CN101829065B - Lansoprazole composition freeze-dried powder for injection - Google Patents
Lansoprazole composition freeze-dried powder for injection Download PDFInfo
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Abstract
The invention relates to lansoprazole composition freeze-dried powder for injection. The lansoprazole composition freeze-dried powder is characterized by comprising lansoprazole used as a main material, meglumine, mannitol, sodium hydrogensulfite and ethylene diamine tetraacetic acid, wherein the proportion of the components is 3:(0.1-1):(1-20):(0.01-0.5):(0.01-0.5); preferably, the proportion is 3:(0.5-1):(10-20):(0.1-0.3):(0.05-0.3); and more preferably, the proportion is 3:1:20:0.2:0.2. The preparation method comprises the following steps of: dissolving the raw material and the auxiliary materials by adding water; regulating the pH value; adding active carbon for decolorizing; filtering for decarburizing; fine filtering by using a filter membrane; sub-packaging; cooling to -50 to -46 DEG C according to a speed of 1-1.2 DEG C/minute; preserving heat and freezing for 3 hours; vacuumizing to 15Pa; uniformly heating up to -22 to -18 DEG C within 7-9 hours and then preserving heat for 1-2 hours; uniformly heating up to 3-7 DEG C within 4-6 hours and then heating up to 40 DEG C within 4 hours; preserving heat and drying for 3 hours; and packaging and storing after inspection.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of proton pump inhibitor class medicine, is a kind of Lansoprazole composition freeze-dried powder for injection in particular.
Background technology
Lansoprazole (Lansoprazole) is second proton pump inhibitor class antiulcerative in the world of being developed by Wu Tian company after omeprazole (Omeprazole).This product is formally put on market in France by military field pharmaceutical factory and Houde company (belonging to Roussel Uclaf company) at the beginning of 1992, this product belongs to the excretory medicine of gastric acid inhibitory of substituted benzimidazole class, be the excretory medicine of a kind of novel gastric acid inhibitory, it acts on the H of parietal cell
+-K
+-ATP enzyme.Make the H of parietal cell
+Can not be transported in the stomach and go, so that the gastric acid amount greatly reduces in the gastric juice, is used for duodenal ulcer, gastric ulcer, reflux esophagitis clinically, the treatment of a left side-Ai (Zollinger-Ellison) syndrome (gastrinoma), evident in efficacy, helicobacter pylori there is inhibitory action.Since above-mentioned enzyme the similar proton pump of effect, so lansoprazole is known as proton pump inhibitor again.Lansoprazole and phenylpropyl alcohol thiazolyl product thereof show very fast bactericidal activity, and the phenylpropyl alcohol thiazole is easier to form in human stomach.Thereby the bactericidal action of lansoprazole is strengthened.More than these effects all help the healing of peptic ulcer.Add that lansoprazole has imported fluorine element in its structure, it is absorbed rapidly.Bioavailability improves.So comparatively fast relief of symptoms is accelerated ulcer healing.
Lansoprazole of the present invention (Lansoprazole), its chemical name: 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-the 1H-benzimidazole.Its chemical structural formula is:
CAS:103577-45-3; Molecular formula: C
16H
14F
3N
3O
2S; Molecular weight: 369.37; Present white to khaki loose block or powder
Lansoprazole usually is made into freeze-drying preparation for injection because unstable under acidic condition, avoids because oral and decomposed by stomach acids destroy under one's belt.Pre-freeze cooling rate in its preparation process, drying stage programming rate, time etc. all produce a very large impact properties of product.
As adopting arginine among the CN200410036486 is stabilizing agent, and lactose is an excipient, carries out lyophilizing and handles.And arginine is unstable under alkali condition, decomposes easily, and it is cosolvent that sodium hydroxide has been adopted in this invention, and its pH scope is up to 11-12.5.Like this should the prepared medicine of invention will certainly be owing to arginic decomposition instability.
The freeze drying process that adopts in CN200410065853 is for to be refrigerated to medicinal liquid-40～-35 ℃, freezing 5～7h, and the vacuum drying 20～30h that slowly heats up again is warming up to 10 ℃ again, dry 2～4h.Yet he adds medicinal liquid was descended freezing 2 hours at-30～-35 ℃ in concrete enforcement, according to 2～4 ℃ of/hour intensifications of speed, and to 30 ℃, dry 2～4 hours again.
The employing mass ratio is 3: 1: 6 a lansoprazole among the CN97199638: meglumine: mannitol prepares lyophilized powder, but does not specifically provide freeze-drying process.
CN200610025754 mixes 10-50 part lansoprazole, 1-5 part sodium hydroxide, 2-20 part meglumine and 20-100 part mannitol, packing after the decolouring degerming, ℃ froze 6 hours then-40, be warming up to-20 ℃ of dryings 8 hours, rise to-10 ℃ of dryings 4 hours, rise to 0 ℃ of drying 2 hours again, rise to 25 ℃ of dryings 2 hours again.Its process is too complicated, and commercial production is difficulty comparatively, and does not provide the critical datas such as programming rate in each stage.
CN200610045935 is a major ingredient with 15-30 part Lansoprazole sodium, add 5-50 part mannitol or meglumine and prepare the freeze dried Lansoprazole sodium powder, its detailed freeze-drying process is :-40～-45 ℃ of pre-freeze 4～6h, resublime 28～36h, per hour heat up 1～2 ℃, to 35～45 ℃.
CN200510017379 discloses a kind of preparation scheme of lansoprazole sodium salt again, wherein relate to the preparation of its lyophilized formulations of example: with lansoprazole sodium salt 32g, meglumine 10g, mannitol 60g is obtain solution respectively, the mannitol solution carbon decoloring, merge the latter two solution, merge with sodium salt solution again, membrane filtration ,-35 ℃ froze 4 hours, be warming up to-15 ℃ of drying under reduced pressure 9 hours, and be warming up to 35 ℃ of dryings 7 hours (vacuum 13.3Pa) again.
If excipient was less when the inventor found according to the prior art for preparing Lansoprazole freeze-dried powder through overtesting, be 1: 2 as lansoprazole among patent CN97199638 and the CN200510017379 and mannitol ratio, prepared to go out the freeze-dried powder outward appearance not full, even the situation of subsiding is arranged.The analysis of causes may be very few for the lyophilized powder consumption, causes the sublimation process excipient not have fully to form to have the skeleton of excellent support effect, and cause outward appearance not full.
In view of this, special proposition the present invention.
Summary of the invention
The object of the invention is to provide a kind of Lansoprazole composition freeze-dried powder for injection.
To achieve these goals, the technical solution used in the present invention is:
A kind of Lansoprazole composition freeze-dried powder for injection, described Lansoprazole composition freeze-dried powder component is: major ingredient lansoprazole, meglumine, mannitol, sodium sulfite and disodiumedetate, its ratio are 3: 0.1～1: 1～20: 0.01～0.5: 0.01～0.5; Be preferably 3: 0.5～1: 10～20: 0.1～0.3: 0.05～0.3; More preferably 3: 1: 20: 0.2: 0.2.
Should be furnished with the filter that the aperture is 1.2 μ m when all requiring quiet to use in the Lansoprazole freeze-dried powder preparation of prior art, so that remove issuable precipitate in the infusion process.Sedimentary situation takes place, analysis is the influence of different quality level of being infused, some metal ion generation complex reactions in the main constituent of medicine and the transfusion (0.9% sodium chloride injection and 5% glucose injection) produce precipitate and separate out, and cause occurring clinical adverse.
The inventor has problems in this regard for solving domestic production enterprise when the formulation and technology of this product of design, on the basis of a large amount of experiment sievings, selects lansoprazole and EDTA-2Na to be used in combination, and the two ratio is 3: 0.01～0.5; Be preferably 3: 0.05～0.3; More preferably 3: 0.2, not only the particulate matter of product self obtains fine raising and control, simultaneously, also effectively prevented the metal ion generation complex reaction in the lansoprazole and transfusion (0.9% sodium chloride injection and 5% glucose injection) in quiet process, avoid producing precipitation and separate out, thereby solved this product clinical drug safety problem in this regard.
According to foregoing Lansoprazole composition freeze-dried powder for injection, described Lansoprazole composition freeze-dried powder mean diameter is 50～200nm, and porosity is 90%～98%.
Preferred mean diameter is 100～150nm, and porosity is 95～98%.
More preferably mean diameter is 120nm, and porosity is 97%.
Lansoprazole composition freeze-dried powder of the present invention has littler fineness of the particles, and higher porosity, has improved the redissolution performance so greatly, has reduced the redissolution time, and has reduced the solution placement of preparation back and separated out solid probability.
According to Lansoprazole composition freeze-dried powder for injection noted earlier, its preparation method is:
(1) dosing: supplementary material is added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH, add water for injection to liquor capacity and be lansoprazole 100 times with sodium hydroxide;
(2) decolouring: in the medicinal liquid for preparing, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity through 0.22 μ m degerming microporous filter membrane fine straining and be lansoprazole 630 times, packing false add plug;
(3) lyophilizing
A, pre-freeze: the freeze drying box temperature is reduced to 0～5 ℃, divide and install to such an extent that medicinal liquid is placed 20～40min in freeze drying box, again freeze drying box is cooled to-37～-43 ℃ with 35～45 ℃/min speed, be warming up to-15～-10 ℃ then, insulation 0.5～1h, be cooled to-50～-46 ℃ with 40～50 ℃/min speed then, be incubated freezing 2 hours
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15～20Pa, at the uniform velocity slowly freeze drying box was warming up to-15～-10 ℃ then at 12～16 hours, be incubated 5 hours,
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.1～0.2 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
In the above-mentioned described Lansoprazole composition freeze-dried powder for injection, usually adopt the water for injection of 100 times of lansoprazoles to dissolve in the prior art, and the present invention gropes through a large amount of experiments, find to use a large amount of water for injection that main ingredient is dissolved, carry out lyophilization then, can reduce the particle diameter of product significantly.
The Lansoprazole freeze-dried powder particle diameter of prior art for preparing has 500～1000nm usually, and the present invention can be reduced to 50～200nm.Analysis may be a large amount of solvent, has significantly disperseed the distribution of solute, thereby has reduced because the molecule contact that molecular motion causes.So just make the product that obtains after the lyophilizing have littler particle diameter.
The inventor gropes through a large amount of experiments, finds to take pre-freeze method of the present invention, can be so that the medicine that lyophilizing makes bulk multi-hole more, and solubility improves a lot during clinical use.
In addition,, can reach under the same degree of drying, avoid the influence of higher temperature, make the stability of medicine be improved for product component by further adjustment distillation and exsiccant freeze-drying curve.
In the above-mentioned Lansoprazole composition freeze-dried powder for injection, step (3) a pre-freeze can more preferably be reduced to 3 ℃ with the freeze drying box temperature, divide the medicinal liquid that installs to place 30min in freeze drying box, again freeze drying box is cooled to-40 ℃ with 40 ℃/min speed, be warming up to-13 ℃ then, insulation 0.7h is cooled to-48 ℃ with 45 ℃/min speed then, is incubated freezing 2 hours.
In the above-mentioned Lansoprazole composition freeze-dried powder for injection, step (3) b distillation can more preferably be evacuated to 17Pa, at the uniform velocity slowly freeze drying box was warming up to-13 ℃ at 14 hours.
In the above-mentioned Lansoprazole composition freeze-dried powder for injection, step (3) c drying can also be preferably again freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.1 ℃/min.
In foregoing Lansoprazole composition freeze-dried powder for injection, the described adjustment of step (1) pH and add water for injection can be with reference to the operation of prior art.The present invention preferably is adopted as and adjusts pH is 10～12.
In foregoing Lansoprazole composition freeze-dried powder for injection, it is 0.1% of liquor capacity that the present invention can also further preferably adopt the described medical activated carbon consumption of step (2).
Lansoprazole composition freeze-dried powder provided by the present invention and preparation method thereof has following advantage:
(1) Lansoprazole composition freeze-dried powder employing lansoprazole provided by the present invention is 3: 18～20 with excipient mannitol ratio, makes product appearance full, has better solubility property.
(2) Lansoprazole composition freeze-dried powder provided by the present invention has littler fineness of the particles, and higher porosity, makes medicine redissolution performance strengthen greatly.
(3) Lansoprazole composition freeze-dried powder provided by the present invention takes rapidly fluid temperature to be reduced to the pre-freeze temperature, and will heat up stage by stage, make that the product water content is lower, improved the quality of product, simultaneously also increase distillation efficient, at utmost reduced energy consumption.
(4) lansoprazole steady quality provided by the present invention is easy to use, is beneficial to storing, and its preparation method is simple, is easy to suitability for industrialized production.
The specific embodiment
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
Embodiment 1
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 2g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～12 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 120nm, and porosity is 97%.
Embodiment 2
With lansoprazole 30g, meglumine 10g, mannitol 180g, sodium sulfite 2g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 110nm, and porosity is 98%.
Embodiment 3
With lansoprazole 30g, meglumine 10g, mannitol 220g, sodium sulfite 1g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH11～12 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 130nm, and porosity is 97%.
Embodiment 4
With lansoprazole 30g, meglumine 10g, mannitol 190g, sodium sulfite 3g and disodiumedetate 3g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH11～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 105nm, and porosity is 98%.
Embodiment 5
With lansoprazole 30g, meglumine 10g, mannitol 210g, sodium sulfite 2g and disodiumedetate 1g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10.5～12 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 125nm, and porosity is 95%.
Embodiment 6
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 1g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 120nm, and porosity is 95%.
Embodiment 7
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 3g and disodiumedetate 1g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 5 ℃, put into the medicinal liquid that branch installs, place 40min, again freeze drying box is cooled to-43 ℃ with 45 ℃ of/minute speed in freeze drying box, be warming up to-15 ℃ then, be incubated 1 hour, be cooled to-46 ℃ with 40 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 20Pa, in 16 hours, at the uniform velocity slowly freeze drying box is warming up to-15 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 155nm, and porosity is 96%.
Embodiment 8
With lansoprazole 30g, meglumine 10g, mannitol 195g, sodium sulfite 2g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 4 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-38 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-12 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 15 hours, at the uniform velocity slowly freeze drying box is warming up to-12 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 160nm, and porosity is 98%.
Embodiment 9
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 2g and disodiumedetate 1g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 2 ℃, put into the medicinal liquid that branch installs, place 25min, again freeze drying box is cooled to-40 ℃ with 43 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-49 ℃ with 48 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 18Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-11 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.2 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 130nm, and porosity is 95%.
Embodiment 10
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 3g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-42 ℃ with 38 ℃ of/minute speed in freeze drying box, be warming up to-14 ℃ then, be incubated 0.8 hour, be cooled to-47 ℃ with 43 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 13 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 115nm, and porosity is 96%.
Embodiment 11
With lansoprazole 30g, meglumine 10g, mannitol 205g, sodium sulfite 2g and disodiumedetate 1g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 19Pa, in 16 hours, at the uniform velocity slowly freeze drying box is warming up to-10 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 140nm, and porosity is 93%.
Embodiment 12
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 1g and disodiumedetate 3g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 4 ℃, put into the medicinal liquid that branch installs, place 32min, again freeze drying box is cooled to-41 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-12 ℃ then, be incubated 0.8 hour, be cooled to-46 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 80nm, and porosity is 97%.
Embodiment 13
With lansoprazole 30g, meglumine 10g, mannitol 185g, sodium sulfite 3g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-13 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 100nm, and porosity is 92%.
Embodiment 14
With lansoprazole 30g, meglumine 10g, mannitol 215g, sodium sulfite 2g and disodiumedetate 0.5g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 3 ℃, put into the medicinal liquid that branch installs, place 28min, again freeze drying box is cooled to-40 ℃ with 40 ℃ of/minute speed in freeze drying box, be warming up to-12 ℃ then, be incubated 0.7 hour, be cooled to-48 ℃ with 46 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 18Pa, in 14 hours, at the uniform velocity slowly freeze drying box is warming up to-14 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.2 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 180nm, and porosity is 91%.
Embodiment 15
With lansoprazole 30g, meglumine 10g, mannitol 200g, sodium sulfite 2g and disodiumedetate 2g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 4 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 42 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.6 hour, be cooled to-50 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 15 hours, at the uniform velocity slowly freeze drying box is warming up to-12 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 120nm, and porosity is 93%.
Embodiment 16
With lansoprazole 30g, meglumine 1g, mannitol 200g, sodium sulfite 5g and disodiumedetate 5g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 4 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 42 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.6 hour, be cooled to-50 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 15 hours, at the uniform velocity slowly freeze drying box is warming up to-12 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 125nm, and porosity is 94%.
Embodiment 17
With lansoprazole 30g, meglumine 10g, mannitol 10g, sodium sulfite 0.1g and disodiumedetate 0.1g add in the dosing cylinder, add 2500ml water for injection and be stirred to whole dissolvings, regulate pH10～11.5 with sodium hydroxide, add water for injection to 3000ml, in the medicinal liquid for preparing, add medical activated carbon, wherein medical activated carbon weight is 0.1% of liquor capacity, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity and be lansoprazole 630 times, be distributed into 1000 bottles, the false add plug, freeze drying box is cooled to 4 ℃, put into the medicinal liquid that branch installs, place 30min, again freeze drying box is cooled to-40 ℃ with 42 ℃ of/minute speed in freeze drying box, be warming up to-13 ℃ then, be incubated 0.6 hour, be cooled to-50 ℃ with 45 ℃ of/minute speed then, be incubated freezing 2 hours, open vacuum valve and be evacuated to 17Pa, in 15 hours, at the uniform velocity slowly freeze drying box is warming up to-12 ℃ then, is incubated 5 hours, at the uniform velocity be warming up to 20 ℃ with 0.1 ℃ of/minute speed again, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.Prepared lyophilized powder mean diameter detects through scanning electron microscope and is 50nm, and porosity is 97%.
The present invention also further provides following test example, so that effect of the present invention is described further:
Test example 1
This test example has been investigated the effect of medical activated carbon absorption pyrogen
Table 1, pyrogen adsorption effect
The detection method of this test example can be with reference to 2005 editions second appendix XI E of Chinese Pharmacopoeia bacterial endotoxins test.Data are the average of 10 parallel tests in the form, and the water of each time test and other reagent, vessel are with batch sterilization treatment, to avoid because reagent or instrument vessel carry the influence of endotoxin for result of the test.
The prescription that this test example adopts is the prescription of embodiment 1, and the parameter of embodiment 1 is also adopted in the dosing of preparation method and lyophilizing operation, and difference only is the operation that step (2) is decoloured mutually.
Wherein 1 is that 2～5 pairs of medical activated carbon consumptions are adjusted according to embodiment 1 decolouring operation, and 8,9 have investigated the influence of mixing time and whipping temp.
According to the result as can be seen, when adopting technical solution of the present invention, test fluid is still negative at 0.125EU/ml, and has reduced activated carbon dosage, and is then positive at 0.125EU/ml.
Though when strengthening activated carbon dosage, and when prolonging mixing time and improving whipping temp, still negative at 0.125EU/ml, but consider absorption for effective ingredient, and temperature is to the influence of effective ingredient, and the consideration of cost, so decolorization employing technical solution of the present invention is good.
Test example 2
This test example has been investigated the influence of lyophilizing parameter for the product solubility
Table 2, product redissolution performance-solubility property
| ? | 1? | 2? | 3? | 4? | 5? |
| 0 month (s) | 2? | 3? | 7? | 10? | 5? |
| 6 months (s) | 3? | 5? | 15? | 30? | 10? |
| 12 months (s) | 5? | 8? | 25? | 42? | 17? |
| 24 months (s) | 10? | 15? | 55? | 76? | 34? |
Table 3, product redissolution performance-solid are separated out
| ? | 1? | 2? | 3? | 4? | 5? |
| 1 day | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out |
| 3 days | Nothing is separated out | Nothing is separated out | Nothing is separated out | Separate out a small amount of | Nothing is separated out |
| 10 days | Nothing is separated out | Nothing is separated out | Separate out a small amount of | Separate out a small amount of | Nothing is separated out |
| 30 days | Nothing is separated out | Nothing is separated out | Separate out more | Separate out in a large number | Separate out a small amount of |
This experiment is packed for to carry out preparation of product according to the production scale method, and every group of test sample produced 1000 bottles, get 50 bottles at random at every group, add 15ml water for injection respectively, same model agitator is provided with 100 times/min of identical frequency of vibration, get each cell mean then, insert table.
All according to embodiment 1 preparation, preparation process is reference example 1 process also for each group prescription, and each group difference only is freeze-drying process.
Wherein 1 is to carry out according to embodiment 1 operation, and 2 for carrying out according to embodiment 6 operations;
3 freeze-drying process are: the medicinal liquid that branch is installed is cooled to-48 ℃ by 1.1 ℃ of/minute speed, be incubated freezing 3 hours, open vacuum valve and be evacuated to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, heat preservation and dryness 1 hour, in 5 hours, at the uniform velocity be warming up to 5 ℃ again, then medicinal liquid at the uniform velocity be warming up to 40 ℃ in 4 hours, heat preservation and dryness 3 hours;
4 freeze-drying process are: divide the medicinal liquid install-43 ℃ of following pre-freezes 5 hours, resublime 28～36 hours per hour heats up 1.5 ℃, is warming up to 40 ℃;
5 for to carry out lyophilizing according to embodiment 1 freeze-drying curve, handles to the 3000ml rear decoloring but add water for injection, and fine straining is no longer added water for injection after surveying pH value and content, and directly carries out lyophilization.
As can be seen from the above table, freeze-drying process provided by the present invention can increase substantially the redissolution speed of product, and after product was placed a period of time, the performance of redissolving was higher than prior art products by it by it.And use a large amount of water for injection to dissolve, can further improve solubility property.And the product that adopts preparation method preparation of the present invention is more stable after dissolving, and is difficult for separating out solid matter, has improved patient's drug safety greatly.
Test example 3
This test example has been investigated Lansoprazole composition freeze-dried powder stability provided by the present invention
Table 4, accelerated test
| ? | 0 month | 1 month | 2 months | 3 months | 6 months |
| 1? | 99.96％? | 99.95％? | 99.93％? | 99.90％? | 99.72％? |
| 2? | 99.95％? | 99.94％? | 99.92％? | 99.88％? | 99.70％? |
| 3? | 99.95％? | 99.94％? | 99.90％? | 99.82％? | 99.63％? |
| 4? | 99.96％? | 99.92％? | 99.85％? | 99.70％? | 99.28％? |
Table 5, long term test
| ? | 0 month | 3 months | 6 months | 9 months | 12 months | 18 months |
| 1? | 99.96％? | 99.96％? | 99.95％? | 99.93％? | 99.90％? | 99.85％? |
| 2? | 99.95％? | 99.95％? | 99.92％? | 99.90％? | 99.87％? | 99.82％? |
| 3? | 99.95％? | 99.93％? | 99.89％? | 99.85％? | 99.80％? | 99.72％? |
| 4? | 99.96％? | 99.93％? | 99.86％? | 99.82％? | 99.73％? | 99.62％? |
This experiment is packed for to carry out preparation of product according to the production scale method, and every group of test sample produced 1000 bottles, gets 50 bottles at random at every group, detects stability data according to 2005 editions appendix XIX of Chinese Pharmacopoeia C method, gets each cell mean then, inserts table.
All according to embodiment 1 preparation, preparation process is reference example 1 process also for each group prescription, and each group difference only is freeze-drying process.
Wherein 1 is to carry out according to embodiment 1 operation, and 2 for carrying out according to embodiment 6 operations;
3 freeze-drying process are: the medicinal liquid that branch is installed is cooled to-48 ℃ by 1.1 ℃ of/minute speed, be incubated freezing 3 hours, open vacuum valve and be evacuated to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, heat preservation and dryness 1 hour, in 5 hours, at the uniform velocity be warming up to 5 ℃ again, then medicinal liquid at the uniform velocity be warming up to 40 ℃ in 4 hours, heat preservation and dryness 3 hours;
4 freeze-drying process are: divide the medicinal liquid install-43 ℃ of following pre-freezes 5 hours, resublime 28～36 hours per hour heats up 1.5 ℃, is warming up to 40 ℃;
As can be seen from the above table, freeze-drying process provided by the present invention can increase substantially the stability of product.
Test example 4
This test example has been investigated the metal ion content of Lansoprazole composition freeze-dried powder provided by the invention.
Table 6 resultant metal ion concentration and solid are separated out situation
| ? | 1? | 2? | 3? |
| The EDTA-2Na consumption | 2g? | 0.05g? | 0? |
?
| Content of beary metal | 4/(1×10 6) | 8/(1×10 6) | 15/(1×10 6) |
| Placed 10 days | No solid is separated out | No solid is separated out | There is solid to separate out |
| Placed 30 days | No solid is separated out | There is solid to separate out | There is solid to separate out |
| Placed 3 months | No solid is separated out | There is solid to separate out | There is solid to separate out |
1 is embodiment 1 product in the last table, and 2 for to be adjusted into 0.05g with the EDTA-2Na consumption, and 3 for not adding EDTA-2Na, and other compositions are just the same, and preparation method is also in full accord, prepares according to embodiment 1 method.
Last table explanation, the Lansoprazole composition freeze-dried powder of employing technical solution of the present invention can effectively be eliminated the influence of metal ion.
The other embodiments of the invention product has also all been done similar experiment, has the trend similar with the above table data.Because length is limit, the inventor enumerates no longer one by one.
Test example 1
Use the nitrogen adsorption method in 30 ℃, and based on BET adsorption equation testing product specific surface area, used software is ASAP2010-M surface area analysis module, gets the product 200mg sample cell of packing into, degassing 4h detects.
Claims (6)
1. Lansoprazole composition freeze-dried powder for injection, it is characterized in that, described Lansoprazole composition freeze-dried powder component is: lansoprazole, meglumine, mannitol, sodium sulfite and disodiumedetate, its ratio are lansoprazole 3 weight portions, meglumine 0.5～1 weight portion, mannitol 10～20 weight portions, sodium sulfite 0.1～0.3 weight portion, disodiumedetate 0.05～0.3 weight portion; Mean diameter is 100～150nm, and porosity is 95～98%;
Described Lansoprazole composition freeze-dried powder for injection preparation method is:
(1) dosing: supplementary material is added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulating pH with sodium hydroxide is 10～12, add water for injection to liquor capacity and be lansoprazole 100 times;
(2) decolouring: in the medicinal liquid for preparing, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate reuse 0.22 μ m degerming microporous filter membrane fine straining then, filtrate is surveyed pH value, content, add water for injection to liquor capacity through 0.22 μ m degerming microporous filter membrane fine straining and be lansoprazole 630 times, packing false add plug; Described medical activated carbon weight consumption is 0.1% of a liquor capacity;
(3) lyophilizing
A, pre-freeze: the freeze drying box temperature is reduced to 0～5 ℃, divide and install to such an extent that medicinal liquid is placed 20～40min in freeze drying box, again freeze drying box is cooled to-37～-43 ℃ with 35～45 ℃/min speed, be warming up to-15～-10 ℃ then, insulation 0.5～1h, be cooled to-50～-46 ℃ with 40～50 ℃/min speed then, be incubated freezing 2 hours
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15～20Pa, at the uniform velocity slowly freeze drying box was warming up to-15～-10 ℃ then at 12～16 hours, be incubated 5 hours,
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.1～0.2 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
2. Lansoprazole composition freeze-dried powder for injection according to claim 1 is characterized in that, lansoprazole, meglumine, mannitol, sodium sulfite and disodiumedetate, and its ratio is 3: 1: 20: 0.2: 0.2; Described ratio is a weight ratio.
3. Lansoprazole composition freeze-dried powder for injection according to claim 1 and 2 is characterized in that, described Lansoprazole composition freeze-dried powder mean diameter is 120nm, and porosity is 97%.
4. Lansoprazole composition freeze-dried powder for injection according to claim 1, it is characterized in that, step (3) a pre-freeze is for to reduce to 3 ℃ with the freeze drying box temperature, divide the medicinal liquid that installs to place 30min in freeze drying box, again freeze drying box is cooled to-40 ℃ with 40 ℃/min speed, is warming up to-13 ℃ then, insulation 0.7h, be cooled to-48 ℃ with 45 ℃/min speed then, be incubated freezing 2 hours.
5. Lansoprazole composition freeze-dried powder for injection according to claim 1 is characterized in that, step (3) b distilled to being evacuated to 17Pa, at the uniform velocity slowly freeze drying box was warming up to-13 ℃ at 14 hours.
6. Lansoprazole composition freeze-dried powder for injection according to claim 1 is characterized in that, step (3) c is dry for freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.1 ℃/min.
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