CN104173299A - Freeze-drying method for injection ligustrazine - Google Patents
Freeze-drying method for injection ligustrazine Download PDFInfo
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Abstract
The invention belongs to the technical field of freeze-drying, and in particular discloses a freeze-drying method for injection ligustrazine. The freeze-drying method comprises the following steps: precooling a sterile ligustrazine solution, vacuuming, performing sublimation-drying, and performing decomposition-drying, thereby obtaining a freeze-dried ligustrazine powder injection, wherein the vacuum degree of the sublimation process does not exceed a threshold A; the threshold A is greater than or equal to 20mu bar and less than or equal to 1000mu bar; the sterile ligustrazine solution comprises ligustrazine, pharmaceutically acceptable auxiliary materials and injection water. According to the freeze-drying method disclosed by the invention, by controlling the vacuum degree of the sublimation process, the situation that the prepared freeze-dried ligustrazine powder injection shrinks is effectively avoided, the yield of the freeze-dried ligustrazine powder injection and the quality stability of a finished product are improved, products of different batches are relatively stable in quality, the national quality standard is met, and thus the freeze-drying method is relatively applicable to industrial on-scale production.
Description
Technical field
The invention belongs to Freeze Drying Technique field, specially refer to a kind of freeze-drying method of hydrochloride for injection ligustrazine.
Background technology
Ligustrazine is the active component extracting from Rhizoma Chuanxiong, and chemical name is tetramethylpyrazine, and molecular formula is C
18h
12n
2, now can synthetic.Ligustrazine is one of effective ingredient of Rhizoma Chuanxiong treatment cardiovascular and cerebrovascular disease, research is found, ligustrazine has inhibitory action to the human platelet aggregation of adenosine diphosphate (ADP), arachidonic acid and PAF (platelet activating factor) induction, and the platelet of having assembled is had to depolymerisation.In addition, it is expansible small artery also, improves microcirculation and increases cerebral blood flow.
At present, ligustrazine is made to various pharmaceutical dosage forms for clinical treatment, wherein, in the control of cardiovascular and cerebrovascular disease, be most widely used.In clinical practice, ligustrazine hydrochloride is Common drugs, and it is often with drug administration by injection.Hydrochloride for injection ligustrazine is a kind of prescription drugs, is applicable to cerebral blood supply insufficiency, cerebral thrombosis, coronary heart disease, vasculitis, vascular surgery, Vasculocardiology Deparment, Neurology Department.Finding finds, the side effect of hydrochloride for injection ligustrazine is little, kidney, heart, brain are had to certain protective effect, so one of this medicine is clinical commonly used drug, the huge market demand.
In pharmaceutical preparation production process, hydrochloride for injection ligustrazine is made into lyophilized injectable powder.Ligustrazine hydrochloride lyophilized injectable powder is made up of ligustrazine hydrochloride, adjuvant and water for injection lyophilizing.The problems such as existing hydrochloride for injection ligustrazine exists in vacuum lyophilization process that yield is lower, the content fluctuation of ligustrazine hydrochloride is larger in products obtained therefrom, are mainly manifested in product atrophy have occurred, and substandard product is many.This has caused some ligustrazine hydrochloride not meet state quality standard, even directly affects quality stability, the safety in utilization of gained ligustrazine hydrochloride.
Freeze Drying Technique refers to be freezed aqueous solution at low temperatures, then under vacuum state, moisture wherein is directly distilled without liquid condition, dried like this material, its physics, chemistry and shape are substantially constant, loss of effective components is little, rehydration good, and sealing retention cycle is long.In the freezing dry process of medicine, can produce multiple stress, the property of medicine, quality stability to freeze-dried drug have a significant impact, therefore medicine freezing dry process is carried out to appropriate design, for obtaining steady quality, using safe drugs tool to be of great significance.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of freeze-drying method of hydrochloride for injection ligustrazine.Freeze-drying method provided by the invention has improved the yield of ligustrazine hydrochloride lyophilized injectable powder, and gained ligustrazine hydrochloride lyophilized injectable powder steady quality, meets state quality standard, is more conducive to the industrialized great production of ligustrazine hydrochloride.
In order to realize goal of the invention of the present invention, the present invention adopts following technical scheme:
The freeze-drying method that the invention provides a kind of hydrochloride for injection ligustrazine, it comprises:
Get aseptic ligustrazine hydrochloride aqueous solution, through pre-cooling, evacuation, sublimation drying, parsing-desiccation, obtains ligustrazine hydrochloride lyophilized injectable powder;
Vacuum in this sublimation drying process is no more than threshold value A;
This threshold value A meets: 20 μ bar≤threshold value A≤1000 μ bar;
This aseptic ligustrazine hydrochloride aqueous solution comprises ligustrazine hydrochloride, pharmaceutically acceptable adjuvant and water for injection.
In the freezing dry process of existing ligustrazine hydrochloride, can select higher vacuum, higher vacuum is conducive to improve the sublimation drying speed of ligustrazine hydrochloride; Or whole freezing dry process is no longer controlled vacuum after evacuation reaches a vacuum.But, the present invention finds in the time that the vacuum in control sublimation drying process is no more than threshold value A in the time carrying out sublimation drying, 20 μ bar≤threshold value A≤1000 μ bar, can effectively prevent the generation of gained ligustrazine hydrochloride lyophilized injectable powder atrophy, also reduce the loss of the ligustrazine hydrochloride content in freezing dry process; And the present invention also finds under this vacuum degree condition, the moisture of gained ligustrazine hydrochloride lyophilized injectable powder is stable, has improved the quality stability of finished product, meets state quality standard.Compare conventional higher vacuum, the present invention can also effectively reduce energy consumption, and energy savings, is more suitable for industrialized great production.
Preferably, in freeze-drying method provided by the invention, the threshold value A in sublimation drying process meets: 100 μ bar≤threshold value A≤1000 μ bar.More preferably: 300 μ bar≤threshold value A≤1000 μ bar.Further be preferably: in some embodiments of the invention, the threshold value A in sublimation drying process is 20 μ bar, 100 μ bar, 300 μ bar, 800 μ bar or 1000 μ bar to 300 μ bar≤threshold value A≤800 μ bar.
In some embodiments of the invention, for the vacuum realizing in sublimation drying process is no more than 100 μ bar≤threshold value A≤1000 μ bar, more preferably 300 μ bar≤threshold value A≤1000 μ bar, be 300 μ bar≤threshold value A≤800 μ bar in certain embodiments, can be in freeze-drying process, in the time that vacuum reaches threshold value B in sublimation drying process, carry out evacuation, till being evacuated to vacuum and being less than the vacuum in evacuation step; Wherein threshold value B meets: (threshold value A-50 μ bar) < threshold value B≤threshold value A.
Preferably, in freeze-drying method provided by the invention, after sublimation drying, before parsing-desiccation, also comprise the step of aeration;
Till this aeration to pressure reaches 999999.9 μ bar～1013250 μ bar.
Preferably, in freeze-drying method provided by the invention, aeration, to atmospheric pressure, before parsing-desiccation, also comprises: aeration 5 minutes～20 minutes, and to maintain pressure be atmospheric pressure.In some embodiments of the invention, in freeze-drying method provided by the invention, at aeration to atmospheric pressure, before parsing-desiccation, also comprise: aeration 10 minutes, and to maintain pressure be atmospheric pressure.
In some embodiments of the invention, in freeze-drying method provided by the invention, aeration is gases used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area.
In the present invention, after sublimation drying, before parsing-desiccation, carry out aeration, not only for parsing-desiccation provides pressure, reduce the volatilization of principal agent, the step of aeration can also improve the speed of parsing-desiccation.Experimental result confirms, the present invention also finds, aeration, to atmospheric pressure, then continues to maintain this pressure 5 minutes～20 minutes, can make pressure be evenly distributed in container, can avoid a large amount of volatilizations of principal agent for parsing-desiccation when providing power.
Preferably, in freeze-drying method provided by the invention, pre-cooling comprises first pre-cold-peace the second pre-cooling.
Preferably, in freeze-drying method provided by the invention, the temperature of the first pre-cooling is-40 DEG C～-50 DEG C.
Preferably, in freeze-drying method provided by the invention, the time of the first pre-cooling is 1 hour～2 hours.
In some embodiments of the invention, in freeze-drying method provided by the invention, the rate of temperature fall that aseptic ligustrazine hydrochloride aqueous solution is cooled to the temperature of the first pre-cooling is 15 DEG C～20 DEG C/h.In other embodiment of the present invention, the speed of this cooling is 20 DEG C/h.
Preferably, in freeze-drying method provided by the invention, the temperature of the second pre-cooling is-55 DEG C～-65 DEG C.
Preferably, in freeze-drying method provided by the invention, the time of the second pre-cooling is 0.5 hour～2 hours.
In some embodiments of the invention, in freeze-drying method provided by the invention, it is 10 DEG C～25 DEG C/h by the first rate of temperature fall being pre-chilled in the second precooling process.In other embodiment of the present invention, this rate of temperature fall is 20 DEG C/h.
In some embodiments of the invention, pre-cooling in the present invention is divided into two steps, i.e. first pre-cold-peace the second pre-cooling, after finishing, the first pre-cooling is specially to the process that completes the second pre-cooling: maintain-40 DEG C～-50 DEG C first pre-cooling after 1 hour～2 hours, start to lower the temperature as the speed of 10 DEG C～25 DEG C/h taking speed, to 55 DEG C～-65 DEG C, enter the second pre-cooling, maintain this temperature 0.5 hour～2 hours, completed the second pre-cooling.
In the present invention, the effect of the first pre-cooling is freezing sample, makes ligustrazine hydrochloride aqueous solution be refrigerated to product eutectic point.The effect of the second pre-cooling is to-55 DEG C～-65 DEG C, for lyophilization provides low-temperature receiver by cold-trap refrigeration.Compare a conventional step pre-cooling, the present invention is divided into two step pre-coolings by pre-cooling and 1. can avoids a step pre-cooling dynamical system under-supply, causes the meticulous situation generation that causes later stage dry rate excessively to be delayed of product pre-freeze crystal formation; 2. can avoid the quick pre-freeze of special kinds requirement and low-temperature receiver cannot be provided; 3. avoid sample temperature in lower step evacuation to rise simultaneously.
Preferably, in freeze-drying method provided by the invention, sublimation drying comprises the first sublimation drying and the second sublimation drying.
Preferably, in freeze-drying method provided by the invention, the temperature of the first sublimation drying is-15 DEG C～-5 DEG C.In some embodiments of the invention, the temperature of the first sublimation drying is-10 DEG C.
Preferably, in freeze-drying method provided by the invention, the temperature of the first distillation is-15 DEG C～-5 DEG C, and the time maintaining is 2 hours～3 hours.In some embodiments of the invention, the time of the first sublimation drying is 3 hours.
In some embodiments of the invention, in freeze-drying method provided by the invention, the heating rate that is warming up to the temperature of the first sublimation drying by the temperature after evacuation is 3 DEG C～7 DEG C/h.In some embodiments of the invention, this intensification efficiency is 5 DEG C～6 DEG C/h.
Preferably, in freeze-drying method provided by the invention, the temperature of the second sublimation drying is 5 DEG C～20 DEG C.In other embodiment of the present invention, the temperature of the second sublimation drying is 15 DEG C.
Preferably, in freeze-drying method provided by the invention, after the second sublimation drying temperature is 5 DEG C～20 DEG C, holding time is 2 hours～4 hours.In some embodiments of the invention, the time of the second sublimation drying is 3 hours.
In some embodiments of the invention, in freeze-drying method provided by the invention, the heating rate that is warming up to the temperature of the second sublimation drying by the temperature of the first sublimation drying is 3 DEG C～7 DEG C/h.In some embodiments of the invention, this intensification efficiency is 3 DEG C～5 DEG C/h.
In some embodiments of the invention, sublimation drying of the present invention is divided into two steps, the first sublimation drying and the second sublimation drying, be specially: maintain-15 DEG C～-5 DEG C, within 2 hours～3 hours, carry out after the first sublimation drying, be warming up to 5 DEG C～20 DEG C with the heating rate of 3 DEG C～7 DEG C/h, carry out the second sublimation drying, maintain this temperature 2 hours～4 hours, completed the second sublimation drying.
In the present invention, one step sublimation drying of routine is divided into two steps, i.e. the first sublimation drying and the second sublimation drying, the first step after dry temperature is-15 DEG C～-5 DEG C, continue the dry time be within 2 hours～3 hours, can make products temperature distillation (heating) to infinite approach-15 DEG C～-5 DEG C of scopes; In like manner, after second step the second sublimation drying temperature is 5 DEG C～20 DEG C, holding time is within 2 hours～4 hours, to make products temperature distillation (heating) to 5 DEG C～20 DEG C of infinite approachs; Thereby reduce the gap of displays temperature and actual temperature; And one-step method cannot instruct too greatly actual production in sublimation drying back segment temperature and actual temperature difference, can cause product moisture higher.
Preferably, in freeze-drying method provided by the invention, parsing-desiccation comprises the first parsing-desiccation and the second parsing-desiccation.
Preferably, in freeze-drying method provided by the invention, the temperature of the first parsing-desiccation is 50 DEG C～60 DEG C.In some embodiments of the invention, the temperature of the first parsing-desiccation is 60 DEG C.
Preferably, in freeze-drying method provided by the invention, the time of the first parsing-desiccation is 30 minutes～60 minutes.In some embodiments of the invention, the time of the first parsing-desiccation is 30 minutes.
Preferably, in freeze-drying method provided by the invention, the temperature of the second parsing-desiccation is 45 DEG C～50 DEG C.In some embodiments of the invention, the temperature of the second parsing-desiccation is 48 DEG C.
Preferably, in freeze-drying method provided by the invention, the time of the second parsing-desiccation is 3 hours～3.5 hours.In some embodiments of the invention, the time of the second parsing-desiccation is 3 hours.
In some embodiments of the invention, parsing-desiccation of the present invention is divided into two steps, i.e. the first parsing-desiccation and the second parsing-desiccation, be specially: maintain 50 DEG C～60 DEG C, 30 minutes～60 minutes and carry out after the first parsing-desiccation, be cooled to 45 DEG C～50 DEG C, carry out the second parsing-desiccation, maintain this temperature 3 hours～3.5 hours, completed the second parsing-desiccation.
In the present invention, one step parsing-desiccation of routine is divided into two steps, i.e. the first parsing-desiccation and the second parsing-desiccation, can avoid a step parsing-desiccation after parsing-desiccation completes because the too short product quality that causes of holding time under set point of temperature is undesirable, particularly moisture item.
Preferably, in freeze-drying method provided by the invention, the pharmaceutically acceptable adjuvant in aseptic ligustrazine hydrochloride aqueous solution comprises carrier and/or pH adjusting agent.
In some embodiments of the invention, in freeze-drying method provided by the invention, the carrier in aseptic ligustrazine hydrochloride aqueous solution is mannitol.
In other embodiment of the present invention, in freeze-drying method provided by the invention, the pH adjusting agent in aseptic ligustrazine hydrochloride aqueous solution is sodium dihydrogen phosphate.
In some embodiments of the invention, in freeze-drying method provided by the invention, by percentage to the quality, in aseptic ligustrazine hydrochloride aqueous solution, the content of ligustrazine hydrochloride is 3.60%～4.40%.
In other embodiment of the present invention, in freeze-drying method provided by the invention, by percentage to the quality, in aseptic ligustrazine hydrochloride aqueous solution, the content of carrier is 4.5%～5.50%.
In other embodiment of the present invention, in freeze-drying method provided by the invention, the consumption of pH adjusting agent is: reach pH2.3～pH2.5 with the pH value in aseptic ligustrazine hydrochloride aqueous solution.
The invention provides a kind of freeze-drying method of hydrochloride for injection ligustrazine, this freeze-drying method comprises: get aseptic ligustrazine hydrochloride aqueous solution, and through pre-cooling, evacuation, sublimation drying, parsing-desiccation, obtains ligustrazine hydrochloride lyophilized injectable powder; Vacuum in this sublimation drying process is no more than threshold value A; This threshold value A meets: 20 μ bar≤threshold value A≤1000 μ bar; This aseptic ligustrazine hydrochloride aqueous solution comprises ligustrazine hydrochloride, pharmaceutically acceptable adjuvant and water for injection.Experimental result confirms, freeze-drying method provided by the invention is by controlling the vacuum in sublimation drying process, effectively prevent the generation of gained ligustrazine hydrochloride lyophilized injectable powder atrophy, the yield of ligustrazine hydrochloride lyophilized injectable powder, the quality stability of finished product are improved, make each batch products quality more stable, meet state quality standard, be more suitable for industrialized great production.
Detailed description of the invention
The invention discloses a kind of freeze-drying method of hydrochloride for injection ligustrazine.Those skilled in the art can be with reference to this paper content, realizes its application, special needs to be pointed out is, and all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Preparation method of the present invention is described by preferred embodiment, and related personnel obviously can change this paper preparation method in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
Freeze-drying method reagent used and the raw material of a kind of hydrochloride for injection ligustrazine provided by the invention all can be buied by market.
In order to make those skilled in the art can understand better technical scheme of the present invention, below in conjunction with embodiment, further set forth the present invention:
The preparation of embodiment 1 hydrochloride for injection ligustrazine freeze dried injecta
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 4.00% ligustrazine hydrochloride, 5.00% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.00mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-50 DEG C, is continued to 1 hour;
C: evacuation: start evacuation, reach after 250 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
D: sublimation drying: oil temperature is risen to after-10 DEG C, keep 2 hours; Again oil temperature is risen to after 15 DEG C, keep 3 hours;
F: parsing-desiccation: oil temperature is risen to after 55 DEG C, keep 0.5 hour; Again oil temperature is risen to after 50 DEG C, keep 3 hours;
G: tamponade, outlet, to obtain final product.
Attention: stop being evacuated to the whole process of steps d between completing from step c, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 1000 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 250 μ bar closes in the time that vacuum exceedes 950 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 2 hydrochloride for injection ligustrazine freeze dried injectas
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.5, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.88% ligustrazine hydrochloride, 4.85% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.03mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier;
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-40 DEG C, is continued to 2 hours;
C: evacuation: start evacuation, reach after 150 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
D: sublimation drying: oil temperature is risen to after-5 DEG C, keep 2 hours; Again oil temperature is risen to after 20 DEG C, keep 2 hours;
E: parsing-desiccation: oil temperature is risen to after 60 DEG C, keep 0.5 hour; Again oil temperature is risen to after 50 DEG C, keep 3 hours;
F: tamponade, outlet, to obtain final product.
Attention: stop being evacuated to the whole process of steps d between completing from step c, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 800 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 150 μ bar closes in the time that vacuum exceedes 750 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 3 hydrochloride for injection ligustrazine freeze dried injectas
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.4, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 4.40% ligustrazine hydrochloride, 5.50% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 0.97mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-45 DEG C, is continued to 1.5 hours;
C: evacuation: start evacuation, reach after 100 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
D: sublimation drying: oil temperature is risen to after-5 DEG C, keep 2 hours; Again oil temperature is risen to after 10 DEG C, keep 3.5 hours;
E: parsing-desiccation: oil temperature is risen to after 60 DEG C, keep 0.5 hour; Again oil temperature is risen to after 48 DEG C, keep 3.5 hours;
F: tamponade, outlet, to obtain final product.
Attention: stop being evacuated to the whole process of steps d between completing from step c, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 300 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 100 μ bar closes in the time that vacuum exceedes 250 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 4 hydrochloride for injection ligustrazine freeze dried injectas
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.4, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 4.05% ligustrazine hydrochloride, 5.06% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 0.99mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier;
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-55 DEG C, is continued to 1 hour;
C: evacuation: start evacuation, reach after 20 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
D: sublimation drying: oil temperature is risen to after 20 DEG C, keep 2 hours; Front case aeration, to pressure 1013250 μ bar, keeps, after 10 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
E: parsing-desiccation: oil temperature is risen to 45 DEG C, keep 3.5 hours;
F: tamponade, outlet, to obtain final product.
Attention: stop being evacuated to the whole process of steps d between completing from step c, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 100 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 20 μ bar closes in the time that vacuum exceedes 50 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 5 hydrochloride for injection ligustrazine freeze dried injectas
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.90% ligustrazine hydrochloride, 4.88% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.03mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-50 DEG C, is continued to 1.5 hours;
C: evacuation: start evacuation, reach after 20 μ bar when vacuum is evacuated to, maintain vacuum and be no more than 20 μ bar;
D: sublimation drying: oil temperature is risen to after 15 DEG C, keep 3.5 hours; Front case aeration to pressure is 999999.9 μ bar, keeps, after 25 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
E: parsing-desiccation: oil temperature is risen to 49 DEG C, keep after 3 hours;
F: tamponade, outlet, to obtain final product.
Attention: the whole process between completing to steps d after step c is evacuated down to 20 μ bar, before vacuum freeze drier, case vacuum must not exceed 20 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 6 hydrochloride for injection ligustrazine freeze dried injectas
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.60% ligustrazine hydrochloride, 4.50% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.05mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: the first pre-cooling: by extremely-40 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 2 hours with the speed of 20 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-55 DEG C, is continued to 2 hours;
D: evacuation: start evacuation, reach after 150 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
E: the first sublimation drying: oil temperature is risen to after-10 DEG C with the speed of 5 DEG C/h, keep 3 hours;
F: the second sublimation drying and aeration: with the speed of 5 DEG C/h, oil temperature is risen to 15 DEG C, keep after 3 hours, front case aeration to 1013250 μ bar, keeps, after 10 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 60 DEG C, keep after 30 minutes, then freeze oil temperature is down to 48 DEG C, be incubated 3 hours;
H: tamponade, outlet, to obtain final product.
Attention: from steps d stops being evacuated to step f aeration in whole process, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 800 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 150 μ bar closes in the time that vacuum exceedes 750 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 7 ligustrazine hydrochloride lyophilized injectable powders
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 4.20% ligustrazine hydrochloride, 5.25% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.05mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: the first pre-cooling: by extremely-50 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 1 hour with the speed of 15 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-65 DEG C, is continued to 0.5 hour;
D: evacuation: start evacuation, reach after 20 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
E: the first sublimation drying: oil temperature is risen to after-15 DEG C with the speed of 6 DEG C/h, keep 2 hours;
F: the second sublimation drying and aeration: with the speed of 3 DEG C/h, oil temperature is risen to 20 DEG C, keep after 2 hours, front case aeration to pressure is 999999.9 μ bar, keeps, after 25 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 50 DEG C, keep after 60 minutes, then freeze oil temperature is down to 50 DEG C, be incubated 3 hours;
H: tamponade, outlet, to obtain final product.
Attention: from steps d stops being evacuated to step f aeration in whole process, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 100 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 20 μ bar closes in the time that vacuum exceedes 50 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 8 ligustrazine hydrochloride lyophilized injectable powders
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.5, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.92% ligustrazine hydrochloride, 4.90% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.02mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: the first pre-cooling: by extremely-45 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 1.5 hours with the speed of 18 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-60 DEG C, is continued to 1.5 hours;
D: evacuation: start evacuation, reach after 250 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
E: the first sublimation drying: oil temperature is risen to after-5 DEG C with the speed of 7 DEG C/h, keep 2.5 hours;
F: the second sublimation drying and aeration: with the speed of 7 DEG C/h, oil temperature is risen to 5 DEG C, keep after 4 hours, front case aeration to 1013250 μ bar, keeps, after 5 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 60 DEG C, keep after 30 minutes, then freeze oil temperature is down to 45 DEG C, be incubated 3.5 hours;
H: tamponade, outlet, to obtain final product.
Attention: from steps d stops being evacuated to step f aeration in whole process, before vacuum freeze drier, case vacuum must not exceed threshold value A, threshold value A is 1000 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 250 μ bar closes in the time that vacuum exceedes 950 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The preparation of embodiment 9 ligustrazine hydrochloride lyophilized injectable powders
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 4.04% ligustrazine hydrochloride, 5.05% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 0.99mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier;
B: the first pre-cooling: by extremely-48 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 1.8 hours with the speed of 20 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-58 DEG C, is continued to 1 hour;
D: evacuation: start evacuation, reach after 100 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
E: the first sublimation drying: oil temperature is risen to after-8 DEG C with the speed of 3 DEG C/h, keep 2 hours;
F: the second sublimation drying and aeration: with the speed of 4 DEG C/h, oil temperature is risen to 10 DEG C, keep after 3 hours, front case aeration to pressure is 1000000 μ bar, keeps, after 15 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 55 DEG C, keep after 45 minutes, then freeze oil temperature is down to 47 DEG C, be incubated 3.3 hours;
H: tamponade, outlet, to obtain final product.
Attention: from steps d stops being evacuated to step f aeration in whole process, case vacuum must not threshold value A before vacuum freeze drier, threshold value A is 300 μ bar, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 100 μ bar closes in the time that vacuum exceedes 250 μ bar.
The quality evaluation result of the ligustrazine hydrochloride that the freeze-drying method providing according to the present embodiment prepares is in table 1.
The quality evaluation of embodiment 10 hydrochloride for injection ligustrazine freeze dried injectas
Get the ligustrazine hydrochloride lyophilized injectable powder that embodiment 1 to embodiment 9 prepares and carry out accelerated test, investigate the quality of ligustrazine hydrochloride lyophilized injectable powder provided by the invention.The hydrochloride for injection ligustrazine freeze dried injecta preparing with matched group 1 to matched group 3 in contrast.The preparation method of the hydrochloride for injection ligustrazine freeze dried injecta of each matched group is as follows:
Matched group 1:
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.60% ligustrazine hydrochloride, 4.50% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.05mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: the first pre-cooling: by extremely-40 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 2 hours with the speed of 20 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-55 DEG C, is continued to 2 hours;
D: evacuation: start evacuation, reach after 300 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
E: the first sublimation drying: oil temperature is risen to after-10 DEG C with the speed of 5 DEG C/h, keep 3 hours;
F: the second sublimation drying and aeration: with the speed of 5 DEG C/h, oil temperature is risen to 15 DEG C, keep after 3 hours, front case aeration is to atmospheric pressure normal pressure, i.e. 1013250 μ bar, keep, after 10 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 60 DEG C, keep after 30 minutes, then freeze oil temperature is down to 48 DEG C, be incubated 3 hours;
H: tamponade, outlet, to obtain final product.
Attention: from steps d stops being evacuated to step f aeration in whole process, case vacuum must not exceed 1200 μ bar before vacuum freeze drier, must open that vacuum unit starts evacuation until vacuum is evacuated to after reaching 350 μ bar closes in the time that vacuum exceedes 1100 μ bar.
Matched group 2:
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be the aseptic ligustrazine hydrochloride aqueous solution of 2.3 preparation, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: 3.60% ligustrazine hydrochloride, 4.50% mannitol, and the water of surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.05mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: the first pre-cooling: by extremely-40 DEG C of case before vacuum freeze drier (conduction oil) oil temperature refrigeration, continue 2 hours with the speed of 20 DEG C/h;
C: the second pre-cooling: vacuum freeze drier rear cabinet refrigeration, to-55 DEG C, is continued to 2 hours;
D: evacuation: start evacuation, reach after 10 μ bar when vacuum is evacuated to, maintain vacuum and be no more than 10 μ bar;
E: the first sublimation drying: oil temperature is risen to after-10 DEG C with the speed of 5 DEG C/h, keep 3 hours;
F: the second sublimation drying and aeration: with the speed of 5 DEG C/h, oil temperature is risen to 15 DEG C, keep after 3 hours, front case aeration to pressure is atmospheric pressure normal pressure, i.e. 1013250 μ bar, keep, after 10 minutes, stopping aeration; Aeration gas used is the gained pure air through 0.2 μ m air filtering core aseptic filtration in B level clean area;
G: parsing-desiccation: oil temperature is risen to 60 DEG C, keep after 30 minutes, then freeze oil temperature is down to 48 DEG C, be incubated 3 hours;
H: tamponade, outlet, to obtain final product.
Attention: in whole process, before vacuum freeze drier, case vacuum must not exceed 10 μ bar from steps d stops being evacuated to step f aeration.
Matched group 3:
Accurately measure ligustrazine hydrochloride, mannitol, add water, and with sodium dihydrogen phosphate regulate pH value be 2.3, prepare aseptic ligustrazine hydrochloride aqueous solution, by percentage to the quality, the aseptic ligustrazine hydrochloride aqueous solution of gained comprises following component: the water of 3.60% ligustrazine hydrochloride, 4.50% mannitol and surplus.Aseptic gained hydrochlorate ligustrazine aqueous solution 1.05mL/ is propped up, be sub-packed in glass bottle.
According to the following steps gained ligustrazine hydrochloride aqueous solution is carried out to lyophilization and prepares lyophilized injectable powder:
A: the glass bottle that is loaded with aseptic ligustrazine hydrochloride aqueous solution is pushed in vacuum freeze drier (manufacturer: Shanghai Tofflon Science and Technology Co., Ltd., model LYO-40 (SIP, CIP));
B: pre-cooling: case before vacuum freeze drier (conduction oil) oil temperature refrigeration, to-50 DEG C, is continued to 1 hour;
C: evacuation: start evacuation, reach after 250 μ bar when vacuum is evacuated to, close vacuum unit, stop evacuation;
D: sublimation drying: oil temperature is risen to after-10 DEG C, keep 2 hours; Again oil temperature is risen to after 15 DEG C, keep 3 hours;
E: parsing-desiccation: oil temperature is risen to after 55 DEG C, keep 0.5 hour; Again oil temperature is risen to after 50 DEG C, keep 3 hours;
F: tamponade, outlet, to obtain final product.
The indices of outward appearance, yield and the products obtained therefrom of the hydrochloride for injection ligustrazine freeze dried injecta that Statistics Implementation example 1 to embodiment 9, matched group 1 to matched group 3 prepare respectively.
The indices of evaluating ligustrazine hydrochloride lyophilized injectable powder quality according to official quality standands evaluation criterion and enterprise-quality standard, the statistical result of each group indices is in table 1.
Get the up-to-standard hydrochloride for injection ligustrazine freeze dried injecta that embodiment 1 to embodiment 9, matched group 1 to matched group 3 prepare, in the proof box of 25 DEG C ± 2 DEG C of temperature, relative humidity 65% ± 5%, intensity of illumination: 4500LX ± 500LX, place 6 months, respectively the 0th, the sampling at the end of month of 1,2,3,6 month carries out the investigation of stability key project, the results are shown in Table 2.
The indices of each group products obtained therefrom of table 1
Known according to experimental result in table 1, compare matched group 1, matched group 2, matched group 3, qualification rate, total qualification rate of the indices of the ligustrazine hydrochloride lyophilized injectable powder that embodiment 1 to embodiment 9 prepares are promoted significantly, significant difference (P < 0.05), the generation that can effectively prevent the atrophy of ligustrazine hydrochloride lyophilized injectable powder by the vacuum of sublimation drying in control freezing dry process is described, and then improved the qualification rate of the indices of ligustrazine hydrochloride lyophilized injectable powder, finally improve its yield.
Compare embodiment 1 to embodiment 3, the indices qualification rate of the ligustrazine hydrochloride lyophilized injectable powder that embodiment 4, embodiment 5 prepare is further improved, significant difference (P < 0.05), illustrate after sublimation drying, before parsing-desiccation, aeration can further improve the yield of ligustrazine hydrochloride lyophilized injectable powder; And the indices qualification rate of the ligustrazine hydrochloride lyophilized injectable powder that embodiment 6 to embodiment 9 prepares is further promoted, significant difference (P < 0.05).
Table 2 accelerated test testing result
Table 2 is that the up-to-standard hydrochloride for injection ligustrazine freeze dried injecta for preparing of embodiment 1 to embodiment 9, matched group 1 to matched group 3 is in the proof box of 25 DEG C ± 2 DEG C of temperature, relative humidity 65% ± 5%, intensity of illumination: 4500LX ± 500LX, place 6 months, respectively the 1st, the sampling at the end of month of 2,3,6 months carries out stability key project and investigates statistical table.
From table 2, experimental result is known, compares matched group 1, matched group 2, matched group 3, and embodiment 1 all conforms with the regulations in character, clarity of solution and the color accelerated in investigation to implementing the 9 ligustrazine hydrochloride lyophilized injectable powders that prepare; Related substance, moisture, acidity, labelled amount all change less, steady quality, illustrate by controlling the vacuum of sublimation drying in freezing dry process and can effectively control ligustrazine hydrochloride lyophilized injectable powder inherent quality, and then improved quality in ligustrazine hydrochloride lyophilized injectable powder effect duration, reduced quality risk.And the sample of matched group 1, matched group 2, matched group 3 character, clarity of solution in accelerating to investigate is all against regulation, related substance, moisture, acidity all change greatly, and particularly in the time of accelerated test 6th month, three indexs all exceed or approach enterprise-quality critical field.
From table 2, experimental result is known, compare embodiment 1 to embodiment 3, related substance, moisture, the acidity of the ligustrazine hydrochloride lyophilized injectable powder that embodiment 4, embodiment 5 prepare, labelled amount all changes less, illustrate after sublimation drying, before parsing-desiccation, aeration can further improve the inherent quality of ligustrazine hydrochloride lyophilized injectable powder; And the accelerated stability of the ligustrazine hydrochloride lyophilized injectable powder that embodiment 6 to embodiment 9 prepares examine wipe index change still less, quality is more stable.
In sum, the yield of the ligustrazine hydrochloride lyophilized injectable powder that the preparation method that the embodiment of the present invention 1 to embodiment 9 provides prepares is high, end product quality stable, meets state quality standard, is more suitable for industrialized great production.
Below be only the preferred embodiment of the present invention, it should be pointed out that above-mentioned preferred implementation should not be considered as limitation of the present invention, protection scope of the present invention should be as the criterion with claim limited range.For those skilled in the art, without departing from the spirit and scope of the present invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a freeze-drying method for hydrochloride for injection ligustrazine, is characterized in that, comprising:
Get aseptic ligustrazine hydrochloride aqueous solution, through pre-cooling, evacuation, sublimation drying, parsing-desiccation, obtains ligustrazine hydrochloride lyophilized injectable powder;
Wherein, the vacuum in described sublimation drying process is no more than threshold value A;
Described threshold value A meets: 20 μ bar≤threshold value A≤1000 μ bar;
Described aseptic ligustrazine hydrochloride aqueous solution comprises ligustrazine hydrochloride, pharmaceutically acceptable adjuvant and water for injection.
2. freeze-drying method according to claim 1, is characterized in that, after described sublimation drying, before described parsing-desiccation, also comprises the step of aeration;
Till described aeration to pressure reaches 999999.9 μ bar～1013250 μ bar.
3. freeze-drying method according to claim 1 and 2, is characterized in that, described evacuation gained vacuum is 20 μ bar～250 μ bar.
4. according to the freeze-drying method described in any one in claims 1 to 3, it is characterized in that, described pre-cooling comprises first pre-cold-peace the second pre-cooling.
5. according to the freeze-drying method described in any one in claim 1 to 4, it is characterized in that, described sublimation drying comprises the first sublimation drying and the second sublimation drying.
6. according to the described freeze-drying method of claim 5, it is characterized in that, the temperature of described the first sublimation drying is-15 DEG C～-5 DEG C; The time of described the first sublimation drying is 2 hours～3 hours.
7. freeze-drying method according to claim 5, is characterized in that, the temperature of described the second sublimation drying is 5 DEG C～20 DEG C; The time of described the second sublimation drying is 2 hours～4 hours.
8. according to the freeze-drying method described in any one in claim 1 to 7, it is characterized in that, described parsing-desiccation comprises the first parsing-desiccation and the second parsing-desiccation.
9. freeze-drying method according to claim 8, is characterized in that, the temperature of described the first parsing-desiccation is 50 DEG C～60 DEG C; The time of described the first parsing-desiccation is 30 minutes～60 minutes.
10. freeze-drying method according to claim 8, is characterized in that, the temperature of described the second parsing-desiccation is 45 DEG C～50 DEG C; The time of described the second parsing-desiccation is 3 hours～3.5 hours.
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Address after: Yueyang economic and Technological Development Zone Industrial Park Road 414100 Hunan Kanwan chisi city in Yueyang Province Patentee after: Hunan Kelun Pharmaceutical Co., Ltd. Address before: Chengguan town of Yueyang County in Hunan province 414000 Yueyang Rong Road (county eco industrial park No. 3) Patentee before: Hunan Kelun Pharmaceutical Co., Ltd. |