule), with commercially available sample (specification: 0.1g, lot number:, place 6 months (sample segment is uprightly placed, and sample segment makes medicine fully contact with plug the content broken back upside down of shaking) under the condition of relative humidity 75% A643880D) in 40 ℃ of temperature.At duration of test the 1st, 2,3, take a sample 6 the end of month respectively, character to sample, the plug outward appearance, again dissolution time, the clarity of solution and color, acid-base value, moisture, visible foreign matters, particulate matter, plug and seal of vessel, bacterial endotoxin, aseptic, impurity, D-isomer and content are investigated and (are at first investigated the sample of upside down, when the sample of upside down is investigated the sample that result and 0 month are no longer investigated upright placement when more constant, when the sample of upside down checks that item relatively had significant change with 0 month, cut-off stands up the sample of putting and investigates this with method, is the variation or the incompatible variation that causes with plug of medicine of medicine self with differentiation).
Table 7 accelerated test check result
Get by result of the test, except that the color of quickening sample solution in June is slightly deepened, the investigation result of other project with more all do not have significant change in 0 month, properties of samples is stablized; Investigate the result with the contrast of commercially available sample and show that this product impurity content is low, stability is higher than commercially available sample; The sample that accelerated test is investigated is the sample of upside down, and the result shows that sample and the plug compatibility and plug and seal of vessel are all good.
(3) long term test
Adopt three batches of pemetrexed disodium freeze-dried injections of the process preparation of embodiment 1, lot number: 091101,091102,091103, (XiLin is bottled for the simulation commercially available back, add the papery capsule), with commercially available sample (specification: 0.1g, lot number: A643880D) in 25 ℃ of temperature, place under the condition of relative humidity 60%, respectively at the 3rd, 6 samplings at the end of month are to the character of sample, the plug outward appearance, again dissolution time, the clarity of solution and color, acid-base value, moisture, visible foreign matters, particulate matter, plug and seal of vessel, bacterial endotoxin, aseptic, impurity, D-isomer and content are investigated.
Table 8 long term test check result
Got by above-mentioned investigation result, sample of the present invention is stable in properties under this condition; With the contrast of commercially available sample investigate the result as can be known this product stability apparently higher than commercially available sample.
(4) compatibility experiment
Get above-mentioned lot number: 1 bottle of 091101 pemetrexed disodium freeze-dried injection, add 0.9% sodium chloride injection 20ml and make dissolving, make the solution that concentration is 25mg/ml, reuse 0.9% sodium chloride injection is diluted to 100ml, as compatibility solution, under room temperature, stand upside down to place, investigate outward appearance, pH value, clarity and color, visible foreign matters, particulate matter, impurity, D-isomer and content in the compatibility solution 24 hours and the compatibility of compatibility solution and plug.Result of the test shows in the compatibility solution chamber relaxing the bowels with purgatives of warm nature 24 hours stable, satisfies clinical use needs.
Determine after deliberation that in addition this product can be stored 36 months at ambient temperature.
Claims (8)
1. a pemetrexed disodium freeze-dried injection is characterized in that, described pemetrexed disodium freeze-dried injection is made up of pemetrexed disodium and mannitol, and the mass ratio of described pemetrexed disodium and mannitol is 1: 0.6～2.0.
2. pemetrexed disodium freeze-dried injection according to claim 1 is characterized in that the mass ratio of described pemetrexed disodium and mannitol is 1: 0.8～1.6, most preferably is 1: 1.2.
3. pemetrexed disodium freeze-dried injection according to claim 1 is characterized in that the impurity content of described pemetrexed disodium freeze-dried injection is not higher than 0.28%, and moisture is not higher than 1.59%.
4. the preparation method of claim 1 or 3 described pemetrexed disodium freeze-dried injections is characterized in that described preparation method comprises the steps:
(a) in Agitation Tank, add water for injection earlier, add the pemetrexed disodium of recipe quantity again, be stirred to dissolving fully;
(b) in Agitation Tank, add the mannitol of recipe quantity again, continue to stir and make medicinal liquid become clear and bright solution, regulate the medicinal liquid pH value, replenish water for injection, stir with hydrochloric acid solution or sodium hydroxide solution;
(c) add medicinal carbon, stirring and adsorbing adopts the circulation mode decarburization of decarburization limit, limit, aseptic filtration;
(d) with the solution packing of step (c) gained, the false add plug carries out lyophilization, and lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: behind the evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5～0.55 ℃/min to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.70～0.74 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-43～-47 ℃ with the speed of 0.70～0.74 ℃/min again, continue insulation 3～5 hours, be evacuated to the interior vacuum of case and reach 10Pa;
The primary drying stage: shelf temperature adopts staged to heat up, and intensification-insulation hockets, and every intensification 10 minutes then is incubated 5 minutes, and the speed of intensification is 0.44～0.51 ℃/min, treats that temperature rises to-3～-1 ℃, continues insulation 3～5 hours;
The redrying stage: shelf temperature is risen to 14～16 ℃ with the speed of 0.50～0.63 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.18～0.22 ℃/min, after treating that temperature of articles in the redrying reaches 35 ℃, continue insulation after 3 hours, whole freeze-drying process finishes, and feeds nitrogen, the total head plug detects qualified back outlet.
5. the preparation method of pemetrexed disodium freeze-dried injection according to claim 4 is characterized in that, when adding pemetrexed disodium in the step (a), the solution temperature in the Agitation Tank is controlled between 0～10 ℃.
6. the preparation method of pemetrexed disodium freeze-dried injection according to claim 4 is characterized in that, in the step (b), regulates medicinal liquid pH value to 7.0～7.5 with the hydrochloric acid solution of 0.1mol/L or the sodium hydroxide solution of 0.1mol/L.
7. the preparation method of pemetrexed disodium freeze-dried injection according to claim 4, it is characterized in that, in the step (c), the amount that adds active carbon is the 0.2%g/ml of medicinal liquid cumulative volume, after the stirring and adsorbing 30 minutes, filter and 0.22 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane decarburization, germ tight filter of 0.22 μ m.
8. the preparation method of pemetrexed disodium freeze-dried injection according to claim 4 is characterized in that, step (d) is preferably:
The pre-freeze stage: behind the evacuation, inflated with nitrogen is reduced to-3 ℃ with shelf temperature with the speed of 0.5 ℃/min afterwards again to normal pressure, is incubated 0.5 hour, reduce to-30 ℃ with the speed of 0.72 ℃/min again, stop cooling, be incubated 1 hour, slowly be warming up to-5 ℃, be incubated 1 hour, reduce to-45 ℃ with the speed of 0.72 ℃/min again, be incubated 4 hours, it is 10pa that last evacuation makes the interior vacuum of case;
The primary drying stage: the speed that shelf heats up is 0.48 ℃/min, treats that temperature rises to-3 ℃, continues insulation 4 hours;
The redrying stage: shelf temperature is risen to 15 ℃ with the speed of 0.57 ℃/min, be incubated 1 hour, shelf continues to be warming up to 40 ℃ with the speed of 0.2 ℃/min, continues insulation 3 hours.
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| CN103784454B (en) * | 2014-01-22 | 2015-11-18 | 海南锦瑞制药有限公司 | A kind of pharmaceutical composition containing pemetrexed disodium compound |
| CN105726492A (en) * | 2014-12-08 | 2016-07-06 | 博瑞生物医药（苏州）股份有限公司 | Freeze-dried powder injection of pemetrexed dipotassium and preparation method thereof |
| CN108226455A (en) * | 2017-12-25 | 2018-06-29 | 湖北华强科技有限责任公司 | A kind of fast appraisement method of butyl rubber plug and lyophilized preparation drug compatibility |
| EA038700B1 (en) * | 2018-04-26 | 2021-10-07 | Тютор С.А.С.И.Ф.И.А. | Method of producing a pharmaceutical composition of disodium pemetrexed |
| CN108992413A (en) * | 2018-09-03 | 2018-12-14 | 四川汇宇制药有限公司 | A kind of pemetrexed disodium freeze-dried injection and preparation method thereof |
| CN109223720A (en) * | 2018-09-12 | 2019-01-18 | 南京康舟医药科技有限公司 | The preparation method of injection Terlipressin freeze drying powder injection |
| CN109223720B (en) * | 2018-09-12 | 2020-11-27 | 南京康舟医药科技有限公司 | Preparation method of terlipressin acetate freeze-dried powder injection for injection |
| CN115252564A (en) * | 2022-08-30 | 2022-11-01 | 海南锦瑞制药有限公司 | Preparation method of pemetrexed disodium for injection |
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| CN102106833B (en) | 2012-05-02 |
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